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=Chapter XIV The Fetal Endocrine Glands=
=Chapter XIV The Fetal Endocrine Glands=


Qui: lcnowledge of endocrine functions during prenatal life is
Our knowledge of endocrine functions during prenatal life is fragmentary as may be expected from the fact that adult glands of internal secretion are still incompletely understood and their relationship to one another only partly determined. There seems to be little doubt that a few of the maternal hormones do influence embryonic deve1opment, but not all can pass the placental barriers The present deftciency of information concerning placental transmission of hormones is a factor limiting any discussion of their activities in the fetus. Perhaps the secretions of the fetus itself are equally or more important than those of the mother for the well being and normal metabolism of the new individual. It is with their functions that we shall be especially concerned.
fragmentary as may be expected from the fact that adult glands of
internal secretion are still incompletely understood and their
relationship to one another only partly determine-d. There
seems to be little doubt that a few of the maternal hormones do
influence embryonic deve1opment, but not all can pass the pla—
cental barriers The present deftciency of information concem—
ing placental transmission of hormones is a factor limiting any
discussion of their activities in the fetus. Perhaps the secretions
of the fetus itself are equally or more important than those of the
mother for the well being and normal metabolism of the new
individual. It is with their functions that we shall be especially
concerned.


THE SUPRARENAL OORTBX


Among all the endocrine glands of the humazfetus the
==The Suprarenal Cortex==
suprarenals manifest the most remarlcable peculiaritiesks 3 Exam—
ination of them in the still—born infant reveals that they are proportionately very much larger than at any time after birthx in fact
they form o.2 per cent of the entire body weight. Those of the
adult constitute only o.o1 per cent.4 The reason for their great
size is found in an hypertrophy of the innermost cortical cells


sforming a layer to which the names, X-zone, fetal cortex and
Among all the endocrine glands of the human fetus the suprarenals manifest the most remarlcable peculiaritiesks 3 Examination of them in the still—born infant reveals that they are proportionately very much larger than at any time after birthx in fact they form o.2 per cent of the entire body weight. Those of the adult constitute only o.o1 per cent.4 The reason for their great size is found in an hypertrophy of the innermost cortical cells forming a layer to which the names, X-zone, fetal cortex and androgenic zone have been applied. Only the outer rim of the embryonic gland differentiates into the characteristic suprarenal cortex of the adult, and it does not come into prominence until after prenatal life.


androgenic zone have been applied. Only the outer rim of the
embryonic gland difkerentiates into the characteristic suprarenal
cortex of the adult, and it does not come into prominence until
after prenatal life.


The androgenic zone of the fetal suprarenal undergoes involution rapidly after birthF and as it disappears the size of the gland
The androgenic zone of the fetal suprarenal undergoes involution rapidly after birthF and as it disappears the size of the gland becomes actually -as well as relatively smaller. The growth curve of the human suprarenal gland is reproduced in Fig. 66.C The gland loses one—third of its birth weight during the first postnatal week, one-half in the first three months and fouplifths by the end of the first year. Thereafter, a slow growth takes place and at puberty the suprarenal again attains the weight it had at the end of the fetal life ; but the androgenic Zone is no longer recognizable. This characteristically fetal part of the suprarenal gland has been identiiied in the cat,7 Inouse,8 rabbit9 and in one strain of rats.10 It seems to be absent, or at least not present as a comparable distinct layer of cells, in the albino rat and some other animals.
becomes actually -as well as relatively smaller. The growth curve
of the human suprarenal gland is reproduced in Fig. 66.C The
gland loses one—third of its birth weight during the first postnatal
week, one-half in the first three months and fouplifths by the


191
192 PHYSIOLOGY OF THE FETUS


» end of the first year. Thereafter, a slow growth takes place and at
The physiologic signiHcance of the hypertrophiecl fetal cortex of the suprarenal gland is not understood. That it is closely related to other endocrine organs is quite certain. A possible influence of Inaternal sex hormones upon the growing feta1 suprarenal is suggestecl by the closely parallel growth curve of the uterus in prenatal and early postnatal life (Fig. 67) . Involution of the X-2one of young male Ihice is accomplished under the influence of testicular hormone.
puberty the suprarenal again attains the weight it had at the end
of the fetal life ; but the androgenic Zone is no longer recognizable. This characteristically fetal part of the suprarenal gland
has been identiiied in the cat,7 Inouse,8 rabbit9 and in one strain of
rats.10 It seems to be absent, or at least not present as a comparable distinct layer of cells, in the albino rat and some other
anitnals.


The physiologic signiHcance of the hypertrophiecl fetal cortex
of the suprarenal gland is not understood. That it is closely re—


c« B «? 4 6 F J« ZZ « 36 II ZU
Fig. 66. — Growth of the human suprarenal glands (weight) during fetal like (c—B) and after birth. (scammon: «The Measurement of Maus« Und: dünn. Press.)
. Ase f« Yes-·.
Fig. 66.-—Growth of the human suprarenal glands (weight) during fetal like (c—B)
and after birth. (scammon: «The Measurement of Maus« Und: dünn. Press.)


lated to other endocrine organs is quite certain. A possible influence of Inaternal sex hormones upon the growing feta1 suprarenal is suggestecl by the closely parallel growth curve of the
uterus in prenatal and early postnatal life (Fig. 67) . Involution
of the X-2one of young male Ihice is accomplished under the in—
fluence of testicular horrnoneU


It has been suggested that the fetal suprarenaLgland elaborates an anclromirnetic substance.I2- I« Its ability to maintain the
prostates of the castrated immature mouse and rat, which degenerate when gonads and suprarenals are removed, demonstrates
THE FETAL ENDOCRINE GLANDS lgs


an andromimetic property quite clearly-P«- 15 «« Recentlzy however,
It has been suggested that the fetal suprarenaLgland elaborates an anclromirnetic substance.I2- I« Its ability to maintain the prostates of the castrated immature mouse and rat, which degenerate when gonads and suprarenals are removed, demonstrates an andromimetic property quite clearly-P«- 15 «« Recentlzy however, evidence has been advanced which indicates that carefully prepared extracts of fetal and of other X—2one—bearing glands do not have androgenic propertiesss but it is possible that the amount of suprarenal tissue extracted was too small to produce eifects. should it prove that androgens are laclcingx one would have to discard the attractive hypothesis that the androgenic cortex serves directly to protect the fetus against an excessive iniluence of maternal estrogens reaching it through the placental barrier.
evidence has been advanced which indicates that carefully prepared extracts of fetal and of other X—2one—bearing glands do not
have androgenic propertiesss but it is possible that the amount
of suprarenal tissue extracted was too small to produce eifects.
should it prove that androgens are laclcingx one would have to
discard the attractive hypothesis that the androgenic cortex serves
directly to protect the fetus against an excessive iniluence of maternal estrogens reaching it through the placental barrier.


a---»»!
OF« Z Z 4 6 J« E) «? ««- Jö X r«AXJD Bär-«.
Fig. 67.-Growth of the hutnan Uterus (length) during ketal like (c-—B) and after
birth. (scammon: «The Measurement of Man," Univ. Minn. Press.)


75
Fig. 67. - Growth of the hutnan Uterus (length) during ketal like (c-—B) and after birth. (scammon: «The Measurement of Man," Univ. Minn. Press.)


 


The possibility that cortin or a cortin-like hormone is forrned by the feta1 suprarenal gland has received attention. Some investigators have reported that the survival times of adrenalectomized cats and dogs are prolonged during advanced pregnancy.17szI9 Others failed to substantiate this at the end of gestation,20 but even if it is true there is no proof that a fetal secretion protected the mother. Progesterone maintains life and growth in ferrets and rats in the absence of suprarenal glands,2I-««’3 and the functional corpus luteum of pregnant adrenalectomized anirnals does the Same« Adrenalectomy of pregnant rats during gestation results in an increase in weight of the fetal glandsW as will be seen in Table 22.




The possibility that cortin or a cortin-like hormone is forrned
Tanm 22
by the feta1 suprarenal gland has received attention. Some
 
investigators have reported that the survival times of adrenalectomized cats and dogs are prolonged during advanced pr«eg—
Tun Bringe-IS or Aussicht-Demut Denn-ro Pagen-mer III-on kur- Wntenks or rat; Fast-Hi« sur-Hauptn- Gunvs
nancy.I7szI9 Others failed to substantiate this at the end of gestation,20 but even if it is true there is no proof that a fetal secretion
 
protected the mother. Progesterone maintains life and growth
Time of adrenaleetomy No. of Average Ist. Ave. set. of suprarenal of mothek litters of fetuses (gm.) glands of fetuses (mg.) « d« 9 o« 9 Unoperated eontrols . . . . . . 18 5 .84 5.t»)8 0.90 0.82 14th day of FeSUItIOIL . . . . 15 4 .96 4.78 LLZ I .l8 7th day of Feste-tion . . . . . . 10 4 .70 4.51 1.17 Lls
in ferrets and rats in the absence of suprarenal glands,2I-««’3 and
 
the functional corpus luteum of pregnant adrenalectomized anirnals does the Same« Adrenalectomy of pregnant rats during
 
gestation results in an increase in weight of the fetal glandsW as
Attempts have been made to destroy the suprarenal g1ands by means of intrauterine surgery to observe effects on other fetal endocrine organskk but it proved impossible to obtain clear—cut results because of the magnitude of technical difficulties.
will be seen in Table ge.
 
==The Suprarenal Medulla==
 
The medulla of the suprarenal gland has an embryonic origin very different from that of the cortex. It is formed by cells which arise from the primordia of sympathetic ganglia and which begin to migrate into the already prominent cortical bodies at about seven weeks gestation in man. cells of the suprarena1 medulla as well as of certain other small glandular bodies of similar embryonic origin (e.g., the aortic paraganglia) possess a retnarld able afkinity for chrome compounds with which they take on a brown color. This chromaffin reaction has been demonstrated to be elicitable iirst at about the time extracts of embryonic suprarenal tissue begin to produce pharmacologic responses characteristic of epinephrin749


IZ
194 Pnrsxoroor or THE: rETUs


Tanm 22
Many have investigated the activities of the embryonic and fetal suprarenal medulla by this histochemical method as well as by other chemical and sensitive physiologic techniques Epinephrindilce reactions are obtainable from suprarenal extracts prepared from chiclc embryos as early as the eighth day of incubation although similar extracts of other embryonic tissues give negative resultsFHI Epinephrin is formed, or at least stored, in the medulla of the glands in many fetal mammals before the middle of gestation.32-39 The medullary cells show the chromaliin reaction at the 17th to 18th day in the pig and both physiologic and histochemical tests reveal the presence of an epinephrins lilce substance at the time migration of medullary cells into the cortical bodies is first observablekssfs The epinephrin content of fetal glands has been reported to be greater than in the adult; more was found in female than in rnale fetuses. A correlation between appearance of epinephrin in the suprarena1 of the rat and the origin of fetal movements has been suggested but this seems to be coincidental.


Tun Bringe-IS or Aussicht-Demut Denn-ro Pagen-mer III-on kur- Wntenks or rat;
Fast-Hi« sur-Hauptn- Gunvs


Time of adrenaleetomy No. of Average Ist. Ave. set. of suprarenal
In sharp contrast with results obtained in most rnamma1s, human fetal suprarenal extracts give negative or only very slightly positive tests for epinephrine 4144 However, in full term infants as well as prematures which lived for a short time somewhat more definite reactions were obtained. The near fai1 ure to obtain epinephrin-lilce responses from human fetal suprarenal extracts may be contrasted with the observation that the paraganglia yielded definite amounts of epinephrin in one instance:43
of mothek litters of fetuses (gm.) glands of fetuses (mg.)
« d« 9 o« 9
Unoperated eontrols . . . . . . 18 5 .84 5.t»)8 0.90 0.82
14th day of FeSUItIOIL . . . . 15 4 .96 4.78 LLZ I .l8
7th day of Feste-tion . . . . . . 10 4 .70 4.51 1.17 Lls


Human suprarenal at birth - 0.0I arg. epinephrin per OR? Hm. Fluid.


