Paper - Studies on the physiology of reproduction (1933) 5

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Andersen DH. and Kennedy HS. Studies on the physiology of reproduction: V. The adrenal cortex in pregnancy and lactation. (1933) J Physiol. 77(2): 159-73.

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This 1933 historic paper by Andersen and Kennedy describes the adrenal cortex in pregnancy and lactation.


See also by this author: Andersen DH. Studies on the physiology of reproduction: I. The effect of thymectomy and of season on the age and weight of puberty in the female rat. (1932) J Physiol. 14;74(1):49-64. PMID 16994258

Andersen DH. Studies on the physiology of reproduction: II. The effect of thymectomy on the age of puberty in the male rat. (1932) J Physiol. 74(2):207-211. PMID 16994270

Andersen DH. Studies on the physiology of reproduction: III. The effect of thymectomy on fertility in the rat. (1932) J Physiol. 74(2):212-3. PMID 16994271

Andersen DH. and Kennedy HS. Studies on the physiology of reproduction. IV. Changes in the adrenal gland of the female rat associated with the oestrous cycle. (1932) J Physiol. 76, 247-260.

Andersen DH. and Kennedy HS. Studies on the physiology of reproduction: V. The adrenal cortex in pregnancy and lactation. (1933) J Physiol. 77(2): 159-73.

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Studies on the Physiology of Reproduction

V. The Adrenal Cortex in Pregnancy and Lactation

By Dorothy H. Andersen and Helen S. Kennedy.

From the Department of Pathology, College of Physicians and Surgeons, Columbia University, New York City.

Introduction

Our finding, in recent experimental work (Andersen and Kennedy, 1932), of a significant difference between the adrenal weight of the rat at oestrus and at dioestrus has led us to investigate the adrenal changes in pregnancy. Without a preliminary knowledge of the changes in the nonpregnant animal it is impossible to have carefully standardized controls for the pregnant ones, and such knowledge has not been available to former workers. It was hoped that a series of pregnant rats of the same strain, kept on the same diet and in the same environment as that used in our former experiment, might yield valuable information.

Most recent text-books and reviews refer to an hypertrophy of the adrenals during pregnancy as an accepted fact. A careful analysis of the literature on the subject reveals that this belief is based on a rather small amount of data, and that the controls used in most of the experiments were inadequate, not only because the cestrus changes were unknown and disregarded, but because the possibility of an excessive hypertrophy of the cortex in pregnant animals that are infected over the non-pregnant ones as suggested by Donaldson [1924] in rats was not considered. Moreover, the changes described in the literature vary not only in different species, but in the same species as studied by different people. It is possible that not all mammalian adrenals respond similarly to pregnancy. The work on each species will therefore be considered separately.

Most of the work has been done on rodents, especially on guinea-pigs. The first report was by Guieyesse [1899, 1901], who gave a lucid description of various changes in the adrenals of his pregnant animals, the chief of which were the following: the cells of the middle third of the cortex were increased in size and contained larger vacuoles; the cells of the inner portion of the fascicularis contained a greater number of granules staining with iron hematoxylin; and those of the reticularis contained a greater number of these siderophil granules as well as an increase in pigment granules. He found no mitoses and concluded that the increase was in the size, not in the number of cells. The zona glomerulosa was unchanged. The animals were killed between the tenth and fifty-second day of pregnancy. The chief criticisms of his work are that his controls were males, except for one immature female 2 months old, that no records of the number and ages of animals were given, and that no note was made as to infections in his animals. In view of the large size of the female adrenal as compared with the male, the first of these objections goes far to invalidate his findings as the specific effect of pregnancy. Marrassini [1906] reported on ten pregnant guinea-pigs with nine non-pregnant female and fourteen male controls, and described an increase of lipoids in the fascicularis but no change in the other zones. He found a greater variation in the weight of the adrenals in both nonpregnant and pregnant females than in the males. The three animals killed in early pregnancy resembled the non-pregnant females, while the three in late pregnancy and the four killed post-partum had larger adrenals. Inspection of his figures reveals the fact that six of the female non-pregnant animals were much lighter in weight than the pregnant ones. The remaining four are in the same weight range as the pregnant ones, if the probable weight of the uterine contents be considered, and the adrenals in these animals are in the same range of weight as the pregnant ones, rather less, if relative weight be considered. The male adrenals are smaller than those of the non-pregnant females according to his figures, although he describes them as being about the same. Ciulla [1910] also confirmed Guieyesse, but mentioned no controls and gave but few details. He also studied the proteolytic enzymes of cortical tissue and found about the same quantity in pregnant and non-pregnant animals, with wide variations. He quotes Costa [1906] as reporting a decrease in the lipolytic and proteolytic activity of the adrenal cortex during pregnancy. Kolmer [1912] examined three pregnant, six lactating, and three non-pregnant guinea-pigs and confirmed the findings of Guieyesse with the addition of many mitoses at about the time of parturition. Kolde [1913] also confirmed the findings of Guieyesse in his study of four pregnant and two non-pregnant animals, one of the latter being very old. These observations are based on so few animals, in view of the range of variation of adrenal weight, that they may be disregarded. Sternberg [1915] had a series of thirteen pregnant, eight postpartum, and five non-pregnant control guinea-pigs and confirmed Guieyesse as to hypertrophy of the fascicularis with increased lipoid and without mitoses. He also described an hypertrophy of the glomerular zone. He includes a table of data which reveals the fact that actual weights are reported on only three of the five controls and that these three are small animals. Calculation of the weight of adrenal per kg. of body weight based on his data gives a result in the controls within the same range as in the pregnant animals, Sternberg’s work can therefore be disregarded.

