Gonadotropic Effect Research Articles

COMPARATIVE BIOLOGIC RESPONSES TO THE INTERNATIONAL STANDARD AND COMMERCIAL CHORIONIC GONADOTROPINS

THE AVAILABILITY of an established standard for chorionic gonadotropin (the II designation for the gonadotropic principle from human pregnancy urine— J L Bulletin of the Health Organization of the League of Nations (I)) should materially assist in establishing and maintaining uniformity both as to potency and stability of commercially available preparations. The recommendations for the use of the above standard for the comparative determinations of gonadotropic activity in units on immature female rats depends upon the observation of a direct or indirect gonadotropic effect, shown by morphological changes in the gonads, and the observations of secondary changes in the accessory reproductive organs, in animals not deprived of their gonads. When this type of test is used, the absence of substances causing such changes in the accessory reproductive organs should be assured by control tests on animals deprived of their gonads. On the basis of these recommendations, which have been adopted by the U. S. P.

INFLUENCE OF THE THYROID ON THE RESORPTION OF GONADOTROPIC HORMONES

STUDIES (1–4) have shown that thyroidectomy in immature female rats will increase the ovarian response to injections of hypophyseal gonadotropic extracts but not to the injection of pregnancy serum extracts. Fluhmann (3) found that thyroid feeding decreased the gonadotropic effect of both types of preparations (pituitary or placental) and suggested, since the latter was free of thyrotropic principle while the former contained thyrotropic principle, that an induced condition of hyperthyroidism was produced by the injection of pituitary extracts in normal rats, this condition being responsible for the lessened response. The pregnancy extract not containing the thyrotropic factor was equally effective in normal and thyroidectomized animals. Leonard (5), however, found that pituitary and urinary (castrate and testes tumor) gonadotropic extracts free from thyrotropic hormone were more effective in the absence of the thyroid and Leonard, Hisaw and Fevold (6) observed that the addition of thyrotropic hormone to ...

SYNERGISM OF ESTROGENS WITH PITUITARY GONADOTROPINS IN HYPOPHYSECTOMIZED RATS1

IT HAS BEEN KNOWN ever since the pioneer work of Walsh, Cuyler and McCullagh in 1934 (1) that spermatogenesis in the rat could be maintained after hypo-physectomy by the prompt and continued injection of male sex hormone. No corresponding maintenance of ovarian function by estrogenic substances had been observed until recently when Williams (2) reported an increase in the weight of ovaries of hypophysectomized rats implanted with diethylstilbestrol, and an augmentation of the gonadotropic effect of pregnant mare serum in animals simultaneously receiving stilbestrol. Pencharz (3) has also noted an increased ovarian size due to enlargement of follicles following the treatment of hypophysectomized rats with stilbestrol and other estrogens. Even more interesting is his observation of great augmentation of ovarian weights and the formation of large follicles and corpora lutea in animals given certain estrogens together with chorionic gonadotropin.

GROWTH AND DEVELOPMENT OF SIX GENERATIONS OF ALBINO RATS UNDER TREATMENT WITH THYMOCRESCIN1

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...

Testosterone Propionate, a Bisexual Hormone in the American Chameleon

SummaryTestosterone propionate enlarges the Mullerian duct, keratinizes the cloaca and produces estrous behavior in Anolis. It also enlarges the epididymis, ductus deferens and sexual segment of the kidney, while producing male sex behavior. It has a gonado-tropic effect on the ovary but not on the testis.

Alleged Gonadotropic Effect of Royal Jelly

Alleged Gonadotropic Effect of Royal Jelly

GROWTH OF VITAMIN DEFICIENT RATS TREATED WITH THYMOCRESCIN11

ONE OF us (W.O.N., I) has recently reviewed the literature on thymic physiology, but a few historical points need emphasis here. In 1929 Asher and Ratti (2) reported growth promotingeffects of aqueous extracts of calf thymus. They found that young rats, maintained in darkness on McCollum/s rachitogenic diet and injected with thymic extract, continued to grow and showedno clinical or histological evidence of rachitis. Asher (3) has reviewed the subsequent work of his group and set forth the procedure for the preparation of the most potent extracts. These have marked growth promoting and gonadotropic effects in dosages as low as 1 mg./day on animals on deficient diets. The material is characterizedas a protein and lipid-free polypeptide. Following Asher/s procedure (3), 150 kg. of fresh calf thymus were processed, yielding 263 gm. of dry thymocrescin.2

Gonadotropic Response to Subcutaneous and Intraperitoneal Injections of Urine Prolan in White Rats

SummaryComparing the gonadotropic response of the organism to subcutaneous or intraperitoneal administration of pregnancy urine prolan the following results were secured: (1) If the minimum dose is split up into 6 portions intraperitoneal and subcutaneous administration are equally effective. (2) If the minimum dose is split up into 3 portions the intraperitoneal route is approximately half as effective as the subcutaneous one. (3) If the minimum dose is given in one injection the intraperitoneal administration is about 1/10 as effective as subcutaneous. (4) Using the subcutaneous standardization method with minute doses as e.g., 1 RU (estrous effect) the gonadotropic effect of 6 subthreshold doses is less marked than that of one single threshold dose.