Attempts have been made to destroy the suprarenal g1ands by
Human paraganglion at birth - 0.24 rag- epinephrin per 0.1I Hm. sind.
means of intrauterine surgery to observe effects on other fetal


endocrine organskk but it proved impossible to obtain clear—cut
Any relationship between low content of epinephrin and the presence of a very prominent androgenic cortical zone in man is undetermined.
results because of the magnitude of technical difkiculties


THE SUPRARENAL MEDULLA
==The Sex Hormones==


The medulla of the suprarena1 gland has an embryonic origin
An excellent consideration of embryologic development of sex with a review of all but the latest literature has appeared recently.45 We are limited here to only a small part of this interesting subject.
very different from that of the cortex. It is formed by cells which
arise from the primordia of sympathetic ganglia and which begin
to migrate into the already prominent cortical bodies at about
seven weeks gestation in man. cells ok the suprarena1 medulla
as well as of certain other small glandular bodies of similar embryonic origin (e.g., the aortic paraganglia) possess a retnarld
able afkinity for chrome compounds with which they take on a
brown color. This chromafkin reaction has been demonstrated
to be elicitable iirst at about the time extracts of embryonic suprarenal tissue begin to produce pharmacologic responses characteristic of epinephrink749


Many have investigated the activities ok the embryonic -and
fetal suprarenal medulla by this histochemical method as well
as by other chemical and sensitive physiologic techniques Epinephrindilce reactions are obtainable from suprarenal extracts pre—
pared from chiclc embryos as early as the eighth day of incubation although similar extracts of other embryonic tissues give
negative resultsFHI Epinephrin is formed, or at least stored,
in the medulla of the glands in many fetal mammals before the
middle of gestation.32-39 The medullary cells show the chromaliin reaction at the 17th to 18th day in the pig and both physiologic and histochemical tests reveal the presence of an epinephrins
lilce substance at the time migration of. iznedullary cells into the
THE« FETAL ENDOCRINE GLANDS 195


cortical bodies is first observablekssfs The epinephrin content
The male gonads produce substances with androgenic properties in prenatal life. 1t was demonstrated that extracts prepared from the testes of fetal calves are similar to those from the adult and the hormonal yield per unit weight of tissue is greater. 46 It is probable that the male sex glands begin to elaborate secretions about as soon as their sex can be differentiated, which is the sixth day in the incubating chiclc and the seventh weelc in man. The ovary is recognizable as such about a weelc later than the testes.
of fetal glands has been reported to be greater than in the adult;
more was found in female than in rnale fetusesPs A correlation
between appearance of. epinephrin in the suprarena1 of th«e rat
and the origin of fetal movements has been suggestedxm but this
seems to be coincidental.


In sharp contrast with results obtained in most rnamma1s,
human fetal suprarenal extracts give negative or only very
slightly positive tests for epinephrinJHss 4144 However, in- full
term infants as well as prematures which lived for a short time
somewhat more definite reactions were obtained. The near fai1—
ure to obtain epinephrin-lilce responses from human fetal suprarenal extracts may be contrasted with the observation that the
paraganglia yielded definite amounts of epinephrin in one in—
stance:43


kluman suprarenal at birth - 0.0I arg. epinephrin per OR? Hm. Flur-d.
The best indication we have that fetal androgens are active in early prenatal life is that forthcoming from a study of freemartins in cattle.47 48 The freemartin is an intersexed or masculinized female calf which deve1ops under conditions of chorionic fusion in which vascu1ar anastomoses are estab1ished between the placentas of adjacent male and female fetuses. The male is always a normal individual: It is believed that the hormone elaborated by the fetal male gonadscirculates in the conjoined blood streams, acting upon the female twin’s Miillerian or female duct derivatives to inhibit their normal development and upon its Wolllian or masculine duct derivatives to stimulate their abnormal dilferentiatiom When vascular connections are not established between adjacent fetuses of opposite sex no freemartin results, but the calves are normal male and female.


Etunan paraganglion at birth - 0.24 rag- epinephria per 0.1I Hm. sind.


Any relationship between low content of epinephrin and the
A similar freemartin condition has been described in swine.49 It should be noted that the placentas of both cattle and swine are relatively ineflicient from the standpoint of permeabi1ity. A high degree of placental fusion, apparently with vascular union, was observed in one instance of synchorial twinning in the cat.50 The fetuses were of opposite sexes, were sexually normal in every way, and were sulliciently advanced in development to make it appear certain that the female twin would not have become a freemartin. similarly synchorial twins of opposite sexes are encountered in other animals and man,51- 32 but freemartins have not been reported. It will probably be prolitable to- learn how the transmission of fetal male sex hormones across the placental barrier is related to the phenomenon in question. It is difficult to see how the freemartin condition can be so limited unless the diffusibility of embryonic testicular hormones is greater in the deciduate types of placentas which therefore never allow hormones to accumulate in suilicient amounts to stimulate the Wolflian derivatives of the genetically female twin.
presence of a very prominent androgenic cortical zone in man is


undetermined
Im: sEx Blond-muss


An excellent consideration of embryologic development of
It would carry us too far alield to inquire deeply into the extensive experimental studies on production of pseudohermaphrodism in the lower animals« success has been attained in mams mals at several laboratories recentlyks Injections of pregnant rats with large doses of testosterone and related preparations bring about abnormal development of the potentially male ducts of genetically female young. It is necessary to administer the hormone before the 16th day of gestation to obtain the most marked effects.54 This is about one day before the WolHian ducts begin to regress The intersexed individuals produced experimentally resemble the naturally occurring freemartins in certain particulars.  
sex with a review of all but the latest literature has appeared
recentlyxss We are limited here to only a small part of this interesting subject.


The male gonads produce substances with androgenic properties in prenatal life. 1t was demonstrated that extracts prepared
from the testes of fetal calves are similar to those from the adult
and the hormonal yield per unit weight of tissue is greaterKS It
is probable that the male sex glands begin to elaborate secretions
about as soon as their sex can be differentiated, which is the sixth
day in the incubating chiclc and the seventh weelc in man. The
ovary is recognizable as such about a weelc later than the testes.


The best indication we have that fetal androgens are active
Male offspring of rats receiving large doses of estrogens before the Izth day of gestation have been markedly feminizedPs Thus a converse of nature’s freemartin has been induced with excessive female sex hormones. The extent to which the mother’s own hormones may inliuence normal development of sex in the fetus is not understood. It is known that the fetal uterus exhibits a marked hypertrophy and diminishes in size after intimate contact with the mother is abolished by birth. The mammary glands of newborn infants of both sexes show enlargement and may secrete transientlys It is possible that this production of «witch milk" is stimulated by the same maternal hormonal mechanism that leads to the preparation of the mother’s breasts for lactation.
in early prenatal life is that forthcoming from a study of freemartins in cattle.47s 48 The freemartin is an intersexed or mascu—
linized female calf which deve1ops under conditions of chorionic
fusion in which vascu1ar anastomoses are estab1ished between the
196 PHYSIOLOGY oF THE. FETus


placentas of adjacent male and female fetuses. The male is always a normal individual: It is believed that the hormone elab—
orated by the fetal male gonadscirculates in the conjoined blood
streams, acting upon the female twin’s Miillerian or female duct
derivatives to inhibit their normal development and upon its
Wolllian or masculine duct derivatives to stimulate their abnormal
dilferentiatiom When vascular connections are not established
between adjacent fetuses of opposite sex no freemartin results,
but the calves are normal male and female.


A. similar freemartin condition has been described in swine.49
==The Thyroid Gland==
It should be noted that the placentas of both cattle and swine are
relatively ineflicient from the standpoint of permeabi1ity. A high
degree of placental fusion, apparently with vascular union, was
observed in one instance of synchorial twinning in the cat.50 The
fetuses were of opposite sexes, were sexually normal in every way,
and were sulliciently advanced in development to make it appear
certain that the female twin would not have become a freemartin.
similarly synchorial twins of opposite sexes are encountered in
other animals and man,51- 32 but freemartins have not been re—
ported. It will probably be prolitable to- learn how the transmission of fetal male sex hormones across the placental barrier
is related to the phenomenon in question. It is diflicult to see how
the freemartin condition can be so limited unless the diffusibility
of embryonic testicular hormones is greater in the deciduate types
of placentas which therefore never allow hormones to accumulate in suilicient amounts to stimulate the Wolflian derivatives of
the genetically female twin.


It would carry us too far alield to inquire deeply into the ex—
The ability of the fetal {{thyroid}} to secrete at an early period seems to have been established. Iodine has been identilied in the gland at the 2nd or zrd month of gestation in cattle, sheep and swiness and in man at least as early as the 6th month» The amount is said to increase toward the end of prenatal life but to be low as compared with the adult gland, perhaps because storage of colloid is not so marked in the fetus« There is no close correlation between the maternal and fetal blood content of hormone iodine, a fact which suggests that the fetus is secreting its own hormone. The presence of thyreoglobulin in the human fetus at the zrd and 4th months has been established by means of an immunologic precipitin reaction.59
tensive experimental studies on production of pseudohermaphrodism in the lower animals« success has been attained in mams
mals at several laboratories recentlyks Injections of pregnant rats
with large doses of testosterone and related preparations bring
about abnormal development of the potentially male ducts of
genetically female young. It is necessary to administer the hormone before the 16th day of gestation to obtain the most marked
effects.54 This is about one day before the WolHian ducts begin
to regress The intersexed individuals produced experimentally
resemble the naturally occurring freemartins in certain particu
lars.
THE! FETAL ENDOCRINB GLANDS 197


Male ofkspring of rats receiving large doses of estrogens before
Amphibian metamorphosis and growth can be inlluenced by extracts and transplants of avian and mammalian fetal thyroid glands. In several, it may be said that the thyroid« becomes active at about the time its structure begins to resemble that of the adult. This is on the iith day of incubation in the chickW In calves colloid is present as early as the end« and differentiation is comp1eted between the 4th and 6th prenatal monthsz at this time extracts serve to bring about metamorphosis in the axolotl, a salamander which normally retains the larval state throughout life.30 Extracts prepared from the glands of pig fetuses 7 cm. long proved to be inactive, but those from 9 cm. pig fetuses produced reactions comparable with adult thyroids; correlatively, the adult structure was nearly attained at 9 cm.» When bits of the thyroid gland from a 3-months-old human fetus (1o cm. C. R. length) were transplanted into larvae of a toad, accelerated development took place, and trarisplants from 5-months-old human fetuses had more marked efkectsYs Control experiments with bits of fetal muscle gave negative results. It was found that the thyroid gland of the youngenfetus had already deve1oped col1oid Iilled vesicles.
the Izth day of gestation have been markedly feminizedPs Thus
a converse of nature’s freemartin has been induced with excessive
female sex hormones. The extent to which the mother’s own
hormones may inliuence normal development of sex in the fetus
is not understood. It is known that the fetal uterus exhibits a
marked hypertrophy and diminishes in size after intimate contact with the mother is abolished by birth. The mammary glands
of newborn infants of both sexes show enlargement and may
secrete transientlys It is possible that this production of «witch
milk" is stimulated by the same maternal hormonal mechanism
that leads to the preparation of the mother’s breasts for lactation.


THE TEYROID GLAND


The ability of the fetal thyroid to secrete at an early period
Little is known about placenta! transmission of the thyroid secretions. In swine, horses, cattle and sheep, animals with adeciduate placentas, it appears that there is no transmission. In geographical regions where iodine deliciency is prevalent the offspring of these animals are born in a state of athyreosis while the mothers show little or no evidence of the iodine lack.C4- S« It seems sthat the fetal requirements of iodine are greater than those of the mother and that the fetus cannot draw upon the mother’s hormone but must manufacture its own. Iodine feeding during pregnancy corrects this deliciency, and the newborn pigs are then normal. In man, on the other hand, it seems probable that the mother’s hormone is available to the fetus because it can traverse the placental barrier. Human infants born without or with atrophic thyroid glands exhibit none of the symptoms of myxedema, but a latent athyreosis soon manifests itself.S3-71
seems to have been established. Iodine has been identilied in the
gland at the 2nd or zrd month of gestation in cattle, sheep and
swiness and in man at least as early as the 6th month» The
amount is said to increase toward the end of prenatal life but to
be low as compared with the adult gland, perhaps because storage
of colloid is not so marked in the fetus« There is no close correlation between the maternal and fetal blood content of hormone
iodine, a fact which suggests that the fetus is secreting its own
hormoneIs The presence of thyreoglobulin in the human fetus at
the zrd and 4th months has been established by means of an
immunologic precipitin reaction.59


Amphibian metamorphosis and growth can be inlluenced by
==The Parathyroid Glands==
extracts and transplants of avian and mammalian fetal thyroid
glands. In several, it may be said that the thyroid« becomes active
at about the time its structure begins to resemble that of the
adult. This is on the iith day of incubation in the chickW In
calves colloid is present as early as the end« and differentiation is
comp1eted between the 4th and 6th prenatal monthsz at this time
extracts serve to bring about metamorphosis in the axolotl, a
salamander which normally retains the larval state throughout
life.30 Extracts prepared from the glands of pig fetuses 7 cm.
long proved to be inactive, but those from 9 cm. pig fetuses produced reactions comparable with adult thyroids; correlatively,
the adult structure was nearly attained at 9 cm.» When bits of
198 PHYsmLooY oF THE: FETUS


the thyroid gland from a 3-months-old human fetus (1o cm. C. R.
Practically nothing is known of function of fetal parathyroid glands. Injections of parathyroid hormone into dog fetuses bring on an elevation of the calcium level of the fetal, but not the maternal blood. This suggests that the parathyroid secretion does not pass the placenta in the species studied.72 Attempts have been made to determine the effects of fetal glands of dogs after thyroparathyroidectomy of the mothers. It was found that tetany developed just as soon as it did in nonpregnant animalsJss ««
length) were transplanted into larvae of a toad, accelerated development took place, and trarisplants from 5-months-old human
fetuses had more marked efkectsYs Control experiments with bits
of fetal muscle gave negative results. It was found that the thyroid
gland of the youngenfetus had already deve1oped col1oid Iilled
vesicles.


