Sexual Skin Research Articles

Tolerance of the Rhesus Monkey to Pituitrin Injections and Absence of Uterine Bleeding Following Injection

The following experiments were performed to test the possible r∘Cle of pituitrin in the causation of menstrual bleeding. Incidentally the high tolerance of the Rhesus monkey to pituitrin was demonstrated. By observing! the vascular phenomena in intra-ocular transplants of the endometrium Markee has shown that the most constant feature of menstruation is the constriction of the spiral arterioles of the functionalis layer. In view of the further finding of Hartman and Firor that menstrual bleeding could be elicited in monkeys from which the anterior but not the posterior pituitary had been removed, it seemed reasonable to suppose that pituitrin might be responsible for the vasoconstriction that leads to necrosis and sloughing of the functionalis in menstruation. Preliminarily, a number of female monkeys were injected with large doses of pituitrin to determine tolerance as well as the effect of the drug on the sex color, which has also been shown to be a vascular phenomenon, Two experiments are cited. Monkey No. 7, 15-year-old female having constantly red buttocks and nipples, shade No. 9 on a color scale of 10. Bleedings occurred on September 19, November 1, 1934, and January 31, 1935. On December 11, 1934, five units of pituitrin were injected intravenously. Clotting of blood was prevented by the use of a calculated amount of heparin. In 3 minutes the color of nipples and sex skin had dropped to 7; in 4 minutes to 6; in 7 minutes to 4. In 12 minutes it was back to 7. Monkey No. 108, old female, buttocks constantly red—9 on a scale of 10. On December 11, 1934, day 7 of the cycle, 10 units of pituitrin were injected intravenously. The right and the left sides of the sex skin blanched at different rates, as follows: in 2 minutes, 7 and 6 respectively; in 3 minutes, 6 and 4; in 5 minutes, 5 and 3; in 6 minutes, 4 and 2. Although the injection was made into the right saphenus vein it was the left half of the sex skin that suffered the greater blanching.

The occurrence of an oestrogenic substance in the sexual skin of monkeys

The occurrence of an oestrogenic substance in the sexual skin of monkeys

Length of Gestation Period and Menstrual Cycle in the Chimpanzee

THIS note should have been written a year ago, but during the preceding two years I was working at the Anthropoid Experiment Station of Yale University, in Orange Park, Florida, U.S.A., in a rather isolated place without adequate library facilities, and therefore had no opportunity to read Dr. R. C. Clarke's notes on the birth of a chimpanzee1, in which he states: ” Although the preconceived idea is that the period of gestation [in the chimpanzee] is nine months I cannot help feeling that it is five months, at any rate all the evidence points to it in this case” (1, p. 732). Dr. Clarke does not give either the menstrual history of his female preceding the time (December 1, 1933) when she was ” properly served” or the date of the infant's birth. On the basis of information given in the article by J. M. Wyatt and G. M. Vevers2 and the time of acceptance of Dr. Clarke's publication one can surmise that the infant was born in the first half of May, 1934. The parents of the infant had lived together for a period prior to the first observation of proper mating, during which time there was a ” certain amount of sexual play”. Because of this fact there is a possibility that the date of conception assumed by Dr. Clarke is not correct. The female may have been fertilised during one of sexual play. The December swelling and acceptance of the male do not preclude this possibility, for there are records proving that chimpanzee females may have swellings of the sex skin and be receptive during the gestation period4.

Further Studies of Sex Skin Reactions in Macaca Mulatta

It has previously been reported that the sex skin reactions of rhesus macaques, which can be called forth by injection of oestriol, eventually spread over a wide extra-genital area if the injections of this hormone are continued for longer than a month. Minor degrees of this extra-genital oedema can be observed in many untreated cyclic females at certain periods of the year, but the full manifestations possible after prolonged oestriol treatment have not been observed to date in a considerable experience with untreated macaques. In the further study of these phenomena, it was of interest to see whether the results obtained with oestriol could be duplicated with oestrone. Also, in view of the symmetrical character of the sex skin reactions, it was felt desirable to investigate a few relationships of the segmental nerve supply of the affected areas to the reactions occurring therein. Females only were used. Two adult castrates, one adolescent castrate, and 2 adolescent but acyclic intact animals were injected subcutaneously once daily for 48, 48, 74, 74 and 76 days respectively with 500 y of crystalline-folliculine (Girard) dissolved in corn oil. A typical experiment will show that the responses previously elicited by oestriol were duplicated by the use of oestrone. Monkey No. 885, a 4275 gm. female castrate, had been used during the original experiments with oestriol, but had received no treatment for 7 months.

