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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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| 558
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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. ri:,,ii of the uterus of a castrated monkey which had received 1.0 mg. estradiol |
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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 | |
| 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 |
| | | may have by making an incision through |
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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 | |
| the anterior wall of the uterus (Hisaw, | | the anterior wall of the uterus (Hisaw, |
| 1950) . A castrated monkey was given 10 ixg. | | 1950) . A castrated monkey was given 10 ixg. |
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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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| bearing on the response of the endometrium | | bearing on the response of the endometrium |
| 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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| ESTROGEN AND PROGESTERONE
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| 563
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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 | | The uteri of these two castrated monkeys were opened from fundus to cer\'ix by an incision |
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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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| 565
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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 |
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| PHYSIOLOGY OF GONADS
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| the morphologic and physiologic features | |
| that are known for anovulatory and ovulatory cycles can be reproduced in castrated | | that are known for anovulatory and ovulatory cycles can be reproduced in castrated |
| monkeys by estrogen and progesterone. | | monkeys by estrogen and progesterone. |
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| If one designs an experiment to simulate | | If one designs an experiment to simulate |
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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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| 567
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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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| FiG. 9.9. Uterus of a castrated monkey that received 10 fig. estradiol and 1 mg. progesterone | | FiG. 9.9. Uterus of a castrated monkey that received 10 fig. estradiol and 1 mg. progesterone |
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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
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| 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 | | A similar synergistic action can be seen in |
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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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| 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.) |
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| through the opening of the fistula. Within a
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| few days tongue-like processes of endometrial tissue are thrust out of the opening
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| with each uterine contraction and are entirely or i^artially withdrawn at each relaxation.
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| Such outgrowths are difficult to protect | | Such outgrowths are difficult to protect |
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| 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, |
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| | |
| 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. |
| | |
|
| |
|
|
| |
|
Line 1,103: |
Line 939: |
|
| |
|
|
| |
|
| ESTROGEN AND PROGESTERONE
| | Fig. 9.12. The endometnuin of a castrated monkey that had received 10 /xg. estradiol |
| | and 1 mg. progesterone daily for 99 days. |
|
| |
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|
| |
|
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| |
|
| 569
| |
|
| |
|
| | | Even though in such experiments the endometrium has been under the influence of |
| | | both estrogen and progesterone for a year |
| | | and has undergone extremely abnormal |
| Fig. 9.12. The endometnuin of a castrated monkey that had received 10 /xg. estradiol
| | modification, it yet is capable of responding |
| and 1 mg. progesterone daily for 99 days.
| | to estrogen in a more or less characteristic |
| | | way when progesterone is stopped and in |
| | |
| | |
| 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 | |
| both estrogen and progesterone for a year | |
| and has undergone extremely abnormal | |
| modification, it yet is capable of responding | |
| to estrogen in a more or less characteristic | |
| way when progesterone is stopped and in | |
|
| |
|
|
| |
|
Line 1,149: |
Line 968: |
|
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|
| |
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|
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| 570
| |
|
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| |
|
| |
| PHYSIOLOGY OF GONADS
| |
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| |
|
| | | Fig. 9.13. The endometrium shown m .4 is (h;i( from a castraled mdiik.N wlml, l,a,l |
| | |
| 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 | | 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 | | magnification. The endometrium is almost entirely a modified stroma in which glandular |
Line 1,186: |
Line 997: |
|
| |
|
|
| |
|
| 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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| |
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| |
| ESTROGEN AND PROGESTERONE
| |
|
| |
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| |
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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. |
|
| |
|
|
| |
| PHYSIOLOGY OF GONADS
| |
|
| |
|
| |
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| |
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| |
| :^a.
| |
|
| |
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| |
| :^^--.^
| |
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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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| |
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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 1,326: |
Line 1,105: |
| the cervix are shown at the left and the entrance | | the cervix are shown at the left and the entrance |
| to the fundus is at the right. | | to the fundus is at the right. |
|
| |
|
| |
|
| |
| ESTROGEN AND PROGESTERONE
| |
|
| |
|
| |
|
| |
| 573
| |
|
| |
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| |
|
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 |
| | 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. |
|
| |
|
|
| |
|
| | | This reaction to estrogen as seen in the |
| 574
| | cervix of castrated monkeys is initiated by |
| | | growth of small undifferentiated cells below |
| | |
| | |
| 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
| |
| Fluhmann (1954) did not find it as frequently as in nonpregnant women.
| |
| | |
| This reaction to estrogen as seen in the | |
| cervix of castrated monkeys is initiated by | |
| growth of small undifferentiated cells below | |
| the columnar mucous cells of the secretory | | the columnar mucous cells of the secretory |
| epithelium. Fluhmann (1954) suggests that | | epithelium. Fluhmann (1954) suggests that |
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. |
| | |
| | |
| ESTROGEN AND PROGESTERONE
| |
| | |
| | |
|
| |
|
| 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. |
|
| |
|
|
| |
|
|
| |
| 576
| |
|
| |
|
| |
|
| |
| PHYSIOLOGY OF GONADS
| |
|
| |
|
|
| |
|
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;^ | |
| | |
|
| |
|
|
| |
|
| 4* ' V ^ §
| |
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| |
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| |
|
Line 1,611: |
Line 1,349: |
|
| |
|
|
| |
|
| 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 |
| | | of the cycle. A maximal size is attained by |
| | | the middle of the cycle followed by a rapid |
| ESTROGEN AND PROGESTERONE
| | regression and loss of edema which at least |
| | |
| | |
| | |
| 577
| |
| | |
| | |
| | |
| nounced swelling during the follicular phase
| |
| of the cycle. A maximal size is attained by | |
| the middle of the cycle followed by a rapid | |
| regression and loss of edema which at least | |
| in the baboon is associated with a marked | | in the baboon is associated with a marked |
| increase in the output of urine (Gillman, | | increase in the output of urine (Gillman, |
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: |
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| 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 |
| | 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. |
|
| |
|
|
| |
|
| | | The physiologic function of progesterone |
| 582
| | is the conversion of an estrogen-endometrium into a progestational endometrium |
| | | suitable for receiving and nourishing a developing blastocyst. Such an endometrium |
| | |
| | |
| 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
| |
| into consideration the synergistic interaction of the two hormones on the endometrium.
| |
| | |
| The physiologic function of progesterone | |
| is the conversion of an estrogen-endometrium into a progestational endometrium | |
| suitable for receiving and nourishing a developing blastocyst. Such an endometrium | |
| is adapted for this specific reproductive | | is adapted for this specific reproductive |
| function and accordingly its physiologic nature must be quite different from that of the | | function and accordingly its physiologic nature must be quite different from that of the |
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 |
| | |
| | |
| | |
| the endometrium of three species of South | |
| American monkeys known to menstruate. | | American monkeys known to menstruate. |
| He also found that the coiled vessels of the | | He also found that the coiled vessels of the |
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, |
| | | 1957). The reduction in thickness is clue primariiy to loss of ground substance from the |
| | | stroma, and conversely, the outstanding |
| | |
| 586
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| than i.< commonly thought (Bartehnez, | |
| 1957). The reduction in thickness is clue primariiy to loss of ground substance from the | |
| stroma, and conversely, the outstanding | |
| feature of repair is the increase in stromal | | feature of repair is the increase in stromal |
| ground substance (Fig. 9.23). ^Mitoses are | | ground substance (Fig. 9.23). ^Mitoses are |
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. |
| | |
| | |
| | |
| 588
| |
| | |
| | |
| | |
| 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 | | 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. | | monkey (Macaca mulatto). Cancer, 11, 810816. |
| | |
| HiSAW, F. L., .4ND Lendrum, F. C. 1936. Squamous metaplasia in the cervical glands of the | | HiSAW, F. L., .4ND Lendrum, F. C. 1936. Squamous metaplasia in the cervical glands of the |
| monkey following oestrin administration. Endocrinology, 20, 228-229. | | monkey following oestrin administration. Endocrinology, 20, 228-229. |
| | |
| | |
| HiSAW, F. L., Meyer, R. K., axd Fevold, H. L. | | 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:/^
| |
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| | |
| c
| |
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| | |
| 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
| |
| 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.
| |
| | |
| Br.\chet, J. 1957. Biochemical Cytology. New
| |
| York : Academic Press, Inc.
| |
| | |
| 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.
| |
| | |
| 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.
| |
| | |
| 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.
| |
| | |
| Chalmers, J. R., Dickson, G. T., Elks, J., and
| |
| 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.,
| |
| 114, 136-160.
| |
| | |
| Cooper, Sir Astley P. 1840. On the Anatomy oj
| |
| the Breast. London: Longmans, Orme, Green,
| |
| Brown & Longmans.
| |
| | |
| Cotes, P. M., Crichton, J. A., Folley, S. J., and
| |
| Young, F. G. 1949. Galactopoietic activity
| |
| | |
| | |
| | |
| 634
| |
| | |
| | |
| | |
| PHYSIOLOGY OF GONADS
| |
| | |
| | |
| | |
| of purified anterior pituitary growth hormone.
| |
| Nature, London, 164, 992-993.
| |
| | |
| CowiE, A. T. 1949. The relative growth of the
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SECTION C Physiology of the Gonads and Accessory Organs
Action of Estrogen and Progesterone on the Reproductive Tract of Lower Primates
Frederick L. Hisaw, Ph.D.
The Biological Lab0Rat0Rif:S, Harvard Tniversity, Cambridge, Massachusetts
and
Frederick L. Hisaw, Jr., Ph.D.
Department Of Zoology, Oregon State College, Corvallis, Oregon
I. Introduction
Cyclic menstruation is the most characteristic feature of primate reproduction, and
distinguishes it from the estrous cycle of
lower mammals. This cardinal primate
event is heralded by the bloody uterine
effluent emanating from the vagina, whereas
in estrus the dominant characteristic is a
sudden modification in behavior featuring
an intense mating drive. However, the internal secretions that regulate the various
events in the menstrual and estrous cycles
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
cycle and is associated with ovulation. In contrast, menstruation occurs in the cycle
midway between times of ovulation and is
not accompanied by an increase in sexual
activity. From earliest times menstruation
has been recognized as degenerative: the
characteristic odor, and the necrotic changes
in the lining of the uterus, part of which is
cast off at this time, sustain this interpretation. Therefore, menstruation is at the
opposite phase of the cycle from estrus. It
is such an obvious event that menstrual
cycles are dated from the onset of bleeding.
Menstruation is not analogous to the proestrous bleeding in the dog or cow nor to the
slight bleeding of primates at midpoint between menstrual periods (Hartman, 1929).
The study of menstruation was at first almost entirely the province of the clinician
and the material for investigation limited to
w^omen. Hitschmann and Adler (1907),
Meyer (1911), Schroder (1914). Novak and
Te Linde (1924), and Bartelmez (1933) are
among many of the earlier investigators who
contributed descriptions of the cyclic
changes in the human endometrium. The
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
more recent contributors are Bartelmez (1937), Latz and Reiner (1942), Haman
(1942), Knaus (1950), Mazer and Israel
(1951), and Crossen (1953).