Little is known about placenta! transmission of the thyroid
==The Thymus==
secretions. In swine, horses, cattle and sheep, animals with
adeciduate placentas, it appears that there is no transmission. In
geographical regions where iodine deliciency is prevalent the offspring of these animals are born in a state of athyreosis while the
mothers show little or no evidence of the iodine lack.C4- S« It
seems sthat the fetal requirements of iodine are greater than those
of the mother and that the fetus cannot draw upon the mother’s
hormone but must manufacture its own. Iodine feeding during
pregnancy corrects this deliciency, and the newborn pigs are then
normal. In man, on the other hand, it seems probable that the
mother’s hormone is available to the fetus because it can traverse
the placental barrier. Human infants born without or with
atrophic thyroid glands exhibit none of the symptoms of myxe—
dema, but a latent athyreosis soon manifests itself.S3-71


THE PARATIIYROID GLANDS
Although the {{thymus}} is usually considered with the glands of internal secretion, it is doubtful if it logically belongs there. By 3 months in man, the thymus has the appearance of a lymphoid organ with cortex and medulla already in evidence. There is no anatomical basis for the belief that the sgland elaborates a hormone and few attempts have been made to study the fetal thymus from the standpoint of its endocrine function.30


Practically nothing is known of function of fetal parathyroid
glands. Injections of parathyroid hormone into dog fetuses bring
on an elevation of the calcium level of the fetal, but not the maternal blood. This suggests that the parathyroid secretion does
not pass the placenta in the species studied.72 Attempts have been
made to determine the effects of fetal glands of dogs after thyroparathyroidectomy of the mothers. It was found that tetany de—
veloped just as soon as it did in nonpregnant animalsJss ««


THE TIIYMUS
Extracts of thymus seem to exert no elfects when fed to tadPoles, although opinion has been divided on this questions«- «« An extract of calf thymus, to which the name "thymocrescin" was given, has been reported to produce marked acceleration of growth in young rats when injected in daily doses as small as 1 mg.79


Although the thymus is usually considered with the glands of
internal secretion, it is doubtful if it logically belongs there. By
3 months in man, the thymus has the appearance of a lymphoid
organ with cortex and medulla already in evidence. There is no
anatomical basis for the belie,f that the sgland elaborates a hormone
THE« FBTAL BNDOCRINE GLANDS 199


and few attempts have been made to study the fetal thymus from
Another extract prepared in an entirely different way resulted in even more marked effects in the hands of Rowntree and his colleaguesko This material was injected intraperitoneally in i cc. doses into rats over long periods including gestation and lactation; the young of succeeding generations were similarly treated. Elfects on the olkspring of the first animals were not signijicant but the second and subsequent generations showed remarkable changes. They were larger at birth, more of them survived and their postnatal development was delinitely speeded. The young rats became sexually mature precociously. Maximum effects were found in the eighth and tenth generations. It was necessary to keep giving the treatments and not miss a generation or the effects were promptly dissipated. From the more recent reports it seems that it was necessary to inject the extracts into females only.
the standpoint ·of its endocrine function.30s «« ««


Extracts of thymus seem to exert no elfects when fed to tadPoles, although opinion has been divided on this questions«- ««
An extract of calf thymus, to which the name «thymocrescin" was
given, has been reported to produce marked acceleration of
growth in young rats when injected in daily doses as small as
1 .mg.79


Another extract prepared in an entirely different way resulted
Other investigators have attempted to reproduce these very interesting results. but so far no adequate confirmation has been reported» The biologic effects of certain iodine-reducing substances (glutathione, ascorbic acid, cysteine) have been found to simulate those of the thymus extracts in certain particulars.
in even more marked effects in the hands of Rowntree and his
colleaguesko This material was injected intraperitoneally in i cc.
doses into rats over long periods including gestation and lactation; the young of succeeding generations were similarly treated.
Elfects on the olkspring of the first animals were not signijicant
but the second and subsequent generations showed remarkable
changes. They were larger at birth, more of them survived and
their postnatal development was delinitely speeded. The young
rats became sexually mature precociously. Maximum effects
were found in the eighth and tenth generations. It was necessary to keep giving the treatments and not miss a generation or
the effects were promptly dissipated. From the more recent re—
ports it seems that it was necessary to inject the extracts into
females onlyFI


0ther investigators have attempted to reproduce these very
==The Hypophysis==
interesting results. but so far no adequate confirmation has been
reported» The biologic effects of certain iodine-reducing sub—
stances (glutathione, ascorbic acid, cysteine) have been found to
simulate those of the thymus extracts in certain particularsPI


Im; nrpopkkrsxs
A few studies have been made on placental transmission of hypophyseal extracts but we know Iittle about hormone elaboration by the fetus itself. When pituitrin was injected into rabbit fetuses no muscular contractions were observed in the mother.83 This suggests, but does not prove, that the substance failed to pass the placenta. Anterior lobe extract did not produce any evidence of its usual gonadotropic activity in the mother when it was introduced into the fetuses« Furthermore, this hormone failed to appear in the fetal fluids after it had been injected into the mother; at least, the administration of these fluids to other adult rabbits fai1ed to bring about ovulatory changesss These experiments seem to show that there is very little if any transmission of the large molecules of the anterior lobe gonadotropic factor even in the hemosendothelial type of placenta.


A few studies have been made on placental transmission of
hypophyseal extracts but we know Iittle about hormone elaboration by the fetus itself. When pituitrin was injected into rabbit
fetuses no muscular contractions were observed in the mother.83
This suggests, but does not prove, that the substance failed to
pass the placenta. Anterior lobe extract did not produce any
evidence of its usual gonadotropic activity in the mother when
it was introduced into the fetuses« Furthermore, this hormone
failed to appear in the fetal fluids after it had been injected into
200 PHYSIOLOGY OF THE FETUS


the «mother; at least, the administration of these fluids to other
The fetal hypophysis seems to be capable of elaborating several active principlesPss VHV A pressor substance has been found at 6 months in man. similar studies have been made in fetuses of cattle, sheep and swine in which the response was found relatively earlier. The guinea pig uterine strip method served to demonstrate the oxytocic princip1e about as early as the pituitary glarid can be recognized macroscopicallzn It was found in appreciable amounts in pigs and sheep at term.
adult rabbits fai1ed to bring about ovulatory changesss These
experiments seem to show that there is very Iittle if any transmission of the large molecules of the anterior lobe gonadotropic
factor even in the hemosendothelial type of p1acenta.


The fetal hypophysis seems to be capable of elaborating several active principlesPss VHV A pressor substance has been found
at 6 months in man. similar studies have been made in fetuses
of cattle, sheep and swine in which the response was found relatively earlier. The guinea pig uterine strip method served to
demonstrate the oxytocic princip1e about as early as the pituitary
glarid can be recognized macroscopicallzn It was found in appreciable amounts in pigs and sheep at term.


The melanophoreexpanding hormone has been identified in
The melanophore expanding hormone has been identified in the fetal hypophysis It was found in the glands from calf fetuses of 3 months gestation but was not there at 2 months. It was present in pigs of only 2o mm. c. R. length.30- 88
the fetal hypophysis It was found in the glands from calf fetuses
of 3 months gestation but was not there at 2 months. It was present in pigs of only Zo mm. c. R. length.30- 88


Gonadotropic and growth promoting factors of the anterior
Gonadotropic and growth promoting factors of the anterior lobe seem to make their appearance rather late in fetal life, and the former is later than the latter.90 In fetal pigs the gonadotropic response was obtained from glands at the 2o to 21 ern. stage, a short time before the end of gestation but was not found earlier. The general body growth response could be obtained at the 9 to 13 cm. stage which was just about the same time the thyroid hormone made its appearancesEs 90
lobe seem to make their appearance rather late in fetal life, and
the former is later than the latter.90 In fetal pigs the gonadotropic
response was obtained from glands at the 2o to 21 ern. stage, a
short time before the end of gestation but was not found earlier.
The general body growth response could be obtained at the 9 to
13 cm. stage which was just about the same time the thyroid hormone made its appearancesEs 90


SECRETIN
==Secretin==


Extracts of the proximal portion of the fetal small intestine
Extracts of the proximal portion of the fetal small intestine have been found to cause secretion of pancreatic juice when injected into adult animals with pancreatic Hstu1as.9I·9f The earliest period at which secretin has been obtained from the human fetus is 414 months. The exact source of the hormone is unknown and attempts to ascribe it to the chromalkn cells of the duodenum93 seem to be entirely unjustified
have been found to cause secretion of pancreatic juice when in—
jected into adult animals with pancreatic Hstu1as.9I·9f The earliest
period at which secretin has been obtained from the human fetus
is 414 months. The exact source of the hormone is unknown
and attempts to ascribe it to the chromalkn cells of the duodenum93 seem to be entirely unjustiöed


THE ENDOCRINE PANCREAS
==The Endocrine Pancreas==


The endocrine function of the pancreas is vested in the cells
The endocrine function of the {{pancreas}} is vested in the cells of the islands of Langerhans These make their appearance in the third month of human gestation but it is not known how early they become capable of secreting. The acinar portion of the gland does not begin to produce its proteolytic ferment before about the 5th month,93 and Banting and Best took advantage of the fact that island tissue is functional earlier when they chose the pancreas of the fetal calf as a source of antidiabetic principle in their early search for insulin.97 Many have discussed the possibility that fetal insulin plays an important röle in carbohydrate metabolism of the fetus and have pointed to a correlation between the appearance of glycogen in the liver and the development of island tissue in the pancreassss 99 but the relationship is still somewhat unsatisfactorily established because the influence of maternal secretion acting through the placenta is diflicult to evaluate. It is said not to pass the placenta from fetal to maternal sides.83 Administration of insulin to pregnant cats failed to reduce the blood sugar level of the fetuses near term. This suggests that the placenta is impervious at the time, but at earlier stages similar results were not obtainedEoo Further discussion of this question will be found in Chapter XVI.
of the islands of Langerhans These make their appearance in the
third month of human gestation but— it-.is not known how early
THE FETAL ENDOCRINE GLANDS 201


they become capable of secreting. The acinar portion of the
gland does not begin to produce its proteolytic ferment before
about the 5th month,93 and Banting and Best took advantage of
the fact that island tissue is functional earlier when they chose the
pancreas of the fetal calf as a source of antidiabetic principle in
their early search for insulin.97 Many have discussed the possibility that fetal insulin plays an important röle in carbohydrate
metabolism of the fetus and have pointed to a correlation between
the appearance of glycogen in the liver and the development of
island tissue in the pancreassss 99 but the relationship is still somewhat unsatisfactorily established because the influence of maternal
secretion acting through the placenta is diflicult to evaluate. It is
said not to pass the placenta from fetal to maternal sides.83 Administration of insulin to pregnant cats failed to reduce the blood
sugar level of the fetuses near term. This suggests that the pla—
centa is impervious at the time, but at earlier stages similar results
were not obtainedEoo Further discussion of this question will be
found in Chapter XVI »


In birds, where all metabolic processes must be managed by
In birds, where all metabolic processes must be managed by the fetus itself, an insulin-like substance has been found in the unincubated eggJOI However, it is not present in the tissues of the early chick embryo until after the pancreatic islets are formed.
the fetus itself, an insulin-like substance has been found in the
unincubated eggJOI However, it is not present in the tissues of
the early chick embryo until after the pancreatic islets are formed.


The ofkspring of diabetic animals are not diabetic and as a ruIe
seem to possess healthy glandsW This is not always true in man
where hypertrophy and hyperplasia of islands and postpartum
hypoglycemic deaths are encountered in infants born of diabetic
womenJos Although hyperplastic pancreatic islands are not.
found in all instances, careful searching might show the condition
to be more prevalent.