Action of Gonadotropic Hormone from Pregnant Mare's Serum on Ovaries of Rhesus Monkeys.

Since the demonstration of Cole and Hart that the blood serum of pregnant mares contains large amounts of gonadotropic hormone, this hormone has been the subject of much investigation. Although the recent work of Catchpole and Lyons indicates a placental origin of the hormone, it has been found to have biological effects similar to those found in the pituitary gland and to differ markedly from the chorionic hormone of human pregnancy. Thus the experiments of Evans, et al., have shown that the hormone of the pregnant mare is able to cause a marked enlargement of the ovaries of hypophysectomized rats, and it has been found to possess a pronounced stimulating effect on the testes and the comb growth of infantile cocks (Hamburger) just like the anterior pituitary hormone, while the gonadotropic hormone from the urine of human pregnancy is ineffective in this respect. The difference between the effects of extracts of human pregnancy urine and extracts of anterior pituitary or from castrate urine on the ovary of the monkey has been previously reported (Engle, Smith and Engle). It has been of interest, therefore, to investigate the effects of an active extract of the serum of pregnant mares on the follicular structure and activity of the ovary of the macacus monkey. Six females, 5 preadolescent and one adult, have been used in this preliminary experiment, the details of which are set forth in Table I. The results have indicated that, regarding the functional activity and structural changes of the ovary of the monkey, the active principle of pregnant mare's serum closely resembles that found in urine of castrate women. The oestral response of the sex skin of the monkey, seen on day 5 or 6 of treatment, is quite similar to that obtained by oestrin, A.P. or C.U. (Allen, Hisaw et al., Engle), and progresses characteristically until the conclusion of treatment after 10 days.

Some uterine effects obtained in female monkeys during continued oestrin administration, with especial reference to the cervix uteri

Observations particularly of the cervix of 4 female castrate rhesus monkeys given large doses of estrin are reported. Estrin (amniotin Squibb) in corn oil was injected daily for 60 80 110 or 170 days. At autopsy squamous cells apparently new growths not connected with the vaginal epithelium were seen in circumscribed areas throughout the cervical glands. The most extensive replacement of columnar cells by squamous cells was at the cervical apex . Growth was in the direction of the lumen and did not penetrate the supporting tissues; in general it did not show malignant characteristics. The greatest endometrial proliferation occurred in the animal treated for only 60 days this result suggesting the possibility of an exhaustion effect. There was a periodic flushing and blanching of the sexual skin during the latter portion of the injections and unexplained uterine bleeding was observed.

The effects of prolonged œstriol administration upon the sex skin of macaca mulatta

The work of Collings (1926), Allen (1927, 1928), Morrell (1930), and Parkes and Zuckerman (1931) on rhesus monkeys has established the fact that the brilliant coloration of the skin about the genitalia and the face, loosely referred to as the sex skin, and seen in both the female and male of this species, can be called forth by the administration of œstrous-producing hormone. Parkes and Zuckerman could not produce it in the case of one castrate male rhesus and a castrate female bonnet monkey. M. radiata , but they obtained in an ovariectomized baboon the full swelling seen during the follicular phase, and Dohrn, Hohlweg and Schoeller (1932, 1933) working with both male and female baboons and employing crystalline “ progynon,” were uniformly successful in eliciting a reaction, which in the male specimens of this species consisted of a remarkable œdema of the genitalia. In the present paper we should like to report our own experiments concerning this particular skin reaction to œstriol. Material and Technique Eight macaques, including one immature and four adolescent animals, were studied. Of the total, five were normal animals, four of these being males. The remaining three comprised one castrate male and two hypophysectomized-castrate females.

