Search

The status of research on the physiologic control of fertility is reviewed. Each of the steps for both male and female reproduction is vulnerable to interference. Inhibition of ovulation can be produced by inhibiting gonadotropin secretion. Norethynodrel and norethisterone are 2 preparations which offer effective contraceptive control when taken regularly. These compounds may inhibit spermatogenesis as well but have the side effect of inhibiting androgenic hormone thus reducing potentia and libido. Inhibition of gonadotropic action on the gonads can be accomplished in animal experimentation with Lithospermum ruderale extracts. Investigation of the biologic activity of the extracts are in progress. Immunologic procedures for contraception include use of antibodies to agglutinate substances in semen formation of antibodies against germ cells and immunochemical inhibition of reproductive hormones. Interference with early development of the zygote is possible with MER-25 an analogue of a synthetic estrogen Tace. Early experiments indicate it is possible to destroy eggs before the leave the fallopian tubes. M-xylohydroquinone prevents nidation by its effect on the endometrium. Interference with embryonic development after nidation can by accomplished with folic acid inhibitors which block normal amino acid incorporation in protein synthesis. Spermatogenesis can be inhibited with nitrofurans which however have unpleasant side effects. Alkylating agents effect spermatogenesis. Application of heat to testes will also interupt spermatogenesis. Interference with sperm passage is effected through vasectomy. This operation may prove an acceptable contraceptive method if its reversibility can be increased.

RECENT STUDIES have demonstrated that the estrogenic substances are definitely related to carcinoma of the mammary gland. This was be′ lieved to be true for many years, but it remained for Lacassagne (i) and others to show, by the administration of large amounts of estrogenic hormone to mice for many months, that true mammary carcinoma could be induced. That the estrogenic hormone may be involved in the etiology of neoplastic growths of the uterus has been suspected. Indeed, Witherspoon (2), on the basis of the observation that fibromyomas are frequently associated with cystic ovaries, suggested that the former may be due to a stimulation of the uterine muscle and connective tissue by estrogenic hormone.During the past two years we have injected 137 female guinea pigs with estrogenic hormone in oil solution for periods ranging from 3 weeks to 14 months. About 50 of these animals are still under treatment

FIFTEEN of the cases described in the companion papers (1 and 2) were available for treatment. Therapy was deemed advisable for some because of their eunuchoidism, for others because of their climacteric symptoms but for most because of their lack of vigor and subnormal muscular strength. Those with marked gynecomastia, but with otherwise fairly normal development, were given androgenic therapy in order to gauge its effect upon the excessive breast development. Therapy consisted of daily injections of testosterone propionate5 given intramuscularly 5 times weekly to 14 of the 15 subjects. Methyl testosterone was administered sublingually in the form of specially compressed tablets or in the form of a liquid (dissolved in propylene glycol) in several instances. Implantation of 6 to 8 free testosterone pellets, weighing 75 mg. each, was undertaken in 5 Cases. In four instances determinations of the gonadotrophic excretion before, during and after therapy were made.

While the participation of some extra-insular factor in pancreatic diabetes had been suspected for many years it remained for Houssay and Biasotti (1), as a climax to a long series of experiments, to demonstrate that the anterior hypophysis plays an important role in carbohydrate metabolism. They were able to show that pancreatectomy in the hypophysectomized toad or dog as a rule is not followed by the usual sequelae of pancreatic deprivation. These animals instead of dying within a few days of acute diabetes often survive for many months. Confirmation of Houssay’s studies has appeared from several sources (2, 3, 4, 5) so that it would appear to be well established that the anterior pituitary secretes a hormone which in some fashion elevates the blood sugar. The modified form of diabetes observed in hypophysectomized animals suggested the possibility of securing the same result by suppressing the ‘diabetogenic’2 factor with oestrone. This procedure, based on the demonstration (6, 7, 8) that oestrone exert...

BBRK, J. E. Clinical experience with dihydrotachysterol in the management of idiopathic hypocalcemia.Report of a case. To appear in this Journal.A case of hypocalcemia is reported. The etiology is not certain but appeared to be of hypoparathyroidorigin. The more common therapeutic agents were ineffectual, but dihydrotachysterol (A.T. 10)pioved very successful. Detailed studies are presented of the serum calcium levels during the period ofhospitalization and follow’up.CANZANELLI, A., R. GUILD AND D. RAPPORT. Further observations on the effect of thyroglobulin andO2 consumption of tissues in vitro. To appear in this Journal.Using a Warburg’Barcroft differential manometer system the effect of thyroglobulin and thyroxinupon the in vitro O2 consumption of guinea’pig kidney, testis and heart was investigated. At lowerlevels of metabolism thyroglobulin stimulated the metabolism of each of these tissues.