The possibility that during prenatal life fetal insulin can
The offspring of diabetic animals are not diabetic and as a ruIe seem to possess healthy glandsW This is not always true in man where hypertrophy and hyperplasia of islands and postpartum hypoglycemic deaths are encountered in infants born of diabetic women. Although hyperplastic pancreatic islands are not found in all instances, careful searching might show the condition to be more prevalent.
protect the diabetic mother has been discussed by several investigators. It was discovered by Carlson and his colleaguesIM W
that the urine of completely pancreatectomized dogs remained
free from sugar when the .operation was performed in late stages
of pregnancy. This suggested that fetal island tissue had, supported both the mother and fetuses, for after parturition the
mother exhibited glycosuria. These experiments have been adequately confirmedW and similar conditions app«arently occur
in the human.I07 Completely depancreatized dogs maintained in
202 PHYSIOLOGY OF THE FETUs


good hea1th by diet and insu1in therapy can conceive and give
birth to normal pups. They show an increased carbohydrate tolerance kor only about two weeks prior to labor. However, an even
greater tolerance appears after birth during lactationz it would
seem that the results previously ascribed entirely to ketal insulin
are more probab1y due largely to increased utilization ok carbohydrates by the fetuses and, after birth, by the nursing puppies.
We cannot be sure that the ketal insulin plays any part in protecting the diabetic mother. It is quite reasonable to suppose that
it is more important kor the utilization ok sugar received by the


ketus krom the mother.
The possibility that during prenatal life fetal insulin can protect the diabetic mother has been discussed by several investigators. It was discovered by Carlson and his colleaguesIM W that the urine of completely pancreatectomized dogs remained free from sugar when the .operation was performed in late stages of pregnancy. This suggested that fetal island tissue had, supported both the mother and fetuses, for after parturition the mother exhibited glycosuria. These experiments have been adequately confirmedW and similar conditions app«arently occur in the human.I07 Completely depancreatized dogs maintained in good hea1th by diet and insu1in therapy can conceive and give birth to normal pups. They show an increased carbohydrate tolerance kor only about two weeks prior to labor. However, an even greater tolerance appears after birth during lactationz it would seem that the results previously ascribed entirely to ketal insulin are more probab1y due largely to increased utilization of carbohydrates by the fetuses and, after birth, by the nursing puppies. We cannot be sure that the ketal insulin plays any part in protecting the diabetic mother. It is quite reasonable to suppose that it is more important kor the utilization of sugar received by the fetus krom the mother.


Glycogen appears in the liver ok the deve1oping chick at 7 days
ok incubation. This is about three days before delinitive islands
ok Langerhans make their appearance. Between the tenth and
thirteenth days the glycogen content ok liver cells diminishes and


the metabolic rate and respiratory quotient increase, although
Glycogen appears in the liver of the deve1oping chick at 7 days of incubation. This is about three days before delinitive islands of Langerhans make their appearance. Between the tenth and thirteenth days the glycogen content of liver cells diminishes and the metabolic rate and respiratory quotient increase, although there is no rise in the blood sugar concentration. Thus it appears that an increased utilization of carbohydrate by the embryo is correlated with the advent of kunction in suprarenal medulla pancreatic islands and thyroid glands.
there is no rise in the blood sugar concentration. Thus it appears that an increased utilization ok carbohydrate by the embryo
is correlated with the advent ok kunction in suprarenal medulla.
pancreatic islands and thyroid glandsÄss «


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PHYSIOLOGY OF THE« FETUs
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THE FETAL ENDOCRINE GLANDS 205


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Los. Daltorh A. J. 1937. Anat. Ren, 68: 393.
 
=Chapter XV Fetal Nutrition and Metabolism=
 
PARAPLACENTAL NUTRITION
 
THE maternal organism not only breathes and excretes for the
ketus but it also digests kood and kurnishes nutriments needed kor
the growth ok the new individual. In early stages ok development
the intimacy between embryo and mother is slight, and until a
close approximation to the endometrium is ekkected nutrition can
not be accomplished by direct processes which characterize the
older and more advanced types ok placental circulatory Systems.
An intermediate substance ok transient nutritional value to the
early embryo is provided by secretion ok the uterine glands, by
transudation and especially by erosion ok the endometrium and
production ok tissue detritus in response to implantation ok the
newly arrived blastocyst. To this paraplacental nutriment, the
name histotrophe may be applied.I-4
 
In mammals with relatively simple epithelio-chorial and syn—
desmo-chorial p1acentas, such as the horse and sheep, quite a
different histotrophic material bathes the chorionic surkace
throughout gestation. This, the «uterine mi11c," is composed predominantly ok secretions and transudates from the intact uterine
epithelium. Its high kat- content gives it the appearance ok dilute
millc.
 
It is doubtkul ik histotrophic nutrition can be ok real signikicance in man and other primates for more than a kew days during
implantation) A yollc-sac placenta develops early in the rat, and
with it a more eiiicient mechanism kor nutrition. The passage
ok substances through the yollcssac epithelium ok the rat has been
demonstrated very clearly.0- 7 0ne can not consider that the processes involved are entirely histotrophic in those animals in which
uterine millc is laclcing.
 
With the kormation ok endothelio-chorial, hemo—chorial and
hemo-endothelial (deciduate) placentas in carnivores, primates
and rodents, histotrophe plays only a. Jninor and transient part
 
206
FETAL NUTRITION AND MBTABOLISM 207
 
and nutrition becomes possible largely by processes similar to
those occurring in the tissues ok the body itseltl The substances
which pass more directly from one blood stream to the other have
been designated hemotrophe. Thus Bonet’s term «embryotrophe" has given way to a more usekul classiiicatiom
 
Bmbryofrophe
Eistotrophe klemotrophe
l . I . I . I « I
Ikansient Uterme milk. Diikusible Nitrogenous substances
endometrial Nutrition substances substances (e.y., lipids)
detritus, etc. throughout (gases, ok high truly
Nutrition kor gestation in dextrose and molecular absorbed b)implanting ungulatea inorganic weight which trophoblast
blastoeyssz eompounds) are diikuss and yolkssac
requiring no ible but epitheliunh
resynthesia require
 
resynthesia
 
PLACENTAL PERMEABEITY
 
N utrition ok the fetus is closely dependent upon the manner
and ekkiciency with which materials are transmitted across the
placental barrier. It must be born in mind that the physiologic
characteristics ok the placenta are not constant throughout development, nor are they the same in all species ok mammals. Furthermore, the chorio-allantoic attachment is not the only means
ok contact between the ketus and motherz in some species, e.g.,
the rat, a yollosac placenta ok very dilkerent structure is known
to serve concomitantly throughout gestationsk The term «the
placenta« rekers as a rule to the combined ectoplacenta and yollc—
sac placenta when used in rekerence to kunctioxx Density and
number ok tissue layers separating maternal and fetal blood
streams vary, as was pointed out in Chapter I. For these reasons
one must exercise caution in attempting to draw conclusions regarding the permeability ok one type of placenta based upon experiments with a different type.
 
The subject ok placental permeability is much too extensive ito
be discussed in detail, but a few signiiicant observations can be
considered such observations inquire into the characteristics ok
materials which make their way across the living membranes, and
into the nature ok the processes involved in their passage.
 
Particulate matten even when microscopic in size, kails to pass
208 PHYSIOLOGY oF THE: FETUs
 
the most advanced hemo-endothelial placentas. Formerly there
was much discussion of this, but the fact is now well establishedF
certain ultræmicroscopic particles in colloidal solutions do pass,
and the dye trypan blue seems to be one lying on the borderline
between the transmissible and non—transmissible substances in the
hemo-endothelial placentas. This dye does not traverse the
endothelio-chorial type found in the cat.?
 
That a relationship exists between the molecular weight of
substances and their ability to pass through placentas can scarcely
be doubted. 0xygen, carbon dioxide and many chemical com—
pounds of low molecular weight traverse membranes of all placentas. Tabulation of data available ·up to 1931 will be found
in N eedham’s10 «Chemical Embryology" (Table 227) . From this
it appears that the thinner the barrier, the more permeable it is
to materials of large molecular size. 0n the other hand, it has
been demonstrated that the thin chorionic trophoblast plates of
the early rat placenta are actually less permeable than the much
thiclcer yoll(-sac epithelium to the dye, toluidin blue.
 
A very close parallelism exists between the ability of colloidal
dye solutions to diffuse in iilms of 2o to 30 per cent gelatin and the
efliciency of their transmission from the mother to the fetuses of
rats and mice.U These and other observationsW have frequently
been cited as evidence that the placenta acts largely in the capacity of an ultra-iilter. There is ample evidence, however, that the
fat solubility of materials in the blood streams, their pH and
ionic charges at the membrane play important röles in governing
placental permeability. "Furthermore, one can not tell whether
the experiments with colloidal dyes demonstrate passage through
the ectoplacenta, the yolldsac placenta or a combination of both.
 
Although a number of investigations have led» to the conclusion that species differences exist at term in respect to permes
ability of dye solutions,9 other chemical solutions« and antibodiesss few experiments have been concerned with the changes
talcing place throughout the course of development of any one
species. Recently, however, it was demonstrated that the permeability of the rabbit’s placenta to agglutinins and hemolysins in—
creases during the course of gestation.14 The ratio of the titre of
the fetuses to that of the mother plotted against the gestation-age
forms a sigmoid curve (Fig. 68)'. Permeability is clearly related
FETAL NUTRITION AND METABOLISM 209
 
to the changing histologic structure of the placenta during gestationss «
 
The two principal theories concerning the nature of the placental barrier merit further study. Many recent observers have
favored the view that it is essentially an inert semipermeable
membrane, but advocates of the concept of a vital function are
not lacking. A preformed rcgulatory mechanism, inferring a
secretory process, has been suggcstedJs
 
Those who favor the ultra-iilter theory believe that substances
pass from mother to fetus, or in the reverse direction, by diffusion
and filtration, that physical processes alone govern the transmis
tIIIII--I
tIIIIgIII
ssIIZIIIs
tgtZIIIIs
I-IssUII
 
II Z( 2
 
 
 
 
O
G
 
 
Z
 
 
 
Rotte-Pers! Fuss-Hofstaat Tit-se
 
 
 
Period of Gestaden-days
 
Fig. 68.—Permeability of the rabbit placenta to antibodies at different times during
prenatal life. (Rodo1fo: J. Exp. Zool» Vol. 68, 1934.)
 
sion and that molecular size plays an important part in determining which shall and which shall not cross the barrier.10-U-17- 18
This seems to be well established for gases, dextrose and a number
of chemical compounds of relatively low molecular weight, including some of the products of fetal metabolism. The subject
has been reviewed by schlossmanW who concludes that, aside from
endocrine activities, there is not the slightest reason to believe that
the placenta and its chorionic epithelium has a truly secretory
function. He believes that even in the instances of seemingly
vitalistic activities, physical principles in the last analysis can ex—
plain transmission. Nevertheless it is reasonable to adhere to the
concept of absorption in the trophoblast.. The recent studies on
 
14
210 PHYSIOLOGY OF THE FETUs
 
metabolism of lipids provide strong circumstantial evidence for
the vitalistic theoryäs
 
With the recognition of functional properties of the yollc-sac
in some animals, the question of secretory function talces on re—
newed interest. In structure as well as in physiologic reaction to
perfusion of the maternal blood vessels with various chemical and
dye solutions, the yollcssac placenta of the rat appears to be an
organ for absorptionks 7 When more attention has been paid to
the functions of this organ, as well as to factors of age and species
differences, our lcnowledge of the passage of the nutriment from
mother to fetus will undoubtedly be advanced far beyond its
 
present state.
UETAZOLISM oF cumoknmmrns
 
The body of the fetus is bui-It from chemical substances which
are available in the mother’s blood. Energy needed by the fetus
is derived from the same source. Indeed, all the prenatal require·
ments are met by processes of intermediary metabolism. The
most readily available substance is carbohydrate in the form of
dextrose which serves as the important energy source for the fetus.
 
Dextrose can pass from mother to fetus across the placental
barrier in all mammalskHs Human fetal bloodssugar concentration is always a little lower than that of the mother near term.
For example, Morriss found averages of 1 15 mg. per cent in the
fetus and 132 Ins. per cent in the motherkl indicating that there
is a gradient of flow towards the fetus. A similar condition pre—
vails in most mammalssks 23 but not in the pig and cow in which
the concentration is lower in maternal than in fetal blood.23- 24
The reason for these species differences is not clear, but they may
be related to placental structural variations and to histotrophe as
an intermediate nutriment. Much of our information has been
obtained at the end of gestation or is based on averaged data of
different prenatal ages. A more complete study is available in the
incubating chiclc.25 The blood-sugar concentration maintains a
reasonably constant level up. to the 16th day; thereafter it rises
and surpasses the adult level at about hatching time, which is the
21st day. Fetal blood—sugar concentration varies with gestation
age in mammals too. For example, it decreases toward term in
the cow but increases marlcedly in the spguinea pig and rabbitkss 27
FETAL NUTRITION AND METABOLISM 211
 
It is apparent that a simple filtration across the placental barrier is
not the only mechanism governing the blood-sugar level in the
fetus.
 