CYCLICAL CHANGES IN THE VAGINA AND VULVA OF THE FERRET

The vagina and vulva of the ferret undergo well‐marked cyclical changes in correlation with those of the ovaries and uterus.During the anœstrum the vulva is small and the connective tissue of which it is mainly composed is compact. The vagina during this period is lined by a low columnar epithelium consisting of only two or three rows of cells and without a cornified layer.During the pro‐œstrum and œstrus the vulva swells up to about fifty times its anœstrous size, the submucous connective tissue becoming spongy and the nuclei of the cells widely separated. The vaginal epithelium is several layers in thickness, and in the deeper part the cells become high and squamous. There is a pronounced cornified layer. Later, during cestrus, the cornified layer begins to slough, the process being continued over some time. The entire period represents the “follicular stage” of LOEB and other authors, and is presumably brought about by the action of œstrin. The vulval swelling serves the purpose of facilitating effective copulation which in the ferret is very prolonged.During pregnancy and pseudo‐pregnancy (the latter condition in the ferret only occurring under experimental conditions as after copulation with a vasectomised male) the vulva is reduced to its ancestrous size. The reduction is accompanied by lymphoid degeneration and an invasion of leucocytes. The vaginal epithelium becomes reduced to a low columnar or cubical structure. There is no cornified layer, this being completely shed during œstrus. This period clearly represents the “luteal phase” in the ovarian cycle.It is to be noted that the vulval swelling and other characteristics of the follicular stage terminate with ovulation just as does the swelling of the sexual skin in the Primate, as described by ZUCKERMAN and PARKES.The description of the changes here recorded are in general agreeument with the observations by PARKES (1930) on the vaginal smear at different stages of the cycle in the ferret.The vaginal cycle in the ferret is in a general way similar to that of the dog, as described by EVANS and COLE. It may be again remarked, however, that pseudo‐pregnancy only occurs under experimental conditions in the ferret, yet under the influence of pro‐gestin secreted by the corpus luteum the vagina and vulva undergo similar changes during both pregnancy and pseudo‐pregnancy.

15. The Menstrual Cycle of the Primates.‐Part III. The Alleged Breeding‐season of Primates, with special reference to the Chacma Baboon (Papio porcarius)

Summary. During March, April, and May of 1930 observations were made in South Africa on the Chacma Baboon (Papio porcarius). Baboon packs, in which were nursing females as well as females with sexual skin swelling, were seen in the Eastern and Western Provinces. On May 4th twelve females belonging to the same pack were killed near Grahamstown, in the Eastern Province. Four were non‐pregnant: one of these was menstruating, one was in the pre‐ovulation, and two in the post‐ovulation phase of the cycle. Five were pregnant: the first of these had an embryo 2·5 mm. in length, the second one of 16·5 mm., the third one of 19 mm., the fourth one of 65 mm., and the fifth an apparently full‐term male fœtus with a crown‐rump length of 230 mm. Three were lactating, and their babies were caught alive. Data are provided regarding the times of milk‐tooth eruption in baboons, indicating that two of the babies were about two months old and the third about four months. A complete reproductive cycle in the baboon—the shortest interval of time between two births by the same female—is approximately a year. The females shot on May 4th were representative of practically all stages of the cycle. This proves that the Chacma Baboon has no demarcated breeding season, but that it can give birth at any time of the year. The question of the breeding of other Old World primates is discussed. Records of monkey births in captivity indicate that most Old World primates can conceive at any time. The possibility that there exists a seasonal variation in the monkey's conceptility rate does not conflict with the underlying fact that, the baboon, and probably most other Old World primates, has no demarcated breeding‐season. There is a fundamental distinction between mammals with a fixed anœstrus, like the ferret, and mammals like the baboon that have no anœstrus.

Menstruation and the Anterior Pituitary.

The prevailing gynecological opinion in the textbooks and the gynecological literature generally holds that menstruation is due to the degeneration of the corpus luteum and that the menstrual flow proceeds exclusively from a “pregravid” (swollen, congested, secreting) endometrium. We contend that this is a post hoc, propter hoc argument, a time relation mistaken for cause and effect, a conclusion without the slightest experimental evidence. The chief facts that have called this generally accepted notion in question were the outcome of the work of Geo. W. Corner, who found that periodic uterine bleeding in monkeys often does occur from uteri not at all enlarged and unaccompanied by corpora lutea in the ovaries. This conclusion has been corroborated by a very extensive series of observations involving scores of laparotomies and hundreds of rectal palpations of the organs in fully adult monkeys of the Carnegie colony at Baltimore. On the basis of these findings and other considerations which will not be taken up at this place, the senior writer has contended that there is an active substance originating outside the ovaries that causes the periodic bleeding which we call menstruation. Over a dozen hypophysectomies (Dr. Firor) have enabled us to announce that it is the anterior pituitary that elaborates the substance causing uterine bleeding. The evidence is as follows: 1. Ablation of the hypophysis abolishes the cycle, the sex organs atrophy, the sex skin becomes pale as in the pre-adolescent female. 2. Administration of ovarian hormone (Allen-Doisy in the form of Amniotin Squibb) to a female monkey, whether ovariectomized or not, causes the bleeding. Even a one-year-old baby, of the “equivalent age” of a 3- or 4-year-old girl, can be made to bleed with as little as 90 rat units.