The earlier concepts regarding the menstrual cycle were based primarily on the
changes occurring in the human endometrium and for convenience of description the
cycle was divided into four stages or periods. The first of these was the period of
active menstruation, and the length of the
cycle was dated from its onset. Most authors agreed that menses began by leaking
of blood from superficial vessels to form
lakes under the surface epithelium and that
there was some sloughing of tissue after the
beginning of bleeding. There was considerable disagreement as to the amount of destruction and loss of tissue; estimates of
various authors ranged from very little to
almost complete denudation of the surface.
Bartelmez (1933) emphasized both the wide
individual variability of the amount of tissue lost and differences in the stage of development of the endometria at the time of
menstruation.
The second period immediately following
menstruation began with regeneration of the
surface epithelium, which started sometimes
before menstrual bleeding had ceased and
was completed in a very short time. This
lieriod included the 5 to 7 days after cessation of menses, during which the endometrium grew in thickness. Frequent mitoses
were recognized, especially in the glands
which lengthened but remained straight and
tubular.
The third ("interval") period, lasting 6
to 10 days, was characterized by a somewhat thickened endometrium, still with
straight glands and showing little evidence
of secretory activity. At first this was considered a quiescent period as indicated by
the term "interval." However, as will be
shown later, such a characterization was not
justified from the physiologic viewpoint.
The fourth period, called the premenstrual period, included the 10 days or 2
weeks before menstruation. During this
phase the glands continued to increase in
size and became distended, coiled, or even
sacculated. The glandular cells increased
in height, and there was evidence of glycogen mobilization and secretion. Next, the
epithelium became "frayed out" along the outer borders, then decreased in height, indicating secretory depletion. Decidual cells
appeared in the stroma at this time. The
endometrium was much thickened and extremely hyperemic. At the height of this
period the endometrium was approximately
5 mm. in thickness, as compared with V2
mm. toward the end of menses. The term
premenstrual was usually applied to this
phase but today the term progestational
would seem preferable.
During and after these descriptions of the
changes in the human endometrium, many
attempts were made to locate the time of
ovulation in the menstrual cycle. When it
was found, as will be discussed later, that
ovulation occurred approximately midway
between two menses, and was preceded by
follicular growth and followed by development of a corpus luteum, it became customary to refer to the two halves of the menstrual cycle as the follicular phase and the
luteal phase. One advantage of this descriptive terminology was the emphasis it placed
on the homology of the two phases of the
menstrual cycle in primates with the follicular and luteal phases of the estrous cycles of lower mammals.
A theory to explain menstruation, widely
adopted in 1920, was formulated from this
morphologic evidence. The essentials were
that menstruation occurs because the lining
of the uterus, prepared for implantation of
the ovum, degenerates if fertilization of the
egg does not occur. This required that ovulation and corpus luteum formation precede
the i^remenstrual changes in the endometrium. Subsequent research disclosed that
menstrual cycles frequently occur in which
ovulation does not take place and bleeding
results from the breakdown of an "interval"
rather than a progestational endometrium.
The discovery of anovulatory cycles not
only brought about a revision of ideas regarding an explanation for menstruation
but also raised questions as to what constituted a normal menstrual cycle. The length
of the cycle and the amount and duration of
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,
the biologic purpose of the menstrual cycle is reproduction wliicli obviously cannot l)0
fulfilled unless an ovum is made available
for fertilization. Therefore, in this sense it
seems quite clear that anovulatory cycles
should be considered incomplete and abnormal.
The investigation of changes taking place
in the uterine endometrium at various periods of the menstrual cycle in women was
confronted with many difficulties, the chief
one being that of obtaining normal tissue
representative of specific times of the cycle.
The entire uterus and both ovaries are essential for proper evaluations and it was
rarely possible to meet these requirements.
The material for such studies came from
autopsies and surgery and tissues usually
had suffered postmortem changes or the
surgical condition was one involving serious
pelvic disease. There have been, however,
a goodly number of instances in which
these difficulties were adequately overcome
(Stieve, 1926, 1942, 1943, 1944; Allen, Pratt,
Newell and Bland, 1930) and the clinic will
continue to make important contributions
(Rock and Hertig, 1942; Hertig and Rock,
1944), but quite early the need became obvious for a suitable primate that could be
used as an experimental animal for research
on the different aspects of the physiology
of reproduction.
Since the initial observations by Corner
(1923) on the menstrual cycles of captive
rhesus monkeys iMacaca mulatta) , more
has been learned about the physiology of
reproduction of this animal than any other
primate. Monkeys of this species thrive under laboratory conditions, which has made
it possible to devise accurately controlled
experiments on normal healthy animals and
obtain reliable information on the menstrual cycle, gestation, fetal development,
and the interaction of hormones concerned
with regulating reproductive processes.
Other features that make the rhesus monkey such an attractive animal for these purposes are the many morphologic and physiologic attributes that are strikingly like
those of the human being. Tiic modal length
of their menstrual cycles is 28 days but
there is wide variation (Corner, 1923; Hartman, 1932; Zuckcrman, 1937a). From an
analysis of 1000 cycles recorded for some
80 females of different ages, Zuckerman (1937a) found an average cycle length of
33.5 ± 0.6 days, and the mode 28 days with
an over-all range of 9 to 200 days. Ovulation
occtu's api:)roximately midway between two
menstrual periods, most between the 11th
and 14th days (Hartman, 1932, 1944; van
Wagenen, 1945, 1947), and although these
animals breed at all seasons of the year
many cycles are anovulatory, especially
during the hot summer months (Eckstein
and Zuckerman, 1956). A method developed
by Hartman for detecting the exact time of
ovulation by palpation of the ovaries in the
unanesthetized animal greatly facilitated
the timing of events of the menstrual cycle.
This procedure also made it possible to determine the age of corpora lutea with great
accuracy (Corner, 1942, 1945) and correlate their develojiment and involution with
corresponding changes in the endometrium
(Bartelmez, 1951 ) and, in ju-egnancy, with
the exact age of developing embryos ( Wislocki and Streeter, 1938; Heuser and
Streeter, 1941).
The primary purpose of the present discussion is to review the results of experimental investigations of physiologic processes occurring in the female reproductive
tract of lower primates during the menstrual
cycle, and particularly those processes that
are under hormonal control. The brief introductory presentation of basic observations could be greatly extended and we take
up the discussion of endocrine problems
knowing that we must return often to the
work of these authors and that of others to
be cited, as conclusions based on experimental data take on meaning only in terms
of normal function.
II. Ovarian Hormones and Growth of the Genital Tract
The changes that are repeated in different parts of the reproductive tract with each
menstrual cycle are produced by ovarian
hormones, estrogens, and progesterone. The
dominant hormone of the follicular phase is
estradiol-17/y, which is secreted by the
Graafian follicle, and in the tissues is readily transformed in i)art to estrone, an estrogenic metabolite. Progesterone, secreted by
the corinis luteum, is jirimarily a hormone
of the luteal phase of the cycle. However,
small amounts of progesterone may appear ill the blood of monkeys as early as the 7th
(lay and attain a concentration of 1 fxg. per
ml. of serum at ovulation, whereas a maximal concentration of 10 /xg. per ml. is
reached at approximately the middle of the
luteal phase (Forbes, Hooker and Pfeiffer,
1950; Bryans, 1951). Also, some estrogen is
present during the luteal phase, probably
secreted by the corpus luteum (estrogens
can be obtained from luteal tissue) or it
may be partially derived from developing
follicles. It is unlikely that estrogen is ever
entirely absent during a normal menstrual
cycle or that the presence of progesterone is
completely restricted to the luteal phase.
The dependence of the reproductive tract
on ovarian hormones is strikingly demonstrated by the profound atrophy that follows surgical removal of the ovaries. A progressive decrease in size of the Fallopian
tubes, uterus, cervix, and vagina takes place,
and usually, the involution of the uterine
endometrium involves tissue loss and bleeding, commonly referred to as post castrational bleeding. Dramatic as these effects
may seem, it is equally dramatic to find
that these atrophic structures can be restored entirely to their original condition by
the administration of ovarian hormones.
Therefore, it is seen at the beginning that
investigations dealing with the physiology
of the female reproductive tract of primates
in large measure involve a study of the independent and combined actions of estrogens and progesterone on the activities of
the various structures concerned.
Much can be learned about the action of
ovarian hormones by observing the changes
they produce in the gross appearance of the
atrophied reproductive tract of castrated
animals. Daily injections of an estrogen in
doses equivalent to 1000 I.U. or more for
10 days or a fortnight will restore the uterus,
cervix, and vagina to a condition comparal)le with that found in a normal monkey at
the close of the follicular phase of a menstrual cycle (Fig. 9.1A). If a similar castrated monkey is given 1 or 2 mg. of progesterone daily for the same length of time,
very little if any change in size of the reproductive organs results. However, if first
the normal condition is restored by giving
estrogen and then is followed by the progesterone treatment, the size of the uterus is maintained but that of the cervix and
vagina decreases to an extent approaching
that in a castrated animal (Fig. 9.1B). Such
experiments show that an estrogen promotes
growth of the reproductive tract whereas
progesterone is comparatively ineffective
when given alone. Yet progesterone can
maintain the size of the uterus when administered following an estrogen treatment but
it does not prevent involution of the cervix
and vagina.
An additional feature of the growth-stimulating action of the ovarian hormones is
brought out when estrogen and progesterone
are administered concurrently. If, after repair of the reproductive tract of a castrated
animal has been accomplished by a series of
injections of estrogen, both estrogen (1000
I.U.) and progesterone (1 or 2 mg.) are
given daily for 20 days, it will be found that
the uterus is larger than when either hormone is given alone for a similar length of
time, whereas the cervix and vagina have
involuted and are approximately the size
found in animals given only progesterone.
Thus it can be demonstrated that a synergistic effect on growth of the uterus occurs
when the two hormones are given simultane
FiG. 9.1. Reproductive tracts of three adolescent
monkeys which were castrated and given estrogen
daily for approximately 3 weeks. A shows the condition at the conclusion of the estrogen treatment,
B the condition following the injection of progesterone for an additional three weeks, and C the
effects of continuing the treatment with both estrogen and progesterone for a like period.
ously whereas in the cervix and vagina the
growth -stimulating action of estrogen is
inhibited by progesterone (Fig. 9.1C). This
presents a most interesting situation in
which the combined actions of two hormones on three closely associated structures
of the reproductive tract join in a synergistic effort in promoting the growth of the
uterus although progesterone prevents estrogen from affecting growth of the cervix
and vagina.
These changes in gross morphology in
response to the ovarian hormones are reflected in the histology of the responding
tissues. Also, the character of the response
differs depending upon the physiologic nature of the tissue concerned; therefore, for
the sake of clarity each will be discussed
separately. The first of these to be considered is the uterus and particularly growth
of the endometrium.
It has been reported (Hisaw, 1935, 1950)
that growth of the endometrium, as induced
by estrogen, is limited. That is, a dosage of
estrogen capable of maintaining the endometrium of a castrated animal for an indefinite period without the occurrence of
bleeding, stimulates rapid growth for approximately the first 2 weeks. Within this
time a maximal thickness of the endometrium is attained which remains constant or
may become less during the course of treatment (Fig. 9.2). Engle and Smith (1935)
made similar observations. They found that
the endometria of castrated monkeys receiving estrogen for 100 days or longer were
thinner than endometria of animals on estrogen for a much shorter time. Also, on
prolonged treatment, the stroma of the endometrium becomes dense and the lumen
small whereas the size of the uterus remains
about the same. In fact, they state that in
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
days. Depression in the endometrium of anterior wall of D is the result of a biopsy taken
a year previously. (From F. L. Hisaw, in A Si/niposium on Steroid Hormones, University
of Wisconsin Press, 1950.)
four experimental animals the only well developed fundus was found in the animal on
the shortest treatment, i.e., 60 days.