Verdozzi[1914, 1917] presented a series of twenty-four pregnant and twenty post-partum animals, and a description of the adrenal in the nonpregnant controls, the number of which was not given. He calculated the relative weight and made from his data a chart, in which there is a high peak at the end of the first half of gestation produced by the figures from two animals. The remaining figures for pregnant animals are low on the average but vary greatly. In eleven post-partum animals the young were left with the mother, and in nine they were removed. The figures for the former series are definitely higher than for the latter and appear significant. ‘

The most recent work on guinea-pigs is that by Castaldi [1922] on a series of eleven pregnant animals with a number of non-pregnant controls, of various ages, of which six were older than 3 months. He confirmed Guieyesse. A study of the figures which he presents shows so great a variation that the difference is not significant, especially if the relative weight is calculated.

Other rodents that have been studied are the rat, mouse and rabbit. Herring [1920] found that the mean relative adrenal weight in nine pregnant rats was 0-22 g./kg. and in nine non-pregnant controls it was 0-20 g./kg., a difference that is not significant in view of the variation and the number of animals. Donaldson, in twenty-nine pregnant and lactating rats, with a mean body weight of 167 g., found a mean relative adrenal weight of 45-3 mg., while in twenty-nine non-pregnant controls with a mean body weight of 163 g. the mean adrenal weight was 44-7 mg., or practically the same. He pointed out a most interesting fact, that the infected pregnant animals had a much higher adrenal weight than the infected non-pregnant ones. Forty-seven pathological controls with a mean body weight of 174 g. had a mean adrenal weight of 47-9 mg., while fifty-one pathological pregnant and lactating rats with a mean body weight of 163 g. had a mean adrenal weight of 57-8 mg. In a later study Donaldson [1928] showed that the relative volumes of the medulla and cortex were the same in pregnant and non-pregnant animals.

In mice the problem is complicated by the presence, in this species, of the X-zone lying between the fascicularis and medulla. Three workers, with an adequate number of animals, have described a decrease in size of the adrenals and the rapid disappearance of this zone during pregnancy [Tamura, 1926; Howard-Miller, 1927; Deanesly, 1928]; HowardMiller [1927] and Deanesly [1928] describe this phenomenon as the hastening of the normal age involution of this zone. All three workers investigated the presence of cestrus changes: adrenal hypertrophy was described by Masuiand Tamura [1926], but was not found by HowardMiller [1927] and Deanesly [1928].

Gottschau [1883] made the first observations on rabbits. In a series of twenty pregnant rabbits and nineteen non-pregnant females, he observed a slight decrease in size in the adrenals of the pregnant animals, while the adrenals of seven males were still smaller. Elliott and Tuckett [1906] give low figures in two pregnant and three non-pregnant females. Ciulla analysed the cortex of rabbits for fat and lecithine and found that the fat content was 10 p.c. by weight in the non-pregnant and 18 p.c. in the pregnant animals. Lecithine formed 50 p.c. of this in the non-pregnant and 72 p.c. in the pregnant. He gave but few details, and did not mention the number of animals, the age and weight, or the sex of the controls. K olde [1913] found no difference between five pregnantand eleven non-pregnant females. Sternberg [1915], who studied eight pregnant and two lactating rabbits and five non-pregnant controls, reported changes similar to those in guinea-pigs. He gives complete data on only one control, but states that there is hypertrophy in the pregnant animals. This finding, in the face of the previous work and his inadequate controls, leaves one sceptical of his work, not only on rabbits, but also on guinea-pigs.

