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| '''SECTION C Physiology of the Gonads and Accessory Organs''' | | '''SECTION C Physiology of the Gonads and Accessory Organs''' |
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| Department Of Zoology, Oregon State College, Corvallis, Oregon | | Department Of Zoology, Oregon State College, Corvallis, Oregon |
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| | __TOC__ |
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| I. Introduction 556 | | ==I. Introduction== |
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| II. Ovarian Hormones and Growth of
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| THE Genital Tract 558
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| III. Effects of Progesterone on the
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| Uterus 565
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| IV. Synergism between Estrogen and
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| Progesterone 567
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| V. Experimentally Produced Implantation Reactions 571
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| VI. The Cervix Uteri 572
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| VII. The Vagina 575
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| VIII. Sexual Skin 576
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| IX. Menstruation 578
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| X. The Mechanism of Menstru.^tion. . 583
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| XI. References 586
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| I. Introduction
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| Cyclic menstruation is the most characteristic feature of primate reproduction, and | | Cyclic menstruation is the most characteristic feature of primate reproduction, and |
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| are the same, and this similarity is fundamentally more significant than the key descriptive differences just mentioned. Estrus | | are the same, and this similarity is fundamentally more significant than the key descriptive differences just mentioned. Estrus |
| comes at the peak of the growth phase of the | | comes at the peak of the growth phase of the |
| cycle and is associated with ovulation. In | | cycle and is associated with ovulation. In contrast, menstruation occurs in the cycle |
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| contrast, menstruation occurs in the cycle | |
| midway between times of ovulation and is | | midway between times of ovulation and is |
| not accompanied by an increase in sexual | | not accompanied by an increase in sexual |
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| physiology of the menstrual cycle and attendant morphologic changes have continued to be an area of active research interest | | physiology of the menstrual cycle and attendant morphologic changes have continued to be an area of active research interest |
| in science and medicine. Among the many | | in science and medicine. Among the many |
| more recent contributors are Bartelmez | | more recent contributors are Bartelmez (1937), Latz and Reiner (1942), Haman |
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| 556
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| ESTROGEN AND PROGESTERONE
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| 557
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| (1937), Latz and Reiner (1942), Haman | |
| (1942), Knaus (1950), Mazer and Israel | | (1942), Knaus (1950), Mazer and Israel |
| (1951), and Crossen (1953). | | (1951), and Crossen (1953). |
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| sacculated. The glandular cells increased | | sacculated. The glandular cells increased |
| in height, and there was evidence of glycogen mobilization and secretion. Next, the | | in height, and there was evidence of glycogen mobilization and secretion. Next, the |
| epithelium became "frayed out" along the | | epithelium became "frayed out" along the outer borders, then decreased in height, indicating secretory depletion. Decidual cells |
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| outer borders, then decreased in height, indicating secretory depletion. Decidual cells | |
| appeared in the stroma at this time. The | | appeared in the stroma at this time. The |
| endometrium was much thickened and extremely hyperemic. At the height of this | | endometrium was much thickened and extremely hyperemic. At the height of this |
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| bleeding are approximately the same regardless of whether or not ovulation has | | bleeding are approximately the same regardless of whether or not ovulation has |
| taken place. The gross features of menstruation under these two conditions are indistinguishable one from the other. However, | | taken place. The gross features of menstruation under these two conditions are indistinguishable one from the other. However, |
| the biologic purpose of the menstrual cycle | | the biologic purpose of the menstrual cycle is reproduction wliicli obviously cannot l)0 |
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| PHYSIOLOGY OF GONADS
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| is reproduction wliicli obviously cannot l)0 | |
| fulfilled unless an ovum is made available | | fulfilled unless an ovum is made available |
| for fertilization. Therefore, in this sense it | | for fertilization. Therefore, in this sense it |
| seems quite clear that anovulatory cycles | | seems quite clear that anovulatory cycles |
| should be considered incomplete and abnormal. | | should be considered incomplete and abnormal. |
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| The investigation of changes taking place | | The investigation of changes taking place |
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| on the different aspects of the physiology | | on the different aspects of the physiology |
| of reproduction. | | of reproduction. |
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| Since the initial observations by Corner | | Since the initial observations by Corner |
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| there is wide variation (Corner, 1923; Hartman, 1932; Zuckcrman, 1937a). From an | | there is wide variation (Corner, 1923; Hartman, 1932; Zuckcrman, 1937a). From an |
| analysis of 1000 cycles recorded for some | | analysis of 1000 cycles recorded for some |
| 80 females of different ages, Zuckerman | | 80 females of different ages, Zuckerman (1937a) found an average cycle length of |
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| (1937a) found an average cycle length of | |
| 33.5 ± 0.6 days, and the mode 28 days with | | 33.5 ± 0.6 days, and the mode 28 days with |
| an over-all range of 9 to 200 days. Ovulation | | an over-all range of 9 to 200 days. Ovulation |
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| the exact age of developing embryos ( Wislocki and Streeter, 1938; Heuser and | | the exact age of developing embryos ( Wislocki and Streeter, 1938; Heuser and |
| Streeter, 1941). | | Streeter, 1941). |
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| The primary purpose of the present discussion is to review the results of experimental investigations of physiologic processes occurring in the female reproductive | | The primary purpose of the present discussion is to review the results of experimental investigations of physiologic processes occurring in the female reproductive |
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| of normal function. | | of normal function. |
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| II. Ovarian Hormones and Growth | | ==II. Ovarian Hormones and Growth of the Genital Tract== |
| of the Genital Tract | |
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| The changes that are repeated in different parts of the reproductive tract with each | | The changes that are repeated in different parts of the reproductive tract with each |
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| the corinis luteum, is jirimarily a hormone | | the corinis luteum, is jirimarily a hormone |
| of the luteal phase of the cycle. However, | | of the luteal phase of the cycle. However, |
| small amounts of progesterone may appear | | small amounts of progesterone may appear ill the blood of monkeys as early as the 7th |
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| ESTROGEX AND PROGESTERONE
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| 559
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| ill the blood of monkeys as early as the 7th | |
| (lay and attain a concentration of 1 fxg. per | | (lay and attain a concentration of 1 fxg. per |
| ml. of serum at ovulation, whereas a maximal concentration of 10 /xg. per ml. is | | ml. of serum at ovulation, whereas a maximal concentration of 10 /xg. per ml. is |
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| cycle or that the presence of progesterone is | | cycle or that the presence of progesterone is |
| completely restricted to the luteal phase. | | completely restricted to the luteal phase. |
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| The dependence of the reproductive tract | | The dependence of the reproductive tract |
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| in large measure involve a study of the independent and combined actions of estrogens and progesterone on the activities of | | in large measure involve a study of the independent and combined actions of estrogens and progesterone on the activities of |
| the various structures concerned. | | the various structures concerned. |
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| Much can be learned about the action of | | Much can be learned about the action of |
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| very little if any change in size of the reproductive organs results. However, if first | | very little if any change in size of the reproductive organs results. However, if first |
| the normal condition is restored by giving | | the normal condition is restored by giving |
| estrogen and then is followed by the progesterone treatment, the size of the uterus | | estrogen and then is followed by the progesterone treatment, the size of the uterus is maintained but that of the cervix and |
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| is maintained but that of the cervix and | |
| vagina decreases to an extent approaching | | vagina decreases to an extent approaching |
| that in a castrated animal (Fig. 9.1B). Such | | that in a castrated animal (Fig. 9.1B). Such |
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| it does not prevent involution of the cervix | | it does not prevent involution of the cervix |
| and vagina. | | and vagina. |
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| An additional feature of the growth-stimulating action of the ovarian hormones is | | An additional feature of the growth-stimulating action of the ovarian hormones is |
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| effects of continuing the treatment with both estrogen and progesterone for a like period. | | effects of continuing the treatment with both estrogen and progesterone for a like period. |
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| 560
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| PHYSIOLOGY OF GONADS
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| I'll,. (1.2. I'll n Ml lour i-a.-^tra(c>d monkeys wliicli were givi^i 10 /ug. estradiol daily for 10
| | Fig.,. (1.2. I'll n Ml lour i-a.-^tra(c>d monkeys wliicli were givi^i 10 /ug. estradiol daily for 10 |
| to 78 days. A was given estrogen for 10 days, B for 30 days, C for 60 days, and D for 78 | | to 78 days. A was given estrogen for 10 days, B for 30 days, C for 60 days, and D for 78 |
| days. Depression in the endometrium of anterior wall of D is the result of a biopsy taken | | days. Depression in the endometrium of anterior wall of D is the result of a biopsy taken |
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| of Wisconsin Press, 1950.) | | of Wisconsin Press, 1950.) |
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| ESTROGEN AND PROGESTERONE
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| 561
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| such endometria are surprisingly inactive. | | such endometria are surprisingly inactive. |
| Although they are dependent on the presence of estrogen and may bleed within about | | Although they are dependent on the presence of estrogen and may bleed within about |
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| Mitotic Response of
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| Uterine Lpithelium
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| TO looo I. u. Estrogen
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| PER D«y.
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| but that large doses produce injurious effects. | | but that large doses produce injurious effects. |
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| 562
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| PHYSIOLOGY OF GONADS
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| Fig. 9.4. .4. i'v'< — ' ri:,,ii of the uterus of a castrated monkey which had received 1.0 mg. estradiol | | Fig. 9.4. .4. ri:,,ii of the uterus of a castrated monkey which had received 1.0 mg. estradiol |
| daily for 35 days. Compare with B which shows the | | daily for 35 days. Compare with B which shows the |
| effects of 1/10 this dosage (100 fig. daily) when | | effects of 1/10 this dosage (100 fig. daily) when |
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| The increase in tonus of the uterine musculature, a known effect of estrogen, has | | The increase in tonus of the uterine musculature, a known effect of estrogen, has |
| been considered as possibly exercising a restrictive influence on growth of the endo | | been considered as possibly exercising a restrictive influence on growth of the endometrium. An attempt has been made to remove this containing influence the muscle |
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| metrium. An attempt has been made to remove this containing influence the muscle
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| may have by making an incision through | | may have by making an incision through |
| the anterior wall of the uterus (Hisaw, | | the anterior wall of the uterus (Hisaw, |
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| was not closed and after hemorrhage was | | was not closed and after hemorrhage was |
| completely controlled the uterus was returned to the abdomen. | | completely controlled the uterus was returned to the abdomen. |
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| Examination of the uterus at the conclusion of the experiment showed no indications | | Examination of the uterus at the conclusion of the experiment showed no indications |
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| held open by suturing a wire loop into the | | held open by suturing a wire loop into the |
| incision. Yet the incision closed and no unusual growth of the endometrium was detected (Fig. 9.6). | | incision. Yet the incision closed and no unusual growth of the endometrium was detected (Fig. 9.6). |
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| Observations under these conditions are | | Observations under these conditions are |
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| to estrogen. | | to estrogen. |
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| The surgical procedure used by Hisaw
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| ( 19501 for preparing utero-abdominal fistulae foi' studies of the exj^erimental induction
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| of endometrial growth by estrogen and progesterone was a modification of that used
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| by van Wagenen and Morse (1940) for ob
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| | The uteri of these two castrated monkeys were opened from fundus to cer\'ix by an incision |
| | through the anterior wall while the animals were receiving estrogen. Part of the endometrium |
| | of the anterior wall was removed and the incision in the myometrium was not closed. |
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| ESTROGEN AND PROGESTERONE
| | Fig. 9.5. Estradiol, 10 fig., was given daily for 7 days; the uterus was opened and the animal |
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| Figs. 9.5 and 9.6
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| The uteri of these two castrated monkeys were opened from fundus to cer\'ix by an incision
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| through the anterior wall while the animals were receiving estrogen. Part of the endometrium
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| of the anterior wall was removed and the incision in the myometrium was not closed.
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| Fig. 9.5. Estradiol, 10 fig., was given daily for 7 days; the uterus was opened and the animal | |
| continued on 30 /xg. estradiol daily for 40 days. (From F. L. Hisaw, in A Sy7nposiii7n on Steroid | | continued on 30 /xg. estradiol daily for 40 days. (From F. L. Hisaw, in A Sy7nposiii7n on Steroid |
| Hormones, University of Wisconsin Press, 1950.) | | Hormones, University of Wisconsin Press, 1950.) |
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| | | The surgical procedure used by Hisaw |
| serving changes in the endometrium (luring
| | ( 19501 for preparing utero-abdominal fistulae foi' studies of the exj^erimental induction |
| | of endometrial growth by estrogen and progesterone was a modification of that used |
| | by van Wagenen and Morse (1940) for observing changes in the endometrium (luring |
| the normal menstrual cycle. This procedure | | the normal menstrual cycle. This procedure |
| makes frequent inspections possible either | | makes frequent inspections possible either |
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| growth reactions of the endometrium in this | | growth reactions of the endometrium in this |
| area are of particular interest. | | area are of particular interest. |
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| PHYSIOLOGY OF GONADS
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| arterioles, nor did ischemia occur during involution previous to bleeding. It seems that | | arterioles, nor did ischemia occur during involution previous to bleeding. It seems that |
| the response of this tissue to estrogen is like | | the response of this tissue to estrogen is like |
| that found in other experiments but the absence of ischemia preceding bleeding is ex | | that found in other experiments but the absence of ischemia preceding bleeding is exceptional. The endometrium on the anterior |
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| ceptional. The endometrium on the anterior
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| and posterior walls of uterine fistulae invariably showed ischemia for several hours | | and posterior walls of uterine fistulae invariably showed ischemia for several hours |
| before active bleeding following the withdrawal of estrogen. | | before active bleeding following the withdrawal of estrogen. |
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| Markee (1940) approached the problem | | Markee (1940) approached the problem |
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| events taking place at menstruation can be | | events taking place at menstruation can be |
| seen and recorded, since the transplants regress and bleed at each menstrual period. | | seen and recorded, since the transplants regress and bleed at each menstrual period. |
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| ESTROGEN AND PROGESTERONE
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| connective tissue of the stroma. Glycogen | | connective tissue of the stroma. Glycogen |
| may be present at the basal ends of epithelial cells beneath the nuclei (Overholser and | | may be present at the basal ends of epithelial cells beneath the nuclei (Overholser and |
| Nelson, 1936) but it apparently is not readily released under the action of estrogen | | Nelson, 1936) but it apparently is not readily released under the action of estrogen alone (Lendrum and Hisaw, 1936; Engle |
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| alone (Lendrum and Hisaw, 1936; Engle | |
| and Smith, 1938) . The glands of the endometrium maintain a straight tubular structure with some branching near the muscle | | and Smith, 1938) . The glands of the endometrium maintain a straight tubular structure with some branching near the muscle |
| layers. The condition produced experimentally in the monkey's uterus by short term | | layers. The condition produced experimentally in the monkey's uterus by short term |
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| that present in the normal animal at midcycle, or even a few days later if ovulation | | that present in the normal animal at midcycle, or even a few days later if ovulation |
| does not occur. | | does not occur. |
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| If, however, an estrogen treatment is continued for several months conditions develop in the uterus that are not found | | If, however, an estrogen treatment is continued for several months conditions develop in the uterus that are not found |
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| fistulae, and in exteriorized uteri. | | fistulae, and in exteriorized uteri. |
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| III. Effects of Progesterone | | |
| on the Uterus | | ==III. Effects of Progesterone on the Uterus== |
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| It has been mentioned that a menstrual | | It has been mentioned that a menstrual |
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| phase of the cycle can be duplicated in a | | phase of the cycle can be duplicated in a |
| castrated monkey by the injection of estrogen. Likewise, the progestational condition | | castrated monkey by the injection of estrogen. Likewise, the progestational condition |
| characteristic of the luteal phase can be developed by giving progesterone. In fact, all | | characteristic of the luteal phase can be developed by giving progesterone. In fact, all the morphologic and physiologic features |
| | that are known for anovulatory and ovulatory cycles can be reproduced in castrated |
| | monkeys by estrogen and progesterone. |
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| | | If one designs an experiment to simulate |
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| | the normal cycle in a castrated monkey |
| | | then estrogen should be given first to develop the conditions of the follicular phase |
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| PHYSIOLOGY OF GONADS
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| the morphologic and physiologic features
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| that are known for anovulatory and ovulatory cycles can be reproduced in castrated
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| monkeys by estrogen and progesterone.
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| If one designs an experiment to simulate | |
| the normal cycle in a castrated monkey | |
| then estrogen should be given first to develop the conditions of the follicular phase | |
| followed by progesterone for the progestational development of the luteal phase. Experience has shown that this is the most effective procedure for the production of a | | followed by progesterone for the progestational development of the luteal phase. Experience has shown that this is the most effective procedure for the production of a |
| progestational endometrium. Progesterone, | | progestational endometrium. Progesterone, |
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| for this purpose were planned on this principle (Hisaw, Meyer and Fevold, 1930; Hisaw, 1935; Engle, Smith and Shelesnyak, | | for this purpose were planned on this principle (Hisaw, Meyer and Fevold, 1930; Hisaw, 1935; Engle, Smith and Shelesnyak, |
| 1935). | | 1935). |
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| The first noticeable effect of progesterone | | The first noticeable effect of progesterone |
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| epithelium. The nuclei under the influence | | epithelium. The nuclei under the influence |
| of estrogen in doses which reproduce the | | of estrogen in doses which reproduce the |
| conditions of the follicular phase of a normal cvcle, are situated niostlv in the basal | | conditions of the follicular phase of a normal cvcle, are situated niostlv in the basal half of the cells, some of them touching the |
| | basement membrane. The nuclei retreat |
| | from the basement membrane when progesterone is given leaving a conspicuous clear |
| | zone. This zone is produced by intracellular |
| | deposits of glycogen. These early changes |
| | usually appear before pronounced spiraling |
| | and dilation of the glands. |
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| half of the cells, some of them touching the
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| basement membrane. The nuclei retreat
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| from the basement membrane when progesterone is given leaving a conspicuous clear
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| zone. This zone is produced by intracellular
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| deposits of glycogen. These early changes
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| usually appear before pronounced spiraling
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| and dilation of the glands.
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| Secretion begins in response to estrogenic | | Secretion begins in response to estrogenic |
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| thickened walls. Such uteri tend to be somewhat smaller than normal and are soft and | | thickened walls. Such uteri tend to be somewhat smaller than normal and are soft and |
| pHable. | | pHable. |
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| Thus, it is seen that when growth is produced in the endonietiiuni of a castrated | | Thus, it is seen that when growth is produced in the endonietiiuni of a castrated |
| monkey by giving estrogen and then continued on injections of progesterone, there | | monkey by giving estrogen and then continued on injections of progesterone, there |
| follows a sequential development of all | | follows a sequential development of all |
| stages of the luteal phase of a normal menstiual cycle terminating in secretory exhaustion. However, this condition cannot | | stages of the luteal phase of a normal menstiual cycle terminating in secretory exhaustion. However, this condition cannot be maintained by continuing the progesterone treatment, and involutionary processes |
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| ESTROGEN AND PROGESTERONE
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| be maintained by continuing the progesterone treatment, and involutionary processes | |
| set in and the endometrium is reduced to a | | set in and the endometrium is reduced to a |
| thin structure. Yet, such degenerate endometria are dependent upon progesterone | | thin structure. Yet, such degenerate endometria are dependent upon progesterone |
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| prevent bleeding. | | prevent bleeding. |
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| IV. Synergism between Estrogen | | |
| and Progesterone | | ==IV. Synergism between Estrogen and Progesterone== |
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| There is considerable evidence that in | | There is considerable evidence that in |
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| the influence of estrogen was not enhanced | | the influence of estrogen was not enhanced |
| by relieving muscle tension by a midline incision through the anterior wall of the | | by relieving muscle tension by a midline incision through the anterior wall of the |
| uterus. Now, if a similar operation is per | | uterus. Now, if a similar operation is performed on the uterus of a monkey that is |
| | receiving 10 /tg. estradiol daily and the |
| | treatment continued with the addition of a |
| | daily dose of 1 mg. progesterone, there usually follows a rapid growth of endometrial |
| | tissue out through the incision until by |
| | about 3 weeks a mass is formed which approximates the size of the entire uterus (Fig. |
| | 9.9). If this experiment is repeated and the |
| | same dosage of progesterone is given without estrogen, there is no outgrowth of the |
| | endometrium (Fig. 9.10). |
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| University of Wisconsin Press, 1950.) | | University of Wisconsin Press, 1950.) |
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| formed on the uterus of a monkey that is
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| receiving 10 /tg. estradiol daily and the
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| treatment continued with the addition of a
| | A similar synergistic action can be seen in |
| daily dose of 1 mg. progesterone, there usually follows a rapid growth of endometrial
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| tissue out through the incision until by
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| about 3 weeks a mass is formed which approximates the size of the entire uterus (Fig.
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| 9.9). If this experiment is repeated and the
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| same dosage of progesterone is given without estrogen, there is no outgrowth of the
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| endometrium (Fig. 9.10).
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| A similar synergistic action can be seen in | |
| utero-abdominal fistulae. We have mentioned that estrogen does not cause excessive | | utero-abdominal fistulae. We have mentioned that estrogen does not cause excessive |
| growth of the endometrium under these conditions. However, endometria that have | | growth of the endometrium under these conditions. However, endometria that have |
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| mg. progesterone are added daily to the | | mg. progesterone are added daily to the |
| treatment. By the 4th or 5th day lobes of | | treatment. By the 4th or 5th day lobes of |
| blood-red endometrium begin to protrude | | blood-red endometrium begin to protrude through the opening of the fistula. Within a |
| | few days tongue-like processes of endometrial tissue are thrust out of the opening |
| | with each uterine contraction and are entirely or i^artially withdrawn at each relaxation. |
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| PHYSIOLOGY OF GONADS
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|
Line 1,035: |
Line 870: |
| F. L. Hisaw, in A Syiyiposium on Steroid Hormones, University of Wisconsin Press, 1950.) | | F. L. Hisaw, in A Syiyiposium on Steroid Hormones, University of Wisconsin Press, 1950.) |
|
| |
|
| through the opening of the fistula. Within a
| |
| few days tongue-like processes of endometrial tissue are thrust out of the opening
| |
| with each uterine contraction and are entirely or i^artially withdrawn at each relaxation.
| |
|
| |
|
| Such outgrowths are difficult to protect | | Such outgrowths are difficult to protect |
Line 1,061: |
Line 893: |
| given, passes through the same stages as | | given, passes through the same stages as |
| those following the injection of only progesterone; i.e., presecretory swelling of the | | those following the injection of only progesterone; i.e., presecretory swelling of the |
| glandular epithelium, active secretion, and | | glandular epithelium, active secretion, and secretory exhaustion. The endometrium, |
| | |
| | |
| | |
| secretory exhaustion. The endometrium, | |
| however, is considerably thicker than when | | however, is considerably thicker than when |
| a comparable dose of progesterone is given | | a comparable dose of progesterone is given |
Line 1,091: |
Line 919: |
| for 200 days or a year further changes in | | for 200 days or a year further changes in |
| the endometrium occur. By 200 days the | | the endometrium occur. By 200 days the |
| epithelium of the surface mucosa and glands | | epithelium of the surface mucosa and glands is lost except for small glandular vestiges |
| | along the musciilaris at the base of the endometrium. There are no glands, coiled arteries, or large blood vessels in what one |
| | might yet call the functionalis. All that remains is a modified stroma that resembles |
| | decidual tissue (Fig. 9.13.4 and B). It is also |
| | of interest that these endometria will menstruate if the treatment is discontinued and |
| | in most if the injections of progesterone are |
| | stopped and estrogen continued, but not if |
| | estrogen is stopped and progesterone continued. |
| | |
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| |
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| |
|
Line 1,100: |
Line 936: |
| by 10 /xg. estradiol and 2 mg. progesterone daily | | by 10 /xg. estradiol and 2 mg. progesterone daily |
| for 31 davs. | | for 31 davs. |
|
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| ESTROGEN AND PROGESTERONE
| |
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| 569
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|
Line 1,117: |
Line 944: |
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| is lost except for small glandular vestiges
| |
| along the musciilaris at the base of the endometrium. There are no glands, coiled arteries, or large blood vessels in what one
| |
| might yet call the functionalis. All that remains is a modified stroma that resembles
| |
| decidual tissue (Fig. 9.13.4 and B). It is also
| |
| of interest that these endometria will menstruate if the treatment is discontinued and
| |
| in most if the injections of progesterone are
| |
| stopped and estrogen continued, but not if
| |
| estrogen is stopped and progesterone continued.
| |
|
| |
|
| Even though in such experiments the endometrium has been under the influence of | | Even though in such experiments the endometrium has been under the influence of |
Line 1,150: |
Line 969: |
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| 570
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|
| | Fig. 9.13. The endometrium shown m .4 is (h;i( from a castraled mdiik.N wlml, l,a,l |
| | received 10 /xg- estradiol and 2 mg. progesterone daily for 200 days. In B, jiart of ilie endometrium of a snndai animal given the same treatment for 312 days is shown at a higher |
| | magnification. The endometrium is almost entirely a modified stroma in which glandular |
| | epithelium and coiled arteries are absent. Only vestiges of glands are present in the basal |
| | area next to the myometrium. |
|
| |
|
| PHYSIOLOGY OF GONADS
| | One of the most interesting aspects of |
| | |
| | |
| | |
| | |
| | |
| Fk;. 9.13. The endometrium shown m .4 is (h;i( from a castraled mdiik.N wlml, l,a,l
| |
| received 10 /xg- estradiol and 2 mg. progesterone daily for 200 days. In B, jiart of ilie endometrium of a snndai animal given the same treatment for 312 days is shown at a higher
| |
| magnification. The endometrium is almost entirely a modified stroma in which glandular
| |
| epithelium and coiled arteries are absent. Only vestiges of glands are present in the basal
| |
| area next to the myometrium.
| |
| | |
| One of the most interesting aspects of | |
| these observations is that these effects were | | these observations is that these effects were |
| jiroduced by dosages of estrogen and progesterone that are very probably within the | | jiroduced by dosages of estrogen and progesterone that are very probably within the |
Line 1,186: |
Line 997: |
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|
| Fir;. 9.14. Uterus of a castrated monkey which
| | Fig. 9.14. Uterus of a castrated monkey which |
| was given 10 ixg. of estradiol and 2 mg. progesterone daily for 307 days at which time the | | was given 10 ixg. of estradiol and 2 mg. progesterone daily for 307 days at which time the |
| injections of progesterone were stopped and estrogen continued for 20 days. Bleeding occurred the | | injections of progesterone were stopped and estrogen continued for 20 days. Bleeding occurred the |
Line 1,193: |
Line 1,004: |
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| ESTROGEN AND PROGESTERONE
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| 571
| |
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|
Line 1,221: |
Line 1,026: |
| at the same time it assists in the destruction of the coiled arteries in the endometrium. | | at the same time it assists in the destruction of the coiled arteries in the endometrium. |
|
| |
|
| V. Experimentally Produced | | |
| Implantation Reactions | | ==V. Experimentally Produced Implantation Reactions== |
|
| |
|
| Progestational endometria of the normal | | Progestational endometria of the normal |
Line 1,228: |
Line 1,033: |
| proliferations which seem identical with | | proliferations which seem identical with |
| those found at normal implantation sites of | | those found at normal implantation sites of |
| fertilized ova (Figs. 9.16 and 9.171 (Hisaw, | | fertilized ova (Figs. 9.16 and 9.171 (Hisaw, 1935; Hisaw, Creep and Fevold, 1937; Wislocki and Streeter, 1938; Rossman, 1940). |
| | |
| | |
| | |
| 1935; Hisaw, Creep and Fevold, 1937; Wislocki and Streeter, 1938; Rossman, 1940). | |
| The proliferated cells originate from the | | The proliferated cells originate from the |
| surface and glandular epithelium and grow | | surface and glandular epithelium and grow |
Line 1,243: |
Line 1,044: |
| attain the proportions of giant cells and | | attain the proportions of giant cells and |
| many are multinucleated. | | many are multinucleated. |
| | |
|
| |
|
| The development of the plaques is most | | The development of the plaques is most |
Line 1,254: |
Line 1,056: |
| Wislocki and Streeter ( 1938,1 found that implantation plaques during pregnancy and | | Wislocki and Streeter ( 1938,1 found that implantation plaques during pregnancy and |
| those experimentally induced underwent ajjl^roximately the same development arid | | those experimentally induced underwent ajjl^roximately the same development arid |
| subsequent degeneration except for modifications produced by the invading troplio | | subsequent degeneration except for modifications produced by the invading trophoblast. Rossman (1940j made an extensive |
| | morphologic study of these epithelial proliferations and concluded that they should |
| | be regarded as typical metaplasias \vith an |
| | embryotrophic function. |
|
| |
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| |
| PHYSIOLOGY OF GONADS
| |
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| :^a.
| |
|
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| :^^--.^
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| tx: ^ .
| |
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|
Line 1,275: |
Line 1,066: |
| Fig. 9.16. An area of the normal implantation | | Fig. 9.16. An area of the normal implantation |
| site of a developing ovum. (From Carnegie Institution, No. C467.) | | site of a developing ovum. (From Carnegie Institution, No. C467.) |
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Line 1,287: |
Line 1,072: |
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|
| | | ==VI. The Cervix Uteri== |
| blast. Rossman (1940j made an extensive
| |
| morphologic study of these epithelial proliferations and concluded that they should
| |
| be regarded as typical metaplasias \vith an
| |
| embryotrophic function.
| |
| | |
| VI. The Cervix Uteri | |
|
| |
|
| The cervix uteri of the rhesus monkey is | | The cervix uteri of the rhesus monkey is |
Line 1,329: |
Line 1,108: |
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|
| ESTROGEN AND PROGESTERONE
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|
| | | Fig. 9.19. Sagittal section of the cervix of a pregnant monkey showing conditions present |
| | |
| 573
| |
| | |
| | |
| | |
| | |
| Fig. 9.19. Sagittal section of the cervix of a pregnant monkey showing conditions present | |
| just previous to parturition on the 154th day of gestation. The dominant features are | | just previous to parturition on the 154th day of gestation. The dominant features are |
| dilation of the cervical canal and reduction of the cervical lips (shown at the left) and the | | dilation of the cervical canal and reduction of the cervical lips (shown at the left) and the |
Line 1,367: |
Line 1,138: |
| to the action of estrogen and the sudden periodic drops in blood estrogen caused secretion and consequent regression. However, it | | to the action of estrogen and the sudden periodic drops in blood estrogen caused secretion and consequent regression. However, it |
| is not clear how this could account for the | | is not clear how this could account for the |
| abundant secretion of the cervical glands in | | abundant secretion of the cervical glands in the presence of high levels of estrogen during |
| | | late pregnancy (Fig. 9.19). |
| | |
|
| |
|
| the presence of high levels of estrogen during
| |
| late pregnancy (Fig. 9.19).
| |
|
| |
|
| Much has been learned regarding the | | Much has been learned regarding the |
Line 1,383: |
Line 1,151: |
| amount of secretion induced by estrogen | | amount of secretion induced by estrogen |
| never equals that of the last half of pregnancy, and it usually subsides if the injections are continued for several months. | | never equals that of the last half of pregnancy, and it usually subsides if the injections are continued for several months. |
| | |
|
| |
|
| Under conditions of chronic treatments | | Under conditions of chronic treatments |
Line 1,392: |
Line 1,161: |
| Similar lesions may be found in the cervix | | Similar lesions may be found in the cervix |
| uteri of women (Fluhmann, 1954). They | | uteri of women (Fluhmann, 1954). They |
| seem especially prone to occur under conditions characterized by excessive production of estrogen, such as hyperplasia of the | | seem especially prone to occur under conditions characterized by excessive production of estrogen, such as hyperplasia of the endometrium (Hellman, Rosenthal, Kistner |
| | |
| | |
| | |
| 574
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| endometrium (Hellman, Rosenthal, Kistner | |
| and Gordon, 1954) and granulosa-cell tumors of the ovary. Various degrees of metaplasia may occur in the cervix during pregnancy both in the mother and newborn but | | and Gordon, 1954) and granulosa-cell tumors of the ovary. Various degrees of metaplasia may occur in the cervix during pregnancy both in the mother and newborn but |
| Fluhmann (1954) did not find it as frequently as in nonpregnant women. | | Fluhmann (1954) did not find it as frequently as in nonpregnant women. |
| | |
|
| |
|
| This reaction to estrogen as seen in the | | This reaction to estrogen as seen in the |
Line 1,475: |
Line 1,233: |
| progesterone are started after metaplastic | | progesterone are started after metaplastic |
| growths have been formed in response to | | growths have been formed in response to |
| estrogen, further growth is inhibited and | | estrogen, further growth is inhibited and the keratinized cells of the lesion become |
| | vacuolated and are lost. |
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|
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| ESTROGEN AND PROGESTERONE
| |
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| |
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| |
|
| |
| the keratinized cells of the lesion become
| |
| vacuolated and are lost.
| |
|
| |
|
| In contrast with the effects of estrogen | | In contrast with the effects of estrogen |
Line 1,504: |
Line 1,255: |
| treatment (see chapter by Zarrow). | | treatment (see chapter by Zarrow). |
|
| |
|
| VII. The Vagina | | |
| | ==VII. The Vagina== |
|
| |
|
| The general features of the vaginal smear | | The general features of the vaginal smear |
Line 1,527: |
Line 1,279: |
|
| |
|
| Cellular proliferation is less rapid during | | Cellular proliferation is less rapid during |
| the luteal phase and apparently cells are | | the luteal phase and apparently cells are desquamated more rapidly than they are replaced. Consequently there is a decrease in |
| | |
| | |
| | |
| desquamated more rapidly than they are replaced. Consequently there is a decrease in | |
| the thickness of the epithelium in the luteal | | the thickness of the epithelium in the luteal |
| phase which may include an almost complete loss of the cornified zone (Davis and | | phase which may include an almost complete loss of the cornified zone (Davis and |
Line 1,556: |
Line 1,304: |
|
| |
|
|
| |
|
| l''i(.. U.21. the vaginal epithelium of a castuUMJ
| | Fig. U.21. the vaginal epithelium of a castuUMJ |
| monkej' showing growth antl cornification induced | | monkej' showing growth antl cornification induced |
| by estrogen. | | by estrogen. |
|
| |
|
|
| |
|
|
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| 576
| |
|
| |
|
| |
|
| |
| PHYSIOLOGY OF GONADS
| |
|
| |
|
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| |
|
Line 1,593: |
Line 1,335: |
| noticeable decrease in the intensity of cornification, which in the monkey is never as | | noticeable decrease in the intensity of cornification, which in the monkey is never as |
| pronounced as in rodents, and under these | | pronounced as in rodents, and under these |
| conditions is quite incomplete, each cell retaining a conspicuous nucleus. Partly cornified cells may be present for several weeks | | conditions is quite incomplete, each cell retaining a conspicuous nucleus. Partly cornified cells may be present for several weeks when both estrogen and progesterone are |
| | given, but eventually they almost entirely |
| | disappear and the epithelium attains a condition resembling that of late pregnancy. |
|
| |
|
|
| |
|
|
| |
| .-•^ss;^
| |
|
| |
|
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| |
| 4* ' V ^ §
| |
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|
Line 1,611: |
Line 1,349: |
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| |
|
|
| |
|
| when both estrogen and progesterone are
| |
| given, but eventually they almost entirely
| |
| disappear and the epithelium attains a condition resembling that of late pregnancy.
| |
|
| |
|
| The inhibitory effect of progesterone on | | The inhibitory effect of progesterone on |
Line 1,645: |
Line 1,380: |
| the vagina. | | the vagina. |
|
| |
|
| VIII. Sexual Skin | | |
| | ==VIII. Sexual Skin== |
|
| |
|
| A so-called sexual skin is jiresent in most | | A so-called sexual skin is jiresent in most |
Line 1,654: |
Line 1,390: |
| the monkey (Macaca), the baboon (Papio), | | the monkey (Macaca), the baboon (Papio), |
| and the chimpanzee (Pan). The sexual skin | | and the chimpanzee (Pan). The sexual skin |
| of t!ie baboon and chimpanzee undergo jiro | | of t!ie baboon and chimpanzee undergo pronounced swelling during the follicular phase |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 577
| |
| | |
| | |
| | |
| nounced swelling during the follicular phase
| |
| of the cycle. A maximal size is attained by | | of the cycle. A maximal size is attained by |
| the middle of the cycle followed by a rapid | | the middle of the cycle followed by a rapid |
Line 1,680: |
Line 1,405: |
| Nissen and Yerkes, 1943). | | Nissen and Yerkes, 1943). |
|
| |
|
| A w^ell developed sexual skin is present | | |
| | A well developed sexual skin is present |
| in the monkey {Macaca mulatta) only during adolescence. With the appearance of | | in the monkey {Macaca mulatta) only during adolescence. With the appearance of |
| the menstrual cycles the sexual skin undergoes a process of maturation into the adult | | the menstrual cycles the sexual skin undergoes a process of maturation into the adult |
Line 1,692: |
Line 1,418: |
| maturation of the sexual skin have been described in considerable detail by several investigators (Hartman, 1932; Zuckerman, | | maturation of the sexual skin have been described in considerable detail by several investigators (Hartman, 1932; Zuckerman, |
| van Wagenen and Gardiner, 1938) . | | van Wagenen and Gardiner, 1938) . |
| | |
|
| |
|
| The sexual skin has been of considerable | | The sexual skin has been of considerable |
Line 1,709: |
Line 1,436: |
| estrogen and progesterone in endometrial | | estrogen and progesterone in endometrial |
| growth and menstruation. | | growth and menstruation. |
| | |
|
| |
|
| That the development and edema of the | | That the development and edema of the |
| sexual skin of adolescent rhesus monkeys | | sexual skin of adolescent rhesus monkeys |
| depend on the ovaries was first demon | | depend on the ovaries was first demonstrated by Allen ( 1927 ) . Involution and loss |
| | |
| | |
| strated by Allen ( 1927 ) . Involution and loss
| |
| of color follow castration, and the normal | | of color follow castration, and the normal |
| condition can be restored by the injection | | condition can be restored by the injection |
Line 1,727: |
Line 1,452: |
| the response of the sexual skin to subsequent estrogen treatments is limited to a | | the response of the sexual skin to subsequent estrogen treatments is limited to a |
| change in color. | | change in color. |
| | |
|
| |
|
| Similar experiments have been performed | | Similar experiments have been performed |
Line 1,738: |
Line 1,464: |
| skin of the genital area of the rhesus monkey in that it does not "mature" under the | | skin of the genital area of the rhesus monkey in that it does not "mature" under the |
| influence of estrogen. | | influence of estrogen. |
| | |
|
| |
|
| When large doses of estrogen are given to | | When large doses of estrogen are given to |
Line 1,761: |
Line 1,488: |
| progesterone are added to the treatmeiu | | progesterone are added to the treatmeiu |
| after full development of the sexual skin | | after full development of the sexual skin |
| has been induced by estrogen, there is a | | has been induced by estrogen, there is a noticeable loss of edema by the 4th or 5th |
| | |
| | |
| | |
| 578
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| noticeable loss of edema by the 4th or 5th | |
| day followed by rapid involution and reduction of the turgid folds of skin to loose, | | day followed by rapid involution and reduction of the turgid folds of skin to loose, |
| flabby wrinkles within about 10 days. When | | flabby wrinkles within about 10 days. When |
Line 1,781: |
Line 1,496: |
| skin of castrated adult monkeys (Hisaw, | | skin of castrated adult monkeys (Hisaw, |
| Greep and Fevold, 1937; Hisaw, 1942). | | Greep and Fevold, 1937; Hisaw, 1942). |
| | |
|
| |
|
| The interaction of estrogen and i)rogesterone on the sexual skin of rhesus monkeys can best be demonstrated by the reaction of the skin of the sexual area in | | The interaction of estrogen and i)rogesterone on the sexual skin of rhesus monkeys can best be demonstrated by the reaction of the skin of the sexual area in |
Line 1,799: |
Line 1,515: |
| most remarkable eventuation of such treatment is menstruation which usually begins | | most remarkable eventuation of such treatment is menstruation which usually begins |
| on about the 10th day (Hisaw, 1942). | | on about the 10th day (Hisaw, 1942). |
| | |
|
| |
|
| Involution of the sexual skin and menstruation following a single injection of | | Involution of the sexual skin and menstruation following a single injection of |
Line 1,813: |
Line 1,530: |
| was not associated with menstruation. However, when the dose was increased to 20 mg. | | was not associated with menstruation. However, when the dose was increased to 20 mg. |
| both deturgescence of the sexual skin and | | both deturgescence of the sexual skin and |
| menstruation occurred. These effects pro | | menstruation occurred. These effects produced by progesterone in the presence of |
| | |
| | |
| duced by progesterone in the presence of
| |
| endogenous estrogen have much in common | | endogenous estrogen have much in common |
| with those described above as occurring in | | with those described above as occurring in |
Line 1,822: |
Line 1,536: |
| treatments. | | treatments. |
|
| |
|
| IX. Menstruation | | |
| | ==IX. Menstruation== |
|
| |
|
| An experimental ai^proach to the physiology of menstruation dates from the observations of Allen (1927) that uterine | | An experimental ai^proach to the physiology of menstruation dates from the observations of Allen (1927) that uterine |
Line 1,840: |
Line 1,555: |
| without bleeding (Werner and Collier, 1933; | | without bleeding (Werner and Collier, 1933; |
| Zuckerman, 1937b, d). | | Zuckerman, 1937b, d). |
| | |
|
| |
|
| Estrogen also will inliihit i)ostop('rative | | Estrogen also will inliihit i)ostop('rative |
Line 1,853: |
Line 1,569: |
| treatment is started during the follicular | | treatment is started during the follicular |
| phase (Zuckerman, 1935. 1936a). | | phase (Zuckerman, 1935. 1936a). |
| | |
|
| |
|
| Progesterone, in contrast with estrogen, | | Progesterone, in contrast with estrogen, |
| will prevent menstruation from an endometrium representative of any stage of the normal cycle. It will delay onset of the next menses even when the treatment is started only | | will prevent menstruation from an endometrium representative of any stage of the normal cycle. It will delay onset of the next menses even when the treatment is started only a few days before the expected menstruation (Corner, 1935; Corner and Allen, 1936) . |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 579
| |
| | |
| | |
| | |
| a few days before the expected menstruation (Corner, 1935; Corner and Allen, 1936) . | |
| Also, the bleeding that invariably follows | | Also, the bleeding that invariably follows |
| the discontinuance of a long treatment with | | the discontinuance of a long treatment with |
Line 1,874: |
Line 1,579: |
| Smith and Shelesnvak, 1935; Zuckerman, | | Smith and Shelesnvak, 1935; Zuckerman, |
| 1936b). | | 1936b). |
| | |
|
| |
|
| An impression held by many of the earlier investigators was that progesterone | | An impression held by many of the earlier investigators was that progesterone |
Line 1,896: |
Line 1,602: |
| (hiring the follicular j^hase of the cycle | | (hiring the follicular j^hase of the cycle |
| (Zondek and Rozin, 1938; Rakoff, 1946). | | (Zondek and Rozin, 1938; Rakoff, 1946). |
| | |
|
| |
|
| These observations have been confirmed | | These observations have been confirmed |
Line 1,910: |
Line 1,617: |
| can be obtained in this way in a castrated | | can be obtained in this way in a castrated |
| animal seems to be related to the size of the | | animal seems to be related to the size of the |
| initial dose of estrogen used to induce withdrawal bleeding. This also applies to pro | | initial dose of estrogen used to induce withdrawal bleeding. This also applies to progesterone-withdrawal bleeding, so the effect does not depend upon the particular |
| | |
| | |
| gesterone-withdrawal bleeding, so the effect does not depend upon the particular
| |
| hormone used to obtain the bleeding. It also | | hormone used to obtain the bleeding. It also |
| is of interest that such conditioning of the | | is of interest that such conditioning of the |
Line 1,925: |
Line 1,629: |
| common with those of Phelps (1947) who | | common with those of Phelps (1947) who |
| also studied the influence of previous treatment on experimental menstruation in monkeys. | | also studied the influence of previous treatment on experimental menstruation in monkeys. |
| | |
|
| |
|
| There seems to be a quantitative relationship between the dosage of progesterone | | There seems to be a quantitative relationship between the dosage of progesterone |
Line 1,943: |
Line 1,648: |
| bleeding. Similar observations were made | | bleeding. Similar observations were made |
| previously by Zuckerman (1936a, 1937d). | | previously by Zuckerman (1936a, 1937d). |
| | |
|
| |
|
| These experimental results give grounds | | These experimental results give grounds |
Line 1,953: |
Line 1,659: |
| and induce phases of uterine bleeding in | | and induce phases of uterine bleeding in |
| rapid succession in normal monkeys | | rapid succession in normal monkeys |
| (Krohn, 1951). So too can testosterone prevent estrogen-withdrawal bleeding (Hart | | (Krohn, 1951). So too can testosterone prevent estrogen-withdrawal bleeding (Hartman, 1937; Engle and Smith, 1939; Duncan, |
| | |
| | |
| 580
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| man, 1937; Engle and Smith, 1939; Duncan,
| |
| Allen and Hamilton, 1941) and inhibit progesterone-withdrawal bleeding as well (Engle and Smith, 1939). Testosterone also will | | Allen and Hamilton, 1941) and inhibit progesterone-withdrawal bleeding as well (Engle and Smith, 1939). Testosterone also will |
| precipitate bleeding during an estrogen | | precipitate bleeding during an estrogen |
Line 2,004: |
Line 1,699: |
| respond" to the estrogen treatment. When | | respond" to the estrogen treatment. When |
| the 1 mg. ]irogesterone is given on the 20th | | the 1 mg. ]irogesterone is given on the 20th |
| day of estrogen treatment the edema of th(^ | | day of estrogen treatment the edema of the sexual skin will have attained its maximal |
| | |
| | |
| | |
| sexual skin will have attained its maximal | |
| development. The first indication of an effect of progesterone is a slight loss of edema | | development. The first indication of an effect of progesterone is a slight loss of edema |
| and color of the sexual skin which appears | | and color of the sexual skin which appears |
Line 2,024: |
Line 1,715: |
| extend over no more than 5 days the time | | extend over no more than 5 days the time |
| between the first injection and bleeding remains approximately the same. | | between the first injection and bleeding remains approximately the same. |
| | |
|
| |
|
| Similar observations have been made by | | Similar observations have been made by |
Line 2,047: |
Line 1,739: |
| physiology of the reaction in both animals | | physiology of the reaction in both animals |
| seems to be the same. | | seems to be the same. |
| | |
|
| |
|
| The most important fact l)rought out by | | The most important fact l)rought out by |
Line 2,055: |
Line 1,748: |
| time (Zarrow, Shoger and Lazo-Wasem, | | time (Zarrow, Shoger and Lazo-Wasem, |
| 1954). In general it is considered the most | | 1954). In general it is considered the most |
| ephemeral of the sex steroids and is probablv inactivated within at least a few hours | | ephemeral of the sex steroids and is probablv inactivated within at least a few hours after it is administered. It seems more lilvely |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 581
| |
| | |
| | |
| | |
| after it is administered. It seems more lilvely | |
| that progesterone modifies the sexual skin | | that progesterone modifies the sexual skin |
| in a way that renders it unresponsive to estrogen and that about a fortnight is required | | in a way that renders it unresponsive to estrogen and that about a fortnight is required |
Line 2,086: |
Line 1,767: |
| of the menstrual cycle there is reason to believe that similar reactions were going on | | of the menstrual cycle there is reason to believe that similar reactions were going on |
| in the endometrium of the uterus. | | in the endometrium of the uterus. |
| | |
|
| |
|
| Endometrial regression, as described by | | Endometrial regression, as described by |
Line 2,107: |
Line 1,789: |
| (Markee, Davis and Hinsey, 1936), it probably is a phenomenon that always precedes | | (Markee, Davis and Hinsey, 1936), it probably is a phenomenon that always precedes |
| menstruation. | | menstruation. |
| | |
|
| |
|
| It seems from these observations that the | | It seems from these observations that the |
| changes in the endometrium preceding menstruation are initiated by a sudden with | | changes in the endometrium preceding menstruation are initiated by a sudden withdrawal of a stimulus on which the endometrium at the time relies for the maintenance |
| | |
| | |
| drawal of a stimulus on which the endometrium at the time relies for the maintenance
| |
| of a particular physiologic condition, and | | of a particular physiologic condition, and |
| bleeding and tissue loss are incidents that | | bleeding and tissue loss are incidents that |
Line 2,142: |
Line 1,822: |
| an exteriorized uterus (Fig. 9.7) in a monkey that is receiving 10 fig. estradiol daily | | an exteriorized uterus (Fig. 9.7) in a monkey that is receiving 10 fig. estradiol daily |
| (Hisaw, 1950). | | (Hisaw, 1950). |
| | |
|
| |
|
| Uterine bleeding precipitated by administering progesterone during an estrogen | | Uterine bleeding precipitated by administering progesterone during an estrogen |
Line 2,148: |
Line 1,829: |
| with the action of estrogen on the endometrium. Therefore, it is assumed that an animal receiving both estrogen and progesterone is in a sense "deprived" of estrogen. | | with the action of estrogen on the endometrium. Therefore, it is assumed that an animal receiving both estrogen and progesterone is in a sense "deprived" of estrogen. |
| That is, when the two hormones are given | | That is, when the two hormones are given |
| simultaneously, progesterone itself is capable of maintaining the endometrium without bleeding; but when it is stopped, the | | simultaneously, progesterone itself is capable of maintaining the endometrium without bleeding; but when it is stopped, the suggestion is that the animal is physiologically deprived of estrogen and literally deprived of progesterone (Corner, 1951). Although this view is in descriptive agreement |
| | |
| | |
| | |
| 582
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| suggestion is that the animal is physiologically deprived of estrogen and literally deprived of progesterone (Corner, 1951). Although this view is in descriptive agreement | |
| with the observed facts the idea of the inhibitory effect of progesterone does not take | | with the observed facts the idea of the inhibitory effect of progesterone does not take |
| into consideration the synergistic interaction of the two hormones on the endometrium. | | into consideration the synergistic interaction of the two hormones on the endometrium. |
| | |
|
| |
|
| The physiologic function of progesterone | | The physiologic function of progesterone |
Line 2,183: |
Line 1,853: |
| presence of estrogen. In fact, it seems probable that rarely if ever does progesterone | | presence of estrogen. In fact, it seems probable that rarely if ever does progesterone |
| perform its function in the absence of estrogen (Hisaw, 1959; chapter by Zarrow). | | perform its function in the absence of estrogen (Hisaw, 1959; chapter by Zarrow). |
| | |
|
| |
|
| After consideration of the endometrial | | After consideration of the endometrial |
Line 2,194: |
Line 1,865: |
| or the discontinuance of progesterone, even | | or the discontinuance of progesterone, even |
| though estrogen is present, is due to a decrease or absence of progesterone. | | though estrogen is present, is due to a decrease or absence of progesterone. |
| | |
|
| |
|
| It also has become less certain that menstruation at the conclusion of an anovulatory cycle is really an estrogen-withdrawal | | It also has become less certain that menstruation at the conclusion of an anovulatory cycle is really an estrogen-withdrawal |
| bleeding. This is possible, of couisc, but at | | bleeding. This is possible, of couisc, but at the same time the exceedingly small amount |
| | |
| | |
| | |
| the same time the exceedingly small amount | |
| of progesterone required to induce bleeding | | of progesterone required to induce bleeding |
| in the presence of estrogen makes it difficult | | in the presence of estrogen makes it difficult |
Line 2,216: |
Line 1,884: |
| dosage of progesterone to induce unquestionable progestational changes in the endometrium and much less will cause bleeding. These observations indicate that the | | dosage of progesterone to induce unquestionable progestational changes in the endometrium and much less will cause bleeding. These observations indicate that the |
| minimal effective concentration of progesterone in the blood may be less than is possible to detect by our present methods. | | minimal effective concentration of progesterone in the blood may be less than is possible to detect by our present methods. |
| | |
|
| |
|
| This also seems to hold for the human being. Estimates of secretion and metabolism | | This also seems to hold for the human being. Estimates of secretion and metabolism |
Line 2,238: |
Line 1,907: |
|
| |
|
| These findings and the wide variation in | | These findings and the wide variation in |
| the amount of prc'gnancdiol excreted during | | the amount of prc'gnancdiol excreted during a menstrual cycle (Venning and Browne, |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 58.3
| |
| | |
| | |
| | |
| a menstrual cycle (Venning and Browne, | |
| 1937) suggest that, even in the absence of | | 1937) suggest that, even in the absence of |
| ovulation, sufficient progesterone may be | | ovulation, sufficient progesterone may be |
Line 2,290: |
Line 1,947: |
| growth is attained (Hisaw, 1942), it seems | | growth is attained (Hisaw, 1942), it seems |
| plausible that the effectiveness of a dosage | | plausible that the effectiveness of a dosage |
| of estrogen only slightly alcove the thresh | | of estrogen only slightly alcove the threshold for bleeding may be decreased sufficiently by the endogenous progesterone from |
| | extra-ovarian sources to precipitate bleeding. |
|
| |
|
|
| |
| old for bleeding may be decreased sufficiently by the endogenous progesterone from
| |
| extra-ovarian sources to precipitate bleeding.
| |
|
| |
|
| Although it is obvious that the normal | | Although it is obvious that the normal |
Line 2,307: |
Line 1,962: |
| events is set in motion that leads up to active bleeding. | | events is set in motion that leads up to active bleeding. |
|
| |
|
| X. The Mechanism of Menstruation | | |
| | ==X. The Mechanism of Menstruation== |
|
| |
|
| The immediate cause and mechanism of | | The immediate cause and mechanism of |
Line 2,331: |
Line 1,987: |
| coils. (3) The increased coiling of the arteries retards the circulation of blood | | coils. (3) The increased coiling of the arteries retards the circulation of blood |
| through them and their branches. This stasis | | through them and their branches. This stasis |
| begins 1 to 3 davs before the onset of the | | begins 1 to 3 davs before the onset of the flow, and is associated with leukocytosis in |
| | the endometrium. (4) The portion of the |
| | coiled arteries located adjacent to the muscularis constricts 4 to 24 hours before the |
| | onset of the flow. This vasoconstriction persists throughout the menstrual period except when individual coiled arteries relax |
| | and blood circulates through them for a few |
| | minutes. Markee postulated that the immediate cause of menstruation under these |
| | conditions was the injurious effect of anoxemia upon the tissues of the endometrium |
| | l)rought about by mechanical compression |
| | and constriction of the coiled arteries. |
| | Therefore, the coiled arteries and their modifications become the central feature upon |
| | which the theory is based. |
|
| |
|
|
| |
|
| |
| 584
| |
|
| |
|
| |
|
| |
| PHYSIOLOGY OF GONADS
| |
|
| |
|
| |
|
| |
|
| |
| Repair
| |
|
| |
|
|
| |
|
Line 2,361: |
Line 2,015: |
|
| |
|
|
| |
|
| flow, and is associated with leukocytosis in
| | |
| the endometrium. (4) The portion of the
| |
| coiled arteries located adjacent to the muscularis constricts 4 to 24 hours before the
| |
| onset of the flow. This vasoconstriction persists throughout the menstrual period except when individual coiled arteries relax
| |
| and blood circulates through them for a few
| |
| minutes. Markee postulated that the immediate cause of menstruation under these
| |
| conditions was the injurious effect of anoxemia upon the tissues of the endometrium
| |
| l)rought about by mechanical compression
| |
| and constriction of the coiled arteries.
| |
| Therefore, the coiled arteries and their modifications become the central feature upon
| |
| which the theory is based.
| |
|
| |
|
| Although this offers an explanation for | | Although this offers an explanation for |
Line 2,377: |
Line 2,021: |
| it is known that menstruation can occur in | | it is known that menstruation can occur in |
| the absence of coiled arteries. Kaiser (1947) | | the absence of coiled arteries. Kaiser (1947) |
| showed that no spiral arteries are present in | | showed that no spiral arteries are present in the endometrium of three species of South |
| | | American monkeys known to menstruate. |
| | |
| | |
| the endometrium of three species of South | |
| American monkeys known to menstruate. | |
| He also found that the coiled vessels of the | | He also found that the coiled vessels of the |
| endometrium could be destroyed almost | | endometrium could be destroyed almost |
Line 2,399: |
Line 2,039: |
| with the exception of the absence of coiled | | with the exception of the absence of coiled |
| arteries; even so, it also will bleed when | | arteries; even so, it also will bleed when |
| the treatment is stopped. Even a more | | the treatment is stopped. Even a more drastic destruction of endometrial structures occurs when both estrogen and progesterone are given for several months. Not |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 58c
| |
| | |
| | |
| | |
| drastic destruction of endometrial structures occurs when both estrogen and progesterone are given for several months. Not | |
| only are the coiled arteries destroyed but | | only are the coiled arteries destroyed but |
| also the glands and the luminal epithelium. | | also the glands and the luminal epithelium. |
Line 2,418: |
Line 2,046: |
| of this, bleeding follows discontinuance of | | of this, bleeding follows discontinuance of |
| the treatment. | | the treatment. |
| | |
|
| |
|
| These observations prove conclusively | | These observations prove conclusively |
Line 2,430: |
Line 2,059: |
| transplants in ovariectomized monkeys receiving estrogen and progesterone, and concluded that the primary function of the | | transplants in ovariectomized monkeys receiving estrogen and progesterone, and concluded that the primary function of the |
| coiled arteries is concerned with vascularization of the implantation site of a developing embryo. | | coiled arteries is concerned with vascularization of the implantation site of a developing embryo. |
| | |
|
| |
|
| There also is reason for doul^ting that | | There also is reason for doul^ting that |
Line 2,453: |
Line 2,083: |
| means of a tourniquet for periods of 1 to 8V4 | | means of a tourniquet for periods of 1 to 8V4 |
| hours, and in two instances for 19 hours. | | hours, and in two instances for 19 hours. |
| This procedure did not precijiitate uterine | | This procedure did not precijiitate uterine bleeding nor did it hasten the onset of an |
| | |
| | |
| | |
| bleeding nor did it hasten the onset of an | |
| expected bleeding following estrogen withdrawal. In fact, when the uterus was deprived of blood for periods longer than 3 | | expected bleeding following estrogen withdrawal. In fact, when the uterus was deprived of blood for periods longer than 3 |
| hours impairment of the bleeding response | | hours impairment of the bleeding response |
Line 2,495: |
Line 2,121: |
| monkeys and the human being. He emphasizes changes taking place in the connective | | monkeys and the human being. He emphasizes changes taking place in the connective |
| tissue elements of the stroma and points out | | tissue elements of the stroma and points out |
| that much less tissue is lost at menstruation | | that much less tissue is lost at menstruation than i.< commonly thought (Bartehnez, |
| | |
| | |
| | |
| 586
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| than i.< commonly thought (Bartehnez, | |
| 1957). The reduction in thickness is clue primariiy to loss of ground substance from the | | 1957). The reduction in thickness is clue primariiy to loss of ground substance from the |
| stroma, and conversely, the outstanding | | stroma, and conversely, the outstanding |
Line 2,518: |
Line 2,132: |
| stromal connective tissue of the endometrium by a sudden withdrawal of a supporting hormonal stimulus. | | stromal connective tissue of the endometrium by a sudden withdrawal of a supporting hormonal stimulus. |
|
| |
|
| XI. References | | |
| | ==XI. References== |
|
| |
|
| Allen, E. 1927. The menstrual CA'cle in the monkey, Macacus rhesus: observations on normal | | Allen, E. 1927. The menstrual CA'cle in the monkey, Macacus rhesus: observations on normal |
Line 2,562: |
Line 2,177: |
| in the menstrual cycle of the monkey. Endocrinology, 48, 733-740. | | in the menstrual cycle of the monkey. Endocrinology, 48, 733-740. |
|
| |
|
| BrxTo.N, C. L. 1940. Pregnanediol determina | | BrxTo.N, C. L. 1940. Pregnanediol determinations as an aid in clinical diagnosis. Am. J. |
| | |
| | |
| tions as an aid in clinical diagnosis. Am. J.
| |
| Obst. & Gynec, 40, 202-211. | | Obst. & Gynec, 40, 202-211. |
|
| |
|
Line 2,637: |
Line 2,249: |
|
| |
|
| Engle, E. T., .and S.mith, P. E. 1935. Some uterine effects obtained in female monkeys during | | Engle, E. T., .and S.mith, P. E. 1935. Some uterine effects obtained in female monkeys during |
| continued estrin administration, with especial | | continued estrin administration, with especial reference to tlio r('i\ ix uteri. Auat. Rec, 6, |
| | |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
| | |
| 587
| |
| | |
| | |
| | |
| reference to tlio r('i\ ix uteri. Auat. Rec, 6, | |
| 471-483. | | 471-483. |
|
| |
|
Line 2,711: |
Line 2,311: |
| utilization of crystalline progesterone. Endocrinology, 25, 13-16. | | utilization of crystalline progesterone. Endocrinology, 25, 13-16. |
|
| |
|
| Hamilton, C. E. 1949. Observations on the cervi | | Hamilton, C. E. 1949. Observations on the cervical mucosa of the Rhesus monkey. Contr. EnibryoL, Carnegie Inst. Washington, 33, 81-101. |
| | |
| | |
| cal mucosa of the Rhesus monkey. Contr. EnibryoL, Carnegie Inst. Washington, 33, 81-101.
| |
|
| |
|
| H.artman, C. G. 1929. Three types of uterine | | H.artman, C. G. 1929. Three types of uterine |
Line 2,776: |
Line 2,373: |
| Soc. Exper. Biol. & Med., 36, 840-842." | | Soc. Exper. Biol. & Med., 36, 840-842." |
|
| |
|
| His.\w, F. L.. AND Creep, R. O. 1938. The inhibition of uterine bleeding with estradiol and | | His.\w, F. L.. AND Creep, R. O. 1938. The inhibition of uterine bleeding with estradiol and progesterone and associated endometrial modifications. Endocrinology, 23, 1-14. |
|
| |
|
| | His.\w, F. L., .^ND His.wv, F. L., Jr. 1958. Spontaneous carcinoma of the cervix uteii in a |
| | monkey (Macaca mulatto). Cancer, 11, 810816. |
|
| |
|
| | HiSAW, F. L., .4ND Lendrum, F. C. 1936. Squamous metaplasia in the cervical glands of the |
| | monkey following oestrin administration. Endocrinology, 20, 228-229. |
|
| |
|
| 588
| |
|
| |
|
| | | HiSAW, F. L., Meyer, R. K., axd Fevold, H. L. |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| progesterone and associated endometrial modifications. Endocrinology, 23, 1-14.