The mitotic activity in the epithelium of
the glands and surface mucosa also indicates
a limited effect of estrogen. This can be
demonstrated to best advantage in the endometria of castrated monkeys that have been
on estrogen for different lengths of time and
have received an injection of colchicine 8
hours before their uteri were removed. A
comparison of the number of cells in mitosis
per square centimeter of surface mucosa at
10, 30, 45, and 60 days is shown in Figure
9.3. From this it can be seen that mitotic
activity approaches that in a castrated animal. Although the five points used in drawing the curve are quite inadequate for an
accurate analysis of the mitotic response in
the epithelial components of the endometrium, they do show that cell division is
most rapid soon after the beginning of an
estrogen treatment and subseciuently declines.
The loss of responsiveness of the endometrium to estrogen seems related more to the
length of treatment than to dosage of hormone. An endometrium of normal thickness
can be produced in 2 or 3 weeks at a dosage
level of estrogen that will not maintain the
growth induced for longer than about 40
days without bleeding (Hisaw, 1935; Engle
and Smith, 1935; Zuckerman, 1937b). The
response to a low dosage of estrogen that
will prevent bleeding during the course of
treatment (about 10 /xg. estradiol-17/8 daily)
is one of rapid endometrial growth at first,
as has been described, followed by a thinning of the endometrium. The refractoriness
of the endometrium to estrogen becomes so
pronounced after about 100 days of treatment that very few cell divisions are seen in
the epithelium of the glands and surface
mucosa. The general morphology of the endometrium retains the characteristic appearance of the follicular phase of the menstrual cycle except that the stroma is
usually more dense and the cells of the
glandular epithelium have large deposits of
glycogen between the nucleus and the basement membrane. However, metabolically
such endometria are surprisingly inactive.
Although they are dependent on the presence of estrogen and may bleed within about
Fig. 9.3. The number of mitoses per square centimeter of surface epithelium of the endometrium in
a castrated monkey and in four castrated animals
given 10 /xg. estradiol daily for 10, 30, 45, and 60
days, respectively. One-tenth of actual number of
mitoses is shown on the ordinate. (From F. L.
Hisaw, in A Symposium on Steroid Hormones, University of Wisconsin Press, 1950.)
48 hours if the treatment is stopped, the
activity of their oxidative enzymes and the
ratio of nucleoproteins (RNA:DNA) are
about the same as in the involuted endometria of castrated animals.
The effects that accompany moderate estrogenic stimulation become exaggerated in
several respects when large doses of estrogen
are given for an extended period. The disparity between the area of myometrium and
endometrium becomes greater as the treatment progresses (Fig. 9.4). Kaiser (1947)
described the destruction of the spiraled
arterioles of the endometrium in monkeys
given large doses of estrogen and Hartman,
Geschickter and Speert (1941) reported the
reduction of the reproductive tract to the
size of that of a juvenile animal by the end
of 18 months during which injections of
large doses of estrogen were supplemented
by subcutaneous implantation of estrogen
pellets. These observations not only show
that the endometrium becomes unresponsive
to estrogen when the treatment is prolonged
but that large doses produce injurious effects.
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
effects of 1/10 this dosage (100 fig. daily) when
gi\en for 185 days.
The limited response of the endometrium
to estrogen is in some respects surprising in
view of its remarkable growth potentialities and regenerative capacity. These qualities were dramatically demonstrated by
Hartman (1944) who dissected out as carefully as possible all of the endometrium
from the uterus of a monkey and wiped the
uterine cavity with a rough swab and yet
the undetected endometrial fragments that
remained were capable of restoring the entire structure. Also, considering the enormous increase in size of the uterus during
gestation, it is even more difficult to account for the rather sharp limitation of
growtli under the influence of estrogen.
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 endometrium. An attempt has been made to remove this containing influence the muscle
may have by making an incision through
the anterior wall of the uterus (Hisaw,
1950) . A castrated monkey was given 10 ixg.
estradiol daily for 21 days at which time the
operation was performed and the treatment
continued with 30 ^g. estradiol daily for 40
days. The uterus was laid open by a sagittal incision from fundus to cervix and most
of the endometrium was removed from the
anterior wall. This caused gaping of the incised uterus and exposure of the endometrium on the posterior wall. The incision
was not closed and after hemorrhage was
completely controlled the uterus was returned to the abdomen.
Examination of the uterus at the conclusion of the experiment showed no indications
that endometrial growth had been enhanced.
The muscularis had reunited and only a few
small bits of endometrium were found in the
incision (Fig. 9.5). It seemed probable that
the purpose of the experiment had been defeated by rapid repair of the uterus. Therefore, a similar experiment was done in which
the musculature of the incised uterus was
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).
Observations under these conditions are
necessarily limited to those made on the
uterus when it is removed at the conclusion
of an experiment and comparisons must be
made between uteri of different animals.
Obviously, it would be more desirable if the
response of an individual endometrium
could be followed during the course of treatment. It is possible to meet most of these
requirements under conditions afforded by
utero-abdominal fistulae, exteriorized uteri,
and endometrial implants in the anterior
chamber of the eye. In continuing our discussion we first shall present information
obtained by such techni(iues that have a
bearing on the response of the endometrium
to estrogen.
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.
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
Hormones, University of Wisconsin Press, 1950.)
Fig. 9.6. Estradiol, 10 ^g., was given daily for 7 days; the uterus was opened and the treatment continued at a dosage of 30 /ig. estradiol daily for 20 days. (From F. L. Hisaw, in A
Symposium on Steroid Hormones, University of Wisconsin Press, 1950.)
The surgical procedure used by Hisaw
( 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
makes frequent inspections possible either
by hand lens or dissecting microscope, of
most of the upper part of the endometrium
on the anterior and posterior walls of the
uterus. The elliptic slit formed by the endometrium of the two opposing walls can be
located easily, the two sides pressed apart
by any small smooth instrument, and the
surface of the endometrium examined.
Changes in thickness of the endometrium
cannot be ascertained without resorting to
biopsies but it is free to grow out of the
opened uterus if it is so inclined. However,
in such preparations the growth produced in
the endometrium by daily injections of 10
fjig. estradiol for periods of 2 or 3 weeks is
not sufficient to show any tendency whatever to grow out through the fistular opening or obstruct examination of the walls of
the uterus. The limited growth observed in
these experiments is in agreement with that
obtained with estrogen on intact and incised
uteri.
The cervix uteri of the rhesus monkey is
sufficiently long to make it possible to bring
the entire fundus to the exterior through a
midal)dominal incision. Advantage of this
was taken in an attempt to exteriorize the
uterus and maintain it outside the body for
long enough periods to make it possible to
study the growth responses of the endometrium (Hisaw, 1950). These preparations
did not i)rove satisfactory in all respects but
they did contribute a number of interesting
observations.
The operational i^rocedure used in these
experiments involved dividing the uterus
transversely from fundus to cervix so that
the anterior wall was deflected downward
and the posterior wall upward (Fig. 9.7).
The endometrium of the exteriorized uterus
is difficult to maintain but with proper care
it seems to retain its normal condition for
at least the first few days after the uterus
is opened. Small localized areas of ischemia
can be seen to come and go, probably action
of the coiled arteries, and there is a periodic
general blanching of the endometrium associated with rhythmic contractions of the
muscularis. This, however, does not seem
true of the whole endometrium. A zone surrounding the internal os of the cervix tends
to retain its blood-red color even during
strong contractions of the uterus and the
growth reactions of the endometrium in this
area are of particular interest.
Fig. 9.7. Exteriorized uteii. The uteri were divided transversely from fundus to cervix.
The anterior half is seen deflected to the right and the posterior half to the left. A and B
are of the same uterus taken 13 days after exteriorization showing the "blush" and "blanch"
reaction of uterine contractions. It can be seen that during blanching the endometrium
of the cervix does not become ischemic. C. Uterus 18 days after exteriorization, showing
response to estrogen. Ridges formed by growth of the endometrium surrounding the internal OS of the cervix can be seen at the upper edge of the photograph. D, taken 83 days
after exteriorization, shows response produced by a series of injections of 10 ^ig. estradiol
and 1 mg. progesterone daily. The transverse ridge is formed by the two opposed lips of
endometrium derived from the area surrounding the internal os of the cervix. Growth when
the two hormones are given is greater than when only estrogen is injected. (From F. L.
Hisaw, in A Symposium on Steroid Hormones, University of Wisconsin Press, 1950.)
The endometrium on the exposed anterior
and posterior halves of the uterus underwent
deterioration despite the best of care that
could be given, but that surrounding the internal OS of the cervix survived and retained
its capacity to grow, in one animal, for as
long as 9 months. When estrogen was given
this endometrium grew rapidly and within
a few days stood out as large elliptic lips
surrounding the internal os (Fig. 9.7).
Within 2 to 3 weeks the lips appeared to
reach their full size and further growth was
slow or absent. When estrogen treatments
were discontinued the endometrial lips underwent bleeding within a few days and
were entirely lost. At no time were activities
observed that could be ascribed to coiled
arterioles, nor did ischemia occur during involution previous to bleeding. It seems that
the response of this tissue to estrogen is like
that found in other experiments but the absence of ischemia preceding bleeding is exceptional. The endometrium on the anterior
and posterior walls of uterine fistulae invariably showed ischemia for several hours
before active bleeding following the withdrawal of estrogen.
Markee (1940) approached the problem
of endometrial growth in monkeys by studying the changes that occur in bits of endometrial tissue transplanted to the anterior
chamber of the eye. Such transplants retain
in large measure the normal morphology of
endometrial tissue and changes in their cyclic growth parallel those going on simultaneously in the uterus. So much so that if
the animal has an ovulatory cycle, the ocular implants show conditions characteristic
of both the follicular and luteal phases, but
if ovulation fails to occur then the luteal
phase is omitted. Also, the morphologic
events taking place at menstruation can be
seen and recorded, since the transplants regress and bleed at each menstrual period.
These ingenious experiments will be referred
to often in the course of our discussion but
at present the response of endometrial
transplants in the eye to estrogen is of primary interest.
Monkeys having ocular transplants were
given 200 to 300 R.U. of estrone daily for
about 1 to 3 months. The transplants did
not grow to a certain size and then remain
stationary, but instead periods of rapid
growth were interrupted by periods of regression which usually involved a marked
decrease in size, and if regression was extensive and rapid, bleeding ensued. It also
was found that these episodes of regression
in the transplants were usually accompanied
by a decrease in the size of the uterus.
Comparisons between the results of these
experiments and those we have discussed
previously may be misleading since it seems
that only 1 of the 5 animals (no. 295) used
was castrated. Also, the dosage of estrogen
was not sufficient to maintain the endometrium of the uterus for an indefinite period
without bleeding and this also was reflected
in the transplants. It seems questionable
that the growth capacity of endometrial
transplants in the eye can be determined unless sufficient estrogen is given to prevent
bleeding in the uterus. Therefore, it would
seem that these experiments contribute less
to an analysis of the effects of estrogen on
endometrial growth than they do to an understanding of the events that precede and
accompany menstruation.