BISCHOFF, H. W., AND W. R. LYONS. Immunologic investigation of hypophyseal tnammotropic prepara′tions. To appear in this Journal. Mammotropic (lactogenic) preparations made from beef or sheep pituitaries were found to be an′tigenically indistinguishable as far as could be determined by the technics employed for active and passive anaphylaxis, Dale and Arthus reactions, precipitin and complement fixation tests. As little as 12 micro′grams of beef or sheep mammotropin sufficed to produce anaphylaxis in sensitized guinea pigs, whereas normal guinea pigs receiving 20 milligrams showed no bad effects. Severe skin reactions were produced in rabbits sensitized to either beef or sheep mammotropin when they were injected intradermally with 1.0 mg. of either beef or sheep mammotropin. The mammotropic preparations were free from serum proteins and whether made from beef or sheep pituitaries they produced in rabbits, precipitins or complement fixing antibodies capable of reacting equally well to like concentrations o...

When female rats are treated for a brief postcopulatory period with an adequate dose of 1-(rho-2-diethylaminoethoxyphenyl)-1-phenyl-2-p-anis ylethanol (MER-25) implantation never occurs. The animals enter a period of pseudopregnancy characteristic of rats following sterile mating and upon resumption of estrous cycles are completely capable of bearing normal litters. Results of experiments indicate that the antife rtility effects of MER-25 are exerted prior to exit of ova from the oviducts. The compound does not act by preventing decidua development nor by interfering with postcopulatory maintenance of luteal body function. Histologic evidence indicates that ova of females treated with MER-25 undergo degeneration after extrusion of the second polar body.(AUTHORS MODIFIED)

A considerable amount of progress has been made since the original studies on the lactogenic hormone of the anterior pituitary by Strieker and Greuter (1), Corner (2), and Nelson and Pfiffner (3, 4), toward an understanding of the physiology of milk secretion. These and other confirmatory studies were made on animals with intact hypophyses and thoroughly demonstrated the relation of the anterior lobe to the initiation of lactation. The ablation of the pituitary in lactating animals demonstrated the necessity of that gland for the maintenance of milk secretion. See Nelson (5) for a review of these studies. It was reasonable to suppose that the administration of lactogenic hormone to hypophysectomized animals would result in the initiation of lactation. However, the results of such studies have been conflicting. Lyons, Chaikoff and Reichert (6) and McPhail (7, 8) reported the initiation of lactation in hypophysectomized dogs, ferrets, and cats while Selye, Collip and Thomson (9) were unable to do so in the ...

IN SPITE of the concerted efforts which have been made to clarify the functional position and metabolic significance of nucleic acids very little in the way of established interpretations can be offered. Caspersson (1950) and Brachet (1950) have discussed the significance of nucleic acids in the synthesis of cellular proteins, Claude (1940, 1941, 1942, and 1948) has shown that cytoplasmic pentose nucleic acid (PNA) occurs in combination with phospholipids and Hevesy (1948) and Davidson (1950) have pointed out certain relationships between PNA and the components of the acid-soluble phosphorus (ASP) fraction. It has been reported that fasting and protein-poor diets (Davidson and Waymouth, 1944; Davidson, 1945), ischemia (Drochmans, 1947), adrenccorticotrophic hormone and high carbohydrate diet (Baker, et al., 1948), and hypophysectomy (Geschwind, Li and Evans, 1950) all cause a decrease in pentcse nucleic acid (PNA) but no change in desoxypentose nucleic acid (DNA) in the liver.

With recent progress in the field of endocrine physiology we are recognizing the existence of an extensive inter-relationship among the various endocrine glands and their hormonal products. In some instances these relations appear to be of a reciprocal nature, i.e., each of a pair of interrelated glands exerts a controlling influence on the other member of the pair. The relation between the anterior hypophysis and the gonads would appear to be of this nature, and, furthermore, evidence is at hand which indicates that this relationship is active in the control of certain other physiological activities. In this paper it is proposed, in addition to outlining the general theory, to present physiological and histological evidence of the action of the gonad hormones on the anterior hypophysis and to consider the control of certain other physiological activities. Although the earlier studies† of many others indicated the existence of a reciprocal influence between the anterior hypophysis and the gonads, Moore an...