| |
| His.\w, F. L., .^ND His.wv, F. L., Jr. 1958. Spontaneous carcinoma of the cervix uteii in a
| |
| monkey (Macaca mulatto). Cancer, 11, 810816.
| |
| HiSAW, F. L., .4ND Lendrum, F. C. 1936. Squamous metaplasia in the cervical glands of the
| |
| monkey following oestrin administration. Endocrinology, 20, 228-229.
| |
| HiSAW, F. L., Meyer, R. K., axd Fevold, H. L. | |
| 1930. Production of a premenstrual endometrium in castrated monkeys by ovarian hormones. Proc. Soc. Exper. Biol. & Med., 27, | | 1930. Production of a premenstrual endometrium in castrated monkeys by ovarian hormones. Proc. Soc. Exper. Biol. & Med., 27, |
| 400-403. | | 400-403. |
| | |
| HiTSCHMANN, F., AND Adler, L. 1907. Die Lehre | | HiTSCHMANN, F., AND Adler, L. 1907. Die Lehre |
| von der Endometritus. Ztschr. Geburtsh. u. | | von der Endometritus. Ztschr. Geburtsh. u. |
| GynJik., 60, 63-86. | | GynJik., 60, 63-86. |
| | |
| Kaiser, I. H. 1947. Absence of coiled arterioles | | Kaiser, I. H. 1947. Absence of coiled arterioles |
| in the endometrium of menstruating New | | in the endometrium of menstruating New |
| World monkeys. Anat. Rec, 99, 353-363. | | World monkeys. Anat. Rec, 99, 353-363. |
| | |
| Kaufmann, C, Westphal, U., and Zander, J. 1951. | | Kaufmann, C, Westphal, U., and Zander, J. 1951. |
| Untersuchungen liber die biologische Bedeutang der Ausscheidungsprodukte des Gelbkcirperhormons. Arch. Gynak., 179, 247-299. | | Untersuchungen liber die biologische Bedeutang der Ausscheidungsprodukte des Gelbkcirperhormons. Arch. Gynak., 179, 247-299. |
| Knaus, H. 1950. Die Physiologie der Zeugung
| |
|
| |
|
| des Menschen. Wien: Wilhelm Maudrich. | | Knaus, H. 1950. Die Physiologie der Zeugung des Menschen. Wien: Wilhelm Maudrich. |
| | |
| Krohn, p. L. 1951. The induction of menstrual | | Krohn, p. L. 1951. The induction of menstrual |
| bleeding in amenorrhoeic and normal monkeys | | bleeding in amenorrhoeic and normal monkeys |
| by progesterone. J. Endocrinol., 7, 310-317. | | by progesterone. J. Endocrinol., 7, 310-317. |
| | |
| Krohn, P. L. 1955. The induction of cyclic uterine bleeding in normal and spayed rhesus monkeys by progesterone. J. Endocrinol., 12, 6985. | | Krohn, P. L. 1955. The induction of cyclic uterine bleeding in normal and spayed rhesus monkeys by progesterone. J. Endocrinol., 12, 6985. |
| | |
| Krohn, P. L., and Zuckerman, S. 1937. Water | | Krohn, P. L., and Zuckerman, S. 1937. Water |
| metabolism in relation to the menstrual cycle. | | metabolism in relation to the menstrual cycle. |
| J. Physiol., 88, 369-387. | | J. Physiol., 88, 369-387. |
| | |
| Latz, L. J., and Reiner, E. 1942. Further studies | | Latz, L. J., and Reiner, E. 1942. Further studies |
| on the sterile and fertile periods in women. | | on the sterile and fertile periods in women. |
| Am. J. Obst. & Gynec, 43, 74-79. | | Am. J. Obst. & Gynec, 43, 74-79. |
| | |
| Lendrum, F. C., .and Hisavv^ F. L. 1936. Cytology | | Lendrum, F. C., .and Hisavv^ F. L. 1936. Cytology |
| of the monkey endometrium under influence of | | of the monkey endometrium under influence of |
| follicidar and corpus luteum hormones. Proc. | | follicidar and corpus luteum hormones. Proc. |
| Soc. Exper. Biol. & Med., 34, 394-396. | | Soc. Exper. Biol. & Med., 34, 394-396. |
| | |
| Lopez Columbo de Allende, I., and Orias, O. 1950. | | Lopez Columbo de Allende, I., and Orias, O. 1950. |
| Cytology of the Human Vagina. New York: | | Cytology of the Human Vagina. New York: |
| Paul B. Hoeber, Inc. | | Paul B. Hoeber, Inc. |
| | |
| Lopez Colu.mbo de Allende, I., Shorr, E., and Hartman, C. G. 1945. A comparative study of the | | Lopez Colu.mbo de Allende, I., Shorr, E., and Hartman, C. G. 1945. A comparative study of the |
| vaginal smear cycle of the rhesus monkey and | | vaginal smear cycle of the rhesus monkey and |
| the human. Contr. Embryol., Carnegie Inst. | | the human. Contr. Embryol., Carnegie Inst. |
| Washington, 31, 1-26. | | Washington, 31, 1-26. |
| M.arkee, J. E. 1940. Menstruation in intraocular endometi'ial tr;msplants in the I'hesus monkey. Contr. Embrvol., Carnegie Inst. Washington, 28, 219-308.
| | |
| | Markee, J. E. 1940. Menstruation in intraocular endometi'ial tr;msplants in the I'hesus monkey. Contr. Embrvol., Carnegie Inst. Washington, 28, 219-308. |
| | |
| Markee, J. E. 1946. Morphologic and endocrine | | Markee, J. E. 1946. Morphologic and endocrine |
| basis foi' menstrual bleeding. In Progress in | | basis foi' menstrual bleeding. In Progress in |
| Gynecology, Meigs and Sturgis, Eds. Vol. II, | | Gynecology, Meigs and Sturgis, Eds. Vol. II, |
| pp. 37-47. New York: (hune and Stiattdii. | | pp. 37-47. New York: (hune and Stiattdii. |
| | |
| Markee, J. E., and Berg, B. 1944. Cyclic fluctuations in blood estrogen as a possible cause of | | Markee, J. E., and Berg, B. 1944. Cyclic fluctuations in blood estrogen as a possible cause of |
| menstruation. Stanford Med. Bull., 2, 55-60. | | menstruation. Stanford Med. Bull., 2, 55-60. |
| | |
| Markee, J. E., D.wis, J. H., and Hinsf.y, J. C. | | Markee, J. E., D.wis, J. H., and Hinsf.y, J. C. |
| 1936. Uterine bleeding in spinal iii()nk(>vs. | | 1936. Uterine bleeding in spinal iii()nk(>vs. |
| Anat. Rec, 64, 231-245. | | Anat. Rec, 64, 231-245. |
|
| |
|
| |
|
| |
|
| Mazer, C, and Israel, S. L. 1951. Diagnosis and | | Mazer, C, and Israel, S. L. 1951. Diagnosis and |
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Line 2,488: |
| early human development. Am. J. Obst. & | | early human development. Am. J. Obst. & |
| Gynec, 44, 973-983. | | Gynec, 44, 973-983. |
| | |
| RossM.AN, I. 1940. The decidual reaction in the | | RossM.AN, I. 1940. The decidual reaction in the |
| rhesus monkey {Macaca mulatta). I. The | | rhesus monkey {Macaca mulatta). I. The |
| epithelial proliferation. Am. J. Anat., 66, 277365. | | epithelial proliferation. Am. J. Anat., 66, 277365. |
| | |
| Schroder, R. 1914. Uber das Verhalten der Uterusschleimhaut um die Zeit der Menstruation. | | Schroder, R. 1914. Uber das Verhalten der Uterusschleimhaut um die Zeit der Menstruation. |
| Monatsschr. Geburtsh. u. Gynak., 39, 3-21. | | Monatsschr. Geburtsh. u. Gynak., 39, 3-21. |
| Seeg.ar, E. G. 1940. The histologic effect of progesterone on hyperplastic endometria. Am. J.
| | |
| | Seegar, E. G. 1940. The histologic effect of progesterone on hyperplastic endometria. Am. J. |
| Obst. & Gynec, 39, 469-476. | | Obst. & Gynec, 39, 469-476. |
| S.mith, O. W., and S.mith, G. V. 1951. Endocrinology and related phenomena of the human
| | |
| | Smith, O. W., and S.mith, G. V. 1951. Endocrinology and related phenomena of the human |
| menstrual cvcle. Recent Progr. Hormone Res., | | menstrual cvcle. Recent Progr. Hormone Res., |
| 7, 209-253. | | 7, 209-253. |
|
| |
|
| So.MMKKVILLK, I. V ., AND MaRRIAN, G. F. 1950.
| | SoMMKKVILLK, I. V ., AND MaRRIAN, G. F. 1950. Urinary excretion of prcgnanediol in human |
| | |
| I'rinary excretion of prcgnanediol in human
| |
| subjects following the administration of progesterone and of pregnane-3a:20a-diol. I3iochem. J., 46, 285-289. | | subjects following the administration of progesterone and of pregnane-3a:20a-diol. I3iochem. J., 46, 285-289. |
| Stieve, H. 1926. Di(> regelmassigen Verliinderungen der Muskulatur und des Bindegewebs in
| |
|
| |
|
| |
|
| |
| ESTROGEN AND PROGESTERONE
| |
|
| |
|
| |
|
| |
| 589
| |
|
| |
|
| |
|
| | | Stieve, H. 1926. Di(> regelmassigen Verliinderungen der Muskulatur und des Bindegewebs in der meuschlichen Gebarmutter in ihier Abhangigkeit von der Follikelreife und der Aiisbildung eines gelben Korpers, nebst Beschreibung eines menschlichen Eies im Zustand der |
| der meuschlichen Gebarmutter in ihier Abhangigkeit von der Follikelreife und der Aiisbildung eines gelben Korpers, nebst Beschreibung eines menschlichen Eies im Zustand der | |
| ersten Reifteilung. Ztschr. mikroskop.-anat. | | ersten Reifteilung. Ztschr. mikroskop.-anat. |
| Forsch, 6, 351-397. | | Forsch, 6, 351-397. |
Line 2,974: |
Line 2,565: |
| A. 1954. The rate of disappearance of exogenous progesterone from the blood. J. Clin. | | A. 1954. The rate of disappearance of exogenous progesterone from the blood. J. Clin. |
| Endocrinol., 14, 645-652. | | Endocrinol., 14, 645-652. |
|
| |
|
| |
|
| |
|
| Zondek, B. 1953. Does menstrual blood contain | | Zondek, B. 1953. Does menstrual blood contain |
Line 3,046: |
Line 2,635: |
| Zuckerman, S., van W.agenen, G., and Gardiner, R. | | Zuckerman, S., van W.agenen, G., and Gardiner, R. |
| H. 1938. The sexual skin of the rhesus monkey. Proc Zool. Soc, London, ser. A., 108, | | H. 1938. The sexual skin of the rhesus monkey. Proc Zool. Soc, London, ser. A., 108, |
| 385-401. | | 385-401. |
| | |
| | |
| | |
| 10
| |
| | |
| | |
| | |
| THE MAMMARY GLAND
| |
| AND LACTATION
| |
| | |
| A. T. Cowie and S. J. FoUeij
| |
| | |
| NATIONAL INSTITUTE FOR RESEARCH IN DAIRYING, SHINFIELD,
| |
| READING, ENGLAND
| |
| | |
| | |
| | |
| I. Introduction
| |
| | |
| I. Introduction 590
| |
| | |
| II. Development of the Mammary
| |
| | |
| Gland 591
| |
| | |
| A. Histogenesis 591
| |
| | |
| B. Normal Postnatal Development . 593
| |
| | |
| 1. Methods of assessing mammary
| |
| | |
| development 593
| |
| | |
| 2. Mammary development in the
| |
| | |
| nonpregnant female 594
| |
| | |
| 3. Mammary growth in the male . . 595
| |
| | |
| 4. Mammary development during
| |
| | |
| pregnancy 596
| |
| | |
| 5. Mammary involution 598
| |
| | |
| C. Experimental Analysis of Hormonal
| |
| | |
| Influences 598
| |
| | |
| 1. Ovarian hormones in the animal
| |
| | |
| with intact pituitary 598
| |
| | |
| 2. Anterior pituitary hormones. . . 601
| |
| | |
| 3. Metabolic hormones (corticoids,
| |
| | |
| insulin, and thyroid hormones) 604
| |
| III. Endocrine Influences in Milk Secretion 606
| |
| | |
| A. Anterior Pituitary Hormones 606
| |
| | |
| 1. Initiation of secretion (laeto
| |
| genesis) 606
| |
| | |
| 2. Maintenance of milk secretion —
| |
| | |
| galactopoiesis 609
| |
| | |
| 3. Suckling stimulus and the main
| |
| tenance of lactation 611
| |
| | |
| B. Hormones of the Adrenal Corte.x . . 612
| |
| | |
| C. Ovarian Hormones 613
| |
| | |
| D. Thyroid Hormones 617
| |
| | |
| E. Parathyroid Hormone 618
| |
| | |
| F. Insulin 619
| |
| | |
| IV. Removal of Milk from the Mammary
| |
| | |
| Glands: Physiology of Suckling
| |
| AND Milking 619
| |
| | |
| A. Milk-Ejection Reflex 619
| |
| | |
| B. Role of the Neurohypophysis 621
| |
| | |
| C. Milk-Ejection Hormone 622
| |
| | |
| D. Effector Contractile Mechanism of
| |
| | |
| the Mammary Gland 623
| |
| | |
| E. Inhibition of Milk Ejection 624
| |
| | |
| | |
| | |
| F. Neural Pathways of the Milk-Ejec
| |
| tion Reflex 625
| |
| | |
| G. Mechanism of Suckling 626
| |
| | |
| V. Relation between the Reflexes
| |
| | |
| Concerned in the Maintenance of
| |
| Milk Secretion and Milk Ejection 627
| |
| VI. Pharmacologic Blockade of the Reflexes Concerned in the Maintenance OF Milk Secretion and
| |
| | |
| Milk E.tection 630
| |
| | |
| VII. Conclusion 632
| |
| | |
| VIII. References 632
| |
| | |
| This account of the hormonal control of
| |
| the mammary gland is in no way intended
| |
| as an exhaustive treatment of mammary
| |
| gland physiology, but rather an attempted
| |
| synthesis of current knowledge which it is
| |
| hoped will be of interest as an exposition of
| |
| the authors' conception of the present status
| |
| of the subject. Since the publication of the
| |
| second edition of this book, the emphasis
| |
| in the field under review has tended to shift
| |
| towards the development of quantitative
| |
| techniques for assessing the degree of mammary development, towards attempts at a
| |
| ])enetration into the interactions of hormones with the biochemical mechanisms of
| |
| the mammary epithelial cells, and towards
| |
| an increasing preoccupation with the interplay of nervous and endocrine influences
| |
| in certain phases of lactation. The reader's
| |
| acquaintance with the classical foundations
| |
| of the subject as described in the second
| |
| edition of this book (Turner, 1939) and in
| |
| other subsequent reviews (Follcy, 1940;
| |
| Petersen, 1944, 1948; Folley and Malpress,
| |
| 1948a, b; Mayer and Klein. 1948, 1949;
| |
| Follev, 1952a, ]9r)6; Dabelow. 1957) will
| |
| | |
| | |
| | |
| 590
| |
| | |
| | |
| | |
| MAMMARY GLAXD AND LACTATION
| |
| | |
| | |
| | |
| 591
| |
| | |
| | |
| | |
| therefore be assumed and used as a point
| |
| of departure for the present account which
| |
| can most profitably be concerned mainly
| |
| with developments which have occurred
| |
| since the last edition was published. Reference will freciuently be made to these reviews in which authority will be found
| |
| for the many ex cathedra statements that
| |
| will be made, but original sources will be
| |
| cited wherever appropriate.^
| |
| | |
| As an aid to logical treatment of the subject the scheme of classification proposed
| |
| by Cowie, Folley, Cross, Harris, Jacobsohn
| |
| and Richardson (1951) will be followed in
| |
| this chapter. Besides introducing a system of
| |
| terminology in respect of the physiology
| |
| of suckling or milking, these writers have
| |
| put forward a classification scheme which
| |
| is an extension of one previously proposed
| |
| by one of the present authors (Folley,
| |
| 1947). This scheme considers the phenomenon of lactation as divisible into a number
| |
| of phases as follows:
| |
| | |
| [ [Milk synthesis
| |
| | |
| I Milk secretion ■! Passage of milk from
| |
| I I the alveolar cells
| |
| | |
| Lactation<J [Passive withdrawal of
| |
| | |
| ij milk
| |
| | |
| JThe milk-ejection re[ Hex
| |
| | |
| | |
| | |
| Milk removal
| |
| | |
| | |
| | |
| I
| |
| | |
| As is logical and customary, discussion of
| |
| lactation itself will be preceded by consideration of mammary development.
| |
| | |
| II. Development of the Mammary
| |
| Gland
| |
| | |
| A. HISTOGENESIS
| |
| | |
| References to the earlier work on the
| |
| histogenesis of the mammary gland in various species will be found in Turner ( 1939,
| |
| | |
| ^ Within the last 10 years there have been
| |
| several symposia devoted to the problems of the
| |
| physiology of lactation. The proceedings of these
| |
| symposia have been published: Mecanisme physiologie de la secretion lactee. Strasbourg, 1950,
| |
| Colloqvies Internationaux du Centre National de
| |
| la Recherche Scientificiue. XXXII, 1951, Paris;
| |
| Svmposium sur la physiologie de la lactation,
| |
| Montreal, 1953, Rev. Canad. Biol., 13, No. 4. 1954;
| |
| .Symposium sur la physiologie de la lactation,
| |
| Brussels, 1956, Ann. endocrinol. 17, 519; A Discussion on the Physiology and Biochemistry of Lactation. London. 1958, Proc. Roy. Soc, .ser. B, 149,
| |
| 301.
| |
| | |
| | |
| | |
| 1952,) and Folley (1952a). There have also
| |
| been studies on the opossum (Plagge, 1942) ,
| |
| the mouse and certain wild rodents (Raynaud, 1949b), the rhesus monkey (Speert,
| |
| 1948), and man (Williams and Stewart,
| |
| 1945; Tholen, 1949; Hughes, 1950).
| |
| | |
| A question which in the last decade has
| |
| been receiving attention is whether the prenatal differentiation and development of the
| |
| mammary primordium is hormonally controlled. According to Balinsky (1950a, b),
| |
| the mitotic index of the mammary bud in
| |
| the embryo of the mouse and rabbit is lower
| |
| than that of the surrounding epidermis and
| |
| he concludes that differentiation of the bud
| |
| is due not to cellular proliferation (growth)
| |
| but to a process of aggregation ("morphogenetic movement") of epidermal cells. This
| |
| author also reports that for some time after
| |
| its formation, the mammary bud is cjuiescent as regards growth, thus exhibiting
| |
| negative allometry compared with the whole
| |
| embryo, until the sprouting of the primary
| |
| duct initiates a phase of positive allometry.
| |
| The cjuestion is, what is the stimulus responsible for the onset of this allometric
| |
| phase? Is the growth and ramification of the
| |
| duct primordium, like that of the adult duct
| |
| system, due to the action of estrogen emanating from the fetal gonad or from the
| |
| mother?
| |
| | |
| Hardy (1950) has shown that dift'erentiation and growth of the mammary bud of
| |
| the mouse could proceed in explants from
| |
| the ventral body wall of the embryo, cultured in vitro, even when no primordia
| |
| were present at the time of explantation
| |
| (10-day embryo). Primary and then secondary mammary ducts and a streak canal
| |
| differentiated and a developmental stage
| |
| similar to that in the 7-day-old mouse could
| |
| be reached. Balinsky (1950b) was also able
| |
| to observe the formation and growth of
| |
| mammary buds in approximately their normal locations in a minority of cases in which
| |
| body-wall explants of 10-day mouse embryos were cultivated in vitro. Discounting
| |
| the rather remote possibility that the effects
| |
| were due to minute amounts of sex hormones
| |
| present in the culture media, these observations indicate that hormonal influences are
| |
| not necessary for the prenatal stages of
| |
| mammary develo]iment, and in accord with
| |
| | |
| | |
| | |
| 592
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| this Balinsky ( 1950b j found that addition
| |
| of estrogens or mouse pituitary extract to
| |
| the culture medium had no effect on the
| |
| growth of the mammary rudiment in vitro.
| |
| | |
| On the other hand, extensive studies by
| |
| Raynaud (1947c, 1949b) of the sex difference in the histogenesis of the mammary
| |
| gland in the mouse, first described by Turner and Gomez (1933), indicate that the
| |
| mammary rudiment is sensitive to the influence of exogenous gonadal steroids during
| |
| the prenatal stages. The mammary bud in
| |
| the strain of mouse studied by Raynaud
| |
| shows no sex differences in development until the 15th to 16th day at which time the
| |
| genital tract, hitherto indifferent, begins to
| |
| differentiate. Coincident with this the mammary bud in the male becomes surrounded
| |
| by a condensation of special mesenchymal
| |
| cells the action of which constricts the bud
| |
| at its junction with the epidermis from
| |
| which it ultimately becomes completely
| |
| detached (Fig. 10.1). The inguinal glands
| |
| seem particularly susceptible to this influence because they exhibit this effect
| |
| earlier than the thoracic glands and in some
| |
| strains the second inguinal bud in the male
| |
| tends to disappear completely. Sex differences in the prenatal development of the
| |
| mammary rudiment in certain species of
| |
| wild mouse were also described by Raynaud
| |
| (1949b).
| |
| | |
| The fact that, after x-ray desti'uction of
| |
| the gonad in the 13-day male mouse embryo,
| |
| the mammary bud remains attached to the
| |
| epidermis and the duct primordia ramify
| |
| in a manner similar to the primordia in the
| |
| female shows that this phenomenon of detachment of the mammary bud is due to the
| |
| action of the fetal testis (Raynaud and
| |
| Frilley, 1947, 1949). That the masculinizing action of the fetal testis seems to be
| |
| due to the hormonal secretion of a substance having the same effect as testosterone
| |
| is suggested by the fact that injection of testosterone into the pregnant mother causes
| |
| the mammary buds in the female embryo to
| |
| undergo the male type of development (Fig.
| |
| 10.1). Here again the inguinal glands seem
| |
| most sensitive because sufficiently high
| |
| doses in many cases cause complete disappearance of the primordia of the second
| |
| inguinal glands (Raynaud, 1947a. 1949a).
| |
| | |
| | |
| | |
| On the other hand, destruction of the fetal
| |
| gonad in the female has no effect on the
| |
| development of the mammary bud (Raynaud and Frilley, 1947, 1949), yet the lattW
| |
| is not completely indifferent to the action
| |
| of estrogen because high doses of estrogen
| |
| administered to the mother, or lower doses
| |
| injected early into the embryo itself inhibit
| |
| the growth of the mammary bud (Raynaud.
| |
| 1947b, 1952; Raynaud and Raynaud, 1956,
| |
| 1957), an effect reminiscent of the well
| |
| known action of excessive doses of estrogen
| |
| on the adult mammary duct system (for
| |
| reference see Folley, 1952a) . In pouch young
| |
| of the opossum, on the other hand, Plagge
| |
| (1942) found that estrogen treatment stimulated growth of the mammary duct primordia. Similarly in the fetal male mouse
| |
| low doses of estrogen stimulate growth
| |
| of the mammary bud (Raynaud, 1947d),
| |
| but this may be an indirect effect ascribable to estrogen's antagonizing the inhibitory action of the fetal testis.
| |
| | |
| The problem of the histogenesis of the
| |
| teat has also come under experimental attack. Raynaud and Frilley (1949) showed
| |
| that the formation of the ''epithelial hood,"
| |
| the circular invagination of the epidermis
| |
| surrounding the mammary bud which constitutes the teat anlage in the mouse, is not
| |
| hormonally determined since its appearance
| |
| was not prevented by the irradiation of the
| |
| fetal ovary at the 13th day of life. In the
| |
| male mouse the epithelial hood does not
| |
| normally appear and the male is born without teats. This is undoubtedly due to the
| |
| action of the fetal testis inasmuch as the
| |
| teat anlagen develop in the male embryos
| |
| whose testes are irradiated at 13 days (Raynaud and Frilley, 1949).
| |
| | |
| The foregoing observations jioint to an
| |
| ahormonal type of development for the teat
| |
| and mammary bud in the female fetus, at
| |
| least in the mouse, although the mammary
| |
| bud is specifically susceptible to the action
| |
| of excess exogenous estrogen which can inliibit its development without affecting that
| |
| of other skin gland ])rimordia. The mammary hud is a'so sus('ei)tible to the action
| |
| of anch'ogen which in the normal male fetus
| |
| not only dii-ects its development along charact(M-istic lines, but also suppresses the formation of the teat.
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 593
| |
| | |
| | |
| | |
| | |
| | |
| PwokcTiL del
| |
| | |
| | |
| | |
| Fig. 101. Sex difference in the development of the mammaiy bud of the fetal mouse and
| |
| effect of androgen on the histogenesis of the female mammary bud. A. First inguinal gland
| |
| of female fetus (15 days, 17 hours). B. First inguinal gland of male fetus (15 days, 17 hours).
| |
| C. Second inguinal gland of female fetus (15 days, 16 hours) from a mother receiving testosterone propionate. D. First inguinal gland of female fetus from the same litter as that in C.
| |
| (From A. Ravnaud, Ann. endocrinol., 8, 248-253, 1947.)
| |
| | |
| | |
| | |
| For further information on the morphogenesis of the mammary ghmd, the reader
| |
| is referred to the recent detailed accounts
| |
| by Dabelow (1957) and Raynaud (1960).
| |
| | |
| B. NORM.\L POSTNATAL DEVELOPMENT
| |
| | |
| 1. Methods of Assessing Mammary Development
| |
| | |
| In the last two decades the increasing
| |
| availability of the ovarian hormones in pure
| |
| form and the prospect of the large scale
| |
| practical application of fundamental knowledge of the hormonal control of the mammary gland to the artificial stimulation of
| |
| udder growth and lactation in the cow, have
| |
| together effected a demand for greater accuracy in studying and assessing the degree
| |
| of mammary development. Various quantitative and objective procedures have now
| |
| been evolved which allow results of developmental studies to be subjected to statistical
| |
| investigation. These methods have been re
| |
| | |
| | |
| viewed recently (Folley, 1956) and we need
| |
| but mention them briefly.
| |
| | |
| In those species in which, save in late
| |
| pregnancy, the mammae are more or less
| |
| flat sheets of tissue, the classical wholemount preparations have been the basis for
| |
| several quantitative studies. From such
| |
| preparations the area covered by the duct
| |
| systems can be measured by suitable means
| |
| (e.g., as in our studies on the rat mammary
| |
| gland; Cowie and Folley, 1947d), thus providing an accurate measure of duct extension. Such measurements, however, give no
| |
| information on the morphologic changes
| |
| within this area and so a semiquantitative
| |
| scoring system to assess the degree of duct
| |
| complexity has been used in conjunction
| |
| with the measurements of area (see Cowie
| |
| and Folley, 1947d) . More reliable and objective techniciues for measuring duct complexity were later developed in our laboratory by
| |
| Silver (1953a) and Flux (1954a). Species
| |
| such as the guinea pig in which the gland,
| |
| | |
| | |
| | |
| 594
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| even when immature, is three-dimensional
| |
| demand other methods. For such cases a precise but rather tedious method has been
| |
| described by Benson, Cowie, Cox and Goldzveig (1957) which involves the determination of the volume of glandular tissue from
| |
| area measurements of serial sections of the
| |
| gland in conjunction with semiquantitative
| |
| scoring procedures for assessing the morphologic characteristics of the tissue.
| |
| | |
| Particularly applicable to the lactating
| |
| gland is the procedure developed by Richardson (see Cowie, Folley, Malpress and
| |
| Richardson, 1952; Richardson, 1953) for assessing the total internal surface area of the
| |
| mammary alveoli. It is of interest to note
| |
| in passing that this technique is based on
| |
| that developed by Short (1950) for measuring the surface area of the alveoli in the
| |
| lung, the similarity in the geometry of the
| |
| two organs allowing ready transference of
| |
| the method from one to the other.
| |
| | |
| At present these quantitative procedures
| |
| have the disadvantage of being slow and
| |
| time consuming, and it seems likely that
| |
| their further development will involve the
| |
| use of electronic scanning methods to speed
| |
| up the examination of the tissues. Of recent
| |
| introduction are some biochemical procedures for assessing changes in mammary
| |
| development. The desoxyribonucleic acid
| |
| (DNA) content of any particular type of
| |
| cell is said to be remarkably constant (see
| |
| Vendrely, 1955, for review) and the amount
| |
| of DNA in a tissue has been used as a reference standard directly related to the number
| |
| of cells present in a tissue and to provide an
| |
| estimate of the number of cells formed during the developmental phases of a gland or
| |
| tissue (see Leslie, 1955, for review). Studies
| |
| on DNA changes which occur in the mammary gland during pregnancy and lactation
| |
| have been made in the rat by Kirkham and
| |
| Turner (1953), Grecnbaum and Slater
| |
| (1957a), Griffith and Turner (1957), and
| |
| Shimizu (1957). It should be noted, however, that some authorities have doubts as
| |
| to the constancy under all conditions of the
| |
| DNA content of a cell (see Brachet, 1957)
| |
| and results obtained by this technique
| |
| should be interpreted with some caution
| |
| (see also Griffith and Turner, 1957). Other
| |
| chemical methods for assessing mammary
| |
| development include (a) the determination
| |
| | |
| | |
| | |
| of the iron content of the gland, based on
| |
| the observation that iron retention occurs in
| |
| the epithelium of the mammary glands of
| |
| mice (Rawlinson and Pierce, 1950) ; (b)
| |
| whole-mount autoradiographs using P^(Lundahl, Meites and Wolterink, 1950) ;
| |
| and (c) determination of the total content
| |
| of alkaline phosphatase in the mammary
| |
| gland (Huggins and Mainzer, 1957, 1958).
| |
| | |
| In view of the relative rapidity of the biochemical methods it seems likely that they
| |
| will be used increasingly in the future.
| |
| | |
| A technique of clinical interest allowing
| |
| the qualitative assessment of changes in
| |
| mammary structure in the breast of pregnant and lactating women is the radiographic method described by Ingleby, Moore
| |
| and Gershon-Cohen (1957).
| |
| | |
| To those seeking information of the microscopic anatomy of the human mammary
| |
| gland we would recommend the excellent
| |
| and beautifully illustrated review by Dabelow (1957), and new facts on the cytologic changes occurring during milk secretion will be found in the electron microscopic
| |
| study of the rat mammary gland by Bargmann and Knoop (1959), and of the mouse
| |
| mammary gland by Hollmann (1959).
| |
| | |
| Having briefly outlined the various quantitative methods of assessing mammary development we will now consider recent
| |
| studies on normal mammary growth.
| |
| | |
| 2. Mammary Development in the X on pregnant Female
| |
| | |
| It has been the general belief that until
| |
| puberty the mammary ducts show little
| |
| growth, but more precise studies in which
| |
| the rate of increase in mammary gland area
| |
| has been related to the increase in body size
| |
| have now shown that in the monkey, rat,
| |
| and mouse a phase of ra])id duct growth is
| |
| initiated before puberty.
| |
| | |
| The first use of this procrdure, relative
| |
| gi'owth analysis (for terminology see Huxley and Teissier, 1936), for the quantitative
| |
| investigation of mammary duct growth was
| |
| made by Folley, Guthkelch and Zuckerman
| |
| (1939), who showed that over a wide range
| |
| of body weights, the breast in the nonpregnant female rhesus monkey grows faster
| |
| than the body as a whole. Subsequently,
| |
| more detailed studies of the dynamics of
| |
| mammary growth using relative growth
| |
| | |
| | |
| | |
| MAMMARY GLAXD AND LACTATION
| |
| | |
| | |
| | |
| 595
| |
| | |
| | |
| | |
| olO.
| |
| | |
| | |
| | |
| rCMALC RATS
| |
| | |
| ACt$ : i - lOO DAYS
| |
| | |
| | |
| | |
| C 22 NO DAY
| |
| | |
| | |
| | |
| | |
| LOC„ CBOOY WtlCHT C>
| |
| | |
| | |
| | |
| Fig. 10.2. Relative mammary gland growth in the female hooded Norway
| |
| Cowie. J. Endocrinol.. 6, 145-157, 1949.)
| |
| | |
| | |
| | |
| (From A.T.
| |
| | |
| | |
| | |
| analysis were made in the rat by Cowie
| |
| (1949) and Silver (1953a, b) and in the
| |
| mouse by Flux (1954a, b), and their results
| |
| will now be summarized. In the rat the
| |
| total mammary area increased isometrically
| |
| with the body surface (a = 1.1 as compared
| |
| with the theoretic value of 1.0) until the
| |
| 21st to 23rd day when a phase of allometry
| |
| (a = 3.0) set in. The onset of the allometric
| |
| phase could be prevented by ovariectomy on
| |
| the 22nd day (see Fig. 10.2). Since estrous
| |
| cycles do not begin until the 35th to 42nd
| |
| day in this strain of rat, it is clear that the
| |
| rapid extension of the mammary ducts began well before puberty. In the immature
| |
| male rat the increase of mammary area on
| |
| body surface was slightly but significantly
| |
| allometric; this was not altered by castration at the 22nd day. Earlier ovariectomy,
| |
| i.e., when the pups were 10 days old, was
| |
| followed by a phase of slightly allometric
| |
| growth of the mammary glands in the fe
| |
| | |
| | |
| males (a = 1.5). With regard to the female
| |
| mouse (CHI strain) a i)hase of marked allometry in mammary duct growth set in
| |
| about the 24th day (a = 5.2) which could
| |
| also be prevented by prior ovariectomy.
| |
| | |
| It is clear that the presence of the ovary
| |
| is essential for the change from isometry to
| |
| allometry, but the nature of the mechanisms
| |
| governing the change is still uncertain (for
| |
| further discussion, see Folley, 1956).
| |
| | |
| 3. Mammary Growth in the Male
| |
| | |
| The testes have apparently little effect on
| |
| mammary duct extension in the rat inasmuch as the gland in the male grows isometrically or nearly so and its specific
| |
| growth rate is unaffected by castration. Castration at 21 days, however, does prevent
| |
| for a time development of the lobules of alveoli, first described by Turner and Schultze
| |
| (1931 ) , which are characteristic of the mammary gland in the male rat. Eventually.
| |
| | |
| | |
| | |
| 596
| |
| | |
| | |
| | |
| PHY,SI(3L0GY OF GONADS
| |
| | |
| | |
| | |
| however, some alveoli do develop in the
| |
| mammae of immaturely castrated male rats
| |
| (Cowie and Folley, 1947d; Cowie, 1949;
| |
| Ahren and Etienne, 1957) and it has been
| |
| ])Ostulated that these arise from the enhanced production by the adrenal cortex of
| |
| mammogenic steroids (androgens or progesterone) due to the hormone imbalance
| |
| brought about by gonadectomy (see Folley,
| |
| 1956 L
| |
| | |
| In a recent study, Ahren and Etienne
| |
| (1957) have shown that the ducts and alveoli in the mammary gland of the male rat
| |
| are remarkable in that their epithelial lining
| |
| is unusually thick, being composed of several layers of cells. It had been previously
| |
| noted by van Wagenen and Folley (1939)
| |
| and Folley, Guthkelch and Zuckerman
| |
| (1939) that testosterone caused a thickening
| |
| of the mammary duct epithelium in the
| |
| monkey and sometimes papillomatous outgrowths of epithelium into the lumen of the
| |
| duct. It would thus seem that, although the
| |
| hormone of the testis is capable of eliciting
| |
| alveolar development, these alveoli and
| |
| ducts differ from those occurring in the female in the nature of their epithelium. It
| |
| w^as further observed by Ahren and Etienne
| |
| (1957) that in the castrated male rat the
| |
| alveoli, which eventually developed, had a
| |
| simple epithelial lining somewhat similar to
| |
| that seen in the normal female rat, suggesting that, if the adrenals are responsible, the
| |
| mammogenic steroid is more likely to be
| |
| progesterone than an androgen.
| |
| | |
| A study of considerable clinical interest is
| |
| that of Pfaltz (1949) on the developmental
| |
| changes in the mammary gland in the
| |
| human male. The greatest development
| |
| reached was at the 20th year; by the 40th
| |
| year there occurred an atrophy first of the
| |
| l)arenchyma and later of the connective
| |
| tissue. In the second half of the fifth decade
| |
| there was renewed growth of the parenchyma and connective tissues. The hormonal background of these changes and the
| |
| possible relationship with prostatic hyjiertrophy are discussed by Pfaltz. (Further
| |
| details of the microscopic anatomy of the
| |
| mammary gland of the human male may be
| |
| found in the studies by Graumann, 1952,
| |
| 1953, and Dabclow, 1957.)
| |
| | |
| | |
| | |
| 4- Mammary Development during Pregnancy
| |
| | |
| It has been customary to divide mammary changes during pregnancy into two
| |
| phases, a phase of growth and a secretory
| |
| phase. In the former there occurs hyperplasia of the mammary parenchyma
| |
| whereas, in the latter, the continued increase
| |
| in gland size is due to cell hypertrophy and
| |
| the distension of the alveoli with secretion
| |
| (see Folley, 1952a j . Although it was realized
| |
| that these two phases merged gradually, recent studies have confirmed earh^ reports
| |
| {e.g., those of Cole, 1933; Jeffers, 1935) that
| |
| a wave of cell division occurs in the mammary gland towards the end of parturition
| |
| or at the beginning of lactation. Al'tman
| |
| (1945) described a doubling in number of
| |
| cells per alveolus, in the mammary gland
| |
| of the cow at parturition, but the statistical
| |
| significance of his findings is difficult to
| |
| assess. More recently, how^ever, Greenbaum
| |
| and Slater (1957a) found that the DNA
| |
| content of the rat mammary gland doubled
| |
| between the end of pregnancy and the 3rd
| |
| day of lactation, a finding which they interpret as resulting in the main from hyperplasia of the gland cells. Likewise in the
| |
| mouse mammary gland, Lewin (1957) observed between parturition and the 4th day
| |
| of lactation a great increase both in the
| |
| DNA content of the mammary gland and
| |
| in the total cell count. Studies on the factors
| |
| controlling this wave of cell division are
| |
| awaited with interest. Also associated with
| |
| the onset of copious milk secretion is a considerable increase in cell volume and coincident ally the mitochondria elongate and may
| |
| increase in diameter (Howe, Richardson and
| |
| Birbeck, 1956). Cross, Goodwin and Silver
| |
| (1958) have followed the histologic changes
| |
| in the mammary glands of the sow, by
| |
| means of a biopsy technique, at the end of
| |
| pregnancy, during parturition, and at weaning. At the end of pregnancy there was a
| |
| ])i'()gr('ssi\-c' distension of the alveoli, the
| |
| existing hyaline eosinoi)hilic secretion within
| |
| the alveoli was gradually replaced by a basophilic material, and fat globules appeared.
| |
| At i)arturition the alveoli were contracted
| |
| and their walls appeared folded (Fig. 10.3).
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 597
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 10.3. Sections of biopsy specimens from the mammary gland of a sow before and
| |
| din-ing parturition. A. Six days before parturition: the mammary alveoh are small and contain a nongranular eosinophilic secretion. B. Two days before parturition: alveoli have increased in size and fat globules are conspicuous. C. Fifteen hours before parturition: alveoli
| |
| are now distended with secretion which consists of an outer zone of eosinophilic material
| |
| and fat globules, and a central zone of basophilic granular secretion. D. During parturition:
| |
| alveoli contracted with folded epithelium and sparse secretion. (From B. A. Cross, R. F. W.
| |
| Goodwm and L A. Silver, J. Endocrinol., 17, 63-74, 1958.)
| |
| | |
| | |
| | |
| 598
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| 5. Mam /nary Involution
| |
| | |
| The involutionary changes which occur in
| |
| the mammary gland after weaning in various species were described in the previous
| |
| edition of this book (Turner, 1939) and in a
| |
| later review by Folley (1952a). Since that
| |
| time, a few further studies have appeared.
| |
| | |
| There is evidence that the course of the
| |
| histologic changes in the regressing mammary gland may differ according to whether
| |
| the young are weaned after lactation has
| |
| reached its peak and is declining, or whether
| |
| they are removed soon after parturition,
| |
| when the effects of engorgement with milk
| |
| seem to be more marked (see, for example,
| |
| Williams, 1942, for the mouse). In rats
| |
| whose young were weaned soon after parturition Silver (1956) was able to re-establish lactation provided suckling was resumed
| |
| within 4 or 5 days; after that time irreversible changes in the capillary blood supply to the alveoli had set in. A further point
| |
| arises from a study on the cow by Mosimann
| |
| (1949) which indicates that the course of
| |
| the regressive changes in a gland which has
| |
| undergone one lactation only may differ
| |
| from those seen in glands from muciparous
| |
| animals. Oshima and Goto (1955) have used
| |
| quantitative histometric methods in a study
| |
| of the involuting rat mammary gland ; the
| |
| values which they obtained for the percentage parenchyma 7 to 10 days after removal of the young agree quite well with
| |
| tiiose reported by Benson and Folley
| |
| ( 1957b) for rats weaned at the 4th day and
| |
| killed 9 days later.
| |
| | |
| The biochemical changes occurring in
| |
| mammary tissue during involution arc of
| |
| some interest and have been studied in our
| |
| laboratory by McNaught (1956, 1957). She
| |
| studied mammary slices taken from rats
| |
| whose young were removed at the 10th day
| |
| and also slices from suckled glands, the escajie of milk from which was prevented by
| |
| ligation of the galactophores, the other
| |
| glands in the same animals remaining intact
| |
| and serving as controls. Her results, some of
| |
| whichare summarized in Figure 10.4, suggest that functional changes which may be
| |
| taken as indicative of involution (decrease
| |
| in oxygen up-take, respiratory quotient
| |
| (R.Q.), and glucose up-take; increase in
| |
| lactic acid prcxUiction ) are seen as early as
| |
| | |
| | |
| | |
| 8 to 12 hours after weaning. Continued
| |
| suckling without removal of milk retards
| |
| the onset of these changes, but only for some
| |
| hours. Injections of oxytocin into the rats
| |
| after weaning (see page 607) did not retard
| |
| these biochemical changes. Essentially simihii' results were independently reported by
| |
| Ota and Yokoyama (1958) and Mizuno and
| |
| Chikamune (i958).
| |
| | |
| C. EXPERIMENTAL ANALYSIS OF HORMONAL
| |
| INFLUENCES
| |
| | |
| 1. Ovarian Hortnones in the Animal with
| |
| Intact Pituitary
| |
| | |
| We shall see later (page 602) that the
| |
| mammogenic effects of the ovarian hormones are largely dependent on the integrity
| |
| of the a'nterior pituitary and thus to analyze accurately the role of hormones in mammary development it is necessary to use hypophysectomized animals. Information of
| |
| considerable academic and practical importance has been obtained, however, from
| |
| studies in the animal with intact pituitary
| |
| and these we shall now consider.
| |
| | |
| Early studies involving hormone administration pointed to the conclusion that estrogens were in general resi)onsible for the
| |
| growth of the mammary (hicts, whereas progesterone was necessary for complete lobulealveolar growth (see reviews, l)y Turner,
| |
| 1939; Folley and Malpress, 1948a; Folley,
| |
| 1952a). The foundation for i^liis general
| |
| statement is now more sure, for as a result
| |
| of experimental studies over the last 10
| |
| years, what seemed to be exceptions to this
| |
| generalization have been shown to be otherwise. In some species (mouse, rat, guinea
| |
| \)ig, and monkey) it is true that progesterone alone, if given in sufficiently large doses,
| |
| will evoke duct and alveolar development in
| |
| the ovariectomized animal, but this is probably a pharmacologic rather than a physiologic effect. There are great differences in
| |
| the response of the mammary ducts to estrogen and on this basis it has become usual to
| |
| divide species into three broad categories
| |
| (see FoUey, 1956). It is, however, necessary
| |
| to add the warning that in the estrogentre.'ited spayed animal progesterone from the
| |
| a(h'eiial eoiiex may synergize with the exogenous estrogen (see Folley, 1940; Trentin
| |
| and 1'ui'iier, 1947; Hohn, 1957) and it mav
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 599
| |
| | |
| | |
| | |
| O2 Uptake
| |
| | |
| | |
| | |
| G\
| |
| | |
| | |
| | |
| ucose
| |
| | |
| | |
| | |
| uptake
| |
| | |
| | |
| | |
| | |
| Lactic acid
| |
| production.
| |
| | |
| | |
| | |
| s 12
| |
| ■Hours
| |
| | |
| Fig. 10.4. Oxygen uptake, respiratory quotient, glucose uptake, and lactic acid production
| |
| of mammary gland slices from lactating rats killed at various times after weaning (A — A)
| |
| and from rats in which svickling was maintained, but in which the galactophores of certain
| |
| | |
| glands were ligatured (• •) to prevent the escape of milk, the nonligatured glands
| |
| | |
| (O O) acting as controls. (Courtesy of Dr. M. L. McNaught.)
| |
| | |
| | |
| | |
| be that the I'eal basis for the categories is
| |
| to be found largely in differences in endogenous progesterone production by the adrenal
| |
| cortex.
| |
| | |
| The first category comprises those in
| |
| which estrogens, in what are believed to be
| |
| physiologic doses, evoke primarily and
| |
| mainly duct growth; alveoli may appear,
| |
| but only if high doses are given and the
| |
| administration is prolonged. Examples of
| |
| this class are the mouse, rat, rabbit, and cat.
| |
| Silver (1953a), using the relative-growth
| |
| technique, has obtained information on the
| |
| | |
| | |
| | |
| levels of estrogen necessary for normal
| |
| mammary duct growth in the nonpregnant
| |
| rat. In the young ovariectomized rat, the
| |
| normal mammary growth rate was best imitated by injecting 0.1 ;u,g. estradiol dipropionate every second day (from 21 days of
| |
| age) and increasing the dose step- wise with
| |
| body weight. In the ovariectomized mouse,
| |
| Flux (1954a) found it necessary to give
| |
| 0.055 /jLg. estrone daily to attain mammarv
| |
| duct growth comparable with that obser\-( . i
| |
| in intact mice.
| |
| | |
| In the second category are those s]:»ecies
| |
| | |
| | |
| | |
| (JOO
| |
| | |
| | |
| | |
| PHYSIOLOGY OI-' GONADS
| |
| | |
| | |
| | |
| in which estrogen in physiologic doses causes
| |
| growth of the ducts and the lobule-alveoL^r
| |
| system, the classical example being the
| |
| guinea pig in which functional mammae can
| |
| be developed after gonadectomy in either
| |
| sex by estrogen alone. A recent study by
| |
| Hohn (1957), however, strongly suggests
| |
| that progesterone from the adrenal cortex
| |
| participates in the effect. The earlier view,
| |
| moreover, that complete mammary growth
| |
| can be evoked in the gonadectomized guinea
| |
| l)ig by estrogen alone (Turner and Gomez.
| |
| 1934; Nelson, 1937.) does not find support
| |
| in the recent study of Benson, Cowie, Cox
| |
| and Goldzveig (1957), who, using both subjective and objective methods of assessing
| |
| the degree of mammary development, found
| |
| that over a wide dose range of estrone, further development of the mammary gland
| |
| was obtained when jirogesterone was also
| |
| administered; essentially similar conclusions have been reached by Smith and Richterich (1958).
| |
| | |
| Also in this second category are cattle
| |
| and goats in which, however, the male
| |
| mammary gland is not equipotential with
| |
| that of the female. The early studies on
| |
| these species have been reviewed at length
| |
| by FoUey and Malpress (1948a) and Folley (1952a, 1956). Briefly it may be said
| |
| that these studies clearly showed that estrogen alone induced extensive growth of lobule-alveolar tissue of which the functional
| |
| capacity was considerable although the milk
| |
| yields in general were less than those expected from similar animals after parturition. The response to estrogen treatment
| |
| was, moreover, very erratic. It was generally
| |
| believed that the deficiencies of this treatment could be made good if progesterone
| |
| were also administered, a view supported by
| |
| the observations of Mixner and Turner
| |
| (1943) that the mammary gland of goats
| |
| treated with estrogens, when examined histologically, showed the i)resence of cystic
| |
| alv(>oli, an abnormality which tended to
| |
| disappear when jirogestcrone was also administered.
| |
| | |
| When progesterone became more readily
| |
| available, an extensive study of the role of
| |
| estrogen and progesterone in mammary development in the goat was carried out
| |
| (Cowie, Folley, ^lalpress and Richai'dson.
| |
| | |
| | |
| | |
| 1952; Benson, Cowie, Cox, Flux and Folley,
| |
| 1955). The mammary tissue was examined
| |
| histologically and the procedure devised by
| |
| Richardson (see page 594) used to estimate
| |
| the area and "porosity" of the alveolar epithelium. The udders grown in immaturely
| |
| ovariectomized virgin goats by combined
| |
| treatment with estrogens and progesterone
| |
| in various proportions and at different absolute dose levels were compared with udders resulting from treatment with estrogen
| |
| alone. As in the earlier observations of Mixner and Turner (1943) , histologic abnormalities were noted, the more widespread being
| |
| a marked deficiency of total epithelial surface, associated with the presence of cystic
| |
| alveoli, in the udders of the estrogen-treated
| |
| animals. The addition of progesterone prevented the appearance of many of these abnormalities and increased the surface area
| |
| of the secretory epithelium. JMoreover, when
| |
| estrogen and progesterone were given in a
| |
| suitable ratio and absolute level the milk
| |
| yields obtained were remarkably uniform
| |
| as between different animals and the glandular tissue was virtually free from abnormalities.
| |
| | |
| Studies in the cow have been less extensive, but there is evidence that both estrogen
| |
| and progesterone are necessary for complete
| |
| normal mammary development (Sykes and
| |
| Wrenn, 1950, 1951; Reineke, INIeites, Cairy
| |
| and Huffman, 1952; Flux and Folley, cited
| |
| by Folley, 1956; Meites, 1960).
| |
| | |
| The case for the inclusion of the monkey
| |
| in the present category has been strengthened by the excellent monograph of Speert
| |
| ( 1948) who has had access to more extensive
| |
| material than many of the earlier workers
| |
| whose results are reviewed by him (see also
| |
| Folley, 1952a). The sum total of available
| |
| evidence now justifies the conclusion that
| |
| estrogen alone will cause virtually complete
| |
| growth of the duct and lobule-alveolar systems of the monkey breast. Extensive lobulealveolar development in the monkey breast
| |
| in response to estrogen is shown in Figure
| |
| 10.5. The synergistic effect of estrogen and
| |
| jirogesterone on the monkey breast has not
| |
| yet been adequately studied, but from available evidence it does not seem to be very
| |
| dramatic. If it is permissible to argue from
| |
| pi'iinates to man. it seems jiossible that coidd
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 601
| |
| | |
| | |
| | |
| | |
| Fig. 10.5. Wliole mounts of breast of an ovariectomized immature female rhesus monkey
| |
| before (left) and after (right) e.strogen treatment. (From H. Speert, Contr. Embrvol.,
| |
| Carnegie Inst. Washington, 32, 9-65, 1948.)
| |
| | |
| | |
| | |
| the necessary experiments be done the
| |
| human breast would show a considerable
| |
| growth response to estrogen alone.
| |
| | |
| Finally, in the third category are those
| |
| species in which estrogen in physiologic
| |
| doses causes little or no mammary growth.
| |
| The bitch and probably the ferret seem to
| |
| belong to this class (see Folley, 1956).
| |
| | |
| There has been considerable discussion
| |
| in the past regarding the ratio of progesterone to estrogen optimal for mammary
| |
| growth. Only recently, however, has this
| |
| question been fully investigated in any species. Benson, Cowie, Cox and Goldzveig
| |
| (1957) have shown that in the guinea pig
| |
| the absolute quantities of progesterone and
| |
| estrogen are the crucial factors in controlling
| |
| mammary growth; altering the dose levels
| |
| but maintaining the ratio gave entirely different growth responses. In view of the
| |
| varying ability of the different estrogens to
| |
| stimulate mammary duct growth (Reece,
| |
| 1950) it is essential in discussing ratios to
| |
| take into consideration the nature of the
| |
| estrogen used, a fact not always recognized
| |
| in the past.
| |
| | |
| 2. Anterior Pituitary Hormones
| |
| | |
| Soon after the discovery by Strieker and
| |
| Grueter (1928, 1929) of the lactogenic effects of anterior iiituitarv extracts, it was
| |
| | |
| | |
| | |
| shown that anterior i)ituitary extracts had a
| |
| mammogenic effect in the ovariectomized
| |
| animal and that the ovarian steroids had
| |
| little or no mammogenic effect in hypophysectomized animals. C. W. Turner and his
| |
| colleagues postulated that mammogenic activity of the anterior pituitary was due to
| |
| specific factors which they termed "mammogens"; other workers, in particular
| |
| W. R. Lyons, believed the mammogenic effect was due to prolactin. The theory of specific mammogens has been fully reviewed in
| |
| the past (Trentin and Turner, 1948; Folley
| |
| and Malpress, 1948a) and we do not propose
| |
| to discuss it further for there is now little
| |
| evidence to support it. Damm and Turner
| |
| ( 1958) , while recently seeking new evidence
| |
| for the existence of a specific pituitary mammogen, concur in the view expressed by
| |
| Folley and Malpress (1948a) that final
| |
| proof of the existence of a specific mammogen will depend on the development of
| |
| l)etter assay techniques and the characterization or isolation of the active principle.
| |
| | |
| The mammogenic effects of prolactin were
| |
| observed in the rabbit by Lyons (1942)
| |
| who injected small quantities of prolactin
| |
| directly into the galactophores of the suitably prepared mammary gland. IV'Iilk secretion occurred but Lyons also noted that the
| |
| l)rolactin caused active growth of the alveo
| |
| | |
| | |
| 602
| |
| | |
| | |
| | |
| PHYSIOLOGY OF CIOXADS
| |
| | |
| | |
| | |
| lar epithelium. Recently, Mizuno, lida and
| |
| Naito (1955) and Mizuno and Naito (19561
| |
| have confirmed Lyons' observations on the
| |
| mammogenic effect of intracluct injections
| |
| of prolactin in the rabbit both by histologic
| |
| and biochemical means (DNA estimations)
| |
| and there seems little doubt that the prolactin is capable of exerting a direct effect
| |
| on the growth of the mammary parenchyma,
| |
| at least in the rabbit whose pituitary is intact.
| |
| | |
| In the last 18 years much information on
| |
| the role of the anterior pituitary in mammary growth has been obtained by Lyons
| |
| and his colleagues in studies on hypophysectomized, hypophysectomized-ovariectomized, and hypophysectomized-ovariectomized-adrenalectomized (triply operated)
| |
| rats of the Long-Evans strain. In 1943
| |
| Lyons showed that in the hypophysectomized-ovariectomized rat, estrogen + progesterone + prolactin induced lobulealveolar development, but the degree of
| |
| development was less than that obtained
| |
| in the ovariectomized rat with intact pituitary receiving estrogen and progesterone.
| |
| When supplies of purified anterior-pituitary hormones became available the experiments were extended (Lyons, Li and
| |
| Johnson, 1952) and it was shown that if
| |
| somatotrophin (STH) was added to the
| |
| hormone combination of estrogen -f progesterone + prolactin, the degree of lobulealveolar development obtained in the hypophysectomized-ovariectomized rat was
| |
| much enhanced. The omission of prolactin
| |
| from the hormonal tetrad prevented lobulealveolar development from occurring. In
| |
| the hypophysectomized-ovariectomized-adrenalectomized rat the above hormonal tetrad could also evoke lobule-alveolar development, provided the animals were given
| |
| saline to drink (Lyons, Li, Cole and Johnson, 1953). In yet more recent experiments
| |
| Lyons, Li and Johnson (1958) observed that
| |
| somatotrophin has a direct stimulatory effect on duct growth, but in the hypophysectomized-ovariectomized rat, the presence of
| |
| estrogen is also necessary to evoke normal
| |
| duct development (Fig. 10.6a, b, c) ; Likewise, in the triply operated rat, STH plus
| |
| estrogen is mammogenic, but the presence of
| |
| a corticoid is r('([ui]'ed to o])tain full duct de
| |
| | |
| | |
| velopment (Fig. 10.6r/). Lyons and his colleagues were able to build up the mammary
| |
| glands of triply operated rats from the state
| |
| of bare regressed ducts to full prolactational
| |
| lobule-alveolar development by giving estrogen + STH + corticoids for a period of
| |
| 10 days to obtain duct proliferation followed by a further treatment (for 10 to 20
| |
| days) with estrone + progesterone -I- STH
| |
| -I- prolactin + corticoid to induce lobulealveolar development. Alilk secretion could
| |
| then be induced by a third course of treatment lasting about 6 days in which only
| |
| prolactin and corticoids were given (Fig.
| |
| 10. 6e, /). Essentially similar results have
| |
| been obtained in studies with the hooded
| |
| Norway rat (Cowie and Lyons, 1959).
| |
| | |
| Studies on mammogenesis in the hypophysectomized mouse have revealed some
| |
| differences in the response of the mammary
| |
| gland of this species in comparison with
| |
| that of the rat and indications of strain
| |
| differences within the species. The mammary gland of the hypophysectomized male
| |
| weanling mouse of the Strong A2G strain
| |
| shows no response to the ovarian steroids
| |
| alone, to prolactin, or to STH alone, but it
| |
| responds with vigorous duct proliferation
| |
| to combinations of estrogen + progesterone
| |
| + prolactin, or of estrogen 4- progesterone
| |
| + STH (Hadfield, 1957; Hadfield and
| |
| Young, 1958). In the hypophysectomized
| |
| male mouse of the CHI strain slight duct
| |
| growth occurs in response to estrogen +
| |
| jirogesterone and this is much enhanced
| |
| when STH is also given; the further addition of prolactin then results in alveolar
| |
| development (Flux, 1958). Extensive studies
| |
| in triply operated mice of the C3H 'HeCrgl
| |
| strain have been reported by Nandi (1958a,
| |
| b). In this strain some duct growth was observed in triply operated animals in response to steroids alone (estrogen -I- progesterone + corticoids), but normal duct
| |
| develojmient was believed to be due to the
| |
| action of estrogen + STH + corticoids, a
| |
| conclusion in agreement with Lyons' observations in the rat. Extensive lobuleahcohii' development could be induced by
| |
| a number of hormone coml)inations, one
| |
| of the most effective being estrogen + progesterone + corticoids + prolactin + STH,
| |
| milk secretion occurring when the ovarian
| |
| | |
| | |
| | |
| MAMMARY C5LAND AND LACTATION
| |
| | |
| | |
| | |
| 603
| |
| | |
| | |
| | |
| | |
| Fig. 10.6. Typical areas of whole mounts of the abdominal mammary gland of rat.s after
| |
| the following treatments: A. Untreated rat on day 31, 14 days after hypophysectomy. The
| |
| gland has regressed to a bare duct system. B. Rat hypophysectomized and ovariectomized on
| |
| day 30 and injected daily with 2 mg. somatotrophin (STH) for 7 days. Note the presence
| |
| of end clubs, r. Rat treated as in B but which received, in addition to the STH, 1 ^g. estrone.
| |
| Note profuse eiid-rhil' ] iroliferatiou. D. Rat li.\|M)]ili\s(>ctomized on day 30. ovariectomized
| |
| and adri'nali^ctoinized on day 60, and injected daily from days 60 to 69 with 1 mg. STH +
| |
| 0.1 mg. DCA + 1 fig. estrone. Note again the profuse number of end buds indicative of
| |
| duct proliferation. E. Same treatment as in D followed by 10 days treatment with 5 mg.
| |
| prolactin + 2 mg. STH + 1 /xg. estrone + 2 mg. progesterone + 0.1 mg. DCA + 0.05 mg.
| |
| prednisolone acetate. Note excellent lobule-alveolar growth. F. Same treatment as in D
| |
| followed by 20 days treatment with 5 mg. prolactin + 2 mg. STH + 1 fig. estrone + 2 mg.
| |
| progesterone + 0.1 mg. DCA + 0.05 mg. prednisolone acetate; thereafter given 0.1 mg. prolactin locally over this gland and 0.1 mg. DCA + 0.1 mg. prednisolone acetate systemically for
| |
| 6 days. Note fully developed lobules with ah'eoli filled with milk. (All glands at the same
| |
| magnification.) (From W. R. Lyons. C. H. Li and R. E. Johnson, Recent Progr. Hormone
| |
| Res., 14, 219-254, 1958.)
| |
| | |
| | |
| | |
| 604
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| steroids were withdrawn, while the })rohictin, STH, and Cortisol were continued. A
| |
| further interesting observation made by
| |
| Nandi is that in the C3H/HeCrgl mouse
| |
| STH can replace prolactin in the stimulation of all phases of mammary development
| |
| and in the induction of milk secretion; enhanced effects were obtained, however, when
| |
| prolactin and STH were given together.
| |
| Nandi also considers that progesterone
| |
| plays a greater role in duct development in
| |
| the mouse than in the rat.
| |
| | |
| The above experiments clearly indicate
| |
| that both in the triply operated rat and
| |
| mouse, it is possible to build up the mammary gland to the full prolactational state
| |
| by injecting the known ovarian, adrenal
| |
| cortical, and anterior pituitary hormones.
| |
| There would thus seem to be no necessity
| |
| to postulate the existence of other unidentified pituitary mammogens. It must be
| |
| recognized, however, that in normal pregnancy the placenta may be an important
| |
| source of mammogenic hormones. The placenta of the rat contains a substance or substances possessing luteotrophic, mammogenic, lactogenic, and crop-sac stimulating
| |
| properties, but it is uncertain whether this
| |
| material is identical with pituitary prolactin
| |
| (Averill, Ray and Lyons, 1950; Canivenc,
| |
| 1952; Canivenc and Mayer, 1953; Ray,
| |
| Averill, Lyons and Johnson, 1955). There
| |
| is also some evidence of the presence of a
| |
| somatotrophin-like principle in rat placenta
| |
| (Ray, Averill, Lyons and Johnson, 19551.