A COMPARISON OF FOUR METHODS OF BIOASSAY FOR THE GONADOTROPIC FACTORS

THE OBJECT of a gonadotropic assay is to evaluate the amount and kind of gonadotropic stimulation produced by a given extract, whether derived from the gland, blood or urine. The factor or factors producing such stimulation cause follicle growth and Iuteiniz3.tion in the ovaries. Follicle stimulation is followed by produc′tion of estrogen which, in rodents, causes proliferative changes in the uterine mucosa and breasts as well as mucification of the vaginal epithelium. Luteini- 23.tion (corpus luteum formation) produces progesterone which induces secretory changes in the estrogen-stimulated uterine and mammary epithe′lium. The gonadotropic effect may be evaluated directly from the ovaries or indirectly by evaluation of the ovarian action initiated by the gonadotropic factors, as manifested by the secondary effects produced on the rest of the genital system (uterus, vagina, breasts).

Progonadotropic Augmentary Immune Sera after Protracted Injection of Hypophyseal Gonadotropic Hormone in Rabbits

SummaryFollowing protracted injection in 16 rabbits of gonadotropic hormone derived from different sources we succeeded in one case in producing a progonadotropic serum, after treatment consisting of daily injections for a period of 5 months. 0.025 cc of this serum was able to multiply by 8 the gonadotropic effect of an aqueous extract of rat pituitaries, Control experiments showed that this augmentary effect was specific: it was neither obtained with normal serum acting on extracts of the rat pituitary, nor with progonadotropic serum acting on gonadotropic hormones of a different origin, Viz., of human pituitaries.

Growth and Metamorphosis of Anuran Larvae on Thymus Extracts.

Since the early experiments of Gudernatsch,1 who produced an acceleration of growth and a delay of metamorphosis of tadpoles fed upon fresh thymus tissue, several investigators have obtained diverse results by feeding thymus glands, either fresh or dried, to amphibian larvae. Uhlenhuth2, 3 found that when only thymus tissue was given to newly hatched urodeles, their growth was retarded. This was attributed to the particular food value of the thymus since the animals grew at a normal rate when other food was added to the diet. Contrary to the above observations, Kahn4 and Romeis5 found that thymus accelerated the growth of amphibian larvae. Swingle,6 however, fed fresh and powdered thymus to Rana larvae and observed no retardation or acceleration of growth or metamorphosis. The rather extensive literature has been covered in a brief review by Gudernatsch.7Asher and Ratti8 prepared a thymus extract, thymocrescin, which in their hands has produced marked acceleration of growth as well as a gonadotropic effect...

Gonadotropic Action of Testosterone Propionate on the Immature Mouse Ovary

SummarySingle injections of testosterone propionate produced a gonadotropic effect on the mouse ovary. Follicle stimulation resulted but lutein tissue did not form. Other investigators have suggested that the ovarian response to this hormone is dependent on the pituitary.7

Gonadotropic Effect of Androgens upon the Immature Rat Ovary

Butenandt and Kudzus have reported that androgenic substances administered to immature female rats cause premature opening of the vagina. The present study was undertaken to determine whether the androgens produce this effect directly upon the genital tract or indirectly through the ovary. Eighteen rats (comprising 5 litters), varying in age from 27 to 30 days, were used in this study. Twelve were given a single injection of androgen in sesame oil; 6 controls were given an equal quantity of pure sesame oil. Seven of the animals were injected with testosterone propionate and 5 with androstenediol, the dosage varying from 1 to 5 mg. The time of the opening of the vagina was noted in each case. Laparotomies were performed and one ovary removed at intervals varying from 60 to 96 hours after the administration of the androgen. The animals were sacrificed at periods varying from 96 to 228 hours after the injection and the remaining ovary was then removed. At corresponding intervals, the ovaries were removed from the control animals. The ovaries were examined microscopically in serial sections. Opening of the vagina occurred in all androgen-injected animals within 72 hours after the injection. Follicle stimulation was noted as early as 60 and 72 hours after the injection. Corpora lutea were found as early as 96 hours and as late as 192 hours after androgen administration. The ovaries of all the 12 injected animals exhibited some gonadotropic effect, either follicle stimulation, luteinization or both. The uteri in all these animals were markedly enlarged. In the 6 control rats, the vaginas remained closed and the ovaries were negative. Eighteen rats (comprising 5 litters), varying in age from 27 to 30 days, were used in this study. Twelve were given a single injection of androgen in sesame oil; 6 controls were given an equal quantity of pure sesame oil.