Antihormone formation in patients receiving gonadotropin therapy is discussed. The information presented was obtained for the most part from studies of the effects of sheep pituitary gonadotropin in infertile men and of hog pituitary gonadotropin in women. It has been demonstrated that prolonged administration of gonadotropic hormones derived from 1 species to an individual of a different species can elicit formation of substances capable of preventing the action of the administered hormones. These inhibitory sustances have been termed antihormones and are similar to if not identical with antibodies. Antihormones formed during Month 2 or 3 of treatment in each of 7 infertile men receiving daily injections of sheep pituitary FSH and in 4 women and 2 men who received hog pituitary FSH. Antihormone titers reached peak levels within 1 month after stopping treatment and usually remained at detectable levels for 2 to 4 months. In men receiving FSH no definite changes occurred in number motility or morphology of sperm during Month 1 of treatment. Antihormones formed during Month 2 of treatment resulting in inhibition of spermatogenesis. The administration of FSH to 7 patients having functioning ovaries produced prompt increases in estrogen excretion cystic follicular enlargement of the ovaries and breast changes indicative of increased estrogen secretion. Antihormones appeared during Month 2 or 3 treatment in each of 4 patients who received hog FSH for periods of 2 months or longer. 2 of the patients were individuals in whom temporary cessation of ovarian function was considered desirable. The inhibitory effects of the antihormones were seen most clearly with repeat courses of therapy. With second or third courses of treatment no stimulatory effects were observed. Antihormone titers promptly increased estrogen excretion fell to low levels and amenorrhea and menopausal symptoms were observed in some patients.

Administration of synthetic androgens was begun on the 2nd day after hypophysectomy and continued 20 days. Testosterone and transandrostenediol were the least effective in maintaining spermatogenesis. Dehydroisoandrosterone and cisandrostenedione were as active as the more potent androsterone from an andorgenic standpoint. Androstanedione and androstenedione had about the same androgenic activity as androsterone but were more effective in maintaining the testes. The capacity of these substances to maintain spermatogenesis was unrelated to their androgenic activity as based on either the capon comb or rat-accessory tests. It was shown that treatment must be begun soon after ablation of the hypophysis. They are not effective in reinitiating spermatogenesis.

SummaryProgesterone in doses of 1-2 mg per day extended the lives of young adrenalectomized rats in half of the cases throughout a 20-day treatment period. On the basis of equivalent dosage, it was...

4 steroids progesterone 17alpha-ethyl-19-nortestosterone (Nilevar) 17alpha-ethinyl-19-nortestosterone (Norlutin) and 17-alpha-e thinyl-17-hydroxyestren-3-one (Enovid) were each given to groups of normal adult males to assess their effect upon spermatogenesis and the urinary excretion of gonadotropins estrogens 17-ketosteroids and pregnanediol. All 4 steroids induced a state of azoospermia in all of the 19 subjects. Within a relatively brief period following the withdra wal of therapy the sperm count of most subjects returned to or exceeded pretreatment levels. Testicular biopsies obtained at a time when all subjects were at azoospermia levels showed damage compatible wi th the finding of azoospermia in the Norlutin and Enovid therapy groups. The biopsies obtained from subjects of the progesterone and Nilevar therapy groups presented a picture of moderately active spermatogenesis. A complete loss of libido was noted by every subject during the latter part of the therapy period and during the early part of the recovery period. Total urinary gonadotropin titers were found to be unaltered by progesterone Norlutin and Enovid. Nilevar suppressed urinary gonadotropin titers although the magnitude of suppression could not be quantitated. By their clinical and hormonal effects Norlutin and Enovid manifested nearly identical activity. Progesterone and Nilevar appeared to influence hormonal excretion patterns in a different manner. Gross observations indicate that Norlutin and Enovid may possess and anabolic activity similar to that of Nilevar. 17-ketosteroid excretion was uniformly suppressed by all 4 steroids whereas pregnanediol excretion was found to be unaltered.(AUTHORS MODIFIED)

The effect of triethylenemelamine on male rat fertility was investigated. Two dose levels were employed. A dose of 0.05 mg./kg. administered intra-peritoneally five times each week for four weeks produced no histologically demonstrable effect on the germinal epithelium; however, it produced sub-fertility or infertility in the treated animals. The infertility was observed to be due to intrauterine death of fetuses in females inseminated by the treated males. There was also an indication that in some cases preimplantation death of the inseminated ova could have occurred. A dose of 0.2 mg./kg. daily for five days produced, in addition to the above-described effect on fertility, a destruc-tion of spermatogonia followed by a maturation depletion of the germinal epithelium. The apparent similarity between the effects of triethylenemelamine and x-irradiation on the germinal cells is discussed.