| |
| | |
| 3. Metabolic Hormones {Corticoids, Insulin,
| |
| and Thyroid Hormones)
| |
| | |
| We have already noted that Lyons and
| |
| his colleagues were able to obtain full duct
| |
| development in the triply operated rat only
| |
| when corticoids were given. Early studies
| |
| of the role of the adrenals in mammary development have given conflicting and uncertain results (see review by Folley,
| |
| 1952a). Recent studies have not entirely
| |
| clarified the position. Flux (1954b) tested
| |
| a number of 11 -oxygenated corticoids, and
| |
| found that not only were they devoid of
| |
| mammogenic activity in the ovariectomized
| |
| virgin mouse, but that they inhibited the
| |
| gi'owth-promoting effects of estrogen on the
| |
| mammary ducts, whereas 11-desoxycorticosterone acted synergistically with estro
| |
| | |
| | |
| gen in promoting duct growth. In subsequent
| |
| studies it was shown that injections of adrenocorticotrophin (ACTH) into intact
| |
| female mice did not influence mammary
| |
| growth (Flux and ]\lunford, 1957), but
| |
| that Cortisol acetate in low doses (12.5 /^g.
| |
| l)er day) stimulated mammary development in ovariectomized and in ovariectomized estrone-treated mice, whereas at
| |
| higher levels (25 and 50 ftg. per day) it was
| |
| without effect (Munford, 1957). In the virgin rat, on the other hand, glucocorticoids
| |
| are said to stimulate mammary growth and
| |
| to induce milk secretion (Selye, 1954; Johnson and Meites, 1955). Some light on these
| |
| conflicting results has been shed by the
| |
| studies of Ahren and Jacobsohn (1957)
| |
| who investigated the effects of cortisone on
| |
| the mammary glands of ovariectomized
| |
| and of ovariectomized-hypophysectomized
| |
| rats, both in the presence and absence of
| |
| exogenous ovarian hormones. In the hypophysectomized animals, cortisone promoted
| |
| enlargement and proliferation of the epithelial cells lining the duct walls, but normal growth and differentiation did not occur, nor did the addition of estrogen and
| |
| progesterone appreciably alter these effects ;
| |
| in rats with intact pituitaries, however,
| |
| cortisone stimulated secretion but not
| |
| mammary growth, whereas the addition of
| |
| estrogen and progesterone promoted both
| |
| growth and al)undant secretion. Ahren and
| |
| Jacobsohn concluded that "the effect elicited by cortisone in the mammary gland
| |
| should be analysed with due regard to the
| |
| endocrine state of the animal both as to its
| |
| effects on the structures of the mammary
| |
| gland and to the consequences resulting
| |
| from an eventual upset of the general metabolic equilibrium." They consider that in
| |
| circumstances optimal for mammary gland
| |
| growth and maintenance of homeostasis
| |
| the predominant actions of cortisone are enhancement of alveolar growth and stimulation of secretion, whereas under conditions
| |
| ill which the metabolic actions of cortisone
| |
| are not efficiently counteracted, gland
| |
| growth is either inhibited or an abnormal
| |
| development of certain iiianimaiy cells
| |
| may be e^■()ked.
| |
| | |
| That the general metabolic milieu may
| |
| indeed profoundly influence the response
| |
| of the iiuuiimarv gland to hormones has
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 605
| |
| | |
| | |
| | |
| been emiiha.-^ized by the recent experiments
| |
| of Jacobsohn and her colleagues. Following
| |
| on the work of Salter and Best (1953) who
| |
| showed that hypophysectomized rats could
| |
| be made to resume body growth by the injections of long-acting insulin, Jacobsohn
| |
| and her colleagues (Ahren and Jacobsohn,
| |
| 1956; Ahren and Etienne, 1958; Ahren,
| |
| 1959) found that treatment with estrogen
| |
| and progesterone would stimulate considerable mammary duct growth in hypophysectomized-gonadectomized rats when given
| |
| with suitable doses of long-acting insulin
| |
| (Fig. 10.7). This growth-supporting effect
| |
| of insulin could be nullified if cortisone was
| |
| also administered (Ahren and Jacobsohn,
| |
| 1957) but could be enhanced by giving thyroxine (Jacobsohn, 1959).
| |
| | |
| The thyroid would thus appear to be another endocrine gland whose hormones affect
| |
| | |
| | |
| | |
| mammary growth intlirectly by altering the
| |
| metabolic environment. Studies in this field,
| |
| reviewed by Folley (1952a, 1956), indicate
| |
| that in the rat some degree of hypothyroidism enhances alveolar development wdiereas
| |
| in the mouse, hypothyroidism seems to
| |
| inhibit mammary development. Chen, Johnson, Lyons, Li and Cole (1955) have shown
| |
| that mammary growth can be induced in
| |
| hypophysectomized - adrenalectomized-thyroidectomized rats by giving estrone, progesterone, prolactin, STH, and Cortisol, no
| |
| replacement of the thyroid hormones being
| |
| necessary.
| |
| | |
| These investigations on the effect of the
| |
| metabolic environment on mammary development seem to ])e opening up new avenues
| |
| of approach to the advancement of our
| |
| understanding of the mechanisms of mammary growth and we would recommend.
| |
| | |
| | |
| | |
| | |
| | |
| 0-5 cm.
| |
| | |
| | |
| | |
| | |
| | |
| Fig. 10.7. Whole mount preparation of .second thoracic mammary gland of : ^. Ovariectomized rats injected with estrone and progesterone. B. Hypophysectomized-ovariectomized
| |
| rat injected with estrone and progesterone. C. Hypophysectomizcd-o\ariectomized rat. D.
| |
| Hypophysectomized-ovariectomized rat injected with estrone, progesterone, and insulin.
| |
| (From K. Ahren and D. Jacobsohn, Acta physiol. scandinav., 37, 190-203, 1956.)
| |
| | |
| | |
| | |
| GOG
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| to those seeking further information about
| |
| this important new fiekl, the recent review
| |
| by Jacobsohn (19581.
| |
| | |
| III. Endocrine Influences in Milk
| |
| Secretion
| |
| | |
| A. ANTERIOR PITUITARY HORMONES
| |
| | |
| 1. Initiation of Secretion iLactogenesis)
| |
| | |
| The early experiments leading to the
| |
| view that the anterior pituitary was not
| |
| only necessary for the initiation of milk
| |
| secretion, but in fact i)rovided a positive
| |
| lactogenic stimulus, are now well known
| |
| and the reader is referred to the reviews by
| |
| Folley (1952a, 1956) and Lyons (1958) for
| |
| further particulars. That pituitary prolactin
| |
| can evoke milk secretion in the suitably
| |
| de\-eloped mammary gland of the rabbit
| |
| with intact pituitary has been amply confirmed, and the original experiments of
| |
| Lyons (1942) involving the intraduct injection of prolactin have been successfully
| |
| repeated by Meites and Turner (1947) and
| |
| | |
| | |
| | |
| | |
| Fk;. 10.8. Liictation.'il lespon.scs in pseudoincgnant rabbit to different doses of prolactin injeclcd
| |
| intraductallv. (Fiom T. R. Bradley and P. M.
| |
| Clarke, J. Endo.ninol., 14, 28-36, 1956.)
| |
| | |
| | |
| | |
| Bradley and Clarke (1956) (Fig. 10.8).
| |
| However, endogenous pituitary hormones
| |
| may have participated in the response in
| |
| such experiments and in the last 20 years
| |
| there has been considerable discussion as to
| |
| whether prolactin should be regarded as
| |
| the lactogenic hormone or as a component
| |
| of a lactogenic complex. This whole question
| |
| has been fully discussed in recent years (see
| |
| Folley, 1952a, 1956) and it now seems
| |
| reasonably certain that lactogenesis is a
| |
| response to the co-operative action of more
| |
| than one anterior pituitary hormone, that
| |
| is, to a lactogenic hormone complex of which
| |
| prolactin is an important component, as
| |
| first suggested by Folley and Young (1941 ) .
| |
| The recent reports by Nandi (1958a, b)
| |
| that STH -I- Cortisol can induce milk secretion in triply operated mice with suitably
| |
| developed glands is further strong evidence
| |
| against regarding prolactin as the lactogenic
| |
| hormone.
| |
| | |
| Secretory activity is evident in the mammary gland during the second half of pregnancy, but abundant milk secretion does
| |
| not set in until parturition or shortly thereafter. The nature of the mechanism controlling the initiation of abundant secretion has
| |
| been the subject of speculation for many
| |
| years. The earlier theories w^ere discussed
| |
| l)y Turner ( 1939 ) in the second edition of
| |
| this book, and included the theory put
| |
| forward by Nelson with reference to the
| |
| guinea pig, that the high levels of blood
| |
| estrogen in late pregnancy suppressed the
| |
| secretion or release of prolactin from the
| |
| pituitary and had also a direct inhibitory
| |
| cttcct on the mammary parenchyma, the
| |
| fall in the levels of estrogen occurring at
| |
| parturition then allowing the anterior pituitary to exert its full lactogenic effect. This
| |
| concept proved inadequate to exjilain observations in other species and it was later
| |
| extended by Folley and Malpress (1948b)
| |
| to embrace the concept of two thresholds
| |
| for oi:)posing influences of estrogen upon
| |
| jiituitary lactogenic function, a lower
| |
| threshold for stimulation and a higher one
| |
| for inhibition. Subsequent observations on
| |
| the inhibitory role of progesterone, in the
| |
| pix'sence of estrogen, on milk secretion, however, necessitated further modification of
| |
| the theorv. Before discussing these modifica
| |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 607
| |
| | |
| | |
| | |
| tions it is convenient to refer to the ingenious theory put forward by Meites and
| |
| Turner (1942a, b; 1948) which was based on
| |
| their extensive investigation of the prolactin content of the pituitary in various
| |
| physiologic and experimental states. According to Meites and Turner, estrogen
| |
| elicits the secretion of prolactin from the
| |
| anterior pituitary thereby causing lactogenesis, whereas progesterone is an inhibitory agent, operative in pregnancy, inhibiting or over-riding the lactogenic action of
| |
| estrogen. The induction of lactation was
| |
| thus ascribed to a fall in the body level
| |
| of progesterone relative to that of estrogen
| |
| heheved to occur at the time of parturition.
| |
| Subsequent studies in the rabbit by jVIeites
| |
| and Sgouris (1953, 1954) revealed that
| |
| combinations of estrogen and progesterone
| |
| could inhibit, at the mammary gland level,
| |
| the lactogenic effects of exogenous prolactin.
| |
| This effect was, however, relative and by increasing the prolactin or decreasing the steroids, lactogenesis ensued. Inasmuch as the
| |
| theory of Meites and Turner did not take
| |
| into account the eventuality that estrogen
| |
| and progesterone act at the level of the mammary gland, Meites ( 1954) modified the con('ei)t, postulating that milk secretion was
| |
| held in check during pregnancy first by the
| |
| combined effect of estrogen and progesterone which make the mammary gland refractory to prolactin and, secondly, by a
| |
| low rate of prolactin secretion. The role of
| |
| progesterone in over-riding the stimulatory
| |
| effect of estrogen on the pituitary he now
| |
| considered to be of only minor importance.
| |
| Meites also explained the continuance of
| |
| lactation in pregnant animals by postulating that the initial level of prolactin was
| |
| sufficiently high as a result of the suckling
| |
| stimulus to overcome the inhibitory action
| |
| of the ovarian hormones on the mammary
| |
| gland. One of us (Folley, 1954, 1956) put
| |
| forward a tentative theory, combining various features of previous hypotheses, which
| |
| seemed capable of harmonizing most of
| |
| the known facts regarding the initiation of
| |
| milk secretion. In this it was emphasized
| |
| that measurements of the prolactin content
| |
| of the pituitary were not necessarily indicative of the rate of prolactin release (a recent
| |
| study bv Grosvenor and Turner (1958c)
| |
| | |
| | |
| | |
| lends further support to this contention)
| |
| and were best considered as largely irrelevant; low circulating levels of estrogen
| |
| activate the lactogenic function of the anterior pituitary whereas higher levels tend
| |
| to inhibit lactation even in the absence of
| |
| the ovary; lactogenic doses of estrogen
| |
| may be deprived of their lactogenic action
| |
| by suitable doses of progesterone, the combination then acting as a potent inhibitor
| |
| of lactation, this being the influence operating in pregnancy; at parturition the relative fall in the progesterone to estrogen ratio
| |
| removes the inhibition which is replaced by
| |
| the positive lactogenic effect of estrogen
| |
| acting unopposed.
| |
| | |
| It was observed by Gaines in 1915 that
| |
| although a colostral secretion accumulated
| |
| in the mammary gland during pregnancy,
| |
| the initiation of copious secretion was associated with functioning of the contractile
| |
| mechanisms in the udder responsible for
| |
| milk ejection; later Petersen (1944) also
| |
| suggested that the suckling or milking stimulus might be partly responsible for the
| |
| onset of lactation. Recent studies have provided evidence that this may well be so,
| |
| and these will be considered later when discussing the role of the suckling and milking
| |
| stimulus in the maintenance of milk secretion (see page 611).
| |
| | |
| During the past decade a fair amount of
| |
| information has been obtained about the
| |
| biochemical changes which occur in mammary tissue near the time of parturition,
| |
| and which are almost certainly related to
| |
| lactogenesis. The earlier work has been reviewed in some detail by one of us (Folley,
| |
| 1956) and need only be referred to briefly
| |
| here.
| |
| | |
| Folley and French (1949), studying rat
| |
| mammary gland slices incubated in media
| |
| containing glucose, showed that — QOo increased from a value of about 1.3 in late
| |
| pregnancy to a value of about 4.4 at day
| |
| 1 of lactation, and thereafter increased
| |
| still further. At the same time the R.Q.
| |
| which was below unity (approximately
| |
| 0.83) at the end of pregnancy, increased to
| |
| unity soon after parturition, and by day
| |
| 8 had reached a value of 1.62 at approximately which level it remained for the rest
| |
| of the lactation period. In accord with the
| |
| | |
| | |
| | |
| G08
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| increased respiratory activity of the tissue
| |
| about the time of parturition in the rat
| |
| mammary gland, Moore and Nelson (1952)
| |
| reported increases in the content of certain
| |
| respiratory enzymes, succinic oxidase and
| |
| cytochrome oxidase, in the guinea pig mammary gland at about this time. Greenbaum
| |
| and Slater (1957b) made similar observations about mammary gland succinic oxidase in the rat. Recent work is beginning to
| |
| throw light on the metabolic pathways involved in this increase in respiratory activity. Thus McLean (1958a) has adduced
| |
| evidence indicating an increase in the activity of the pentose phosphate pathway
| |
| in the rat mammary gland at about the time
| |
| of parturition. Mammary gland slices taken
| |
| from rats at various stages of the lactation
| |
| cycle were incubated in media containing
| |
| either glucose 1-C^^ or glucose 6-C^-^, and
| |
| the amount of radioactivity appearing in
| |
| the respiratory CO2 was determined. The
| |
| results given in Figure 10.9 show that although the recovery of C^^'Oo from C-6 was
| |
| relatively unaffected by the initiation of lactation, the C^^Oo originating from C-1 began a striking increase at the time of
| |
| parturition (see also Glock, McLean and
| |
| Whitehead, 1956, and Glock and McLean,
| |
| 1958, from which Figure 10.9 was taken).
| |
| | |
| | |
| | |
| pregnancy
| |
| | |
| | |
| | |
| in\'oliition
| |
| | |
| | |
| | |
| | |
| Imc;. 1().<», The relative amounts of C'Oi; formed
| |
| fioin iiiilucosc 1-C'^ and glucose 6-C" by rat niani
| |
| maiy gland slices. O O, C'^Oi formed from
| |
| | |
| glucose 1-C^'. • • . C^'Oi! formed from glucose
| |
| | |
| 6-C". (From G. E. Glock and P. McLean, Proc.
| |
| Roy. Soc, London, ser. B, 149, 354-362, 1958.)
| |
| | |
| | |
| | |
| Despite the well known pitfalls which surround the interpretation of C-1: C-6 quotients in experiments such as these, it seems
| |
| clear that lactation is associated with an
| |
| increase in the metabolism of glucose by
| |
| the pentose phosphate cycle, whereas the
| |
| proportion going by the Embden-Meyerhof
| |
| jmthway would appear to be relatively unaffected. These conclusions are supported by
| |
| the fact that the levels in rat mammary
| |
| tissue of two enzymes concerned in this
| |
| pathway of glucose breakdown, glucose
| |
| 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, show very striking increases at the time of parturition
| |
| (Glock and McLean, 1954; McLean, 1958a).
| |
| Other enzymes concerned in glucose breakdown whose activities in mammary tissue
| |
| begin to increase at parturition are hexokinase and phosphoglucose isomerase (]\IcLean, 1958a). In connection with the glucose metabolism of rat mammary tissue it
| |
| may be noted that addition of insulin to
| |
| the incubation medium markedly increases
| |
| the — QOo and R.Q. of rat mammary slices
| |
| metabolizing glucose or glucose plus acetate
| |
| (see page 619), and that this tissue only
| |
| becomes sensitive to insulin just after parturition (Balmain and Folley, 1951). It
| |
| is interesting to speculate which of the two
| |
| above-mentioned pathways of glucose
| |
| breakdown in mammary tissue resjjonds to
| |
| the action of insulin. According to Abraham,
| |
| Cady and Chaikoff (1957) addition of insulin in vitro increased the production by
| |
| lactating rat mammary slices of C^'^Oo from
| |
| glucose l-C^'*, but not from glucose 6-C^'*,
| |
| which might indicate that insulin stimulates
| |
| preferentially the pentose phosphate pathway. Against this, insulin increased the incorporation of both these carbon atoms
| |
| (and also the 3:4 carbon atoms of glucose)
| |
| into fatty acids of the slices to about the
| |
| same extent. McLean (1959) believes that
| |
| the stimulatory effect of insulin on the
| |
| pentose jihosphate pathway in the lactating
| |
| rat mammary gland is secondary to its
| |
| stimulating effect on lipogenesis. The latter
| |
| l)rocess generates the oxidized form of tril)hosphopyridine nucleotide (TPN) which is
| |
| needed for the first two steps of the pentose
| |
| phosphate cycle.
| |
| | |
| The inci-casc in the R.Q. of mammary
| |
| | |
| | |
| | |
| MAMMARY GLAXD AND LACTATION
| |
| | |
| | |
| | |
| 009
| |
| | |
| | |
| | |
| tissue beginning at parturition observed
| |
| by Folley and French (1949) was interi:)reted as indicating that this tissue assumes
| |
| the power of effecting net fatty acid synthesis from ghicose at this time. Much subsequent evidence confirming this idea has
| |
| been reviewed by Folley (1956). It only
| |
| rt'mains to add that Ringler, Becker and
| |
| Nelson (1954), Lauryssens, Peelers and
| |
| Donck (1956), and Read and Moore (1958)
| |
| ha^-e shown that the amount of coenzyme
| |
| A in mammary tissue undergoes an increase
| |
| at parturition. Moreover, the recent findings
| |
| of McLean (1958b), who showed that the
| |
| levels of pyridine nucleotides in the mammary gland of the rat begin to increase
| |
| at parturition, reaching a high level by the
| |
| end of lactation, may be significant in this
| |
| connection. McLean found that although
| |
| the increase in the tissue levels of diphosl^hopyridine nucleotide was almost entirely
| |
| due to an increase in the oxidized form
| |
| (DPN), in the case of TPN it was the reduced form (TPNH) which increased. The
| |
| latter might well be used for reductive syntheses such as lipogenesis.
| |
| | |
| The rate of synthesis of milk constituents
| |
| other than fat must also begin to increase at
| |
| parturition, and Greenbaum and Greenwood
| |
| (1954) showed that an increase in the levels
| |
| of glutamic aspartic transaminase and of
| |
| glutamic dehydrogenase in rat mammary
| |
| tissue occurs at this time. The authors believe these enzymes are concerned in the
| |
| provision of substrates for the synthesis of
| |
| milk protein. It is significant in connection
| |
| with milk protein synthesis that the mammary gland ribonucleic acid (RNA) in the
| |
| rat undergoes a marked rise at parturition
| |
| (Greenbaum and Slater, 1957a).
| |
| | |
| The above - mentioned biochemical
| |
| changes in mammary tissue which occur at
| |
| al)out the time of parturition are almost
| |
| certainly closely related to the effect on this
| |
| tissue of members of the anterior pituitary
| |
| lactogenic complex, and particularly prolactin. Attempts have been made to elicit
| |
| the characteristic respiratory changes, described above, in mammary slices in vitro
| |
| by addition of prolactin and adrenal glucocorticoids to the incubation medium (see
| |
| Folley, 1956). So far, however, definitive results luive not been obtained and it is doubt
| |
| | |
| | |
| ful whether any biochemical changes in
| |
| lactating mammary gland slices in vitro
| |
| have been demonstrated which could with
| |
| certainty be ascribed to the action of prolactin (in this connection see also Bradley
| |
| and Mitchell. 1957).
| |
| | |
| 2. Maintenance of Milk Secretion — Galactopoiesis
| |
| | |
| It is well known that the removal of the
| |
| pituitary of a lactating animal will end
| |
| milk secretion (for references see Folley,
| |
| 1952a). The cessation of milk secretion has
| |
| been generally ascribed to the loss of the
| |
| anterior lobe, but when the importance of
| |
| the neurohypophysis in milk ejection became established (see page 621), it was
| |
| clear that in the hypophysectomized animal
| |
| it was necessary to distinguish between a
| |
| failure in milk secretion and a failure in
| |
| milk ejection, since either would lead to
| |
| failure of lactation. It has now been shown
| |
| in the rat that adequate oxytocin therapy
| |
| ensuring the occurrence of milk ejection
| |
| after hypophysectomy will not restore lactation (Cowie, 1957) and it may thus be
| |
| concluded that the integrity of the anterior
| |
| lobe is essential for the maintenance of
| |
| milk secretion. The effect of hypophysectomy on milk secretion is dramatic, because in the rat, milk secretion virtually
| |
| ceases within a day of the operation and
| |
| biochemical changes in the metabolic activity of the mammary tissue can be detected within 4 to 8 hours (Bradley and
| |
| Cowie, 1956). It is of interest to note that
| |
| these metabolic changes are similar to those
| |
| observed during mammary involution (see
| |
| page 598).
| |
| | |
| Since the second edition of this book,
| |
| there have been surprisingly few studies on
| |
| replacement therapy in hypophysectomized
| |
| lactating animals. In such studies we would
| |
| stress the need for rigorous methods of
| |
| assessing the efficacy of treatment. In the
| |
| past the presence of milk in the gland as
| |
| revealed by macroscopic or microscopic
| |
| examination has been regarded as an indication of successful replacement. This,
| |
| however, gives no measure of the degree of
| |
| maintenance of lactation and some measure
| |
| of the daily milk yield of such animals
| |
| should be obtained (see also Cowie, 1957).
| |
| | |
| | |
| | |
| GIO
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| It is abo now obvious that oxytocin may
| |
| have to be injected to ensure milk ejection;
| |
| under certain circumstances, however, the
| |
| neurohypophyseal tissue remaining after
| |
| the removal of the posterior lol^e may be
| |
| capable of releasing oxytocin and permitting milk ejection (see Benson and Cowie,
| |
| 1956; Bintarningsih, Lyons, Johnson and Li.
| |
| 1957, 1958).
| |
| | |
| The earliest report on the maintenance
| |
| of lactation after hypophysectomy is that of
| |
| Gomez (1939, 1940), who found that hypophysectomized lactating rats could rear
| |
| their litters if given anterior-pituitary extract, adrenal cortical extracts, glucose, and
| |
| posterior pituitary extract. These experiments are difficult to assess because they are
| |
| reported only in abstract, but the use of posterior pituitary extract at a time when the
| |
| role of oxytocin in milk ejection was not
| |
| generally recognized is worthy of note. Recently, slight maintenance of milk secretion
| |
| in hypophysectomized rats has been obtained with prolactin alone, and greater
| |
| maintenance when adrenocorticotrophic
| |
| hormone ( ACTH I or STH was administered
| |
| with prolactin (Cowie, 1957). Similar
| |
| studies were reported by Bintarningsih,
| |
| Lyons, Johnson and Li (1957, 1958) (see
| |
| also Lvons, Li and Johnson, 1958) in which
| |
| | |
| | |
| | |
| I «
| |
| | |
| c
| |
| | |
| -^ 4
| |
| | |
| -0
| |
| | |
| I 1
| |
| | |
| | |
| | |
| £
| |
| | |
| | |
| | |
| Z -6
| |
| | |
| | |
| | |
| z
| |
| | |
| | |
| | |
| J
| |
| | |
| | |
| | |
| E
| |
| | |
| | |
| | |
| :^ 2 ^^,
| |
| | |
| | |
| | |
| TV
| |
| | |
| 2 ^
| |
| | |
| | |
| | |
| Fig. 10.10. Effect on the luilk yield of the cow
| |
| of injected hormones of the anterior pituitary.
| |
| (From the results of P. M. Cotes, J. A. Crichton,
| |
| S. J. Folley and F. G. Young, Nature, London.
| |
| 164, 992-993, 1919.)
| |
| | |
| | |
| | |
| considerable maintenance of milk secretion
| |
| was obtained in hypophysectomized rats
| |
| with prolactin and certain corticoids. Of
| |
| related interest is the observation by Elias
| |
| (1957) that Cortisol and prolactin can induce secretory activity in explants of mouse
| |
| mammary gland growing on a synthetic
| |
| medium. (Tissue culture techniques have
| |
| been little exploited in mammary studies
| |
| and further developments in this field may
| |
| be expected.)
| |
| | |
| The evidence to date suggests that, in the
| |
| rat, prolactin is an essential component of
| |
| the hormone complex involved in the maintenance of lactation with ACTH and STH
| |
| also participating, but further studies are
| |
| recjuired to determine the most favorable
| |
| balance of these factors.
| |
| | |
| Preliminary studies on the maintenance of
| |
| lactation in the goat after hypophysectomy
| |
| suggest that both prolactin and STH are important in the initiation and maintenance of
| |
| milk secretioii (Cowie and Tindal, 1960).
| |
| Our knowledge of the process in other species is derived from studies on the effect
| |
| of exogenous anterior pituitary hormones
| |
| on established lactation in intact animals—
| |
| galactopoietic effects (for reference see
| |
| Folley, 1952a, 1956). In the cow, considerable increase in milk yield can be obtained
| |
| by injecting STH (Cotes, Crichton, Folley
| |
| and Young, 1949), whereas prolactin has
| |
| a negligible galactopoietic effect (Fig. 10.10;
| |
| for discussion see also Folley, 1955). Recently the precise relationship between the
| |
| dose of STH (ox) and the lactational response in the cow was established in our laboratory by Hutton (1957) who observed a
| |
| highly significant linear relationship between log doses of STH (single injection)
| |
| and the increase in milk yield obtained (Fig.
| |
| 10.11 ) ; increases in fat yield relative to the
| |
| yield of nonfatty solids also occurred. In the
| |
| lactating rat, on the other hand, STH has
| |
| no galactopoietic effect (Meites, 1957b;
| |
| Cowie, Cox and Naito, 1957), whereas prolactin has (Johnson and Meites, 1958). Such
| |
| studies must be interpreted with caution as
| |
| endogenous pituitary hormones were present ; nevertheless, it seems reasonable to
| |
| conclude that STH is likely to be an impoi'tant factor in the maintenance of lactation in the row.
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 611
| |
| | |
| | |
| | |
| mq qro\Om hormone (onthmeTTc scale)
| |
| | |
| | |
| | |
| fa-25 12-5 25-0 50-0
| |
| | |
| | |
| | |
| 100-0
| |
| | |
| | |
| | |
| 200-0
| |
| | |
| | |
| | |
| S-«^0
| |
| | |
| | |
| | |
| | |
| 'Zoo-o
| |
| | |
| | |
| | |
| Fig. 10. IL Effect of graded doses of growth hormone on milk yield of row. Upper curve,
| |
| doses plotted on arithmetic scale. Lower curve, doses plotted on logarithmic scale. (From
| |
| J. B. Hutton, J. Endocrinol., 16, 115-125, 1957.)
| |
| | |
| | |
| | |
| C)ther hormones of the anterior pituitary
| |
| in all probability influence milk secretion
| |
| through their target glands and these will
| |
| be dealt with later.
| |
| | |
| 3. Suckling Stimulus and the Maintenance
| |
| of Lactation
| |
| | |
| It has been long believed that regular
| |
| milking is an important factor in maintaining lactation and that if milk is allowed
| |
| to accumulate in the gland, as occurs at
| |
| weaning, atrophy of the alveolar epithelium
| |
| and glandular involution occur. Evidence
| |
| in support of this concept was obtained in
| |
| studies showing that ligature or occlusion of
| |
| | |
| | |
| | |
| the main ducts of some of the mammae of a
| |
| lactating animal resulted in atrophy of the
| |
| glands concerned although the other glands
| |
| were suckled normally (Kuramitsu and
| |
| Loeb, 1921; Hammond and Marshall, 1925;
| |
| Fauvet, 1941a). Studies by Selye and his
| |
| colleagues, however, revealed that such
| |
| occluded glands did not atrophy as quickly
| |
| as did glands of animals in which the suckling stimulus was no longer maintained
| |
| (Selye, 1934; Selye, Collip and Thomson,
| |
| 1934) and it was postulated that the suckling stimulus evoked from the anterior
| |
| pituitary the secretion of prolactin which
| |
| maintained the secretory activity of the
| |
| gland. This theory has been widely accepted
| |
| | |
| | |
| | |
| 012
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| although it has been suggested that a complex of hormones rather than prolactin alone
| |
| is released (Folley, 1947). Williams (1945)
| |
| showed that prolactin could in fact maintain the integrity of the mammary gland in
| |
| the unsuckled mouse thus mimicking the
| |
| effects of the suckhng stimulus; other supporting evidence has been reviewed by
| |
| Folley (1952a). Recent studies in goats,
| |
| however, have shown that milk secretion
| |
| may continue more or less at the normal
| |
| level after complete denervation of the udder (Tverskoi, 1958; Denamur and Martinet, 1959a, b, 1960) and it may be that in
| |
| some species the suckling or milking stimulus is loss important in the maintenance of
| |
| milk secretion.
| |
| | |
| Milk secretion is essentially a continuous
| |
| process whereas the suckling or milking
| |
| stimulus is intermittent ; indeed the milking
| |
| stimulus may be of remarkably brief duration (in the cow about 10 minutes in all per
| |
| 24 hours) and it is therefore likely that the
| |
| stimulus triggers off the release of sufficient
| |
| galactopoietic complex to maintain mammary function for some hours. Grosvenor
| |
| and Turner (1957b) reported that suckling
| |
| causes a rapid drop in the prolactin content
| |
| of the pituitary in the rat, and that the
| |
| prenursing level of prolactin in the pituitary
| |
| is not fully regained some 9 hours later.
| |
| It is difficult, however, to relate pituitary
| |
| levels of prolactin to the rate of its secretion into the circulation and, although these
| |
| observations are interesting, further advances are unlikely until a method of assay
| |
| for blood prolactin becomes available and
| |
| the "half-life" of prolactin in circulation is
| |
| known.
| |
| | |
| The experiments of Gregoire (1947) on
| |
| the maintenance of involution of the thymus
| |
| during nursing suggests that the suckling
| |
| stimulus releases ACTH which, as we have
| |
| seen, is galactopoietic in the rat; thus, so far
| |
| as the rat is concerned, there would appear
| |
| to be good evidence that the suckling stimulus releases at least two known important
| |
| components of the galactopoietic complex.
| |
| | |
| The milking and suckling stimulus is also
| |
| responsible for eliciting the milk-ejection
| |
| reflex and the relation between the two reflexes will be discussed later in this chapter
| |
| (sec ])age 619 1.
| |
| | |
| | |
| | |
| B. HORMONES OF THE ADRENAL CORTEX
| |
| | |
| Adrenalectomy results in a marked inhibition of milk secretion and the early experiments in this field were reviewed by
| |
| Turner in 1939. Since then, however, purified adrenal steroids have become available
| |
| enabling further analysis to be made of the
| |
| role of the adrenal cortex in lactation.
| |
| | |
| Gaunt, Eversole and Kendall (1942) considered that in the rat the defect in milk
| |
| secretion after adrenalectomy could be repaired by the administration of the adrenal
| |
| steroids most closely concerned with carbohydrate metabolism, whereas we came to
| |
| the somewhat opposing view that the defect
| |
| was best remedied by those hormones
| |
| primarily concerned with electrolyte metabolism (Folley and Cowie, 1944; Cowie and
| |
| Folley, 1947b, c). The reasons for these
| |
| differing observations are not yet entirely
| |
| clear. Virtually complete restoration of
| |
| milk secretion was subsequently obtained
| |
| in our strain of rat by the combined administration of desoxycorticosterone acetate
| |
| (DCA) and cortisone, or with the halogenated steroids, 9a-chlorocortisol and 9afluorocortisol (Cowie, 1952; Cowie and
| |
| Tindal, 1955; Cowie and Tindal, unpublished; see also Table 10.1). It would therefore seem that both glucocorticoid and
| |
| mineralocorticoid activity was necessary to
| |
| maintain the intensity of milk secretion at
| |
| its normal level. The interesting observation
| |
| was made by Flux (1955» and later confirmed by Cowie and Tindal (unpublished)
| |
| that the ovaries contribute to the maintenance of lactation after adrenalectomy, a
| |
| contribution which could be simulated in the
| |
| adrenalectomized-ovariectomized rat by the
| |
| administration of 3 mg. progesterone daily.
| |
| The differences in the size of the ovarian
| |
| contribution may partly accoimt for the apparent differences in various strains of rat of
| |
| the relative importance of mineralo- and
| |
| glucocorticoids in sustaining milk secretion
| |
| after adrenalectomy. The only other species
| |
| in which the maintenance of lactation after
| |
| adrenalectomy has been studied is the goat
| |
| in which, as in the rat, lactation can be
| |
| maintained with cortisone and desoxycorticosterone, the latter being apparently the
| |
| more critical steroid (Cowie and Tindal.
| |
| 1958; Figs. 10.12a, b).
| |
| | |
| | |
| | |
| MAMM.\RY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 613
| |
| | |
| | |
| | |
| There have been several studies on the
| |
| effects of corticoids and adrenocortieotrophin on lactation in the intact animal.
| |
| ACTH and the corticoids depress lactation
| |
| in the intact cow (Fig. 10.10) (Cotes, Crichton, Folley and Young, 1949; Flux, Folley
| |
| and Rowland, 1954; Shaw, Chung and
| |
| Bunding, 1955; Shaw, 1955), whereas in the
| |
| rat ACTH and cortisone have been reported
| |
| as exhibiting galactopoietic effects (Meites,
| |
| private communication; Johnson and
| |
| Meites, 1958). With larger doses of cortisone, however, an inhibition of milk secretion in the rat has been reported (MercierParot, 1955).
| |
| | |
| The main function of the cortical steroids
| |
| in lactation is still uncertain. They may act
| |
| in a "supporting" or "permissive" manner
| |
| (see Ingle, 1954), maintaining the alveolar
| |
| cells in a state responsive to the galacto])oictic complex, or they may act by maintaining the necessary levels of milk precursors in the blood.
| |
| | |
| Biochemical studies are, however, Ix'ginning to add to our information on the role
| |
| of the corticoids in lactation. In the rat,
| |
| adrenalectomy prevents the increase in liver
| |
| and mammary gland arginase which occurs
| |
| during normal lactation and it has been
| |
| suggested that this depression of arginase
| |
| activity interferes with deamination of
| |
| amino acids, and thereby inhibits any increase in gluconeogenesis from protein and
| |
| thus starves the mammary gland of nonnitrogenous milk precursors (Folley and
| |
| Greenbaum, 1947, 1948). As there is little
| |
| arginase in the mammary gland of other
| |
| species {e.g., rabbit, cow, goat, sheep), this
| |
| mechanism may not have general validity
| |
| (for further discussion see Folley, 1956).
| |
| Other biochemical studies have suggested
| |
| that the steroids of the adrenal cortex may
| |
| be concerned in mammary lipogenesis, but
| |
| the results so far have been conflicting and
| |
| no firm conclusions can as yet be drawn
| |
| (see Folley, 1956).
| |
| | |
| C. OVARIAN HORMONES
| |
| | |
| There is no evidence that ovariectomy has
| |
| any deleterious effect on lactation (Kuramitsu and Loeb, 1921; de Jongh, 1932; Folley and Kon, 1938; Flux, 1955); neither
| |
| is there evidence for the belief, once
| |
| | |
| | |
| | |
| TABLE 10.1
| |
| | |
| Replacement therapy in lactating rats
| |
| | |
| adrenalectomized on the fourth
| |
| | |
| day of lactation
| |
| | |
| (From A. T. Cowie and S. J. Folley,
| |
| | |
| J. Endocrinol., 5, 9-13, 1947.)
| |
| | |
| | |
| | |
| Treatment
| |
| | |
| | |
| Number of
| |
| Litters
| |
| | |
| | |
| Number
| |
| | |
| of Pups
| |
| | |
| per
| |
| | |
| Litter
| |
| | |
| | |
| Litter-growth
| |
| | |
| Index*
| |
| gm. + S.E.
| |
| | |
| | |
| Control
| |
| | |
| Adrenalectomy
| |
| | |
| Adrenalectomy + cortisone + DC A (tablet
| |
| implantsf)
| |
| | |
| | |
| 8
| |
| | |
| 9
| |
| | |
| 7
| |
| | |
| | |
| 8
| |
| 8
| |
| 8
| |
| | |
| | |
| 15.6 + 0.5
| |
| | |
| 7.5 ± 0.6
| |
| 14.9 ± 0.6
| |
| | |
| | |
| | |
| (Above results from Cowie, 1952)
| |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| 6
| |
| | |
| | |
| 8
| |
| | |
| | |
| 14.5 ± 0.8
| |
| | |
| | |
| Adrenalectomy
| |
| | |
| | |
| 6
| |
| | |
| | |
| 8
| |
| | |
| | |
| 6.2 ± 0.4
| |
| | |
| | |
| Adrenalectomy + chloro
| |
| | |
| 5
| |
| | |
| | |
| 8
| |
| | |
| | |
| 13.1 ± 0.5
| |
| | |
| | |
| cortisol (100 Mg per
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| day)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| (Above results from Cowie and Tindal, 1955)
| |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| 8
| |
| | |
| | |
| 12
| |
| | |
| | |
| 17.7 ± 0.8
| |
| | |
| | |
| Adrenalectomy
| |
| | |
| | |
| 8
| |
| | |
| | |
| 12
| |
| | |
| | |
| 7.5 ± 0.5
| |
| | |
| | |
| Adrenalectomy + ovari
| |
| | |
| 5
| |
| | |
| | |
| 12
| |
| | |
| | |
| 3.6 ± 0.5
| |
| | |
| | |
| ectomy
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Adrenalectomy + ovari
| |
| | |
| 7
| |
| | |
| | |
| 12
| |
| | |
| | |
| 14.5 ± 0.7
| |
| | |
| | |
| ectomy + fiuorocorti
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| sol (200 Mg per day)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| (Above results from Cowie and Tindal,
| |
| unpublished)
| |
| | |
| * The litter-growth index is defined as the mean
| |
| daily gain in weight per litter over the 5-day period from the 6th to the 11th days.
| |
| | |
| t 2 X 11 mg. tablets cortisone giving mean daily
| |
| absorption of 850 ^ig., and 1 X 50 mg. tablet DCA
| |
| giving mean daily absorption of 360 ng.
| |
| | |
| widely held, that ovariectomy increases
| |
| and prolongs lactation in the nonpregnant
| |
| cow (see Richter, 1936).
| |
| | |
| Although the integrity of the ovary is
| |
| not essential for the maintenance of lactation, there can be no doubt that ovarian
| |
| hormones, in certain circumstances, profoundly influence milk secretion. Estrogens
| |
| have long been regarded as possessing the
| |
| power to inhibit lactation, a concept on
| |
| which Nelson based his theory of the mechanism of lactation initiation (see page 606 1 .
| |
| Some workers, however, have expressed
| |
| doubts that the effect is primarily on milk
| |
| secretion, and have suggested that in ex
| |
| | |
| | |
| 614
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| periments on laboratory animals the apparent failure in milk secretion could be a
| |
| secondary effect due to either a toxic action
| |
| of the estrogen causing an anorexia in the
| |
| mother, interference with milk ejection, or
| |
| disturbance of maternal behavior or to toxic
| |
| effects on the young, whose growth rate
| |
| serves as a measure of lactational performance, through estrogens being excreted in
| |
| milk. The evidence to date shows that in
| |
| | |
| | |
| | |
| the intact rat estrogens even in very low
| |
| doses inhibit milk secretion, their action
| |
| depending on the presence of the ovary ; the
| |
| ovarian factor concerned appears to be progesterone, estrogen and progesterone acting
| |
| locally on the mammary gland and rendering it refractory to the lactogenic complex. In the ovariectomized rat much larger
| |
| doses of estrogen are necessary to inhibit
| |
| lactation, and the evidence is not entirely
| |
| | |
| | |
| | |
| Body
| |
| | |
| | |
| | |
| Goat 478
| |
| | |
| | |
| | |
| weight ^^L
| |
| :.) 45 L
| |
| | |
| Plasma Na
| |
| (m-equiv./l.) ^^^^
| |
| | |
| Plasma K
| |
| (m-equiv./l
| |
| | |
| Milk K 40 (m-equiv./l.) 30
| |
| | |
| | |
| | |
| Milk Na ,
| |
| | |
| (m-equiv./l.)
| |
| | |
| | |
| | |
| Solids-notfat (%)
| |
| | |
| Yield of
| |
| solids-notfat (g)
| |
| Fat (%)
| |
| | |
| | |
| | |
| Milk yield
| |
| (kg)
| |
| | |
| | |
| | |
| Goat died-*
| |
| | |
| 5 15 25 4 14 24
| |
| Mgr. Apr.
| |
| | |
| | |
| | |
| Fig. 10.12i4. Effect of replaconi(>nt therapy with (losoxycoiticostcM-oiu
| |
| c-ortisone aoetate (CA) on milk yield, milk composition, and concent
| |
| | |
| | |
| | |
| (DCA) and
| |
| tion of Na and K
| |
| in milk and blood plasma of the goat after adrenalectomy. Duration of replacement therapy
| |
| (pellet implantation) indicated by horizontal lines; the names of steroids and their mean
| |
| daily absorption rates are given adjacent to the lines. Note in Figure 12.4 the considerable
| |
| maintenance of milk vield with DCA alone. See also Figure 12/?. (From A. T. Cowic and
| |
| J. S. Tindal. J. Endocrinol., 16, 403-414, 1958.)
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 6L
| |
| | |
| | |
| | |
| Goat 515
| |
| | |
| | |
| | |
| Body 5Q _
| |
| weight —
| |
| | |
| (kg) 40
| |
| 150
| |
| Plasma Na ^ ^.
| |
| / /I \ ^40 —
| |
| | |
| (m-equiv./l) —
| |
| | |
| 130
| |
| | |
| | |
| | |
| Plasma K
| |
| (m-equiv./l)
| |
| | |
| | |
| | |
| Milk K
| |
| (m-equiv./l.)
| |
| | |
| | |
| | |
| Milk Na
| |
| (m-equiv./l.)
| |
| | |
| Solids-not- ^ H
| |
| | |
| fat {%) 7 U
| |
| | |
| Yield of 200
| |
| solids-not- —
| |
| | |
| fat (g) 100
| |
| Fat (- ^
| |
| | |
| | |
| | |
| Fat yield
| |
| | |
| | |
| | |
| Milk yield
| |
| (kg)
| |
| | |
| | |
| | |
| | |
| 13 23 2 12 22 2 12 22
| |
| Oct. Nov Dec.
| |
| | |
| Fig. 12B.
| |
| | |
| | |
| | |
| 11 21 31 10 20
| |
| | |
| Jan. Feb
| |
| | |
| | |
| | |
| conclusive that there is a true inhibition of
| |
| milk secretion (see Cowie, 1960). In the
| |
| cow estrogen in sufficient doses depresses
| |
| milk yield, but its mode of action has not
| |
| been fully elucidated. In women, estrogens
| |
| are used clinically to suppress unwanted
| |
| lactation, but as the suckling stimulus is
| |
| also removed about the same time, the role
| |
| of the estrogen is difficult to assess (see
| |
| Meites and Turner, 1942a).
| |
| | |
| | |
| | |
| It has been well established that progesterone by itself has no effect on milk secretion (see Folley, 1952a), save in the adrenalectomized animal (see page 612), and
| |
| so it would appear that the physiologic
| |
| inhibition of lactation is effected Ijy estrogen
| |
| and progesterone acting synergistically as
| |
| first demonstrated by Fauvet (1941b) and
| |
| confirmed by others including Masson
| |
| (1948), Walker and Matthews (1949),
| |
| | |
| | |
| | |
| GIG
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| Cowie, FoUey, Malpress and Richarcl.son
| |
| (1952J,, and Meites and Sgouris (1954).
| |
| There is clear evidence that the estrogenprogesterone combination acts at least
| |
| partly on the mammary parenchyma (Desclin, 1952; Meites and Sgouris, 1953) but
| |
| the mechanism of the action is unknown.
| |
| The hormonal interplay and complex endocrine interactions in the process of lactation
| |
| inhibition with estrogen has recently been
| |
| discussed at length by von Berswordt-Wallrabe (1958).
| |
| | |
| Lactogenic effects of estrogens have already been mentioned; these have been
| |
| demonstrated most strikingly in cows and
| |
| goats, in which milk secretion has been induced in udders being developed by exogenous estrogen. These experiments have
| |
| been reviewed in some detail by Folley and
| |
| Malpress (1948b) and Folley (1956).^ It is
| |
| generally assumed that estrogens act by
| |
| | |
| | |
| | |
| stimulating the production of lactogenic and
| |
| galactopoietic factors by the anterior
| |
| pituitary. In experiments on the ovariectomized goat we have shown (Cowie,
| |
| Folley, Malpress and Richardson, 1952;
| |
| Benson, Cowie, Cox, Flux and Folley, 1955)
| |
| that it is possible to select a daily dose of
| |
| estrogen which will induce mammary
| |
| growth but relatively little secretion in the
| |
| sense that the udder does not become tense
| |
| and distended as will happen when a lower
| |
| dose of estrogen is given — an observation we
| |
| may quote in support of the "double-threshold" theory of estrogen action. The lactogenic effect of the lower dose of estrogen
| |
| could be abolished, however, by administering progesterone simultaneously with the
| |
| estrogen (Fig. 10.13), an observation in
| |
| accord with those of other workers on the
| |
| rabbit and rat (see above).
| |
| | |
| In 1936 one of us (Folley, 1936) reported
| |
| | |
| | |
| | |
| | |
| Fig. 10.13. Photographs of goat uddois dovelopcd by daily injections of hoxoostiol (HX)
| |
| with and without progesterone (PG). The hibels indicate the daily dose in mg. of each
| |
| substance. (Results from A. T. Cowie, S. J. Folley, F. H. Malpre.ss and K. C. Ricliardson,
| |
| J. Endocrinol., 8, 64-88, 1952.)
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| GK
| |
| | |
| | |
| | |
| that certain dose levels of estrogen in the
| |
| lactating cow produced long-lasting changes
| |
| in milk composition characterized by increases in the percentages of fat and nonfatty solids. This was regarded as an example of galactopoiesis and was termed the
| |
| "enrichment" effect. The effect, however, w^as
| |
| somewhat erratic and it has recently been
| |
| re-investigated by Hiitton (1958) who confirmed and extended the earlier observations.
| |
| Hutton found that galactopoietic responses
| |
| (Figs. 10.14 and 10.15) were obtained only
| |
| within a restricted dose range, the limits
| |
| of which were affected by the stage of pregnancy and the breed of the cow. Hutton
| |
| further concluded that in the normal cow
| |
| changes in milk composition and yield associated with advancing pregnancy were
| |
| probably determined by the progressive rise
| |
| of blood estrogen levels.
| |
| | |
| D. THYROID HORMONES
| |
| | |
| Studies on the effect of removal of the
| |
| thyroids on milk secretion have been reviewed by one of us (Folley, 1952a) ; the
| |
| evidence strongly suggests that the thyroid
| |
| glands are not essential for milk secretion,
| |
| but in their absence the intensity and duration of lactation is reduced. Histologic and
| |
| cytologic studies of the thyroid of the lactating cat suggest that there is a considerable outpouring of the thyroid secretion in
| |
| the early stages of lactation (Racadot,
| |
| 1957), and Grosvenor and Turner (1958b)
| |
| have reported that the thyroid secretion
| |
| rate is higher in lactating than in nonlactating rats.
| |
| | |
| Since the last edition of this l)ook, a great
| |
| volume of experimental results has been
| |
| published on the use of thyroid-active materials for increasing the milk yield of cows.
| |
| These experiments have been extensively
| |
| reviewed by Blaxter (1952) and Meites
| |
| (1960) and we need here only touch on the
| |
| salient points.
| |
| | |
| In the early studies i^reparations of dried
| |
| thyroid gland were fed to cows or injections
| |
| of DL-thyroxine were given, but the use on
| |
| a large scale of thyroid-active materials
| |
| for increasing the milk yield of cows only
| |
| became feasible when it was shown that
| |
| certain iodinated proteins exhibited thyroidlike activitv when given in the feed. Al
| |
| | |
| | |
| 9-9
| |
| 97
| |
| | |
| o 9-3
| |
| ^ 9-1
| |
| | |
| | |
| | |
| 8-9
| |
| | |
| | |
| | |
| •'' Guernsey
| |
| | |
| | |
| | |
| Shorthorn
| |
| | |
| | |
| | |
| 8-5
| |
| | |
| | |
| | |
| •^U^ri
| |
| | |
| I L
| |
| | |
| | |
| | |
| 20 40 60 80 100
| |
| | |
| Oestradiol monobenzoite (mg)
| |
| | |
| Fig. 10.14. Effect of graded doses of estradiol
| |
| benzoate on percentage of nonfatty solids in milk
| |
| from cows of three breeds. (From J. B. Hutton,
| |
| J. Endocrinol., 17, 121-133, 1958.)
| |
| | |
| Oestradiol monobenzoate (mg) (arith. scale)
| |
| | |
| 10 20 30 40 50
| |
| | |
| | |
| | |
| | |
| 6-25 12-5 250 500
| |
| | |
| Oestradiol monobenzoate (mg) (log scale)
| |
| | |
| Fig. 10.15. Effect of graded doses of estradiol
| |
| benzoate on fat content of cows' milk. Upper curve,
| |
| doses plotted on arithmetic scale. Lower curve,
| |
| doses plotted on logarithmic scale. (From J. B.
| |
| Hutton, J. Endocrinol., 17, 121-133, 1958.)
| |
| | |
| though these materials were readily made
| |
| and were economical for large-scale use, they
| |
| possessed several disadvantages. Their activity was difficult to assay and standardize,
| |
| they were frequently unpalatable, and their
| |
| administration entailed a considerable intake of iodine which could be undesirable.
| |
| Nevertheless, a large number of experiments
| |
| were carried out all over the world with
| |
| this type of material. In 1949, however, a
| |
| new and improved method for the synthesis
| |
| of L-thyroxine was developed (Chalmers,
| |
| Dickson, Elks and Hems, 1949) and thyroxine became available in large quantities.
| |
| It was then shown jjy Bailey, Bartlett and
| |
| Folley (1949) that this material was ealac
| |
| | |
| | |
| 618
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ,
| |
| | |
| | |
| | |
| | |
| | |
| | |
| /" \^
| |
| | |
| | |
| Cont-rol.
| |
| | |
| | |
| | |
| | |
| A<' / " "^ - ^*
| |
| | |
| | |
| — • DO m§.
| |
| | |
| | |
| | |
| | |
| .^''\ / V- -' v;.
| |
| | |
| | |
| 100 m|.
| |
| | |
| | |
| | |
| | |
| ^..^-Av / V
| |
| | |
| | |
| 150mg.
| |
| | |
| | |
| | |
| | |
| ^^^4?^^/ . V
| |
| | |
| | |
| | |
| | |
| | |
| | |
| ,.-•*.. \ vv / .^-r \ \
| |
| | |
| | |
| • — •• tva --^-^ y \ \ \
| |
| | |
| | |
| •••\-'^\ \ x- ^ .. \ ^
| |
| | |
| | |
| \. *-^ '• •■*— . \ \
| |
| | |
| | |
| *■*•—., \ \ \ \
| |
| | |
| | |
| | |
| | |
| .... -.... "•N-:w<r:Viy: y^
| |
| | |
| | |
| Sl-art of hrcAhnc.ih \\ y' i'
| |
| | |
| | |
| hrc iXhuciil' \\ //
| |
| | |
| | |
| \v/y
| |
| | |
| | |
| \ V /
| |
| | |
| | |
| \ /
| |
| | |
| | |
| \ /
| |
| | |
| | |
| \/
| |
| | |
| | |
| V
| |
| | |
| | |
| | |
| 10
| |
| | |
| | |
| | |
| 50
| |
| | |
| | |
| | |
| 50
| |
| | |
| | |
| | |
| Dau5
| |
| | |
| | |
| | |
| Fig. 10.16. Effect of L-thyroxine given in the feed on the milk yield of groups of cows
| |
| (the indicated dose levels were fed daily). (From G. L. Bailey, S. Bartlett and S. J. Folley,
| |
| Nature, London, 163, 800. 1949.)
| |
| | |
| | |
| | |
| topoietic when ]ed to lactating cows in daily
| |
| doses of about 100 mg. (Fig. 10.16). It had,
| |
| moreover, none of the drawbacks of the
| |
| iodinated proteins, its purity could be
| |
| checked chemically, it was odorless and
| |
| tasteless. AVith the introduction of synthetic thyroxine, iodinated proteins have
| |
| become obsolete as galactopoietic agents.
| |
| | |
| The more recently isolated 3:5:3-triiodo-L-thyronine, reported to be 5 to 7
| |
| times more active than thyroxine in various
| |
| biologic tests in small animals and also in
| |
| man, has little or no effect on the milk yield
| |
| when fed to cows, but is somewhat more
| |
| active than thyroxine in promoting galactopoiesis when administered subcutaneously,
| |
| which suggests that the material is inactivated in the gut, probably in the rumen
| |
| f Bartlett, Burt, Folley and Rowland, 1954).
| |
| | |
| The extensive experiments on galactopoiesis in dairy cattle with thyroxine and
| |
| thyroid-active substances have made it
| |
| possible to reach reasonably firm conclusions as to the practical value of the procedure. There is great variability in the
| |
| response to treatment; in general a better
| |
| response is ol)taincd during the decline of
| |
| lactation than at the peak and end of lactation. The use of thyroid-active substances
| |
| | |
| | |
| | |
| in animals undergoing their first, second,
| |
| or third lactation is of doubtful benefit because the boost in yield is largely cancelled
| |
| out by a shortening of the lactation period. Short-term administration at suitable
| |
| times can result in considerable galactopoiesis, but this is frequently followed by marked
| |
| falls in yield when the administration of
| |
| thyroid-active material ends. The administration of thyroid-active materials to
| |
| dairy cows, if carried out with due care,
| |
| has no ill effects on the health and reproductive abilities of the cows (see Leech
| |
| and Bailey, 1953) , but because of the rather
| |
| small net gain in yield (about 3 per cent)
| |
| the practical application of the procedure
| |
| seems to be limited.
| |
| | |
| The mode of action of thyroxine and
| |
| thyroid-active substances on milk secretion
| |
| is uncertain. It is tmlikely that it is a
| |
| specific effect on the alveolar cells; rather
| |
| is it probably related to the effects of
| |
| the thyroid hormone on the general metabolic rate.
| |
| | |
| E. PARATHYROm HORMONE
| |
| | |
| The early studies on the influence of the
| |
| parathyroid glands on milk secretion indicated, as might be expected from their
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| ()19
| |
| | |
| | |
| | |
| role in calcium metabolism, that the parathyroids were important in the maintenance
| |
| of secretion (see review by Folley, 1952a).
| |
| Indeed in the rat, we demonstrated that
| |
| the severe impairment of milk secretion previously observed in "thyroidectomized" rats
| |
| was due not to the removal of the thyroids,
| |
| but to the simultaneous ablation of the
| |
| l)arathyroids (Cowie and Folley, 1945).
| |
| This observation has since been confirmed
| |
| and extended by Munson and his colleagues
| |
| (Munson, 1955) who demonstrated an influence on the calcium-concentrating mechanism of the mammary glands. Within 24
| |
| hours of parathyroidectomy the concentration of calcium in the milk of the lactating
| |
| rat was increased markedly despite a
| |
| greatly depressed level of calcium in the
| |
| serum; there was also a decrease in water
| |
| content of the milk, but this did not entirely
| |
| account for the increase in calcium content
| |
| since the calcium content expressed as mg.
| |
| per gm. milk solids was significantly higher
| |
| after parathyroidectomy (Toverud and
| |
| Munson, 1956). Further studies in this field
| |
| are awaited with interest.
| |
| | |
| F. INSULIN
| |
| | |
| Early experiments (see review by Folley,
| |
| 1952a) indicated that the endocrine pancreas might influence mammary function in
| |
| two ways; indirectly by way of the general
| |
| intermediary metabolism by which the supply of milk precursors may be regulated,
| |
| and directly through its role in the carbohydrate metabolism of the mammary gland
| |
| itself.
| |
| | |
| Most recent studies have been concerned
| |
| with the effect of insulin on mammary tissue in vitro. Mammary gland slices from
| |
| lactating rats actively synthesize fat from
| |
| small molecules, glucose, and glucose plus
| |
| acetate, but not from acetate alone (Folley
| |
| and French, 1950). The addition of insulin
| |
| to the incubation medium very markedly
| |
| increases the R.Q. (see Table 10.2) and
| |
| glucose uptake of the tissue slices and experiments with isotopes show that the rate
| |
| of fat synthesis is increased (Balmain, Folley and Glascock, 1952). Mammary gland
| |
| slices from lactating sheep, on the other
| |
| hand, can utilize acetate alone but not glucose alone for fat synthesis (Folley and
| |
| French, 1950) and sheep tissue is not re
| |
| | |
| | |
| TABLE 10.2
| |
| | |
| Effect of different substrates and of insulin on the
| |
| | |
| respiratory quotient (R.Q.) of lactating mammary
| |
| | |
| gland slices from various species
| |
| | |
| (From S. J. Follev and M. L. McNaught, Brit.
| |
| | |
| M. BulL, 14, 207-211, 1958.)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Respiratory
| |
| Quotients
| |
| | |
| | |
| Anlrml
| |
| | |
| | |
| Substrate
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Without
| |
| insulin
| |
| | |
| | |
| With
| |
| insulin
| |
| | |
| | |
| Mouse
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 1.90
| |
| | |
| | |
| 2.14
| |
| | |
| | |
| | |
| | |
| Glucose + acetate
| |
| | |
| | |
| 1.46
| |
| | |
| | |
| 2.14
| |
| | |
| | |
| Rat
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 1.57
| |
| | |
| | |
| 1.80
| |
| | |
| | |
| | |
| | |
| Acetate
| |
| | |
| | |
| 0.82
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Glucose + acetate
| |
| | |
| | |
| 1.53
| |
| | |
| | |
| 2.03
| |
| | |
| | |
| Guinea pig
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 1.17
| |
| | |
| | |
| | |
| | |
| Rabbit
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 1.30
| |
| | |
| | |
| _
| |
| | |
| | |
| | |
| | |
| Acetate
| |
| | |
| | |
| 0.92
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Glucose -t- acetate
| |
| | |
| | |
| 1.24
| |
| | |
| | |
| 1.67
| |
| | |
| | |
| Sheep
| |
| | |
| | |
| Glucose
| |
| Acetate
| |
| | |
| | |
| 0.88
| |
| 1.09
| |
| | |
| | |
| 1.09
| |
| | |
| | |
| | |
| | |
| Glucose + acetate
| |
| | |
| | |
| 1.52
| |
| | |
| | |
| 1.50
| |
| | |
| | |
| Goat
| |
| | |
| | |
| Glucose
| |
| | |
| | |
| 0.86
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Acetate
| |
| | |
| | |
| 1.17
| |
| | |
| | |
| —
| |
| | |
| | |
| Cow
| |
| | |
| Glucose
| |
| | |
| | |
| 0.84
| |
| | |
| | |
| _
| |
| | |
| | |
| | |
| | |
| Acetate
| |
| | |
| | |
| 1.12
| |
| | |
| | |
| —
| |
| | |
| | |
| | |
| sponsive to insulin in vitro. This clear-cut
| |
| species difference is interesting and underlines the need for further study. It is of
| |
| passing interest to note that the response
| |
| in vitro of rat mammary tissue to insulin
| |
| has been made the basis of a highly specific
| |
| in vitro bio-assay for insulin (Fig. 10.17)
| |
| (Balmain, Cox, Folley and McNaught,
| |
| 1954; McNaught, 1958)!
| |
| | |
| Further references and discussion on the
| |
| role of insulin in mammary function and
| |
| lipogenesis will be found in the reviews by
| |
| Folley (1956), and Folley and McNaught
| |
| (1958, 1960).
| |
| | |
| IV. Removal of Milk from the
| |
| | |
| Mammary Glands: Physiology
| |
| | |
| of Suckling and Milking
| |
| | |
| A. MILK-EJECTION REFLEX
| |
| | |
| Since the second edition of this book,
| |
| there have been major advances in our
| |
| knowledge of the physiology of milk removal. In the mammary gland the greater
| |
| | |
| | |
| | |
| 620
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| 22
| |
| | |
| | |
| rs 2-5//g/ml.
| |
| | |
| | |
| 20
| |
| | |
| | |
| yT
| |
| | |
| | |
| ■~^
| |
| | |
| | |
| yO
| |
| | |
| | |
| i 18
| |
| | |
| | |
| - Cf
| |
| | |
| | |
| >
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| -o
| |
| | |
| | |
| | |
| | |
| ■;;16
| |
| | |
| | |
| - i:/^
| |
| | |
| | |
| c
| |
| | |
| | |
| | |
| | |
| u=
| |
| | |
| | |
| | |
| | |
| «14
| |
| | |
| | |
| / J3 as^g/mi.
| |
| | |
| | |
| 8 12
| |
| | |
| | |
| Z' j^p^ £) 0-Vg/ml.
| |
| | |
| | |
| — 10
| |
| | |
| | |
| y rf^ ,-fP
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 1
| |
| 3 8
| |
| | |
| | |
| si r^^ r-f^ y^ Control
| |
| | |
| | |
| o °
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| M J
| |
| | |
| | |
| A y^ ^cr ,^y^
| |
| | |
| | |
| 4J
| |
| | |
| | |
| | |
| | |
| z
| |
| | |
| | |
| Pr( .iif^ jy''^^
| |
| | |
| | |
| 4
| |
| | |
| | |
| ^ M^ ^r^
| |
| | |
| | |
| 2
| |
| | |
| | |
| L_l 1 1 1 1 \ 1 \ 1 1 \ 1
| |
| | |
| | |
| | |
| 15 30
| |
| | |
| | |
| | |
| 60 90 120
| |
| | |
| Time (min)
| |
| | |
| | |
| | |
| 150
| |
| | |
| | |
| | |
| Fig. 10.17. Effect of various concentrations of
| |
| insulin on the respiratory metabolism of slices
| |
| of rat mammarj' glands. (From J. H. Balmain, C. P.
| |
| Cox, S J. Folley and M. L. McNaught, J. Endocrinol., 11, 269-276, 1954.)
| |
| | |
| portion of the milk secreted by the alveohir
| |
| cells in the intervals between suckling or
| |
| milking remains within the alveoli and the
| |
| fine ducts. Only a small portion passes into
| |
| the larger ducts and cisterns or sinuses from
| |
| which it can be immediately removed by
| |
| suckling, milking, or cannulation; its removal requires no maternal participation
| |
| and has been termed passive withdrawal
| |
| (see Cowie, Folley, Cross, Harris, Jacobsohn and Richardson, 1951, and page 612).
| |
| The larger portion of the milk in the alveoli
| |
| and fine ducts becomes available only with
| |
| the active participation of the mother and
| |
| requires the reflex contraction of special cells
| |
| (see page 623) surrounding the alveoli in response to the milking or suckling stimulus
| |
| to eject the milk from the alveoli and fine
| |
| ducts into the cistern and sinuses of the
| |
| gland. The occurrence of this reflex has long
| |
| been known, although its true nature has
| |
| only recently been generally recognized.^
| |
| | |
| -H. K. Waller {Clinical Slujlits un Lnrfallon,
| |
| London: Heinemann, 1938), and later one of us
| |
| (S. J. Folley, Physiology and Biochemistry of Lactation, London and Edinburgh: Oliver & Boyd,
| |
| 1956) have drawn attention to the fact that the
| |
| theme of the "milk-ejection reflex" was the inspiration of a paiming by II Tintoretto entitled "The
| |
| Origin of the Milky Way" which hangs in the
| |
| | |
| | |
| | |
| 111 the past it has been termed the "draught"
| |
| in lactating women (see Isbister, 1954) and
| |
| the "let-down" of milk in the cow. The
| |
| latter term is particularly misleading since
| |
| it implies the release of some restraint,
| |
| whereas there is, in fact, an active and
| |
| forceful expulsion of milk from the alveoli
| |
| and we have, therefore, urged that this term
| |
| be no longer used in scientific literature and
| |
| that it be replaced by the term "milk ejection" (Folley, 1947; Cowie, Folley, Cross,
| |
| Harris, Jacobsohn and Richardson, 1951),
| |
| a term, incidentally, which was used by
| |
| Gaines in 1915 in his classical researches
| |
| on the phenomenon (see below j.
| |
| | |
| The true nature of the milk removal process was for many years not recognized,
| |
| probably because it was assumed that the
| |
| mammary gland could not contain all the
| |
| milk obtainable at a milking, and this assumption made it necessary to postulate a
| |
| very active secretion of milk during suckling
| |
| or milking. Even as late as 1926 two phases
| |
| of milk secretion were described in the cow ;
| |
| the first phase was one of slow secretion
| |
| occurring between milkings, the second
| |
| phase was one of very active secretion occurring in response to the milking stimulus
| |
| when a volume of milk about equal to that
| |
| produced in the first phase was secreted in
| |
| a matter of a few minutes (Zietzschmann,
| |
| 1926). That some physiologic mechanism
| |
| | |
| National Gallery, London. Both authors point out
| |
| tliat the picture shows evidence of a considerable
| |
| intuiti^■e understanding of the physiologic nature
| |
| of the milk-ejection reflex. Thus, it illustrates, first,
| |
| that the application of the suckling stimulus causes
| |
| a considerable increase in intranianiinai >• jiressure
| |
| resulting, in this instance, in a sjnni cii' milk from
| |
| the nipples, and second, that ihv Muklmg stimulus
| |
| applied to one nipple gives rise to a systemic rather
| |
| than a localized effect, for the milk is forcibly
| |
| ejected from the suckled and unsuckled breasts
| |
| ahke. The same theme was also treatetl by Rubens
| |
| in a picture called "The Birth of the Milky Way"
| |
| which can be seen in the Prado Museum, Madrid.
| |
| This picture differs from Tintoretto's in one important detail, the stream of milk coming only from
| |
| one breast.
| |
| | |
| The forcible ejection of milk from the nipple has
| |
| doubtless been the subject of many statues. An example known to the authors is the fountain in the
| |
| Sfiuare at Palos Verdes, near Los Angeles, California. The center piece of this fountain has a nude
| |
| female torso at each of its four corners from whose
| |
| nipples spurt streams of water.