THE RESULTS OF ORAL ADMINISTRATION OF AMNIOTIN TO MONKEYS*

In previous experimental work we showed that when amniotin is administered by the vaginal route 2.5 times as much was necessary as when injected subcutaneously to produce an artificial sex cycle. This ratio was found to be the same in spayed rats and in ovariectomized monkeys. Until the present time no satisfactory evidence has been given to show whether or not the follicular hormone is active when given by mouth. Many have thought that the hormone was destroyed by the digestive enzymes. Hannan claims that he obtained an estrus reaction in spayed rats when he administered 100 times the ordinary dosage. We administered amniotin by stomach tube to the ovariectomized monkeys (Macacus rhesus) in our colony. After some preliminary difficult in getting the stomach tube inserted no trouble was experienced. The amniotin was administered once a day for five consecutive days. All monkeys used had been under observation for months. All were completely ovariectomized. The ordinary commercial preparation of amniotin and special solutions of the hormone in alcohol and glycerin were used. No difference was noted in either the types of reaction nor the amounts necessary. Vaginal spreads were taken daily and observations made of the condition of the sexual skin.

OVAEIAN HORMONE EFFECTS IN OVARIECTOMIZED MONKEYS

In earlier experiments reported from this laboratory effects of ovarian and placental extracts2 upon adult and immature monkeys have been described (Allen, 1, 2, 3). This work has demonstrated first, that the reddening and swelling of the “sexual skin” and also the growth which normally occurs in the genital organs and mammary glands during the first half of the menstrual cycle may be induced by administration of this hormone and, second, that experimental menstrual periods follow cessation of injections of hormone in a majority of ovariectomized monkeys. In the above experiments, however, full pre-menstrual development of the glands of the endometrium was not obtained. Consequently it appeared that the experimental menstrual periods in these ovariectomized animals corresponded more nearly to those occurring in normal monkeys in the absence of ovulation (Van Herwerden, 4, and Corner, 5). It seemed desirable therefore to continue the experiments with increased dosages of hormone in an attempt to ascertain ...

Reactions of immature monkeys (Macacus rhesus) to injections of ovarian hormone

AbstractSeries of injections of ovarian hormone have been made into normal and ovariectomized immature animals. Injections were made twice daily for twenty‐two days. The total dose exceeded 1000 rat units per animal.Effects noted in the living animals were the appearance of reddening and swelling of the ‘sexual skin’ and change of the cell content of the vaginal smear to the interval type of the mature animal. Measurements made at operation, before and after injections, indicated considerable enlargement of both the cervix and body of the uterus. The thymus glands of the injected animals weighed significantly less than those of the controls. Histologic study of the genital tract showed extreme thickening of the vaginal walls, considerable growth of the uterine epithelium and glands, hypertrophy of the muscle layers of the uterus, and advanced differentiation of the epithelium of the uterine tubes.The ovaries of the injected normal animal were smaller and contained fewer primordial and medium‐sized follicles than those of the controls. The presence of large numbers of atretic follicles, especially large flattened scars from former relatively well‐developed follicles also suggests a harmful effect of this amount of ovarian hormone upon follicular development. Several stages of elimination of ova from polyovular follicles were also observed. There was marked growth in the ducts and an increase in the number of alveoli of the mammary glands.

Sex Characteristics in Monkeys.

Female monkeys during sexually mature life show the sex characteristics of reddening and swelling of the skin about the external genital organs, on the buttocks and medial surfaces of the thighs. These phenomena disappear after double ovariectomy and can again be induced in spayed animals by injections of ovarian and placental extracts. Three male monkeys in our colony had never shown this cutaneous reddening. (It has, however, been reported that male monkeys may show this reddening during the breeding season.) During the late summer and fall the 'sexual skin'rf a large 7-year-old male began to redden. During November and December the regions affected covered an area 15×13 cm. in extent. The reddening reached a moderate intensity but never approached the maximum 'sexual skin'rolor of the mature female. From our experiments with ovarian hormone in inducing this condition in spayed animals, it seemed logical to infer that this condition in the male might be due to the male sex hormone. Needels had previously reported a series of blood tests in our monkeys by a modified Manoilov technique, a test supposed to distinguish male from female blood. To our great surprise the blood of this fully grown, finely developed, 6-year-old male had consistently given a'lemale'reaction. Two younger males, one of which was immature, returned typical'lale'rests. This test seemed essentially a reduction reaction, the male blood usually causing a greater reduction of the reagents than the female blood. But Needel's results indicated fluctuation especially in females when tests were repeated upon the same individuals. Consequently a graded series of color standards were prepared for comparison. The tests ranged from no decolorization (‘female’) to complete decolorization (‘male’). Several conclusions were drawn : (1) There was a distinct variation in individual female monkeys during the menstrual cycle.