In summary, it seems clear that the outstanding effect of estrogen on the uterus of
the monkey is one of growth (Allen, 1927,
1928). The involuted uterus of a castrated
animal can be restored to its normal size in
2 or 3 weeks by daily injections of adequate
amounts of estrogen. At this time there is an
increase in vascularity, a clear-cut hyperemia as seen in rodents. There also is secretion of luminal fluid (Sturgis, 1942) but this
does not distend the uterus as in the mouse
and rat. This is accompanied by an increase
in tissue fluid, especially in epithelial tissues
(surface epithelium and glands) , and in the
connective tissue of the stroma. Glycogen
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 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
layers. The condition produced experimentally in the monkey's uterus by short term
treatments with estrogen is equivalent to
that present in the normal animal at midcycle, or even a few days later if ovulation
does not occur.
If, however, an estrogen treatment is continued for several months conditions develop in the uterus that are not found
during the follicular phase of a normal menstrual cycle. When the daily dose of estrogen
is small menstruation occurs at intervals
during the treatment (Zuckerman, 1937b)
and probably marks periods of endometrial
regression as observed by Markee (1940) in
eye transplants, but if the dosage is increased by a sufficient amount (about 10
/xg. estradiol- 17/3 daily) injections may be
continued for a year or longer without
bleeding. Although the size of the uterus remains within the range of normal variation
as the injections are continued, the myometrium tends to increase in thickness and the
endometrium becomes thinner, a condition
not corrected by further increases in dosage
or by prolonging the treatment. The cause
responsible for the limited response of the
endometrium under these conditions is not
known but apparently is not a restrictive influence of the myometrium as similar responses are given when the endometrium is
exposed by incising the uterus, in abdominal
fistulae, and in exteriorized uteri.
III. Effects of Progesterone on the Uterus
It has been mentioned that a menstrual
cycle, in which ovulation occurs, can be conveniently divided into a follicular and a
luteal phase. The follicular phase extends
from menstruation to ovulation and the
luteal phase from ovulation to the following
menstruation. It has been shown in the
previous discussion that the endometrial
modifications characteristic of the follicular
phase of the cycle can be duplicated in a
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 the morphologic and physiologic features
that are known for anovulatory and ovulatory cycles can be reproduced in castrated
monkeys by estrogen and progesterone.
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
progestational endometrium. Progesterone,
as compared with estrogen, is a weak growth
jH'omoter and although it can produce progestational changes in the atrophic endometrium of a castrated monkey when given in
large doses, its action is greatly facilitated
when preceded by estrogen. The first experiments in which progesterone was used
for this purpose were planned on this principle (Hisaw, Meyer and Fevold, 1930; Hisaw, 1935; Engle, Smith and Shelesnyak,
1935).
The first noticeable effect of progesterone
is an elongation of the epithelial cells of the
surface membrane and necks of the glands.
When the treatment is continued, this effect progresses down the gland towards the
base. This change is followed closely by a
rearrangement of the nuclei which is more
pronounced in the glands than in the surface
epithelium. The nuclei under the influence
of estrogen in doses which reproduce the
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.
Fig. 9.8. Uterus of a castratefl monkey which
was given 2 mg. progesterone daily tor 113 days.
The endometrium is thin but bleeding occiu\s when
such treatment is stopped. The myometrimn is
soft and pliable and ilir l)lood vessels are cnlarsed
and have thick wails.
Secretion begins in response to estrogenic
stimulation and increases greatly as progestational changes are established. It appears first in the necks of the glands and
progresses basalward. The surface epithelium takes a less conspicuous part in secretion and is usually reduced to a thin membrane when injections of progesterone are
continued until a fully developed progestational endometrium is established. This progressive action of progesterone is such that
it is possible to find all conditions in a single
gland from active secretion and fraying in
the neck region through primary swelling to
an unmodified condition at the base.
When treatment is continued for 25 to 30
days at doses of about 2.0 mg. daily, the
glands enter a state that has been called
"secretory exhaustion" (Hisaw, 1935). This
condition also is seen first in the necks of
the glands and progresses toward the base.
The glandular epithelium decreases in
thickness, and active secretion, as judged
by fraying of the cells, is absent. The glands
may become narrow and straight and the
endometrium may resemble that in castration atrophy. These involutionary changes
become even more pronounced if the treatment is continued for several months or a
year (Fig. 9.8). The endometrium by this
time is extremely thin. The glands are
straight, short, and narrow, and the stroma
very dense. The myometrium is thick in proportion to the endometrium and the uterine
blood vessels are large and have greatly
thickened walls. Such uteri tend to be somewhat smaller than normal and are soft and
pHable.
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
follows a sequential development of all
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
set in and the endometrium is reduced to a
thin structure. Yet, such degenerate endometria are dependent upon progesterone
and will bleed within about 48 hours if the
injections are stopped. It also was found
that after discontinuence of progesterone
daily injections of 10 /i.g. estradiol may not
prevent bleeding.
IV. Synergism between Estrogen and Progesterone
There is considerable evidence that in
primates progesterone under normal conditions rarely if ever produces its effects in the
absence of estrogen. Large quantities of estrogen are present in human corpora lutea
(Allen, Pratt, Newell and Bland, 1930) and
during pregnancy the placenta secretes estrogens as well as progesterone (Diczfalusy,
1953) . This apparently is a common feature
of primates, as indicated by the excretion of
estrogens in the urine of pregnant chimpanzees and rhesus monkeys (Allen, Diddle,
Burford and Elder, 1936; Fish, Young and
Dorfman, 1941 ; Dorfman and van Wagenen, 1941). Also, correlated with this is
the observation that estrogen and progesterone when given concurrently produce a
greater effect on the uterus of castrated
monkeys than either alone (Hisaw, Greep
and Fevold, 1937; Engle, 1937; Hisaw and
Greep, 1938; Engle and Smith, 1938) and
that an ineffective dose of progesterone is
greatly potentiated by estrogen. This synergistic effect of the two hormones on the
uterus of monkeys is quite different from
their action on the uteri of laboratory rodents and rabbits. In these animals the effects of progesterone can be inhibited quite
easily by a surprisingly small dose of estrogen (see chapter 7).
The synergism between estrogen and progesterone in the promotion of endometrial
growth can be demonstrated to best advantage under the conditions of some of the
physiologic preparations that have been discussed. For instance, it was shown (Fig.
9.5) that growth of the endometrium under
the influence of estrogen was not enhanced
by relieving muscle tension by a midline incision through the anterior wall of the
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).
FiG. 9.9. Uterus of a castrated monkey that received 10 fig. estradiol and 1 mg. progesterone
daily for 18 days, at which time the uterus was
opened from fundus to cervix and most of the
endometrium of the anterior wall removed. The
incision was not closed and the treatment was
continued for an additional 20 days. (From F. L.
Hisaw, in A Symposium on Steroid Hormones,
University of Wisconsin Press, 1950.)
A similar synergistic action can be seen in
utero-abdominal fistulae. We have mentioned that estrogen does not cause excessive
growth of the endometrium under these conditions. However, endometria that have
reached their maximal response to estrogen
will show a resumption of growth if 1 or 2
mg. progesterone are added daily to the
treatment. By the 4th or 5th day lobes of
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.
Fig. 9.10. Uteru.s of a castrated monkey which
was given 1 mg. progesteione (lail>' for 18 days
following an estrogen treatment. The uterus was
opened as described for Figure 9.9, and the injections of progesterone continued for 20 days. (From
F. L. Hisaw, in A Syiyiposium on Steroid Hormones, University of Wisconsin Press, 1950.)
Such outgrowths are difficult to protect
from mechanical injury and consequent tissue loss so it is not possible to determine accurately how much endometrium is produced in a given time. In one experiment an
animal was kept on 10 fxg. estradiol and 2
mg. progesterone daily for 98 days and it
was found that the endometrium continued
to grow, but the rate seemed considerably
slow^er toward the conclusion of the treatment than at the beginning. How long an
endometrium would continue to grow under
these conditions was not determined, but it
is obvious that much more endometrial tissue was produced by the treatment than is
ever found at one time in the uterus of a
monkey during a normal menstrual cycle.
This takes on added significance when it is
compared with the endometrial response in
the intact uterus of an animal given the
same dosage of estrogen and progesterone
for a similar length of time.
The progestational development of the
endometrium, when both hormones are
given, passes through the same stages as
those following the injection of only progesterone; i.e., presecretory swelling of the
glandular epithelium, active secretion, and secretory exhaustion. The endometrium,
however, is considerably thicker than when
a comparable dose of progesterone is given
alone, and secretory exhaustion may not be
so pronounced by the 30th day (Fig. 9.11).
The glandular epithelium in the necks of
the glands may be reduced to a thin membrane scarcely thicker than the nuclei
whereas some secretion is usually present in
the dilated basal parts of the glands. Also
dilation of the glands in the basalis is
more pronounced following a 30-day estrogen-])rogesterone treatment than when the
same amount of progesterone is given separately.
Secretory exhaustion appears to be the
initial indication of an involutionary process that ensues when an estrogen-progesterone treatment is continued for a long time
(Hisaw, 1950). When a combination of the
two hormones, known to be capable of producing a large uterus with a thick, fully develojied, progestational endometrium within
al)out 20 days, is given for 100 days, an
astonishingly different endometrium results
(Fig. 9.12). It is thin, the stroma is dense
and the narrow straight glands are reduced
to cords of cells in the basal area. The condition is one suggesting inactivity and atrophy.
When such dosages of estrogen and i)rogesterone are given to castrated monkeys
for 200 days or a year further changes in
the endometrium occur. By 200 days the
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.
Fk;. 9.11, .\ late i)r()ges1ati()iial condition produced in the endometrium of a castrated monkey
by giving 10 (ig. estradiol daily for 18 days followed
by 10 /xg. estradiol and 2 mg. progesterone daily
for 31 davs.
Fig. 9.12. The endometnuin of a castrated monkey that had received 10 /xg. estradiol
and 1 mg. progesterone daily for 99 days.
Even though in such experiments the endometrium has been under the influence of
both estrogen and progesterone for a year
and has undergone extremely abnormal
modification, it yet is capable of responding
to estrogen in a more or less characteristic
way when progesterone is stopped and in
jections of estrogen continued. Apparently
within about three weeks the modified endometrium is replaced, under the influence of
estrogen, by one that has few glands which
tend to be cystic, a mesenchymatous stroma,
and no coiled arteries (Fig. 9.14).
Under similar circumstances, if estrogen
is stopped and jjrogesterone is continued, the
modified endometrium is lost without bleeding and there is almost no repair of the endometrium even after a period of 3 weeks.
There seems to be an incompatability between the epithelial outgrowths from the
mouths of the glands and the underlying
stroma of the denuded surface. Consequently the epithelium crumbles away and
epithelization of the raw surface is not accomplished (Fig. 9.15j. How long this condition could continue has not been determined.
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.