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 621
| |
| | |
| | |
| | |
| was involved in the discharge of preformed
| |
| milk from the mammary gland had, however, been recognized. Schafer (1898) considered that milk discharge was aided by
| |
| contraction of plain muscle w^ithin the
| |
| gland and pressure on the alveoli produced
| |
| by vasodilation.
| |
| | |
| The first full investigation of the physiology of milk removal was that by Gaines
| |
| in 1915. Unfortunately, his remarkably accurate observations and perspicacious
| |
| conclusions aroused little general interest
| |
| and were almost wholly overlooked for
| |
| more than quarter of a century. It is now
| |
| of interest to recall the more important of
| |
| Gaines' observations. First, he made a clear
| |
| distinction between milk ejection and milk
| |
| secretion — "Milk secretion, in the sense
| |
| of the formation of the milk constituents,
| |
| is one thing; the ejection of the milk from
| |
| the gland after it is formed is quite another
| |
| thing. The one is probably continuous; the
| |
| other, certainly discontinuous." Secondly,
| |
| he concluded that "Nursing, milking and the
| |
| insertion of a cannula in the teat, excite a
| |
| reflex contraction of the gland musculature
| |
| and expression of milk. There is a latent
| |
| period of 35 to 65 seconds. . . . Removal of
| |
| milk from the gland is dependent on this
| |
| reflex, and it may be completely inhibited
| |
| l)y anaesthesia. The conduction in the reflex
| |
| arc is dependent upon the psychic condition
| |
| of the mother." He also observed that the
| |
| increased flow of milk following the latent
| |
| period after stimulation was associated wath
| |
| a steep rise in pressure within the gland
| |
| cistern and that the reflex could be conditioned. Thirdly, with reference to the gland
| |
| capacity, he reported that "the indication
| |
| is that practically the entire quantity of
| |
| milk obtained at any one time is present
| |
| as such in the udder at the beginning of
| |
| milking." Lastl3^ he confirmed earlier observations that injections of posterior pituitary extract caused a flow of milk in the
| |
| lactating animal and he postulated that
| |
| "pituitrin has a muscular action on the active mammary gland causing a constriction
| |
| of the milk ducts and alveoli with a consequent expression of milk. This action
| |
| holds, also, on the excised gland in the
| |
| absence of any true secretory action." Gaines
| |
| regarded the milk-ejection reflex as a
| |
| | |
| | |
| | |
| l)urely neural arc although he emphasized
| |
| that the effect was "very similar to that
| |
| produced by pituitrin." All that is required
| |
| to bring these views of milk ejection in line
| |
| with present day concepts is to recognize
| |
| that the reflex arc is neurohormonal in character, the efferent component of which is
| |
| a hormone released from the neurohypophysis. When Gaines was carrying out these
| |
| experiments hardly anything was known of
| |
| neuro-endocrine relationships and there was
| |
| no background of knowledge to lead anyone
| |
| to conceive that the effects of the posterior
| |
| pituitary extract might represent a physiologic rather than a pharmacologic effect.
| |
| In 1930 Turner and Slaughter hinted at
| |
| a possible physiologic role of the posterior
| |
| pituitary in milk ejection and, as we have
| |
| noted (page 610), Gomez (1939) used posterior pituitary extract in replacement therapy given to hypophysectomized lactating
| |
| rats. It was not until 1941, however, that
| |
| the role of the posterior pituitary in milk
| |
| ejection was seriously postulated by Ely
| |
| and Petersen (1941) who, having shown in
| |
| the cow that milk ejection occurred in the
| |
| mammary gland to which all efferent nerve
| |
| fibers had been cut, suggested that the reflex
| |
| was neurohormonal, the hormonal component being derived from the posterior pituitary, and being, in all likelihood, oxytocin.
| |
| The neurohormonal theory of Ely and Petersen and the subsequent work of Petersen and
| |
| his colleagues (see reviews by Petersen,
| |
| 1948; and Harris, 1958), unlike the earlier
| |
| work of Gaines, aroused wide interest and its
| |
| practical applications permitted rationalization of milking techniques in the cowshed
| |
| thereby improving milk yields. Despite the
| |
| attractiveness of the concept, however, a
| |
| further 10 years were to elapse before unequivocal evidence of the correctness of the
| |
| theory was forthcoming and this evidence
| |
| we shall now briefly review.
| |
| | |
| B. ROLE OF THE NEUROHYPOPHYSIS
| |
| | |
| The first reliable indication that the
| |
| suckling or milking stimulus does in fact
| |
| cause an outpouring of neurohypophyseal
| |
| hormones were the observations that inhibition of diuresis occurred following the
| |
| application of the milking or suckling
| |
| stimulus (Cross, 1950; Peeters and Cous
| |
| | |
| | |
| 622
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| sens, 1950; Kalliala and Karvoncn, 1951;
| |
| Kalliala, Karvonen and Leppanen, 1952).
| |
| It was also shown that electrical stimulation
| |
| of the nerve paths to the posterior pituitary
| |
| resulted in milk ejection (Cross and Harris,
| |
| 1950, 1952; Andersson, 1951a, b, c; Popovich, 1958 », and that when lesions were
| |
| placed in these tracts the milk-ejection reflex was abolished (Cross and Harris, 1952) .
| |
| | |
| Further evidence was adduced when it
| |
| was found that removal of the posterior
| |
| pituitary immediately abolished the milkejection reflex in the lactating rat, and that
| |
| it was necessary to inject such animals several times a day with oxytocin if their litters
| |
| were to be reared (Cowie, quoted by Folley,
| |
| 1952b). Earlier workers had claimed that
| |
| the posterior lolie was not essential for lactation (Smith, 1932; Houssay, 1935), but an
| |
| explanation of these discordant conclusions
| |
| was provided when it was shown that the
| |
| impairment of the reflex after removal of
| |
| the posterior lobe is not permanent and that
| |
| the reflex re-establishes itself after some
| |
| weeks, presumably because the remaining
| |
| portions of the neurohypophysis take over
| |
| the functions of the posterior lobe (Benson
| |
| and Cowie, 1956). That the neurohypophysis participates in milk ejection would now
| |
| appear to be beyond question.
| |
| | |
| The discovery of the role of the neurohypophyseal hormones in milk ejection has
| |
| provided an explanation of some longstanding clinical observations on what has been
| |
| termed the natural "sympathy" between
| |
| the uterus and the breasts. Thus the beneficial effects of the suckling stimulus and the
| |
| occurrence of the "draught" {i.e., milk ejection) in causing uterine contraction after
| |
| parturition were emphasized over a century
| |
| ago by both Smith (1844) and Patcrson
| |
| (1844). 0})servations have also been made
| |
| on the I'cciprocal process of stimuli arising
| |
| from the reproductive organs apparently
| |
| causing milk ejection. In domestic animals
| |
| two such examples were mentioned by Martiny (1871). According to Herodotus, the
| |
| Scythians milk their mares thus: "They
| |
| take l)lowpipes of bone, very like flutes, and
| |
| put them into the genitals of the mares and
| |
| blow with their mouths, others milk. And
| |
| they say that the I'cason why thoy do so is
| |
| this, that when the marc's \-cins ai'c filled
| |
| | |
| | |
| | |
| with air, the udder cometh down" (translation by Powell, 1949). Kolbe (1727) described a similar procedure of blowing air
| |
| into the vagina used by the Hottentots when
| |
| milking cows which were normally suckled
| |
| by calves and in which, presumably, milk
| |
| ejection did not occur in response to hand
| |
| nnlking. A drawing depicting this procedure
| |
| from Kolbe's book was recently published in
| |
| the Ciba Zeitschrift (No. 84^ 1957) along
| |
| with a photograph of African natives still
| |
| using the method!-^
| |
| | |
| In 1839, Busch described the occurrence
| |
| of milk ejection, the milk actually spurting
| |
| from the nipple, in a lactating woman during coitus. A satisfactory explanation of
| |
| these curious observations is now forthcoming. Harris (1947) suggested that coitus
| |
| might cause the liberation of oxytocin from
| |
| the neurohypophysis and, within the next
| |
| few years it was demonstrated that stimulation of the reproductive organs evoked milk
| |
| ejection in the cow (Hays and VanDemark.
| |
| 1953) and reports confirmatory of Busch's
| |
| long forgotten observations also appeared
| |
| (Harris and Pickles, 1953; Campliell and
| |
| Petersen, 1953).^
| |
| | |
| C. MILK-EJECTIOX HORMONE
| |
| | |
| There is much circumstantial evidence
| |
| to confirm the belief that the milk-ejection
| |
| hormone is oxytocin (see Cowie and Policy.
| |
| 1957). Attemi)ts, however, to demonstrate
| |
| oxytocin in the blood after application of
| |
| the milking stimulus have given rather inconclusive results. Early claims that the
| |
| hormone could be demonstrated in blood are
| |
| | |
| ^ A similar drawing, also apparently from Kolbe '.•<
| |
| book, has been used in the campaign for clean milk
| |
| production! Heineman (1919) discussing sanitary
| |
| l^recautions in the cowshed says of the picture
| |
| "another picture shows a nude Hottentot milking
| |
| a cow while another one is liolding the tail of the
| |
| cow to prevent its dropping into the open pail.
| |
| This ])icture might well serve as a model to some
| |
| modern producers who do not take such precautions
| |
| and calmly lift the tail out of the milk with their
| |
| hands wlicn it hnjipens to switch into the pail."
| |
| | |
| ' W(- h;i\(' hi'cii able to find only one painting
| |
| illustrating this plienomenon. It is a picture by a
| |
| contemporary French painter, Andre Masson, entitled "Le Viol" and painted in 1939. It illustrates
| |
| in Masson 's personal idiom the act of rape and it is
| |
| interesting to note that a stream of milk is depicted
| |
| as being I'orcibly (\iected from one breast of the
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 623
| |
| | |
| | |
| | |
| of doiil)tful validity, because the milk-ejection effect observed may have been due to
| |
| 5-hydroxytryptamine (see Linzell, 1955),
| |
| and more recent attempts to assay the level
| |
| of oxytocin in the blood have not been
| |
| entirely satisfactory or conclusive. There
| |
| seem to be other polypeptide substances in
| |
| blood which possess oxytocic activity, although the thiogly collate inactivation test
| |
| indicates that these are different from oxytocin (Robertson and Hawker, 1957), and
| |
| no marked changes in the blood oxytocic
| |
| activity associated with suckling or milking
| |
| have been detected (Hawker and Roberts,
| |
| 1957; Hawker, 1958). However, it would
| |
| seem doubtful whether the present assay
| |
| techniques are sufficiently sensitive and specific to detect changes in blood oxytocin of
| |
| the magnitude likely to be associated with
| |
| milking or suckling. In the lactating cow
| |
| the intravenous injection of 0.05 to 2.0 I.U.
| |
| oxytocin will cause milk ejection (Bilek and
| |
| .Tanovsk>% 1956; Donker, 1958), in the goat
| |
| 0.01 to 1 I.U. (Cowie, cited by Folley,
| |
| 1952b; Denamur and Martinet, 1953), in
| |
| the sow 0.2 to 1.0 I.U. (Braude, 1954; Whittlestone, 1954; Cross, Goodwin and Silver,
| |
| 1958) in the rabbit 0.05 I.U. (Cross, 1955b) ,
| |
| and in the lactating woman 0.01 I.U. (Beller, Krumholz and Zeininger, 1958) . If these
| |
| (loses give any indication of the quantity
| |
| of endogenous oxytocin released, then the
| |
| concentration in the peripheral blood is
| |
| likely to be very small ; indeed Cross, Goodwin and Silver (1958) calculated that a
| |
| threshold dose (10 mU.) of oxytocin in
| |
| the sow w^ould give a plasma concentration
| |
| of about 1 (U,U. per ml, and until it can be
| |
| shown that the assay techniques are sufficiently sensitive to detect the changes
| |
| in oxytocin concentration produced by intravenous injections of "physiologic" doses
| |
| of oxytocin, no great reliance can be placed
| |
| on the results of assays.
| |
| | |
| Attempts have been made to demonstrate
| |
| alterations in the hormone content of the
| |
| neural lobe following the suckling or milking stimulus. In the goat and cow no detectable changes have been reported, but in
| |
| the smaller species (dog, cat, rat, guinea
| |
| pig) decreases have been described (see
| |
| Cowie and Folley, 1957). It is likely that in
| |
| many species the amount released is small
| |
| | |
| | |
| | |
| relative to the total hormone content of the
| |
| gland and within the limits of error of the
| |
| | |
| assay.
| |
| | |
| D. EFFECTOR CONTRACTILE MECHANISM OF
| |
| THE MAMMARY GLAND
| |
| | |
| In the last 10 years considerable research
| |
| has been devoted to a study of the effector
| |
| contractile tissue in the mammary gland;
| |
| this work has recently been reviewed in
| |
| some detail (see Folley, 1956) and only the
| |
| salient features need be mentioned here.
| |
| | |
| Although earlier histologists had from
| |
| time to time figured myoepithelial or "basket" cells in close association with the mammary alveoli, the morphology and distribution of the cells remained vague until
| |
| Richardson (1949) published a detailed and
| |
| illuminating description (Fig. 10.18). His
| |
| beautiful observations have since been confirmed and supplemented by Linzell (1952)
| |
| and Silver (1954). Richardson also disposed
| |
| of the oft repeated view that smooth-muscle fibers around the alveoli played an iml)ortant role in milk ejection. From a study
| |
| of the general orientation of the myoepithelial cells and the precise relationship between
| |
| these cells and the folds in the secretory epithelium from contracted glands, Richardson
| |
| considered it reasonable to regard the myoepithelium as the contractile tissue in the
| |
| mammary gland which responds to oxytocin
| |
| causing contraction of the alveoli and widening of the ducts. The evidence adduced by
| |
| Richardson, although good, was nevertheless circumstantial, and it was desirable that
| |
| attempts be made to visualize the contraction of the myoepithelial cells in response to
| |
| oxj^tocin. In this connection it is of interest
| |
| to recall that Gaines (1915) reported that
| |
| when a drop of pituitrin was placed on the
| |
| cut surface of the mammary gland from a
| |
| lactating guinea pig, minute white dots appeared within a few seconds beneath the
| |
| pituitrin and slowly swelled to tiny milky
| |
| rivulets streaming beautifully through the
| |
| clear liquid. Much later the local effects of
| |
| posterior pituitary extract on the mammary
| |
| gland were studied by Zaks (1951) in the
| |
| living mouse, when it was reported that it
| |
| caused contraction of the alveoli and expansion of the ducts. These observations
| |
| were considerablv extended bv Linzell
| |
| | |
| | |
| | |
| 624
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| | |
| Fig. 10.18. Surface view of contracted alveoli (of goat) showing myoepithelial cells.
| |
| (Courtesy of K. C. Richardson.)
| |
| | |
| | |
| | |
| | |
| Fig. 10.19. Recording of pressure changes witliin
| |
| a galactophore of a forcibly restrained lactating
| |
| rabbit. The litter was allowed to suckle the noncannulated mammary glands but obtained only
| |
| 8 gm. milk, there being only a slight rise in the
| |
| milk pressure probably associated with a slight
| |
| contraction of the myoepithelium in response to
| |
| mechanical stimulation. When 5 mU. oxytocin were
| |
| injected (5P) there was a rapid milk ejection
| |
| response which could be inhibited by injecting 1
| |
| yug. adrenaline (lA) just before the oxytocin. After
| |
| a few minutes 5 mU. oxytocin were again effective
| |
| and the litter obtained 44 gm. milk when they were
| |
| allowed to suckle. A more complete milk ejection
| |
| respon.so was obtained with 50 mU. oxytocin (50P)
| |
| and the young obtained a further 59 gm. milk.
| |
| Anesthesia did not enhance the milk-ejection response to 50 mU. oxytocin. During emotional inhibition of milk ejection the mammary gland thus
| |
| remains responsive to oxytocin. (From B. A. Cross,
| |
| J. Endocrinol., 12, 29-37, 1955.)
| |
| | |
| | |
| | |
| (19ooi who studied the local effects of
| |
| liighly purified oxytocin and vasopressin
| |
| and a number of other drugs on the mammnry gland, and confirmed that oxytocin
| |
| and vasopressin produced alveolar contraction and widening of the ducts. Although in
| |
| these experiments the myoepithelial cells
| |
| themselves could not be visualized, nevertheless the effects observed leave little
| |
| doubt that the effector mechanism was the
| |
| niyoei)ithelium.
| |
| | |
| The myoepithelium is responsive to stimuli other than those arising from the presence of neurohypophyseal hormones in the
| |
| blood inasmuch as partial milk ejection
| |
| may occur in response to local mechanical
| |
| stimulation of the mammary gland (Cross,
| |
| 1954; Yokoyama, 1956; see also Fig. 10.191.
| |
| These observations may explain the recent
| |
| reports by Tverskoi (1958) and Denamuiand Martinet (1959a, b) that milk yields
| |
| can be maintained in goats in the absence of
| |
| the milk-ejection reflex.
| |
| | |
| E. INHIBITION OF MILK EJECTION
| |
| | |
| (laines (1915) stressed that the conduction in the milk-ejection reflex pathway was
| |
| dei)endent on the psychic condition of the
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 625
| |
| | |
| | |
| | |
| mother. Many years later Ely and Petersen
| |
| (1941) confirmed this and, having shown
| |
| that injections of adrenaline blocked the
| |
| milk-ejection reflex, postulated that the increased blood level of adrenaline in emotionally disturbed cows interfered with the
| |
| action of oxytocin. In the last few years, the
| |
| nature of the inhibitory mechanisms has
| |
| been more fully investigated. Braude and
| |
| Mitchell (1952) showed in the sow that
| |
| adrenaline exerts at least part of its inhibitory effect at the level of the mammary
| |
| gland and that, whereas the injection of
| |
| adrenaline before the injection of oxytocin
| |
| blocked milk ejection, less inhibition occurred if both were given together. Cross
| |
| (1953, 1955a) confirmed these observations
| |
| in the rabbit and demonstrated that electrical stimulation of the posterior hypothalamus (sympathetic centers) inhibited the
| |
| milk-ejection response to injected oxytocin,
| |
| an effect which was abolished after adrenalectomy. Cross concluded from his experiments that any central stimulation causing
| |
| sympathetico-adrenal activity inhibits the
| |
| milk-ejection response and that the effect
| |
| appears to depend on a constriction of the
| |
| mammary blood vessels resulting from the
| |
| release of adrenaline and excitation of the
| |
| sympathetic fibers to the mammary glands.
| |
| Whereas such a mechanism could account
| |
| for the emotional disturbance of the reflex.
| |
| Cross was careful to point out that there
| |
| was no direct proof that this was so and he
| |
| later demonstrated (Cross, 1955b) that in
| |
| rabbits in which emotional inhibition of
| |
| milk ejection was present, milk ejection
| |
| could be effected by the injection of oxytocin (Fig. 10.19). In such cases there was
| |
| clearly no peripheral inhibitory effect of
| |
| milk ejection. Cross concluded that the main
| |
| factor in emotional disturbance of the milkejection reflex is a partial or complete inhibition of oxytocin release from the posterior pituitary gland. At present nothing is
| |
| known of the nature of this central inhibitory mechanism.^
| |
| | |
| ^ A curious form of the suckling stimulus is illustrated in carvings which siumount the main door
| |
| of the church of Sainte Croix in Bordeaux. The
| |
| carvings illustrate penances prescribed for wrong
| |
| doers who have committed one of the seven deadly
| |
| sins. The penance for indulgence in the sin of luxiu y
| |
| is the application to the breasts of serpents or toads.
| |
| | |
| | |
| | |
| Inhibition of the milk ejection reflex may
| |
| also occur when the mammary gland becomes engorged with secretion to such an
| |
| extent that the capillary circulation is so reduced that oxytocin can no longer reach the
| |
| myoepithelium (Cross and Silver, 1956;
| |
| Cross, Goodwin and Silver, 1958).
| |
| | |
| F. NEURAL PATHWAYS OF THE
| |
| MILK-EJECTION REFLEX
| |
| | |
| Interpretation of some of the earlier
| |
| studies on neural pathways is difficult because investigators did not realize that, although the milk ejection reflex normally
| |
| occurs in response to the suckling stimulus,
| |
| it can become conditioned and can then occur in response to visual or auditory stimuli
| |
| associated with the act of nursing. In such
| |
| cases an apparent lack of effect on milk
| |
| ejection of section of nerves or nerve tracts
| |
| would not necessarily imply that the nerves
| |
| normally carrying the stimuli arising from
| |
| the suckling had not been cut. Studies on
| |
| the effects of hemisection of the spinal cord
| |
| in a few goats led Tsakhaev (1953) to the
| |
| conclusion that the apparent pathway used
| |
| by the milk-ejection stimulus was uncrossed. More recently pathways within the
| |
| spinal cord have been investigated by Eayrs
| |
| and Baddeley (1956) who found inter alia
| |
| that lactation in the rat was inhibited by
| |
| lesions to the lateral funiculi, and by section
| |
| of the dorsal roots of nerves supplying the
| |
| segments in which the suckled nipples were
| |
| situated. With few exceptions hemisection
| |
| of the spinal cord abolished lactation when
| |
| the only nipples available for suckling
| |
| were on the same side as the lesion, but not
| |
| when the contralateral nipples were available. It was concluded that the pathway
| |
| used by the suckling stimulus enters the
| |
| central nervous system by the dorsal routes
| |
| and ascends the cord deep in the lateral
| |
| funiculus of the same side. Inasmuch as in
| |
| these experiments lactation was assessed
| |
| from the growth curve of the pups, it is not
| |
| always clear whether the failure of lactation
| |
| was due to a cessation of milk secretion or to
| |
| loss of the milk-ejection reflex. It was noted,
| |
| however, that injections of oxytocin in some
| |
| | |
| It may be questioned whether this unusual form of
| |
| the suckling stimulus would not inhibit rather than
| |
| evoke the milk-ejection reflex.
| |
| | |
| | |
| | |
| 626
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| cases restored lactation for up to 2 days
| |
| after it had ceased as a result of lesions of
| |
| the cord which would suggest a primary
| |
| interference with milk ejection. In the goat,
| |
| Andersson (1951b) considered that stimuli may reach the hypothalamus by way of
| |
| the medial lemniscus in the medulla, but
| |
| little definite information is available concerning the pathways used by the stimuli
| |
| to reach the hypothalamus and there is here
| |
| scope for further investigations. (For further discussion see review by Cross, 1960.)
| |
| From the hyopthalamus there is little doubt
| |
| that the route to the posterior lobe is by
| |
| way of the hypothalamo-hypophyseal tract
| |
| which receives nerve fibers from the cells in
| |
| the hypothalamic nuclei, and in the main
| |
| from the paraventricular and supra-optic
| |
| nuclei. It was generally assumed that the
| |
| posterior lobe hormones were secreted in
| |
| the posterior lobe from the pituicytes in response to stimuli passing down the hypothalamo-hypophyseal tract. In the last decade, however, much evidence has come to
| |
| light which suggests that the so-called posterior lobe hormones are in fact elaborated
| |
| in the cells of the hypothalamic nuclei and
| |
| are then transported down the axones as a
| |
| neurosecretion and stored in the posterior
| |
| lobe (see Scharrer and Scharrer, 1954).
| |
| | |
| Before leaving the neural pathways of the
| |
| milk-ejection reflex, brief reference must be
| |
| made to the recent discovery by Soviet physiologists that there is also a purely nervous
| |
| reflex (segmental in nature) involved in the
| |
| ejection of milk. It is said that within a few
| |
| seconds of the application of the milking
| |
| stimulus, reflex contraction of the smooth
| |
| muscle in the mammary ducts occurs, causing a flow of milk from the ducts into the
| |
| cistern. This reflex contraction of the smooth
| |
| muscle is also believed to occur in response
| |
| to stimuli arising within the gland between
| |
| milkings thus aiding the redistribution of
| |
| milk in the udder. This purely nervous reflex
| |
| is stated to occur some 30 to 60 seconds before the reflex ejection of milk from the alveoli by oxytocin (for further details sec
| |
| review by Baryshnikov, 1957). The conditioned reflexes associated with suckling and
| |
| milking have been the subject of numerous
| |
| investigations l)y Grachev (see Grachev,
| |
| | |
| | |
| | |
| 1953, 1958) ; these and other Russian researches into the motor apparatus of the udder have been fully reviewed by Zaks
| |
| (1958).
| |
| | |
| G. MECHANISM OF SUCKLING
| |
| | |
| In the past, various theories have been
| |
| put forward as to how the suckling obtains
| |
| milk from its mother's mammary gland. In
| |
| the human infant some considered that the
| |
| lips formed an airtight seal around the nipple and areola thus allowing the child to
| |
| suck, whereas others believed that compression of the lacteal sinuses between the gums
| |
| aided the expulsion of the milk (see Ardran,
| |
| Kemp and Lind, 1958a, b for review) . In the
| |
| calf the act of suckling was studied by
| |
| Krzywanek and Briiggemann (1930) who
| |
| described how the base of the teat was
| |
| pinched off between upper and lower jaws
| |
| and the teat compressed from its base towards its tip by a stripping action of the
| |
| tongue. Smith and Petersen (1945) on the
| |
| other hand, concluded that the calf wrapped
| |
| its tongue round the teat and obtained milk
| |
| by suction.
| |
| | |
| Much misunderstanding about the nature
| |
| of the act of suckling has arisen because the
| |
| occurrence of milk ejection was overlooked
| |
| or its significance was not appreciated. As a
| |
| result, the idea became prevalent that success or failure in obtaining milk could be
| |
| reckoned solely in terms of the power behind
| |
| the baby's suction. This erroneous concept
| |
| was vigorously attacked by Waller (1938),
| |
| who pointed out that once the "draught"
| |
| had occurred the milk at times flowed so
| |
| freely from the breast that the baby had to
| |
| break off and turn its head to avoid choking.
| |
| A similar observation had been made by Sir
| |
| Astley Cooper in 1840 who in describing the
| |
| "draught" in nursing women wrote, "If the
| |
| nipple be not immediately caught by the
| |
| child, the milk escapes from it, and the child
| |
| when it receives the nipple is almost choked
| |
| l)y the rapid and abundant flow of the fluid;
| |
| if it lets go its hold, the milk spurts into the
| |
| infant's eyes." An even earlier comment was
| |
| made by Soranus, a writer on paediatrics in
| |
| the cai'ly half of the second century A.D.,
| |
| that it was unwise to allow the infant to fall
| |
| asleep at the breast since the milk some
| |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 627
| |
| | |
| | |
| | |
| times flowed without suckling and the infant
| |
| choked. It must thus be emphasized that
| |
| once milk ejection has occurred the milk in
| |
| the gland cisterns or sinuses is under considerable pressure and the suckling has
| |
| merely to overcome the resistance of the
| |
| sphincters in the nipple or teat to obtain the
| |
| milk.
| |
| | |
| Recently the use of cineradiograjihy has
| |
| allowed a more accurate analysis of the
| |
| mechanism of suckling. Studies by Ardran,
| |
| Kemp and Lind (1958b) have shown that
| |
| the human infant sucks the nipple to the
| |
| back of the mouth and forms a "teat" from
| |
| the mother's breast; when the jaw is raised
| |
| this teat is compressed between the upper
| |
| gum and the tip of the tongue resting on
| |
| the lower gum, the tongue is then applied
| |
| to the lower surface of the "teat" from before backwards pressing it against the hard
| |
| palate. Suction may assist the flow of milk
| |
| so expressed from the nipple, but is only of
| |
| secondary importance. Studies by Ardran,
| |
| Cowie and Kemp (1957, 1958) in the goat
| |
| have extended these observations, because
| |
| it was possible in this species to follow the
| |
| withdrawal, from the udder, of milk made
| |
| radiopaque with barium sulfate. As with
| |
| the infant, the neck of the teat was obliterated between the tongue and the palate of
| |
| the kid and the contents of the teat sinus
| |
| were displaced into the mouth cavity by a
| |
| suitable movement of the tongue; while
| |
| the first mouthful w^as being displaced into
| |
| the pharynx, the jaw and tongue were lowered to allow the refilling of the teat sinus.
| |
| The normal method of obtaining milk is,
| |
| therefore, for the suckling to occlude the
| |
| neck of the teat and then to expel the contents of the teat sinus by exerting positive
| |
| pressure on the teat (120 mm. Hg in the
| |
| goat), so forcing the contents through the
| |
| teat canal or nipple orifices into the mouth
| |
| cavity, a process which may be aided by
| |
| negative pressure created at the tip of the
| |
| teat. Human infants, goat kids, and calves
| |
| can obtain milk through rubber teats by
| |
| suction alone provided the orifice is large
| |
| enough (see Krzywanek and Briiggemann,
| |
| 1930; Martyugin, 1944; Ardran, Kemp and
| |
| Lind, 1958a) , but this procedure occurs only
| |
| w^hen the structure of the rubber teat is such
| |
| that the suckling is unable to ol)literate the
| |
| | |
| | |
| | |
| neck of the teat and cannot, therefore, strip
| |
| the contents of the teat by positive pressure.
| |
| | |
| V. Relation between the Reflexes Concerned in the Maintenance of Milk
| |
| Secretion and Milk Ejection
| |
| | |
| We have seen that the suckling or milking stimulus is responsible for initiating the
| |
| reflex concerned wath the maintenance of
| |
| milk secretion and also the milk-ejection reflex; the question now arises as to what extent their arcs share common paths. It
| |
| would seem logical to assume that a common
| |
| path to the hypothalamus exists and parts
| |
| of this, as we have seen, have been partially
| |
| elucidated. Although the hypothalamo-hypophyseal nerve tracts provide an obvious
| |
| link between hypothalamus and the posterior lobe, the connections between the hypothalamus and anterior pituitary are still
| |
| a matter of some controversy. The possible
| |
| avenues of communication to the anterior
| |
| lobe are neural and vascular and these may
| |
| be subdivided into central and peripheral
| |
| neural connections and into portal and systemic vascular connections. The various experimental findings relating to these routes
| |
| have recently been critically discussed by
| |
| Sayers, Redgate and Royce (1958), and by
| |
| Greep and Everett in their chapters in this
| |
| book, and it is clear that at present no definite conclusions can be reached concerning
| |
| their relative importance. So far as the specific question of maintenance of milk secretion is concerned, the experiments of Harris
| |
| and Jacobsohn (1952), which showed that
| |
| pituitary grafts maintained lactation when
| |
| implanted adjacent to the median eminence
| |
| in hypophysectomized rats, were consistent
| |
| with the existence of a hormonal transmitter, passing by w^ay of the hypophyseal portal system. On the other hand, transplantation studies by Desclin (1950, 1956) and
| |
| Everett ( 1954, 1956) have revealed that in
| |
| the rat the anterior lobe can spontaneously
| |
| secrete prolactin in situations remote from
| |
| the median eminence, and Donovan and van
| |
| der Werff ten Bosch (1957) have reported
| |
| that milk secretion continued in rabbits in
| |
| wiiich the pituitary portal vessels had been
| |
| completely destroyed, although there was,
| |
| however, an inferred change in milk composition. Evidence has recentlv been obtained
| |
| | |
| | |
| | |
| 628
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| which has confirmed that pituitary tissue
| |
| grafted under the kidney capsule in rats apparently secretes prolactin and will give
| |
| slight maintenance of milk secretion in hypophysectomized animals, this maintenance
| |
| being considerably enhanced if ACTH or
| |
| STH is also administered (Cowie, Tindal
| |
| and Benson, 1960). It would thus seem
| |
| that the cells of the anterior lobe have
| |
| the ability when isolated from the hypophyseal portal system to secrete prolactin,
| |
| but the experiments cited above allow no
| |
| conclusions to be drawn regarding the route
| |
| by which the galactopoietic function of the
| |
| pituitary is normally controlled.
| |
| | |
| Recent reports that bilateral cervical
| |
| sympathectomy in the lactating goat causes
| |
| a fall in the milk yield suggest that the galactopoietic functions of the anterior lobe
| |
| may be influenced by the sympathetic nervous system (Tsakhaev, 1959; Tverskoy,
| |
| 1960) . Declines in milk yield also occur after
| |
| section of the pituitary stalk in the goat, but
| |
| it is not clear in such cases whether the effects are due to the interruption of nervous
| |
| or vascular pathways within the stalk
| |
| (Tsakhaev, 1959; Tverskoy, 1960). In these
| |
| studies on stalk section the cut ends of the
| |
| pituitary stalk were not separated by a plastic plate, so some restoration of the hyl^ophyseal portal system may have occurred.
| |
| Further experiments on the effects of section of the pituitary stalk on lactation in
| |
| which restoration of the hypophyseal portal
| |
| is prevented by the insertion of a plate are
| |
| being conducted in our laboratory and also
| |
| in the Soviet Union. Another possible mode
| |
| of communication between hypothalamus
| |
| and anterior pituitary has been investigated
| |
| by Benson and Folley (1956, 1957a, b) who
| |
| have suggested that the oxytocin released
| |
| from the neurohypophysis in response to the
| |
| suckling stimulus may directly act on the
| |
| cells of the anterior lobe and stimulate the
| |
| release of the galactopoietic complex. The
| |
| careful anatomic researches of Landsmeer
| |
| (1951), Daniel and Prichard (1956, 1957,
| |
| 1958) and Jewell (1956) have demonstrated
| |
| in several species the existence of direct
| |
| vascular connections from the neurohylK)physis to the anterior lobe so that the
| |
| neurohypophyseal hormones liberated into
| |
| the blood stream would in fact be carried
| |
| | |
| | |
| | |
| direct to the anterior pituitary cells in very
| |
| high concentrations. Clearly such a concept
| |
| would provide a simple explanation of how
| |
| the hormonal integration, coordination, and
| |
| maintenance of mammary function is
| |
| achieved. It has already been noted (see
| |
| page 607) that a connection between milk
| |
| ejection and the onset of copious lactation
| |
| has been suggested. There is considerable
| |
| evidence that oxytocin is liberated during
| |
| parturition in sufficient quantities to cause
| |
| contraction of the alveoli and milk ejection
| |
| (see Harris, 1955; Cross, 1958; Cross, Goodwin and Silver, 1958) ; if, therefore, oxytocin
| |
| can release the lactogenic and galatopoietic
| |
| complexes from the anterior pituitary, a
| |
| simple explanation of the mechanism triggering off the onset of copious milk secretion, before the application of the milking
| |
| stimulus, is available.
| |
| | |
| We must now consider what experimental
| |
| evidence there is to support this rather attractive theory. First, Benson and Folley
| |
| (1956, 1957a, b) demonstrated that regular
| |
| injections of oxytocin can retard mammary
| |
| regression after weaning in a similar fashion to injections of prolactin (see page
| |
| 610), and they have shown that the presence of the pituitary is essential for oxytocin
| |
| to elicit this effect. Synthetic oxytocin
| |
| proved equally effective, thus discounting
| |
| the possibility of a contaminant in natural
| |
| oxytocin being concerned (Fig. 10.20) . These
| |
| experiments have so far only been carried
| |
| out in rats, but they strongly suggest that
| |
| oxytocin can elicit the secretion of prolactin.
| |
| In agreement with this concept are several
| |
| observations that regular injections of oxytocin have galactopoietic effects in lactating
| |
| cows and that oxytocin has luteotrophic effects in rats (see review by Benson, Cowie
| |
| and Tindal, 1958) . There is, moreover, some
| |
| evidence that the suckling stimulus may
| |
| cause the release of vasopressin or the antidiuretic hormone (ADH) from the neurohypoi)hysis (see page 621), and it has been
| |
| shown that ADH or some material closely
| |
| associated with it may cause the secretion of
| |
| ACTH from the anterior lobe (see review
| |
| by Benson, Cowie and Tindal, 1958) ; so
| |
| there are some grounds for supposing that
| |
| the hormones of the posterior lobe evoke
| |
| the secretion of several components of the
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Fig. 10.20. Sections from abdominal mammary gland of rats from wliuli Ur- pups were
| |
| removed on the fourth day of lactation and which received thereafter for 9 daj^s: A. LO
| |
| I.U. synthetic oxytocin three times daily. B. Saline daily. Note the maintenance of gland
| |
| structure in A. (Courtesy of Dr. G. K. Benson.)
| |
| | |
| | |
| | |
| galactopoietic complex from the anterior
| |
| lobe. It was hoped to gain further evidence
| |
| on this point by studies on hypophysectomized rats bearing pituitary homografts
| |
| under the kidney capsule (see Benson,
| |
| Cowie, Folley and Tindal, 1959) . As already
| |
| noted, such grafts secrete prolactin and will
| |
| give a slight maintenance of milk secretion,
| |
| but these grafts will not maintain normal
| |
| milk secretion even when such animals are
| |
| injected with oxytocin and ADH (Cowie,
| |
| Tindal and Benson, 1960). It must, therefore, be assumed that if these posterior
| |
| pituitary hormones are responsible for the
| |
| release of the galactopoietic complex, some
| |
| other hypothalamic factor is also necessary
| |
| to maintain the anterior lobe in a responsive
| |
| condition. Everett (1956) suggested that
| |
| the hypothalamus by way of its neurovascular connections with the anterior lobe,
| |
| normally exerts a partial inhibitory effect on
| |
| prolactin secretion. It may thus be that
| |
| when the anterior lobe is removed from
| |
| hypothalamic influence, the synthetic activities of its cells are centered on prolactin
| |
| | |
| | |
| | |
| production to the detriment of the other
| |
| components of the galactopoietic complex,
| |
| so that these are no longer available for release in response to neurohypophyseal hormones. There is need, however, for experimentation in other species.
| |
| | |
| The theory that the release of the galactopoietic complex is effected by the hormones of the posterior lobe secreted in response to the suckling stimulus is attractive
| |
| in that it appears to afford a simple explanation of the hormonal integration of mammary function, but it must be pointed out
| |
| that the observations on the maintenance of
| |
| mammary structure after weaning by injections of oxytocin do not prove that prolactin
| |
| or the galactopoietic complex is released in
| |
| response to oxytocin under normal conditions of milking or suckling, and more research, particularly in species other than the
| |
| rat, is necessary. Grosvenor and Turner
| |
| (1958a) injected oxytocin into anesthetized
| |
| lactating rats and, on the basis of assays of
| |
| the pituitary content of prolactin, considered
| |
| that oxytocin caused no significant release of
| |
| | |
| | |
| | |
| 630
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| prolactin. They had previously shown that
| |
| there was an immediate fall in the pituitary
| |
| content of prolactin after nursing (Grosvcnor and Turner, 1957b) and therefore
| |
| concluded that their findings were contrary
| |
| to the hypothesis that oxytocin is a hormonal link in the discharge of prolactin.
| |
| This, however, cannot be regarded as conclusive because of the difficulties of relating
| |
| pituitary content of a hormone to blood
| |
| levels of the hormone and also the difficulty
| |
| of determining the physiologic dose of oxytocin, for if the oxytocin is carried directly
| |
| from the neurohypophysis into the anterior
| |
| lobe, then the concentration in the blood
| |
| reaching the anterior lobe may be relatively
| |
| great (see also Cowie and Folley, 1957).
| |
| | |
| Other theories of the reflex maintenance
| |
| of milk secretion have been put forward. In
| |
| 1953 Tverskoi, observing that repeated injections of oxytocin were galactopoietic in
| |
| the goat, suggested that alveolar contraction
| |
| stimulated sensory nerve endings in the
| |
| alveolar walls which reflcxly caused the release of prolactin. It is obvious that his
| |
| observations could be explained on the basis
| |
| of the Benson-Folley theory of direct pituitary stimulation by oxytocin. This possibility was indeed considered by Tverskoi.
| |
| but rejected on the grounds that oxytocin
| |
| did not affect the prolactin content of the
| |
| pituitary (Meites and Turner, 1948). In
| |
| 1957 Tverskoi found it necessary to revise
| |
| his theory, having found that full lactation
| |
| could be maintained in the goat after complete and repeated denervation of the udder
| |
| provided oxytocin was regularly given to
| |
| evoke milk ejection. He then suggested that
| |
| alveolar contraction stimulates the synthetic activities of the mammary epithelium
| |
| causing an uptake of prolactin from the
| |
| blood, the fall in the blood prolactin level
| |
| then stimulating the further production of
| |
| prolactin by the anterior lobe. Although
| |
| these latter observations of Tverskoi might
| |
| again be explained on the basis of direct
| |
| pituitary stimulation by exogenous oxytocin, more recent studies on goats have
| |
| cast doubts on the validity of such an explanation. Tverskoi (1958) and Denannir
| |
| and Martinet (1959a, b, 1960) have shown
| |
| that lactating goats will continue to lactate,
| |
| giving nonnal or onlv niodcratelv reduced
| |
| | |
| | |
| | |
| milk yields after section of all nervous connections between the udder and brain (cord
| |
| section, radicotomy, bilateral sympathectomy) and without their receiving oxytocin
| |
| and in the absence of conditioned milkejection reflexes. It has already been noted
| |
| that milk ejection in such animals may result from mechanical stimulation of the
| |
| myoepithelial cells by udder massage (see
| |
| page 624) , but the release of the galactopoietic complex from the anterior pituitary
| |
| would seem in these goats to have been independent of neurohormonal reflex activities. AVhether in such animals the release is
| |
| spontaneous or dependent on the level of
| |
| hormones in the blood as suggested by
| |
| Tverskoi (1957) is a matter for further research.
| |
| | |
| VI. Pharmacologic Blockade of the Reflexes Concerned in the Maintenance
| |
| of Milk Secretion and Milk Ejection
| |
| | |
| Various attempts have been made to
| |
| investigate the mechanism controlling release of anterior pituitary hormones by the
| |
| use of dibenamine, atropine, and other
| |
| drugs. In reviewing such experiments, Harris
| |
| (1955) concluded that there was no convincing evidence of the participation of
| |
| adrenergic, cholinergic, or histaminergic
| |
| agents in the control of gonadotrophic and
| |
| adrenocorticotrophic hormone release. Recently Grosvenor and Turner (1957a) reported that various ergot alkaloids, dibenamine, and atropine blocked milk ejection
| |
| in the rat; the ergot alkaloids doing so
| |
| within 10 minutes of administration, the
| |
| atropine and dibenamine within 2 to 4 hours.
| |
| Inasmuch as milk ejection occurred in response to exogenous oxytocin, it was concluded that these drugs acted centrally, and
| |
| the presence of adrenergic and cholinergic
| |
| links in the neurohormone arc was postulated to be responsible for the discharge of
| |
| oxytocin. Later, on the basis of assays of
| |
| jntuitary prolactin after nursing in druginjected lactating rats, it was suggested
| |
| that cholinergic and adrenergic links are
| |
| iinohcd in the reflex resi)onsible for prolactin release (Grosvenor and Turner,
| |
| 1958a). Ergot alkaloids, however, administered in our laboratory to lactating rats had
| |
| no significant effect on the lactational per
| |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 631
| |
| | |
| | |
| | |
| fonnance as judged by the growth of the
| |
| litters in comparison with the growth of
| |
| litters of pair-fed control rats, showing that
| |
| apparent inhibitory effects of the alkaloids
| |
| on lactation were due to depressed food intake of the mothers (Tindal, 1956a). Inasmuch as growth of the litter depends on
| |
| efficient milk secretion and milk ejection,
| |
| Tindal's observations seem to throw doubt
| |
| on the importance of the adrenergic link in
| |
| these reflexes. On the other hand, IVIeites
| |
| (1959) has reported that adrenaline and
| |
| acetylcholine can induce or maintain mammary development and milk secretion in
| |
| suitably prepared rats, observations which
| |
| could be interpreted as supporting the presence of adrenergic and cholinergic links as
| |
| postulated by Grosvenor and Turner
| |
| (1958a).
| |
| | |
| There have been clinical reports of women developing galactorrhoea after treatment with trancjuilizing drugs {e.g., Sulman
| |
| and Winnik, 1956; Marshall and Leiberman, 1956; Piatt and Sears, 19561 and interesting observations have recently ap
| |
| | |
| | |
| peared on the lactogenic effects of reserpine
| |
| in animals. Milk secretion has been initiated
| |
| both in virgin rabbits after suitable estrogen
| |
| priming and in the pseudopregnant rabbit
| |
| by reserpine (Sawyer, 1957; Meites, 1957a).
| |
| On the other hand, in our laboratory Tindal
| |
| (1956b, 1958) had been unable to detect
| |
| any mammogenic or lactogenic effects with
| |
| chlorpromazine or reserpine in rabbits
| |
| (Dutch breed), rats, or goats, nor did reserpine stimulate the crop-sac when injected
| |
| into pigeons. Recently, using New Zealand
| |
| White rabbits, Tindal (1960) has induced
| |
| milk secretion with reserpine. The reason
| |
| for these contradictory results is not entirely
| |
| clear, although breed differences in the response would appear to exist in the rabbit.
| |
| In our laboratory, Benson (1958) has shown
| |
| that reserpine is strikingly active in retarding mammary involution in the lactating rat after weaning, the effect being of
| |
| such a magnitude as has so far only been
| |
| equalled by a combination of prolactin and
| |
| STH (Fig. 10.21). It has been tentatively
| |
| suggested that the tranquilizing drugs may
| |
| | |
| | |
| | |
| ^^:f/
| |
| | |
| | |
| | |
| mm\"^>m.-Wi
| |
| | |
| | |
| | |
| | |
| | |
| | |
| ■w^
| |
| | |
| | |
| .•^^:j^-^ f4kr 1"
| |
| | |
| | |
| | |
| | |
| Fig. 10.2L Sections from the abdominal mammary gland of rats from whichthe pujis were
| |
| removed on the fourth day of lactation and which received thereafter for 9 days: A 100 fj.g.
| |
| reserpine daily. B. Sahne dailJ^ Note the retardation of involution effected by reserpine.
| |
| (Courtesy of Dr. G. K. Benson.)
| |
| | |
| | |
| | |
| 632
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| remove .some hypothalamic restraining
| |
| mechanism on the release of jn'olactin and
| |
| probably of other anterior-pituitary hormones (Sulman and Winnik, 1956; Benson,
| |
| Cowie and Tindal, 1958), an effect which,
| |
| if confirmed, may throw light on the behavior of pituitary transplants in sites remote from the median eminence.
| |
| | |
| VII. Conclusion
| |
| | |
| Any reader familiar with the chajiter on
| |
| the mammary gland in the previous edition
| |
| of this book cannot fail to note the main
| |
| directions in which the subject has advanced
| |
| in the intervening two decades. These reflect, as they are bound to do, the road taken
| |
| by the science of endocrinology itself, a road
| |
| leading to greater biochemical understanding on the one hand and to ever closer rapprochement with neurophysiology on the
| |
| other.
| |
| | |
| The mammary gland offers unique opportunities of studying the biochemical mechanisms of hormone action because it is an
| |
| organ with quite exceptional synthetic capabilities, an organ which is perhaps the most
| |
| comprehensive hormone target in the mammalian body. Biochemists are entering this
| |
| promising field in increasing numbers and
| |
| we may expect to reap the fruits of their
| |
| labors in the future.
| |
| | |
| VIII. References
| |
| | |
| Abraham, S., Cady, P., and Chaikoff, I. L. 1957.
| |
| Effect of insulin in vitro on pathways of glucose utilization, other than Embden-Meyerhof,
| |
| in rat mammarv gland. J. Biol. Cliem., 224,
| |
| 955-962.
| |
| | |
| Ahren, K. 1959. The effect of various do.^es of
| |
| estrone and progesterone on the mammary
| |
| glands of castrated hypophysectomized rats
| |
| injected with insulin. Acta endocrinol., 30, 435458.
| |
| | |
| Ahren, K., and Etienne, M. 1957. The development of the mammary gland in normal and
| |
| castrated male rats after the age of 21 days.
| |
| Acta physiol. scandinav., 41, 283-300.
| |
| | |
| Ahren, K., .\nd Etienne, M. 1958. Stimulation
| |
| of mammary glands in hypophysectomized
| |
| male rats treated with ovarian hormones and
| |
| insulin. Acta endocrinol., 28, 89-102.
| |
| | |
| Ahren, K., and Jacoksoun, D. 1956. Mammary
| |
| gland growth in hypophy-sectomized rats injected with ovarian hormones and insulin. Ada
| |
| physiol. scandinav., 37, 190-203.
| |
| | |
| Ahren, K., and Jacobsohn, D. 1957. The action
| |
| of cortisone on tlip mammary glands of rats
| |
| | |
| | |
| | |
| imder various states of hormonal imbalance.
| |
| | |
| Acta phy.siol. scandinav., 40, 254-274.
| |
| [Al'tman, a. D.] A.abTMaH, A. JX. 1945. Hsm
| |
| eneHHH b BbiMenn KopoB b nporiecce pasAOH.
| |
| | |
| Vestnik Zhivotn., 1, 85-96.
| |
| Andersson, B. 1951a. Some observations on the
| |
| | |
| neurohormonal regulations of milk ejection.
| |
| | |
| Acta physiol. scandinav., 23, 1-7.
| |
| Andersson, B. 1951b. The effect and localization
| |
| | |
| of electrical stimulation of certain parts of the
| |
| | |
| brain stem in sheep and goats. Acta physiol.
| |
| | |
| scandinav., 23, 8-23.
| |
| Andersson, B. 1951c. Further studies on the milk
| |
| | |
| ejection mechanism in sheep and goats. Acta
| |
| | |
| physiol. scandinav., 23, 24-30.
| |
| Ardran, G. M., Cowie, A. T., .-^nd Kemp, F. H.
| |
| | |
| 1957. A cineradiographic study of the teat
| |
| sinus during suckling in the goat. Vet. Rec, 69,
| |
| 1100-1101.
| |
| | |
| Ardrax, G. M., Cowie. A. T., and Kemp, F. H.
| |
| | |
| 1958. Further obser\ations on the teat sinus
| |
| of the goat during suckling. Vet. Rec, 70, 808809.
| |
| | |
| Ardran, G. M., Kemp, F. H., and Lind. J. 1958a.
| |
| A cineradiographic studv of bottle feeding.
| |
| Brit. J. Radiol., 31, 11-22.
| |
| | |
| Ardr.\n, G. M., Kemp, F. H., .\nd Lind, J. 1958b.
| |
| A cineradiographic studv of breast feeding.
| |
| Brit. J. Radiol., 31, 156-162.
| |
| | |
| Ardran, G. M., and Kemp. F. H. 1959. A correlation between suckling pres-sures and the movements of the tongue. Acta pediat., 48, 261-272.
| |
| | |
| AvERiLL, S. C, R.\Y, E. W., .\ND Lyons, W. R.
| |
| 1950. Maintenance of pregnancy in hypophysectomized rats with placental implants. Proc.
| |
| Soc. Exper. Biol. & Med., 75, 3-6.
| |
| | |
| Bailey, G. L.. B.artlett, S, and Folley, S. J. 1949
| |
| Use of L-thyroxine by mouth for stimulating
| |
| milk secretion in lactating cows. Nature, London, 163, 800.
| |
| | |
| Balinsky. B. I. 1950a. On the prenatal growth
| |
| of the mammarv gland rudiment in the mouse.
| |
| J. Anat., 84, 227-235.
| |
| | |
| Balin.sky. B. I. 1950b. On the doxelopmental
| |
| lirocos.ses in niammary glands and other e\n(Iciinal slmctures. Tr. Roy. Soc. Edinburgh,
| |
| 62, Part 1, 1-31.
| |
| | |
| Balmaix, J. H., Cox, C. P., FoLLEY, S. J., and
| |
| MrNAUfiHT, M. L. 1954. The bioassay of
| |
| insulin in vitro by manometric measurements
| |
| on slices of mammary glands. J. Endocrinol.,
| |
| 11,269-276.
| |
| | |
| Balmain, J. H., AND FoLi.EY, S. J. 1951. Further
| |
| ob.'^ervations on the iti vitro stimulation bv
| |
| insulin of fat synthesis by lactating mammary
| |
| gland slices. Biochem. J., 49, 663-670.
| |
| | |
| Balmain, J. H., Folley, S. J., and Glascock, R. F.
| |
| 1952. Effects of insulin and of glycerol in
| |
| vitro on the incorporation of (carboxy-C)
| |
| acctale into the fatty acids of lactating mammary gland .slicrs with special refoi-(>nce to sjjc.•ics diffcnences. Biochem. J., 52, 301-306.
| |
| | |
| Bar(;.m\\n. \V., and Knoop, A. 1959. Uber die
| |
| Morpliologie der Milchsekretion. Licht- und
| |
| ("Icktroiii'imiikroskopische Studien an der
| |
| | |
| | |
| | |
| MAMMARY GLAND AND LACTATION
| |
| | |
| | |
| | |
| 633
| |
| | |
| | |
| | |
| Milchdriise der Ratte. Ztschr. Zellforsch., 49,
| |
| 344-388.
| |
| | |
| Bartlett, S., Burt, A. W. A., Folley, S. J. and
| |
| Rowland, S. J. 1954. Relative galactopoietic
| |
| effects of 3:5:3-triiodo-L-thyronine and L-thyroxine in lactating cows. J. Endociinol., 10,
| |
| 192-20L
| |
| | |
| [Baryshxikov, L A.] BapMuiHHKOB, H. A. 1957.
| |
| Pe(j|)neKTopHaH pery.TiHUHH JiaKTaunn. In
| |
| npoo,neMbi OnsHO-norHii II,eHTpanbHOH HepBHott CncTeMbi, pp. 62-72. Moscow, Leningrad:
| |
| Akademiya Nauk S.S.S.R. [Complete translation bv F. Lang in Dairy Science Abstracts,
| |
| 21, 47-53, 1959.
| |
| | |
| Beller, F. K., Krumholz, K. H., and Zeininger, K.
| |
| 1958. Vergleichende Oxytocin-Bestimmungen
| |
| gemessen durch den lactagogen Effect der
| |
| Milchdriise. Acta endocrinoL, 29, 1-8.
| |
| | |
| Benson, G. K. 1958. Effect of reserpine on mammary gland involution, and on other organs in
| |
| the rat. Proc. Soc. Exper. Biol. & Med., 99,
| |
| 550-553
| |
| | |
| Benson, G. K., Cowie. A. T., Cox, C. P., Flux, D.
| |
| S., and Folley, S. J. 1955. Studies on the
| |
| hormonal induction of mammary growth and
| |
| lactation in the goat. II. Functional and
| |
| morphological studies of hormonally developed
| |
| udders with special reference to the effect of
| |
| "triggering" doses of oestrogen. J. Endocrinol.,
| |
| 13, 46-58.
| |
| | |
| Benson, G. K., and Cowie, A. T. 1956. Lactation
| |
| in the rat after hypophysial posterior lobectomy. J. Endocrinol., 14, 54-65.
| |
| | |
| Benson, G. K., Cowie, A. T., Cox, C. P., and
| |
| Goldzveig, S. a. 1957. Effects of oestrone and
| |
| progesterone on the mammary de\'eloi)ment
| |
| in the guinea-pig. J. Endocrinol., 15, 126-144.
| |
| | |
| Benson, G. K., Cowie, A. T., Folley, S. J., and
| |
| TiND.-vL, J. S. 1959. Recent developments in
| |
| endocrine studies on mammary growth and
| |
| lactation. In Recent Progress in the Endocrinology oj Reproduction, C. W. Lloyd, Ed.,
| |
| pp. 457-490. New York: Academic Press, Inc.
| |
| | |
| Benson, G. K., Cowie, A. T., and Tindal, J. S.
| |
| 1958. The pituitary and the maintenance of
| |
| milk secretion. Proc. Rov. Soc, London, ser.
| |
| B, 149, 330-336.
| |
| | |
| Benson, G. K., and Folley, S. J. 1956. Oxytocin
| |
| as stimulator for the release of prolactin from
| |
| the anterior pituitary. Nature, London, 177,
| |
| 700.
| |
| | |
| Benson, G. K., and Folley, S. J. 1957a. Retardation of mammary in\olution in the rat by oxytocin. J. Endocrinol., 14, xl.
| |
| | |
| Benson, G. K., and Folley, S. J. 1957b. The effect of oxytocin on mammary gland in\olution
| |
| in the rat" J. Endocrinol., 16,' 189-201.
| |
| | |
| Bilek, J., AND Janovsky, M. 1956. Studium vlivu
| |
| oxytocin na reflex vylucovdni mleka. Sbornik
| |
| Ceskoslov. akad. zemedelskych, ved 29, 773780.
| |
| | |
| Bint.-^rningsih, Lyons, W. R., Johnson, R. E., and
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| Li, C. H. 1957. Hormonal requirement for
| |
| lactation in the hypophysectomized rat. Anat.
| |
| Rec, 127, 266-267.
| |
| | |
| | |
| | |
| BiNT.^RNixGsiH, Lyons, W. R., Johnson, R. E., .-^nd
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| Li, C. H. 1958. Hormonally induced lactation in hypophysectomized rats. Endocrinology, 63, 540-548.
| |
| | |
| Bl.^xter, K. L. 1952. Some effects of thyroxine
| |
| and iodinated casein in dairy cows and their
| |
| practical significance. Vitamins & Hormones,
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| 10, 217-250.
| |
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| Br.\chet, J. 1957. Biochemical Cytology. New
| |
| York : Academic Press, Inc.