No observations on dogs have been found, but the figures given by Elliott and Tuckett on two pregnant and two lactating cats show about the same relative weight of the adrenals as in the non-pregnant females of his series.

The diagram given by Kolmer [1918], based on observations of eight pregnant, one lactating, sixteen non-pregnant female and twenty-five male moles, indicates adrenal enlargement during the breeding season (February to April) in both sexes. This enlargement was found in both pregnant and non-pregnant animals during the season of rut. The factor of seasonal variation in a hibernating animal complicated the picture.

In man, the most considerable series described in detail is that of Sambalino [1910], who reported a series of twenty-six cases of women dying in pregnancy or the puerperium. Many of these died after an abortion or immediately post-partum of various causes. An abstract of his case histories reveals the following facts: he described marked hypertrophy in three cases, one of which died of pyelonephritis, and the others of puerperal infection; slight to moderate hypertrophy in sixteen cases, the cause of death being hemorrhages in three, eclampsia in three, chronic nephritis in four, post-partum infection in two, pulmonary tuberculosis in one, pneumonia in two and pulmonary thrombosis following femoral thrombosis in one; adrenals of normal size in four cases, dying of acute nephritis, eclampsia, abdominal sarcoma and puerperal infection respectively; and very small adrenals in three cases dying of nephritis (two cases) and pernicious anemia. He concluded that increased vacuolization in the zona fascicularis and increased pigment in the zona reticularis were changes due to pregnancy, and that adenomata were common in the cases of eclampsia and nephritis. However, according to the descriptions of individual cases, these are not always present. Moreover, the size of the adrenal was estimated from its appearance in the microscopic sections. There is no correlation between the degree of hypertrophy and the age of the patient or the number of pregnancies. The constant presence of any one change was not demonstrated. Chirié [1908] reported a series of twenty-eight autopsies on women dying during the terminal portion of pregnancy or soon after parturition. Of these, twelve died of eclampsia, four of nephritis, and the remainder died of various causes, chiefly infection. He observed hypertrophy of the cortex in most of the cases of eclampsia and nephritis with hypertrophy of the medulla in many of these cases. Hypertrophy of the cortex was found twice and hypertrophy of the medulla was not present in the remainder of the series. Cortical adenomata were about equally frequent in all types of cases. He concluded that the hypertrophy was a response to the intoxication resulting from renal changes. Minervini [1904] reported a case of a woman who died in the seventh month of pregnancy from eclampsia, and Gaifami [1907] reported four cases, in two of which the cause of death was streptococcus infection, and in the other two shock from hemorrhage. Both observers described increased lipoid in the fascicularis and increased pigment in the reticularis. Kolde [1913] described the adrenals of five pregnant and five non-pregnant women. He found the zona fascicularis and zona reticularis large, and the glomerulosa small and with mitoses. There were no adenomata in his case of eclampsia. Landau [1915], aware of Sternberg’s work in the same laboratory, in a careful study of three hundred autopsies of adults of both sexes, Was surprised to find no difference between adrenals of the cases dying in pregnancy or during the puerperium (number of cases not given) and the remaining non-pregnant ones. Goormaghtigh [1922] added one case in which he found hypertrophy of the fascicularis with an increase of lipoid, and atrophy of the reticularis. The difficulties of evaluating autopsy material are manifest, especially in view of Donaldson’s observations in rats of marked adrenal hypertrophy in infected animals, but not in uninfected ones, and Goormaghtigh’s observations on the variability of the changes in infections following war wounds.

A critical review thus leads us to the conclusion that the evidence is against hypertrophy of the adrenal during pregnancy in the rat, mouse, rabbit and the cat. The hypertrophy found during the breeding season in the mole is found in both pregnant and non-pregnant animals as well as in males. There remain the conflicting findings of various observers of the guinea-pig. It has been shown that none of the work on the adrenals of pregnant guinea-pigs has been adequately controlled. It is possible that this animal differs in its reactions from other rodents, but the question must be left open until careful work has been.done with non-pregnant female controls of the same breed, age and weight, with a study of possible changes associated with the cestrus cycle and with scrupulous elimination of infected animals. Notwithstanding the limitations of work on postmortem material, the weight of evidence is against hypertrophy of the adrenals in pregnant women.