One of the most interesting aspects of
these observations is that these effects were
jiroduced by dosages of estrogen and progesterone that are very probably within the
range of normal physiology. From this it
appears that although growth of the endometrium is greater when the two hormones
are given together, due to their synergistic
interaction, this does not prevent involutionary changes from setting in when the
treatment is continued for a period of weeks
or months. In fact, greater damage to the
endometrium occurs under the simultaneous
action of the two hormones than when either
is given alone. Also, increasing the dose intensifies the damaging action of both estrogen and progesterone, so much so that very
large doses will almost completely destroy
the endometrium.
The myometrium, however, shows a different response to these treatments. Estrogen stimulates myometrial growth, which is
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
injections of progesterone were stopped and estrogen continued for 20 days. Bleeding occurred the
second day following discontinuance of progesterone. The absence of coiled arteries and the presence of cystic glands and a mesenchymetous stroma
characterize the endometrium.
Fig. 9.15. Uterus of a castrated monkey which was given 10 yug. estradiol and 2 mg. progesterone daily for 275 days at which time estrogen was stopped and progesterone was continued for 21 days. A shows the thin endometrium and dense stroma whereas B shows failure
of formation of a surface epithelium following the loss of the modified functionalis presumably present at the conclusion of treatment with both hormono.^^ (see Fig. 9.13).
intensified both by cln-onic treatment and
high dosage, and seems to be equally effective when it is given alone or in combination with progesterone. Progesterone also
promotes growth of the muscularis but
seems less effective than estrogen and differs from it by causing pronounced thickening of the walls of the arcuate blood vessels.
These vascular changes extend to the coiled
arteries of the endometrium, which are also
affected by high dosages of estrogen. It
seems remarkable that estrogen is capable of
preventing the action of progesterone on the
myometrial blood vessels and correcting
such effects after they are produced and yet
at the same time it assists in the destruction of the coiled arteries in the endometrium.
V. Experimentally Produced Implantation Reactions
Progestational endometria of the normal
menstrual cycle or those produced in castrated monkeys by progesterone, if mechanically traumatized, will develop endometrial
proliferations which seem identical with
those found at normal implantation sites of
fertilized ova (Figs. 9.16 and 9.171 (Hisaw, 1935; Hisaw, Creep and Fevold, 1937; Wislocki and Streeter, 1938; Rossman, 1940).
The proliferated cells originate from the
surface and glandular epithelium and grow
into the surrounding stroma. The reaction
spreads from the point of injury and within
a few days may involve the entire inner
l)ortion of the endometrium bordering the
lumen. The implantation plaques on the 3rd
or 4th day present a fairly homogeneous appearance but soon thereafter certain cells
attain the proportions of giant cells and
many are multinucleated.
The development of the plaques is most
rapid during the first week, by the end of
which cell division is found only in the basal
half of the proliferation and evidence of regression is seen in the superficial portion
adjoining the uterine lumen. After 10 days
degenerative and phagocytic processes are
the dominant features and by 24 days the
ut'prus contains few or no ]iroliferation cells.
Wislocki and Streeter ( 1938,1 found that implantation plaques during pregnancy and
those experimentally induced underwent ajjl^roximately the same development arid
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.
Fig. 9.16. An area of the normal implantation
site of a developing ovum. (From Carnegie Institution, No. C467.)
Fig. 9.17. An experimentally induced implantation reaction in a castrated monkey showing condition 6 days after mechanical traumatization of the
endometrium.
VI. The Cervix Uteri
The cervix uteri of the rhesus monkey is
remarkable for its size and complexity. It
forms a large segment that is set off from
the fundus by a conspicuous constriction at
the level of the internal os (Fig. 9.1). A
sagittal section (Fig. 9.18) shows the cervical canal not straight but thrown into several sharp turns by colliculi that extend
from its walls into the lumen. The largest
of these projects from the midventral wall.
The functional advantage of such tortuosity
of the cervical canal is not obvious but
since the cervix probably serves as a barrier
between the bacterial flora of the vagina and
the corpus uteri, this may be a useful adaptation.
The physiology of the cervix has received
much less attention than has been given the
uterus. This is regrettable in view of the
consideration it must receive in practical
obstetrics and gynecology, as well as the
possibility that physiologically the monkey
cervix may be homologous with that of the
human regardless of morphologic difTerences. Recent observations indicate that
this is indeed quite probable.
Fig. 9.18. Sagittal section of the cervix from a
normal monkey. The vagina and the external os of
the cervix are shown at the left and the entrance
to the fundus is at the right.
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
dilation of the cervical canal and reduction of the cervical lips (shown at the left) and the
coUiculi. (From Carnegie Institution, No. C713.)
Hamilton (1949) made a detailed study
of the changes in the cervix of rhesus monkeys during the menstrual cycle, paying
particular attention to alterations that took
place in the cells of the surface epithelium
of the endocervical canal and the cervical
glands. It was found that heights of the
cells showed consistent increases and decreases during the cycle. The peaks came on
the 3rd, 13th to 15th, and 22nd days, the
greatest of these being the 14th day which
is approximately the time of ovulation. It
also was observed that, following a peak,
secretion was associated with the decline.
Attention was called b3^ Hamilton to the
rather close correlation between the fluctuations in height of the cervical epithelium in
monkeys and the fluctuations observed by
Markee and Berg (1944) in the blood estrogens of the human menstrual cycle. It was
concluded that, if similar changes in estrogen levels also occur in monkeys, one would
be justified in concluding that the increase
in cell height in the cervical mucosa was due
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
abundant secretion of the cervical glands in the presence of high levels of estrogen during
late pregnancy (Fig. 9.19).
Much has been learned regarding the
physiology of the primate cervix from experiments on castrated monkeys. The cervical mucosa is very responsive to estrogen
and castration atrophy can be repaired and
a normal condition maintained by daily injections of small doses. Cervical secretion
may become abundant when an estrogen
treatment is prolonged and especially if
large doses are injected. However, the
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.
Under conditions of chronic treatments
with estrogen metaplastic aberrations invariably appear in the epithelium of the
endocervix. This reaction was first reported
in monkeys by Overholser and Allen ( 1933,
1935) and has been confirmed by many investigators (Engle and Smith, 1935; Hisaw
and Lendrum, 1936; Zuckerman, 1937c (.
Similar lesions may be found in the cervix
uteri of women (Fluhmann, 1954). They
seem especially prone to occur under conditions characterized by excessive production of estrogen, such as hyperplasia of the 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
Fluhmann (1954) did not find it as frequently as in nonpregnant women.
This reaction to estrogen as seen in the
cervix of castrated monkeys is initiated by
growth of small undifferentiated cells below
the columnar mucous cells of the secretory
epithelium. Fluhmann (1954) suggests that
these cells are really undifferentiated cells
of the cervical mucosa which have the potentiality of becoming columnar or squamous or simply undergoing multiplication
and remaining as indifferent or reserve cells.
These cells accumulate, in response to estrogen, to form aggregates of several cells
in thickness and, although this may occur in
any area of the endocervix, it is generally
more pronounced below the base of the
glands. As this process proceeds the columnar mucous cells are pushed outward and
are finally desquamated thus exposing the
underlying metaplastic cells to the lumen of
the gland (Fig. 9.20).
Fig. 9.20. Al.iaph
in a castrated monkey that li.-id rci-civcd 1 nig.
estriol daily for 48 days.
The cells of these lesions undergo a characteristic differentiation. When first formed
they are small, cuboidal, and have spherical nuclei with dense chromatin. As they increase in number those in the center of the
cellular mass become larger and acquire an
eosinophilic cytoplasm. Such collections, as
seen at the base of the cervical glands, may
grow in height and form cone-shaped masses
with the apexes protruding through the mucous epithelium into the lumen or they may
remain as more or less compact structures.
This difference in growth seems to have a
general relation to the dosage of estrogen.
Large doses cause more rapid growth and
cone formation with the loss of cells from
the apex either singly or in groups, whereas
small doses produce slower growth and desquamated cells are seldom seen in the lumen. However, regardless of the rate of
growth, the cells at the base of the lesion
remain undifferentiated and continue as the
principal area of cell proliferation.
Pearl formation is occasionally seen and
may be quite common in animals on low
dosages of estrogen. Under strong estrogenic
stimulation and consequently rapid growth,
these structures apparently are desquamated before they are completely formed.
However, very early stages are frequently
seen and may even be present in small
clumps of metaplastic cells, but they are
more commonly found in the larger collections at the base of the glands. Their appearance is initiated by swelling and disintegration of one or more adjacent cells
that form a center around which epidermidization takes place. Further development
does not proceed under the influence of esti'ogen, beyond the formation of a small central cavity.
The most conspicuous difference between
the metaplastic growths produced by estrogen and true cancer of the cervix in the
monkey (Hisaw and Hisaw, Jr., 1958) is
that the former remain noninvasive even
when the treatment is continued well over
a year. They also involute when the treatiiiciit is discontinued and they do not appeal' when progesterone is given simultaneously with estrogen. When the injections of
progesterone are started after metaplastic
growths have been formed in response to
estrogen, further growth is inhibited and the keratinized cells of the lesion become
vacuolated and are lost.
In contrast with the effects of estrogen
on the cervix, the modifications that occur
as pregnancy advances are remarkable. The
cervix becomes a soft thin-walled structure,
the glands increase in number, and their
lumina become greatly enlarged, pressing
the stroma into thin partitions between
them, and the amount of mucus secreted is
enormous (Fig. 9.19). Attempts at duplicating these changes in castrated animals by
hormone therapy have been only partially
successful. Estrogen produces a solid thickwalled cervix that tends to be larger than
normal, an effect that is especially noticeable in young animals. Progesterone does
not promote cervical growth and repair of
the glands unless large doses are given and
even then there is little if any secretion. The
best results were obtained when both estrogen and progesterone were given and especially so when relaxin was added to the
treatment (see chapter by Zarrow).
VII. The Vagina
The general features of the vaginal smear
of rhesus monkeys have been described by
several investigators (Allen, 1927; Hartman, 1932; Westman, 1932) and a detailed
study of the cellular components at different times of the menstrual cycle has been
made by Lopez Columbo de Allende, Shorr
and Hartman (1945). The changes in the
vagina of a monkey are in most respects like
those found for the human being (Papanicolaou, Traut and Marchetti, 1948; Lopez
Columbo de Allende and Orias, 1950). Epithelial growth and desquamation of cornified cells continue at all stages of the cycle
but at various rates. The epithelium is
thinnest at menstruation and gradually increases in thickness during the follicular
phase, reaching a maximum at ovulation.
At this time there is a well developed basal
area in which numerous mitoses can be seen
and from which many papillae or bulbs"
extend into the underlying stroma. Above
this is an intermediate zone, an interepithelial zone of cornification (so called Dierk's
layer), and a heavily cornified outer zone
(Fig. 9.21).
Cellular proliferation is less rapid during
the luteal phase and apparently cells are desquamated more rapidly than they are replaced. Consequently there is a decrease in
the thickness of the epithelium in the luteal
phase which may include an almost complete loss of the cornified zone (Davis and
Hartman, 1935). The effects are probably
due to progesterone because similar changes
are seen following the introduction of progesterone into a treatment in which estrogen
is being given.
The vaginal epithelium of a castrated
monkey is remarkably sensitive to estrogen.
A small daily dose of 5 to 10 /xg. estradiol
will stimulate growth of an atrophic epithelium of 4 to 8 cells in thickness to one of
60 or even 80 layers thick within 3 weeks.
