High Doses Of Testosterone Research Articles

The influence of androgens on the development of a sex difference in the vasopressinergic innervation of the rat lateral septum.

The vasopressinergic innervation of the lateral septum is much denser in male than in female rats. The present study demonstrates that, under physiological conditions, the development of this sex difference is dependent on the presence of androgens around the seventh postnatal day. It was possible, however, to induce in female or neonatally castrated male rats a fiber density as high as in control males by high doses of testosterone, given in the first, second or even third week of life.

Effect of testosterone on the rate of myofibrillar protein breakdown in castrated and adrenalectomized male rats measured by the urinary excretion of 3-methylhistidine

Urinary output in N τ-methylhistidine (3-MeHis) was used to evaluate changes in myofibrillar protein breakdown rate in the skeletal muscles of castrated and adrenalectomized-castrated young male rats, and the responses of breakdown to testosterone and corticosterone replacement. The castrated rats grew less well than intact control rats and excreted significantly less 3-MeHis. Administration of low and high doses of testosterone restored the weight of the levator ani of the castrated animals but failed to affect growth rate or 3-MeHis output. Although this might suggest that testosterone has an indirect effect on muscle turnover through changes in growth rate, this parallelism was not confirmed by studies on adrenalectomized-castrated rats. Adrenalectomy of castrated rats caused a further reduction in growth rate and in output of 3-MeHis, but administration of testosterone now reduced 3-MeHis output still further while stimulating growth. Treatment of the adrenalectomized-castrated rats with low doses of corticosterone increased growth modestly, while depressing 3-MeHis output, and again output of this metabolite was further reduced when testosterone was added to the treatment, although growth rate was unaffected. Finally, large doses of testosterone given to adrenalectomized-castrated rats receiving excessive amounts of corticosterone did not prevent the growth failure or the increased output of 3-MeHis due to the corticosteroid, though it appeared to reduce the magnitude of the response to corticosterone alone. It is concluded that the effects of testosterone on growth and on 3-MeHis output are not necessarily associated and that the functional status of the adrenal cortex modifies the response of myofibrillar breakdown rate to testosterone treatment.

Suppression of serum gonadotropin levels by testosterone and porcine follicular fluid in castrate male rats.

The identification of the testicular negative feedback hormone(s) regulating the secretion of FSH has been a controversial area, with adherents of an inhibin or testosterone. We castrated and cannulated male rats and gave immediate testosterone replacement by Silastic implants using two doses: the lower for its known marginal suppression of serum LH, and the higher to match serum testosterone in intact males. On day 3, each rat was sampled at 0800 h for testosterone, LH, and FSH and then received charcoal-extracted porcine serum or porcine follicular fluid; blood was again removed at 1800 h. On days 6 and 12, the same procedures were carried out, but on day 7, the steroid implants were removed. On day 3, the testosterone threshold for the suppression of FSH was identical to that for the suppression of LH (≥1.1 ng/ml). The higher dose of testosterone suppressed both LH and FSH to near-intact levels. By day 6, testosterone was less successful in suppressing either LH or FSH. Follicular fluid suppressed FSH ...

Physical and hormonal evaluation of transsexual patients during hormonal therapy.

The optimal hormonal therapy for transsexual patients is not known. The physical and hormonal characteristics of 38 noncastrate male-to-female transsexuals and 14 noncastrate female-to-male transsexuals have been measured before and/or during therapy with various forms and dosages of hormonal therapy. All patients were hormonally and physically normal prior to therapy. Ethinyl estradiol was superior to conjugated estrogen in suppression of testosterone and gonadotropins but equal in effecting breast growth. The changes in physical and hormonal characteristics were the same for 0.1 mg/d and 0.5 mg/d of ethinyl estradiol. The female-to-male transsexuals were well managed with a dose of intramuscular testosterone cypionate of 400 mg/month, usually given 200 mg every two weeks. The maximal clitoral length reached was usually 4 cm. Higher doses of testosterone did not further increase clitoral length or suppression of gonadotropins; lower doses did not suppress the gonadotropins. Based on the information found in this study, we recommend 0.1 mg/d of ethinyl estradiol for the noncastrate male-to-female transsexual and 200 mg of intramuscular testosterone cypionate every two weeks for the noncastrate female-to-male transsexual.