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| Bradley, T. R., and Clarke, P. M. 1956. The
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| response of rabbit mammary glands to locally
| |
| administered prolactin. J. Endocrinol., 14, 2836.
| |
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| Bradley, T. R., and Cowie, A. T. 1956. The effects of hypophysectomy on the in vitro metabolism of mammary gland slices from lactating rats. J. Endocrinol., 14, 8-15.
| |
| | |
| Bradley, T. R., and Mitchell, G. M. 1957. The
| |
| in vitro metabolism of mammary gland slices
| |
| in the presence of posterior pituitary lobe extracts rich in melanophore-dispersing activity.
| |
| J. Endocrinol., 15, 366-373.
| |
| | |
| Braude, R. 1954. Pig nutrition. In Progress in
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| the Physiology of Farm Animals, J. Hammond,
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| Ed., Vol. 1, Ch. 2, pp. 40-105. London: Butterworth & Company, Ltd.
| |
| | |
| Braude, R., and Mitchell, K. G. 1952. Observations on the relationship between oxytocin and
| |
| adrenaline in milk ejection in the sow. J. Endocrinol., 8, 238-241.
| |
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| BuscH, D. W. H. 1839. Das Gcschhi lilslol)en des
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| Weibes in physiologischer, pai lidldgischer und
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| therapeutischer Hinsicht. In Phy.siologie und
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| allgemeine Pathologie des weiblichen Geschlechtslebens. Vol. I. Leipzig, F. A. Brockhaus.
| |
| | |
| Campbell, B., and Petersen, W. E. 1953. Milk
| |
| "let-down" and the orgasm in the human female. Human Biol., 25, 165-168.
| |
| | |
| Canivenc, R. 1952. L'activite endocrine du placenta de la ratte. Arch, anat., 34, 105-118.
| |
| | |
| Canivenc, R., and M.-^yer, G. 1953. Nature du
| |
| facteur luteotrophique de placenta de rat.
| |
| Compt. rend. Soc. biol., 147, 1067-1070.
| |
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| Chalmers, J. R., Dickson, G. T., Elks, J., and
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| Hems, B. A. 1949. The synthesis of thyroxine
| |
| and related substances. V. A synthesis of lthyroxine from L-tvrosine. J. Chem. Soc, 34243433.
| |
| | |
| Chen, L. T., Johnson, R. E., Lyons, W. R., Li, C.
| |
| H., AND Cole, R. D. 1955. Hormonally induced mammary growth and lactation in the
| |
| absence of the thvroid. Endocrinology, 57,
| |
| 153-157.
| |
| | |
| Cole, H. A. 1933. The mammary gland of the
| |
| mouse, during the estrous cycle, pregnancy and
| |
| lactation. Proc Roy. Soc, London, ser. B.,
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| 114, 136-160.
| |
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| Cooper, Sir Astley P. 1840. On the Anatomy oj
| |
| the Breast. London: Longmans, Orme, Green,
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| Reineke, E. p., Meites, J., Cairy, C. F., and
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| Huffman, C. F. 1952. Hormonal induction
| |
| of lactation in sterile cows. In Proceedings
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| Annual Meeting American Veterinary Medical
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| Association, 1952, pp. 325-328. Atlantic City:
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| American Veterinary Medical Association.
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| RicH.^RDSON, K. C. 1949. Contractile tissues in
| |
| the mammary gland, with special reference to
| |
| myoepithelium in the goat. Proc. Roy. Soc.
| |
| London, ser. B, 136, 30-45.
| |
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| RiCH.ARDSON, K. C. 1953. Measurements of the
| |
| total area of secretory epithelium in the
| |
| lactating mammary gland of I he goal. J. Endocrinol., 9, 170-184.
| |
| | |
| RiCHTER. J. 1936. Der p]influss der Kastration
| |
| auf die Milch- und Fleischleistung der Kiihe.
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| Berl. tier. Wchnschr., 277-280, 293-298.
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| | |
| RiNOLER, I., Becker, N., and Nelson, W. L. 1954.
| |
| Coenzyme A and diphosphopyridine luicleotide in guinea pig mammary tissue. .\i(li. Biochem. & Biophys., 52, 348-352.
| |
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| RoHKRTsoN, P. A., AND Hawkkr. P. ^V. 1957. A
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| Salter, J., and Best, C. H. 1953. Insulin as a
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| Sawyer, C. H. 1957. Induction of lactation in the
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| Sayers, G., Redgate, E. S., and Royce, P. C. 1958.
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| ])roduced bv neuroseci'etorv cells. Recent Progr.
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| Selye, H., Collip, J. B., and Thomson, D. L. 1934.
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| Ner\'OUS and hormonal factors in lactation.
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| Shaw, J. C. 1955. See Discussion, p. 486-492 in
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| Shimizu, H. 1957. Biochemical studies on the
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| MAMMARY GLAND AND LACTATION
| |
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| 641
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| |
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| 642
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
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| CSopHHK Ji;oKJiajiOB BTopott Bcecoio3Hofi
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| KoHcbepeHunii no MonoHHOMy Jlejiy, R. B.
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| cejibCKOxosHitcTBeHHbix xnBOTHbix. Moscow,
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| ZiETZSCHMANN, 0. 1926. Bau und Funktion der
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| Physiologie der Milch, 2nd ed., W. Grimmer,
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| Ed., p. 1-35. Berlin: Paul Parey.
| |
| | |
| | |
| | |
| =Some Problems of the Metabolism and Mechanism of Action of Steroid Sex Hormones=
| |
| | |
| Claude A. Villee, Ph.D.
| |
| | |
| Associate Professor Of Biological Chemistry, Harvard University
| |
| | |
| | |
| | |
| I. Introduction 643
| |
| | |
| II. The Biosynthesis op Steroids 643
| |
| | |
| A. Cholesterol 644
| |
| | |
| B. Progesterone 644
| |
| | |
| C. Androgens 645
| |
| | |
| D. Estrogens 647
| |
| | |
| E. Biosynthesis of Other Steroids 647
| |
| | |
| F. Interconversions of Steroids 647
| |
| | |
| G. Catabolism of Steroids (548
| |
| | |
| H. Transport, Conjugation, and Excretion 650
| |
| | |
| III. Effects of Sex Hormones on Inter
| |
| mediary Metabolism 650
| |
| | |
| A. Estrogens 652
| |
| | |
| B. Androgens 659
| |
| | |
| C. Progesterone 660
| |
| | |
| IV. References 661
| |
| | |
| I. Intro<luction
| |
| | |
| The chemical structure of the sex hormones, their isohition from biologic materials, and many of their chemical properties were fully described in the previous
| |
| edition of Sex and Internal Secretions (W.
| |
| M. Allen, 1939; Doisy, 1939; Koch, 1939).
| |
| The major steroid sex hormones were isolated and identified 20 to 30 years ago.
| |
| Estrone, in fact, was crystallized from pregnancy urine by Doisy, Veler and Thayer
| |
| (1929) before the true structure of the steroid nucleus was known. The isolation, identification, and chemical synthesis of estradiol, progesterone, and testosterone were
| |
| accomplished during the 1930's. Additional
| |
| substances with androgenic, estrogenic, or
| |
| progestational activity have subsequently
| |
| been isolated from urine or from tissues but
| |
| these are probably metabolites of the major
| |
| | |
| | |
| | |
| sex steroids. The steroids are now routinely
| |
| synthesized from cholesterol or from plant
| |
| sterols. It would be possible to carry out
| |
| the total synthesis of steroids from simple
| |
| precursors but this is not commercially
| |
| practicable.
| |
| | |
| The two decades since the previous edition have been marked by major advances
| |
| in our understanding of the intermediary
| |
| metabolism of steroids — the synthesis of
| |
| cholesterol from two-carbon units, the conversion of cholesterol to pregnenolone and
| |
| progesterone, and the derivation of corticoids, androgens, and estrogens from progesterone. These advances were made possible
| |
| by the development of vastly improved
| |
| methods for the isolation and identification
| |
| of steroids: chromatography on paper or
| |
| columns, counter-current distribution, labeling with radioactive or heavy isotopes,
| |
| infrared spectroscopy, and so on. There have
| |
| been concomitant increases in the information regarding the sites and mechanisms of
| |
| action of these biologically important substances and the means by which they stimulate or inhibit the growth and activity of
| |
| particular tissues of the body. The following
| |
| discussion will attempt to present a general
| |
| picture of these two fields and not an exhaustive citation of the tremendous body of
| |
| relevant literature.
| |
| | |
| II. The Biosynthesis of Steroids
| |
| | |
| When the steroid hormones were first discovered it was generally believed that each endocrine gland made its characteristic
| |
| steroid by some unique biosynthetic mechanism, one that was independent of those in
| |
| other glands. However, there is now abundant evidence that the biosynthetic paths
| |
| in the several steroid-secreting glands have
| |
| many features which are similar or identical.
| |
| | |
| It is now well established that progesterone is not simply a female sex hormone
| |
| produced by the corpus luteum, but a common precursor of adrenal glucocorticoids
| |
| such as Cortisol and adrenal mineralocorticoids such as aldosterone, androgens, and
| |
| estrogens. The adrenal cortex, ovary, testis,
| |
| and placenta have in common many enzymes for the biosynthesis of steroids. Androgenic tumors of the human ovary, for example, have been shown to produce
| |
| testosterone and its metabolites. The transplantation of an ovary into a castrate male
| |
| mouse will result in the maintenance of the
| |
| male secondary sex characters, which suggests that the normal ovary can also synthesize androgens.
| |
| | |
| A. CHOLESTEROL
| |
| | |
| The early work of Bloch (1951), Rilling,
| |
| Tchen and Bloch (1958), and of Popjak
| |
| (1950) showed that labeled acetate is converted to labeled cholesterol. The pattern of
| |
| the labeling present in the cholesterol synthesized from acetate-1-C^^ or acetate-2-C^''
| |
| as precursor led to speculations as to how
| |
| the steroid nucleus is assembled. Further
| |
| work (Langdon and Bloch, 1953) revealed
| |
| that squalene and certain branched-chain,
| |
| unsaturated fatty acids are intermediates
| |
| in this synthesis. The current hypothesis,
| |
| which is supported by a wealth of experimental evidence, states that two moles of
| |
| acetyl coenzyme A condense to form acetoacetyl coenzyme A, which condenses with a
| |
| third molecule of acetyl coenzyme A to form
| |
| yS-hydroxy-^-methyl glutaric acyl coenzyme
| |
| A (Fig. 11.1). The coenzyme A group is
| |
| removed and the hydroxymethyl glutaric
| |
| acid is reduced to mevalonic acid. Mevalonic
| |
| acid, 3-hydroxy-3-methylpentano-5-lactone,
| |
| is metabolized to a 5-carbon isoprenoid
| |
| compound and three moles of these condense
| |
| to form a 1 5-carbon hydrocarbon. The headto-head condensation of two molecules of
| |
| this 15-carbon compound yields the 30
| |
| | |
| | |
| carbon equalene. This is metabolized, by
| |
| way of lanosterol and the loss of three
| |
| methyl groups, to cholesterol, which seems
| |
| to be the common precursor of all of the
| |
| steroid hormones (Tchen and Bloch, 1955;
| |
| Clayton and Bloch, 1956).
| |
| | |
| The question of whether cholesterol is
| |
| an obligate intermediate in the synthesis of
| |
| steroid hormones has not been definitely
| |
| answered. There is clear evidence that cholesterol is converted to steroids without first
| |
| being degraded to small units and subsequently reassembled. Werbin and LeRoy
| |
| (1954) administered cholesterol labeled
| |
| with both carbon-14 and tritium (H^) to
| |
| human subjects and isolated from their
| |
| urine tetrahydrocortisone, tetrahydrocortisol, androsterone, etiocholanolone and 11ketoetiocholanolone. These substances,
| |
| known to be metabolites of steroid hormones, were labeled with both C^^ and H^
| |
| and the labeled atoms were present in the
| |
| ratio expected if they were derived directly
| |
| from cholesterol. Experiments by Dorfman
| |
| and his colleagues (Caspi, Rosenfeld and
| |
| Dorfman, 1956) also provide evidence for
| |
| the synthesis of steroids via cholesterol.
| |
| Cortisol and 11-desoxycortisol were isolated
| |
| from calf adrenals perfused with acetate-1C^^ and from a patient with an adrenal tumor to whom acetate- 1-C^^ had been administered. It is known that cholesterol
| |
| synthesized from acetate-l-C^'* is labeled in
| |
| carbon 20 but not in carbon 21. The Cortisol
| |
| and 11-desoxycortisol also proved to be labeled in carbon 20 but not in carbon 21.
| |
| This evidence does not, of course, exclude
| |
| biosynthetic paths for the steroids other
| |
| than one by way of cholesterol, but it does
| |
| suggest that cholesterol is at least an important precursor of them. Direct evidence
| |
| that cholesterol is synthesized from squalene
| |
| in man is provided by the experiments of
| |
| Eidinoff, Knoll, Marano, Kvamme, Rosenfeld and Hcllman (1958), who prepared tritiated squalene and administered it orally
| |
| to human subjects. They found that the
| |
| cholesterol of the blood achieved maximal
| |
| specific aeti\'ity in 7 to 21 liours.
| |
| | |
| B. PROCiE.STERONE
| |
| | |
| Cholesterol undergoes an oxidative cleavage of its side chain to yield isocaproic
| |
| acid and pregnenolone (Fig. 11.2). The lat
| |
| | |
| | |
| CH3C0-SC0A
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| SCoA
| |
| | |
| | |
| | |
| 645
| |
| | |
| | |
| | |
| CH^CO-SCoA
| |
| | |
| | |
| | |
| Acetyl CoA
| |
| | |
| | |
| | |
| CH3COCH2CO~SCoA
| |
| | |
| | |
| | |
| Acetoacetyl CoA
| |
| | |
| | |
| | |
| Sesquiterpene
| |
| (15C)
| |
| | |
| | |
| | |
| COOH
| |
| | |
| ► HO— C— CHI ^
| |
| | |
| CO-' SCO A
| |
| | |
| pOH-p methylglutaric acyl Co A
| |
| | |
| | |
| | |
| CHg
| |
| | |
| C-CHI
| |
| | |
| CH
| |
| II
| |
| CHo
| |
| | |
| | |
| | |
| Isoprene unit
| |
| (5C)
| |
| | |
| | |
| | |
| CHO
| |
| | |
| I
| |
| | |
| CHo
| |
| I ^
| |
| | |
| HO-C-CH^
| |
| 1 3
| |
| | |
| CHo
| |
| I 2
| |
| COOH
| |
| | |
| Mevalonic acid
| |
| | |
| | |
| | |
| | |
| | |
| | |
| Squalene Lanosterol Cholesterol
| |
| | |
| (30C) (30C) (27C)
| |
| | |
| Fig. 11.1. Biogenesis of cholesterol.
| |
| | |
| | |
| | |
| ter is dehydrogenated in ring A by the
| |
| enzyme 3-^-ol dehydrogenase and a spontaneous shift of the double bond from the
| |
| A5 , 6 to the A4 , 5 position results in progesterone. Progesterone undergoes successive
| |
| hydroxylation reactions, which require molecular oxygen and reduced triphosphopyridine nucleotide (TPNH), at carbons 17,
| |
| 21, and 11. These hydroxylations yield,
| |
| in succession, 17-a-hydroxy progesterone,
| |
| Reichstein's compound S (ll-desoxy-17-hydroxycorticosterone), and Cortisol (17-a-hydroxvcorticosterone) .
| |
| | |
| | |
| | |
| C. ANDROGENS
| |
| | |
| 17-a-Hydroxy progesterone is also the immediate precursor of androgens and estrogens. Oxidative cleavage of its side chain
| |
| yields A-4-androstenedione, which undergoes reduction to testosterone (Fig. 11.2).
| |
| A-4-Androstenedione may be hydroxylated
| |
| at carbon 11 to yield ll-/3-hydroxy-A-4androstenedione, which is an androgen isolated from human urine. It has also been
| |
| found as a metabolite of certain androgenic
| |
| tumors of the adrenal cortex.
| |
| | |
| | |
| | |
| 04 G
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| CH
| |
| | |
| | |
| Y^ .
| |
| | |
| | |
| socaproic C
| |
| | |
| | |
| =0
| |
| | |
| | |
| | |
| | |
| c=o
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| r^
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 0^-OH
| |
| | |
| | |
| ^r^
| |
| | |
| | |
| | |
| | |
| | |
| HO
| |
| | |
| | |
| HO
| |
| | |
| | |
| J
| |
| | |
| | |
| HO
| |
| | |
| | |
| Cholesterol
| |
| | |
| | |
| Pregnenolone
| |
| | |
| | |
| 17-Hydr
| |
| | |
| | |
| oxy
| |
| | |
| Dehydroepi
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| preg
| |
| | |
| | |
| nenolone
| |
| | |
| | |
| androsterone
| |
| | |
| | |
| CH3
| |
| | |
| | |
| | |
| | |
| | |
| | |
| CH3
| |
| | |
| | |
| | |
| | |
| f3
| |
| | |
| | |
| H-C-OH
| |
| 1
| |
| | |
| | |
| , f
| |
| | |
| | |
| c=o
| |
| | |
| 1
| |
| | |
| | |
| | |
| | |
| 1
| |
| | |
| c=o
| |
| | |
| 1
| |
| | |
| | |
| ^ ■
| |
| | |
| | |
| | |
| | |
| -x^V
| |
| | |
| | |
| t^
| |
| | |
| | |
| | |
| | |
| ^XP""°"
| |
| | |
| | |
| r^^
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ^^<Y
| |
| | |
| | |
| „ijj
| |
| | |
| | |
| - \^Xaj
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| JJ
| |
| | |
| | |
| A -3- Ketopregnene
| |
| | |
| | |
| Progest
| |
| | |
| | |
| erone
| |
| | |
| | |
| 17
| |
| | |
| | |
| -Hydroxy
| |
| | |
| 20-oc-ol
| |
| | |
| | |
| y
| |
| | |
| | |
| | |
| | |
| y
| |
| | |
| | |
| progesterone
| |
| | |
| | |
| CH^OH
| |
| | |
| | |
| X
| |
| | |
| | |
| CH OH
| |
| | |
| | |
| /
| |
| | |
| | |
| | |
| | |
| | |
| | |
| c=o
| |
| | |
| | |
| | |
| | |
| | |
| | |
| 1
| |
| | |
| c=o
| |
| | |
| | |
| | |
| | |
| "
| |
| | |
| | |
| | |
| | |
| Desoxy—
| |
| corticosterone
| |
| | |
| | |
| | |
| CH2OH
| |
| c=o
| |
| | |
| | |
| | |
| 1 7- Hydroxy desoxycorticosterone
| |
| (Reichstein's "S")
| |
| | |
| | |
| | |
| | |
| | |
| CH^OH
| |
| HCO C=0
| |
| | |
| | |
| | |
| .JOJ
| |
| | |
| | |
| | |
| CH^OH
| |
| | |
| c=o
| |
| | |
| | |
| | |
| A -androstenedione
| |
| | |
| | |
| | |
| OH
| |
| | |
| | |
| | |
| | |
| | |
| o ' -- o
| |
| | |
| Corticosterone 18-aldo- 11- desoxy- Cortisol Testosterone
| |
| | |
| corticosterone (Kendall's
| |
| | |
| Cmpd. "F")
| |
| | |
| | |
| | |
| HCO C=0
| |
| | |
| | |
| | |
| | |
| 19 -Hydroxy- ^■^■
| |
| androstenedione
| |
| | |
| | |
| | |
| .;^
| |
| | |
| | |
| | |
| | |
| Aldosterone
| |
| | |
| | |
| | |
| HO
| |
| | |
| Estradiol
| |
| Fig. 11.2. Biosynthetic paths from cholesterol.
| |
| | |
| | |
| | |
| | |
| Estrone
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 647
| |
| | |
| | |
| | |
| D. ESTROGENS
| |
| | |
| A-4-Androstenedione and testosterone are
| |
| precursors of the estrogens. Baggett, Engel,
| |
| Savard and Dorfman (1956) demonstrated
| |
| the conversion of testosterone to estradiol17/? by slices of human ovary. Ryan (1958)
| |
| found that the enzymes to carry out this
| |
| conversion are also present in the human
| |
| placenta, located in the microsomal fraction
| |
| of placental homogenates. Homogenates of
| |
| stallion testis convert labeled testosterone
| |
| to labeled estradiol and estrone. Slices of
| |
| human adrenal cortical carcinoma also have
| |
| been shown to convert testosterone to estradiol and estrone, and Nathanson, Engel
| |
| and Kelley (1951) found an increased urinary excretion of estradiol, estrone, and estriol following the administration of adrenocorticotrophic hormone to castrate women.
| |
| Thus it seems that ovary, testis, placenta,
| |
| and adrenal cortex have a similar biosynthetic mechanism for the production of estrogens and androgens. The first step in
| |
| the conversion of testosterone or A-4-androstenedione to estrogens is the hydroxylation
| |
| at carbon 19, again by an enzymatic process
| |
| which requires molecular oxygen and
| |
| TPNH. Meyer (1955) first isolated and
| |
| characterized 19-hydroxy-A-4-androstene3,17-dione from a perfused calf adrenal.
| |
| When this was incubated with dog placenta
| |
| it was converted to estrone. The steps in the
| |
| conversion of the 19-hydroxy-A-4-androstenedione to estrone appear to be the introduction of a second double bond into ring
| |
| A, the elimination of carbon 19 as formaldehyde, and rearrangement to yield a
| |
| phenolic ring A. The requirements for the
| |
| aromatization of ring A by a microsomal
| |
| fraction of human placenta were studied by
| |
| Ryan (1958). West, Damast, Sarro and
| |
| Pearson (1956) found that the administration of testosterone to castrated, adrenalectomized women resulted in an increased
| |
| excretion of estrogen. This suggests that
| |
| tissues other than adrenals and gonads, presumably the liver, can carry out this same
| |
| series of reactions.
| |
| | |
| E. BIOSYNTHESIS OF OTHER STEROIDS
| |
| | |
| To complete the picture of the interrelations of the biosyntheses of steroids, it
| |
| should be noted that other evidence shows
| |
| | |
| | |
| | |
| that progesterone is hydroxylated at carbon
| |
| 21 to yield desoxycorticosterone and this is
| |
| subsequently hydroxylated at carbon 11 to
| |
| yield corticosterone. Desoxycorticosterone
| |
| may undergo hydroxylation at carbon 18
| |
| and at carbon 11 to yield aldosterone, the
| |
| most potent salt-retaining hormone known
| |
| (Fig. 11.2).
| |
| | |
| Dehydroepiandrosterone is an androgen
| |
| found in the urine of both men and women.
| |
| Its rate of excretion is not decreased on
| |
| castration and it seems to be synthesized
| |
| only by the adrenal cortex. It has been
| |
| postulated that pregnenolone is converted
| |
| to 17-hydroxy pregnenolone and that this,
| |
| by cleavage of the side chain between carbon 17 and carbon 20, would yield dehydroepiandrosterone.
| |
| | |
| F. INTERCONVERSIONS OF STEROIDS
| |
| | |
| The interconversion of estrone and estradiol has been shown to occur in a number
| |
| of human tissues. A diphosphopyridine nucleotide-linked enzyme, estradiol- 17/3 dehydrogenase, which carries out this reaction
| |
| has been prepared from human placenta
| |
| and its properties have been described by
| |
| Langer ancl Engel (1956). The mode of
| |
| formation of estriol and its isomer, 16-epiestriol, is as yet unknown.
| |
| | |
| There are three major types of reactions
| |
| which occur in the interconversions of the
| |
| steroids: dehydrogenation, "hydroxylation,"
| |
| and the oxidative cleavage of the side chain.
| |
| An example of a dehydrogenation reaction
| |
| is the conversion of pregnenolone to progesterone by the enzyme 3-/3-ol dehydrogenase,
| |
| which requires diphosphopyridine nucleotide (DPN) as hydrogen acceptor. This important enzyme, which is involved in the
| |
| synthesis of progesterone and hence in the
| |
| synthesis of all of the steroid hormones, is
| |
| found in the adrenal cortex, ovary, testis,
| |
| and placenta. Other dehydrogenation reactions in which DPN is the usual hydrogen
| |
| acceptor are the readily reversible conversions of A-4-androstenedione ^ testosterone, estrone ^ estradiol, and progesterone
| |
| :;^ A-4-3-ketopregnene-20-a-ol. This latter
| |
| substance, and the enzymes producing it
| |
| from progesterone, have been found by Zander (1958) in the human corpus luteum and
| |
| placenta.
| |
| | |
| The oxidative reactions leading to the
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| introduction of an OH group on the steroid
| |
| nucleus are usually called "hydroxylations."
| |
| Specific hydroxylases for the introduction
| |
| of an OH group at carbons 11, 16, 17, 21, 18,
| |
| and 19 have been demonstrated. All of these
| |
| require molecular oxygen and a reduced
| |
| pyridine nucleotide, usually TPNH. The
| |
| ll-/3-hydroxylase of the adrenal cortex has
| |
| been shown to be located in the mitochondria (Hayano and Dorfman, 1953) . Experiments with this enzyme system, utilizing
| |
| oxygen 18, showed that the oxygen atoms
| |
| are derived from gaseous oxygen and not
| |
| from the oxygen in the water molecules
| |
| (Hayano, Lindberg, Dorfman, Hancock and
| |
| Doering, 1955). Thus this hydroxylation reaction also involves the reduction of molecular oxygen.
| |
| | |
| The oxidative cleavage of the side chains
| |
| of the steroid molecule appears to involve
| |
| similar hydroxylation reactions. The experiments of Solomon, Levitan and Lieberman
| |
| (1956) indicate that the conversion of cholesterol to pregnenolone involves one and
| |
| possibly two of these hydroxylation reactions, with the introduction of OH groups
| |
| at carbons 20 and 22 before the splitting off
| |
| of the isocaproic acid.
| |
| | |
| In summary, this newer knowledge of the
| |
| biosynthetic paths of steroids has revealed
| |
| that the differences between the several
| |
| steroid-secreting glands are largely quantitative rather than qualitative. The testis,
| |
| for example, produces progesterone and
| |
| estrogens in addition to testosterone. The
| |
| change from the secretion of estradiol by
| |
| the follicle to the secretion of progesterone
| |
| by the corpus luteum can be understood as
| |
| a relative loss of activity of an enzyme in
| |
| the path between progesterone and estradiol.
| |
| If, for example, the enzyme for the 17-hydroxylation of progesterone became inactive
| |
| as the follicle cells are changed into the
| |
| corpus luteum, progesterone rather than
| |
| estradiol would subsequently be produced.
| |
| | |
| Knowledge of these pathways also provides an explanation for certain abnormal
| |
| changes in the functioning of the glands.
| |
| Bongiovnnni (1953) and Jailer (1953)
| |
| showed that the adrenogenital syndrome
| |
| results from a loss of an enzyme or enzymes
| |
| for the hydroxylation reactions at carbons
| |
| 21 and 11 of progesterone, which results in
| |
| an impairment in the production of Cortisol.
| |
| | |
| | |
| | |
| The pituitary, with little or no Cortisol to
| |
| inhibit the secretion of adrenocorticotrophic
| |
| hormone (ACTH), produces an excess of
| |
| this hormone which stimulates the adrenal
| |
| to produce more steroids. There is an excretion of the metabolites of progesterone
| |
| and 17-hydroxy progesterone, pregnanediol
| |
| and pregnanetriol respectively, but some of
| |
| the 17-hydroxy progesterone is converted to
| |
| androgens and is secreted in increased
| |
| amount.
| |
| | |
| G. CATABOLISM OF STEROmS
| |
| | |
| Many of the steroid hormones are known
| |
| to act on the pituitary to suppress its secretion of the appropriate trophic hormone,
| |
| ACTH, the follicle-stimulating hormone
| |
| (FSH), or luteinizing hormone (LH). It
| |
| would seem that the maintenance of the
| |
| proper feedback mechanism between steroid-secreting gland and pituitary requires
| |
| that the steroids be continuously inactivated
| |
| and catabolized. The catabolic reactions of
| |
| the steroids are in general reductive in nature and involve the reduction of ketonic
| |
| groups and the hydrogenation of double
| |
| bonds. The reduction of a ketonic group to
| |
| an OH group can lead to the production of
| |
| two different stereoisomers. If the OH group
| |
| projects from the steroid nucleus on the
| |
| same side as the angular methyl groups
| |
| at carbon 18 and carbon 19, i.e., above the
| |
| plane of the four rings, it is said to have
| |
| the yS-configuration and is represented by a
| |
| heavy line. If the OH projects on the opposite side of the steroid nucleus, below
| |
| the plane of the four rings, it is said to
| |
| have the a-configuration and is represented
| |
| by a dotted line. Although both isomers are
| |
| possible, usually one is formed to a much
| |
| greater extent than the other.
| |
| | |
| The first catabolic step is usually the
| |
| reduction of the A4-3-ketone group of ring
| |
| A, usually to 3aOH compounds with the
| |
| hydrogen at carbon 5 attached in the /3configuration. The 5/3-configuration represents the CIS configuration of rings A and B.
| |
| The elimination of the A4-3-ketone group
| |
| greatly decreases the biologic activity of
| |
| the steroid and increases somewhat its solubility in water. This reductive process occurs largely in the liver. Progesterone is
| |
| converted by reduction of its A4-3-ketone
| |
| group to pregnane-3a:20a-diol, and 17-hy
| |
| | |
| | |
| STEROID SEX HORMONES 649
| |
| | |
| EXCRETORY PRODUCTS
| |
| | |
| | |
| | |
| c=o
| |
| | |
| | |
| | |
| | |
| Progesterone
| |
| | |
| | |
| | |
| 1 3
| |
| | |
| HCOH
| |
| | |
| | |
| | |
| | |
| HO H
| |
| | |
| Pregnanediol
| |
| | |
| | |
| | |
| CH,
| |
| | |
| | |
| | |
| | |
| -OH
| |
| | |
| | |
| | |
| 17 Hydroxy progesterone
| |
| | |
| | |
| | |
| CH,
| |
| | |
| | |
| | |
| ^ H-C-OH
| |
| | |
| ■OH
| |
| | |
| | |
| | |
| | |
| HO H
| |
| | |
| Pregnanetriol
| |
| | |
| | |
| | |
| OH
| |
| | |
| | |
| | |
| | |
| | |
| Testosterone
| |
| | |
| | |
| | |
| | |
| Androsterone
| |
| | |
| | |
| | |
| HO
| |
| | |
| | |
| | |
| | |
| /
| |
| | |
| | |
| | |
| androstenedione
| |
| | |
| | |
| | |
| | |
| HO H
| |
| | |
| Etiocholanolone
| |
| | |
| | |
| | |
| Dehydroepiandrosterone
| |
| | |
| Fk;. 11.3. Excretory products of progesterone and androgen
| |
| | |
| | |
| | |
| (Iroxy progesterone is converted to pregnane3a:17a:20a-triol (Fig. 11.3). Testosterone
| |
| and dehydrocpiandroesterone are both converted to A4-androstenedione and the reduction of its A4-3-ketone group results in a
| |
| mixture of androsterone (3a,5a-configuration) and ctiochohmolone (3a,5/?-configuration ) .
| |
| | |
| | |
| | |
| The catabohsm of estradiol is not completely known. Estradiol, estrone, and estriol are found in the urine but they account
| |
| for less than half of an administered dose of
| |
| labeled estradiol. The /3-isomer, 16-epiestriol, and two other phenolic steroids, 16-ahydroxy estrone and 2-methoxyestrone,
| |
| have recently been isolated from normal
| |
| | |
| | |
| | |
| 650
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| urine and are known to be estrogen metabolites (Marrian and Bauld, 1955).
| |
| | |
| H. TRANSPORT, CONJUGATION, AND EXCRETION
| |
| | |
| Steroids circulate in the blood in part as
| |
| free steroids and in part conjugated with
| |
| sulfate or glucuronic acid (c/. review by
| |
| Roberts and Szego, 1953b j . The steroids are
| |
| generally conjugated by the hydroxy 1 group
| |
| at carbon 3 with inorganic sulfate or with
| |
| glucuronic acid. In addition, either the conjugated or nonconjugated forms may be
| |
| bound to certain of the plasma proteins such
| |
| as the ^-globulins (Levedahl and Bernstein,
| |
| 1954) . There is evidence of specific binding
| |
| of certain steroids with particular proteins,
| |
| e.g., the binding of Cortisol to "transcortin"
| |
| (Daughaday, 1956). Between 50 and 80 per
| |
| cent of the estrogens in the blood are present closely bound to plasma proteins. A
| |
| similar large fraction of the other steroid
| |
| hormones is bound to plasma proteins ; presumably this prevents the hormone from being filtered out of the blood as it passes
| |
| through the glomerulus of the kidney. The
| |
| steroids excreted in the urine are largely in
| |
| the conjugated form, as sulfates or glucuronides.
| |
| | |
| The liver plays a prime role in the catabolism of the steroids. It is the major site
| |
| of the reductive inactivation of the steroids
| |
| and their conjugation with sulfate or glucuronic acid. These conjugated forms are more
| |
| water-soluble and the conjugation probably
| |
| promotes their excretion in the urine. Rather
| |
| large amounts of certain steroids, notably
| |
| estrogens, are found in the bile of certain
| |
| species. These estrogens are free, not conjugated; the amount of estrogens present
| |
| in the bile suggests that this is an important pathway by which they are excreted. It has been suggested that the bacteria of the gastrointestinal tract may
| |
| degrade the steroids excreted in the bile and
| |
| further that there is an "enterohepatic circulation" of steroids with reabsorption
| |
| from the gut, transport in the portal system
| |
| to the liver, and further degradation within
| |
| the liver cells.
| |
| | |
| III. Effects of Sex Hormones on
| |
| Intermediary Metabolism
| |
| | |
| The literature concerning the effects of
| |
| hormones on intermediary metabolism is
| |
| | |
| | |
| | |
| voluminous and contains a number of contradictions, some of which are real and
| |
| some, perhaps, are only apparent contradictions. Evidence that a hormone acts at one
| |
| site does not necessarily contradict other
| |
| evidence that that hormone may act on a
| |
| different metabolic reaction. From the following discussion it should become evident
| |
| that there may be more than one site of
| |
| action, and more than one mechanism of
| |
| action, of any given hormone.
| |
| | |
| The hormones are so different in their
| |
| chemical structure, proteins, peptides,
| |
| amino acids, and steroids, that it would
| |
| seem unlikely, a priori, that they could all
| |
| influence the cellular machinery by comparable means. The basic elements of an
| |
| enzyme system are the protein enzyme, its
| |
| cofactors and activators, and the substrates
| |
| and products. A hormone might alter the
| |
| over-all rate of an enzyme system by altering the amount or activity of the protein
| |
| enzyme, or by altering the availability to
| |
| the enzyme system of some cofactor or substrate molecule. Some of the mechanisms
| |
| of hormone action which have been proposed are these. (1) The hormone may alter
| |
| the rate at which enzyme molecules are
| |
| produced de novo by the cell. (2) The hormone may alter the activity of a preformed
| |
| enzyme molecule, i.e., it may convert an
| |
| inactive form of the enzyme to an active
| |
| form. (3) The hormone may alter the permeability of the cell membrane or the
| |
| membrane around one of the subcellular
| |
| structures within the cell and thus make
| |
| substrate or cofactor more readily available
| |
| to the enzyme. Or, (4) the hormone may
| |
| serve as a coenzyme in the system, that is,
| |
| it may be involved in some direct fashion
| |
| as a partner in the reaction mediated by the
| |
| enzyme. Each of these theories has been
| |
| advanced to explain the mode of action of
| |
| the sex hormones.
| |
| | |
| The problem of the hormonal control of
| |
| metabolism has been investigated at a variety of biologic levels. The earliest experiments were done by injecting a hormone
| |
| into an intact animal and subsequently
| |
| measuring the amount of certain constituents of the blood, urine, or of some tissue.
| |
| There are several difficulties with such experiments. All of the homeostatic mechanisms of the animal operate to keep condi
| |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 651
| |
| | |
| | |
| | |
| tions constant and to minimize the effects
| |
| of the injected hormone. In addition, there
| |
| is a maze of interactions, some synergistic
| |
| and some antagonistic, between the different
| |
| hormones both in the endocrine gland and
| |
| in the target organs, so that the true effect
| |
| of the substance injected may be veiled. Our
| |
| growing understanding of the interconversions of the steroid hormones warns us that
| |
| an androgen, for example, may be rapidly
| |
| converted into an estrogen, and the metabolic effects observed on the administration
| |
| of an androgen may, at least in part, result
| |
| from the estrogens produced from the injected androgen.
| |
| | |
| To eliminate some of the confusing effects
| |
| of these homeostatic mechanisms some investigators remove the liver, kidneys, and
| |
| other viscera before injecting the hormone
| |
| under investigation. Such eviscerated preparations have been used by Levine and his
| |
| colleagues in their investigations of the
| |
| mode of action of insulin (c/. Levine and
| |
| Goldstein, 1955).
| |
| | |
| Other investigators have incubated slices
| |
| of liver, kidney, muscle, endocrine glands,
| |
| or other tissues in glass vessels in a chemically defined medium and at constant temperature. Such experiments have the advantage that metabolism can be studied
| |
| more directly, oxygen consumption and carbon dioxide production can be measured
| |
| manonietrically, and aliquots of the incubation medium can be withdrawn for chemical
| |
| and radiochemical analyses. The amounts of
| |
| substrate, cofactors, and hormone present
| |
| can be regulated and the interfering effects
| |
| of other hormones and of other tissues are
| |
| eliminated. Theoretically, working with a
| |
| simpler system such as this should lead to
| |
| greater insight into the physiologic and
| |
| chemical events that occur when a hormone
| |
| is added or deleted. The chief disadvantage
| |
| of this experimental system is that it is
| |
| difficult to prove that the conditions of the
| |
| experiment are "physiologic." With tissue
| |
| slices there is the possibility that the cut
| |
| edges of the cells may introduce a sizeable
| |
| artifact. Kipnis and Cori (1957) found that
| |
| the rat diaphragm, as it is usually prepared
| |
| for experiments in vitro, has an abnormally
| |
| large extracellular space and is more permeable to certain pentoses than is the intact
| |
| diaphragm.
| |
| | |
| | |
| | |
| It has been postulated that a hormone
| |
| may influence the metabolism of a particular cell by altering the permeability of the
| |
| cell membrane or of the membrane around
| |
| one of the subcellular particles. Experiments
| |
| with tissue homogenates, in which the cell
| |
| membrane has been ruptured and removed,
| |
| provide evidence bearing on such theories.
| |
| If an identical hormone effect can be obtained in a cell-free system, and if suitable
| |
| microscopic controls show that the system is indeed cell-free, the permeability
| |
| theory may be ruled out.
| |
| | |
| Ideally the hormone effect should be
| |
| studied in a completely defined system,
| |
| with a single crystalline enzyme, known
| |
| concentration of substrates and cofactors,
| |
| and with known concentration of the pure
| |
| hormone. Colowick, Cori and Slein (1947)
| |
| reported that hexokinase extracted from
| |
| diabetic muscle has a lower rate of activity
| |
| than hexokinase from normal muscle and
| |
| that it could be raised to the normal rate
| |
| by the addition of insulin in vitro. The
| |
| reality of this effect has been confirmed by
| |
| some investigators and denied by others
| |
| who were unable to repeat the observations.
| |
| Cori has suggested that the decreased rate
| |
| of hexokinase activity in the diabetic results from a labile inhibitor substance produced by the pituitary. Krahl and Bornstein
| |
| (1954) have evidence that this inhibitor is
| |
| a lipoprotein which is readily inactivated
| |
| by oxidation.
| |
| | |
| The two hormones whose effects can be
| |
| demonstrated reproducibly in an in vitro
| |
| system at concentrations in the range which
| |
| obtains in the tissues are epinephrine (or
| |
| glucagon) and estradiol (and other estrogens) . Epinephrine or glucagon stimulates
| |
| the reactivation of liver phosphorylase by
| |
| increasing the concentration of adenosine3'-5'-monophosphate (Haynes, Sutherland
| |
| and Rail, 1960), and estrogens stimulate an
| |
| enzyme system found in endometrium,
| |
| placenta, ventral i)rostate of the rat, and
| |
| mammary gland. The estrogen-stimulable
| |
| enzyme was originally described as a DPNlinked isocitric dehydrogenase, but the estrogen-sensitive enzyme now appears to be
| |
| a transhydrogenase which transfers hydrogens from TPN to DPN (Talalay and Williams-x\shman, 1958; Yillee and Hngerman,
| |
| 1958).
| |
| | |
| | |
| | |
| 052
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| The various tissues of the body respond in
| |
| quite different degrees to the several hormones. This difference in response is especially marked with the sex hormones.
| |
| Those tissues which respond dramatically
| |
| to the administration of a hormone are
| |
| termed the "target organs" of that hormone. Just what, at the cellular level, differentiates a target organ from the other
| |
| tissues of the body is not known exactly
| |
| but there is evidence that each kind of tissue is characterized by a certain pattern of
| |
| enzymes. The pattern of enzymes is established, by means as yet unknown, in the
| |
| course of embryonic differentiation. The
| |
| enzyme glucose 6-phosphatase, which hydrolyzes glucose 6-phosphate and releases
| |
| free glucose and inorganic phosphate, is
| |
| present in liver but absent from skeletal
| |
| muscle. Even though a given reaction in
| |
| two different tissues may be mediated by
| |
| what appears to be the same enzyme, the
| |
| enzymes may be different and subject to
| |
| different degrees of hormonal control. Henion and Sutherland (1957) showed that the
| |
| phosphorylase of liver responds to glucagon
| |
| but the phosphorylase of heart muscle does
| |
| not. Further, the two enzymes are immunologically distinct. An antiserum to purified
| |
| liver phosphorylase will not react with heart
| |
| phosphorylase to form an inactive antigenantibody precipitate, but it does react in
| |
| this manner with liver phosphorylase. Further, perhaps more subtle, differences between comparable enzymes from different
| |
| tissues have appeared when lactic dehydrogenases from liver, heart, skeletal muscle,
| |
| and other sources were tested for their rates
| |
| of reaction with the several analogues of the
| |
| pyridine nucleotides now available (Kaplan. Ciotti, Hamolsky and Bicbcr, 1960).
| |
| p]xtension of this technique may reveal differences in response to added hormones.
| |
| | |
| In addition to these differences in the response to a hormone of the tissues of a
| |
| single animal, there may be differences in
| |
| the response of the comparable tissues of
| |
| different species to a given dose of hormone.
| |
| Estrone, estriol, and other estrogens have
| |
| different potencies relative to estradiol in
| |
| different species of mammals. There are
| |
| slight differences in the amino acid sequences of the insulins and vasopressins
| |
| from flifferent species and quite marked
| |
| | |
| | |
| | |
| differences in the chemical structure (Li and
| |
| Papkoff, 1956) and physiologic activity
| |
| (Knobil, Morse, Wolf and Greep, 1958)
| |
| of the pituitar}^ growth hormones of cattle
| |
| and swine, on the one hand, and of primates, on the other.
| |
| | |
| A. ESTROGENS
| |
| | |
| The amount or activity of certain enzymes in the target organs of estrogens
| |
| has been found to vary with the amount of
| |
| estrogen present. Examples of this phenomenon are /^-glucuronidase (Odell and
| |
| Fishman, 1950) , fibrinolysin (Page, Glendening and Parkinson, 1951), and alkaline
| |
| glycerophosphatase (Jones, Wade, and
| |
| Goldberg, 1953). Kochakian (1947) reported that the amount of arginase in the
| |
| rat kidney increased after the injection of
| |
| estrogens. Enzyme activity is increased by
| |
| other hormones as well; for example, progesterone has been found to increase the
| |
| activity of phosphorylase (Zondek and
| |
| Hestrin, 1947) and of adenosine triphosphatase (Jones, Wade, and Goldberg, 1952).
| |
| | |
| In most experiments the amount of enzyme present has been inferred from its
| |
| activity, measured chemically or histochemically under conditions in which the
| |
| amount of enzyme is rate-limiting. This
| |
| does not enable one to distinguish between
| |
| an actual increase in the number of molecules of enzyme present in the cell and an
| |
| increase in the activity of the enzyme molecules without change in their number. A
| |
| few enzymes can be measured by some
| |
| other property, such as absorption at a
| |
| specific wavelength, by which the actual
| |
| amount of enzyme can be estimated (see
| |
| review by Knox, Auerbach, and Lin, 1956).
| |
| Knox and Auerbach (1955) found that the
| |
| activity of the enzyme tryptophan peroxidase-oxidase (TPO) of the liver was
| |
| decreased in adrenalectomized animals and
| |
| increased by the administration of cortisone. Knox had shown previously that
| |
| th(> administration of the substrate of
| |
| the enzyme, tryptophan, would lead
| |
| to an increase in the activity of the enzyme which was maximal in 6 to 10
| |
| hours. Evidence that the increased activity
| |
| of enzyme following the administration of
| |
| cortisone represents the synthesis of new
| |
| protein molecules is supplied by experi
| |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 653
| |
| | |
| | |
| | |
| ments in which it was found that the increase in enzyme activity is inhibited by
| |
| ethionine and this inhibition is reversed
| |
| by methionine. The amino acid analogue
| |
| ethionine is known to inhibit protein synthesis and this inhibition of protein synthesis is overcome by methionine.
| |
| | |
| The injection of estrogen into the immature or castrate rodent produces a striking uptake of water by the uterus followed
| |
| by a marked increase in its dry weight
| |
| (Astwood, 1938). Holden (1939) postulated that the imbibition of water results
| |
| from vasodilatation and from changes in the
| |
| permeability of the blood vessels of the
| |
| uterus. There is clear evidence (Mueller,
| |
| 1957) that the subsequent increase in dry
| |
| weight is due to an increased rate of synthesis of proteins and nucleic acids. The
| |
| sex hormones and other steroids could be
| |
| pictured as reacting with the protein or
| |
| lipoprotein membrane around the cell or
| |
| around some subcellular structure like a
| |
| surface-wetting agent and in this way inducing a change in the permeability of the
| |
| membrane. This might then increase the
| |
| rate of entry of substances and thus alter
| |
| the rate of metabolism within the cell.
| |
| This theory could hardly account for the
| |
| many notable specific relationships between
| |
| steroid structure and biologic activity.
| |
| Spaziani and Szego (1958) postulated that
| |
| estrogens induce the release of histamine in
| |
| the uterus and the histamine then alters the
| |
| permeability of the blood vessels and produces the imbibition of water secondarily.
| |
| | |
| The uterus of the ovariectomized rat is
| |
| remarkably responsive to estrogens and
| |
| has been widely used as a test system.
| |
| After ovariectomy, the content of ribonucleic acid of the uterus decreases to a
| |
| low level and then is rapidly restored after
| |
| injection of estradiol (Telfer, 1953). A
| |
| single injection of 5 to 10 yu,g. of estradiol
| |
| brings about (1) the hyperemia and water
| |
| imbibition described previously; (2) an
| |
| increased rate of over-all metabolism as
| |
| reflected in increased utilization of oxygen
| |
| (David, 1931; Khayyal and Scott, 1931;
| |
| Kerly, 1937; MacLeod and Reynolds, 1938;
| |
| Walaas, Walaas and Loken, 1952a; Roberts
| |
| and Szego, 1953a) ; (3) an increased rate
| |
| of glycolysis (Kerly, 1937; Carroll, 1942;
| |
| Stuermer and Stein, 1952; Walaas, Walaas
| |
| | |
| | |
| | |
| and Loken, 1952b; Roberts and Szego,
| |
| 1953a) ; (4) an increased rate of utilization
| |
| of phosphorus (Grauer, Strickler, Wolken
| |
| and Cutuly, 1950; Walaas and Walaas,
| |
| 1950) ; and (5) tissue hypertrophy as reflected in increased dry weight (Astwood,
| |
| 1938), increased content of ribonucleic acid
| |
| and protein (Astwood, 1938; Telfer, 1953;
| |
| Mueller, 1957), and finally, after about
| |
| 72 hours, an increased content of desoxyribonucleic acid (Mueller, 1957).
| |
| | |
| An important series of experiments by
| |
| Mueller and his colleagues revealed that
| |
| estrogens injected in vivo affect the metabolism of the uterus which can be detected
| |
| by subsequent incubation of the uterus in
| |
| vitro with labeled substrate molecules.
| |
| Mueller (1953) first showed that pretreatment with estradiol increases the rate
| |
| of incorporation of glycine-2-C^'* into uterine protein. He then found that estrogen
| |
| stimulation increases that rate of incorporation into protein of all other amino acids
| |
| tested: alanine, serine, lysine, and tryptophan. The peak of stimulation occurred
| |
| about 20 hours after the injection of estradiol. In further studies (Mueller and Herranen, 1956) it was found that estrogen
| |
| increases the rate of incorporation of glycine-2-C^^ and formate-2-C^'* into protein,
| |
| lipid, and the purine bases, adenine and
| |
| guanine, of nucleic acids. A stimulation of
| |
| cholesterol synthesis in the mouse uterus
| |
| 20 hours after administration of estradiol
| |
| was shown by Emmelot and Bos (1954).
| |
| | |
| In more detailed studies of the effects of
| |
| estrogens on the metabolism of "one-carbon
| |
| units" Herranen and Mueller (1956) found
| |
| that the incorporation of serine-3-C^'* into
| |
| adenine and guanine was stimulated by
| |
| pretreatment with estradiol. The incorporation was greatly decreased when unlabeled
| |
| formate was added to the reaction mixture
| |
| to trap the one-carbon intermediate. In
| |
| contrast, the incorporation of C^^02 into
| |
| uridine and thymine by the surviving uterine segment was not increased by pretreatment with estradiol in vivo (Mueller,
| |
| 1957).
| |
| | |
| To delineate further the site of estrogen
| |
| effect on one-carbon metabohsm, Herranen
| |
| and Mueller (1957) studied the effect of
| |
| estrogen pretreatment on serine aldolase,
| |
| the enzyme which catalyzes the equilibrium
| |
| | |
| | |
| | |
| 654
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| between serine and glycine plus an active
| |
| one-carbon unit. They found that serine
| |
| aldolase activity, measured in homogenates of rat uteri, increased 18 hours after
| |
| pretreatment in vivo with estradiol. It
| |
| seemed that the estrogen-induced increase
| |
| in the activity of this enzyme might explain
| |
| at least part of the increased rate of onecarbon metabolism following estrogen injection. They found, however, that incubation of uterine segments in tissue culture
| |
| medium (Eagle, 1955) for 18 hours produced a marked increase in both the activity
| |
| of serine aldolase and the incorporation of
| |
| glycine-2-C^'* into protein. The addition of
| |
| estradiol to Eagle's medium did not produce
| |
| a greater increase than the control to
| |
| which no estradiol was added. Uterine segments taken from rats pretreated with estradiol for 18 hours, with their glycine-incorporating system activated by hormonal
| |
| stimulation, showed very little further
| |
| stimulation on being incubated in Eagle's
| |
| medium for 18 hours. With a shorter period
| |
| of i^retreatment with estradiol, greater stimulation occurred on subsequent incubation
| |
| in tissue culture fluid. These experiments
| |
| suggest that the hormone and the incubation in tissue culture medium are affecting
| |
| the same process, one which has a limited
| |
| capacity to respond. When comparable experiments were performed with other
| |
| labeled amino acids as substrates, similar
| |
| results were obtained.
| |
| | |
| Mueller's work gave evidence that a considerable number of enzyme systems in the
| |
| uterus are accelerated by the administration
| |
| of estradiol — not only the enzymes for the
| |
| incorporation of serine, glycine, and formate
| |
| into adenine and guanine, but also the enzymes involved in the synthesis of fatty
| |
| acids and cholesterol and indejX'ndent enzymes for the activation of amino acids by
| |
| the formation of adenosine monoiihosphate
| |
| (AMP) derivatives. The initial step in
| |
| protein synthesis has been shown to be the
| |
| activation of the carboxyl grou]) of the
| |
| amino acid with transfer of energy from
| |
| ATP, the formation of AMP -"amino
| |
| acid, and the release of jiyrophosphate
| |
| (Hoagland, Keller and Zamecnick, 1956).
| |
| This reversible step was studied with homogenates of uterine tissue, P^--labeled
| |
| ]n'rni)liosi)liate, and a variety of amino
| |
| | |
| | |
| | |
| acids (Mueller, Herranen and Jervell,
| |
| 1958). Seven of the amino acids tested,
| |
| leucine, tryptophan, valine, tryosine, methionine, glycine, and isoleucine, stimulated the
| |
| exchange of P^^ between pyrophosphate and
| |
| ATP. Pretreatment of the uteri by estradiol
| |
| injected in vivo increased the activity
| |
| of these three enzymes. The activating
| |
| effect of mixtures of these amino acids
| |
| was the sum of their individual effects,
| |
| from which it was inferred that a specific
| |
| enzyme is involved in the activation of
| |
| each amino acid. Since estrogen stimulated the exchange reaction with each of
| |
| these seven amino acids, Mueller concluded that the hormone must affect the
| |
| amount of each of the amino acid-activating enzvmes in the soluble fraction of the
| |
| cell.
| |
| | |
| Mueller (1957) postulated that estrogens
| |
| increase the rate of many enzyme systems
| |
| both by activating preformed enzyme molecules and by increasing the rate of de novo
| |
| synthesis of enzyme molecules, possibly by
| |
| removing membranous barriers covering the
| |
| templates for enzyme synthesis. To explain
| |
| why estrogens affect these enzymes in the
| |
| target organs, but not comparable enzymes
| |
| in other tissues, one would have to assume
| |
| that embryonic differentiation results in
| |
| the formation of enzymes in different tissues
| |
| which, although catalyzing the same reaction, have different properties such as
| |
| their responsiveness to hormonal stimulation.
| |
| | |
| As an alternative hypothesis, estrogen
| |
| might affect some reaction which provides
| |
| a substance required for all of these enzyme reactions. The carboxyl group of
| |
| amino acids must be activated by ATP before the amino acid can be incorporated
| |
| into proteins; the synthesis of both purines
| |
| and pyrimidines requires ATP for the
| |
| activation of the carboxyl group of certain
| |
| precursors and for several other steps; the
| |
| synthesis of cholesterol requires ATP for
| |
| the conversion of mevalonic acid to
| |
| squalene; and the synthesis of fatty acids
| |
| is also an energy-requiring process. Thus if
| |
| (>strogens acted in some way to increase the
| |
| amount of biologically useful energy, in
| |
| the form of ATP or of energy-rich thioesters
| |
| such as acetyl coenzyme A, it would increase
| |
| the rate of synthesis of all of these compo
| |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 655
| |
| | |
| | |
| | |
| nents of the cell. This would occur, of course,
| |
| only if the supply of ATP, rather than the
| |
| amount of enzyme, substrate, or some other
| |
| cofactor, were the rate-limiting factor in the
| |
| synthetic processes.
| |
| | |
| When purified estrogens became available, they were tested for their effects on
| |
| tissues in vitro. Estrogens added in vitro increased the utilization of oxygen by the rat
| |
| uterus (Khayyal and Scott, 1931) and the
| |
| rat pituitary (Victor and Andersen, 1937).
| |
| The addition of estradiol- 17^ at a level of
| |
| 1 fxg. per ml. of incubation medium increased
| |
| the rate of utilization of oxygen and of
| |
| pyruvic acid by slices of human endometrium and increased the rate at which labeled glucose and pyruvate were oxidized to
| |
| C^-^Os (Hagerman and Villee, 1952, 1953a,
| |
| 1953b) . In experiments with slices of human
| |
| placenta similar results were obtained and
| |
| it was found that estradiol increased the
| |
| rate of conversion of both pyruvate-2-C^'*
| |
| and acetate-l-Ci4 to C^^Os (Villee and
| |
| Hagerman, 1953) . From this and other evidence it was inferred that the estrogen acted
| |
| at some point in the oxidative pathway
| |
| common to pyruvate and acetate, i.e., in the
| |
| tricarboxylic acid cycle.
| |
| | |
| Homogenates of placenta also respond to
| |
| estradiol added in vitro. With citric acid as
| |
| substrate, the utilization of citric acid and
| |
| oxygen and the production of a-ketoglutaric
| |
| acid were increased 50 per cent by the
| |
| addition of estradiol to a final concentralion of 1 fjig. per ml. (Villee and Hagerman,
| |
| 1953). The homogenates were separated by
| |
| differential ultracentrifugation into nuclear,
| |
| mitochondrial, microsomal, and nonparticulate fractions. The estrogen-stimulable system was shown to be in the nonparticulate
| |
| fraction, the material which is not sedimented by centrifugating at 57,000 X g
| |
| for 60 minutes (Villee, 1955). Experiments
| |
| with citric, as-aconitic, isocitric, oxalosuccinic, and a-ketoglutaric acids as substrates and with fluorocitric and transaconitic acids as inhibitors localized the
| |
| estrogen-sensitive system at the oxidation
| |
| of isocitric to oxalosuccinic acid, which then
| |
| undergoes spontaneous decarboxylation to
| |
| a-ketoglutaric acid (Villee and Gordon,
| |
| 1955). Further investigations using the enzymes of the nonparticulate fraction of
| |
| the human placenta revealed that, in ad
| |
| | |
| | |
| dition to isocitric acid as substrate, only
| |
| DPN and a divalent cation such as Mg+ +
| |
| or Mn++ were required (Villee, 1955; Gordon and Villee, 1955; Villee and Gordon,
| |
| 1956). The estrogen-sensitive reaction was
| |
| formulated as a DPN-linked isocitric dehydrogenase:
| |
| | |
| Isocitrate + DPN* -^ a-ketoglutarate
| |
| | |
| + CO2 + DPXH + H*
| |
| | |
| It was found that the effect of the hormone on the enzyme can be measured by
| |
| the increased rate of disappearance of citric
| |
| acid, the increased rate of appearance of
| |
| a-ketoglutaric acid, or by the increased
| |
| rate of reduction of DPN, measured spectrophotometrically by the optical density at
| |
| 340 m/x. As little as 0.001 /xg. estradiol per
| |
| ml. (4 X 10~^ m) produced a measurable
| |
| increase in the rate of the reaction, and
| |
| there was a graded response to increasing
| |
| concentrations of estrogen. The dose-response curve is typically sigmoid. This system has been used to assay the estrogen
| |
| content of extracts of urine (Gordon and
| |
| Villee, 1956) and of tissues (Hagerman,
| |
| Wellington and Villee, 1957; Loring and
| |
| Villee, 1957).
| |
| | |
| Attempts to isolate and purify the estrogen-sensitive enzyme were not very successful. By a combination of low temperature
| |
| alcohol fractionation and elution from calcium phosphate gel a 20-fold purification
| |
| was obtained (Hagerman and Villee, 1957).
| |
| However, as the enzyme was purified it was
| |
| found that an additional cofactor was required. Either uridine triphosphate (UTP)
| |
| or ATP added to the system greatly
| |
| increased the magnitude of the estrogen effect and, subsequently, adenosine diphosphate (ADP) was recovered from the incubation medium and identified by paper
| |
| chromatography (Villee and Hagerman,
| |
| 1957). Talalay and Williams-Ashman
| |
| (1958) confirmed our observations and
| |
| showed that the additional cofactor was
| |
| triphosphopyridine nucleotide (TPN) which
| |
| was required in minute amounts. This finding was confirmed by Villee and Hagerman
| |
| (1958) and the estrogen-sensitive enzyme
| |
| system of the placenta is now believed to be
| |
| a transhydrogenase which catalyzes the
| |
| transfer of hydrogen ions and electrons
| |
| | |
| | |
| | |
| 656
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| fromTPNHtoDPN:
| |
| | |
| TPXH + DPN^ -> DPNH + TPN^
| |
| | |
| The transhydrogenation system can be
| |
| coupled to glucose 6-phosphate dehydrogenase as well as to isocitric dehydrogenase
| |
| (Talalay and Williams-Ashman, 1958; Villee and Hagerman, 1958) and presumably
| |
| can be coupled to any TPNH-generating
| |
| system.
| |
| | |
| If the estrogen-stimulable transhydrogenation reaction were readily reversible, an
| |
| enzyme such as lactic dehydrogenase which
| |
| requires DPN should be stimulated by
| |
| estrogen if supplied with substrate amounts
| |
| of TPN, catalytic amounts of DPN, and
| |
| a preparation from the placenta containing
| |
| the transhydrogenase. Experiments to test
| |
| this prediction were made using lactic dehydrogenase and alcohol dehydrogenase of
| |
| both yeast and liver (Villee, 1958a). It was
| |
| not possible to demonstrate an estrogen
| |
| stimulation of either enzyme system in
| |
| either the forward or the reverse direction.
| |
| The stimulation of the lactic dehydrogenase-DPN oxidase system of the rat uterus
| |
| by estrogens administered in vivo reported
| |
| by Bever, Velardo and Hisaw (1956)
| |
| might be explained by the stimulation of
| |
| a transhydrogenase, but it has not yet been
| |
| possible to demonstrate a coupling of this
| |
| transhydrogenase and lactic dehydrogenase.
| |
| | |
| The stimulating effect of a number of
| |
| steroids has been tested with a system in
| |
| which the transhydrogenation reaction is
| |
| coupled to isocitric dehydrogenase (Villee
| |
| and Gordon, 1956; Hollander, Nolan and
| |
| Hollander, 1958). Estrone, equilin, equilenin, and 6-ketoestradiol have activities
| |
| essentially the same as that of estradiol17 j3. Samples of 1 -methyl estrone and 2methoxy-estrone had one-half the activitj''
| |
| of estradiol. Estriol is only weakly estrogenic in this system; 33 fig. estriol are less
| |
| active than 0.1 fig. estradiol- 17/3 (Villee,
| |
| 1957a). The activities of estriol and 16epiestriol are similar, whereas 16-oxoestradiol is more active than either, with about
| |
| 10 per cent as much activitv as csti'adiol17/3.
| |
| | |
| Certain analogues of stilbestrol have been
| |
| shown to be anti-estrogens in vivo. When
| |
| applied topically to the vagina of the rat,
| |
| they prevent the cornification normally in
| |
| | |
| | |
| duced by the administration of estrogen
| |
| (Barany, Morsing, Muller, Stallberg, and
| |
| Stenhagen, 1955). One of these, 1,3-di-phydroxyphenylpropane, was found to be
| |
| strongly anti-estrogenic in the placental
| |
| system in vitro: it prevented the acceleration of the transhydrogenase-isocitric dehydrogenase system normally produced by
| |
| estradiol- 17/3 (Villee and Hagerman, 1957).