One of the first things that is noticed as the
vaginal epithelium thickens is the numerous
mitotic figures in the stratum germinativum
followed by a marked increase in the number of epithelial papillae along the basement membrane. This condition of rapid
growth, cornification, and loss of cells into
the vaginal lumen is typical of the follicular
phase of the menstrual cycle and can be
maintained indefinitely.
Fig. U.21. the vaginal epithelium of a castuUMJ
monkej' showing growth antl cornification induced
by estrogen.
Progesterone, in contrast with estrogen,
does not produce rapid growth of the vaginal epithelium but at the same time it is
not without an effect. The vaginal epithelium, weeks or months after castration, has
relatively few papillae projecting from its
basal border into the underlying stroma.
When progesterone is given, this condition
is changed but not in a spectacular way.
There is very slow growth without cornification. The epithelium remains thin but the
papillae become more numerous. These are
mostly small epithelial buds which tend to
remain solid but may show enlargement of
the cells in their centers.
When estrogen and progesterone are given
concurrently, the effects of estrogen on the
vaginal mucosa are modified. If an estrogen
treatment has continued for a sufficient time
to produce full cornification and then progesterone is added, the first indication of an
inhibition of estrogen is a decrease in mitotic activity. This is followed by a continuation of cornification and loss of cells
faster than they are replaced ; consequently,
most of the functionalis is lost and the epithelium becomes thinner. There is also a
noticeable decrease in the intensity of cornification, which in the monkey is never as
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 when both estrogen and progesterone are
given, but eventually they almost entirely
disappear and the epithelium attains a condition resembling that of late pregnancy.
Fig. 9.22. ^^•tgi^al epithelium of a pregnant monkey showing condition on the 154th day of gestation. (From Carnegie Institution, No. C713.)
The inhibitory effect of progesterone on
the action of estrogen is shown perhaps even
better when a castrated monkey having a
fully involuted reproductive tract is first
given progesterone for a few days and then
(>strogen is added to the treatment, or when
injections of the two hormones are started
at the same time. In such experiments estrogen has little effect on the vaginal mucosa
even in doses that would produce marked
cornification if given alone. These observations show that a fully cornified vaginal
epithelium cannot be produced or maintained by estrogen when an effective dosage
of progesterone is included in the treatment
(Hisaw, Greep and Fevold, 1937).
Estrogens and progesterone are the dominant hormones of gestation and their simultaneous action is reflected by the changes
in the vaginal epithelium. The fully cornified vagina, present at the time of ovulation,
is gradually modified as pregnancy progresses into a condition strikingly like that
seen in experiments when estrogen and progesterone are given concurrently. In late
pregnancy the most striking feature of the
thin, uncornified epithelium is the presence
of numerous epithelial buds extending
deeply into the underlying stroma. They
may branch and rebranch and along their
course there is conspicuous enlargement of
the more centrally situated cells among
which cavities ai^pear, enlarge, and join
each other (Fig. 9.22). It seems quite probable that this process may be of considerable
importance in increasing the diameter of
the vagina.
VIII. Sexual Skin
A so-called sexual skin is jiresent in most
catarrhine monkeys, is not found in platyriliine monkeys, and among the anthropoids
occurs regularly only in the chimpanzee
I l^]ckstein and Zuckcrman, 1956). Changes
in the sexual skin during the menstrual cycle have been observed most extensively in
the monkey (Macaca), the baboon (Papio),
and the chimpanzee (Pan). The sexual skin
of t!ie baboon and chimpanzee undergo pronounced swelling during the follicular phase
of the cycle. A maximal size is attained by
the middle of the cycle followed by a rapid
regression and loss of edema which at least
in the baboon is associated with a marked
increase in the output of urine (Gillman,
1937a; Krohn and Zuckerman, 1937). The
subsidence of the sexual skin begins approximately at the time of ovulation and remains
in the reduced condition throughout the
luteal phase, followed by a subsequent initiation of swelling during or soon after
menstruation (Zuckerman, 1930, 1937e;
Zuckerman and Parkes, 1932; Gillman and
Gilbert, 1946; Young and Yerkes, 1943;
Nissen and Yerkes, 1943).
A well developed sexual skin is present
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
condition in which cyclic changes in edema
are absent and the most noticeable feature
is a vivid red color. Such coloration is due
to vascular engorgement rather than pigment (Collings, 1926) and involves the
perineum, the buttocks, and may extend for
various distances down the legs and over
the symphysis pubis. The development and
maturation of the sexual skin have been described in considerable detail by several investigators (Hartman, 1932; Zuckerman,
van Wagenen and Gardiner, 1938) .
The sexual skin has been of considerable
interest both as to the nature of its responsiveness to ovarian hormones and the
manner in which its grossly visible changes
during the menstrual cycle parallel events
occurring in the reproductive tract. The
sudden loss of edema at the conclusion of
the follicular phase not only signals ovulation but also raises the question as to
whether the loss of tissue fluid is due to a
decrease in estrogen or is the direct effect
of progesterone. The importance of this
becomes obvious when it is considered that
a similar process also goes on simultaneously
in the endometrium and raises the question
again as to the respective roles played by
estrogen and progesterone in endometrial
growth and menstruation.
That the development and edema of the
sexual skin of adolescent rhesus monkeys
depend on the ovaries was first demonstrated by Allen ( 1927 ) . Involution and loss
of color follow castration, and the normal
condition can be restored by the injection
of estrogen. Also, when estrogen treatment
is continued for several weeks maturation of
the sexual skin occurs and a condition characteristic of that in the adult is established
(Zuckerman, van Wagenen and Gardiner,
1938). The genital area loses its edema and
develops a brilliant red color which is retained as long as estrogen is administered.
Once this mature condition is established
the response of the sexual skin to subsequent estrogen treatments is limited to a
change in color.
Similar experiments have been performed
on the chacma baboon, Papio porcarius
(Parkes and Zuckerman, 1931; Gillman,
1937b, 1938, 1940a). The large sexual skin
of these animals is very responsive to estrogen and development equal to that of the
follicular phase of the menstrual cycle can
be readily induced by daily injections for
about 2 weeks. However, the perineal swelling of the baboon differs from the sexual
skin of the genital area of the rhesus monkey in that it does not "mature" under the
influence of estrogen.
When large doses of estrogen are given to
a rhesus monkey a generalized edema of
the skin occurs beyond the genital area.
This first appears as deeply indented swellings along the sartorii from groin to knee,
and next appears at the base of the tail and
spreads gradually upward until it involves
the entire dorsal portion of the trunk. At the
same time, the skin of the face, scalp, and
supraorbital ridges becomes swollen and
finally the edema may extend out on the
arms and down the legs to the ankles (Bachman, Collip and Selye, 1935; Hartman,
Geschickter and Speert, 1941). A daily
dose of 500 /xg. or more of estriol or estradiol
w^ll produce this condition within 2 to 3
weeks and, when the treatment is continued for an extended period the effect
tends to subside.
Progesterone has a strong inhibitory action on the effects produced by estrogen on
both the genital and extragenital sexual
skin of the monkey. If daily injections of
progesterone are added to the treatmeiu
after full development of the sexual skin
has been induced by estrogen, there is a noticeable loss of edema by the 4th or 5th
day followed by rapid involution and reduction of the turgid folds of skin to loose,
flabby wrinkles within about 10 days. When
estrogen and progesterone are given concurrently to a castrated monkey from the
beginning of treatment edema does not appear but the sexual skin regains its normal
color. In fact, progesterone alone, like estrogen, can restore the color to the sexual
skin of castrated adult monkeys (Hisaw,
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
adolescent animals. The most striking effect
and probably the most important is the
sequence of events initiated by a single
dose of progesterone when given to an animal on continuous estrogen treatment. Under such treatment a full response of the
sexual skin is obtained by the end of 20
days. If at this time 1 mg. progesterone is
given in a single dose and the estrogen
treatment continued uninterruptedly, the
first indication of an effect of the luteal hormone is a slight loss of edema and color of
the sexual skin on the 4th or 5th day thereafter. The sexual skin is markedly reduced
by the 8th day, almost gone by the 9th, and
at the end of about a fortnight regains its
ability to respond to estrogen as shown by
a return of color and swelling. However, the
most remarkable eventuation of such treatment is menstruation which usually begins
on about the 10th day (Hisaw, 1942).
Involution of the sexual skin and menstruation following a single injection of
progesterone also have been produced in the
baboon by Gillman (1940a). He found that
5 mg. progesterone, when given on the 8th
day of a normal menstrual cycle, would
cause an appreciable loss of edema of the
swollen perineal sexual skin by the day after
injection. This was followed by a progressive involution of the perineum until the
13th day and swelling was re-initiated by
the end of the 15th day. Reduction of the
sexual skin at this dosage of progesterone
was not associated with menstruation. However, when the dose was increased to 20 mg.
both deturgescence of the sexual skin and
menstruation occurred. These effects produced by progesterone in the presence of
endogenous estrogen have much in common
with those described above as occurring in
castrated monkeys on continuous estrogen
treatments.
IX. Menstruation
An experimental ai^proach to the physiology of menstruation dates from the observations of Allen (1927) that uterine
bleeding would occur in castrated monkeys
following the discontinuance of an estrogen
treatment. He suggested that normal menstruation is due to a fluctuation in estrogen
secretion and proposed the "estrogen-withdrawal" theory to account for the observed
facts. This concept led to an extensive investigation of the effects of estrogens on the
endometrium and of conditions that modify
their action. It was soon found that in both
castrated monkeys and human beings there
was a quantitative relationship between the
dosage of estrogen given and the maintenance of the endometrium. Bleeding occurred during treatment when the daily dose
of estrogen was small, but with larger doses
a point was reached at which the injections
could be continued for months or even years
without bleeding (Werner and Collier, 1933;
Zuckerman, 1937b, d).
Estrogen also will inliihit i)ostop('rative
bleeding which usually follows total castration, provided the ovaries are removed before or soon after ovulation (Hartman.
1934). With the advent of a corpus luteum
and development of a progestational endometrium it becomes progressively more difficult, following castration, to prevent menstruation by injecting estrogen. Similar
results are obtained when estrogen is given
during a normal menstrual cycle. Small
doses may not prevent the onset of menstruation, but if continued, subsequent menstrual periods are delayed (Corner, 1935).
Large doses when given during the luteal
phase of the cycle do not disturb the normal
menstrual rhythm, but may do so if the
treatment is started during the follicular
phase (Zuckerman, 1935. 1936a).
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 a few days before the expected menstruation (Corner, 1935; Corner and Allen, 1936) .
Also, the bleeding that invariably follows
the discontinuance of a long treatment with
estrogen can be inhibited indefinitely by
giving progesterone (Hisaw, 1935; Engle,
Smith and Shelesnvak, 1935; Zuckerman,
1936b).