The placenta and liver are important depots for carbohydrate
storage in prenatal life. As early as 1858, Claude Bernard demonstrated that the placenta contains glycogen and serves as a «transitory liver« for the embryoks It has been clearly shown that the
glycogen content of the placenta is high in the early part of fetal
life whenlittle or none is in the liver. Only the maternal portion of the placenta contains it.29 A time is reached, however,
when glycogen storage becomes active in the fetal liver; when this
occurs there is a corresponding reduction of storage in the placenta. This crossing over takes place after the elapse of 75 per
cent of the total gestation time in the rat, 82 per cent in the chiclc
and 91 per cent in the rabbitPHI The glycogen content of the
fetal liver rises rapidly toward the end of gestation and is especially high a few days before birth.22 Nevertheless, the amount of
liver glycogen is inconstant at any given period in the fetus and.
varies with the food intalce of the mother. Following 24 hours
of fasting in the rat at full term, the pealc of maternal liver glycogen was reached about four hours sooner than that of the fetuses«
When the average glycogen content in the mother’s liver was o.29
per cent of the total liver weight (fasting1eve1) , that of the fetuses
was 4.95 per cent. At the pealc of storage after feeding, average
values of 3.1 per cent and 1o.6 per cent were found in the mothers
and fetuses respectively. These differences are truly remarlcable.
 
Glycogenic function begins after secretion of bile has startedFs
It has been thought to begin at almost precisely the time the is—
lands of Langerhans differentiate and begin to supply insulin to
the fetal bloodZss ZHC However, it has been demonstrated re—
cently that the livers of incubating chiclcs contain glycogen at
Ieast as early as the 7th day of incubation, although the pancreatic
islands do not appear until the Iith day.3·3 In livers of pig and
sheep fetuses, likewise, glycogen has been observed before the
pancreatic islands are formed. Glycogen is distributed evenly
throughout the chiclc liver after island tissue makes its appearance, but is conlined to the cells around large veins in earlier
embryos. Nearly all livers show glycogen on the seventh, eighth
and ninth days and again after thirteen days, but in the interven212 PHYSIOLOGY oF THE. FETUs
 
ing period fewer contain it. There is no detectable change in the
blood-sugar concentration at this time of rapid glycolysis, even
though the metabolic rate increases and the respiratory quotient
approaches unity. These facts suggest very strongly a relative increase in utilization of carbohydrates as an energy source between
the Ioth and izth days of incubation, and they indicate that the
fetal liver supplies some of this material at this period during
which endocrine functions of thyroid, suprarenal and pancreas
are just becoming established. «
 
The passage of carbohydrate from mother to fetus is a s1ow
process under normal conditions, but it can be accelerated greatly
by injecting insulin into the fetus.37 When this was done it was
found that the glycogen or total carbohydrate content of livers
and muscles of dog fetuses was not infiuenced significantly However, the lactic acid concentration of the fetal blood was raised
a few hours after insulin injection and the difference between its
level in the umbilical artery and vein was increased many times
above the normal. About three-fourths of the dextrose which
passed from the dog to its fetuses to compensate for the experimental fetal insulin hypoglycemia returned to the mother as lactic
acid.22 "
 
The fetal dog is reported to be highly resistant to insulin and
the fetal sheep and goat scarcely respond at all to doses as great
as 415 units per lcilogram. An insulin antagonistic substance
seems to be present in their blood.22- 23 Although insulin fails to
deplete the fetal liver glycogen in dogs, sheep and goats when
given to the fetuses, it·has been observed to do so in rats when
injected into the mother-PS Adrenalectomy of pregnant rats simii
lar1y leads to depletion of the fetal liver glycogenks Apparently
the fetus practices a rigid glycogen economy at theexpense of its
mother’s dextrose, drawing upon its own liver store only in einer—
 
gencies.
METABOLISM 017 LIPIDs
 
Well nourished fetuses are supplied with good stores of fat.
Do they acquire this by transfer through the placenta or must it
be synthesized from simpler materials? Perhaps the fetus is able
to synthesize some from carbohydrates or amino acids, but these
are not the only sources. Certaimlipids are passed from the
FETAL NUTRITION AND METABOLISM 213
 
mother’s blood to that of the fetus by poorly understood mechanisms and thus become available for construction of fat. To what
extent lipids are oxidized by the mammalian fetus for energy is
not known. They form the principal source of energy in birds
during the greater part of the period of incubationKo
 
It has been quite deiinitely determined that the fat which is
fed to a pregnant animah and which is absorbed and stored in its
tissues, does not pass through the placenta unchanged When
stained by sudan III or some other similar dye before feeding,
the body fat becomes intensely colored, but there is not the least
color in the fetuses.39-4I Regardless of the degree of saturation
of the fatty acids available from material fed to the mother, the
fetal fat has an almost unalterable degree of saturation.42 It is
quite different from that of the mother in respect to melting point
and chemical composition, in that it contains much more palmitic
and less oleic and stearic acids.43
 
0ther lines of evidence suggest that there is no direct passage
of lipids across the placenta! membranes. A marked dilkerence
 
«in fatty acid content of maternal and fetal blood has been found.
 
The lipid content of red blood corpuscles is about the same in
infant and adult. However, the blood plasma contained on the
average 948 mg. per cent in the former and 737 mg. per cent in
the latter in one series of estimations.44 Average values in another
series of human newborn infants appear in Table 23345
 
Tut-D 23
Lusrv couposrrron or Gut-arm) Fuss«
 
kapu- Nswkom Isgsggskezkszks
mg.Xl00 ce. mg.Xl00 Oe. »Ja« value«
Tom! lipids ........... .. 589 -i- 87 198 -s- 80 84
Neutral fat . . . . . . . . . . . . . 154 - 42 90 - 50 58
Tom! kam— acids ...... .. 353 -i- 56 140 - 57 40
Totul eholesteroL . . . : . . . 162 -I- 32 84 -l- 15 2l»
Bster eholesterol . . . . . . . . 115 -I- 27 A) -s- 12 l7
Iüsee eholesterol . . . . . . . . . 47 -I- 7 14 -s- 7 80
Phospholipid . . . . . . . . . . . . 196 -l- 23 6l- -I- 32 31
 
0n the other band, the blood passing to the fetus from the
placenta is richer in certain lipids than that returning from the
fetusKC The difference must represent lipids used or stored by
214 PITYSIOLOCLIY OF THE FETUS
 
the growing fetus. Averages of 15 analyses are given in Table
24310
Tut-n 24
Lan) contes-im« or« Ema-m Unten-Iehr- conv Bnoov
 
Artery Vein
 
Ins! 100 Oe. mgjlllll ee.
Phospholipid . . . . . . . . . . . . . . . . . . . . . . . . 16«0 204
Free cholesterol . . . . . . . . . . . . . . . . . . . . . . 55 64
Ester cholesterol . . . . . . . . . . . . . . . . . . . . . 8 18
 
Neutral kat . . . . . . . . . . . . . . . . · . . . . . . . . 116 121
 
Phospholipids are always talcen up in large amounts, and
smaller amounts of free cholesterol may be absorbed by the human placenta. cholesterol esters pass to the fetus when they are
present in sulficient quantities in the mother’s blood. Neutral
fats have been thought to pass in both directions. Lipids continue to be added to the static placental blood by the placenta
after birth of the child. Without malcing a positive statement
concerning the mechanism involved, it may be said that a significant passage of lipids across the placental barrier takes place in
the human near term. It has been estimated that a well nourished
fetus takes up about 50 grams of lipids a day at full term, 40 grams
of which are in the form of phospholipidsås
 
The iipid eempesikieh ek khe pieeehkä and kekus ek the kahhik
at various stages in gestation has been reported« The phospho—
lipid and free cholesterol concentration increase rapidly in the
fetus up to the middle of gestation and then more slowly until
about the final weelc at which time the rate increases again. Up
to the middle of gestation, the placental concentration of« phos—
pholipid decreases while that of ester cholesterol increases. Beyond the midpoint in gestation, the reverse was found. slight increases in neutral fat and free cholesterol were encountered in
the placenta throughout gestation. The results suggest that there
is a greater demand for phospholipid by the fetus than can be met
by the placenta in the middle of gestation. and a late secondary
demand which is compensated near term by increased placental
ability to supply it.
 
Large amounts of fatty acids are accumulated in the liver by
the guinea pig fetus.48 Early irxgestation the liver contains about
FETAL NUTRITION AND METABOLISM 215
 
the same proportion as that of the adult, which is approximately
2 to 4 gramsx its liver fatty acid concentration is already increasing,
and at a few days before birth (8o grams weight) the value reaches
15 grams per cent, while the mother’s liver shows no change. It
drops again to the adult level within 3 or 4 days after birth.
 
The lipids of the fetal liver are much more unsaturated than
those in other fetal tissues and less so than those of the mother’s
liverfs 0ne wonders whether the fetal liver is endowed with
greater ability to desaturate fatty acids than is the mother’s liver
or if it simply receives already desaturated acids from the plaöenta.
The latter seems the more likely, and for the following reasons.
 
When the pregnant animals were fasted and then given
phloridzin it was found that the fetal liver storage of fatty acids
was increased in the early period of gestation (fetuses weighing
30 grams and less) , but no signiticant change occurred in the maternal liver with the dosage used. Furthermore, the fatty acid was
less unsaturated than normal, as would be expected under influence of phloridzin with Inobilization of the connective tissue
fat to the liver. Evidently the fatty acid in the fetal liver, norma1ly encountered, is not transported from the other fetal tissues
but comes from the placenta.
 
Evidence has been presented recently that esterification of
cholesterol by fatty acids takes place in the liver cells of the chick
embryofk Histochemical tests indicated the presence of free
cholesterol, ester cholesteroland cholesterol-fatty acid mixtures in
the liver on the e1eventh day; but in chorio-allantoic grafts of the
liver, in which the host was several days older than the graft, these
substances appeared during the latter part of the seventh day. It
is evident, therefore, that the fetal liver is prepared for its röle
in lipid metabolism some time in advance of the day it actually
begins to work.
 
METABOLISM OF PROTEIN«
 
A great deal of information has been obtained in recent years
regarding the metabolism of proteins in bird fetusesEo but we
still know little about this process in mammals. There are three
principal methods for approaching the question. The chemical
composition of maternal and fetal blood can be compared, the
composition of the embryo itself at different stages of development can be determined, and Hnally the initrogenous waste prod216 Ptivsxotocv oF THE FErUs
 
ucts of combustion in the fetus can be analyzed. We shall ex—
amine evidence obtained in these ways.
 
Food proteins are digested and brolcen down into amino acids
which are absorbed into the mother’s blood. These are used, not
only for tissue metabolism of the mother’s own body, but they
serve as a readily available material out of which the fetus builds
its tissues. Some of the nitrogenous food material together with
nitrogenous waste products can be determined analytically as the
non-protein nitrogen of the fetal blood. It has been found that
non-protein nitrogen concentration of maternal and fetal blood is
practically identicaIZU This suggests that the compounds in question pass through the placenta by simple diffusion.
 
Amino acids of use to the fetus are relatively simple nitrogi
enous compounds which are soluble in the blood p1asma, and it
is known that they are highly ditkusible The human fetal plasma
at term contains about 2 mg. of amino-acid nitrogen per Ioo cc.
more than does that of its mother. In one 8 month premature infant the dilkerence was greater. This makes it seem probable that
simple physical processes are not the only mechanisms involved
in the passage of amino acids through the« placenta.
 
In the case of the nitrogenous waste products, ammonia, urea,
uric acid and creatinine, the concentration in the two blood
streams is almost identical and they probably pass from fetus to
mother by purely physical processes.44 Table 25 summarizes some
of the data on human subjects.
 
, TAVLD 25
 
Armut-n cost-knister- ops Ntstsnoonuovs coupounvs m sum« Bnoov or« IIUUAN Mosknmis
AND Fsskusns ask Fuhr« Tut-tu«
 
 
Motheks blood Fetal blood No. of
 
mg.XI00 cc. mgJ 100 cc.« cases
Nonsprotein nitrogen . . . . . . . . . . . . . 25.2 24 . 9 85
Amino-acid nitrogen (plqsma) . . . . . . 5.5 7.4 10
 
7 . 2 II .9 I premature
 
Urea and ammonia . . . . . . . . . . . . . . . 10.5 I0. 4 16
Uric acid . . . . . . . . . . . . . . . . . . . . . . .. s. 8 8.7 IT
creatinine (plasma) . . . . . . . . . . . . . .« I .67 I .75 I8
- I . 70 I . 78 12
 
Results of analysis of embryonic tissues throughout the course
of gestation demonstrate that the pig. builds very largely with
FETAL NUTRlTlcN AND METABOLISM 217
 
nitrogenous compounds during its early prenatal like. The total
nitrogen content ok the body per unit of dry weight decreases
gradually from the 6 mm. to the so mm. stage and then remains
constant throughout the remaining portion ok the gestation
period. The decrease may be related to an increase ok other nonnitrogenous solids such as carbohydrates, lipids and inorganic
salts. At the so mm. stage, when total nitrogen becomes constant,
the embryo may be said to have attained chemical maturityFo
 
Tut-ti- 26
Aventin Witten-r am) Pvacnivsrhen contain« or· Wann, Ast! am) Nrsraoonu n: PreKarosse«
l
Embryo Ash Nitrogen
Weiter«
Lenglzh Weight P« com; Wes; Dry Wet Dry Ashckree
mm. ging. per cent per eent per eent per eent per eent
24 . . . . . . . . . . . . . . 97 .4 . . . . . . . . . . . . . . . . . . . . . . . . .
 