| |
| The inhibitory power declines as the length
| |
| of the carbon chain connecting the two
| |
| phenolic rings is increased and 1 , 10-di-phydroxyphenyldecane had no inhibitory action. Similar inhibitions of the estradiolsensitive system were observed with stilbestrol, estradiol-17a, and a smaller antiestrogenic effect was found with estriol
| |
| (Villee, 1957a). The inhibition induced
| |
| by these compounds can be overcome by
| |
| adding increased amounts of estradiol-17^.
| |
| When stilbestrol is added alone at low concentration, 10~' M, it has a stimulatory effect equal to that of estradiol-17^ (Glass,
| |
| Loring, Spencer and Villee, 1961).
| |
| | |
| The quantitative relations between the
| |
| amounts of stimulator and inhibitor suggest
| |
| that this inhibition is a competitive one. It
| |
| was postulated that this phenomenon involves a competition between the steroids
| |
| for specific binding sites on the estrogensensitive enzyme (Villee, 1957b; Hagerman
| |
| and Villee, 1957). When added alone, estriol
| |
| and stilbestrol are estrogenic and increase
| |
| the rate of the estrogen-sensitive enzyme.
| |
| In the presence of both estradiol and estriol,
| |
| the total enzyme activity observed is the
| |
| sum of that due to the enzyme combined
| |
| with a potent activator, estradiol- 17^, and
| |
| that due to the enzyme combined with a
| |
| weak activator, estriol. When the concentration of estriol is increased, some of the
| |
| estradiol is displaced from the enzyme and
| |
| the total activity of the enzyme system is
| |
| decreased.
| |
| | |
| Two hypotheses have been proposed for
| |
| the mechanism of action of estrogens on the
| |
| enzyme system of the placenta. One states
| |
| that the estrogen combines with an inactive
| |
| form of the enzyme and converts it to an
| |
| active form (Hagerman and Villee, 1957).
| |
| When this theory was formulated the evidence indicated that the estrogen acted on
| |
| a specific DPN-linked isocitric dehydrogenase. The theory is equally applicable if the
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 657
| |
| | |
| | |
| | |
| estrogen-sensitive enzyme is a transhydrogenase, as the evidence now indicates. The
| |
| results of kinetic studies with the coupled
| |
| isocitric dehydrogenase-transhydrogenase
| |
| system are consistent with this theory
| |
| (Gordon and Villee, 1955; Villee, 1957b;
| |
| Hagerman and Villee, 1957). Apparent
| |
| binding constants for the enzyme-hormone
| |
| complex (Gordon and Villee, 1955j and for
| |
| enzyme-inhibitor complexes have been calculated (Hagerman and Villee, 1957).
| |
| | |
| The observation that estradiol and estrone, which differ in structure only by a
| |
| pair of hydrogen atoms, are equally effective in stimulating the reaction suggested
| |
| that the steroid might be acting in some way
| |
| as a hydrogen carrier from substrate to
| |
| pyridine nucleotide (Gordon and Villee,
| |
| 1956). Talalay and Williams-Ashman
| |
| (1958) suggested that the estrogens act as
| |
| coenzymes in the transhydrogenation reaction and postulated that the reactions were:
| |
| | |
| Estrone + TPNH + H*
| |
| | |
| — Estradiol + TPN^
| |
| | |
| Estradiol + DPN+
| |
| | |
| — Estrone + DPNH + H*
| |
| | |
| | |
| | |
| Sum : TPNH
| |
| | |
| | |
| | |
| H*
| |
| | |
| | |
| | |
| - DPN^
| |
| — TPN^ + H^
| |
| | |
| | |
| | |
| DPNH
| |
| | |
| This formulation implies that the estrogen-sensitive transhydrogenation reaction
| |
| is catalyzed by the estradiol-17y3 dehydrogenase characterized by Langer and Engel
| |
| (1956). This enzyme was shown by Langer
| |
| (1957) to use either DPN or TPN as hydrogen acceptor but it reacts more rapidly
| |
| with DPN. Ryan and Engel (1953) showed
| |
| that this enzyme is present in rat liver, and
| |
| in human adrenal, ileum, and liver. However, no estrogen-stimulable enzyme is
| |
| demonstrable in rat or human liver (Villee,
| |
| 1955). The nonparticulate fraction obtained
| |
| by high speed centrifugation of homogenized rabbit liver rapidly converts estradiol
| |
| to estrone if DPN is present as hydrogen
| |
| acceptor, but does not contain any estrogenstimulable transhydrogenation system.
| |
| | |
| It will not be possible to choose between
| |
| these two hypotheses until either the estrogen-sensitive transhydrogenase and the
| |
| estradiol dehydrogenase have been separated or there is conclusive proof of their
| |
| | |
| | |
| | |
| identity. Talalay, Williams-Ashman and
| |
| Hurlock (1958) reported a 100-fold purification of the dehydrogenase without separation of the transhydrogenase activity
| |
| and found that both activities were inhibited identically by sulfhydryl inhibitors.
| |
| In contrast, Hagerman and Villee (1958)
| |
| obtained partial separation of the two activities by the usual techniques of protein
| |
| fractionation, and reported that a 50 per
| |
| cent inhibition of transhydrogenase is obtained with p-chloromercurisulfonic acid at
| |
| a concentration of 10~^ m whereas 10"^ m
| |
| p-chloromercurisulfonic acid is required for
| |
| a 50 per cent inhibition of the dehydrogenase. The evidence that these two activities are mediated by separate and distinct proteins has been summarized by
| |
| Villee, Hagerman and Joel (1960).
| |
| | |
| The transhydrogenase present in the
| |
| mitochondrial membranes of heart muscle
| |
| was shown by Ball and Cooper (1957) to be
| |
| inhibited by 4 X 10"^ m thyroxine. The
| |
| estrogen-sensitive transhydrogenase of the
| |
| placenta is also inhibited by thyroxine (Villee, 1958b). The degree of inhibition is a
| |
| function of the concentration of the thyroxine and the inhibition can be overcome by
| |
| increased amounts of estrogen. Suitable control experiments show that thyroxine at
| |
| this concentration does not inhibit the glucose 6-phosphate dehydrogenase or isocitric
| |
| dehydrogenase used as TPNH-generating
| |
| systems to couple with the transhydrogenase. Triiodothyronine also inhibits the
| |
| estrogen-sensitive transhydrogenase but
| |
| tyrosine, diiodotyrosine and thyronine do
| |
| not. The thyroxine does not seem to be
| |
| inhibiting by binding the divalent cation,
| |
| Mn + + or ]Mg+ + , required for activity, for
| |
| the inhibition is not overcome by increasing
| |
| the concentration of the cation 10-fold.
| |
| | |
| In the intact animal estrogens stimulate
| |
| the growth of the tissues of certain target
| |
| organs. The estrogen-sensitive enzyme has
| |
| been shown to be present in many of the
| |
| target organs of estrogens: in human endometrium, myometrium, placenta, mammary
| |
| gland, and mammary carcinoma, in rat ventral prostate gland and uterus, and in mammotrophic-dependent transplantable tumors
| |
| of the rat and mouse pituitary. In contrast,
| |
| it is not demonstrable in comparable preparations from liver, heart, lung, brain, or
| |
| | |
| | |
| | |
| 658
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| kidney. The growth of any tissue involves
| |
| the utilization of energy, derived in large
| |
| part from the oxidation of substrates, for
| |
| the synthesis of new chemical bonds and for
| |
| the reduction of substances involved in the
| |
| synthesis of compounds such as fatty acids,
| |
| cholesterol, purines, and pyrimidines.
| |
| | |
| The physiologic responses to estrogen
| |
| action, such as water imbibition and protein
| |
| and nucleic acid synthesis, are processes not
| |
| directly dependent on the activity of transhydrogenase. However, all of these processes
| |
| are endergonic, and one way of increasing
| |
| their rate would be to increase the supply of
| |
| biologically available energy by speeding
| |
| up the Krebs tricarboxylic acid cycle and
| |
| the flow of electrons through the electron
| |
| transmitter system. Much of the oxidation
| |
| of substrates by the cell produces TPNH,
| |
| whereas the major fraction of the biologically useful energy of the cell comes from the
| |
| oxidation of DPNH in the electron transmitter system of the cytochromes. Hormonal
| |
| control of the rat of transfer of hydrogens
| |
| from TPN to DPN could, at least in theory,
| |
| influence the over-all rate of metabolism in
| |
| the cell and secondarily influence the
| |
| amount of energy available for synthetic
| |
| processes. Direct evidence of this was shown
| |
| in our early experiments in which the oxygen consumption of tissue slices of target
| |
| organs was increased by the addition of
| |
| estradiol (Hagerman and Villee, 1952; Villee and Hagerman, 1953).
| |
| | |
| This theory assumes that the supply of
| |
| energy is rate-limiting for synthetic processes in these target tissues and that the
| |
| activation of the estrogen-sensitive enzyme
| |
| does produce a significant increase in the
| |
| supply of energy. The addition of estradiol
| |
| in vitro produces a significant increase in
| |
| the total amount of isocitric acid dehydrogenated by the placenta (Villee, Loring
| |
| and Sarner, 1958) . Slices of endometrium to
| |
| which no estradiol was added in vitro
| |
| utilized oxygen and metabolized substrates
| |
| to carbon dioxide at rates which paralleled
| |
| the levels of estradiol in the blood and urine
| |
| of the patient from whom the endometrium
| |
| was obtained (Hagerman and Villee,
| |
| esses in these target tissues and that the
| |
| 1953b). Estradiol increases the rate of synthesis of ATP by liomogenates of human
| |
| | |
| | |
| | |
| placenta (Villee, Joel, Loring and Spencer,
| |
| 1960).
| |
| | |
| The reductive steps in the biosynthesis of
| |
| steroids, fatty acids, purines, serine, and
| |
| other substances generally require TPNH
| |
| rather than DPNH as hydrogen donor. The
| |
| cell ordinarily contains most of its TPN
| |
| in the reduced state and most its DPN in
| |
| the oxidized state (Glock and McLean,
| |
| 1955). If the amount of TPN+ is ratelimiting, a transhydrogenase, by oxidizing
| |
| TPN and reducing DPN, would permit
| |
| further oxidation of substrates such as isocitric acid and glucose 6-phosphate, which
| |
| require TPN+ as hydrogen acceptor and
| |
| which are key reactions in the Krebs tricarboxylic acid cycle and the hexose monophosphate shunt, respectively. Furthermore,
| |
| the experiments of Kaplan, Schwartz, Freeh
| |
| and Ciotti (1956) indicate that less biologically useful energy, as ATP, is obtained
| |
| when TPNH is oxidized by TPNH cytochrome c reductase than when DPNH is
| |
| oxidized by DPNH cytochrome c reductase.
| |
| Thus, a transhydrogenase, by transferring
| |
| hydrogens from TPNH to DPN before
| |
| oxidation in the cytochrome system, could
| |
| increase the energy yield from a given
| |
| amount of TPNH produced by isocitrate or
| |
| glucose 6-phosphate oxidation. The increased amount of biologically useful energy
| |
| could be used for growth, for protein and
| |
| nucleic acid synthesis, for the imbibition of
| |
| water, and for the other physiologic effects
| |
| of estrogens.
| |
| | |
| Estrogen stimulation of the transhydrogenation reaction would tend to decrease
| |
| rather than increase the amount of TPNH
| |
| in the cell. Thus the estrogen-induced stimulation of the synthesis of steroids, fatty
| |
| acids, proteins, and purines in the uterus
| |
| can be explained more reasonably as due to
| |
| an increased supply of energy rather than
| |
| to an increased supply of TPNH.
| |
| | |
| The theory that estrogens stimulate transhydrogenation by acting as coenzymes
| |
| which are rapidly and reversibly oxidized
| |
| and reduced does not explain the pronounced estrogenic activity in vivo of stilbestrol, 17a-ethinyl estradiol, or bfsdehydrodoisynolic acid, for these substances do
| |
| not contain groups that could be readily
| |
| oxidized or reduced. The exact mechanism
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| (359
| |
| | |
| | |
| | |
| of action of estrogens at the biochemical
| |
| level remains to be elucidated, but the
| |
| data available permit the formulation of a
| |
| detailed working hypothesis. The notable
| |
| effects of estrogens and androgens on behavior (see chapter by Young) are presumably due to some direct or indirect effect of the hormone on the central nervous
| |
| system. The explanation of these phenomena
| |
| in physiologic and biochemical terms remains for future investigations to provide.
| |
| | |
| B. ANDROGENS
| |
| | |
| Although there is a considerable body of
| |
| literature regarding the responses at the biologic level to administered androgens and
| |
| progesterone, much less is known about the
| |
| site and mechanism of action of these hormones than is known about the estrogens.
| |
| The review by Roberts and Szego (1953b)
| |
| deals especially with the synergistic and
| |
| antagonistic interactions of the several
| |
| steroidal sex hormones.
| |
| | |
| The rapid growth of the capon comb following the administration of testosterone
| |
| has been shown to involve a pronounced
| |
| increase in the amount of mucopolysaccharide present, as measured by the content
| |
| of glucosamine (Ludwig and Boas, 1950;
| |
| Schiller, Benditt and Dorfman, 1952). It
| |
| is not known whether the androgen acts by
| |
| increasing the amount or activity of one of
| |
| the enzymes involved in the synthesis of
| |
| polysaccharides or whether it increases the
| |
| amount or availability of some requisite
| |
| cofactor. Many of the other biologic effects
| |
| of androgens do not seem to involve
| |
| mucopolysaccharide synthesis and the
| |
| relation of these observations to the
| |
| other roles of androgens remains to he determined.
| |
| | |
| Mann and Parsons (1947) found that
| |
| castration of rabbits resulted in a decreased
| |
| concentration of fructose in the semen.
| |
| Within 2 to 3 weeks after castration the
| |
| amount of fructose in the semen dropped
| |
| to zero, but rapidly returned to normal following the subcutaneous implantation of a
| |
| pellet of testosterone. Fructose reappeared
| |
| in the semen of the castrate rat 10 hours
| |
| after the injection of 10 mg. of testosterone
| |
| (Rudolph and Samuels, 1949). The coagulating gland of the rat, even when trans
| |
| | |
| | |
| planted to a new site in the body, also responds by producing fructose when the host
| |
| is injected with testosterone. The amount
| |
| of citric acid and ergothioneine in the semen
| |
| is also decreased by castration and increased by the implantation of testosterone
| |
| pellets (Mann, 1955). The experiments of
| |
| Hers (1956) demonstrate that fructose
| |
| is produced in the seminal vesicle by
| |
| the reduction of glucose to sorbitol and
| |
| the subsequent oxidation of sorbitol to
| |
| fructose. The reduction of glucose requires TPNH as hydrogen donor and the
| |
| oxidation of sorbitol requires DPN as
| |
| hydrogen acceptor. The sum of these two
| |
| reactions provides for the transfer of hydrogens from TPNH to DPN. If androgens
| |
| act as cofactors which are reversibly oxidized and reduced, and thus transfer hydrogens from TPNH to DPN as postulated
| |
| by Talalay and Williams-Ashman (1958),
| |
| one would expect that an increased amount
| |
| of androgen, by providing a competing system for hydrogen transfer, would decrease
| |
| rather than increase the production of fructose. The marked increases in the citric
| |
| acid and ergothioneine content of semen
| |
| are not readily explained by this postulated
| |
| site of action of androgens.
| |
| | |
| An increase in the activity of /3-glucuronidase in the kidney has been reported
| |
| following the administration of androgens
| |
| (Fishman, 1951). This might be interpreted
| |
| as an arlaptive increase in enzyme induced
| |
| by the increased concentration of substrate,
| |
| or by a direct effect of the steroid on the
| |
| synthesis of the enzyme.
| |
| | |
| The respiration of slices of prostate gland
| |
| of the dog is decreased by castration or by
| |
| the administration of stilbestrol (Barron
| |
| and Huggins, 1944). The decrease in respiration occurs with either glucose or pyruvate
| |
| as substrate. The seminal vesicle of the rat
| |
| responds similarly to castration. Rudolph
| |
| and Samuels (1949) found that respiration
| |
| of slices of seminal vesicle is decreased by
| |
| castration and restored to normal values
| |
| within 10 hours after the injection of testosterone. Experiments by Dr. Phillip Corfman in our laboratory with slices of prostate
| |
| gland from patients with benign prostatic
| |
| hypertrophy showed that oxygen utilization
| |
| was reduced 50 per cent by estradiol added
| |
| | |
| | |
| | |
| 660
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| in vitro at a level of 1 /xg. per ml. Respiration of slices of the ventral prostate gland
| |
| of the rat is decreased by castration and increased by administered testosterone (Nyden and Williams-Ashman, 1953). These
| |
| workers showed that lipogenesis from acetate-l-C^* in the prostate is also significantly diminished by castration and
| |
| restored to normal by administered testosterone.
| |
| | |
| The succinic dehydrogenase of the liver
| |
| has been found to be increased by castration
| |
| and decreased by the administration of testosterone (Kalman, 1952; Rindani, 1958),
| |
| the enzyme is also inhibited by testosterone
| |
| added in vitro (Kalman, 1952). In contrast,
| |
| Davis, Meyer and McShan (1949) found
| |
| that the succinic dehydrogenase of the
| |
| prostate and seminal vesicles is decreased
| |
| by castration and increased by the administration of testosterone.
| |
| | |
| An interesting example of an androgen
| |
| effect on a specific target organ is the decreased size of the levator ani and
| |
| other perineal muscles of the rat following castration. The administration of
| |
| androgen stimulates the growth of these
| |
| muscles and increases their glycogen content
| |
| (Leonard, 1952). However, their succinoxidase activity is unaffected by castration
| |
| or by the administration of testosterone.
| |
| Courrier and Marois (1952) reported that
| |
| the growth of these muscles stimulated by
| |
| androgen is inhibited by cortisone. The
| |
| remarkable responsiveness of these muscles
| |
| to androgens in vivo gave promise that
| |
| slices or homogenates of this tissue incubated with androgens might yield clues as to
| |
| the mode of action of the male sex hormones. Homogenates of perineal and masseter muscles of the rat responded to androgens administered in vivo with increased
| |
| oxygen consumption and ATP production
| |
| iLoring, Spencer and Villee, 1961). The experiments suggested that the activity of
| |
| DPNH-cytochromo r reductase in these
| |
| tissues is controlled by aiKh'ogeiis.
| |
| | |
| C. PROGESTERONE
| |
| | |
| Attempts to clarify the biochemical basis
| |
| of the role of progesterone have been hampered by the requirement, in most instances,
| |
| for a previous stimulation of the tissue by
| |
| estrogen. The work of Wade and Jones
| |
| | |
| | |
| | |
| (1956a, b) demonstrated an interesting effect of progesterone added in vitro on several aspects of metabolism in rat liver mitochondria. Progesterone, but not estradiol,
| |
| testosterone, 17a-hydroxyprogesterone, or
| |
| any of several other steroids tested, stimulated the adenosine triphosphatase activity
| |
| of rat liver mitochondria. This stimulation
| |
| is not the result of an increased permeability
| |
| of the mitochondrial membrane induced by
| |
| progesterone, for the stimulatory effect is
| |
| also demonstrable with mitochondria that
| |
| have been repeatedly frozen and thawed to
| |
| break the membranes. Other experiments
| |
| showed that ATP was the only substrate
| |
| effective in this system ; progesterone did not
| |
| activate the release of inorganic phosphate
| |
| from AMP, ADP, or glycerophosphate.
| |
| | |
| In other experiments with rat liver mitochondria (Wade and Jones, 1956b), progesterone at a higher concentration (6 X lO"'*
| |
| m) was found to inhibit the utilization of
| |
| oxygen with one of the tricarboxylic acids
| |
| or with DPNH as substrate. This inhibition
| |
| is less specific and occurred with estradiol,
| |
| testosterone, pregnanediol, and 17a-hydroxy progesterone, as well as with progesterone. The inhibition of respiration by high
| |
| concentrations of steroids in vitro has been
| |
| reported many times and with several different tissues; it seems to be relatively unspecific. Wade and Jones were able to show
| |
| that progesterone inhibits the reduction of
| |
| cytochrome c but accelerates the oxidation
| |
| of ascorbic acid. They concluded that progesterone may perhaps uncouple oxidation
| |
| from phosphorylation in a manner similar
| |
| to that postulated for dinitrophenol. The
| |
| site of action of this uncoupling appears to
| |
| be in the oxidation-reduction path between
| |
| DPNH and cytochrome c. Mueller (1953)
| |
| found that progesterone added in vitro decreases the incorporation of glycine-2-C^'*
| |
| into the protein of strips of rat uterus, thus
| |
| counteracting the stimulatory effect of estradiol administered in vivo.
| |
| | |
| Zander (1958) reported that A4-3-ketopregnene-20-a-ol and A4-3-ketopregnene20-^-ol arc effective gestational hormones
| |
| in the mouse, rabbit, and man, although
| |
| somewhat less active in general than is
| |
| progesterone. An enzyme in rat ovary which
| |
| converts progesterone to pregnene-20-a-ol,
| |
| and also catalyzes the reverse reaction, was
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 661
| |
| | |
| | |
| | |
| described by Wiest (1956). The conversion
| |
| occurred when slices of ovary were incubated with DPN. Wiest postulated that
| |
| the progesterone-pregnene-20-a-ol system
| |
| might play a role in hydrogen transfer, in
| |
| a manner analogous to that postulated by
| |
| Talalay and Williams-Ashman (1958) for
| |
| estrone-estradiol- 17^, but his subsequent
| |
| experiments ruled out this possibility, for
| |
| he was unable to demonstrate any progesterone-stimulable transhydrogenation reaction.
| |
| | |
| The nature of the effect of progesterone
| |
| and of estrogens on myometrium has been
| |
| investigated extensively by Csapo. Csapo
| |
| and Corner (1952, 1953) found that ovariectomy decreased the maximal tension of
| |
| the myometrium and decreased its content
| |
| of actomyosin. The administration of estradiol to the ovariectomized rabbit over a
| |
| period of 7 days restored both the actomyosin content and the maximal tension of the
| |
| myometrium to normal. The concentration
| |
| of ATP and of creatine phosphate in the
| |
| myometrium is decreased by ovariectomy
| |
| but is restored by only 2 days of estrogen
| |
| treatment. This suggests that the effect on
| |
| intermediary metabolism occurs before the
| |
| effect on protein {i.e., actomyosin) synthesis. Csapo (1956a) concluded that estrogen
| |
| is a limiting substance in the synthesis of
| |
| the contractile proteins of myometrium, but
| |
| he could not differentiate between an effect
| |
| of estrogen on some particular biosynthetic
| |
| reaction and an effect of estrogen on some
| |
| fundamental reaction which favors synthesis in general. He was unable to demonstrate
| |
| any comparable effect of progesterone on
| |
| the contractile actomyosin-ATP system of
| |
| the myometrium.
| |
| | |
| Other observations provide an explanation for the well known effect of progesterone in decreasing the contractile activity of
| |
| myometrium, not by any effect on the contractile system itself, but in some previous
| |
| step in the excitation process. Under the
| |
| domination of progesterone the myometrial
| |
| cells have a decreased intracellular concentration of potassium ions and an increased
| |
| concentration of sodium ions (Horvath,
| |
| 1954). The change in ionic gradient across
| |
| the cell membrane is believed to be responsible for the altered resting potential and
| |
| the partial depolarization of the cell mem
| |
| | |
| | |
| brane which results in decreased conductivity and decreased pharmacologic reactivity
| |
| of the myometrial cell. The means by which
| |
| progesterone produces the changes in ionic
| |
| gradients is as yet unknown. Csapo postulates that the hormone might decrease the
| |
| rate of metabolism which in turn would
| |
| lessen the rate of the "sodium pump" of the
| |
| cell membrane. The contractile elements,
| |
| the actomyosin-ATP system, are capable of
| |
| full contraction but, because of the partial
| |
| block in the mechanism of excitation and of
| |
| propagation of impulses (Csapo, 1956b),
| |
| the muscle cells cannot operate effectively;
| |
| the contractile activity remains localized.
| |
| Csapo (1956a) showed that the progesterone
| |
| block is quickly reversible and disappears if
| |
| progesterone is withdrawn for 24 hours. He
| |
| concluded that the progesterone block is
| |
| necessary for the continuation of pregnancy
| |
| and that its withdrawal is responsible for
| |
| the onset of labor.
| |
| | |
| ]\Iost investigators who have speculated
| |
| about the mode of action of steroids —
| |
| whether they believe the effect is by activating an enzyme, by altering the permeability of a membrane, or by serving as a
| |
| coenzyme in a given reaction— have emphasized the physical binding of the steroid to
| |
| a protein as an essential part of the mechanism of action or a preliminary step to
| |
| that action. They have in this way explained
| |
| the specificities, synergisms, and antagonisms of the several steroids in terms of the
| |
| formation of specific steroid-protein complexes. The differences between different
| |
| target organs, e.g., those that respond to
| |
| androgens and those that respond to estrogens, can be attributed to differences in the
| |
| distribution of the specific proteins involved
| |
| in these binding reactions. Viewed in this
| |
| light, the problem of the mode of action of
| |
| sex hormones becomes one aspect of the
| |
| larger problem of the biochemical basis of
| |
| embryonic differentiation of tissues.
| |
| | |
| IV. References
| |
| | |
| Allen, W. M. 1939. Biochemistry of the corpus
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| |
| | |
| Roberts, S., and Szego, C. M. 1953a. The influence of steroids on uterine respiration and
| |
| glycolysis. J. Biol. Chem., 201, 21-29.
| |
| | |
| Roberts, S., and Szego, C. M. 1953b. Steroid
| |
| interactions in the metabolism of reproductive
| |
| target organs. Physiol. Rev., 33, 593-629.
| |
| | |
| Rudolph, G. G., and S.amuels, L. T. 1949. Early
| |
| effects of testosterone propionate on the seminal vesicles of castrate rats. Endocrinology,
| |
| 44, 190-196.
| |
| | |
| Ryan, K. 1958. Conversion of androgens to
| |
| estrogens bv human placental microsomes.
| |
| Fed. Proc, 17, 1382.
| |
| | |
| Ryan, K. J., and Engel, L. L. 1953. The interconversion of estrone and estradiol-17i3 by rat
| |
| liver slices. Endocrinology, 52, 277-286.
| |
| | |
| Schiller, S., Benditt, E., and Dorfman, A. 1952.
| |
| Effect of testosterone and cortisone on the
| |
| hexosamine content and metachromasia of
| |
| chick combs. Endocrinology, 50, 504-510.
| |
| | |
| Solomon, S., Levitan, P., and Lieberman, S. 1956.
| |
| Possible intermediates between cholesterol and
| |
| pregneneolone in corticosteroidogenesis. Abstract. Proc. Canad. Physiol. Soc, Rev. Canad.
| |
| Biol., 15, 282.
| |
| | |
| Spaziani, E., and Szego, CM. 1958. The influence of estradiol and Cortisol on uterine histamine of the ovariectomized rat. Endocrinology, 63, 669-678.
| |
| | |
| Stuermer, V. M., .AND Stein, R. J. 1952. Cytodynamic properties of the human endometrium. V. Metabolism and the enzymatic activity of the human endometrium during the
| |
| menstrual cycle. Am. J. Obst. & Gynec, 63,
| |
| 359-370.
| |
| | |
| Tal.alay, p., and Williams-Ashman, H. G. 1958.
| |
| Activation of hydrogen transfer between pyridine nucleotides bv steroid hormones. Proc
| |
| Nat. Acad. Sc, 44, 15-26.
| |
| | |
| Tal.alay, P., Willi.ams-Ashman, H. G., and HurLOCK, B. 1958. Steroid hormones as coenzymes of hydrogen transfer. Science, 127, 1060.
| |
| | |
| Tchen, T. T., and Bloch, K. 1955. In vitro
| |
| conversion of squalene to lanosterol and cholesterol. J. Am. Chem. Soc, 77, 6085-6086.
| |
| | |
| Telfer, M. a. 1953. Influence of estradiol on
| |
| nucleic acids, respiratory enzymes and the
| |
| distribution of nitrogen in the rat uteru.*.
| |
| Arch. Biochem., 44, 111-119.
| |
| | |
| Victor, J., and Andersen, D. H. 1937. Stimulation of anterior hypophysis metabolism by
| |
| theelin or dihydrotheelin. Am. J. Physiol., 120,
| |
| 154-166.
| |
| | |
| Villee. C. A. 1955. An estradiol-induccd stimulation of citrate utilization by placenta. J.
| |
| Biol. Chem., 215, 171-182.
| |
| | |
| Villee, C. A. 1957a. Effects of estrogens and
| |
| antiestiogens in vitro. Cancer Res.. 17, 507511.
| |
| | |
| | |
| | |
| STEROID SEX HORMONES
| |
| | |
| | |
| | |
| 665
| |
| | |
| | |
| | |
| ViLLEE, C. A. 1957b. Role of estrogens in regulating the metabolism of the placenta and
| |
| endometrium. Fertil. & Steril., 8, 156-163.
| |
| | |
| ViLLEE, C. A. 1958a. Estrogens and uterine enzymes. Ann. New York Acad. Sc, 75, 524534.
| |
| | |
| ViLLEE, C. A. 1958b. Antagonistic effects of estrogens and thyroxine on an enzyme system
| |
| in vitro. In Proceedings IV International Congress Biochemistry {Vienna), p. 115. London:
| |
| Pergamon Press.
| |
| | |
| ViLLEE, C. A., AND GoRDON, E. E. 1955. Further
| |
| studies on the action of estradiol in vitro.
| |
| J. Biol. Chem., 216, 203-214.
| |
| | |
| ViLLEE, C. A., AND GoRDON, E. E. 1956. The
| |
| stimulation by estrogens of a DPN-linked
| |
| isocitric dehydrogenase from human placenta.
| |
| Bull. Soc. chim. belg., 65, 186-201.
| |
| | |
| ViLLEE, C. A., AND Hagerman, D. D. 1953. Effects
| |
| of estradiol on the metabolism of himian placenta in vitro. J. Biol. Chem., 205, 873-882.
| |
| | |
| ViLLEE, C. A., and Hagerman, D. D. 1957. Studies
| |
| on the estrogen-sensitive isocitric dehydrogenase of the human placenta. In Proceedings
| |
| International Syniposiinn Enzyme Chemistry.
| |
| {Japan), Vol. 1, p. 287. Tokyo: Maruzen.
| |
| | |
| ViLLEE, C. A., AND H.\GER.MAN, D. D. 1958. On the
| |
| identity of the estrogen-sensitive enzyme of
| |
| human placenta. J. Biol. Chem., 233, 42-48.
| |
| | |
| ViLLEE, C. A., Hagerman, D. D., and Joel, P. B.
| |
| 1960. An enzyme basis for the physiologic
| |
| functions of estrogens. Recent Progr. Hormone
| |
| Res., 16, 49-69.
| |
| | |
| ViLLEE, C. A., Joel. P. B., Loring, J. M., .\nd Spencer, J. M. 1960. Estrogen stimulation of
| |
| ATP production and protein svnthesis. Fed.
| |
| Proc, 19, 53.
| |
| | |
| ViLLEE, C. A., Loring, J. M.. and Sarner, A. 1958.
| |
| | |
| | |
| | |
| Isocitric dehydrogenases of the placenta. Fed
| |
| Proc, 17, 328.
| |
| | |
| Wade, R., and Jones, H. W., Jr. 1956a. Effect
| |
| of progesterone on mitochondrial adenosinetriphosphatase. J. Biol. Chem., 220, 547-551.
| |
| | |
| Wade, R., and Jones, H. W., Jr. 1956b. Effect
| |
| of progesterone on oxidative phosphorylation.
| |
| J. Biol. Chem.. 220, 553-562.
| |
| | |
| Walaas, O., and Walaas, E. 1950. The metabolism of uterine muscle studied with radioactive phosphorus P^". Acta physiol. scandinav
| |
| 21, 18-26.
| |
| | |
| Wal-aas, O.. Wal.aas, E., .\nd Loken, F. 1952a.
| |
| The effect of estradiol monobenzoate on the
| |
| metaboli-sin of rat uterine muscle. Acta endocrinol., 10,201-211.
| |
| | |
| Wal.'^as, 0., Walaas, E., and Loken, F. 1952b.
| |
| The effect of estradiol monobenzoate on the
| |
| metabolism of the rat endometrium. Acta endocrinol., 11, 61-66.
| |
| | |
| Werbin, H. and LeRoy, G. V. 1954. Cholesterol:
| |
| a precursor of tetrahydrocortisone in man. J.
| |
| Am. Chem. Soc, 76, 5260-5261.
| |
| | |
| West. C. D., Damast, B. L., Sarro, S. D., and
| |
| Pearson, 0. H. 1956. Conversion of testosterone to estrogens in castrated, adrenalectomized human females. J. Biol. Chem., 218,
| |
| 409-418.
| |
| | |
| WiEST, W. G. 1956. The metabolism of progesterone to A4-pregnen-20a-ol-3-one in eviscerated female rats. J. Biol. Chem., 221, 461467.
| |
| | |
| Zander, J. 1958. Gestagens in human pregnancy.
| |
| In Proceedings Conference on Endocrinology
| |
| of Reproduction, C. W. Lloyd, Ed. New York:
| |
| Academic Press, Inc.
| |
| | |
| Zondek, B., and Hestrin, S. 1947. Phosphorylase
| |
| activity in human endometrium. Am. J. Obst.
| |
| ct Gvnec, 54, 173-175.
| |
| | |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS ON ENDOCRINE SECRETIONS
| |
| | |
| James H. Leathern, Ph.D.
| |
| | |
| PROFESSOR OF ZOOLOGY, RUTGERS, THE STATE UNIVERSITY,
| |
| NEW BRUNSWICK, NEW JERSEY
| |
| | |
| | |
| | |
| I. Introduction' 666 I, Introduction
| |
| | |
| II. Nature of Problems in Nutritional -j-. -, .^ ^ ,• ,• t ,
| |
| | |
| Studies 668 Despite the accumulation of many data
| |
| | |
| A. Thyroid Cxland, Nutrition, and Re- in the field of reproductive endocrinology
| |
| | |
| production ()68 during the past 20 years and the long es
| |
| B. Adreiial Gland, Nutrition, and Re- ^ _^ tablished awareness of a nutritional in
| |
| C. Diabetef^Mellitus, Nutrition, and '' ^f^f on fertility and fecundity, knowl
| |
| Reproduction ()72 edge bearing on nutrition and the endocrine
| |
| | |
| D. Sterile-Obese Syndrome 673 glands subserving reproduction has ad
| |
| E. Diet and the Liver 673 vanced comparatively slowly. However, re
| |
| III. Hypophysis and Diet 674 markable advances have been made in each
| |
| | |
| A. Inanition 674 speciality SO that nutritional-endocrine
| |
| | |
| ^roein. .. w problems should continue to be a fruitful
| |
| | |
| C. Carbohvdrate and Fat ()7() ^ „ ^i-r^x i-ii
| |
| | |
| D Vitamins 676 ^^^^^ ^^^' ^tudy. Data which have yet to
| |
| | |
| IV. Male Reproductive System (i77 be obtained eventually w'ill contribute to
| |
| | |
| A. Testis 677 the coherence one would prefer to present
| |
| | |
| 1. Inanition 677 now.
| |
| | |
| 2. Protein 678 'y\^q endocrinologist appreciates the deli
| |
| 4 Vitamins (i8() ^^^^ balance which exists between the hy
| |
| B. Influence of Nutrition on the Respon- ' pophysis and the gonads. In a sense, a simi
| |
| siveness of Male Reproductive Tis- lar interdependence exists between nutrition
| |
| | |
| sues to Hormones 681 and the endocrine glands, including those
| |
| | |
| 1. Testis ■ . . 681 ^j^|-^ reproductive functions. Not only does
| |
| | |
| 2. feeminal vesicles and i)rostate 682 x •<• • n xi • j i -•
| |
| | |
| V. Female Reproductive System 683 nutrition influence synthesis and release of
| |
| | |
| A. Ovaries 683 hormones, but hormones in turn, through
| |
| | |
| 1. Inanition 683 their regulation of the metabolism of pro
| |
| 2. Protein 684 teins, carbohydrates, and fats, influence nu
| |
| 3. Carbohydrate 685 trition. Thus, dietary deficiencies may create
| |
| | |
| 5 Vitamins 685 endocrine imbalance, and endocrine imbal
| |
| B. Influence of Nutrition on the ResiK)n- '^^ce may create demands for dietary fac
| |
| siveness of Female Pe])ro<luct ive tors. It follows, therefore, that, in any conTissues to Hormones 687 sideration of this interrelationship, one must
| |
| | |
| 1 . Ovary ... 687 consider not only undernutrition and lack of
| |
| | |
| 2. uterus and vagina 688 -n c j \ l ^ i ^ cc i. r
| |
| | |
| 3. Mammary gland 689 specific foods, but also possible effects of
| |
| | |
| C. Pregnancy. . 689 antithyroid substanccs in foods, antimetab
| |
| VI. Concluding Remarks 693 olites, and overnutrition, especially for the
| |
| | |
| VII.Pkferencks (;!)4 child (Forbes, 1957).
| |
| | |
| 666
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 667
| |
| | |
| | |
| | |
| Our understanding of the means by which
| |
| hormones exert their effects is relatively
| |
| slight, as is our knowledge of the biochemical mechanisms by w^hich supplements and
| |
| deficiencies of vitamins and amino acids
| |
| influence hormone action. Nevertheless,
| |
| support for the statement that modifications
| |
| of nutrition influence endocrine gland secretions or hormone action on distant target organs or tissues is provided by an
| |
| enumeration of a few basic cell components
| |
| requiring proteins, lipids, and vitamins.
| |
| (1) Proteins combine with lipids to form
| |
| lipoproteins which are essential features
| |
| of the internal and external cellular membranes and interfaces. Hormones, as well as
| |
| nutrition, influence cell membranes and
| |
| therefore cell transport is affected. It is well
| |
| known that hormones influence electrolyte
| |
| and carbohydrate transfer and recently an
| |
| endocrine control of amino acid transport
| |
| was demonstrated (Noall, Riggs, Walker
| |
| and Christensen, 1957). The effect of modifications of nutrition on the capacity of hormones to influence cell transport must await
| |
| study. (2) Enzymes are proteins with chemically active surfaces and often include nonprotein groups such as vitamins. Nutritional
| |
| and hormonal changes cause alterations in
| |
| enzyme concentrations (Knox, Auerbach
| |
| and Lin, 1956). Vitamin, mineral, and fat
| |
| deficiencies favor a decrease in enzymes,
| |
| whereas protein deficiencies have varied effects (Van Pilsum, Speyer and Samuels,
| |
| 1957). Enzyme changes caused by hormones
| |
| appear to be a consequence of metabolic
| |
| adaptations. The importance of a nutritional base on which a hormone can express
| |
| an effect on the enzymes of the reproductive
| |
| organs can only be determined after further
| |
| data have been obtained. (3) Proteins combined with nucleic acids become nucleoproteins, some of which are organized in the
| |
| cytoplasm and may be templates for cellular protein synthesis. Other nucleoproteins
| |
| are contained in the nucleus. Nutrition and
| |
| hormones influence tissue nucleoproteins
| |
| but studies involving the reproductive organs are few. How^ever, one possible cause
| |
| of human infertility is low desoxyribose
| |
| nucleic acid in the sperm ("Weir and Leuchtenberger, 1957).
| |
| | |
| Proteins are characteristic components of
| |
| | |
| | |
| | |
| tissues and hypophyseal hormones are protein in nature; also the major portion of
| |
| gonadal dry weight is protein. Such being
| |
| the case, it is important to appreciate that
| |
| the protein composition of the body is in
| |
| a dynamic state and that proteins from the
| |
| tissues and from the diet contribute to a
| |
| common metabolic pool of nitrogen. This
| |
| metabolic pool contains amino acids which
| |
| may be withdrawn for rebuilding tissue
| |
| protein and for the formation of new protein
| |
| for growth. Obviously, the character of the
| |
| metabolic pool of nitrogen reflects dietary
| |
| protein level and quality. A food protein
| |
| which is deficient in one or more amino
| |
| acids will restrict tissue protein synthesis.
| |
| Hormones also influence the metabolic pool
| |
| by affecting appetite as well as absorption,
| |
| utilization, and excretion of foods, and thus
| |
| hormones could accentuate the effect of a
| |
| poor diet, or create demands beyond those
| |
| normally met by an adequate diet. In addition a study of the tissues and organs of
| |
| the body reveals that contributions to the
| |
| metabolic pool are not uniform, thus one
| |
| tissue or organ may be maintained at the
| |
| expense of another. In protein deprivation
| |
| in adults the liver quickly contributes increased amounts of nitrogen to the metabolic
| |
| pool whereas the testis does not. On the
| |
| other hand, protein contributions to the
| |
| nitrogen pool by the hypophysis, and the
| |
| amino acid withdrawals needed for hormone
| |
| synthesis, are unknown. Data suggesting
| |
| that the addition of specific nutrients to
| |
| diets improves hypophyseal hormone synthesis have been presented (Leathem,
| |
| 1958a).
| |
| | |
| In 1939 jNIason rightfully emphasized the
| |
| need for vitamins in reproduction. Since
| |
| then, much additional knowledge has been
| |
| obtained. Vitamins of the B complex have
| |
| been more clearly identified and a better
| |
| understanding of their function has been
| |
| gained. Thiamine is important for carbohydrate metabolism, pyridoxine for fat metabolism, and the conversion of tryptophan
| |
| to nicotinic acid, and vitamin B12 may be
| |
| involved in protein synthesis. In addition,
| |
| vitamins have been found to serve as coenzymes, and folic acid to be important for
| |
| estrogen action on the uterus. Tliosr. and
| |
| | |
| | |
| | |
| 668
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| many other findings prompt a survey of the
| |
| relationships of vitamins to reproduction.
| |
| | |
| It is the intention of the author to review
| |
| enough of the evidence which interrelates
| |
| nutrition and reproduction to create an
| |
| awareness of the problems in the area.
| |
| Reviews dealing with the general subject
| |
| of hormonal-nutritional interrelationships
| |
| have been presented (Hertz, 1948; Samuels,
| |
| 1948; Ershoff, 1952; Zubiran and GomezMont, 1953; Meites, Feng and Wilwerth,
| |
| 1957; Leathem, 1958a,). Other reviews have
| |
| related reproduction to nutrition with emphasis on laboratory (Mason, 1939; Guilbert, 1942; Lutwak-Mann, 1958) and farm
| |
| animals (Reid, 1949; Asdell, 1949), and on
| |
| protein nutrition (Leathem, 1959b, c). An
| |
| encyclopedic survey of the biology of human nutrition has been made by Keys,
| |
| Brozec, Hernschel, Michelsen and Taylor
| |
| (1950).
| |
| | |
| II. Nature of Problems in Nutritional
| |
| Studies
| |
| | |
| A. THYEOID GLAND, NUTRITION, AND
| |
| REPRODUCTION
| |
| | |
| Normal development of the reproductive
| |
| organs and their proper functioning in
| |
| | |
| TABLE 12.1
| |
| Ovarian response to chorionic gonadrotrophin,
| |
| | |
| as modified by thiouracil and diet
| |
| | |
| (From J. H. Leathem, in Recent Progress in
| |
| | |
| the Endocrinology of Reproduction, Academic
| |
| | |
| Press, Inc., New York, 1959.)
| |
| | |
| | |
| | |
| Diet
| |
| | |
| | |
| Ovarian Weight
| |
| | |
| | |
| Cholesterol
| |
| | |
| | |
| Total
| |
| | |
| | |
| Free
| |
| | |
| | |
| 18 per cent casein .
| |
| | |
| 18 tier cent +
| |
| | |
| I'hiouracil
| |
| | |
| per cent casein . .
| |
| per cent + thiouracil
| |
| | |
| 18 per cent gelatin . . .
| |
| | |
| | |
| mg.
| |
| | |
| 87
| |
| 342
| |
| | |
| 59
| |
| 133
| |
| | |
| 59
| |
| 186
| |
| 27.5
| |
| | |
| | |
| %
| |
| 0.41
| |
| | |
| 0.20
| |
| | |
| 0.47
| |
| | |
| 0.22
| |
| | |
| 0.66
| |
| 0.26
| |
| 1.56
| |
| | |
| | |
| 0.18
| |
| 0.12
| |
| 0.23
| |
| 0.15
| |
| | |
| 0.22
| |
| | |
| | |
| 18 per cent -f
| |
| thio uracil
| |
| | |
| | |
| 0.18
| |
| 18
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Chorionic gonadotrophin = 10 I. U. X 20 days.
| |
| | |
| | |
| | |
| adults are dependent not only on the endocrine glands composing the hypophysealgonadal axis, but on others as well. The
| |
| importance of the thyroid, although not
| |
| the same for all species, is readily apparent
| |
| from the effects of prolonged hypo- and
| |
| hyperthyroid states on reproduction. Many
| |
| of these effects have been enumerated elsewhere (chapters by Albert, by Young on the
| |
| ovary, and by Zarrow) , but others also are
| |
| important. Thus steroid production may be
| |
| altered in hypothyroid animals; certainly
| |
| its metabolism is influenced. Myxedema is
| |
| associated with a profound change in androgen metabolism. Endogenous production of
| |
| androsterone is very low and subnormal
| |
| amounts of administered testosterone are
| |
| converted to androsterone. Triiodothyronine
| |
| corrects this defect (Hellman, Bradlow,
| |
| Zumoff, Fukushima and Gallagher, 1959).
| |
| The gonads of male and female offspring of
| |
| cretin rats are subnormal. The testes may
| |
| contain a few spermatocytes but no spermatozoa, and Leydig cells seem to secrete
| |
| little or no androgen. The ovaries may contain a few small follicles with antra, but
| |
| corpora lutea are absent and ovarian lipid
| |
| and cholesterol concentrations are very
| |
| low. Nevertheless, the gonads are competent to respond to administered gonadotrophin with a marked increase in weight.
| |
| However, administration of chorionic gonadotrophin to the hypothyroid rat stimulated follicular cyst formation rather than
| |
| folliculogenesis and corpora lutea formation
| |
| (Leathem, 1958b), but, for even this aberrant development, dietary protein was required (Leathem, 1959b) (Table 12.1). The
| |
| relationship between hypothyroidism and
| |
| ovarian function may provide a clue to a
| |
| possible origin of ovarian cysts, long known
| |
| to be a common cause of infertility and associated reproductive disorders. Clinical
| |
| cases of untreated myxedema exhibit ovarian cysts, and rats made hypothyroid for
| |
| eight months, had a higher percentage of
| |
| cystic ovaries than did euthyroid rats
| |
| (Janes, 1944).
| |
| | |
| The reproductive system of the adult
| |
| male is less affected than that of the immature male by a decrease in thyroid function, just as the testis of the adult is less
| |
| likely to reflect a change in protein nutrition
| |
| which is sufficient to alter the immature rat
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 669
| |
| | |
| | |
| | |
| testis. On the other hand, the lack of
| |
| demonstrable thyroid dysfunction in the
| |
| adult male does not exclude the possibility
| |
| of an effect of thyroid hormone on reproduction. The conversion of thyroxine to triiodothyronine may be hindered (Morton,
| |
| 1958) . Thyroxine was found to decrease the
| |
| number of active cells in the semen and to
| |
| reduce motility, whereas triiodothyronine
| |
| increased the number of active spermatozoa
| |
| (Farris and Colton, 1958; Reed, Browning
| |
| and O'Donnell, 1958j. Small dosages of thyroxine stimulated spermatogenesis in the
| |
| mouse, rabbit, and ram (Maqsood, 1952)
| |
| and were beneficial in normal guinea pigs
| |
| and rats (Richter and Winter, 1947; Young,
| |
| Rayner, Peterson and Brown, 1952).
| |
| | |
| In many species reproduction occurs despite hypothyroidism, but fecundity may
| |
| be subnormal (Peterson, Webster, Rayner
| |
| and Young, 1952). Feeding an antithyroid
| |
| drug, thiouracil, to female rats may or may
| |
| not prevent pregnancy, but it reduces the
| |
| number of young per litter. Thiouracil feeding continued through lactation will decrease litter size (Leathem, 1959b). Hypothyroid guinea pigs gave birth to some live
| |
| young, but the percentage approached normal only when thyroxine was administered
| |
| (Hoar, Goy and Young, 1957). Pregnant
| |
| euthyroid animals responded to thyroxine
| |
| by delivering more living young than normal control pigs (Peterson, Webster, Ravner and Young, 1952) . The extent to which
| |
| such effects are consequences of the reduction in appetite, metabolism, and absorption of food from the gut which are associated with hypothyroidism has not been
| |
| determined.
| |
| | |
| Hyperthyroidism, on the other hand, will
| |
| increase the appetite and enhance absorption of food from the gut, as the increased
| |
| metabolism requires more calories, minerals,
| |
| vitamins, choline, and methionine. In adult
| |
| rats hyperthyroidism induces a marked loss
| |
| in body fat and accelerates protein catabolism. The two effects, if unchecked, result
| |
| in loss of body weight and death. In immature males hyperthyroidism slows gain
| |
| in body weight, retards testis growth and
| |
| maturation, and abolishes androgen secretion (Table 12.2). Altering dietary protein
| |
| in adult animals failed to modify the thyroid hormone effects, thereby suggesting
| |
| | |
| | |
| | |
| TABLE 12.2
| |
| | |
| Effects of diet and thyroid {0.2 'per
| |
| | |
| cent) on immature rats
| |
| | |
| (From J. H. Leathem, in Recent Progress in
| |
| | |
| the Endocrinology of Reproduction, Academic
| |
| | |
| Press, Inc., New York, 1959.)
| |
| | |
| | |
| | |
| Diet
| |
| | |
| | |
| Testis Weight
| |
| | |
| | |
| Seminal
| |
| | |
| | |
| (Casein) X 30 Days
| |
| | |
| | |
| Actual
| |
| | |
| | |
| Relative
| |
| | |
| | |
| Vesicles
| |
| | |
| | |
| 20 per cent
| |
| | |
| 20 per cent +
| |
| thyroid
| |
| | |
| 6 per cent
| |
| | |
| 6 per cent +
| |
| thyroid
| |
| | |
| per cent
| |
| | |
| per cent -|thyroid
| |
| | |
| | |
| mg.
| |
| 1G94
| |
| | |
| 1090
| |
| | |
| 825
| |
| | |
| 245
| |
| | |
| 140
| |
| | |
| 95
| |
| | |
| | |
| mg./lOOgm.
| |
| | |
| 1035
| |
| | |
| 881
| |
| 1232
| |
| | |
| 650
| |
| | |
| 346
| |
| | |
| 261
| |
| | |
| | |
| mg.
| |
| 88
| |
| | |
| 9
| |
| 16
| |
| | |
| 7
| |
| 7
| |
| 6
| |
| | |
| | |
| | |
| that the metabolic demands of other tissues
| |
| were making increased withdrawals from
| |
| the metabolic pool of nitrogen and thus
| |
| hindering testis growth. In euthyroid rats, a
| |
| 6 per cent protein diet will permit testis
| |
| growth in the absence of a gain in body
| |
| weight, but hyperthyroidism prevents this
| |
| preferential effect. Although Moore (1939)
| |
| considered the effect of thyroid hormone on
| |
| reproduction as possibly due to general body
| |
| emaciation, the testis seems to be less responsive than the body as a whole. Adult
| |
| rats fed 0.2 per cent desiccated thyroid
| |
| exhibited no correlation between loss of
| |
| body weight, change in testis weight, or
| |
| protein composition of testis at two levels
| |
| of casein and lactalbumin (Leathem,
| |
| 1959b) . The testes were seemingly not influenced by the metabolic nitrogen changes
| |
| which caused a loss in carcass nitrogen
| |
| and an associated increase in kidney and
| |
| heart nitrogen.
| |
| | |
| The mechanism of thyroid hormone action on reproduction is far from clear. As
| |
| we have noted, a part of its action may be
| |
| through the regulation of nutritional processes. Thyroid function is influenced by
| |
| the biologic value of the dietary protein
| |
| (Leathem, 1958a) and the specifie amino
| |
| acids fed (Samuels, 1953). In turn, an
| |
| altered thyroid function will influence the
| |
| nitrogen contributions to the metabolic pool
| |
| by reducing appetite and absorption from
| |
| | |
| | |
| | |
| 670
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| the gut, and by changing the contributions
| |
| of nitrogen to the metabolic pool made by
| |
| the body tissues. Hypothyroidism interferes
| |
| with the refilling of body protein stores;
| |
| consequently, protein needs of the reproductive organs may not be fully met (Leathern, 1953). It is consistent with this
| |
| opinion that testis recovery from protein
| |
| deprivation in hypothyroid rats was aided
| |
| by thyroxine treatment (Horn, 1955).
| |
| | |
| Conversion of carotene to vitamin A may
| |
| be prevented by hypothyroidism, suggesting
| |
| that a subnormal amount of this vitamin
| |
| may contribute to fetal loss. An increased
| |
| intake of B vitamins might be required as
| |
| hypothyroidism aggravates a vitamin B12
| |
| deficiency, and increased intake of B vitamins enhances the capacity of young rats to
| |
| withstand large doses of thiouracil (Meites,
| |
| 1953). Although a reduced metabolic rate
| |
| might seemingly reduce vitamin requirements, more efficient metabolic activities,
| |
| in the absence of hormonal stimuli, seem to
| |
| occur when vitamin intake is increased
| |
| (Meites, Feng and Wilwerth, 1957).
| |
| | |
| Reproduction is influenced by effects
| |
| which are the opposite of a number of
| |
| those just cited, i.e., effects of malnutrition
| |
| on thyroid function. The need for iodine in
| |
| the prevention of goiter is well known.
| |
| However, certain foods prevent the utilization of iodine in the synthesis of thyroid
| |
| hormone. The foods containing an antithyroid or goitrogenic agent, as tested in
| |
| man, include rutabaga, cabbage, brussels
| |
| sprouts, cauliflower, turnip, rape, kale, and
| |
| to a lesser extent peach, pear, strawberry,
| |
| spinach, and carrot (Greer and Astwood,
| |
| 1948). A potent goitrogen isolated from
| |
| rutabaga is L-5-vinyl-2-thiooxazolidine
| |
| ((ireer, 1950, 1956). Reduced food intake
| |
| will decrease the thyroid gland response to
| |
| goitrogens (Gomez-Mont, Paschkis and
| |
| Cantarow, 1947; Meites and Agrawala,
| |
| 1949), the uptake of I^^^ (Meites, 1953),
| |
| and the level of thyrotrophic hormone in
| |
| laboratory animals (D'Angelo, 1951). The
| |
| thyroid changes associated with malnutrition in man arc uncertain (Zubiran and
| |
| Gomez-Mont, 1953). However, a decreased
| |
| functioning of the gland in anorexia nervosa, followed by an increased functioning
| |
| on refeeding (Poiioff, Lasche, Nodine,
| |
| | |
| | |
| | |
| Schneeberg and \'ieillard, 1954), is suggestive of a direct nutritional need.
| |
| | |
| Changes in the thyrotrophic potency of
| |
| the rat hypophysis have been observed in
| |
| various vitamin deficiencies. Thiamine deficiency may increase thyroid function, but
| |
| vitamin A deficiency may have the opposite
| |
| effect (Ershoff, 1952). The difficulties inherent in the assay of thyroid-stimulating
| |
| hormone (TSH) , even by current methods,
| |
| prevent one from drawing definite conclusions from the available data.
| |
| | |
| Immature animals given thyroxine are
| |
| retarded in growth and do not survive. However, increasing dietary thiamine, pyridoxine, or vitamin B12 improves the ability of
| |
| the young rat to withstand large dosages
| |
| of thyroid substances (Meites, 1952), as
| |
| does methionine (Boldt, Harper and Elvehjem, 1958). Consideration must also be
| |
| given to the need for nutritional factors
| |
| which play a minor role in normal metabolic
| |
| states but increase in importance in stress.
| |
| Thus yeast and whole liver contain antithyrotoxic substances (Drill, 1943; Ershoff,
| |
| 1952; Overby, Frost and Fredrickson,
| |
| 1959).
| |
| | |
| Excessive thyroid hormone will prevent
| |
| maturation of the ovary and in adult rats
| |
| will cause ovarian atrophy with a cessation
| |
| of estrous cycles. Addition of yeast to the
| |
| diet permitted estrous cycles to continue
| |
| (Drill, 1943), but gonadal inhibition in the
| |
| immature animal was not ]3revented. However, whole liver or its w^ater-insoluble fraction counteracted the gonadal inhibition induced by hyperthyrodism in immature
| |
| rats (Ershoff, 1952). Biochemical mechanisms by which these dietary supplements
| |
| can benefit rats given excessive quantities
| |
| of hormone are unknown.
| |
| | |
| B. .\DREXAL GLAND, NUTRITION, AND
| |
| REPRODUCTION
| |
| | |
| The problem of the relationship between
| |
| adrenal steroid secretions and the reproductive system is one that still requires
| |
| clarification. Furthermore, the possible influences of nutrition can only be inferred
| |
| from the effects of adrenal steroids on the
| |
| major metabolic systems of the body.
| |
| | |
| In the female there is a close relationshiji
| |
| between the adrenal and the estrous and
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| iul
| |
| | |
| | |
| | |
| menstrual cycles (Zuckerman, 1953; chapter by Young on the ovary). The ovary
| |
| would seem to require cortical steroids for
| |
| the normal functioning of its own metabolic
| |
| processes and for those which it influences
| |
| peripherally. The Addisonian patient may
| |
| show ovarian follicular atresia and a loss of
| |
| secondary sex characteristics, and the untreated adrenalectomized rat exhibits a
| |
| decrease in ovarian size and has irregular
| |
| cycles (Chester Jones, 1957). The decline
| |
| in size of the ovary after adrenalectomy
| |
| is due to impaired sensitivity to folliclestimulating hormone (FSH) rather than to
| |
| a decreased production of FSH, and the
| |
| ovarian response is corrected by cortisone
| |
| (Mandl, 1954).
| |
| | |
| Reproductive potential is not necessarily
| |
| lost when there is adrenal insufficiency, but
| |
| pregnancy is not well tolerated by women
| |
| with Addison's disease. Furthermore, adrenalectomy in rats at the time of mating or
| |
| 4 to 6 days after mating resulted in abortion. Improved pregnancy maintenance was
| |
| obtained in adrenalectomized rats given
| |
| saline or cortisone acetate (Davis and Plotz,
| |
| 1954) , whereas desoxycorticosterone acetate
| |
| alone extended the pregnancy period beyond
| |
| normal time (Houssay, 1945). Essentially
| |
| normal pregnancies were obtained in adrenalectomized rats given both cortisone
| |
| acetate and desoxycorticosterone acetate
| |
| (Cupps, 1955). Substitution of cortisone
| |
| acetate for adrenal secretions may be incomplete because the adrenal hormone in
| |
| the normal rat is primarily corticosterone
| |
| and because cortisone enhances the excretion of certain amino acids and vitamins. It
| |
| would be interesting to test a diet with a
| |
| high vitamin content on the capacity of an
| |
| adrenalectomized rat to maintain pregnancy, because improved survival of operated rats is obtained by giving vitamin Bio
| |
| (Meites, 1953) or large doses of pantothenic acid, biotin, ascorbic acid, or folic
| |
| acid (Ralli and Dumm, 1952; Dumm and
| |
| Ralli, 1953).
| |
| | |
| An adrenal influence over protein metabolism is well known, but protein nutrition,
| |
| in turn, can influence cortical steroid effectiveness. In fact, an extension of the life
| |
| span of adrenalectomized rats is not obtained with adrenal steroids if the diet
| |
| | |
| | |
| | |
| lacks protein (Leathern, 1958a). A low
| |
| protein diet alone will not improve survival after adrenalectomy, but better survival is obtained when the rats are given
| |
| saline. When the low protein diet was supplemented with methionine, a definite improvement in life span was observed and the
| |
| possibility that cortisone exerts its effect by
| |
| drawing on the carcass for methionine was
| |
| suggested (Aschkenasy, 1955a, b).
| |
| | |
| Reducing dietary casein to 2 per cent
| |
| seriously endangers pregnancy in the rat,
| |
| but the addition of progesterone permits
| |
| 80 per cent of the pregnancies to be maintained. However, removal of the adrenal
| |
| glands counteracts the protective action of
| |
| the progesterone, only 10 per cent of the
| |
| pregnancies continuing to term. Addition
| |
| of methionine to the low casein diet improved pregnancy maintenance, but 1 mg.
| |
| cortisone acetate plus progesterone provided the best results (Aschkenasy-Lelu
| |
| and Aschkenasy, 1957; Aschkenasy and
| |
| Aschkenasy-Lelu, 1957). These data emphasize the importance of nutrition in obtaining an anticipated hormone action. Further investigation might be directed toward
| |
| the study of whole proteins other than casein, for the biologic value of proteins differs from normal when tested in adrenalectomized rats (Leathem, 1958a) .
| |
| | |
| As Albert has noted in his chapter, adrenalectomy has little or no effect on the
| |
| testis. Gaunt and Parkins (1933) found no
| |
| degenerative changes in the testes of adult
| |
| rats dying of adrenal insufficiency, although
| |
| an increase in the testis : body-weight ratios
| |
| was noted in rats fed 18 per cent and 4 per
| |
| cent protein (Aschkenasy, 1955c). If adrenalectomized rats are kept on a maintenance dosage of cortisone acetate for 20
| |
| days and fed dietary proteins of different
| |
| biologic values, one finds that testis-composition of protein, lipid, and glycogen varies in the same manner as in the normal
| |
| rat (Wolf and Leathem, 1955) (Table 12.3).
| |
| | |
| When the adrenal glands are intact, the
| |
| influence of diet on their functional capacity and indeed on the hypophyseal- adrenal
| |
| axis must be considered. Zubiran and Gomez-]\Iont (1953) showed that patients exhibiting gonadal changes associated with
| |
| chronic malnutrition also exhibit adrenal
| |
| | |
| | |
| | |
| 672
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GOXADS
| |
| | |
| | |
| | |
| TABLE 12.3
| |
| | |
| Nutritional effects on the testes of cortisonemaintained adrenalectomized rats
| |
| (From R. C. Wolf and J. H. Leathern,
| |
| Endocrinology, 57, 286, 1955.)
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Testes Composition
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| (per cent)
| |
| | |
| | |
| Treatment
| |
| | |
| | |
| Diet
| |
| | |
| | |
| Testes
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Protein
| |
| | |
| | |
| Lipid
| |
| | |
| | |
| Glycogen
| |
| | |
| | |
| | |
| | |
| | |
| | |
| mg.