Mechanism of Prolan-Antiprolan-Reaction in Simultaneous and Unsimultaneous Application of Both Active Principles

Summary(1) Antiprolan has a paralyzing effect upon prolan in separate as well as in simultaneous injection in the test rat. Nevertheless, the inhibiting effect of antiprolan is stronger if we inject a prolan-antiprolan mixture which has been allowed to stand in the incubator for 2 hours. (2) The antigonadotropic effect can be observed 8 days after the application of antiprolan (100 PAU). During this period the test animal is refractory towards prolan (10 RU). (3) Antiprolan circulates in the blood of the test rat as long as 60 hours after subcutaneous injection. It cannot be proved in the organs of the rats at that time. (4) We are able to retard the gonadotropic effect of prolan in rats up to 24 hours after the injection, if we inject antiprolan within this interval. (5) If applied enterally antiprolan has no effect whatsoever.

The Antigonadotropic Factor. Origin and Preparation

One of us pointed out the fact that in rodents the gonadotropic effect diminishes if prolan from human pregnancy urine is applied in a protracted manner. Since that time the phenomenon has been repeatedly studied. Collip, Selye, et al., explained this as being due to the effect of antihormones, and succeeded in proving in the test-tube experiment the antisubstances against the hormones. Proof of the presence of an antigonadotropic factor can be furnished only by the impairment of the gonadotropic reaction in rodents. As shown by our experiments proof of the antigonadotropic factor by serological methods is not obtainable, pure prolan not forming any precipitins or complement-fixing antibodies. The sera of experimental animals which had been “immunized” with pure prolan over a period of more than 2 months do not show any serological reaction; they evince, however, a highly antigonadotropic effect. The titration of our antigonadotropic sera was performed exclusively by impairing the production of the anterior pituitary reactions (HVR) in rodents. 0.5 cc. of an antigonadotropic serum or the corresponding amount of an antigonadotropic dry powder solution (see below) was mixed with prolan (the latter in increasing amounts), filled up to a total volume of 4 cc, placed in the incubator for 2 hours and finally injected into the experimental animals, infantile female rats 3-4 weeks old, weighing 25 to 30 gm. They were injected 4 times (if there were more than 4 cc. of the injection fluid, 6 times) at equal intervals (12 hours), spread over 36 hours. Sixty hours after the first injection we began with the vaginal smears, at intervals of 12 hours. One hundred and twenty hours after the first injection the animals were killed and ovaries and uteri examined.

Action of Merthiolate on Gonadotropic Effect of Anterior Pituitary Extract

The germicide, “Merthiolate” (C2H5HgS C6H4COONa), should be included in the growing list of substances which may enhance the gonadotropic effect of anterior pituitary extract. In using merthiolate as a germicide in aqueous solutions of gonadotropic pituitary hormone, we discovered by accident that the gonadotropic changes were markedly potentiated because of the presence of low concentrations of the drug. If a dose of anterior pituitary hormone in aqueous solution at a pH of about 7.4 is administered by; subcutaneous injections distributed over several days to immature female rats and causes a moderate but clear-cut increase in ovarian weight, the same solution containing 1-5000 merthiolate (total dose 0.8 mg.) causes twice to three times as great a change as judged by the increase in ovarian weight. The merthiolate is added each day just before injection; it causes no change in the appearance of the water-clear hormone solution. An increase in the effect, roughly proportional to the change in concentration, is produced by increasing the concentration of merthiolate. Maximal potentiation occurs in immature rats receiving toxic but sublethal doses of merthiolate (0.077% or 1-1300; total dose 3.08 mg.). Concentrations of 1-10,000 or lower are without effect. The effect of anterior pituitary extract on the testis of the immature male rat (change in seminal-vesicle weight) is also clearly potentiated by merthiolate. However, the germicide increases neither the proportion of rabbits ovulating nor the number of ruptured follicles in individual rabbits if the effects of the intravenous injection of a solution of an anterior-pituitary extract with and without merthiolate (1-5000 or 1-3000) are compared. Moreover, it does not increase the effect of even crude preparations of prolan on the ovary or testis (seminal vesicles) of the immature rat.