Technique

The animals used were of the same strain and kept on the same diet and under the same conditions as those used in our studies on the adrenal in cestrus [Andersen and Kennedy, 1932]. They were all bred in our laboratory, so that the exact age was known. The majority were killed during their first pregnancy, although one of the uninfected and several of the infected ones had previously had litters. All but five were killed between the ages of 120 and 200 days, the remainder being a few weeks older. The cycles were followed by means of vaginal smears, and the animals were mated for one night during cestrus, so that the exact length of pregnancy was known. They were then killed in groups of four to six at the following periods of pregnancy and lactation: the tenth, eighteenth and twenty-first days of pregnancy; during parturition, with part of the litter born and part unborn; and on the first, seventh, fourteenth and twenty-first days of lactation. In all, the series comprises twenty pregnant and twenty-one lactating rats. Forty-one more animals were used, but these were animals having some infection of the lungs or ears and were made to form a separate series. The experiments were carried on over the course of about 18 months as animals were available, and no seasonal variations were noted.

The animals were killed with chloroform, and the body weight both with and without the products of conception was noted. The animals were examined for infections, especially of the lungs and middle ears. The pituitary, thyroid, adrenals and thymus were then weighed in a closed weighing bottle and fixed in Zenker’s solution. In some cases from each stage one adrenal was fixed in formalin. Both adrenals from eight animals were serially sectioned and stained with hematoxylin and eosin: of these, three were from animals killed on the eighteenth day of pregnancy, two on the first day post-partum, and three from the twentyfirst day of lactation. Frozen sections stained for fat with Scharlach R were made of adrenals from animals of each phase. The series of animals studied in regard to cestrus and dicestrus and previously reported [Andersen and Kennedy, 1932] were used as controls.

The weights of the organs are calculated in terms of g. per kg. of total body weight and of net body weight. The total body weight is considered as the weight of the mother plus the uterus and its contents in the pregnant animals, or plus the weight of the litter in the lactating ones, conceiving of the young either unweaned or unborn as dependent on the mother for nourishment. The net body weight is the weight of the mother after the uterus and contents have been removed, or the weight of the lactating mother without regard to the litter. The results in regard to the adrenals will be reported here, and those in regard to the pituitary and thyroid will be reported in a subsequent paper.

In addition a group of four pseudo-pregnant rats, killed 1 week after mating with a vasectomized male, were included. Four rats killed after an anestrus period of 3 weeks or more, and nine non-pregnant animals dying of spontaneous infections were also studied for comparison.

No animals were used which were known to be infected at the time of mating, and the high percentage of infections is surprising in view of this limitation, the adequate diet, ample light and cage space, and careful attention to cleanliness. All the infected rats had the same type of lung infection so commonly found in rats, in which smaller or larger chronic abscesses are scattered through the lung, with occasional solidification of one or more lobes. A few also had middle ear infections. A few of the animals in the infected series were about a year old, and were among the first to be examined. Unsuspected infections were found much more commonly after the age of 6 months, and for the remainder of the experiment only young animals between 90 and 150 days of age at the time of mating were used. Since the degree of infection cannot be easily measured, and some rats having only a few abscesses had large adrenals, all animals having any evidence of infection whatsoever were eliminated from the

normal series. The calculation of the probable error was made from the formula

2. [ea P.E.=3 W Data.

The mean relative adrenal weight at various stages of pregnancy is given in Table I. It may be seen that in normal animals the relative adrenal weight is about the same in various stages of pregnancy. It is also quite uniform throughout lactation and is slightly heavier than in pregnancy. The largest figure, at 1 day post-partum, is due to a single large reading of 0-332 g./kg. in a rat in which no infection was discovered. This is more than 20 p.c. larger than any other rat of the entire series of normal pregnant or lactating animals, and is in the range of weight found at cestrus. In some cases the rat has a single cestrus period immediately post-partum and it was felt that this might be the case here, but unfortunately no vaginal smear was taken and this point could not be ascertained at the time that the large weight was discovered. The two animals of the same stage which were killed subsequently were carefully examined and had no cestrus changes in the uterus or in the vaginal smear, and, at the same time, had adrenals which corresponded in weight with those of the remaining rats of the series. The point, therefore, remains obscure.