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Corti
| |
| | |
| 20 per cent
| |
| | |
| | |
| 703
| |
| | |
| | |
| 68.5
| |
| | |
| | |
| 30.4
| |
| | |
| | |
| 0.13
| |
| | |
| | |
| sone
| |
| | |
| | |
| casein
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ace
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| tate
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| | |
| | |
| 1211
| |
| | |
| | |
| 70.5
| |
| | |
| | |
| 29.4
| |
| | |
| | |
| 0.15
| |
| | |
| | |
| Corti
| |
| | |
| 20 per cent
| |
| | |
| | |
| 808
| |
| | |
| | |
| 61.0
| |
| | |
| | |
| 31.8
| |
| | |
| | |
| 0.17
| |
| | |
| | |
| sone
| |
| | |
| | |
| wheat
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ace
| |
| | |
| ghiten
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| tate
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| | |
| | |
| 816
| |
| | |
| | |
| 62.3
| |
| | |
| | |
| 32.2
| |
| | |
| | |
| 0.17
| |
| | |
| | |
| Corti
| |
| | |
| 20 per cent
| |
| | |
| | |
| 1014
| |
| | |
| | |
| 64.3
| |
| | |
| | |
| 31.3
| |
| | |
| | |
| 0.17
| |
| | |
| | |
| sone
| |
| | |
| | |
| peanut
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| ace
| |
| | |
| flour
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| tate
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| Control
| |
| | |
| | |
| | |
| | |
| 699
| |
| | |
| | |
| 68.5
| |
| | |
| | |
| 31.3
| |
| | |
| | |
| 0.12
| |
| | |
| | |
| | |
| hypofimction. Several clinical tests permitted the evaluation of subnormal adrenal
| |
| function which, however, did not reach
| |
| Addisonian levels. Malnutrition not onlyreduced hypophyseal adrenocorticotrophic
| |
| hormone (ACTH), but also prevented an
| |
| incomplete response by the adrenal glands
| |
| to injected ACTH. In laboratory rodents,
| |
| anterior hypophyseal function is also influenced by dietary protein and vitamin
| |
| levels (Ershoff, 1952). The importance of
| |
| dietary protein in the hypophyseal-adrenal
| |
| system has recently been re-emphasized
| |
| (Leathem, 1957; Goth, Nadashi and Slader,
| |
| 1958). Furtiiermore, adrenal cortical function is affected by vitamin deficiencies
| |
| (Morgan, 1951), from which it appears
| |
| that pantothenic acid is essential for cortical hormone elaboration (Eisenstcin, 1957).
| |
| Administration of excessive amounts of
| |
| cortical steroids can induce morphologic
| |
| changes which have been compared to inanition (Baker, 1952). Not only is nitrogen
| |
| loss enhanced, but hyperglycemia can also
| |
| be induced which, therefore, increases the
| |
| need for thiamine. Cortical steroids influence the metabolism of various vitamins
| |
| | |
| | |
| | |
| (Draper and Johnson, 1953; Dhyse, Fisher,
| |
| Tullner and Hertz, 1953; Aceto, Li Moli
| |
| and Panebianco, 1956; Ginoulhiac and
| |
| Nani, 1956). H a vitamin deficiency already
| |
| exists, administration of cortisone will aggravate the condition (Meites, Feng and
| |
| Wilwerth, 1957). Nevertheless, drastic effects of therapeutic doses of cortisone on
| |
| reproductive function do not occur. In rare
| |
| cases loss of libido has been reported in
| |
| the male, but mori)hologic changes in the
| |
| testis were not observed (JVladdock, Chase
| |
| and Nelson, 1953). Cortisone has little if
| |
| any effect on the weight of the rat testis
| |
| (Moore, 1953; Aschkenasy, 1957) and does
| |
| not influence testis cholesterol (Migeon,
| |
| 1952). In the female, menstrual disturbances have been noted in association with
| |
| cortisone therapy, with the occurrence of
| |
| hot flashes (Ward, Slocumb, Policy, Lowman and Hench, 1951). However, cortisone
| |
| corrected disturbances during the follicular
| |
| phase, possibly by increasing FSH release
| |
| (Jones, Howard and Langford, 1953). Cortisone also increased the number of follicles
| |
| in the ovary of the rat (Moore, 1953), but
| |
| not in the rabbit. Cortisone administration
| |
| did not prevent the enhanced ovarian response to chorionic gonadotrophin seen in
| |
| hypothyroid rats (Leathem, 1958b) and
| |
| had little effect on mice in parabiosis ( Noumura, 1956).
| |
| | |
| In pregnant female rabbits resorption and
| |
| stunting of fetuses occurred during treatment with large doses of cortisone (Courrier
| |
| and Collonge, 1951). Similar effects were
| |
| noted in mice (LcRoy and Domm, 1951 ;
| |
| Robson and Sharaf, 1951).
| |
| | |
| Some of the metabolic derangements of
| |
| human toxemia of pregnancy have been
| |
| correlated with accelerated secretion of
| |
| adrenal steroids creating a steroid imbalance (see chapter by Zarrow). Cortisone is
| |
| reported to have a beneficial effect on some
| |
| cases (Moore, Jessop, 'Donovan, Barry,
| |
| Quinn and Drury, 1951). Protein inade({uacies may also be etiologic in toxemia and
| |
| further (>xamination of the possibility
| |
| sliould he made.
| |
| | |
| C. DIABETES MELLITUS, NUTRITION, AND
| |
| REPRODUCTION
| |
| | |
| (llycosuria can be induced experimentally
| |
| by starvation, overfeeding, and shifting
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 673
| |
| | |
| | |
| | |
| diet^ from one of high fat content to one
| |
| i; which is isocaloric but high in carbohydrate
| |
| (Ingle, 1948). Force feeding a high carbohydrate diet will eventually kill a rat despite insulin administration aimed at controlling glycosuria (Ingle and Nezamis,
| |
| 1947). In man excessive eating leading to
| |
| obesity increases insulin demand and, in
| |
| many diabetics of middle age, obesity precedes the onset of diabetes. With our present
| |
| knowledge we must conclude that overfeeding is wrong when glycosuria exists and that
| |
| vitamin B supplements may be of value
| |
| in diabetes (Meites, Feng and Wilwerth,
| |
| 1957; Salvesen, 1957).
| |
| | |
| In man urinary 17-ketosteroids and androgen levels are subnormal in diabetes
| |
| (Horstmann, 1950), and in the diabetic rat
| |
| pituitary gonadotrophins are reduced
| |
| (Shipley and Danley, 1947), but testis hyaluronidase does not change (Moore, 1948) .
| |
| When hyperglycemia exists in rats, semen
| |
| ■] carbohydrates increase (Mann and Lutwak-Mann, 1951).
| |
| | |
| Hypoglycemia influences the male reproductive organs. In rats tolbutamide or
| |
| insulin produce lesions of the germinal
| |
| epithelium which can be prevented by
| |
| \' simultaneous administration of glucose.
| |
| When 2 to 5 hypoglycemic comas are induced, such testis injuries increase progressively in number and frequency, and
| |
| only a partial return to normal is observed
| |
| a month later (Mancini, Izquierdo, Heinrich, Penhos and Gerschenfeld, 1959).
| |
| | |
| It is well known that the incidence of
| |
| infertility in the pre-insulin era was high
| |
| in young diabetic women. Fertility is also
| |
| reduced in diabetic experimental animals,
| |
| and rat estrous cycles are prolonged (Davis,
| |
| Fugo and Lawrence, 1947) . Insulin is corrective (Sinden and Longwell, 1949; Ferret,
| |
| Lindan and Morgans, 1950). Pregnancy in
| |
| women with uncontrolled diabetes may
| |
| terminate in abortion or stillbirth, possibly
| |
| l)ecause toxemia of pregnancy is high (Pedersen. 1952). In rats pancreatectomy performed the 8th to 12th day of pregnancy
| |
| increased the incidence of stillbirths (Hultciuist, 1950). In another experiment almost
| |
| one- fourth of 163 animals with diabetes
| |
| induced by alloxan on the 10th to 12th day
| |
| of pregnancy died before parturition and
| |
| | |
| | |
| | |
| about 25 ])er cent of the survivors aborted
| |
| (Angcrvall, 1959).
| |
| | |
| D. STERILE-OBESE SYNDROME
| |
| | |
| A sterile-obese syndrome in one colony of
| |
| mice has been shown to be a recessive monogenic trait (Ingalls, Dickie and Snell, 1950).
| |
| Obesity was transmitted to subsequent generations by way of ovaries that were transplanted from obese donors to nonobese recipients (Hummel, 1957). Obesity was
| |
| transmitted by obese females receiving hormonal therapy and mated to obese males
| |
| kept on restricted food intake (Smithberg
| |
| and Runner, 1957). In addition to the investigations of the hereditary nature of the
| |
| sterile-obese syndrome, the physiologic
| |
| basis for the sterility has been studied in
| |
| reference to the presence of germ cells, viability of ova and sperm, integrity of the
| |
| ovary, and response of the uterus to estrogen (Drasher, Dickie and Lane, 1955). The
| |
| data indicate that sterility in some obese
| |
| males can be prevented by food restriction
| |
| and that sterility in certain obese females
| |
| can be corrected.
| |
| | |
| E. DIET AND THE LIVER
| |
| | |
| The concentration of hormones which
| |
| reaches the target organs in the blood is the
| |
| result of the rate of their production, metabolism, and excretion. How hypophyseal
| |
| hormones are destroyed is not clear, but
| |
| current data make it apparent that pituitary hormones have a short half-life in the
| |
| circulatory system. Exerting a major control over circulating estrogen levels is the
| |
| liver, with its steroid-inactivating systems.
| |
| Zondek (1934) initially demonstrated that
| |
| the liver could inactivate estrogens and this
| |
| finding has had repeated confirmation
| |
| (Cantarow, Paschkis, Rakoff and Hansen,
| |
| 1943; De:\Ieio, Rakoff, Cantarow and
| |
| Paschkis, 1948; Vanderlinde and Westerfield, 1950). Other steroids are also inactivated by the liver with several enzyme
| |
| systems being involved; the relative concentration of these enzymes varies among
| |
| species of vertebrates (Samuels, 1949).
| |
| | |
| The liver is a labile organ which readib.'
| |
| responds to nutritional modifications; the
| |
| induced liver changes alter the steroid-inactivating systems of this organ. Thus, inanition (Drill and Pfeiffer, 1946; Jailer,
| |
| | |
| | |
| | |
| G74
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| 1948) , vitamin B complex deficiency (Segaloff and Segaloff, 1944; Biskind, 1946), and
| |
| protein restriction (Jailer and Seaman,
| |
| 1950) all influence the capacity of the liver
| |
| to detoxify steroids. Reduced protein intake
| |
| is a primary factor in decreasing the effectiveness of the steroid-inactivating system
| |
| (Jailer and Seaman, 1950; Vanderlinde and
| |
| Westerfield, 1950). Rats fed an 8 per cent
| |
| casein diet lose their capacity to inactivate
| |
| estrone within 10 days. However, ascorbic
| |
| acid alone or in combination with glutathione restored the estrone-inactivating system (Vasington, Parker, Headley and Vanderlinde, 1958).
| |
| | |
| Failure of steroids to be inactivated will
| |
| influence the hypophyseal-gonadal axis. In
| |
| turn the excess of estrogen will decrease
| |
| gonadotrophin production by the hypophysis and thus reduce steroid production by
| |
| the gonad. In addition nutritional modifications influence hypophyseal and possibly
| |
| gonadal secretory capacity directly. Conceivably, nutritional alterations could
| |
| modify the amount of steroid secreted or
| |
| interfere with complete steroid synthesis
| |
| by a gland.
| |
| | |
| Fatty infiltration of the liver and a
| |
| general increase in fat deposition occur in
| |
| fed and fasted rats after the injection of
| |
| certain pituitary extracts and adrenal steroids and after the feeding of specific diets.
| |
| Impaired estrogen inactivation has been
| |
| associated with a fatty liver, but Szego and
| |
| Barnes (1943) believe that the major influence is inanition. In fact, estrogens, especially ethinyl estradiol, interfere with
| |
| fatty infiltration of the liver induced by a
| |
| low protein diet (Gyorgy, Rose and Shipley, 1947) or by a choline-deficient diet
| |
| (Emerson, Zamecnik and Nathanson, 1951).
| |
| Stilbestrol, however, did not prevent the increase in liver fat induced by a protein-free
| |
| diet (Glasser, 1957). Estrogens that are
| |
| effective in preventing fatty infiltration may
| |
| act by sparing methionine or choline or by
| |
| inhibiting growth hormone (Flagge, Marasso and Zimmerman, 1958).
| |
| | |
| Ethionino, the antimetabolite of nu'thioniiK', Avill induce a fatty liver and inhibit hepatic protein synthesis in female,
| |
| but not in male rats (Farber and Segaloff,
| |
| 1955; Farber and Corban, 1958). Pretreatment of females with testosterone prevents
| |
| | |
| | |
| | |
| the ethionine effect, but this blockage of
| |
| ethionine action need not be related to
| |
| androgenic or progestational properties of
| |
| steroids (Ranney and Drill, 1957).
| |
| | |
| III. Hypophysis and Diet
| |
| | |
| Studies involving acute and chronic starvation have shown that gonadal hypofunction during inanition is primarily due to
| |
| diminished levels of circulating gonadotrophins. Because of the similarity to
| |
| changes following hypophysectomy, the
| |
| endocrine response to inanition has been
| |
| referred to as "pseudohypophysectomy."
| |
| | |
| A. INANITION
| |
| | |
| The hypophysis has been implicated in
| |
| human reproduction disturbances associated with undernutrition. Hypophyseal
| |
| atrophy and a decrease in urinary gonadotrophins have been observed in chronic
| |
| malnutrition (Klinefelter, Albright and
| |
| Griswold, 1943; Zubiran and Gomez-]\Iont,
| |
| 1953) and anorexia nervosa (Perloff,
| |
| Lasche, Nodine, Schneeberg and Vieillard,
| |
| 1954). Refeeding has restored urinary
| |
| gonadotrophin levels in some cases, but
| |
| hypoj^hyseal damage may result from severe
| |
| food restriction at puberty (VoUmer, 1943;
| |
| Samuels, 1948).
| |
| | |
| The influence of inanition on the reproductive organs of lal)oratory rodents
| |
| is well recognized but the cft'ects on the
| |
| hypophysis cannot be presented conclusively. In support of prior investigations,
| |
| Mulinos and Pomerantz (1941a, b) in rats
| |
| and Giroud and Desclaux (1945) in guinea
| |
| pigs observed a hypophyseal atrophy following chronic underfeeding as well as a
| |
| decrease in cell numbers and mitoses. In
| |
| fact, refeeding after chronic starvation
| |
| resulted in only a partial recovery of hypophyseal weight (Quimby, 1948). Nevertheless, complete starvation did not influence relative gland weight in female rats
| |
| (Meites and Reed, 1949), and cytologic
| |
| evidence (periodic acid-Schiff (PAS) test)
| |
| of an estimated 3- fold increase in gonadoti'ophin content was claimed following
| |
| chronic starvation (Pearse and Rinaldini,
| |
| 1950). Assays of hypophyseal gonadotrophin content in chronically starved rats
| |
| of both sexes have l)een reported as decreased (Mason and Wolfe, 1930; Werner,
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 675
| |
| | |
| | |
| | |
| 1939), unchanged (,]\Iarrian and Parkes,
| |
| 1929; Pomerantz and Mulinos, 1939; Maddock and Heller, 1947; Meites and Reed,
| |
| 1949; Blivaiss, Hanson, Rosenzweig and
| |
| McNeil, 1954), or increased (Rinaldini,
| |
| 1949; Vanderlinde and Westerfield, 1950).
| |
| An increase in pituitary gonadotrophin was
| |
| evident when hormone content was related
| |
| to milligrams of tissue (Meites and Reed,
| |
| 1949). Thus, the hormone release mechanism may fail in starvation, and eventually
| |
| gonadotrophin production will be reduced
| |
| to a minimum (]\laddock and Heller, 1947).
| |
| | |
| Gonadectomy of fully fed rats is followed
| |
| by an increase in hypophyseal gonadotrophin content. Chronic starvation, however, prevented the anticipated changes in
| |
| the pituitary gland following gonadectomy
| |
| in 8 of 12 female rats (Werner, 1939). On
| |
| the other hand, if adult female rats were
| |
| subjected to 14 days of reduced feeding
| |
| 1 month after ovariectomy, no change in
| |
| the elevated gonadotrophin levels was noted
| |
| (Meites and Reed, 1949). In contrast,
| |
| Gomez-Mont (1959) observed above normal
| |
| urinary gonadotrophins in many menopausal and postmenopausal women despite
| |
| undernutrition.
| |
| | |
| It is apparent that uniformity of opinion
| |
| as to how starvation influences hypophyseal
| |
| gonadotrophin content has not been attained. Several explanations can be given for
| |
| the discrepancies. (1) There have been unfortunate variations in experimental design.
| |
| IVIaddock and Heller (1947) starved rats
| |
| for 12 days, whereas Rinaldini (1949) used
| |
| a low calorie diet of bread and milk for
| |
| 30 days. Other variations in feeding have
| |
| included feeding one-half the intake required for growth (Mulinos and Pomerantz,
| |
| 1941b I, regimens of full, one-half, oneciuarter, and no feeding for 7 and 14 days
| |
| (Meites and Reed, 1949), and feeding inadequate amounts of a standard rat diet
| |
| for 1 to 4 months (Werner, 1939). (2)
| |
| Hypophyseal implants and anterior pituitary extracts should not be compared, for
| |
| variable gonadotrophin production may follow implantation procedures, depending on
| |
| whether necrosis or growth occurs (Maddock and Heller, 1947). (3) There has been
| |
| an insufficient standardization of experimental materials. The assay animal has
| |
| usually been the immature female rat, but
| |
| | |
| | |
| | |
| occasionally the immature mouse has been
| |
| used, and Rinaldini (1949) used the hypophysectomized rat.
| |
| | |
| B. PROTEIN
| |
| | |
| The need for specific food elements by
| |
| the hypophysis warrants consideration,
| |
| for the hormones secreted by this gland
| |
| are protein in nature and the amino acids
| |
| for protein synthesis must be drawn from
| |
| body sources. However, dietary protein
| |
| levels can vary from 15 per cent to 30 per
| |
| cent without influencing hypophyseal gonadotrophin content in rats (Weatherby and
| |
| Reece, 1941), but diets containing 80 per
| |
| cent to 90 per cent of casein increased
| |
| hypophyseal gonadotrophin (TuchmannDuplessis and Aschkenasy-Lelu, 1948). Removal of protein from the diet will decrease
| |
| hypophyseal gonadotrophin content in
| |
| adult male rats in comparison with pair-fed
| |
| and ad libitum-ied controls, but the decrease may or may not be significant in a
| |
| 30-day period; luteinizing hormone (LH)
| |
| seemed to be initially reduced. Extension of
| |
| the period of protein depletion another 2
| |
| months resulted in a significant lowering of
| |
| hy]iophyseal gonadotrophin levels (Table
| |
| 12.4) (Leathern, 1958a). On the other
| |
| hand, an increased FSH with no decrease
| |
| in LH activity was observed in the hypophyses of adult female rats following
| |
| 30 to 35 days of protein depletion (Srebnik
| |
| and Nelson, 1957). The available data indicate that not only may a sex difference
| |
| exist, but also that species may differ; restitution of gonadotrophin in the discharged
| |
| rabbit pituitary was not influenced by in
| |
| TABLE 12.4
| |
| | |
| Influence of a protein-free diet on hypophyseal
| |
| | |
| gonadotrophin content
| |
| | |
| (From J. H. Leathern, Recent Progr. Hormone
| |
| | |
| Res., 14, 141, 1958.)
| |
| | |
| | |
| | |
| Days on PFD*
| |
| | |
| | |
| Xo. of Rats
| |
| | |
| | |
| Anterior
| |
| Pituitary
| |
| Weight
| |
| | |
| | |
| Recipient
| |
| Ovarv
| |
| Weight
| |
| | |
| | |
| | |
| | |
| | |
| | |
| nig.
| |
| | |
| | |
| mg.
| |
| | |
| | |
| | |
| | |
| | |
| 9
| |
| | |
| | |
| 8.3
| |
| | |
| | |
| 74
| |
| | |
| | |
| 30
| |
| | |
| | |
| 9
| |
| | |
| | |
| 7.3
| |
| | |
| | |
| 54
| |
| | |
| | |
| 50
| |
| | |
| | |
| 7
| |
| | |
| | |
| 7.0
| |
| | |
| | |
| 33
| |
| | |
| | |
| 90
| |
| | |
| | |
| 17
| |
| | |
| | |
| 6.0
| |
| | |
| | |
| 23
| |
| | |
| | |
| | |
| L^ntreated recipient ovarian weight = 15.4 mg.
| |
| * PFD = Protein-free diet.
| |
| | |
| | |
| | |
| 67G
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| adequate dietary protein (Friedman and
| |
| Friedman, 1940).
| |
| | |
| When anterior pituitar}^ glands of 60gm. male rats were extracted and administered to immature female recipients, ovarian
| |
| weight increased from 13.0 to 37.3 mg.
| |
| After feeding 20 per cent casein or fox chow
| |
| ad libitum for 14 days, the hypophyses of
| |
| male rats contained almost twice as much
| |
| gonadotrophin per milligram of tissue as
| |
| did the hypophyses of the initial controls.
| |
| Removal of protein from the diet for 14
| |
| days, however, reduced hypophyseal gonadotrophin concentration below the level
| |
| of the initial controls (Leathem and Fisher,
| |
| 1959).
| |
| | |
| Data on the hypophyseal hormone content as influenced by specific amino acid
| |
| deficiencies have not come to the author's
| |
| attention. Cytologically, however, Scott
| |
| (1956) noted that an isoleucine-deficient
| |
| diet depleted the pituitary gonadotrophic
| |
| cells of their PAS-positive material and reduced the size of acidophilic cells. Omission
| |
| of threonine, histidine, or tryptophan invoked similar effects. The changes probably represent the interference of a single
| |
| amino acid deficiency with protein metabolism rather than specific effects attributable to the lack of amino acid itself. Excessive amino acid provided by injecting
| |
| leucine, methionine, valine, tyrosine, or
| |
| glycine caused release of gonadotrophin
| |
| (Goth, Lengyel, Bencze, Saveley and Majsay, 1955).
| |
| | |
| Administration of 0.1 mg. stilbestrol for
| |
| 20 days to adult male rats eliminated detectable hypophyseal gonadotrophins. Hormone levels returned during the postinjection period provided the diet contained
| |
| adequate protein, whereas a protein-free diet
| |
| markedly hindered the recovery of hypophyseal gonadotrophins. The gonadotrophin
| |
| content of the pituitary gland correlated
| |
| well with the recovery of the reproductive
| |
| system, indicating that gonadotrophin production was subnormal on ]irotein-free feeding (Leathem, 1958a).
| |
| | |
| C. CAHBOHYDR.\TE .\ND FAT
| |
| | |
| Reproduction does not appear to be influenced by carbohydrates per se and hypophyseal alterations have not been noted.
| |
| | |
| | |
| | |
| Fat-deficient diets, however, do influence
| |
| reproduction and the hypophysis exhibits
| |
| cellular changes. Pituitary glands of female rats fed a fat-free diet contain a subnormal number of acidophiles and an increased number of basophiles (Panos and
| |
| Finerty, 1953) . In male rats the feeding oi
| |
| a fat-free diet increased hypophyseal basophiles, followed progessively by more castration changes (Finerty, Klein and Panos,
| |
| 1957; Panos, Klein and Finerty, 1959).
| |
| | |
| D. VITAMINS
| |
| | |
| Despite the many investigations relating
| |
| reproduction to vitamin requirements, relatively few have involved hypophyseal hormone estimations. Thus in 1955, Wooten,
| |
| Nelson, Simpson and Evans reported the
| |
| first definitive study which related pyridoxine deficiency to hypophyseal gonadotrophin content. Using the hypophysectomized rat for assay, pituitary glands
| |
| from Bo-deficient rats were shown to have
| |
| a 10-fold increase in FSH per milligram of
| |
| tissue and a slightly increased LH content.
| |
| Earlier studies had revealed that vitamin
| |
| Bi-free diets decreased pituitary gonadotrophins in male rats (Evans and Simpson,
| |
| 1930) and a similar effect of the folic acid
| |
| antagonist, aminopterin, in the monkey was
| |
| found later (Salhanick, Hisaw and Zarrow, 1952).
| |
| | |
| Male rats deficient in vitamin A exhibited
| |
| a 43 per cent increase, and castrated vitamin
| |
| A-deficient rats a 100 per cent increase in
| |
| hypophyseal gonadotrophin potency over
| |
| the normal controls (Mason and Wolfe,
| |
| 1930). The increase of gonadotrophin was
| |
| more marked in vitamin A-deficient male
| |
| than in vitamin A-deficient female rats.
| |
| Associated with the increase in hormone
| |
| level was a significant increase in basophile
| |
| cells (Sutton and Brief, 1939; Hodgson,
| |
| Hall, Sweetman, Wiseman and Converse,
| |
| 1946; Erb, Andrews, Hauge and King,
| |
| 1947).
| |
| | |
| A re\-iew of the literature up to 1944 permitted Mason to suggest that the anterior
| |
| hypophysis was not the instigator of reproductive disturbances in vitamin E deficiency. Nevertheless, Griesbach, Bell and
| |
| Livingston (1957), in an analysis of the
| |
| pituitary gland during progessive stages of
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 677
| |
| | |
| | |
| | |
| tocopherol deprivation, observed cytologic
| |
| changes in the hypophysis which preceded
| |
| testis changes. The "peripheral or FSH
| |
| gonadotrophes" increased in number, size,
| |
| and activity. The LH cells exhibited a
| |
| hyperplasia of lesser extent, but possibly
| |
| sufficient to increase LH in circulation and
| |
| to cause hypertrophy of the male accessory
| |
| glands. Gonadotrophic hormone content of
| |
| pituitary glands from vitamin E-deficient
| |
| rats may be decreased (Rowlands and
| |
| Singer, 1936), unchanged (Biddulph and
| |
| Meyer, 1941), or increased to a level between normal and that of the castrate, when
| |
| the adult male rats were examined after 22
| |
| weeks on a deficient diet (Nelson, 1933;
| |
| Drummond, Noble and Wright, 1939).
| |
| Using hypophysectomized male rats as assay animals, evidence was obtained that
| |
| FSH was increased in the pituitary glands
| |
| of vitamin E-deficient male and female rats
| |
| (P'an, Van Dyke, Kaunitz and Slanetz,
| |
| 1949).
| |
| | |
| IV. Male Reproductive System
| |
| | |
| A. TESTIS
| |
| | |
| The two basic functions of the male
| |
| gonads are to produce gametes and secrete
| |
| steroids. Spermatogenic activity can be
| |
| estimated from testis morphology and examination of semen samples. Androgen secretion can be estimated from urinary steroid levels, accessorj^ gland weight, and
| |
| from analyses of accessory sex gland secretions, i.e., fructose and citric acid. In normal maturation in the rabbit, rat, boar,
| |
| and bull, androgen secretion precedes spermatogenesis (Lutwak-Mann, 1958). On this
| |
| basis it would appear that well fed young
| |
| bulls may come into semen production 2 to
| |
| 3 months sooner than poorly fed animals
| |
| (Brat ton, 1957).
| |
| | |
| 1. Inanition
| |
| | |
| Complete starvation will pre^•ent maturation of immature animals. Furthermore,
| |
| marked undernutrition in 700 boys, 7 to 16
| |
| years of age, was associated with genital
| |
| infantilism in 37 per cent and cryptorchidism in 27 per cent (Stephens, 1941).
| |
| Restriction of food intake to one-half of the
| |
| normal in maturing bull calves had a
| |
| | |
| | |
| | |
| marked delaying effect on the onset of
| |
| seminal vesicle secretion, but a lesser delaying effect on spermatogenesis (Davies,
| |
| Mann and Rowson, 1957) . Limiting the food
| |
| intake to one-third of the normal did not
| |
| prevent the immature rat testis from forming spermatozoa at the same time as their
| |
| controls (Talbert and Hamilton, 1955).
| |
| When testis maturation was prevented by
| |
| inanition, a rapid growth and maturation
| |
| occurred on refeeding (Ball, Barnes and
| |
| Visscher, 1947; Quimby, 1948) but Schultze
| |
| (1955) observed that full body size was not
| |
| attained.
| |
| | |
| The reproductive organs of the adult are
| |
| more resistant to changes imposed by diet
| |
| than are those of the immature animal.
| |
| Thus, Mann and Walton (1953) found that
| |
| 23 weeks of underfeeding produced little
| |
| change in sperm density and motility in mature animals although seminal vesicle function was reduced. Li the male rat testis
| |
| hypofunction follows partial or complete
| |
| starvation (]\Iason and Wolfe, 1930; Mulinos and Pomerantz, 1941a; Escudero, Herraiz and Mussmano, 1948), but there is no
| |
| reduction in testicular nitrogen (Addis, Poo
| |
| and Lew, 1936). Loss of Leydig cell function precedes cessation of spermatogenesis
| |
| (Moore and Samuels, 1931) and is evident
| |
| by the atrophy of the accessory sexual organs (^lulinos and Pomerantz, 1941a) and
| |
| by an alteration in accessory gland secretion
| |
| (Pazos and Huggins, 1945; Lutwak-]\Iann
| |
| and Mann, 1950). Evidence of a tubular
| |
| effect is provided by the lack of motile
| |
| sperm (Reid, 1949). Severe dietary restriction is associated with the absence of
| |
| spermatozoa in the seminiferous tubules and
| |
| epididymis (Mason, 1933; Menze, 1941).
| |
| | |
| The human male suffering from chronic
| |
| malnutrition exhibits hypogonadism. The
| |
| testes atrophy and exhibit a decrease in size
| |
| of the seminiferous tubules; basement membrane thickening and small Leydig cells
| |
| are seen. These individuals excrete significantly subnormal amounts of 17-ketosteroids (Zubiran and Gomez-Mont, 19531.
| |
| Acute starvation may also decrease urinary
| |
| 17-ketosteroid and androgen levels as much
| |
| as 50 per cent, with recovery evident on refeeding (Perloff, Lasche, Nodine, Schneeberg and Vieillard. 1954).
| |
| | |
| | |
| | |
| 6/
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| TABLE 12.5
| |
| | |
| Effect of diet on the testes of immature rats
| |
| | |
| (From J. H. Leathern, in Re-productive Phijsiology
| |
| | |
| and Protein Nutrition, Rutgers University
| |
| | |
| Press, New Brunswick, N. J., 1959.)
| |
| | |
| | |
| | |
| Sperm
| |
| | |
| | |
| | |
| Initial control . . .
| |
| 20 per cent X 30
| |
| | |
| days
| |
| | |
| 6 per cent X 30
| |
| | |
| days
| |
| | |
| 3 per cent X 30
| |
| | |
| days
| |
| | |
| per cent X 30
| |
| | |
| days
| |
| | |
| per cent + 5
| |
| per cent liver. ,
| |
| | |
| per cent + 5
| |
| per cent yeast
| |
| | |
| G5 per cent X 30
| |
| davs
| |
| | |
| | |
| | |
| No. of
| |
| Rats
| |
| | |
| | |
| Testis
| |
| | |
| | |
| Weight
| |
| | |
| | |
| | |
| | |
| mg.
| |
| | |
| | |
| mg./lOOgm.
| |
| | |
| | |
| 10
| |
| | |
| | |
| 329
| |
| | |
| | |
| 825
| |
| | |
| | |
| 10
| |
| | |
| | |
| 1694
| |
| | |
| | |
| 1035
| |
| | |
| | |
| 16
| |
| | |
| | |
| 824
| |
| | |
| | |
| 890
| |
| | |
| | |
| 12
| |
| | |
| | |
| 380
| |
| | |
| | |
| 930
| |
| | |
| | |
| 10
| |
| | |
| | |
| 140
| |
| | |
| | |
| 346
| |
| | |
| | |
| 10
| |
| | |
| | |
| 112
| |
| | |
| | |
| 291
| |
| | |
| | |
| 10
| |
| | |
| | |
| 119
| |
| | |
| | |
| 296
| |
| | |
| | |
| 10
| |
| | |
| | |
| 1747
| |
| | |
| | |
| 1040
| |
| | |
| | |
| | |
| | |
| | |
| 100
| |
| | |
| 50
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| 100
| |
| | |
| | |
| | |
| 2. Protein
| |
| | |
| The minimal amount of dietary protein
| |
| which will support reproduction, lactation,
| |
| and growth is 16.7 per cent (Goettsch, 1949) .
| |
| Thus, it is not surprising that maturation
| |
| of testes and accessory sex organs was prevented in immature rats (Horn, 1955) and
| |
| mice (Leathern and DeFeo, 1952) when
| |
| they were fed a protein-free diet for 15 to
| |
| 30 days after weaning. Furthermore, supplements of 5 per cent liver to the casein-free
| |
| diet had no effect. After a month, the testes,
| |
| averaging 329 mg., decreased to 140 mg. in
| |
| rats fed per cent casein, but the weight
| |
| increased to an average of 1694 mg. and
| |
| 1747 mg. in rats fed 20 per cent and 65 per
| |
| cent casein, respectively (Table 12.5). Following protein depletion, there was a decrease in tubular ribonucleic acid and an increase in lipid. Accumulation of gonadal
| |
| lipid in the inactive testis may be an abnormal assimilation of a degenerative nature or simply nonutilization. A diet containing 6 per cent casein permitted the
| |
| formation of spermatozoa in some animals
| |
| (Guilbert and Goss, 1932). When the 6 per
| |
| cent casein diet was fed to immature animals for 30 days 50 per cent of the rats
| |
| exhibited some spermatozoa; in addition,
| |
| testis weight increased slightly and seminal
| |
| | |
| | |
| | |
| vesicle weight doubled, but body weight was
| |
| not improved (Horn, 1955). Thus, as we
| |
| noted earlier, the reproductive system may
| |
| gain special consideration for protein allotments when supplies are limited.
| |
| | |
| Gain in testis weight in immature male
| |
| rats and the biochemical composition of the
| |
| immature testis are influenced by the nutritive value of the protein fed. The testes of
| |
| normal immature rats contain 85 per cent
| |
| water, 10.5 per cent protein, 4.5 per cent
| |
| lipid, and detectable glycogen (Wolf and
| |
| Leathern, 1955). Proteins of lower nutritive
| |
| value (wheat gluten, peanut flour, gelatin ) may permit some increase in testis
| |
| weight, but testis protein concentration decreased, percentage of water increased, and
| |
| lipid and glycogen remained unchanged
| |
| (Table 12.6). The enzyme ^fi-glucuronidase,
| |
| which has frequently been associated with
| |
| growth processes, exhibited no change in
| |
| concentration as the testis matured or was
| |
| jirevented from maturing by a protein-free
| |
| diet (Leathem and Fisher, 1959). Not only
| |
| are the weight and composition of the testis
| |
| influenced by feeding proteins of varied biologic value, but the release of androgen is
| |
| more markedly altered. When a 22-day-old
| |
| male rat was fed a 20 per cent casein diet
| |
| for 30 days, the seminal vesicle and ventral
| |
| prostate weights increased 9- to 10-fold in
| |
| comparison with initial control weight. Sub
| |
| TABLE 12.6
| |
| | |
| Niiiritioiial effects on testis-coin position
| |
| | |
| in immature rats
| |
| | |
| (From R. C. Wolf and J. H. Leathem,
| |
| | |
| Endocrinology, 57, 286, 1955.)
| |
| | |
| | |
| | |
| 20 pel' cent casein
| |
| | |
| 20 per cent wheat
| |
| gluten
| |
| | |
| 20 per cent i)eanut flour
| |
| | |
| 20 i)er cent gelatin
| |
| | |
| 5 per cent casein
| |
| | |
| Fox chow
| |
| | |
| Initial control . .
| |
| | |
| | |
| | |
| No. of
| |
| Rats
| |
| | |
| | |
| Final
| |
| Body
| |
| Weight
| |
| | |
| | |
| | |
| | |
| gm.
| |
| | |
| | |
| 7
| |
| | |
| | |
| 128
| |
| | |
| | |
| 8
| |
| | |
| | |
| 82
| |
| | |
| | |
| 8
| |
| | |
| | |
| 81
| |
| | |
| | |
| 5
| |
| | |
| | |
| 53
| |
| | |
| | |
| 5
| |
| | |
| | |
| 61
| |
| | |
| | |
| 8
| |
| | |
| | |
| 115
| |
| | |
| | |
| 7
| |
| | |
| | |
| 61
| |
| | |
| | |
| | |
| 72.3j30.4
| |
| 04.634.0
| |
| | |
| | |
| | |
| 1468
| |
| 1017
| |
| | |
| 1257 66.1
| |
| 2101
| |
| | |
| | |
| | |
| 28.8
| |
| | |
| | |
| | |
| 0.11
| |
| 0.18
| |
| 0.11
| |
| 0.10
| |
| | |
| | |
| | |
| 684,62.4 29.2 0.26
| |
| 1515'70.3 30.3 0.15
| |
| 273 72. 7:30. 10.19
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 679
| |
| | |
| | |
| | |
| stitution of wheat gluten and peanut flour
| |
| for casein, limited the increase in the weight
| |
| of the seminal vesicles to less than 100 per
| |
| cent. In fact, seminal vesicle weight as related to body weight did not increase in
| |
| animals fed 20 per cent wheat gluten.
| |
| | |
| The withholding of dietary protein from
| |
| an immature rat for 30 days, during which
| |
| time maturation occurs in the fully fed animal, did not impose a permanent damage.
| |
| Refeeding of protein permitted the rapid recovery of testis weight and the appearance
| |
| of spermatoza, 70 per cent of all animals
| |
| having recovered in 30 days when fully fed,
| |
| whereas only 25 per cent recovered when
| |
| 6 per cent casein was fed. Recovery of
| |
| androgen secretion was somewhat slower
| |
| than that of the tubules as estimated by
| |
| seminal vesicle weight.
| |
| | |
| Variations in protein quality are a reflection of amino acid patterns, and amino
| |
| acid deficiencies interfere with testis maturation (Scott, 1956; Pomeranze, Piliero,
| |
| Medeci and Plachta, 1959). Alterations in
| |
| food intake which follow amino acid deficiencies have required forced feeding or
| |
| pair-fed controls, but it is clear from what
| |
| w^as found in the controls that the gonadal
| |
| changes were not entirely due to inanition
| |
| (Ershoff, 1952).
| |
| | |
| If the diet is varied so that caloric intake
| |
| per gram is reduced to half while retaining
| |
| the dietary casein level at 20 per cent, immature rat testis growth is prevented. The
| |
| effect is unlike that obtained with this level
| |
| of protein in the presence of adequate calories. Furthermore, the caloric restriction
| |
| may increase testis glycogen (Leathem,
| |
| 1959c).
| |
| | |
| Protein anabolic levels are higher in the
| |
| tissues of young growing animals and the
| |
| body is more dependent on dietary protein
| |
| level and quality for maintenance of the
| |
| metabolic nitrogen pool than in adult animals. On the other hand, body protein reserves in adult animals permit internal
| |
| shifts of nitrogen to the metabolic pool and
| |
| to tissues when dietary sources are reduced
| |
| or endocrine imbalances are imposed. Thus,
| |
| Cole, Guilbert and Goss (1932) fed a low
| |
| protein diet to adult male rats for 60 to 90
| |
| days before the sperm disappeared, but the
| |
| animals would not mate. Amount of semen
| |
| and sperm produced by sheep have been re
| |
| | |
| | |
| TABLE 12.7
| |
| | |
| Arlult rat testes and seminal vesicles
| |
| | |
| after protein depletion
| |
| | |
| (From J. H. Leatliem, Recent Progr. Hormone
| |
| | |
| Res., 14, 141, 1958.)
| |
| | |
| | |
| | |
| Days on
| |
| | |
| | |
| No. of
| |
| | |
| | |
| Testis
| |
| | |
| | |
| H2O
| |
| | |
| | |
| Protein
| |
| | |
| | |
| Total
| |
| | |
| | |
| Seminal
| |
| | |
| | |
| PFD*
| |
| | |
| | |
| Rats
| |
| | |
| | |
| Weight
| |
| | |
| | |
| Protein
| |
| | |
| | |
| Vesical
| |
| | |
| | |
| | |
| | |
| | |
| | |
| nig.
| |
| | |
| | |
| %
| |
| | |
| | |
| %dry
| |
| | |
| | |
| gm.
| |
| | |
| | |
| mg.
| |
| | |
| | |
| Control
| |
| | |
| | |
| 9
| |
| | |
| | |
| 2852
| |
| | |
| | |
| 85.9
| |
| | |
| | |
| 66.7
| |
| | |
| | |
| 0.28
| |
| | |
| | |
| 1276
| |
| | |
| | |
| 30
| |
| | |
| | |
| 9
| |
| | |
| | |
| 2600
| |
| | |
| | |
| 86.0
| |
| | |
| | |
| 66.1
| |
| | |
| | |
| 0.24
| |
| | |
| | |
| 689
| |
| | |
| | |
| 50
| |
| | |
| | |
| 7
| |
| | |
| | |
| 2398
| |
| | |
| | |
| 85.4
| |
| | |
| | |
| 64.1
| |
| | |
| | |
| 0.22
| |
| | |
| | |
| 320
| |
| | |
| | |
| 90
| |
| | |
| | |
| 25
| |
| | |
| | |
| 1429
| |
| | |
| | |
| 85.7
| |
| | |
| | |
| 69.6
| |
| | |
| | |
| 0.13
| |
| | |
| | |
| 168
| |
| | |
| | |
| | |
| * PFD = Protein-free diet.
| |
| | |
| lated to the dietary protein level (Popoff
| |
| and Okultilschew, 1936). Removal of protein from the diet for 30 days had little
| |
| effect on the adult rat testis weight, spermatogenesis, or nitrogen content (Leathem,
| |
| 1954). However, seminal vesicle w^eight was
| |
| reduced 50 per cent (Aschkenasy, 1954).
| |
| Prolonged protein depletion was required
| |
| before the testis exhibited a loss in protein
| |
| and a reduction in size. A loss of spermatozoa was not observed consistently, although some testes were completely atrophic
| |
| (Table 12.7). Accessory organ weight decrease reflected the disappearance of androgen (Leathem, 1958a). Interstitial cell atrophy has also been noted in rats fed a low
| |
| vegetable protein (cassava) diet (Adams,
| |
| Fernand and Schnieden, 1958).
| |
| | |
| Sterility may or may not be induced with
| |
| diets containing 65 per cent protein (Reid.
| |
| 1949; Leathem, 1959c) but a 15 to 18 per
| |
| cent dietary level of a poor protein such
| |
| as maize or gelatin will decrease sperm motility and increase the number of abnormal
| |
| sperm. The influence of proteins having different nutritional values in support of the
| |
| growth of testes from the level to which
| |
| they were depressed by stilbestrol indicated
| |
| that casein, lactalbumin, and wheat gluten
| |
| are equally competent to support testis
| |
| growth whereas gelatin is deficient. Whole
| |
| proteins may have several amino acid deficiencies, but the administration of amino
| |
| acid antagonists may help to identify important individual amino acids. As an example, ethionine causes severe seminiferous
| |
| tubule atrophy and Leydig cell hypoplasia
| |
| (Kaufman, Klavins and Kinney, 1956;
| |
| Goldberg, Pfau and Ungar, 1959). Studies
| |
| in man have indicated a sharp reduction in
| |
| | |
| | |
| | |
| 680
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| spermatozoa after 9 days on an argininedeficient diet (Holt, Albanese, Shettles,
| |
| Kajdi and Wangerin, 1942).
| |
| | |
| Adequate dietary protein cannot maintain reproductive function if the diet is
| |
| calorie deficient. Thus, a decrease in seminal
| |
| vesicle weight could be related to a decrease
| |
| in dietary calories while protein levels were
| |
| constant (Rosenthal and Allison, 1956).
| |
| However, the accessory gland weight loss
| |
| imposed by caloric restriction could be
| |
| slowed by increasing the dietary protein
| |
| (Rivero-Fontan, Paschkis, West and Cantarow, 1952).
| |
| | |
| Alterations in testis function imposed by
| |
| inadequate protein are corrected when protein is returned to the diet at normal levels
| |
| (Aschkenasy and Dray, 1953). Nevertheless, the nutritional state of the animal as
| |
| a factor influencing recovery has been demonstrated with stilbestrol-treated adult male
| |
| rats. While being fed an 18 per cent casein
| |
| diet, adult male rats were injected with 0.1
| |
| mg. stilbestrol daily for 20 days. Testis
| |
| weight decreased from 2848 to 842 mg.,
| |
| spermatogenesis was abolished, and testis
| |
| water and protein content were significantly
| |
| reduced. Despite a reduction in food intake,
| |
| pair-fed controls exhibited no effect on reproductive organs. When a protein-free diet
| |
| was substituted for the normal diet during
| |
| the administration of stilbestrol, atrophy of
| |
| the reproductive system was observed. Cessation of hormone administration was followed by a rapid return of testicular function toward normal when 18 per cent casein
| |
| was fed both during the injection period
| |
| and the recovery period. Within 30 days
| |
| spermatogenesis and testicular composition
| |
| were fully recovered. However, when 18
| |
| per cent casein was fed in the postinjection
| |
| period to rats that had received a proteinfree diet while being given stilbestrol, recovery was clearly slow. After a month,
| |
| spermatozoa were observed in only 30 per
| |
| cent of the testes and testis weight was subnormal. Despite the seeming similarity of
| |
| response by the two nutritional groups during the injection period, the postinjection recovery on identical dietary intake revealed
| |
| marked differences in rate of recoverv (Leathem, 1958a).
| |
| | |
| | |
| | |
| 3. Fat
| |
| | |
| Linoleic, linolenic, and arachidonic acids
| |
| are designated as essentially fatty acids, but
| |
| the physiologic role of these substances is
| |
| not clearly understood. Nevertheless, the
| |
| male reproductive organs are influenced by
| |
| dietary essential fatty acid levels. High
| |
| fat diets may enhance testicular weight
| |
| (Kaunitz, Slanetz, Johnson and Guilmain,
| |
| 1956) whereas removal of fat from the diet
| |
| resulted in a degeneration of the seminiferous tubules as evidenced by intracellular
| |
| vacuolation and a reduction in spermatids
| |
| and spermatozoa (Panos and Finerty,
| |
| 1954). After 5 months of feeding a fatfree diet, the rat testis may be devoid of
| |
| sperm (Evans, Lepkovsky and Murphy,
| |
| 1934). Testis degeneration occurred despite
| |
| dietary supplements of vitamins A and E
| |
| and in animals whose health appeared quite
| |
| normal (Ferrando, Jacques, Mabboux and
| |
| Prieur, 1955; Ferrando, Jacques, Mabboux
| |
| and SoUogoub, 1955).
| |
| | |
| Weanling rats fed 14 per cent arachis (peanut) oil for 15 weeks exhibited a marked
| |
| impairment of spermatogenesis (Aaes-Jorgensen, Funch and Dam, 1956) and 28
| |
| per cent arachis oil induced testicular damage of such an order that 15 weeks of feeding
| |
| ethyl linoleate did not restore fertility
| |
| (Aaes-Jorgensen, Funch and Dam, 1957).
| |
| | |
| 4. Vitamins
| |
| | |
| Testicular dysfunction as judged by failure of sperm formation or atrophy of the
| |
| secondary sex organs has been observed in
| |
| deprivations of thiamine, riboflavin, pyridoxine, calcium pantothenate, biotin, and
| |
| vitamins A and E. One must distinguish,
| |
| however, between effects of inanition associated w^ith a vitamin deficiency and a
| |
| specific vitamin effect (Skelton, 1950) ; one
| |
| must also consider species differences (Biskind, 1946).
| |
| | |
| There is no question but that vitamin E
| |
| deficiency in the rat results in a specific
| |
| and irreversible damage to the testis. Tubular damage may proceed to the point where
| |
| only Sertoli cells remain and yet the interstitial cells are not influenced (Mason,
| |
| 1939). Similar changes followed vitamin E
| |
| deficiency in the guinea pig (Pappenheimer
| |
| and SchogolefT, 1944; Curto, 1954; Ingel
| |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 681
| |
| | |
| | |
| | |
| man-Siindberg, 1954) , hamster (Mason and
| |
| Mauer, 1957), and bird (Herrick, Eide and
| |
| Snow, 1952; Lowe, Morton, Cunningham
| |
| and Vernon, 1957). However, little or no
| |
| effect of an absence of vitamin E was noted
| |
| in the rabbit (Mackenzie, 1942) and mouse
| |
| (Bryan and Mason, 1941), or in live stock
| |
| (Blaxter and Brown, 1952), or man (Lutwak-Mann, 1958), although vitamin E is
| |
| present in human testes (Dju, Mason and
| |
| Filer, 1958). Treatment of low-fertility
| |
| farm animals with wheat germ oil or tocopherol or the use of this vitamin clinically
| |
| have provided only inconclusive results
| |
| (Beckmann, 1955) . Although some positive
| |
| effects have been reported in man, the results may be due in part at least to the sparing action of tocopherol toward vitamin A.
| |
| | |
| Vitamin A deficiency influences the testis
| |
| but changes are closely associated with the
| |
| degree of inanition. In the rat, a vitamin deficiency sufficient to cause ocular lesions
| |
| did not prevent sperm formation, but a deficiency of such proportions as to cause a
| |
| body weight loss did cause atrophy of the
| |
| germinal epithelium (Reid, 1949). Vitamin
| |
| A deficiency will induce sterility in mice
| |
| (McCarthy and Cerecedo, 1952). A gross
| |
| vitamin deficiency in bulls before expected
| |
| breeding age prevented breeding ; adult bulls
| |
| may exhibit a lower quality semen but they
| |
| remain fertile (Reid, 1949). Vitamin A deficiency induces metaplastic keratinization
| |
| of the epithelium lining the male accessory
| |
| sex organs (Follis, 1948) and thus may influence semen.
| |
| | |
| Testis damage induced by vitamin A deficiency can be reversed, but vitamin A
| |
| therapy in man for oligospermia not due to
| |
| vitamin lack was without effect (Home
| |
| and Maddock, 1952) .
| |
| | |
| Age of the animal and dosage are factors
| |
| which influence the results obtained in male
| |
| rats with administered vitamin A. Immature
| |
| male rats given 250 I.U. of vitamin A per
| |
| gram of body weight daily exhibited a loss
| |
| of spermatocytes, an effect which was accentuated by tocopherol (Maddock, Cohen
| |
| and Wolbach, 1953). Little or no effect of
| |
| similar treatment was observed in adult
| |
| rats. The liver is the major storage depot
| |
| for vitamin A and the fact that the male rat
| |
| liver is more quickly depleted and less capa
| |
| | |
| | |
| ble of storage than is the liver of the female
| |
| should be considered in any attempted correlation of the vitamin and hormone levels
| |
| (Booth, 1952).
| |
| | |
| Other vitamin deficiencies have been
| |
| shown to influence the testis. A lack of
| |
| thiamine had little effect on testis weight,
| |
| but did influence the Leydig cells and prevented growth of the accessory sex organs
| |
| (Pecora and Highman, 1953). A chronic
| |
| lack of ascorbic acid will cause a degeneration of both Leydig cells and seminiferous
| |
| tubules. The effects of vitamin deficiency on
| |
| the testis has been distinguished from those
| |
| due to inanition and have been related to
| |
| changes in carbohydrate metabolism (Mukherjee and Banerjee, 1954; Kocen and
| |
| Cavazos, 1958) . The importance of ascorbic
| |
| acid in the testis as related to function is
| |
| not evident, but concentrations of this vitamin are maximal at 1 week of age (Coste,
| |
| Delbarre and Lacronique, 1953).
| |
| | |
| Serious anatomic and functional impairments of testes were noted in pantothenic
| |
| acid deficiency (Barboriak, Krehl, Cowgill
| |
| and Whedon, 1957), and development of
| |
| the rat testis and seminal vesicles was retarded by a biotin deficiency (Bishop and
| |
| Kosarick, 1951; Katsh, Kosarick and Alpern, 1955), but the animals did not exhibit
| |
| marked alterations in other endocrine organs (Delost and Terroine, 1954). Testosterone hastened the development of vitamin
| |
| deficiency and enhanced the severity of biotin deficiency in both sexes, thereby suggesting a hormone-vitamin relationship
| |
| (Okey, Pencharz and Lepkovsky, 1950). On
| |
| the other hand, testosterone had no effect on
| |
| the tolerance of mice for aminopterin, but
| |
| castration increased the tolerance (Goldin,
| |
| Greenspan, Goldberg and Schoenberg 1950).
| |
| | |
| B. INFLUENCE OF NUTRITION ON THE EE
| |
| SPONSIVENESS OF MALE REPRODUCTIVE
| |
| | |
| TISSUES TO HORMONES
| |
| | |
| 1. Testis
| |
| | |
| a. Inanition. The testes of birds on limited
| |
| food intake were more responsive to hypophyseal gonadotrophin than fully fed birds
| |
| (Byerly and Burrows, 1938; Breneman,
| |
| 1940). In the rat several investigators have
| |
| shown that the testis will respond to gonadotrophin despite inanition (Moore and Sara
| |
| | |
| | |
| 682
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| TABLE 12.8
| |
| | |
| Influence of diet and pregnant mare serum (PMS)
| |
| | |
| on testes and seminal vesicles of
| |
| | |
| immature male mice
| |
| | |
| (From V. J. DeFeo and J. H. Leathern,
| |
| | |
| unpublished.)
| |
| | |
| | |
| | |
| Diet (Per cent
| |
| Protein X Days Fed)
| |
| | |
| | |
| | |
| per cent X 10
| |
| per cent X 10
| |
| per cent X 20
| |
| per cent X 20
| |
| | |
| | |
| | |
| l.u.
| |
| | |
| 3
| |
| | |
| 3
| |
| | |
| | |
| | |
| stage of
| |
| Spermatogenesis
| |
| | |
| | |
| | |
| 4
| |
| 1
| |
| | |
| 1 5
| |
| 5
| |
| | |
| | |
| | |
| Spermatids
| |
| | |
| | |
| | |
| Seminal
| |
| Vesicles
| |
| | |
| | |
| | |
| mg.
| |
| | |
| 2.7
| |
| 4.5
| |
| | |
| 2.7
| |
| 3.5
| |
| | |
| | |
| | |
| uels, 1931; Funk and Funk, 1939; Meites,
| |
| 1953), with a stimulation of Leydig cells,
| |
| an increase in testis size, and, in 40 days,
| |
| a return of spermatozoa. Underfed males injected with gonadotrophin sired litters (Mulinos and Pomerantz, 1941a, b). Improved
| |
| nutrition aided by unknown liver factors
| |
| enhanced the response to androgen in severe human oligospermia (Glass and Russell, 1952).
| |
| | |
| b. Protein. Feeding a protein-deficient
| |
| diet to adult male rats for 60 to 90 days
| |
| did not prevent stimulation of the testes and
| |
| seminal vesicles after pregnant mare's serum
| |
| (PMS) administration (Cole, Guilbert and
| |
| Goss, 1932). As we have noted, immature
| |
| animals are prevented from maturing when
| |
| diets lack protein. Nevertheless, a gonadal
| |
| response to injected gonadotrophin was obtained in immature mice fed a protein-free
| |
| diet for 13 days; tubules and Leydig cells
| |
| were stimulated and androgen was secreted
| |
| (Table 12.8). Refeeding alone permitted a
| |
| recovery of spermatogenesis which was not
| |
| hastened by concomitant PMS (Leathem,
| |
| 1959c).
| |
| | |
| The maintenance of testis weight and
| |
| spermatogenic activity with testosterone
| |
| propionate in hypophysectomized adult
| |
| male rats is well known, but these studies
| |
| have involved adequate nutrition. If hypophysectomized rats were fed a protein-free
| |
| diet and injected with 0.25 mg. testosterone
| |
| propionate daily, testis weight and spermatogenesis were less well maintained than
| |
| in rats fed protein. Testis protein concentra
| |
| | |
| | |
| tion was also reduced. These data suggest
| |
| that influences of nutrition on the testis can
| |
| be direct and are not entirely mediated
| |
| through hypophyeal gonadotrophin changes
| |
| (Leathem, 1959b).
| |
| | |
| c. Fat. The rat fed for 20 weeks on a fatfree diet exhibits a degeneration of the
| |
| seminiferous epithelium within the first
| |
| weeks which progresses rapidly thereafter.
| |
| Chorionic gonadotrophin or rat pituitary extract started during the 20th week failed to
| |
| counteract the tubular degeneration, but
| |
| testosterone propionate proved effective
| |
| (Finerty, Klein and Panos, 1957). The result shows that the ineffectiveness of the
| |
| gonadotrophins could not be due to the failure of androgen release (Greenberg and Ershoff, 1951).
| |
| | |
| d. Vitamins. Gonadotrophins failed to
| |
| promote spermatogenesis in vitamin A(Mason, 1939) or vitamin E- (]Mason,
| |
| 1933; Geller, 1933; Drummond, Noble and
| |
| Wright, 1939) deficient rats, but in another
| |
| experiment the atrophic accessory sex organs of vitamin A-depleted rats were stimulated (Mayer and Goodard, 1951). Lack
| |
| of vitamin A favored an enhanced response
| |
| to PMS when the ratios of seminal vesicle
| |
| weight to body weight were computed
| |
| (Meites, 1953). The failure of gonadotrophins to stimulate testis tubules suggests a
| |
| specific effect of avitaminosis A and E
| |
| (Mason, 1933) on the responsiveness of the
| |
| germinal epithelium.
| |
| | |
| Subnormal responses of rats to PMS, as
| |
| measured by relative seminal vesicle weight,
| |
| were obtained when there were individual
| |
| vitamin B deficiencies, but the influence was
| |
| due largely to inanition (Drill and Burrill,
| |
| 1944; Meites, 1953). Nevertheless, sufficient
| |
| response to chorionic gonadotrophin was obtained so that fructose and citric acid levels
| |
| were restored to normal. Such an effect was
| |
| not observed to follow dietary correction unless an unlimited food intake was allowed
| |
| (Lutwak-Mann. 1958).
| |
| | |
| | |
| | |
| 2. Sc
| |
| | |
| | |
| | |
| il W.siclfx and Prosfate
| |
| | |
| | |
| | |
| a. Inanition. Although the accessory reproductive organs resppnd to direct stimulation despite an inadequate food intake
| |
| (Mooi'c and Samuels. 19311, tlio increase
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 683
| |
| | |
| | |
| | |
| in weight may be subnormal in mice and
| |
| rats (Goldsmith, Nigrelli and Ross, 1950;
| |
| Kline and Dorfman, 1951a, Grayhack and
| |
| Scott, 1952), or above normal in chickens
| |
| (Breneman, 1940). Complete deprivation
| |
| of food reduced the quantity of prostatic
| |
| fluid in the dog, but exogenous androgen restored the volume, increased acid phosphatase, and induced tissue growth (Pazos and
| |
| Huggins, 1945) .
| |
| | |
| 6. Protein. The response of the seminal
| |
| vesicles to androgen was investigated in immature rats, using weight and /5-glucuronidase as end points. Castration and 10 days
| |
| on a protein-free diet preceded the 72-hour
| |
| response to 0.25 mg. testosterone propionate.
| |
| The lack of protein did not prevent a normal weight increase, and enzyme concentration was unchanged. If an 18 per cent diet
| |
| was fed during the 3-day period that the
| |
| androgen was acting, no improvement in
| |
| weight response was noted, but enzyme concentration increased 100 per cent. Thus,
| |
| when protein stores are depleted, the androgen response may be incomplete in the absence of dietary protein (Leathern, 1959c).
| |
| Nevertheless, varied protein levels do not
| |
| influence seminal vesicle weight-response
| |
| when caloric intake is reduced (RiveroFontan, Paschkis, West and Cantarow,
| |
| 1952).
| |
| | |
| c. Vitamins. Vitamin deficiencies do not
| |
| prevent the seminal vesicles from responding to androgen. In fact, in vitamin B deficiency, testosterone restored fructose and
| |
| citric acid levels to normal despite the need
| |
| for thiamine in carbohydrate metabolism
| |
| (Lutwak-Mann and Mann, 1950). In the
| |
| male, unlike the female, the effects of folic
| |
| acid deficiency in reducing responsiveness
| |
| to administered androgen were largely due
| |
| to inanition in both mice and rats (Goldsmith, Nigrelli and Ross, 1950; Kline and
| |
| Dorfman, 1951a) , and vitamin A deficiency
| |
| which leads to virtual castration does not
| |
| prevent an essentially normal response of
| |
| the accessory glands to testosterone propionate (Mayer and Truant, 1949). Restricting the caloric intake of vitamin Adeficient rats retarded the curative effects
| |
| of vitamin A in restoring the accessory sex
| |
| glands of the A-deficient animals (Mason,
| |
| 1939).
| |
| | |
| | |
| | |
| V. Female Reproductive System
| |
| | |
| A. OVARIES
| |
| | |
| 1. Inanition
| |
| | |
| Mammalian species generally exhibit a
| |
| delay in sexual maturation when food intake is subnormal before puberty, and
| |
| ovarian atrophy with associated changes
| |
| in cycles if inanition is imposed on adults.
| |
| In human beings a decrease in fertility and
| |
| a greater incidence of menstrual irregularities were induced by war famine (Zimmer,
| |
| Weill and Dubois, 1944). Ovarian atrophy
| |
| with associated amenorrhea and sterility
| |
| were invoked by chronic undernutrition
| |
| (Stephens, 1941). The ovarian morpliologic
| |
| changes were similar to those of aging.
| |
| Urinary estrogens were subnormal in 22 of
| |
| 25 patients exhibiting amenorrhea associated with limited food intake (Zubiran and
| |
| (_lomcz-Mont, 1953).
| |
| | |
| The nutritional requirements of jM'imates
| |
| other than man have been studied in female
| |
| baboons. The intake of vitamins and other
| |
| essential nutrients was found to be of the
| |
| same order as that recommended for man.