Gonadotropic Excretion in the Male Castrate. Effect of the Male Sex Hormones

Our studies on female castrates showed a great increase in gonadotropic hormone excretion in the urine.1 Two male castrates have now been investigated. In both patients bilateral orchidectomy had been performed for tuberculous epididymitis. In the first patient (L.D.) castration was performed 5 years ago, in the second (L.S.) 8 years ago. In the 1st patient, within 1 week of the operation, severe flushes and sweats occurred and have persisted. The 2nd has suffered from no symptoms.Gonadotropic hormone urine determinations by the acetone precipitation method2 were performed on L.D. for a preliminary period of 22 days. Both follicle stimulating and luteinizing factors were found in the urine. The daily output of follicle stimulating factor varied from 4 to 18 rat units per day; of lutein factor from 4 to 7 1/2 rat units per day. In the second patient, 5 random 48-hour urine specimens were examined. The daily output of lutein factor varied from 4 to 8 R.U. The gonadotropic hormone effects produced in the tes...

Gonadotropic Effects in Hypophysectomized Female Rats of Implants of Pituitaries from Castrated Males

Studies of female rats united parabiotically with castrated males have shown that they are characterized by constant estrus and that their ovaries contain only large follicles (Witschi and others). The phenomenon appears to establish the actual secretion into the blood stream of the follicle stimulating hormone only on the part of the pituitary of the castrated male parabiont. The present study shows that the pituitaries of such castrated males nevertheless contain or “house” appreciable amounts of luteinizing hormone. Young mature males were castrated and after 40 days their pituitaries were implanted into hypophysectomized females 26 days of age. While a dose level was found in which follicles only occurred in the ovaries of the hypophysectomized recipients, double this dose (4 glands) led to the appearance of corpora lutea. Implants of the hypophyses from normal litter brothers produced only follicles at both dose levels. Parallel experiments with normal recipients showed that corpora were produced by both levels of castrate and normal hypophyses. The luteinizing effect of castrate male hypophysis as tested by implantation, therefore, contrasts with the results obtained by parabiosis. The explanation offered for the difference is that the absorption of the implant frees the factor responsible for luteinization, whereas this substance is retained in vivo by the hypophysis of the parabiont.

MAINTENANCE AND REPAIR OF THE REPRODUCTIVE SYSTEM OF HYPOPHYSECTOMIZED MALE RATS BY HYPOPHYSEAL SYNERGIST, PREGNANCY-PROLAN AND COMBINATIONS THEREOF*

Studies on the action of the hypophyseal substance which in small quantities acts synergically to intensify the effect of prolan in normal immature animals or hypophysectomized animals have hitherto been conducted almost exclusively with females. It has been possible, however, to show that with some changes in the conditions of the experiment, typical synergic intensification of prolan effects can be secured with normal immature males. Nevertheless, as was the case with females, crucial evidence of the action of the synergist must be sought in hypophysectomized males. A further interest attaches to the gonadotropic effects of this hypophyseal substance on hypophysectomized males for it has been possible to show that in addition to its complementary or synergic action when combined with prolan, when it is administered alone it exerts selective effects on the testes of hypophysectomized males. The hypophyseal material in question administered at the dose levels and for the time intervals herein reported, un...

THE REPAIR OF THE REPRODUCTIVE SYSTEM OF HYPOPHYSECTOMIZED FEMALE RATS BY COMBINATIONS OF AN HYPOPHYSEAL EXTRACT (SYNERGIST) WITH PREGNANCY-PROLAN*

It is now well known that the substance present in the urine of pregnant women (prolan) provokes characteristic changes in the ovaries of immature mice or rats—changes which consist essentially in the growth of the ovarian follicles, in ovulation, and above all, in luteinization whether of ripe or unripe follicles. It has been equally well established that these changes are more difficult to secure by the administration of this substance to hypophysectomized females (1) (2).† These circumstances led naturally to the assumption that the pituitary gland itself contributes in some obscure Avay to confer gonadotropic effects on prolan. We sought further support for this hypothesis by adding various hypophyseal extracts to prolan to ascertain whether they would enable prolan to exert the abovementioned effects on the ovaries of hypophysectomized females (6). The gonads of hypophysectomized female puppies had been found to be unresponsive to prolan, though treated for a period of 2 months with high daily dosage...