Fig. 1. The relative weight of the adrenal gland in pregnant, lactating, non-pregnant and ancestrus female rats. Body weight approximately 200 g.




TaBxeE I. The mean weight of the adrenal glands in various stages of pregnancy. Uninfected animals

Body weight

in g. Adrenals Total Net g./kg. g./kg. with without total body net body Stage No. young young mg. weight weight 10 days pregnant 4 204 203 41-6 0-205 0-205 18 ,, ” 7 234 208 41-2 0-177 0-200 21 ,, *” 4 255 199 37-9 0-150 0-192 Parturition 4 247 195 42-0 0-171 0-217 1 day post-partum 5 243 197 48-1 0-201 0-248 7 days post-partum 5 253 197 45-2 0-179 0-230 14. =C«, ” 5 351 206 47-7 0-138 0-234 21 ,, ” 6 450 223 48-1 0-108 0-217 Infected animals Body weight in g. Adrenals Total Net g./kg. g./kg. with without total body net body Stage young young mg. weight weight

10 days pregnant 210 209 47-3 0-227 0-227 18 ,, ” 224 201 51-6 0-233 0-262 21, ” 274 230 54-6 0-200 0-239 Parturition

1 day post-partum 7 days post-partum 14 ,,

21 ” ”

259 «218 «S532 (0-208 0-253

373 2lss—(itiBDs« DQ 0-229


The mean weights for the series of pregnant and for the series of nonpregnant animals are given in Table II, with the figures for non-pregnant cestrus, dicestrus, ancestrus animals of approximately the same weight for controls. A group of rats dying of spontaneous lung infections is added for comparison with the less severely infected pregnant and lactating animals. The weights for the pregnant animals correspond with those of the dicestrus series and are much less than those of cestrus. The weights for the lactating animals are higher, with a probable error that


TaBLeE II. The mean absolute and relative weight of the adrenal glands in pregnant and lactating rats as compared with non-pregnant female rats of various types.

Uninfected animals

Adrenals cc Net body Actual g./kg. weight weight net body

Stage No. g. mg. weight Pregnancy 15 204 + 18 40-44 3-4 0-199 + 0-010 Parturition 4 195+ 11 42:04 0-7 0-217 + 0-013 Lactation 21 206 + 18 47-3438 0-232 + 0-021 Pseudo-pregnancy 4 203+ 5 45-8 4+ 3-3 0-227 + 0-021 Cstrus 13 Over 180 49-244-3 0-237 + 0-016 Dicstrus ~ 6 ” 42-04 2-4 0-212 + 0-006 Aneestrus 4 VW7Ai7 29-0 + 3-4 0-164 + 0-018

Rats dying of infection

Infected animals A.

—_ — Adrenals = ]U!V"_"' Net body Actual g./kg. weight weight net body Stage No. g. mg. weight Pregnancy 21 211+ 19 51-5 + 6-1 0-247 + 0-033 Parturition _— — — _ Lactation 20. «2124 22 50-9454 0-243 + 0-024 Pseudo-pregnancy _ — _ _ CEstrus _— _ _ _— Dicestrus — _— _ _— Anestrus _— _— _— — Rats dying of infection 9 160 + 26 690476 0-442 + 0-046

is fairly significant. There is no correlation between the size or total weight of the litter and the size of the adrenal. The adrenal weights for the pseudo-pregnant animals correspond with those of the pregnant ones, as might be expected. The somewhat higher mean is the result of one large figure, while the other three correspond closely with the pregnant ones. It is obvious that hypertrophy of the adrenals in relation to reproductive phenomena in the rat is found in connection with cestrus and to some extent with lactation, but not with pregnancy.

The infected animals show much greater variation in the adrenal weight than the uninfected ones, with some increase in mean relative weight. The figures for the various phases of pregnancy and lactation cannot be interpreted to mean a greater or lesser adrenal sensitivity to infection, because the degree of infection varies and in some groups there are a greater number of severely infected animals. There is a rough correlation between the degree of infection and the degree of adrenal hypertrophy and only a few of the slightly infected animals have larger adrenals than the normal ones. For example, of the five infected rats killed on the tenth day of pregnancy only one was severely infected, with consolidation of one lobe of the lung and many small abscesses in the other lobes, while the remaining four rats had only a few scattered small abscesses. The severely infected rat had an adrenal weighing 0-281 g./kg., while the heaviest of the others weighed 0-228 g./kg. Six of the eleven animals killed on the first day post-partum had quite severe infections, and most of these had large adrenals. The mean weight for this stage is consequently large. The rule does not hold exactly, however, for several of the severely infected animals in the series had small adrenals, and another factor or other factors must be present.