An impression held by many of the earlier investigators was that progesterone
could not produce its effects on the primate
endometrium unless it w^as preceded by the
action of estrogen. It is true, of course, that
progesterone is a comparatively weak
growth promoter and its effects can be demonstrated to best advantage on an endometrium that has been developed by estrogen. However, Hisaw, Greep and Fevold
(1937) produced a progestational endometrium in a monkey that had been castrated
242 days previously by giving synthetic
progesterone. Also, the endometrium of this
animal was found capable of forming a
decidual plaque upon traumatization. Soon
afterwards Hartman and Speert (1941) observed menstruation following the withdrawal of progesterone in castrated monkeys
that had not been given estrogen and more
recently similar results have been reported
by Eckstein ( 1950) . At the same time it has
l)een found that progesterone will induce
menstruation in women suffering from
amenorrhea and also that uterine bleeding
can l)e jirecipitated l)y similar treatment
(hiring the follicular j^hase of the cycle
(Zondek and Rozin, 1938; Rakoff, 1946).
These observations have been confirmed
and extended by Krohn (1951; 1955) who
finds that menstrual bleeding can be induced in monkeys wdth secondary amenorrhea by the injection of 5 daily doses of
progesterone. Progesterone (5 mg. daily for
5 days) also precipitates uterine bleeding
in castrated monkeys at intervals of about
8 days provided the treatment is started
innnediately a menstrual bleeding has been
induced either by removel of the ovaries
or withdrawal of estrogen. The most interesting aspect of these observations is
that the number of short 8-day cycles that
can be obtained in this way in a castrated
animal seems to be related to the size of the
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
hormone used to obtain the bleeding. It also
is of interest that such conditioning of the
endometrium to subsequent responses to the
5-day treatments with progesterone may
last for several months on a continuous regime. It is surprising that such a series of
responses cannot be initiated unless the
first injection of progesterone is given within
6 days following the initial withdrawal
bleeding. These observations have much in
common with those of Phelps (1947) who
also studied the influence of previous treatment on experimental menstruation in monkeys.
There seems to be a quantitative relationship between the dosage of progesterone
given in combination with estrogen and the
ability of estrogen to prevent bleeding after
the injections of progesterone are stopped. It
has been mentioned that once a fully
developed i^rogestational reaction has been
produc(Hl l)y progesterone, it is extremely
difficult, if not impossible, to inhibit menstruation by giving estrogen following the
withdrawal of progesterone. However, Hisaw and Greep (1938) found that progestational endometria produced ijy small
doses of estrogen plus api^roximately 0.5
mg. progesterone daily for 18 to 21 days
did not bleed following progesterone withdrawal when continued on 10 to 20 times the
original dosage of estrogen. In fact, such
endometria were brought back to a condition typical for the action of estrogen and
again transformed into a presecretory progestational state without the intervention of
bleeding. Similar observations were made
previously by Zuckerman (1936a, 1937d).
These experimental results give grounds
for some doubt as to the adequacy of the
estrogen-withdrawal theory to account fully
for menstruation. Not only can progesterone
bring about menstruation without the intervention of estrogen but other steroid hormones are capable of pi'oducing similar effects. Desoxycorticosterone in large doses
can inhibit estrogen-withdrawal bleeding in
castrated monkeys (Zuckerman, 1939, 1951 )
and induce phases of uterine bleeding in
rapid succession in normal monkeys
(Krohn, 1951). So too can testosterone prevent estrogen-withdrawal bleeding (Hartman, 1937; Engle and Smith, 1939; Duncan,
Allen and Hamilton, 1941) and inhibit progesterone-withdrawal bleeding as well (Engle and Smith, 1939). Testosterone also will
precipitate bleeding during an estrogen
treatment (Hisaw, 1943) and in normal
monkeys if given early in the cycle (Krohn,
1951). Just what specific action these compounds have in common that enables them
to produce these effects or whether there are
different modes of action that lead to the
same results is not known, but, before mentioning certain possibilities, it may be helpful to consider information regarding the
influence of estrogen-progesterone interactions on menstruation.
Among the most significant observations
regarding primary causes of menstruation
are a few indications that there may be an
intrinsic difference in the ways in which estrogen and progesterone produce their effects on the endometrium. One of the first
indications of this was the discovery that a
short series of injections of progesterone
during treatment with estrogen will precipitate menstruation (Corner, 1937; Zuckerman, 1937d; Hisaw and Greep, 1938). This
can be demonstrated by giving a castrated
monkey a maintenance dose of estrogen
daily for 2 or 3 weeks, then adding a daily
injection of progesterone for 5 to 10 days
and continuing the estrogen treatment. As
a rule bleeding appears within 2 or 3 days
after stopping progesterone. The most interesting point brought out by such experiments is that bleeding can occur under these
conditions in the presence of an otherwise
maintenance dosage of estrogen.
Perhaps the most surprising as well as
most important fact brought out by subsequent experiments was the small amount of
progesterone required to bring about bleeding under these conditions. It was found that
only a single injection of 1 mg. was required
for animals on chronic treatment with a
maintenance dose of estradiol (1000 LIT.)
and some bled when 0.5 mg. progesterone
was given (Hisaw, 1942). The sequence of
events following the injection of progesterone can be seen to best advantage in an
adolescent monkey whose sexual skin also
respond" to the estrogen treatment. When
the 1 mg. ]irogesterone is given on the 20th
day of estrogen treatment the edema of the sexual skin will have attained its maximal
development. The first indication of an effect of progesterone is a slight loss of edema
and color of the sexual skin which appears
on the 4th or 5th day and by the 9th or 10th
day the edema is almost gone and the sexual
skin is pale. Blood apjiears in the vaginal
lavage between the 7th and 10th days, of
about 70 per cent of the animals on this dosage. The sexual skin may remain markedly
reduced and pale until about the 15th day
after which both color and edema rapidly
return. These effects can also be seen when
1 mg. progesterone is given for a series of
days. However, neither the time of appearance nor loss of edema of the sexual skin is
significantly hastened, and if the injections
extend over no more than 5 days the time
between the first injection and bleeding remains approximately the same.
Similar observations have been made by
Gillman and Smyth (1939) on the South
African baboon iPapio porcarius). They
found that 3 mg. or more of progesterone
when given in a single injection during the
follicular phase of the cycle would cause
the relatively enormous perineal swellings
to pass rapidly through deturgescence and
reach a flabby resting condition within 5 to
7 days, and after a delay of about 24 hours
once again begin to swell. As much as 10 or
15 mg. in a single dose caused perineal deturgescence without bleeding, whereas 20
mg. in a single dose or a total of 15 mg. if
divided into 2 or 3 injections and given at
3 or 4 day intervals, produced both deturgescence and bleeding (Gillman, 1940b).
The l)aboon diff"ers from the monkey in that
larger doses of progesterone are required to
produce the effects and the sexual skin does
not mature" on repeated treatments and
lose its responsiveness; otherwise the basic
physiology of the reaction in both animals
seems to be the same.
The most important fact l)rought out by
these experiments is that the effects of a
single injection of progesterone can continue
in the presence of estrogen for as long as 10
to 15 days. It is highly imi^robable that progesterone lingers in the body for so long a
time (Zarrow, Shoger and Lazo-Wasem,
1954). In general it is considered the most
ephemeral of the sex steroids and is probablv inactivated within at least a few hours after it is administered. It seems more lilvely
that progesterone modifies the sexual skin
in a way that renders it unresponsive to estrogen and that about a fortnight is required
to recover the original condition.
This takes on added significance when the
possibility is considered that effects similar
to those seen in the sexual skin might also
be going on simultaneously in the uterine
endometrium. An appreciable dehydration
of the endometrium occurs just previous to
menstruation (van Dyke and Ch'en, 1936)
and a loss of interstitial fluid before bleeding has been observed in endometrial implants in the eyes of monkeys and described
in detail by Markee (1940) . This was shown
by periodic regression in size and compactness of the grafts which resulted in a decrease in area of 25 to more than 75 per
cent. Because cyclic changes in endometrial
grafts in the eye are correlated with events
of the menstrual cycle there is reason to believe that similar reactions were going on
in the endometrium of the uterus.
Endometrial regression, as described by
Markee, did not always lead to menstruation although it invariably preceded, accompanied, and followed menstrual bleeding.
Menstruation occurred only when regression
was rapid and extensive. This was seen in
the endometrial grafts in the eye during a
normal menstrual cycle at the time of involution of a corpus luteum and during an
anovulatory cycle soon after the involution
of a large follicle. It also begins soon after
the last of a series of injections of estrogen
or i^'ogesterone. A slow decrease in size of
the ocular grafts, without concomitant
bleeding, can be induced in castrated monkeys by gradual withdrawal of estrogen,
and when estrogen is given in amounts that
are inadequate for maintaining the endometrium for an extended period the "break
through" bleeding that eventually ensues is
preceded by a rapid and extensive endometrial regression. Because this reaction also
occurs w^hen menstruation is induced by such
an unusual procedure as spinal transection
(Markee, Davis and Hinsey, 1936), it probably is a phenomenon that always precedes
menstruation.
It seems from these observations that the
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
of a particular physiologic condition, and
bleeding and tissue loss are incidents that
occur during the readjustment necessary for
the return to an inactive state. What this involves is only partly known, but an understanding of the initial changes in the endometrium that usher in menstruation most
certainly holds the explanation of the real
cause. This has been a perennial subject for
discussion and many suggestions and theories have been set forth in an extensive
literature to account for various aspects of
menstruation. Among the more recent general discussions are those by Zuckerman
(1949, 1951), Corner (19511, and Zondek
( 1954 ) .
The estrogen- withdrawal or estrogen-deprivation theory proposed by Edgar Allen
has received more attention than any other.
From what has been mentioned earlier it is
clear that this theory can account for uterine bleeding subsequent to the discontinuance of a series of estrogen injections and
also perhaps menstruation at the conclusion
of an anovulatory cycle. However, it is not
so obvious as to how this theory can explain
the occurrence of menstruation at the close
of the luteal phase of a normal cycle. Estrogen in large doses will not inhibit such
bleeding, but it is postponed if progesterone
is given. It is equally difficult to see how this
theory is helpful in accounting for the fact
that a small dose of progesterone will precipitate bleeding in the presence of a maintenance dosage of estrogen. As little as 2
/xg. progesterone will induce bleeding when
applied topically to the endometrial lips of
an exteriorized uterus (Fig. 9.7) in a monkey that is receiving 10 fig. estradiol daily
(Hisaw, 1950).
Uterine bleeding precipitated by administering progesterone during an estrogen
treatment has been explained on the grounds
that progesterone in some way interferes
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
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
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.
The physiologic function of progesterone
is the conversion of an estrogen-endometrium into a progestational endometrium
suitable for receiving and nourishing a developing blastocyst. Such an endometrium
is adapted for this specific reproductive
function and accordingly its physiologic nature must be quite different from that of the
follicular phase of the cycle. Indeed, it is
known that these two structures (follicular
and luteal phase endometrial are morphologically and biochemically unlike in a number of respects. This gradual transformation,
following ovulation, occurs as progesterone
becomes the dominant hormone, and consequently, as this proceeds, the endometrium
progressively loses competence to respond
to estrogen. However, this does not imply
that estrogen is without effect in the general
economy of the progestational endometrium.
It has been shown in a number of ways that
the action of progesterone on the primate
endometrium is greatly facilitated by the
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).