SummaryBy autotransplantation of both ovaries into the spleen of mature female rats, the ovary continues to be bathed by pituitary gonadotrophins but the pituitary is no longer bathed by estrogens because in essence the liver has been inserted between the ovaries and the pituitary and has inactivated the estrogens.The pituitaries of such rats were assayed for their gonadotrophic content, They more nearly resembled (20.4) that of intact controls (10.3), than that of castrated controls (92.4).From this it was concluded that (1) ovaries normally inactivate gonadotrophins and that the rise of gonadotrophins seen following castration is due to failure of such inactivation to take place. (2) Large and unphysi-ological doses of estrogen are potent inhibitors of pituitary gonadotrophic potency. (3) Physiological amounts of estrogen in the circulation exert very little inhibitory action upon the pituitary.

Since it was confirmed that spermatogenesis could be maintained in hypophysectomized rats by the administration of male hormone extracts this report deals with results obtained with mice. Injections of androgenic hormone were begun on the 2nd day after hypophysectomy and continued for 20 days. Hypophysectomy was later shown to have been complete by serial sections through the sellae turciae. In cases where small fragments of anterior lobe tissue were found this residual tissue did not enhance the effect of the treatment with androgenic substances. Smears of the epididymal head and tail and of the vas deferens were studied for the presence and motility of sperm. The results in mice confirmed those previously obtained with rats. The testes of all animals injected with androgen showed spermatogenesis. Androstanedione proved to be the most effective in maintaining spermatogenesis as well as testes weight although it is less active than testosterone or testosterone propionate in androgenic potency. Androstanediol was slightly less effective. Results were not as striking as in the rats. Microscopic findings were similar to those found in the rats. Degenerat ion of the interstitial cells was not prevented by treatment with androgens. Marked degenerative changes in the seminiferous tubules was prevented for at least 23 days.

ALTHOUGH early workers on the thymus thought that it played a part in the control of growth and development, the work of Park and McClure (i) was – generally conceded to have demonstrated that extirpation of the thymus, in dogs, at least, led to no defects of either growth or development. This status of the thymus was abruptly changed in 1929 when a paper by Asher and Ratti (2) appeared. They found that rats fed McCollum's rachitogenic diet, kept in the dark and injected with aqueous thymus extracts grew, while the uninjected controls were stunted. A long and excellent series of papers by Asher and his coworkers followed and gave additional steps in the purification of the active substance. Asher (3) reviewed the work, which his group has carried on with thymus extracts, for Abderhalden's “Handbuch der biologischen Arbeitsmethoden.” He emphasized the growth and gonadotropic effects of the extract in dosages as low as 1 mg. daily and described in detail the method of extraction which yields this last and m...

RIISFELDT (1, 2), on the basis of studies of hyaluronidase concentration in testes of rats under various experimental conditions, suggested that the spermatocytes are the testicular cells responsible for hyaluronidase production. Steinberger and Nelson (3), analyzing the effects of hypophysectomy, cryptorchidism, and estrogen and androgen treatment on the hyaluronidase concentration and morphological picture of rat testes, secured evidence that cells beyond the stage of spermatocytes, the spermatids, are more likely to be the site of hyaluronidase production than are the spermatocytes. The present study was conducted to provide additional evidence concerning the cell of origin of hyaluronidase in the rate testis.

Investigations during the past few years by Strieker and Giuter (1929), Corner (1930), Nelson and Pfiffner (1930–31), and Turner and Gardner (1931) have established the relation of the anterior hypophysis to the induction of lactation. These various studies have shown that the mammary glands must be developed under the influence of the ovarian hormones before the anterior lobe factor can initiate secretory activity. The degree of development of the glands which is necessary before lactation may be induced and the relative importance of the two ovarian hormones, oestrin (theelin) and progestin (corporin), in the production of gland growth varies in the different species of animals examined. However, it seems definitely established that the mammary glands of any animal must have attained at least the condition present in the adult female of that species before lactation may be induced by the administration of anterior lobe extracts.