Studies of testosterone-induced involution of the bursa of Fabricius

The present investigation deals with the effect of testosterone on each of the tissue components of the bursa of Fabricius: the endodermal epithelium, the mesenchyme, and the hemopoietic stem cells. Tissue combination experiments between testosterone-treated endoderm and normal mesenchyme and vice versa have shown that the androgen damages irreversibly the bursal epithelium. The latter is not seeded by hemopoietic stem cells and cannot undergo follicle formation when treated with high doses of testosterone. This occurs even if it is associated with a nontreated bursal mesenchyme. On the contrary, associations of testosterone-treated mesenchyme with normal endoderm result in normal bursa histogenesis. By using an original test of viability for lymphoid cells based on the application of the quail-chick marker system, we demonstrate that disappearance of hemopoietic cells in the endoderm results from their expulsion from the bursa and not from their death in situ. The conspicuous effect of testosterone on the bursa of Fabricius can be related to the levels of androgen receptors found in the organ. Typical cytosol androgen receptors are demonstrated in both bursal endoderm and mesoderm, although the amount in the former is higher. The concentration of binding sites in the bursa is >10 times higher than that in other organs such as lung and small intestine whose development is not affected by testosterone, contrasting with glucocorticosteroid receptor (measured by labeling with dexamethasone) found in the same concentration in all tissues.

Uterine and lung uteroglobins in the rabbit: Two similar proteins with differential hormonal regulation

Previous studies have shown that several rabbit tissues contain proteins which cross-react in the radioimmunoassay for uteroglobin, a progestin-regulated protein in rabbit uterus (Torkkeli et al. (1977) Mol. Cell. Endocrinol. 9, 101–118). In the present study, a uteroglobin-like protein was purified to an apparent homogeneity from an extra-uterine tissue, rabbit lung, by successive chromatographies on hydroxyapatite, Sephadex G-75, SP-Sephadex, DEAE-cellulose and CM-cellulose. The final preparation behaved homogeneously in various polyacrylamide gel electrophoretic systems and in isoelectric focusing. The uteroglobin-like protein isolated from the lung had very similar physico-chemical and immunological properties to those of uteroglobin present in the rabbit uterine fluid. The two proteins had: (i) the same molecular weight, of approx. 13 000, with a two subunit structure (each approx. M r 7000); (ii) identical behavior in polyacrylamide gel electrophoresis under non-denaturing and denaturing conditions; (iii) the same isoelectric point at pH 5.4; (iv) absence of carbohydrate in the molecule; (v) very similar amino acid compositions; (vi) lack of tryptophan among the amino acids; (vii) the same N-terminal amino acid (glycine), and (viii) indistinguishable immunological characteristics. Collectively, these data strongly suggest that uterine and lung uteroglobins are identical proteins. In contrast to the induction of the uterine uteroglobin by steroids with progestational activity, the synthesis of extra-uterine uteroglobins was not affected by these steroid hormones to any major extent. In keeping with the concept that lung is a target tissue for glucocorticoid action, cortisol and dexamethasone were capable of increasing the concentration of lung uteroglobin 3-fold (from 3 to 9 μg/mg soluble protein). These compounds did not, however, alter the secretion of the uterine protein. Administration of high doses of testosterone and 5α-dihydrotestosterone elevated significantly the content of both uterine and lung uteroglobin. Only approx. one-fifth of the adult pulmonary uteroglobin levels were present in lungs of newborn rabbits indicating that developmental changes occur in the lung uteroglobin content.