After consideration of the endometrial
specializations brought about by ]irogesterone, it seems rather jwintless to hark back
to the follicular phase and inject the past
recoi'd of accomjilishments and prerogatives
that estrogen had at that time into the explanation of an entirely different hormonal
situation. It seems more in keeping with the
facts to state outright that menstruation
following the involution of a corpus luteum
or the discontinuance of progesterone, even
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
bleeding. This is possible, of couisc, but at the same time the exceedingly small amount
of progesterone required to induce bleeding
in the presence of estrogen makes it difficult
to be sure what the situation might be. Even
a negative test for progesterone in the blood,
by our present methods, does not necessarily
indicate the absence of a physiologically effective amount of progesterone. Zarrow,
Shoger and Lazo-Wasem (1954) found that
in rabbits an intramuscular injection of 40
mg. progesterone was required to produce
an appreciable concentration of the hormone in the blood as determined by the
Hooker-Forbes method. Yet, 0.2 mg. progesterone daily for 5 days will produce a
progestational reaction in the uterus equivalent to that of the 5th day of normal pseudopregnancy. In monkeys 0.5 mg. daily when
given with 10 fxg. estradiol is an adequate
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.
This also seems to hold for the human being. Estimates of secretion and metabolism
of progesterone in the human being have
been based primarily on the recovery of its
excretory product sodium pregnanediol glucuronidate in the urine. It seems obvious
that such determinations must be only general approximations because only about 20
per cent of the progesterone secreted or injected can be accounted for by the pregnanediol in the urine. Also, it is generally known
that a physiologically effective dosage of
progesterone does not necessarily lead to the
excretion of pregnanediol (Hamblen, Cuylcr,
Powell, Ashley and Baptist, 1939; Seegar,
1940). In other words, the threshold dose of
progesterone for endometrial stimulation is
l)elow that at which the hormone is excreted
as pregnanediol. In fact, it has been suggested by some investigators that there is
no quantitative relationship between the
l)rogesterone present in the blood and the
pregnanediol excreted in the urine (Buxton,
1940; Sommerville and Marrian, 1950;
Kaufmann, Westphal and Zander, 1951).
These findings and the wide variation in
the amount of prc'gnancdiol excreted during a menstrual cycle (Venning and Browne,
1937) suggest that, even in the absence of
ovulation, sufficient progesterone may be
present to influence menstruation. There
also is the possibility of progestational hormone from some extra-ovarian source, such
as the suprarenal cortex. This was suggested
by Zuckerman (1937b, 1941 j as a possible
explanation for periodic bleeding in monkeys on a constant submaintenance dose of
estrogen. This thought becomes more plausible in view of the fact that progesterone is
one of the precursors in the metabolic synthesis of androgens, estrogens, and adrenal
cortical steroids (Dorfman, 1956). Also, it
has been shown that desoxycorticosterone
acetate is converted to progesterone in vivo
(Zarrow, Hisaw and Bryans, 1950). Therefore, progesterone is not restricted to ovarian luteal function but instead is of rather
general occurrence in the body and the
likelihood is that small amounts are a constant constituent of the blood.
Also, the amount of progesterone from
extra-ovarian sources may fluctuate, as suggested by Zuckerman (1949), and consequently disturb the normal menstrual
rhythm and probably cause bleeding in
monkeys on a continuous submaintenance
dose of estrogen. However, as to the latter,
there is an alternative explanation. Castrated monkeys on a continuous treatment
of 10 fxg. of estradiol daily do not show
"break-through" bleeding, and a synergistic
effect on growth of the uterus is seen when
0.5 mg. or more of progesterone daily is introduced into the treatment. However, the
simultaneous administration of 0.25 mg. or
even 0.125 mg. progesterone daily in similar
exj^eriments results in bleeding between
a!)out the 10th to 16th day of the combination treatment. Thus, a dosage of progesterone less than that required for synergism or
prevention of bleeding when given alone,
modifies the endometrium so that it can no
longer be maintained by 10 fxg. estradiol
daily (Hisaw, Jr., unpublished). When it is
considered that the endometrium becomes
increasingly dependent on estrogen during
a chronic treatment, even after maximal
growth is attained (Hisaw, 1942), it seems
plausible that the effectiveness of a dosage
of estrogen only slightly alcove the threshold for bleeding may be decreased sufficiently by the endogenous progesterone from
extra-ovarian sources to precipitate bleeding.
Although it is obvious that the normal
menstrual cycle is primarily under the control of the ovarian estrogens and progesterone, it is also equally clear that menstruation is not due to a specific hormonal action.
Experimental evidence indicates that any
natural or synthetic compound having the
capacity for promoting growth or sustaining
an existing metabolic state in the endometrium is also capable of inducing withdrawal bleeding. However, this does not imply that all compounds capable of inducing
menstruation do so by the same biochemical
action; in fact, there is considerable evidence that this is not so (see chapter by
Villee). Yet in each instance a series of
events is set in motion that leads up to active bleeding.
X. The Mechanism of Menstruation
The immediate cause and mechanism of
menstruation has continued to be a topic of
special interest for many years and the subject of frequent general discussions. A generalization in keeping with our present
knowledge is that no gross morphologic feature of the endometrium is distinctive of
menstruation. A menstruating endometrium
may be representative of any stage of the
follicular or luteal phase of the cycle. The
most frequently discussed hypothesis regarding the mechanism of menstruation is
that proposed by Markee (1940, 1946)
which is based on direct observations of
vascular changes in endometrial grafts in
the anterior chamber of the eye of monkeys
(see p. 564). The changes observed in the
endometrium shortly before bleeding are,
briefly, as follows. (1) There is extensive
and rapid regression of the endometrium due
to loss of ground substance from the stroma
(Fig. 9.23). (2) The rapid regression brings
about a disproportion between the length of
the coiled arteries and thickness of the endometrium with the formation of additional
coils. (3) The increased coiling of the arteries retards the circulation of blood
through them and their branches. This stasis
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.
Fig. 9.23. A diagram indicating correlated changes in ovary and endometrium during
an ovulatory cycle of rhesus monkey. Thickness of endometrium, density of stroma, gland
form, and three types of arteries are indicated. There is a gradual rise in thickness up to the
time of ovulation, and a brief decline followed by development of the luteal or progestational phase with accumulation of secretion in the glands due to relaxation of the
myometrium. This is followed by loss of ground substance from the stroma, which is the
primary factor in the premenstrual regression of the ischemic phase. This is a prelude to
extravasation and shedding of tissue. Incidentally, secretion is extruded and glands collapse. There is further regression throughout the phase of menstruation. More than the
basal zone (coarse stipple) survives menstruation. During repair, thickening of the endometrium is associated with increase in ground substance in the stroma and growth in the
glands. (From G. W. Bartelmez, 1957, Am. J. Obst. & Gynec, 74, 931-955, 1957, with
some modification of description.)
Although this offers an explanation for
many of the facts, it falls short in that now
it is known that menstruation can occur in
the absence of coiled arteries. Kaiser (1947)
showed that no spiral arteries are present in the endometrium of three species of South
American monkeys known to menstruate.
He also found that the coiled vessels of the
endometrium could be destroyed almost
completely by giving large doses of estrogen
and yet bleeding followed estrogen withdrawal.
Several experimental conditions under
which the coiled vessels of the endometrium
are destroyed have been mentioned in the
present discussion and in each instance
bleeding invariably followed withdrawal of
the supporting stimulus. The extremely
atrophic endometrium present at the conclusion of a prolonged treatment with progesterone (Fig. 9.8) will bleed when the
injections are stopped, and if estrogen injections are started immediately thereafter
the endometrium that develops is normal
with the exception of the absence of coiled
arteries; even so, it also will bleed when
the treatment is stopped. Even a more drastic destruction of endometrial structures occurs when both estrogen and progesterone are given for several months. Not
only are the coiled arteries destroyed but
also the glands and the luminal epithelium.
All that remains is a modified stroma penetrated by a few small blood and lymph vessels and scattered glandular rudiments along
the myometrium (Fig. 9.13). Yet, in spite
of this, bleeding follows discontinuance of
the treatment.
These observations prove conclusively
that the spiral arteries of the endometrium
do not hold the solution to the menstrual
process. However, the descriptive account
by Markee of the events that take place in
the endometrium during the cycle remains
one of the major contributions to our knowledge of the primate endometrium. Phelps
(1946) also made a very careful study of the
vascular changes in intraocular endometrial
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.
There also is reason for doul^ting that
ischemia is a determining factor in the
menstrual process. That constriction of the
endometrial vessels does occur is well established, but that tissue destruction and bleeding are consequences of prolonged anoxemia
may be questioned. The endometrium
around the internal cervical os as seen in
incised exteriorized uteri (Fig. 9.7) contains
very few coiled arteries and does not take
part in the periodic blushing and blanching
of the fundus, but instead remains blood-red
even during menstruation. Also, certain
tongues of endometrium in a uterine fistula
may become crowded by their neighbors to
an extent of being partly or completely deprived of blood, yet they do not bleed even
though their unfavorable situation leads to
deterioration within a few days.
Emmel, Worthington and Allen (1941)
attempted to induce menstruation in monkeys by operative ischemia. Circulation to
the fundus of the uterus was interrupted by
means of a tourniquet for periods of 1 to 8V4
hours, and in two instances for 19 hours.
This procedure did not precijiitate uterine 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
hours impairment of the bleeding response
to estrogen withdrawal was observed, and
19 hours of ischemia caused atrophy of the
uterus without bleeding.
It also has been reported that a toxic substance formed in the endometrium is responsible for menstruation. This menstrual
toxin is supposed to be present in the endometrium just previous to and during menstruation, and to be a substance resembling
or identical with necrosin, a material found
in pleural exudate following an inflammatory reaction (Smith and Smith, 1951).
Zondek (1953) reports that menstrual blood,
when obtained under relatively sterile conditions, is no more toxic to experimental
animals than sterile tissue extracts. He also
found that death of animals given injections
of menstrual blood was due to bacteremia,
an effect that could be prevented by giving
antibiotics. Nor was he able to demonstrate
a toxic substance in the premenstrual or
menstrual endometrium. It might be mentioned in this connection that endometrial
tissue destroyed by experimental ischemia
in the experiments by Emmel, Worthington
and Allen (1941), obviously did not influence menstruation nor did involuting endometrial tissue in uterine fistulae (p. 564).
Therefore, the presence of a specific toxin
that may induce menstruation has not been
conclusively demonstrated.
Regardless of the specific cause of menstruation, the evidence shows that it can
occur in the absence of coiled arteries, endometrial glands, or surface mucosa, and is
unrelated to the thickness of the endometrium. This statement is based on conditions that have been experimentally induced
in the monkey and they strongly indicate
that menstruation, whatever the cause, is a
stromal phenomenon. This view seems to be
in agreement with the observations reported
by Bartelmez in his elegant studies of the
morphology of the endometrium of both
monkeys and the human being. He emphasizes changes taking place in the connective
tissue elements of the stroma and points out
that much less tissue is lost at menstruation than i.< commonly thought (Bartehnez,
1957). The reduction in thickness is clue primariiy to loss of ground substance from the
stroma, and conversely, the outstanding
feature of repair is the increase in stromal
ground substance (Fig. 9.23). ^Mitoses are
rarely seen in the stroma during repair and
arc not abundant enough in any phase according to Bartelmez to account for the observed increase in thickness of the endometrium. Our present knowledge indicates that
an explanation of menstruation may be
found in the metabolic effects induced in the
stromal connective tissue of the endometrium by a sudden withdrawal of a supporting hormonal stimulus.
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