EARLIER studies have shown that activity of the adrenal cortex as well as the hypophysis is necessary for the initiation and maintenance of lactation in the guinea pig (Nelson and Gaunt, 1936, 1937a, 1937b; Gomez and Turner, 1936, 1937). In the rat adrenalectomy does not abolish lactation immediately, but it is necessary in most cases that replacement therapy be given t o obtain a secretion of milk adequate tomaintain the lives of suckling young; and such therapy is necessary in all cases to support normal growth (Literature cited by Gaunt, Eversole and Kendall, 1942). The availability of crystalline adrenal steroids has led to an examination of their capacity to support lactation in adrenalectomized animals. It has been shown (Gaunt, Eversole and Kendall, 1942) that in the adrenalectomized rat 1 mg. daily of 17-hydroxy-ll-dehydro-corticosterone (Compound E of Kendall) would maintain normal lactation.

CHORIONIC gonadotropin is known to stimulate growth and endocrine function of the immature human testis. When administered to cryptorchid boys, it can produce enlargement and descent of the testis and, with sufficient amounts, sexual development. In hypogonadotropic eunuchoids, it produces differentiation and growth of Leydig cells and secretion of androgen (1). Little information is available, however, regarding the effects of chorionic gonadotropin on the mature human testis. The purpose of this study has been to determine the effects of chorionic gonadotropin on the structure and function of the adult human testis. During the course of the investigation, an increase in estrogen excretion was regularly observed when the hormone was administered to men having functioning testes. The source of the estrogen, therefore, became one of the major problems of the study. Previous investigations have indicated that the testis is a major source of estrogen in men: castration results in a drop in urinary estrogen l...

THE search for therapeutic agents effective in male infertility has been relatively fruitless to date. In recent years, hormonal therapy has been considered. Of the various hormones, the ones most likely to succeed would seem to be those that ordinarily stimulate spermatogenesis: the gonadotropins. Of the gonadotropins (from anterior pituitary, pregnancy urine and pregnant mare serum sources), one hormone that is known specifically to stimulate spermatogenesis is follicle-stimulating hormone (FSH) of the anterior pituitary (1). It cannot be expected that FSH will prove effective in all types of male sterility. Several prerequisites are necessary before successful results can reasonably be expected. In addition to the obvious prerequisites, such as patent vas deferens, and the knowledge that the wife is potentially capable of conceiving, we have considered the following conditions to be essential: 1. Testes with potentially reversible defects. In many cases of infertility, the testes are irreparably damage...

IN view of the increased interest in the pituitary body in relation to experimental and clinical endocrinology, and because of the frequent attempts to influence disease through irradiation of the adenomatous or non-adenomatous gland, it has seemed important to study the effects of irradiation of the normal pituitary body of the white rat. During the past twenty years there have been numerous reports on the effects of irradiation of the hypophysis for various gynecological conditions, with varying results. Recently, irradiation of the pituitary has been extended to patients with diabetes mellitus and so-called essential hypertension, again with varying results. The question naturally arises, can the non-adenomatous pituitary gland be influenced with therapeutic doses of x-rays? A partial answer to this question could probably be obtained through animal experimentation. Apparently the first studies on the effects of pituitary irradiation in animals were made by Strauss (1) and Brunner (2), working independ...

THE presence of a “spreading factor” in testes of rats, rabbits and guinea pigs was first observed by Duran-Reynals (1928, 1929). Chain and Duthie (1939, 1940) demonstrated that the “spreading factor” is identical with an enzyme isolated from autolysates of Type II pneumococci by Meyer, Dubos and Smith (1937), and designated by the latter authors as hyaluronidase in view of its capacity to depolymerize hyaluronic acid. Subsequently the concentration of hyaluronidase in testes of rats placed under various experimental conditions has been studied by several investigators. Sprunt et al. (1939) noted a decrease of hyaluronidase concentration in rat testes after 45 days of cryptorchidism. Determinations of the enzyme were made by a biological method of assay—the “spreading reaction.” Utilizing a turbidimetric method of assay, Leonard et al. (1946, 1948) reported a decrease of the enzyme content in testes of hypophysectomized animals and in cryptorchid animals.

FROM the large and heterogenous group of adults with retardation or absence of sexual development two new clinical syndromes have been recently delineated. The first, which includes the association of short stature, retarded sexual development and high urinary gonadotropin titers in women, has been described by Varney, Kenyon and Koch (1), and by Albright, Smith and Fraser (2). The second syndrome represents seminiferous tubule failure accompanied by gynecomastia and high urinary gonadotropins in men and has been described by Klinefelter, Reifenstein and Albright (3). To these two syndromes we should like to add a third which has many features in common with the syndrome described by Kenyon, but occurs in males. In essence the syndrome may be regarded as a functional prepuberal castration. The syndrome as observed by us in 6 cases was characterized by a) presence of Wolfnan duct structures in the scrotum, but absence of functional testes.