647 . . . . . . .. 0 81 94.07 . . . . . . . . ·. 0 699 18 18
 
l0 . . . . . . . . 0 50 98.87 0 558 8.48 0 861 12 99 14 18
 
15 . . . . . . . . 0 98 91.88 0 775 9.00 l 061 12 81 18 52
 
R) . . . . . . . . 2 21 91.14 0 708 8.00 l 108 12 45 18 58
 
50 . . . . . . . . 6 55 91.65 l 086 12.41 0 910 10 91 12 45
 
60 . . . . . . .. 014 85 91.05 . . . . . . . . .. 0 966 l0 80
 
80 . . . . . . .. 26 00 91.59 . . . . . . . . .. 0 915 10 88
 
100 . . . . . . ·. 722 t 91.l8 . . . . . . . . .. 095 1078
 
110 . . . . . . .. 82 2 91.02 l so 14.50 0 972 10 82 12 65
 
120 . . . . . . .. 962 91.26 . . . . . . . . .. 0950 1087
 
160 . . . . . . .. 288 57 91.71 l 849 i 16.28 0 891 l0 75 12 84
 
200 . . . . . . .. 488 0 90.84 . . . . . . . . .. l 014 10 50
 
240 . . . . . . . . 725 0 88.7 2 58 2309 l 288 11 01 14 29
 
Interesting changes in the various kractions ok the total nitrogen have been observed. No signiiicant variation was apparent in
amide, humin and cystine nitrogen but amino nitrogen concentration was increased and that ok the non-amino nitrogen decreased correspondingly during the early stages. There was a kall
in arginine and histidine nitrogen and a deiinite rise in lysine
nitrogen before the 30 mm. steige. Tyrosine showed a gradual
decline throughout development. Glutathione, which is thought
to aid in synthesis ok proteins, increased sharply until 30 mm.
had been reached, after which it gradually decreased. Reciprocal
ontogenetic variations in the nitrogenous substances arginine,
histidine and lysine have been compared with somewhat similar
218 PHYsIoLocY oF THE FETUS
 
phylogenetic variationsPfs E! They may be correlated to some ex—
tent with observations on tumor tissues, from which it appears
that the younger types of neoplasms have the greater content of
arg1n1ne.
 
Many attempts to study nitrogenous excretion in 1namma1ian
fetuses have been made without notable success. It is impossible
to account for all the nitrogen excretion because the greater part
is passed through the placenta, dissipated in the mother’s blood
and removed by her lcidneys. some, but only a small part, is
excreted by the fetal mesonephros and metanephros (see Chapter
VI1l) and passed into the allantoic and amniotic fluids which can
be recovered for analysis.
 
The urea content, in milligrams per ioo grams of human embryo, has been estimated to decrease as the gestation period advancesLo The amount of nitrogen per gram of fetus which is
excreted into the fetal fluid of the ruminating mammals is lilcewise
high in ear1y prenatal life, but decreases sharply and then remains
at a low level throughout the greater part of gestationFfs I» A much
clearer picture of nitrogenous metabolism of the embryo has been
obtained from studies in the chiclc. There. a closed system makes
it possible to obtain all the nitrogenous wastes which- accumulate
in the allantoic sac.59-10 Uric acid begins to collect in the allantois on the iifth day of incubation. The chiclc makes eflicient
use of the available protein, for about 96 per cent of that absorbed
from the egg by the embryo during the first 13 days of incubation
is retained in the embryonic tissues. Some protein is burned by
the chiclcz in fact about« 6 per cent of all organic matter used for
energy during the first two weelcs of incubation is protein.
 
0ne of the most interesting aspects of fetal protein metabolism
is its comparative embryologysw Protein materials are used for
energy in much greater amounts by embryos with an aquatic
habitat than by those which are terrestrial. We may classify
mammalian embryos in the aquatic group with those of ftshes,
amphibians and many invertebrates, for they pour out their ex—
cretions through the placenta into the limitless aqueous environment of the mother’s blood stream and l(idneys. The terrestrial
group includes birds, some reptiles (e.g., lizards, snakes) , arthro—
pods (e.g., insects) and molluslcs (e.g., land snails) . Aquatic
embryos excrete nitrogen principally in« the— forth of ammonia and
FETAL NUTRITION AND METABOLISM 219
 
urea which are very so1ub1e and diffusible end-products and require excessive use of water for their e1imination. From a teleo1ogical viewpoint, one may say that the terrestrial forms must conserve water and consequently have had to devise other methods
of excreting nitrogen. Uric acid is the end-product in these
embryos. If birds had retained urea excretion instead of resorting
to uric acid, and if they had to store it all, their tissues would soon
become high1y saturated with urea because this substance can
dilfuse through the allantois into the body whereas uric acid is
retained, concentrated and precipitated within the allantoic sac
as the water is being absorbed and utilized. In their early development birds recapitulate aquatic stages in respect to their
protein metabolism. During the first 5 days of incubation ammonia and urea are excreted, but on the lifth day a shift is made
to uric acid and the embryo is thus spared a uremic fate.
 
IN ORGANIO IVIETABOLISM
 
It is lcnown that copper is stored in the human Iiver and its
concentration and absolute amount is higher there at birth than
at any subsequent time. Its concentration is greater at birth than
at earlier prenata1 periods.34 copper is essential for hemoglobin
synthesis and its mobilization in the fetal liver is thought to assure
normal blood formation in the postnata1 nursing period during
which the diet is delicient in this element. In contrast to conditions in man it has been reported that the late fetal pig liver
shows no increase in percentage of copper as growth proceedsPsH
The copper reserve of the liver is unusually low in the goat at
birthFS In the incubating chick too the percentage of copper
in the liver declines from the izth day to hatching, although
there is an increase in the actual amount present in the liver
throughout» The difference between pig, goat and chick on the
one hand and man on the other may be explained ,on the basis
of placental permeability. The chiclc must utilize what store it
has in the egg, the pig and goat get their copper from the histotrophe, but man, having a true placenta in which contact between
maternal and fetal blood streams is intimate, may be able to draw
heavily upon maternal stores.
 
It has been suggested that catabolism of maternal hemoglobin
talces place in the human placenta to supply the pigment fraction
220 PHYSIOLOGY OF THE FETUS
 
of the hemoglobin molecule intact to the fetal circulationKs The
iron content of the human placenta gradually increases during development.59 Iron is stored in« the liver during fetal life and for
about two months after birth during which time there is an active physiologic postnatal hemolysis. Thereafter it declines in
amount until the nursing period has passed.s4 Iron is excreted in
the bile but is absorbed again in the fetal intestines.«4 As is true
of copper, the iron reserve of the goat is low at birth," and the percentage concentration of iron declines in the liver of the incubating chicl(.37 The ratio of copper to iron in the chiclc’s tissues,
other than the liver, stays constant throughout incubation. Nonhematin iron in the tissues is small. The metals are utilized and
not stored in such large quantities in the liver for postnatal use
as they are in the human fetus.
 
The efkect on fetal rats of iron deficient diets fed to the
mothers has been investigated recently.·3«0- S! The first pregnancy
brought on marked depletion of maternal liver iron but there
was no anemia; with the advent of a second pregnancy an anemia
did appear. The first litter of rat pups had normal hemoglobin
values, but a reduction in total iron content of the entire body
by about one-half the normal was evident. The second litter
exhibited a reduction of the hemoglobin of the blood and the
total iron content was only one-fourth normal. studies in the
human« reveal that iron deficiency of the fetus may be related
to that of the mother. Infants which are born of anemic mothers
may exhibit hypochromic anemia during the first year. The normal full term infant has a good reserve of liver iron which is
probably fully as important to it as the iron it may salvage from
catabolism of its excess hemoglobin during the early postnatal
period. If it were not for this fact, the human infant would probably exhibit more symptoms than it does when deprived of placental blood by the commonly practiced prompt c1amping of the
umbilical cord at birth.
 
A large series of chemical analyses of human fetuses has been
summarized recently by swanson and Iob.02 content of nitrogen,
calcium, iron and phosphorus throughout the greater part of prenatal life is illustrated in Fig. 69. The retention of these materials
shows a similar pattern of gradually increasing quantities. The
results indicate that there, can— be lit·kle··demand upon the mother’s
FETAL NUTRITION AND METABOLISM 221
 
« zoo
M
 
 
 
PHOSPHORUS
2»L
 
   
 
s o
34587690345670910
Dom-r« »oui«-ZFig. 69.- tent ok nitrogen, iu1n,iron and phospho ok the hutnan ketus
 
between the « c! th and bitt . (swanson sc lob: Am. . bst. sc. cyn., Vol. 38,
 
1939. c. V. Mosby .
 
Fig. 7o.-E.tk ok changes in the cliet ok pregnant rats on calciu ncl phoss
phorus content o eolksprinz (swanson Z: lob: Arn. J. Obs . sc Gynsp . 38, 1939,
c. V. Mosby co.)
222 PHYSIOLOGY OF THE« FETUS
 
reserve of the elements in question during the first halk ok presnancy. In kact it is not Juntil the last two or three months ok
gestation that the ketal requirements become large.
 
calcium and phosphorus are concerned in building skeletal
structures. Their content in the ketus is iniiuenced by vitamin D
in the mother’s diet and apparently by the amount ok exposure to
sunlight.s«4 The eEects ok changing the diet ok pregnant rats
in respect to vitamin D are illustrated in Fig. 7o. When the
mother’s diet, fortiiied by vitamin D, is low in the required
minerals the calcium and phosphorus content ok the ketal body
approaches the normal level, but when the diet has in it the required amounts ok the minerals plus the vitamins the ketal calcium
and phosphorus content exceeds the normal. Thus the ketal
metabolism ok calcium and phosphorus is dependent upon that
ok the mother and the transmission 'ok these substances to the ketus
can be increased by vitamin D adminis·tration. In the human
subject occurrence ok early congenital riclcets is illustrative ok
maternal deiicienciesXE
 
Metabolism ok inorganic substances other than those we have
already considered has been studied less eictensively. The most.
marked changes in all inorganic compounds are encountered in
the kourth lunar month in man. Bekore that time the ketus contains relatively little chlorine, potassium, sodium and magnesium,
but these elements show a marked increase at the kourth monthFs
 
ENERGY METÄBOLISM
 
Oxygen consumption in the ketus has been studied in various
species and by various methods. The most signikicant data relative to amount and rateok utilization have been obtained in the
incubating chiclc and in the sheep ketus. The amounts ok oxygen
used and ok carbon dioxide given oE by the incubating chicl(·increase in proportion to growth in size ok the embryo. At six days
ok incubation oxygen is consumed by the embryo (exclusive ok
its membranes) at the rate ok o.o2 cc.Jgrn.Jmin. This rate de—
clines as growth proceeds and by the nineteenth day reaches
o.oi34 ccJgrnJminFC Barcrokt and his colleagueswi have estimated the rate ok oxygen consumption in the sheep ketus recently
by a direct method. They obtained samples ok ketal blood at
timed intervals akter occludingthei umbilica1 cord and determined
FETAL NUTRITION AND METABOLISM 223
 
its oxygen content. In this way they observed the loss of oxygen
in respect to time and could calculate its utilization per gram ok
the ketal tissue without the complicating kactors ok the placenta
and ketal rnembranes. Their data appear in Table 27. It will
 
Tat-m 27
Oxford: conswrrtorc m sauer« Ferner-s
 
Oxygen eonsumption
 
 
Fetal age Fetal weight
days grams
cc.-mirs. cc.Xgm.Xtain.
III . . . . . . . . . . . . . . . . . . ·. I,200 4.6 0.0038
 
126 . . . . . . . . . . . . . . . . . . . .I 8,000 I2·s 0.004I
 
127 . . . . . . . . . . . . . . . . . . . . 2850 II .2 0. 0089
 
129 . . . . . . . . . . . . . . . . . . 2750 SZL 0.008I·«
 
Is7 . . . . . . . . . . . . . . . . . . . . 8,850 20.0 00052
 
138 . . . . . . . . . . . . . . . . . . . .k FOR) I5.5 0.0042
 
152 . . . . . . . . . . . . . . . . . . . . 2800 I6.4s 0.0048·«
 
 
’«'Authors’ values; errors present but souree unless-wo.
 
be seen that, although the total amount ok oxygen consumed
each minute rises sharply at the beginning ok the last quarter
ok gestation, the rate ok utilization remains nearly constant
throughout the period studied and averages o.oo43 cc.xgrn.jmin.
(excepting the 129 day ketus) . This is a higher value than was
obtained in earlier less satiskactory experiments in the Cambridge
laboratoryss and by other investigators who have used indirect
methods o»k estimation. The oxygen consumption ok human
ketuses at terms bekore labor starts has been estimated to be
1.25 ccJkiloJminO
 
The ratio ok the amount ok carbon dioxide given olk to that ok
cc. carbon dioxide
 
cc. oxygen
embryos ok several species. This, the respiratory quotient, varies
signiHcantly in the chiclc. Most deterrninations during the Hrst
tive days ok incubation have given values in excess ok o.7, some
ok them approaching unity. In vitro experiments on the iive
day chiclc have demonstrated that the quotient is 1.o at this
time« Between the sixth and ninth days ok incubation the respiratory quotient declines to approximately o.7, but it rises again
toward unity between the tenth and thirteenth days. These fluc
oxygen consumed ( ) has been determined in
224 PHYSIOLOGY OF THE« FETUs
 
tuations have been talcen to signify that the embryo utilizes carbohydrates almost exclusively for combustion up to five days, burns
proteins very largely for the next few days and after the tenth
day of incubation resorts to combustion of fat supplemented by
rather large quantities of carbohydrateJo It should .be pointed
out that in the chiclc, which excretes uric acid instead of urea after
the lifth day, a respiratory quotient of o.7 rather than o.8 should
be expected during combustion of proteins. For more detailed information, the reader should refer to original articlesJos W- ««
 
The respiratory quotient of guinea pig fetuses has been determined74 by direct measurement of the oxygen consumption and
carbon dioxide evolution of the mother and her fetuses in utero
before and after occluding the umbilical cords. Quotients of o.9
to 1.2 were obtained for the fetuses in most instances, and o.7 to
o.9 in the mother. Coniirmatory results have been obtained by
others« in experiments using whole rat embryos in vitro (mean
R. O. .—.—. I.o4) . Respiratory quotients of this nature indicate that
mammalian fetuses consume carbohydrates almost exclusively in
their energy metabolism.
 