| |
| Caloric intake varied with the menstrual
| |
| cycle, being least during the follicular phase
| |
| and maximal during the 2 to 7 days preceding menstruation (Gilbert and Gillman,
| |
| 1956). Various diets were also studied to
| |
| assess their importance in maintaining the
| |
| normal menstrual rhythm. The feeding of
| |
| (a) maize alone, (b) assorted vegetables
| |
| and fruit, or (c) maize, skimmed milk, and
| |
| fat led to menstrual irregularities or to
| |
| amenorrhea. The mechanism regulating ovulation was the first to be deranged. The
| |
| addition of various vitamins or of animal
| |
| protein did not correct the menstrual disorders. However, inclusion of ox liver in
| |
| the diet did maintain the menstrual rhythmicity, but the beneficial effect could not
| |
| be attributed to its protein content (Gillman and Gilbert, 1956 ) .
| |
| | |
| In lower mammals that have been studied,
| |
| inanition will hinder vaginal opening, and
| |
| delay puberty and ovarian maturation and
| |
| functioning. In adult rats and mice ostrous
| |
| cycles are interrupted and the reprorUictive
| |
| system becomes atrophic when body weight
| |
| loss exceeds 15 per cent. The ovaries be
| |
| | |
| | |
| 684
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| come smaller, ovulation fails, and large
| |
| vesicular follicles decrease in number with
| |
| an increase in atresia, but primary follicles
| |
| show a compensatory increase (Marrian
| |
| and Parkes, 1929; Mulinos and Pomerantz,
| |
| 1940; Stephens and Allen, 1941; Guilbert,
| |
| 1942; Bratton, 1957). The ovarian interstitial cells mav be markedly altered or absent
| |
| (Huseby and Ball, 1945; Rinaldini, 1949)
| |
| and the ovary may exhibit excessive luteinization (Arvy, Aschkenasy, AschkenasyLelu and Gabe, 1946) or regressing corpora
| |
| lutea (Rinaldini, 1949) . However, the ovarian changes induced by inanition may be
| |
| reversed by refeeding, with a return to reproductive capacity (Ball, Barnes and Visscher, 1947; Schultze, 1955). The effect of
| |
| feed-level on the reproductive capacity of
| |
| the ewe has been reported (El-Skukh, Nulet,
| |
| Pope and Casida, 1955), but one must realize that high planes of nutrition may adversely influence fertility (Asdell, 1949).
| |
| Nevertheless, additional protein and calcium added to an adequate diet extended
| |
| the reproductive life span (Sherman, Pearson, Bal, McCarthy and Lanford, 1956).
| |
| | |
| 2. Protein
| |
| | |
| The availability of just protein has an
| |
| important influence on the female reproductive system. In immature rats ovarian
| |
| maturation was prevented by feeding diets
| |
| containing per cent to 1.5 per cent protein
| |
| (Ryabinina, 1952) and low protein diets decreased the number of ova but without altering their ribonucleic acid (RNA) or glycogen content (Ishida, 1957). Refeeding 18
| |
| per cent protein for only 3 days was marked
| |
| by the appearance of vesicular follicles and
| |
| the release of estrogen in mice previously fed
| |
| a protein-free diet (Leathem, 1958a). In
| |
| experiments involving the opposite extreme,
| |
| in which 90 per cent protein diets were used,
| |
| a retardation of ovarian growth, and a delay in follicular maturation, in vaginal
| |
| opening, and in the initiation of estrous
| |
| cycles were noted (Aschkenasy-Lelu and
| |
| Tuchmann-Duplessis, 1947; TuchniannDuplcssis and Aschkenasy-Lelu, 1948).
| |
| | |
| Adult female rats fed a protein-free diet
| |
| for 30 days exhibited ovaries weighing 22
| |
| mg. compared with ovaries weighing 56 mg.
| |
| from i)air-fed controls fed 18 per cent casein.
| |
| Ovarian glycogen, ascorbic acid, and cho
| |
| | |
| | |
| lesterol were all influenced by protein
| |
| deprivation and anestrum accompanied
| |
| the ovarian changes. Furthermore, uterine
| |
| weight and gl3^cogen decreased in rats fed
| |
| protein-free diets (Leathem, 1959b).
| |
| | |
| In adult rats the feeding of 3.5 per cent
| |
| to 5 per cent levels of protein (GuillDert and
| |
| Gross, 1932) was followed by irregularity
| |
| of the cycles or by their cessation. The
| |
| cycles became normal when 20 to 30 per cent
| |
| protein was fed (Aschkenasy-Lelu and
| |
| Aschkenasy, 1947). However, abnormally
| |
| high levels of casein (90 per cent) induced prolonged periods of constant estrus
| |
| (Tuchmann-Duplessis and AschkenasyLelu, 1947). Nevertheless, not all species
| |
| responded to protein depletion in the same
| |
| manner. For example, the rabbit exhibited
| |
| estrus and ovulation despite a 25 per cent
| |
| body weight loss imposed by to 2 per cent
| |
| protein diets (Friedman and Friedman,
| |
| 1940).
| |
| | |
| Despite a normal level of protein in the
| |
| diet, inadequate calories will interfere with
| |
| reproductive function and induce ovarian
| |
| atrophy (Escudero, Herraiz and Mussmano,
| |
| 1948; Rivero-Fontan, Paschkis, West and
| |
| Cantarow, 1952). Furthermore, the effects
| |
| of 15 per cent and 56 per cent protein levels
| |
| on estrous cycles could not be distinguished
| |
| when calories were reduced 50 per cent (Lee,
| |
| King and Visscher, 1952). Returning mice
| |
| to full feeding after months of caloric deficiency resulted in a sharp increase in reproductive performance well above that expected for the age of the animal (Visscher,
| |
| King and Lee, 1952). This type of rebound
| |
| phenomenon has not been explained.
| |
| | |
| Reproductive failure assigned to dietary
| |
| protein may be a reflection of protein
| |
| quality as well as level. Specific amino acid
| |
| deficiencies lead to cessation of estrus
| |
| (White and AVhite, 1942; Berg and Rohse,
| |
| 1947) and thus feeding gelatin or wheat
| |
| as the protein source and at an 18 per cent
| |
| level was quickly followed by an anestrum
| |
| (Leathem, 1959b). Supplementation of the
| |
| wheat diet with lysine corrected the reproductive abnormalities (Courrier and
| |
| Raynaud, 1932), but neither lysine (Pearson, Hart and Bohstedt, 1937) nor cystine
| |
| (Pearson, 1936) added to a low casein diet
| |
| was beneficial. Control of food intake must
| |
| be considered in studies involving amino
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 685
| |
| | |
| | |
| | |
| acids, for a deficiency or an excess can create an imbalance and alter appetite. Opportunity to study the amino acids in reproduction is now possible because of the work of
| |
| Greenstein, Birnbaum, Winitz and Otey
| |
| (1957) and Schultze (1956) , who maintained
| |
| rats for two or more generations on synthetic diets containing amino acids as the
| |
| only source of protein. Similarly, the amino
| |
| acid needs for egg-laying in hens has been
| |
| reported (Fisher, 1957). Tissue culture
| |
| methods also permit the study of the nutritional requirements of embryonic gonadal
| |
| tissue, the success of avian gonadal tissue in
| |
| culture being judged by survival, growth,
| |
| and differentiation. In experiments in which
| |
| this technique was used it was found that a
| |
| medium made up of amino acids as the basic
| |
| nitrogen source can maintain gonadal explants very successfully, even though the
| |
| choice of amino acids does not exactly correspond to the 10 essential amino acids recommended for postnatal growth (StengerHaffen and Wolff, 1957).
| |
| | |
| 3. Carbohydrate
| |
| | |
| The absence of dietary carbohydrate does
| |
| not appreciably affect the regularity of
| |
| estrous cycles in rats provided the caloric
| |
| need is met. However, the substitution of
| |
| 20 per cent sucrose for corn starch induced
| |
| precocious sexual maturity which was followed by sterility (Whitnah and Bogart,
| |
| 1956). The ovaries contained corpora lutea,
| |
| but the excessive luteinization of unruptured
| |
| follicles suggested a hypophyseal disturbance. Substitution of 20 per cent lactose for
| |
| corn starch had no effect. Increased amounts
| |
| of lactose retarded the gain in body weight
| |
| and blocked ovarian maturation, possibly
| |
| because the animal could not hydrolyze adequate amounts of the disaccharide. Addition of whole liver powder to the diet
| |
| counteracted the depressing action of 45 per
| |
| cent lactose on the ovary (Ershoff, 1949).
| |
| | |
| 4. Fat
| |
| | |
| There seems to be little doubt that dietary
| |
| fat is reciuired for normal cyclic activity,
| |
| successful pregnancy, and lactation, and
| |
| that the requirements for essential fatty
| |
| acids are lower in females than in males
| |
| (Deuel, 1956).
| |
| | |
| Conception, fetal development, and par
| |
| | |
| | |
| turition can take place in animals fed a
| |
| diet deficient in fatty acids (Deuel, Martin
| |
| and Alfin-Slater, 1954) , despite a reduction
| |
| in total carcass arachidonic acid (Kummerow. Pan and Hickman, 1952). Earlier
| |
| reports indicated that a deficiency of essential fatty acids caused irregular ovulation and impaired reproduction (Burr and
| |
| Burr, 1930; Maeder, 1937). The large pale
| |
| ovaries lead Sherman (1941) to relate essential fatty acid deficiency to carotene
| |
| metabolism. In this regard the removal of
| |
| essential fatty acids from an adequate diet
| |
| supplemented with vitamin A and E lead
| |
| to anestrum and sterility while maintaining
| |
| good health (Ferrando, Jacques, Mabboux
| |
| and Prieur, 1955). Perhaps the differences
| |
| in opinion regarding the effects of fatty acid
| |
| deficiency can be related to the duration of
| |
| the experimental period. Panos and Finerty
| |
| (1953) found that growing rats placed on
| |
| a fat-free diet exhibited a normal time for
| |
| vaginal opening, normal ovarian weight,
| |
| follicles, and corpora lutea, although interstitial cells were atrophic. However, regular estrous cycles were noted for only 20
| |
| weeks, thereafter 60 per cent of the animals
| |
| exhibited irregular cycles.
| |
| | |
| A decrease in reproductive function may
| |
| be invoked by adding 14 per cent arachis
| |
| oil to the diet (Aaes-Jorgensen, Funch and
| |
| Dam, 1956) . Increasing dietary fat by adding rape oil did not influence ovarian function but did cause the accumulation of
| |
| ovarian and adrenal cholesterol (Carroll
| |
| and Noble, 1952).
| |
| | |
| Essential fatty acid deficiency is associated with underdevelopment and
| |
| atrophic changes of the uterine mucosa.
| |
| Adding fat to a stock diet enhanced uterine
| |
| weight in young animals at a more rapid
| |
| pace than body weight (Umberger and
| |
| Gass, 1958) .
| |
| | |
| 5. Vitamins
| |
| | |
| Carotenoid pigments are present in the
| |
| gonads of many vertebrates and marine invertebrates, and, in mammals, are particularly prominent in the corpus luteum.
| |
| However, no progress has been made in
| |
| determining either the importance of the
| |
| carotenoids in the ovary or of the factors
| |
| controlling their concentrations. It is well
| |
| known that vitamin A deficiency induces
| |
| | |
| | |
| | |
| 686
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| a characteristic keratinizing metaplasia of
| |
| the uterus and vagina, but estrous cycles
| |
| continue despite the vaginal mucosal
| |
| changes. Furthermore, ovulation occurs
| |
| regularly until advanced stages of deficiency appear. The estrous cycle becomes
| |
| irregular in cattle fed for a long period
| |
| of time on fodder deficient in carotene. The
| |
| corpora lutea fail to regress at the normal
| |
| rate and ovarian follicles become atretic and
| |
| cystic ( Jaskowski, Watkowski, Dobrowolska and Domanski, cited by Lutwak-Mann,
| |
| 1958). The alterations in reproductive organs associated with a lack of vitamin A
| |
| may be due in part to a vitamin E deficiency
| |
| since the latter enhances the rate at which
| |
| liver stores of vitamin A are depleted.
| |
| | |
| Definite effects of hypervitaminosis A
| |
| have been observed on reproduction. Masin
| |
| (1950) noted that estrus in female rats
| |
| could be prolonged by administration of
| |
| 37,000 I.U. of vitamin A daily. The implications, however, have not been studied.
| |
| The effect of hypervitaminosis A may actually induce secondary hypovitaminoses.
| |
| The displacement of vitamin K by excess
| |
| A is almost certain and similar relationships
| |
| appear to exist with vitamin D (Nieman
| |
| and Klein Obbink, 1954).
| |
| | |
| The failure of vitamin E-deficient female rats to become pregnant is apparently
| |
| due to disturbances of the implantation
| |
| process rather than to the failure of ovulation. There is no direct proof of ovarian
| |
| dysfunction (Blandau, Kaunitz and Slanetz,
| |
| 1949). However, the ovary of the rat deficient in vitamin E may have more connective tissue and pigment, and Kaunitz
| |
| (1955) showed by ovarian transplantation
| |
| that some nonspecific ovarian dysfunction
| |
| appears to exist (cited by Cheng, 1959 (.
| |
| Vitamin E is essential for birds, but there
| |
| is little evidence for a dependency in most
| |
| mammals; sheep, cows, goats, and pigs have
| |
| been studied. Treatment of low-fertility
| |
| farm animals with tocopherol has not provided conclusive data favoring its use (Lutwak-Mann, 1958), nor has the treatment
| |
| of human females been rewarded with any
| |
| indication that vitamin E might be helpful
| |
| in cases of abnormal cycles and habitual
| |
| abortion (Beckmann, 1955).
| |
| | |
| No specific reproductive disturbances in
| |
| man, the rhesus monkey, or the guinea pig
| |
| | |
| | |
| | |
| have been associated with vitamin C deficiency (Mason, 1939). Nevertheless, the
| |
| high ascorbic acid content of ovarian and
| |
| luteal tissue and of the adrenal cortex suggests a physiologic role in association with
| |
| steroid synthesis. (3varian ascorbic acid
| |
| varies with the estrous cycle, dropping
| |
| sharply in the proestrum (Coste, Delbarre
| |
| and Lacronique, 1953), and decreasing in
| |
| resjionse to gonadotrophin (Hokfelt, 1950;
| |
| Parlow, 1958). Virtually no ascorbic acid is
| |
| present in bovine follicular fluid (LutwakMann, 1954) or in rat ovarian cyst fluid
| |
| (Blye and Leathem, 1959). Uterine ascorbic
| |
| acid decreased in immature mice treated
| |
| with estrogen, but remained unchanged
| |
| in rats following thiouracil administration
| |
| (Leathem, 1959a). Its role in the uterus
| |
| awaits elucidation.
| |
| | |
| Delayed sexual maturation and ovarian
| |
| atrophy have been described when there
| |
| are deficiencies of thiamine, riboflavin, pyridoxine, pantothenic acid, biotin, and B12
| |
| (Ershoff, 1952; Ullrey, Becker, Terrill and
| |
| Notzold, 1955). However, as we noted when
| |
| deficiencies of the vitamins were being considered, much of the impairment of reproductive function can be related to inanition
| |
| rather than to a vitamin deficiency (Drill
| |
| and Burrill, 1944). Pyridoxine deficiency,
| |
| although not affecting structure (Morris,
| |
| Dunn and Wagner, 1953) , markedly reduces
| |
| the sensitivity of the ovary to administered
| |
| gonadotrophin (Wooten, Nelson, Simpson
| |
| and Evans, 1958) .
| |
| | |
| Bird, frog, and fish eggs contain considerable quantities of vitamins. In fact, the
| |
| daily human requirements for vitamins may
| |
| be contained in a hen's egg and thus it is
| |
| not surprising that hatchability is decreased
| |
| l)y virtually any vitamin deficiency. Lutwak-Mann (1958) has provided an excellent
| |
| survey of these data with numerous references to studies of frogs and fishes. Nearly
| |
| all the B vitamins are present in fish roe
| |
| and the pantothenic acid concentration in
| |
| cod ovaries {Gadus morrhua) exceeds most
| |
| otlicr natural sources. The amount of the
| |
| latter varies with the reproductive cycle,
| |
| d(>creasing to its lowest level before spawning. Riboflavin and vitamin B12 , on the
| |
| other h;ui(l, do not change (Braekkan,
| |
| 1955).
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 687
| |
| | |
| | |
| | |
| B. INFLUENCE OF NUTRITION ON THE RESPONSIVENESS OF FEMALE REPRODUCTIVE TISSUES
| |
| TO HORMONES
| |
| | |
| 1. Ovary
| |
| | |
| a. Inanition. Marrian and Parkes (1929)
| |
| were the first to show that the quiescent
| |
| ovary of the underfed rat can respond to
| |
| injections of anterior pituitary as evidenced
| |
| by ovulation and estrous smears. Subsequently the ovaries of underfed birds, rats,
| |
| and guinea pigs were found to be responsive
| |
| to serum gonadotrophin (Werner, 1939;
| |
| Stephens and Allen, 1941; Mulinos and
| |
| Pomerantz, 1941b; Hosoda, Kaneko, Mogi
| |
| and Abe, 1956). A low calorie bread-andmilk diet for 30 days did not prevent ovarian response to rat anterior pituitary or to
| |
| chorionic gonadotrophin. In these animals
| |
| an increase in ovarian weight with repair
| |
| of interstitial tissue, as well as folhcle
| |
| stimulation and corpus luteum formation,
| |
| were observed (Rinaldini, 1949). Rats from
| |
| which food had been withdrawn for 12
| |
| days could respond to castrated rat pituitary extract with an increase in ovarian
| |
| and uterine weight (Maddock and Heller,
| |
| 1947). Nevertheless, differences in the time
| |
| and degree of responsiveness to administered gonadotrophin were noted in rabbits.
| |
| Animals on a high plane of nutrition responded to gonadotrophin at 12 weeks,
| |
| whereas rabbits on a low plane of nutrition
| |
| responded at 20 weeks and fewer eggs were
| |
| shed (Adams, 1953).
| |
| | |
| b. Protein. Protein or amino acid deficiencies in the rat do not prevent a response
| |
| to administered gonadotrophin (Cole, Guilbert and Goss, 1932; Courrier and Raynaud,
| |
| 1932) . However, the degree and type of
| |
| gonadal response is influenced by the diet.
| |
| Thus, immature female mice fed to 6 per
| |
| cent casein for 13 days exhibited only follicular growth in response to pregnant mare
| |
| serum, whereas the ovarian response in
| |
| mice fed 18 per cent casein was suggestive
| |
| of follicle-stimulating and strongly luteinizing actions (Table 12.9). Furthermore,
| |
| the ovarian response was significantly less
| |
| after 20 days of nonprotein feeding than
| |
| after 10 days of depletion (Leathem,
| |
| 1958a). Ovarian stimulation by a gonadotrophin involves tissue protein synthesis
| |
| and thus the type of whole protein fed
| |
| | |
| | |
| | |
| could influence the responses. Yamamoto
| |
| and Chow (1950) fed casein, lactalbumin,
| |
| soybean, and wheat gluten at 20 per cent
| |
| levels and noted that the response to gonadotrophin as estimated by tissue nitrogen
| |
| was related to the nutritive value of the
| |
| protein. The ovarian weight response to
| |
| chorionic gonadotrophin was less in rats
| |
| fed 20 per cent gelatin than those fed 20
| |
| per cent casein (Leathem, 1959b). Inasmuch
| |
| as the hypophysis may influence the gonadal response to injected hormone despite
| |
| the diet, hypophysectomized rats fed a protein-free diet for 5 weeks and hyophysectomized rats on a complete diet were tested
| |
| for response to gonadotrophins. The response to FSH was not influenced by diet,
| |
| but the protein-depleted rats were twice
| |
| as sensitive to interstitial cell-stimulating
| |
| hormone (ICSH), human chorionic gonadotrophin (HCG), and PMS as the normal
| |
| rats (Srebnik, Nelson and Simpson, 1958).
| |
| Protein-depleted, normal mice were twice as
| |
| sensitive to PMS as fully fed mice (Leathem and Defeo, 1952 1 .
| |
| | |
| c. Vitamins. In the female vitamin B
| |
| deficiencies do not prevent ovarian responses to gonadotrophin (Figge and Allen,
| |
| 1942), but the number of studies is limited.
| |
| Be deficiency in DBA mice was associated
| |
| with an increased sensitivity of the ovary
| |
| to gonadotrophins (Morris, Dunn and Wagner, 1953), whereas pyridoxine deficiency
| |
| in the rat decreased ovarian sensitivity,
| |
| especially to FSH (Wooten, Nelson, Simp
| |
| TABLE 12.9
| |
| | |
| Influence of dietary protein and pregnant mare
| |
| | |
| serum {PMS) on the mouse ovary
| |
| | |
| (From J. H. Leathem, Recent Progr. Hormone
| |
| | |
| Res., 14, 141, 1958.)
| |
| | |
| | |
| | |
| Diet fPer cent
| |
| Protein X Days Fed)
| |
| | |
| | |
| | |
| | |
| c-5,
| |
| | |
| •g-s
| |
| | |
| 1*
| |
| | |
| | |
| k
| |
| | |
| r
| |
| | |
| | |
| 1
| |
| 11
| |
| | |
| | |
| c
| |
| 1
| |
| | |
| | |
| | |
| | |
| I.U.
| |
| | |
| | |
| mg.
| |
| | |
| | |
| | |
| | |
| | |
| | |
| mg.
| |
| | |
| | |
| per cent X 23
| |
| | |
| | |
| | |
| | |
| | |
| 1.2
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| 4.8
| |
| | |
| | |
| per cent X 2.3
| |
| | |
| | |
| 3
| |
| | |
| | |
| 2.8
| |
| | |
| | |
| 13
| |
| | |
| | |
| | |
| | |
| | |
| 10.8
| |
| | |
| | |
| per cent X 13
| |
| | |
| | |
| | |
| | |
| | |
| 1.4
| |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| | |
| 4.9
| |
| | |
| | |
| per cent X 13
| |
| | |
| | |
| 3
| |
| | |
| | |
| 4.4
| |
| | |
| | |
| 16
| |
| | |
| | |
| 1
| |
| | |
| | |
| 15.1
| |
| | |
| | |
| 6 per cent X 13
| |
| | |
| | |
| | |
| | |
| | |
| 3.2
| |
| | |
| | |
| 6
| |
| | |
| | |
| | |
| | |
| | |
| 7.7
| |
| | |
| | |
| 6 per cent X 13
| |
| | |
| | |
| 3
| |
| | |
| | |
| 5.6
| |
| | |
| | |
| 12
| |
| | |
| | |
| 1
| |
| | |
| | |
| 31.9
| |
| | |
| | |
| 18 per cent X 13
| |
| | |
| | |
| | |
| | |
| | |
| 5.0
| |
| | |
| | |
| 10
| |
| | |
| | |
| 2
| |
| | |
| | |
| 51.6
| |
| | |
| | |
| 18 per cent X 13
| |
| | |
| | |
| 3
| |
| | |
| | |
| 8.0
| |
| | |
| | |
| 7
| |
| | |
| | |
| 4
| |
| | |
| | |
| 51.3
| |
| | |
| | |
| | |
| 088
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| son and Evans, 1958 j. Administration of
| |
| vitamin C concomitant witli gonadotropliin
| |
| has been claimed to enhance ovarian response (DiCio and Schteingart, 1942), but
| |
| in another study the addition of ascorbic
| |
| acid inhibited the hiteinizing and ovulating
| |
| action of the gonadotrophin (Desaive,
| |
| 1956).
| |
| | |
| Whether induced by vitamin deficiency
| |
| or by inanition, the anestrum in rats which
| |
| follows 2 to 3 weeks' feeding of a vitamin
| |
| B-deficient diet has been explored as a
| |
| method for the assay of gonadotrophin.
| |
| Pugsley (1957) has shown that there is
| |
| considerable convenience of method and a
| |
| satisfactory precision of response for the
| |
| assay of HCG and pregnant mare serum.
| |
| | |
| 2. Uterus and Vagina
| |
| | |
| a. Inanition. Limited food intake does
| |
| not prevent an increase in uterine weight
| |
| after estrogen. Testosterone propionate will
| |
| markedly increase uterine growth despite
| |
| a 50 per cent reduction in food intake
| |
| (Leathem, Nocenti and Granitsas, 1956).
| |
| Furthermore, dietary manipulations involving caloric and protein levels did not prevent the uteri of spayed rats from responding to estrogen (Vanderlinde and
| |
| Westerfield, 1950). More specific biochemical and physiologic responses must be
| |
| measured because starvation for 4-day periods clearly interferes with deciduoma formation (DeFeo and Rothchild, 1953). A
| |
| start in the direction of studying tissuecomposition changes has been made by
| |
| measuring glycogen. However, no changes
| |
| were noted in uterine glycogen in fasting
| |
| rats (Walaas, 1952), and estrogen promoted
| |
| glycogen deposition in the uteri of starved
| |
| rats as well as in the uteri of fully fed rats
| |
| (Bo and Atkinson, 1953).
| |
| | |
| b. Fat. Interest in the hormone content of
| |
| fat from the tissues of animals treated with
| |
| estrogen for the purpose of increasing body
| |
| weight has raised the question of tissue hormone content. If estrogen was to be detected in tissues, an increase in dietary fat
| |
| was necessary. However, the increase in
| |
| dietary fat decreased the uterine response to
| |
| stilbcstrol (I'mberger and Gass, 1958), thus
| |
| complicating the assay.
| |
| | |
| c. Vitainins. Stimulation of the uterus
| |
| by estrogen does not require tliianiinc, ribo
| |
| | |
| | |
| flavin, pyridoxine, or pantothenic acid. On
| |
| the other hand, a deficiency of nicotinic acid
| |
| appears to enhance the response to low
| |
| doses of estrogen (Kline and Dorfman,
| |
| 1951a, b). However, Bio appears to be
| |
| needed for optimal oviduct response (Kline,
| |
| 1955) and is required for methyl group synthesis from various one-carbon precursors
| |
| including serine and glycine (Johnson,
| |
| 1958).
| |
| | |
| Response of the bird oviduct to stilbestrol
| |
| requires folic acid (Hertz, 1945, 1948). It
| |
| was shown subsequently that stilbestrol and
| |
| estrone effects in frogs, rats, and the rhesus
| |
| monkey also require folic acid. A folic acid
| |
| deficiency can be induced by feeding aminopterin. In this way the estrogen effects
| |
| can be prevented. Aminopterin also prevents
| |
| the action of progesterone in deciduoma
| |
| formation, from which it may be inferred
| |
| that folic acid is necessary for deciduoma
| |
| formation in the rat. Increased steroid or
| |
| folic acid levels can reverse the antagonist's
| |
| effect (Velardo and Hisaw, 1953).
| |
| | |
| The mechanism of folic acid action is not
| |
| clear. It may function in fundamental metabolic reactions linked with nucleic acid
| |
| synthesis. Brown (1953) showed that
| |
| desoxyribonucleic acid could be substituted
| |
| for folic acid in the bird. In the rat aminopterin interferes with the increase in
| |
| uterine nucleic acids, and with nitrogen
| |
| and P-^- uptake by nucleic acids following
| |
| estrogen. Folic acid has been implicated in
| |
| the metabolism of several amino acids
| |
| (Davis, Meyer and McShan, 1956).
| |
| | |
| Rats ovariectomized at weaning and
| |
| maintained on a vitamin E-free diet for
| |
| 6 weeks to 10 months responded to estradiol
| |
| in the same manner as rats supplemented
| |
| with tocopherol. This finding suggests that
| |
| an intimate physiologic relationship between estradiol and vitamin E is not very
| |
| probable (Kaunitz, Slanetz and Atkinson,
| |
| 1949). Nevertheless, vitamin E has been
| |
| re]:»orted to act synergistically with ovarian
| |
| hormones in dc^ciduoma formation (Kehl,
| |
| Douard and Lanfranchi. 1951 ) and to influence nucleic acid turnover (Dinning.
| |
| Simc and Day, 1956).
| |
| | |
| A vitamin-hormone interrelationship is
| |
| apparent when estrogen and vitamin A are
| |
| considered. Vitamin A-deficient female rats
| |
| present evidence of a metaplastic uterine
| |
| | |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 689
| |
| | |
| | |
| | |
| epithelium in 11 to 13 weeks, but similar
| |
| changes failed to develop in ovariectomized
| |
| rats. Vitamin A-deficient castrated rats
| |
| quickly developed symptoms of metaplasia
| |
| when estrogen alone was administered, but
| |
| no adverse effect followed the administration of estrogen combined with vitamin A
| |
| (Bo, 1955, 1956). The vagina is different.
| |
| Its epithelium becomes cornified in vitamin
| |
| A-deficient normal and castrated rats. The
| |
| cornification is histologically indistinguishable from that occurring in the estrous
| |
| rat and can be prevented by vitamin A.
| |
| In fact, vitamin A will quantitatively inhibit the effect of estrogen on the vaginal
| |
| mucosa when both are applied locally
| |
| (Kahn, 1954). Conversion of ^-carotene to
| |
| vitamin A is influenced by tocopherol, vitamin Bi2 , insulin, and thyroid, with evidence
| |
| for and against a similar action by cortisone
| |
| (Lowe and Morton, 1956; Rice and Bo,
| |
| 1958). An additional vitamin-hormone relationship is suggested by the augmentation
| |
| of progesterone action in rabbits given vitamin Do .
| |
| | |
| 3. Mammary Gland
| |
| | |
| Inanition prevents mammary growth, but
| |
| feeding above recommended requirements
| |
| for maintenance and growth from birth
| |
| to the first parturition also seems to interfere with mammary growth. Furthermore,
| |
| steroid stimulation of the mammary gland
| |
| is influenced by nutritional factors. Using
| |
| the male mouse, Trentin and Turner (1941)
| |
| showed that as food intake decreased, the
| |
| amount of estradiol required to produce a
| |
| minimal duct growth w^as proportionately
| |
| increased. In the immature male rat a
| |
| limited food intake prevented the growth of
| |
| the mammary gland exhibited by fully fed
| |
| controls. Nevertheless, the gland was competent to respond to estrogen (Reece, 1950) .
| |
| Inasmuch as the glands of force-fed hypophysectomized rats did not respond to estrogen (Samuels, Reinecke and Peterson,
| |
| 1941; Ahren, 1959), one can assume that,
| |
| despite inanition, a hypophyseal factor was
| |
| present to permit the response of the mammary gland to estrogen. However, inanition
| |
| (IMeites and Reed, 1949) , but not vitamin
| |
| deficiencies (Reece, Turner, Hathaway and
| |
| Davis, 1937), did reduce the content of
| |
| hypophyseal lactogen in the rat.
| |
| | |
| | |
| | |
| Growth of the mammary gland duct in
| |
| the male rat in response to estradiol requires a minimum of 6 per cent casein. Protein levels of 3 per cent and per cent failed
| |
| to support growth of the duct (Reece, 1959) .
| |
| | |
| C. PREGNANCY
| |
| | |
| The human male after attaining adulthood is confronted with the problem of
| |
| maintaining the body tissues built up during
| |
| the growth period. However, in the human
| |
| female it has been estimated that the replacement of menstrual losses may require
| |
| the synthesis of tissue equivalent to 100
| |
| per cent of her body weight (Flodin, 19531.
| |
| In the event of pregnancy and in all viviparous species, the female is presented with
| |
| even more formidable demands and a limitation of nutritional needs can lead to loss
| |
| of the embryo or fetus. The role of nutrition
| |
| at this point in reproduction has always received considerable attention and is complicated by the circumstance that many food
| |
| substances influence pregnancy (Jackson,
| |
| 1959). However, in many instances there is
| |
| no evidence that fetal loss or malformation
| |
| induced by nutritional modifications has
| |
| been the consequence of an endocrine imbalance and thus limitation of the immense
| |
| literature is permissible.
| |
| | |
| During the first 15 days of pregnancy, a
| |
| rat may gain 50 gm. Since the fetuses and
| |
| placentas are small, most of the gain is maternal and is associated with an' increase
| |
| in food intake of as much as 100 calories
| |
| per kilogram of body weight (Morrison,
| |
| 1956). During the first 2 weeks of pregnancy, marked storage of fat and water occurs in the maternal body and the animal's
| |
| positive nitrogen balance is above normal.
| |
| Liver fat also increases (Shipley, Chudzik,
| |
| Curtiss and Price, 1953). The increased food
| |
| intake in early pregnancy may therefore
| |
| provide a reserve for late fetal growth, as
| |
| food intake may decline to 65 per cent of
| |
| the general pregnancy level during the last
| |
| 7 days (Morrison, 1956). During this last
| |
| week, fetal growth is rapid. The rapid
| |
| growth has been related to (1) greater demands of the fetus, (2) greater amounts of
| |
| food in the maternal blood, and (31 greater
| |
| permeability of the placenta. Certainly the
| |
| anabolic potential of fetal tissues is high
| |
| and the mother can lose weight while the
| |
| | |
| | |
| | |
| 690
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| fetuses gain. But it is also important to
| |
| recall that there is a shift in protein, because
| |
| its distribution in organs of pregnant rats
| |
| differs from that in nonpregnant animals
| |
| (Poo, Lew and Addis, 1939). Other changes
| |
| in the maternal organism were enumerated
| |
| b}^ Newton (1952) and by Souders and
| |
| Morgan (1957).
| |
| | |
| A measure of nitrogen balance during
| |
| pregnancy, rather than weight of young at
| |
| birth, has been suggested as a means of
| |
| determining a diet adequate for reproduction (Pike, Suder and Ross, 1954). After
| |
| the 15th day, a retention of body protein
| |
| increases, blood amino nitrogen and amino
| |
| acids decrease, and urea formation decreases. These metabolic activities suggest
| |
| an increase in growth hormone although the
| |
| levels of this hormone have not been estimated (Beaton, Ryu and McHenry, 1955).
| |
| Placental secretions have also been associated with the active anabolic state of the
| |
| second half of pregnancy, because removal
| |
| of the fetuses in the rat did not change the
| |
| anabolic activity, whereas removal of the
| |
| placentas was followed by a return to normal (Bourdel, 1957). A sharp increase in
| |
| liver ribose nucleic acid has been observed
| |
| during late pregnancy in mice and rats and
| |
| the effect attributed to a placental secretion
| |
| or to estrogen. Species differences also influence the results because only a modest
| |
| change in liver RNA was observed in guinea
| |
| pigs and no change occurred in cats (Campbell and Kostcrlitz, 1953; Campbell, Innes
| |
| and Kosterlitz, 1953a, b).
| |
| | |
| Clinical observations have related both
| |
| | |
| TABLE 12.10
| |
| | |
| Nutrition and pregnancy in rats
| |
| | |
| (From J. H. Leathern, in Recent Progress in
| |
| | |
| the Endocrinology of Reproduction, Academic
| |
| | |
| Press, Inc., New York, 1959.)
| |
| | |
| | |
| | |
| | |
| | |
| Calories/kg.
| |
| Body Weight
| |
| | |
| | |
| Fetuses, Day 20
| |
| | |
| | |
| | |
| | |
| No.
| |
| | |
| | |
| Average
| |
| weight
| |
| | |
| | |
| 18 per cent casein
| |
| | |
| 18 per cent casein
| |
| | |
| 6 per cent casein
| |
| | |
| per cent casein
| |
| | |
| 18 per cent gelatin
| |
| | |
| 18 per cent gelatin
| |
| | |
| | |
| 200
| |
| 100
| |
| | |
| 250
| |
| 200
| |
| 200
| |
| 100
| |
| | |
| | |
| 8
| |
| 6
| |
| | |
| | |
| | |
| | |
| | |
| | |
| gm.
| |
| 6.1
| |
| | |
| 3.5
| |
| | |
| | |
| | |
| toxemia of pregnancy (Pequignot, 1956)
| |
| and prematurity to inadequate nutrition
| |
| (Jeans, Smith and Stearns, 1955). The potential role of protein deprivation in the
| |
| pathogenesis of the toxemia of pregnancy
| |
| prompted studies in sheep and rats. In sheep
| |
| nutritionally induced toxemia simulates the
| |
| spontaneous toxemia (Parry and Taylor,
| |
| 1956), but only certain aspects of toxemia
| |
| were observed in the pregnant rat subjected
| |
| to low protein diets. When rats were fed 5
| |
| per cent casein and mated, fluid retention
| |
| was observed (Shipley, Chudzik, Curtiss
| |
| and Price, 1953) and pregnancy was completed in only 48 per cent of the animals
| |
| Curtiss, 1953). Gain in body weight in the
| |
| adult rat and gain in fetal weight were subnormal as the result of a low protein feeding
| |
| during pregnancy.
| |
| | |
| Complete removal of protein from the
| |
| diet beginning at the time of mating did not
| |
| prevent implantation but did induce an 86
| |
| to 100 per cent embryonic loss. The effect
| |
| was not related solely to food intake (Nelson and Evans, 1953) , as we will see in what
| |
| follows when the relationship between protein deficiency and the supply of estrogen
| |
| and progesterone is described. Limiting protein deprivation to the first 9 to 10 days of
| |
| pregnancy will also terminate a pregnancy,
| |
| but when the protein was removed from the
| |
| diet during only the last week of pregnancy,
| |
| the maternal weight decreased without an
| |
| effect on fetal or placental weight (Campbell and Kosterlitz, 1953). As would be anticipated, a successful pregnancy requires
| |
| protein of good nutritional quality and the
| |
| caloric intake must be adequate. Thus, an
| |
| 18 per cent gelatin diet failed to maintain
| |
| pregnancy when 200 calories per kilogram
| |
| were fed, whereas a similar level of casein
| |
| was adequate (Table 12.10). However, reducing caloric intake to 100 calories despite
| |
| an otherwise adequate protein ration influenced the number and size of fetuses
| |
| (Leathern, 1959b). Additional proteins
| |
| should be studied and related to biochemical changes in pregnancy and to the need for
| |
| specific amino acids; for example, elimination of methionine or tryptophan from the
| |
| diet may or may not be followed by resorption (Sims, 1951; Kemeny, Handel, Kertesz
| |
| and Sos, 1953; Albanese, Randall and Holt,
| |
| 1943). Excretion of 10 amino acids was in
| |
| | |
| | |
| NUTRITIONAL EFFECTS
| |
| | |
| | |
| | |
| 691
| |
| | |
| | |
| | |
| creased during normal human pregnancy
| |
| (Miller, Ruttinger and Macey, 1954).
| |
| | |
| That a relationship exists, between the
| |
| dietary requirements just described to the
| |
| endocrine substances which participate in
| |
| the control of pregnancy, is suggested by the
| |
| fact that the deleterious effects of a proteinfree diet on pregnancy in rats have been
| |
| counteracted by the administration of estrone and progesterone. Pregnancy was
| |
| maintained in 30 per cent, 60 to 80 per cent,
| |
| and per cent of protein-deficient animals
| |
| by daily dosages of 0.5 /xg., 1 to 3 fig., and 6
| |
| jug. estrone, respectively. On the other hand,
| |
| injection of 4 to 8 mg. progesterone alone
| |
| maintained pregnancy in 70 per cent of the
| |
| animals (Nelson and Evans, 1955) , and an
| |
| injection of 4 mg. progesterone with 0.5 //.g.
| |
| estrone provided complete replacement
| |
| therapy (Nelson and Evans, 1954). Food
| |
| intake did not increase. The results suggest
| |
| that reproductive failure in the absence of
| |
| dietary protein was due initially to lack of
| |
| progesterone and secondarily to estrogen,
| |
| the estrogen possibly serving as an indirect
| |
| stimulation for luteotrophin secretion and
| |
| release. It is well known that hypophysectomy or ovariectomy shortly after breeding
| |
| will terminate a pregnancy and that replacement therapy requires both ovarian
| |
| hormones. Thus, the protein-deficient state
| |
| differs somewhat from the state following
| |
| hypophysectomy or ovariectomy, but the
| |
| factors involved are not known.
| |
| | |
| Pregnancy alters nutritional and metabolic conditions in such a way that labile
| |
| protein stores of the liver and other parts of
| |
| the body are influenced, but similar effects
| |
| are imposed by a transplanted tumor, especially when it reaches 10 per cent of the
| |
| body weight. ' Thus, transplantation of a
| |
| tumor into a pregnant animal would place
| |
| the fetuses in competition with the tumor for
| |
| the amino acids of the metabolic pool. Under
| |
| these circumstances will the pregnancy be
| |
| maintained? An answer to the question may
| |
| not yet be given. Nevertheless, Bly, Drevets
| |
| and Migliarese (1955) observed various degrees of fetal damage in pregnant rats bearing the Walker 256 tumor, and 43 per cent
| |
| fetal loss was obtained with a small hepatoma (Paschkis and Cantarow, 1958).
| |
| | |
| Essential fatty acid deficiency, at least
| |
| in the initial stages, does not interfere with
| |
| | |
| | |
| | |
| development of the fetuses or parturition in
| |
| the rat, but the pups may be born dead or
| |
| they do not survive more than a few days
| |
| (Kummerow, Pan and Hickman, 1952). A
| |
| more pronounced deficiency has induced
| |
| atrophic changes in the decidua, resorption
| |
| of fetuses, and prolonged gestation. Death
| |
| of the fetuses appears to be secondary to
| |
| placental injury. Hormonal involvement, if
| |
| any, when there is fatty acid deficiency and
| |
| pregnancy seems not to have been investigated.
| |
| | |
| Pregnancy and lactation are major factors influencing vitamin requirements. It is
| |
| not surprising, therefore, that vitamin deficiencies influence the course of a pregnancy. The subject has recently been reviewed by Lutwak-jMann (1958).
| |
| | |
| A deficiency of vitamin A does not noticeably affect early fetal development, but
| |
| later in gestation placental degeneration occurs with hemorrhage and abortion. When
| |
| the deficiency is moderate the pregnancy is
| |
| not interrupted, but the fetuses are damaged
| |
| (Warkany and Schraffenberger, 1944; Wilson, Roth and Warkany, 1953; Giroud and
| |
| Martinet, 1959). In calves and pigs the
| |
| abnormalities are associated with the eyes
| |
| and palate (Guilbert, 1942) ; in birds skeletal abnormalities are seen (Asmundson and
| |
| Kratzer, 1952). The use of hormones in an
| |
| effort to counteract the effects seems to have
| |
| been attempted only in the rabbit where
| |
| 12.5 mg. progesterone improved reproduction impaired by vitamin A lack (Hays and
| |
| Kendall, 1956). Vitamin A excess also
| |
| proves highly detrimental to pregnancy, as
| |
| resorption and malformations occur. Administration of excessive vitamin A on days
| |
| 11 to 13 of pregnancy induced cleft palate in
| |
| 90 per cent of the embryos (Giroud and
| |
| Martinet, 1955) . In another experiment the
| |
| effect of excessive vitamin A was augmented
| |
| by cortisone (Woollam and Millen, 1957).
| |
| | |
| Vitamin E deficiency has long been known
| |
| to influence pregnancy in rodents and fetal
| |
| death appears to precede placental damage
| |
| and involution of the corpora lutea. Gross
| |
| observations of the abnormal embryos have
| |
| been reported (Cheng, Chang and Bairnson, 1957). Estrogen, progesterone, and lactogen were not effective in attempts at corrective therapy (Ershoff, 1943), but estrone
| |
| and progesterone markedly reduced the in
| |
| | |
| | |
| 692
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| cidence of congenital malformations associated with vitamin E lack (Cheng, 1959).
| |
| In the test of a possible converse relationship, estradiol-induced abortion in guinea
| |
| pigs was not prevented by vitamin E (Ingelman-Sundberg, 1958) .
| |
| | |
| Fat-soluble vitamins incorporated in the
| |
| diet may be destroyed by oxidation of the
| |
| unsaturated fatty acids. To stabilize the
| |
| vitamins, the addition of diphenyl-p-phenylenediamine (DPPD) to the diet has
| |
| proven successful, but recent studies show
| |
| that DPPD has an adverse effect on reproduction and thus its use in rat rations
| |
| is contraindicated (Draper, Goodyear, Barbee and Johnson, 1956).
| |
| | |
| Vitamin-hormone relationships in pregnancy have been studied with regard to
| |
| thiamine, pyridoxine, pantothenic acid, and
| |
| folic acid. Thiamine deficiency induced stillbirths, subnormal birth weights, resorption
| |
| of fetuses, and loss of weight in the mother.
| |
| However, as in the case of protein deficiency, pregnancy could be maintained with
| |
| 0.5 fjLg. estrone and 4 mg. progesterone (Nelson and Evans, 1955). Estrone alone had
| |
| some favorable effect on the maintenance
| |
| of pregnancy in thiamine-deficient animals,
| |
| but it was less effective in protein-deficient
| |
| animals.
| |
| | |
| Fetal death and resorptions as well as
| |
| serum protein and nonprotein nitrogen
| |
| (NPN) changes similar to those reported
| |
| for toxemia of pregnancy (Ross and Pike,
| |
| 1956; Pike and Kirksey, 1959) were induced
| |
| by a diet deficient in vitamin Be . Administration of 1 fxg. estrone and 4 mg. progesterone maintained pregnancy in 90 per cent of
| |
| vitamin Be-deficient rats (Nelson, Lyons
| |
| and Evans, 1951). However, the pyridoxinedeficient rat required both steroids to remain pregnant and in this regard resembled
| |
| the hypophysectomized animal (Nelson,
| |
| Lyoas and Evans, 1953). Nevertheless, a
| |
| hypophyseal hormone combination which
| |
| was adequate for the maintenance of pregnancy in the fully fed hypophysectomized
| |
| rat (Lyons, 1951) was only partially successful when there was a deficiency of pyridoxine. An ovarian defect is suggested.
| |
| | |
| The folic acid antagonist, 4-aminopteroylglutamic acid, will rapidly induce the
| |
| death of early implanted embryos in mice.
| |
| | |
| | |
| | |
| rats, and man (Thiersch, 1954j . Removal
| |
| of folic acid from the diet or the addition
| |
| of x-methyl folic acid will induce malformations when low doses are given and resorptions when high doses are given. Furthermore, this effect is obtained even when
| |
| the folic acid deficiency is delayed until
| |
| day 9 of a rat pregnancy or maintained for
| |
| only a 36-hour period. A deficiency of
| |
| pantothenic acid will also induce fetal resorption. The vitamin is required for hatching eggs (Gillis, Heuser and Norris, 1942).
| |
| In animals deficient in folic acid or in
| |
| pantothenic acid, estrone and progesterone
| |
| replacement therapy did not prevent fetal
| |
| loss, suggesting that the hormones cannot
| |
| act (Nelson and Evans, 1956). In the above
| |
| mentioned deficiencies replacement of the
| |
| vitamin is effective. However, vitamins
| |
| other than those specifically deleted may
| |
| provide replacement, thus ascorbic acid
| |
| seems to have a sparing action on calcium
| |
| pantothenate (Everson, Northrop, Chung
| |
| and Getty, 1954) .
| |
| | |
| Pregnancy can be interrupted by altering
| |
| vitamins other than those discussed above,
| |
| but the hormonal aspects have not been
| |
| explored. Thus, the lack of choline, riboflavin, and Bi2 will induce fetal abnormalities and interrupt gestation (Giroud, Levy,
| |
| Lefebvres and Dupuis, 1952; Dryden, Hartman and Gary, 1952; Jones, Brown, Richardson and Sinclair, 1955; Newberne and
| |
| O'Dell, 1958) . Choline lack is detrimental to
| |
| the placenta (Dubnov, 1958), riboflavin
| |
| deficiency may impair carbohydrate use
| |
| (Nelson, Arnrich and Morgan, 1957) and/or
| |
| induce electrolyte disturbances (Diamant
| |
| and Guggenheim, 1957) , and Bjo spares choline and may be concerned with nucleic
| |
| acid synthesis (Johnson, 1958). Excessive
| |
| amounts of Bio are not harmful. It is interesting to note that uterine secretions and
| |
| rabbit blastocyst fluid are rich in vitamin
| |
| B]2 (Lutwak-Mann, 1956), but its presence
| |
| in such large amounts has not been explained.
| |
| | |
| An additional substance, lithospermin, extracted from the plant, Lathijrus odoratus,
| |
| is related to hormone functioning; it is antigonadotrophic when eaten by nonpregnant
| |
| animals and man. The feeding of this substance to prciiiiant rats terminated the pregnancies about the 17th day. Treatment with
| |
| estrogen and progesterone was preventive
| |
| (Walker and Wirtschafter, 1956). It is assumed, therefore, that lithospermin interfered with the production of these hormones.
| |
| A repetition of the experiment on a species
| |
| in which the hypophysis and ovaries are
| |
| dispensable during much of pregnancy
| |
| would be of interest.
| |
| | |
| In retrospect it has been found that a
| |
| deficiency in protein and the vitamins
| |
| thiamine, pyridoxine, pantothenic acid, and
| |
| folic acid individually can interrupt a pregnancy. Furthermore, a combination of estrone and progesterone which is adequate to
| |
| maintain pregnancy after hypophysectomy
| |
| and ovariectomy, is equally effective in protein or thiamine deficiency. This suggests
| |
| that the basic physiologic alteration is a
| |
| deprivation of ovarian hormones. However,
| |
| protein- and thiamine-deficiency states differ from each other as shown by the response to estrogen alone (thiamine deficiency is less responsive), and these states
| |
| differ from hypophysectomy in which estrone alone has no effect. A pyridoxine deficiency seems to involve both ovary and
| |
| hypophysis, for neither steroids nor pituitary hormones were more than partially
| |
| successful in maintaining pregnancy in rats.
| |
| Lastly, pantothenic acid and folic acid
| |
| deficiencies may not create a steroid deficiency. What is involved is not known;
| |
| many possibilities exist. Pantothenic acid,
| |
| for example, participates in many chemical
| |
| reactions. Furthermore, it is known that
| |
| thiamine is essential for carbohydrate metabolism but not for fat metabolism whereas
| |
| pyridoxine is involved in fat metabolism
| |
| and in the conversion of tryptophan to nicotinic acid. It is clear, though, that much
| |
| ground must be covered before the formulation of fruitful hypotheses may be anticipated.
| |
| | |
| VI. Concluding Remarks
| |
| | |
| The development, composition, and normal functioning of the reproductive system
| |
| is dependent on adequate nutrition. However, the requirements are many and only
| |
| gradually are data being acquired which are
| |
| pertinent to the elucidation of the nutritional-gonadal relationship.
| |
| | |
| | |
| | |
| The demands for nutrient substances is
| |
| not always the same. During pregnancy and
| |
| lactation there is a need for supplemental
| |
| feeding. A similar need exists in birds and
| |
| in the many cold-blooded vertebrates in
| |
| which reproduction is seasonal. Atypical endocrine states create imbalances and a need
| |
| for nutrient materials which vary, unpredictably, we must acknowledge, until the
| |
| numerous interrelationships have been clarified.
| |
| | |
| At many points where determination of
| |
| cause and effect are possible, an indirect
| |
| action of dietary factors on reproduction is
| |
| indicated. No other conclusion seems possible in view of the many instances in which
| |
| the effect of dietary deficiencies can be
| |
| counteracted by the administration of a
| |
| hormone or combination of hormones. The
| |
| direct action is not immediately apparent;
| |
| it probably is on the processes by which
| |
| metabolic homeostasis is maintained, and is
| |
| in the nature of a lowering of the responsiveness to the stimuli which normally trigger these processes into action. The processes
| |
| may be those by which pituitary and gonadal hormones are produced or they may be
| |
| the mechanisms by which these hormones
| |
| produce their effects on the genital tracts
| |
| and on the numerous other tissues on which
| |
| they are known to act.
| |
| | |
| Because of the many interrelationships,
| |
| some of which are antagonistic and some
| |
| supportive, determination of the role of specific dietary substances is not easy. For
| |
| those who work with laboratory species,
| |
| the problem is further complicated by the
| |
| many strain differences. For everyone, the
| |
| problem is complicated by the many species
| |
| differences which are the result of an evolution toward carnivorous, herbivorous, or
| |
| omnivorous diets, to say nothing of the
| |
| countless specific preferences within each
| |
| group.
| |
| | |
| Finally, it is something of a paradox in our
| |
| culture that much of our effort has been devoted to investigations of the effects of deficiencies and undernutrition rather than
| |
| to the effects of excesses and overnutrition.
| |
| Much evidence supports the view that in
| |
| the aggregate the latter are fully as deleterious as the former, but the means by which this result is achieved are largely unknown.
| |
| | |
| | |
| | |
| VII. References
| |
| | |
| Aak.s-Jorgensen, E., Funch, J. P., and Dam, H.
| |
| | |
| 1956. Role of fat in diet of rats; influence
| |
| on reproduction of hydrogenated arachis oil
| |
| as sole dietary fat. Brit. J. Nutrition, 10, 317.
| |
| | |
| Aaes-Jorgensen, E., Funch, J. P., and Dam, H.
| |
| | |
| 1957. Role of fat in diet of rats; influence of
| |
| small amount of ethyl linoleate on degeneration of spermatogenic tissue caused by hydrogenated arachis oil as sole dietary fat. Brit. J.
| |
| Nutrition, 11, 298.
| |
| | |
| AcETO, G., Li Moli, S., and Panebianco, N. 1956.
| |
| Influence of adrenocorticotrophin (ACTH) on
| |
| the urinary excretion of thiamine. Acta vitaminol., 10, 175.
| |
| | |
| Adams, C. E. 1953. Mammalian germ cells. Ciba
| |
| Foundation Symposium, 198.
| |
| | |
| Adams, C. W. M., Fernand, V. S. V., and Schnieden,
| |
| H. 1958. Histochemistry of a condition resembling kwashiorkor produced in rodents by
| |
| a low protein-high carbohydrate diet (cassaval). Brit. J. Exper. Path., 39, 393.
| |
| | |
| Addis, T., Poo, L. J., and Lew, W. 1936. The
| |
| ciuantities of protein lost by the various organs
| |
| and tissues of the body during a fast. J. Biol.
| |
| Chem., 115, 111.
| |
| | |
| Ahren, K. 1959. The effect of dietary restriction
| |
| on the mammary gland development produced
| |
| by ovarian hormones in the rat. Acta endocrinol., 31, 137.
| |
| | |
| Albanese, a. a., Randall, R. M., .\nd Holt, L. E.,
| |
| Jr. 1943. The effect of tryptophan deficiency
| |
| on reproduction. Science, 97, 312.
| |
| | |
| Angervall, L. 1959. Alloxan diabetes and pregnancy in the rat. Effects on offspring. Acta
| |
| Endocrinol., suppl. 44, 31, 86.
| |
| | |
| Arvy, L., Aschkenasy, A., Aschkenasy-Lelu, P.,
| |
| AND Gabe, M. 1946. Retentissement d'un regime prolonge d'inanition proteique sur les
| |
| glandes genitales du rat femelle. Compt. rend.
| |
| Soc. biol., 140, 730.
| |
| | |
| Aschkenasy, A. 1954. Action de la testosterone, de la thyroxine ct do la cortisone sur
| |
| revolution de I'anemie et de la leucopenie proteiprives. Le Sang, 25, 15.
| |
| | |
| Aschkenasy, A. 1955a. Influence des proteines
| |
| alimentaires et de divers acides amines sur la
| |
| survie et le poids somatique de i-ats surrenalectomises et de rats surrenalcctomises-castres.
| |
| Ann. endocrinol., 16, 86.
| |
| | |
| Aschkenasy, A. 1955b. Influence des proteines
| |
| alimentaires et de divers acides amines sur la
| |
| survie et sur le poids somatique de rats surrenalcctomises et de rats surrenalectomisescastres. Ann. endocrinol.. 16, 199.
| |
| | |
| Aschkenasy, A. 1955c. Effects de la .surrenalectomie sur les poids relatifs de divers organes
| |
| et tis.sus. Role du facteur temps et influence do
| |
| la richnesse du regime en proteines. J. jjhvsiol.,
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| Paris, 47, 75.
| |
| | |
| | |
| | |
| Aschkenasy, A. 1957. Effets compares de
| |
| I'ACTH, de la cortisone et de la delta-cortisone
| |
| sur les poids de divers organes et tissus chez
| |
| le rat male adulte. Ann. endocrinol., 18, 981.
| |
| | |
| Aschkenasy, A., Aschkenasy-Lelu, P. 1957.
| |
| Nouvelles recerches sur le role des surrenales
| |
| dans la gestation en regime pauvre en proteines. Compt. rend. Soc. biol., 151, 880.
| |
| | |
| Aschkenasy, A., and Dray, F. 1953. Action de
| |
| quelques hormones sur la reprise du poids et
| |
| sur la regeneration des organes apres inanition
| |
| proteique experimental. Compt. rend. Soc.
| |
| biol., 147, 1722.
| |
| | |
| Aschkena.sy-Lelu, p., and Aschkenasy, A. 1947.
| |
| Influence du taux des protides de la ration sur
| |
| le cycle oestral de la rate adulte. Perturbation
| |
| du cycle avec prolongation des oestrus sous
| |
| d'action d'un regime hyperprotidique. Compt.
| |
| rend. Soc. biol., 141, 687.
| |
| | |
| Aschkenasy-Lelu, P., and Aschkenasy^ A. 1957.
| |
| Intervention des surrenales dans la gestation
| |
| en fonction de la teneur de regime en proteines.
| |
| Arch. so. physioL, 11, 125.
| |
| | |
| Aschkenasy-Lelu, P., and Tuchmann-Duplessis,
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| H. 1947. Action d'un regime hyperprotidique
| |
| sur le developpement somaticjue et sexual de la
| |
| jeune rate. c3ompt. rend. Soc. biol., 141, 1166.
| |
| | |
| AsDELL, S. A. 1949. Nutrition and treatment of
| |
| sterility in dairy cattle: a review. J. Dairv Sc.
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| 32, 60.
| |
| | |
| AsMUND.soN, V. S., AND Kr.\tzer, F. H. 1952. Observations on vitamin A deficiency in turkey
| |
| breeding stock. Poultry Sc, 31, 71.
| |
| | |
| Baker, B. L. 1952. Comparison of histological
| |
| changes induced by experimental hyperadrenalcorticalism and inanition. Recent Progr. Hormone Res., 7, 331.
| |
| | |
| Ball, Z. B., B.\rnes, R. H., and Visscher, M. B.
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| 1947. The effects of dietary caloric restriction
| |
| on maturity and senescence, with particular
| |
| reference to fertility and longevitv. Am. J.
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| Physiol., 150, 511.
| |
| | |
| Barborlak, J. J., Krehl, W. A., Cowgill, G. R..
| |
| .-AND Whedon, a. D. 1957. Effect of partial
| |
| pantothenic acid deficiencj' on reproductive
| |
| performance of rat. J. Nutrition, 63, 591.
| |
| | |
| BE.ATON, G. H., Ryu. M. H., and McHenry. E. W.
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| 1955. Studies on the role of growth hormone
| |
| in pregnancy. Endocrinology, 57, 748.
| |
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| Beckmann, R. 1955. Vitamin E (Physiologic,
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| pathologische Physiologie, khnische Bedeutung). Ztschr. Vitamin- Hormon- u. Fermentforsch., 7, 281.
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| Berg, C. P., and Rohse, W. G. 1947. Is sterility
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| induced in growing rats on a tryptoplian deficient diet? Science. 105, 96.
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| BiDDULiMi, C, AND Meyer. R. K. 1941. Tho influence of vitamin E-deficiency on the endocrine glands of rats, particularly on the gonadotrophic hormone content of the pituitary
| |
| gland. Am. J. Physiol., 132, 259.
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| Bishop, D. W., and Ko.s.\rick, E. 1951. Blot in
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| Biskind, M. S. 1946. Nutritional therapy of endocrine disturbances. Vitamins & Hormones,
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| Blandau, R. J., Kauntiz, H., and Slanetz, C. A.
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| 1949. Ovulation, fertilization and transport of
| |
| ova in old vitamin E-deficient rats. J. Nutrition, 38, 97.
| |
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| Blaxter, K. L., and Brown, F. 1952. Vitamin E
| |
| in the nutrition of farm animals. Nutritional
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| Abstr. & Rev., 21, 1.
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| Blivaiss, B. B., Hanson, R. O., Rosenzweig, R. E.,
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| AND McNeil, K. 1954. Sexual development
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| in female rats treated with cortisone. Proc. Soc.
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| Exper. Biol. & Med., 86, 678.
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| Bly, C. G., Drevets, C., and Migliarese, J. F.
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| 1955. Competition between fetal growth and
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| transplanted tumor growth in pregnant rats.
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| |
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| Blye, R. p., and Leathem, J. H. 1959. Ovarian
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| ascorbic acid in gonadotrophin-treated and
| |
| normal hypothyroid rats. Fed. Proc, 18, 49.
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| Bo, W. J. 1955. The effect of ovariectomy on
| |
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| |
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| Bo, W. J. 1956. The relationship between vitamin A deficiency and estrogen in producing
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| Bo, W. J., and Atkinson, W. B. 1953. Histochemical studies on glycogen deposition in
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| Booth, V. H. 1952. Liver storage of vitamin A
| |
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| |
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| Bourdel, G. 1956. L'anabolisme gravidique: ses
| |
| caracteristiques son determinisme. In Proceedings Fourth International Congress of Nutrition, p. 37.
| |
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| Br.\ekkan, O. R. 1955. Role of pantothenic acid
| |
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| |
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| |
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| BR.ATT0N, R. W. 1957. Nutrition and fertility.
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| Breneman, W. R. 1940. Limitation of food consumption as a factor influencing endocrine reactions in the chick. Endocrinolog.y, 26, 1091.
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| Brown, W. O. 1953. Effect of deoxypentose nucleic acid on impaired oviduct response to
| |
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| |
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| Burr, G. O., and Burr, M. M. 1930. On the nature and role of the fatty acids essential in
| |
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| |
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| |
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| |
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| Campbell, R. M., Innes, I. R., and Kosterlitz,
| |
| H. W. 1953a. The role of hormonal and
| |
| | |
| | |
| | |
| dietary factors in the formation of excess
| |
| ribonucleic acid in the livers of pregnant rats.
| |
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| |
| | |
| Campbell, R. M., Innes, I. R., and Kosterlitz,
| |
| H. W. 1953b. Some dietary and hormonal
| |
| effects on maternal, fetal and placental weights
| |
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| |
| | |
| Campbell, R. M., and Kosterlitz, H. W. 1953.
| |
| Species differences in the deoxyribonucleic and
| |
| ribonucleic acid contents of livers of nonpregnant and pregnant mice, guinea pigs and
| |
| cats. J. Endocrinol., 9, 45.
| |
| | |
| Cantarow, a., Paschkis, K. E., Rakoff, A. E., and
| |
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