Hypertrophy of the adrenal in these spontaneous lung infections in the rat occurs also in non-pregnant animals. In a series of nine nonpregnant animals dying of such infections the mean actual adrenal weight was 69-0 mg. and the mean relative adrenal weight was 0-440 g./kg., a figure very much higher than that for the animals with milder infections.

A study of serial sections of the pregnant animals reveals no striking changes from the appearance of the dicstrus rat which has been previously described. There is a little more lipoid in the fascicularis in some of the lactating animals, as shown by the Scharlach R stain on frozen sections, but this is not so striking as to enable one to distinguish between the pregnant, lactating and dicestrus adrenals with any degree of consistency.


Discussion

It is obvious from the data presented here that, in the normal rat, there is no adrenal hypertrophy during pregnancy. The weight and histological appearance correspond with that of non-pregnant dicestrus animals. This does not necessarily hold true for other species, such as the guinea-pig, in which the cestrus cycle is longer. In our series of four rats which had had no eestrus cycles for some weeks, the adrenals were smaller than those of either the dicestrus or pregnant animals. In the short cycle of the rat the post-cestrus or uterine phase of the cycle is so closely followed by the next cestrus that it is difficult to surely distinguish the post-cestrus from the dicestrus phase. It is quite possible that inananimal having a longer cycle, such as the guinea-pig, the adrenals continue to decrease in size after the post-cestrus period, assuming that cestrus hypertrophy in other animals occurs, which is as yet unproven.

An interesting point is brought out by a comparison of the actual weights and the relative weights in relation to the total and net body weights as described above. In a study of the figures for the individual rats it is seen that the most constant figure is that of the relative weight per net body weight. The actual weights vary with the body weights. This greater uniformity and, therefore, greater significance of the relative weight per net body weight over the actual weight is also shown by the probable error, which is about 5-0 p.c. of the mean in the case of the relative weight and 8-6 p.c. of the mean in the case of the actual weight in pregnant animals. The relative weight in relation to the total body weight decreases as the products of conception increase, but varies greatly (Table I). For example, in one rat weighing 196 g. and 54 g. of uterus and contents, the actual adrenal weight is 39-5 mg., the relative weight per total body weight is therefore 0-158 g./kg., while the relative adrenal weight per net weight is 0-202 g./kg. or very near the mean for dicestrus and pregnancy. This means that the physiological burden on the adrenal is not sufficiently increased or altered by cestrus, lactation and infection. Whatever may be the function of the adrenal, it does not appear to be involved in the preparation of nutrient material for the embryos. The embryos themselves acquire relatively large adrenals at a very early stage.

That the adrenals of pregnant rats hypertrophy more readily in the presence of infection than those of non-pregnant animals as suggested by Donaldson [1924] is not clear, since the majority of the non-pregnant female rats of our colony with even a mild degree of infection have long periods of ancestrus. Those with slight infections have the very small adrenals found in the uninfected ancestrus rats, while those with more extensive processes have adrenals of varying sizes up to 0-090 g. A series of non-pregnant infected animals would, therefore, include adrenals both smaller than and as large as those in a series of pregnant infected rats, and the comparison is difficult. In our relatively short series the greater frequency of severe infections during lactation over the number found in the earlier stages of pregnancy may not be significant, but it is suggestive.