Many investigators have studied metabolism during pregnancy.
especially in man, by indirect calorimetric methods.10 Mur1in75
observed a dog during two consecutive pregnancies, one pup being
produced at the lirst and live pups at the second birth. An in—
crease in caloric energy production due to the single fetus could
be detected at the sixth weelcz it amounted to 9 per cent between
the sixth and eighth weelcs. The total energy produced at full
term was proportional to’ the weight of the offspring and was about
equal to that required by the newborn pups (when calculated according to the law of slcin area·) . It amounted to 16.4 gm. cal.J1oo
gar. in the single pregnancy and 16.8 gm. cahxioo gar. in the
multiple pregnancy. The curve of total energy production of the
dog and her pups showed no deflection at birth. The number of
calories formed by the resting pregnant dog plus fetuses, placentas
and membranes was very much the same as the sum of that produced after delivery by the lactating dog and her resting pups.
 
In the human not all investigators have found relationships
quite so simple as those occurring in Mur1in’s experiments in the
dog. some« have reported that excessive heat production in
pregnancy results from some factors other than those of fetal
FBTAL NUTRITION AND METABOLISM 225
 
growth. 0thers"- 78 have been able to account for all of the ex—
cess on the basis of fetal heat production, fmding that the energy
produced by the woman plus her fetus and its accessory structures
at full term is equal to that produced by the lactating woman
and the infant after birth. Recently, Enright and her associatessp
reported that a greater post-partum drop in energy metabolism
than is accountable on the basis of that produced by the fetus
alone occurs in i 5-year-old females, amounting to about three
times the probable basal energy requirements of infants. They
concluded that in pregnant adolescents there appears to be some
factor stimulating metabolism which results in a greater rise than
occurs in more mature women. They suggested that this excessive energy production of immature -girls may be related to thyroid
function, and have presented some evidence that feeding iodized
salt diminished the rise in metabolism during pregnancy.
 
One point which has not been emphasized is worth consideration. The fetus in utero is quiescent and hypotonic whereas the
newborn infant is active and its muscles possess good tonus. If
the energy produced by the newborn is commensurately greater
than that of the full term apneic, hypotonic, quiescent fetus use
will have to conclude that more energy is produced by the woman
(plus the accessory fetal structures but minus the fetus) than is
produced by the post—partum lactating woman. The alternative
assumption is that basal requirements of the hypotonic fetus are
fully as great as in the newborn infant, and this seems unreason—
able.
 
The various calorimetric studies suggest that the fetal metabolic rate remains fairly constant throughout the latter part of
gestation, but during the early period while the embryo is very
small no data are available« Postnatally the rate rises and reaches
a pealc at about the Erst or second year in the human. similar
postnatal pealcs have been observed in other animals such as the
rabbit, mouse and some breeds of pigz others, notably the guinea
pig, show an already declining metabolic rate at birth. These
facts may be related to the maturity of the heat regulating mechanisms in the different species (see chapter VIII) . They suggest
 
«« Oxygen consumption of mammalian eggs during the one— to eightscell stages
ainounts to o.ooo7z c.mm. per egg per hour. When gkowth in size begins the oxygen
oonsumption increasesz on the eighth day of gestation in the rat it amounts to about
«o.o1 c.mm. per hour. This increases to about o.2 drum. in the next two days«
 
Is
226
 
PHYSIOLOGY OF THE FETUS
 
that the metabo1ic rate may in rea1ity be increasing to some ex—
tent throughout prenatal like in man and in the other animals
with a postnatal pealc ok heat production and may have begun to
decline in the others before birth.
 
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t934. lbicl., 47: 3oe.
 
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i93e. Ztsckm Geburtsh. Gynäk., ioe:
i6
 
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{{Footer}}
. Bot-II, E. J. sc J. s. Nicholas i939. scieiice, 9o: 4i i.

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Windle WF. Physiology of the Fetus. (1940) Saunders, Philadelphia.

1940 Physiology of the Fetus: 1 Introduction | 2 Heart | 3 Circulation | 4 Blood | 5 Respiration | 6 Respiratory Movements | 7 Digestive | 8 Renal - Skin | 9 Muscles | 10 Neural Genesis | 11 Neural Activity | 12 Motor Reactions and Reflexes | 13 Senses | 14 Endocrine | 15 Nutrition and Metabolism | Figures

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Chapter XIV The Fetal Endocrine Glands

Our knowledge of endocrine functions during prenatal life is fragmentary as may be expected from the fact that adult glands of internal secretion are still incompletely understood and their relationship to one another only partly determined. There seems to be little doubt that a few of the maternal hormones do influence embryonic deve1opment, but not all can pass the placental barriers The present deftciency of information concerning placental transmission of hormones is a factor limiting any discussion of their activities in the fetus. Perhaps the secretions of the fetus itself are equally or more important than those of the mother for the well being and normal metabolism of the new individual. It is with their functions that we shall be especially concerned.


The Suprarenal Cortex

Among all the endocrine glands of the human fetus the suprarenals manifest the most remarlcable peculiaritiesks 3 Examination of them in the still—born infant reveals that they are proportionately very much larger than at any time after birthx in fact they form o.2 per cent of the entire body weight. Those of the adult constitute only o.o1 per cent.4 The reason for their great size is found in an hypertrophy of the innermost cortical cells forming a layer to which the names, X-zone, fetal cortex and androgenic zone have been applied. Only the outer rim of the embryonic gland differentiates into the characteristic suprarenal cortex of the adult, and it does not come into prominence until after prenatal life.


The androgenic zone of the fetal suprarenal undergoes involution rapidly after birthF and as it disappears the size of the gland becomes actually -as well as relatively smaller. The growth curve of the human suprarenal gland is reproduced in Fig. 66.C The gland loses one—third of its birth weight during the first postnatal week, one-half in the first three months and fouplifths by the end of the first year. Thereafter, a slow growth takes place and at puberty the suprarenal again attains the weight it had at the end of the fetal life ; but the androgenic Zone is no longer recognizable. This characteristically fetal part of the suprarenal gland has been identiiied in the cat,7 Inouse,8 rabbit9 and in one strain of rats.10 It seems to be absent, or at least not present as a comparable distinct layer of cells, in the albino rat and some other animals.


The physiologic signiHcance of the hypertrophiecl fetal cortex of the suprarenal gland is not understood. That it is closely related to other endocrine organs is quite certain. A possible influence of Inaternal sex hormones upon the growing feta1 suprarenal is suggestecl by the closely parallel growth curve of the uterus in prenatal and early postnatal life (Fig. 67) . Involution of the X-2one of young male Ihice is accomplished under the influence of testicular hormone.


Fig. 66. — Growth of the human suprarenal glands (weight) during fetal like (c—B) and after birth. (scammon: «The Measurement of Maus« Und: dünn. Press.)


It has been suggested that the fetal suprarenaLgland elaborates an anclromirnetic substance.I2- I« Its ability to maintain the prostates of the castrated immature mouse and rat, which degenerate when gonads and suprarenals are removed, demonstrates an andromimetic property quite clearly-P«- 15 «« Recentlzy however, evidence has been advanced which indicates that carefully prepared extracts of fetal and of other X—2one—bearing glands do not have androgenic propertiesss but it is possible that the amount of suprarenal tissue extracted was too small to produce eifects. should it prove that androgens are laclcingx one would have to discard the attractive hypothesis that the androgenic cortex serves directly to protect the fetus against an excessive iniluence of maternal estrogens reaching it through the placental barrier.


Fig. 67. - Growth of the hutnan Uterus (length) during ketal like (c-—B) and after birth. (scammon: «The Measurement of Man," Univ. Minn. Press.)


The possibility that cortin or a cortin-like hormone is forrned by the feta1 suprarenal gland has received attention. Some investigators have reported that the survival times of adrenalectomized cats and dogs are prolonged during advanced pregnancy.17szI9 Others failed to substantiate this at the end of gestation,20 but even if it is true there is no proof that a fetal secretion protected the mother. Progesterone maintains life and growth in ferrets and rats in the absence of suprarenal glands,2I-««’3 and the functional corpus luteum of pregnant adrenalectomized anirnals does the Same« Adrenalectomy of pregnant rats during gestation results in an increase in weight of the fetal glandsW as will be seen in Table 22.


Tanm 22

Tun Bringe-IS or Aussicht-Demut Denn-ro Pagen-mer III-on kur- Wntenks or rat; Fast-Hi« sur-Hauptn- Gunvs

Time of adrenaleetomy No. of Average Ist. Ave. set. of suprarenal of mothek litters of fetuses (gm.) glands of fetuses (mg.) « d« 9 o« 9 Unoperated eontrols . . . . . . 18 5 .84 5.t»)8 0.90 0.82 14th day of FeSUItIOIL . . . . 15 4 .96 4.78 LLZ I .l8 7th day of Feste-tion . . . . . . 10 4 .70 4.51 1.17 Lls


Attempts have been made to destroy the suprarenal g1ands by means of intrauterine surgery to observe effects on other fetal endocrine organskk but it proved impossible to obtain clear—cut results because of the magnitude of technical difficulties.

The Suprarenal Medulla

The medulla of the suprarenal gland has an embryonic origin very different from that of the cortex. It is formed by cells which arise from the primordia of sympathetic ganglia and which begin to migrate into the already prominent cortical bodies at about seven weeks gestation in man. cells of the suprarena1 medulla as well as of certain other small glandular bodies of similar embryonic origin (e.g., the aortic paraganglia) possess a retnarld able afkinity for chrome compounds with which they take on a brown color. This chromaffin reaction has been demonstrated to be elicitable iirst at about the time extracts of embryonic suprarenal tissue begin to produce pharmacologic responses characteristic of epinephrin749


Many have investigated the activities of the embryonic and fetal suprarenal medulla by this histochemical method as well as by other chemical and sensitive physiologic techniques Epinephrindilce reactions are obtainable from suprarenal extracts prepared from chiclc embryos as early as the eighth day of incubation although similar extracts of other embryonic tissues give negative resultsFHI Epinephrin is formed, or at least stored, in the medulla of the glands in many fetal mammals before the middle of gestation.32-39 The medullary cells show the chromaliin reaction at the 17th to 18th day in the pig and both physiologic and histochemical tests reveal the presence of an epinephrins lilce substance at the time migration of medullary cells into the cortical bodies is first observablekssfs The epinephrin content of fetal glands has been reported to be greater than in the adult; more was found in female than in rnale fetuses. A correlation between appearance of epinephrin in the suprarena1 of the rat and the origin of fetal movements has been suggested but this seems to be coincidental.


In sharp contrast with results obtained in most rnamma1s, human fetal suprarenal extracts give negative or only very slightly positive tests for epinephrine 4144 However, in full term infants as well as prematures which lived for a short time somewhat more definite reactions were obtained. The near fai1 ure to obtain epinephrin-lilce responses from human fetal suprarenal extracts may be contrasted with the observation that the paraganglia yielded definite amounts of epinephrin in one instance:43

Human suprarenal at birth - 0.0I arg. epinephrin per OR? Hm. Fluid.

Human paraganglion at birth - 0.24 rag- epinephrin per 0.1I Hm. sind.

Any relationship between low content of epinephrin and the presence of a very prominent androgenic cortical zone in man is undetermined.

The Sex Hormones

An excellent consideration of embryologic development of sex with a review of all but the latest literature has appeared recently.45 We are limited here to only a small part of this interesting subject.


The male gonads produce substances with androgenic properties in prenatal life. 1t was demonstrated that extracts prepared from the testes of fetal calves are similar to those from the adult and the hormonal yield per unit weight of tissue is greater. 46 It is probable that the male sex glands begin to elaborate secretions about as soon as their sex can be differentiated, which is the sixth day in the incubating chiclc and the seventh weelc in man. The ovary is recognizable as such about a weelc later than the testes.


The best indication we have that fetal androgens are active in early prenatal life is that forthcoming from a study of freemartins in cattle.47 48 The freemartin is an intersexed or masculinized female calf which deve1ops under conditions of chorionic fusion in which vascu1ar anastomoses are estab1ished between the placentas of adjacent male and female fetuses. The male is always a normal individual: It is believed that the hormone elaborated by the fetal male gonadscirculates in the conjoined blood streams, acting upon the female twin’s Miillerian or female duct derivatives to inhibit their normal development and upon its Wolllian or masculine duct derivatives to stimulate their abnormal dilferentiatiom When vascular connections are not established between adjacent fetuses of opposite sex no freemartin results, but the calves are normal male and female.


A similar freemartin condition has been described in swine.49 It should be noted that the placentas of both cattle and swine are relatively ineflicient from the standpoint of permeabi1ity. A high degree of placental fusion, apparently with vascular union, was observed in one instance of synchorial twinning in the cat.50 The fetuses were of opposite sexes, were sexually normal in every way, and were sulliciently advanced in development to make it appear certain that the female twin would not have become a freemartin. similarly synchorial twins of opposite sexes are encountered in other animals and man,51- 32 but freemartins have not been reported. It will probably be prolitable to- learn how the transmission of fetal male sex hormones across the placental barrier is related to the phenomenon in question. It is difficult to see how the freemartin condition can be so limited unless the diffusibility of embryonic testicular hormones is greater in the deciduate types of placentas which therefore never allow hormones to accumulate in suilicient amounts to stimulate the Wolflian derivatives of the genetically female twin.


It would carry us too far alield to inquire deeply into the extensive experimental studies on production of pseudohermaphrodism in the lower animals« success has been attained in mams mals at several laboratories recentlyks Injections of pregnant rats with large doses of testosterone and related preparations bring about abnormal development of the potentially male ducts of genetically female young. It is necessary to administer the hormone before the 16th day of gestation to obtain the most marked effects.54 This is about one day before the WolHian ducts begin to regress The intersexed individuals produced experimentally resemble the naturally occurring freemartins in certain particulars.


Male offspring of rats receiving large doses of estrogens before the Izth day of gestation have been markedly feminizedPs Thus a converse of nature’s freemartin has been induced with excessive female sex hormones. The extent to which the mother’s own hormones may inliuence normal development of sex in the fetus is not understood. It is known that the fetal uterus exhibits a marked hypertrophy and diminishes in size after intimate contact with the mother is abolished by birth. The mammary glands of newborn infants of both sexes show enlargement and may secrete transientlys It is possible that this production of «witch milk" is stimulated by the same maternal hormonal mechanism that leads to the preparation of the mother’s breasts for lactation.


The Thyroid Gland

The ability of the fetal thyroid to secrete at an early period seems to have been established. Iodine has been identilied in the gland at the 2nd or zrd month of gestation in cattle, sheep and swiness and in man at least as early as the 6th month» The amount is said to increase toward the end of prenatal life but to be low as compared with the adult gland, perhaps because storage of colloid is not so marked in the fetus« There is no close correlation between the maternal and fetal blood content of hormone iodine, a fact which suggests that the fetus is secreting its own hormone. The presence of thyreoglobulin in the human fetus at the zrd and 4th months has been established by means of an immunologic precipitin reaction.59

Amphibian metamorphosis and growth can be inlluenced by extracts and transplants of avian and mammalian fetal thyroid glands. In several, it may be said that the thyroid« becomes active at about the time its structure begins to resemble that of the adult. This is on the iith day of incubation in the chickW In calves colloid is present as early as the end« and differentiation is comp1eted between the 4th and 6th prenatal monthsz at this time extracts serve to bring about metamorphosis in the axolotl, a salamander which normally retains the larval state throughout life.30 Extracts prepared from the glands of pig fetuses 7 cm. long proved to be inactive, but those from 9 cm. pig fetuses produced reactions comparable with adult thyroids; correlatively, the adult structure was nearly attained at 9 cm.» When bits of the thyroid gland from a 3-months-old human fetus (1o cm. C. R. length) were transplanted into larvae of a toad, accelerated development took place, and trarisplants from 5-months-old human fetuses had more marked efkectsYs Control experiments with bits of fetal muscle gave negative results. It was found that the thyroid gland of the youngenfetus had already deve1oped col1oid Iilled vesicles.


Little is known about placenta! transmission of the thyroid secretions. In swine, horses, cattle and sheep, animals with adeciduate placentas, it appears that there is no transmission. In geographical regions where iodine deliciency is prevalent the offspring of these animals are born in a state of athyreosis while the mothers show little or no evidence of the iodine lack.C4- S« It seems sthat the fetal requirements of iodine are greater than those of the mother and that the fetus cannot draw upon the mother’s hormone but must manufacture its own. Iodine feeding during pregnancy corrects this deliciency, and the newborn pigs are then normal. In man, on the other hand, it seems probable that the mother’s hormone is available to the fetus because it can traverse the placental barrier. Human infants born without or with atrophic thyroid glands exhibit none of the symptoms of myxedema, but a latent athyreosis soon manifests itself.S3-71

The Parathyroid Glands

Practically nothing is known of function of fetal parathyroid glands. Injections of parathyroid hormone into dog fetuses bring on an elevation of the calcium level of the fetal, but not the maternal blood. This suggests that the parathyroid secretion does not pass the placenta in the species studied.72 Attempts have been made to determine the effects of fetal glands of dogs after thyroparathyroidectomy of the mothers. It was found that tetany developed just as soon as it did in nonpregnant animalsJss ««

The Thymus

Although the thymus is usually considered with the glands of internal secretion, it is doubtful if it logically belongs there. By 3 months in man, the thymus has the appearance of a lymphoid organ with cortex and medulla already in evidence. There is no anatomical basis for the belief that the sgland elaborates a hormone and few attempts have been made to study the fetal thymus from the standpoint of its endocrine function.30


Extracts of thymus seem to exert no elfects when fed to tadPoles, although opinion has been divided on this questions«- «« An extract of calf thymus, to which the name "thymocrescin" was given, has been reported to produce marked acceleration of growth in young rats when injected in daily doses as small as 1 mg.79


Another extract prepared in an entirely different way resulted in even more marked effects in the hands of Rowntree and his colleaguesko This material was injected intraperitoneally in i cc. doses into rats over long periods including gestation and lactation; the young of succeeding generations were similarly treated. Elfects on the olkspring of the first animals were not signijicant but the second and subsequent generations showed remarkable changes. They were larger at birth, more of them survived and their postnatal development was delinitely speeded. The young rats became sexually mature precociously. Maximum effects were found in the eighth and tenth generations. It was necessary to keep giving the treatments and not miss a generation or the effects were promptly dissipated. From the more recent reports it seems that it was necessary to inject the extracts into females only.


Other investigators have attempted to reproduce these very interesting results. but so far no adequate confirmation has been reported» The biologic effects of certain iodine-reducing substances (glutathione, ascorbic acid, cysteine) have been found to simulate those of the thymus extracts in certain particulars.

The Hypophysis

A few studies have been made on placental transmission of hypophyseal extracts but we know Iittle about hormone elaboration by the fetus itself. When pituitrin was injected into rabbit fetuses no muscular contractions were observed in the mother.83 This suggests, but does not prove, that the substance failed to pass the placenta. Anterior lobe extract did not produce any evidence of its usual gonadotropic activity in the mother when it was introduced into the fetuses« Furthermore, this hormone failed to appear in the fetal fluids after it had been injected into the mother; at least, the administration of these fluids to other adult rabbits fai1ed to bring about ovulatory changesss These experiments seem to show that there is very little if any transmission of the large molecules of the anterior lobe gonadotropic factor even in the hemosendothelial type of placenta.


The fetal hypophysis seems to be capable of elaborating several active principlesPss VHV A pressor substance has been found at 6 months in man. similar studies have been made in fetuses of cattle, sheep and swine in which the response was found relatively earlier. The guinea pig uterine strip method served to demonstrate the oxytocic princip1e about as early as the pituitary glarid can be recognized macroscopicallzn It was found in appreciable amounts in pigs and sheep at term.


The melanophore expanding hormone has been identified in the fetal hypophysis It was found in the glands from calf fetuses of 3 months gestation but was not there at 2 months. It was present in pigs of only 2o mm. c. R. length.30- 88

Gonadotropic and growth promoting factors of the anterior lobe seem to make their appearance rather late in fetal life, and the former is later than the latter.90 In fetal pigs the gonadotropic response was obtained from glands at the 2o to 21 ern. stage, a short time before the end of gestation but was not found earlier. The general body growth response could be obtained at the 9 to 13 cm. stage which was just about the same time the thyroid hormone made its appearancesEs 90

Secretin

Extracts of the proximal portion of the fetal small intestine have been found to cause secretion of pancreatic juice when injected into adult animals with pancreatic Hstu1as.9I·9f The earliest period at which secretin has been obtained from the human fetus is 414 months. The exact source of the hormone is unknown and attempts to ascribe it to the chromalkn cells of the duodenum93 seem to be entirely unjustified

The Endocrine Pancreas

The endocrine function of the pancreas is vested in the cells of the islands of Langerhans These make their appearance in the third month of human gestation but it is not known how early they become capable of secreting. The acinar portion of the gland does not begin to produce its proteolytic ferment before about the 5th month,93 and Banting and Best took advantage of the fact that island tissue is functional earlier when they chose the pancreas of the fetal calf as a source of antidiabetic principle in their early search for insulin.97 Many have discussed the possibility that fetal insulin plays an important röle in carbohydrate metabolism of the fetus and have pointed to a correlation between the appearance of glycogen in the liver and the development of island tissue in the pancreassss 99 but the relationship is still somewhat unsatisfactorily established because the influence of maternal secretion acting through the placenta is diflicult to evaluate. It is said not to pass the placenta from fetal to maternal sides.83 Administration of insulin to pregnant cats failed to reduce the blood sugar level of the fetuses near term. This suggests that the placenta is impervious at the time, but at earlier stages similar results were not obtainedEoo Further discussion of this question will be found in Chapter XVI.


In birds, where all metabolic processes must be managed by the fetus itself, an insulin-like substance has been found in the unincubated eggJOI However, it is not present in the tissues of the early chick embryo until after the pancreatic islets are formed.


The offspring of diabetic animals are not diabetic and as a ruIe seem to possess healthy glandsW This is not always true in man where hypertrophy and hyperplasia of islands and postpartum hypoglycemic deaths are encountered in infants born of diabetic women. Although hyperplastic pancreatic islands are not found in all instances, careful searching might show the condition to be more prevalent.


The possibility that during prenatal life fetal insulin can protect the diabetic mother has been discussed by several investigators. It was discovered by Carlson and his colleaguesIM W that the urine of completely pancreatectomized dogs remained free from sugar when the .operation was performed in late stages of pregnancy. This suggested that fetal island tissue had, supported both the mother and fetuses, for after parturition the mother exhibited glycosuria. These experiments have been adequately confirmedW and similar conditions app«arently occur in the human.I07 Completely depancreatized dogs maintained in good hea1th by diet and insu1in therapy can conceive and give birth to normal pups. They show an increased carbohydrate tolerance kor only about two weeks prior to labor. However, an even greater tolerance appears after birth during lactationz it would seem that the results previously ascribed entirely to ketal insulin are more probab1y due largely to increased utilization of carbohydrates by the fetuses and, after birth, by the nursing puppies. We cannot be sure that the ketal insulin plays any part in protecting the diabetic mother. It is quite reasonable to suppose that it is more important kor the utilization of sugar received by the fetus krom the mother.


Glycogen appears in the liver of the deve1oping chick at 7 days of incubation. This is about three days before delinitive islands of Langerhans make their appearance. Between the tenth and thirteenth days the glycogen content of liver cells diminishes and the metabolic rate and respiratory quotient increase, although there is no rise in the blood sugar concentration. Thus it appears that an increased utilization of carbohydrate by the embryo is correlated with the advent of kunction in suprarenal medulla pancreatic islands and thyroid glands.

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