The question of a possible relationship between the corpus luteum and the adrenal cortex has interested many investigators from Mulon [1906] and Watrin [1914] on. In recent years several papers have appeared which deal with a difference in the survival period of pregnant and non-pregnant animals following adrenalectomy. A prolongation of the survival period in pregnant animals was first described by Stewart [1913] in cats; but the survival period in most of his animals was shorter than is considered usual in non-pregnant animals at the present time. A more marked prolongation of the survival period was reported by Rogoff and Stewart [1927] in a series of seventeen pregnant dogs. The maximum survival period in seventy-four non-pregnant and male animals was 15 days (two dogs), while the majority died between the fourth and twelfth day. Of the seventeen pregnant animals five lived for 13 to 15 days and eight lived over 17 days, some of the latter surviving many weeks. They believed that this prolonged survival period was due to the presence of the corpus luteum, since they also obtained unusually long survival in two non-pregnant animals which were adrenalectomized towards the end of an cestrus period and therefore had corpora lutea. Corey [1928] repeated the experiment on cats and did not find a prolongation of the survival period in twelve pregnant animals as compared with three non-pregnant females and three males. The matter must therefore be left open, although the former report is more convincing, both because of the experience of the workers, and because of the greater significance of positive over negative findings in a question where operative technique is so important. The report by Carr [1931] of a prolonged survival period in pregnant rats may be disregarded, since non-pregnant rats may survive adrenalectomy indefinitely, presumably because of the presence of accessory fragments of cortex. If we accept the findings of Rogoff and Stewart, their interpretation must be left until further elucidation of the cortical function; the two hypotheses that appear possible are that the corpus luteum can act as a substitute for the adrenal cortex—a theory based largely on histological similarities; or that, for some other reason, less of the secretion of the adrenal cortex is necessary during pregnancy.

The present confirmation of Verdozzi’s findings of hypertrophy of the adrenal during lactation does not greatly clarify the question of the relation between the corpus luteum and the adrenal. A large adrenal is found during cestrus when the corpora lutea are not active and during lactation when they are; a small adrenal is found during pregnancy and pseudo-pregnancy when the corpora lutea are active, and during dicestrus when they are not; and a still smaller one during ancestrus when neither corpora nor follicles are active. Yet the pregnant dogs of Rogoff and Stewart survived adrenalectomy longer than the non-pregnant ones. The resolution of these apparently incompatible phenomena into a logical hypothesis cannot be accomplished as yet, but it would seem probable that the relationship between the corpus luteum and the adrenal cortex is not a direct one.

It has not yet been proven that a hypertrophied adrenal is an overactive one, and this will doubtless not be settled until the function of the cortex is known, since the hypertrophy of the adrenal is usually due to hypertrophy of the cortex. The conditions in which hypertrophy has been found are beriberi, starvation [McCarrison, 1921], some infections, cestrus or the mating season, and lactation; these are all occasions of especial strain on the organism. However, other types of strain are not accompanied by adrenal hypertrophy, and the common denominator in this series is not obvious.

Conclusions

  1. The mean actual weight of the adrenals in a series of fifteen pregnant rats is 40-4+ 3-4 mg. The mean weight as expressed in terms of g. per kg. of the body weight of the mother minus the products of conception is 0-198 + 0-010. There is but a small variation in the relative weights so calculated.
  2. The corresponding figures for a group of four rats killed during parturition are 42-0+ 0-7 mg. and 0-217 + 0-013 g./kg. There is no definite change either just before, during, or just after parturition.
  3. The mean actual weight of the adrenals in a series of twenty-one lactating rats is 47-3 + 3-8 mg. The mean relative weight, calculated as described above, is 0-232 + 0-021 g./kg. This is higher than in the pregnant animal, and appears to be a significant increase.
  4. As compared with the non-pregnant controls described in a previous paper it is found that the relative and absolute weight of the adrenal in pregnant rats is the same as in non-pregnant rats examined during dicestrus, and is considerably less than the weight during cestrus. It is greater than the weight in animals killed after a long period of ancestrus. The adrenal weight in lactating animals is slightly less than that during cestrus.
  5. A series of four pseudo-pregnant rats had adrenals resembling those of pregnant animals.
  6. In pregnant and lactating rats which are found at autopsy to have lung infections the adrenal weight is much more variable than in normal animals. In moderate or severe infections it is 25-50 p.c. greater, and in the slight infections it is sometimes greater and sometimes not. The degree of enlargement corresponds roughly to the degree of infection.
  7. The histological appearance of the adrenal in the pregnant animal resembles that in the non-pregnant dicstrus one. The adrenal of the lactating animal contains a little more lipoid in the fascicularis.
  8. A critical survey of the literature reveals that the balance of evidence is against hypertrophy of the adrenals during pregnancy in the rat, mouse, rabbit and cat. There is hypertrophy of the adrenals of both sexes during the season of rut in the mole, but this has not been shown to be characteristic of pregnant animals in particular. The evidence for such hypertrophy in the guinea-pig is not adequately controlled in any series and the truth of the matter is in doubt. The studies on human autopsy material yield conflicting results, although the most reliable work is against such hypertrophy.


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