379. Effect of androgen on the development of the bursa of fabricius in the duck embryo

The present investigation deals with the effect of testosterone on each of the tissue components of the bursa of Fabricius: the endodermal epithelium, the mesenchyme, and the hemopoietic stem cells. Tissue combination experiments between testosterone-treated endoderm and normal mesenchyme and vice versa have shown that the androgen damages irreversibly the bursal epithelium. The latter is not seeded by hemopoietic stem cells and cannot undergo follicle formation when treated with high doses of testosterone. This occurs even if it is associated with a nontreated bursal mesenchyme. On the contrary, associations of testosterone-treated mesenchyme with normal endoderm result in normal bursa histogenesis. By using an original test of viability for lymphoid cells based on the application of the quail-chick marker system, we demonstrate that disappearance of hemopoietic cells in the endoderm results from their expulsion from the bursa and not from their death in situ. The conspicuous effect of testosterone on the bursa of Fabricius can be related to the levels of androgen receptors found in the organ. Typical cytosol androgen receptors are demonstrated in both bursal endoderm and mesoderm, although the amount in the former is higher. The concentration of binding sites in the bursa is >10 times higher than that in other organs such as lung and small intestine whose development is not affected by testosterone, contrasting with glucocorticosteroid receptor (measured by labeling with dexamethasone) found in the same concentration in all tissues.

Effect of sex steroids on choline acetyltransferase and acetylcholinesterase of cerebral hemisphere of male rats of various ages

The specific activities of choline acetyltransferase and acetylcholinesterase of the cerebral hemisphere of 8-, 40- and 80- week old male rats were estimated, and were found to decrease as a function of age. Castration decreases the activities of both the enzymes in young and adult rats. However, in the old, the activity of choline acetyltransferase alone is affected by castration. Testosterone (10 μg/100 g body weight) administered to castrated rats increases the activity of choline acetyltransferase at all ages, whereas 100 μg of testosterone stimulates choline acetyltransferase only in the young castrated rats. Estradiol (10 μg) stimulates choline acetyltransferase in young and adult rats, but not in old rats, whereas 100 μg estradiol is effective in stimulating choline acetyltransferase only in young rats. A low dose of testosterone (10 μg) decreases the activity of acetylcholinesterase in young castrated rats, but increases it in both adult and old rats. A higher dose of testosterone (100 μg) stimulates acetylcholinesterase only in adult rats. Estradiol (10 μg) increases the activity of acetylcholinesterase at all the ages, but a higher dose (100 μg) increases it in castrated young rats only. The data suggest a decline of cholinergic function in the brain of rats after the attainment of maturity. Furthermore, the activities of both choline acetyltransferase and acetylcholinesterase can be altered by sex steroids; however, this is dependent on the age of the animal.

Steroid delta4-5alpha-reductase and 3alpha-hydroxysteroid dehydrogenase in the rat epididymis.

Epididymal δ4-5α-reductase and 3ahydroxysteroid dehydrogenase activities have been measured in intact and in experimental animals. It has been found that the level of 3α-hydroxysteroid dehydrogenase activity in the caput-corpus epididymis does not differ from that of the cauda epididymis. This enzyme's activity in the caputcorpus and cauda epididymis was decreased to 15% of control by castration but could be maintained at control levels in both castrated animals receiving doses of testosterone that maintained the weights of ventral prostate and seminal vesicles and in animals whose efferent ducts were transected. Higher doses of testosterone did not further increase the level of epididymal 3α-hydroxysteroid dehydrogenase activity. δ4-5α-Reductase activity was five times higher in the caput-corpus than in the cauda epididymis of intact animals. The activity of this enzyme was lowered to undetectable levels by castration in both epididymal segments. Administration of testosterone at doses sufficient to main...

Enzyme induction by oral testosterone

Six normal male volunteers ingested a dose of 400 mg free testosterone daily as tablets over 21 days. By the end of treatment intravenous antipyrine half-life had decreased significantly from 8.0 +/- 2.7 to 5.7 +/- 2.6 hr. The subjects eliminated testosterone from serum more rapidly on the twenty-first day of testosterone ingestion than on the first day. Serum albumin, bilirubin, prothrombin, alanine-amino-transferase, and alkaline phosphatases were unchanged during the experiment. It is concluded that oral testosterone treatment induces the hepatic drug-metabolizing system including that of testosterone.

The effects of late thymectomy on the immunosuppressive action of cortisone and testosterone in rats immunized to sheep red blood cells.

The immunological effects of cortisone and testosterone were studied in intact and lately thymectomized rats immunized to sheep red cells. The results showed that the effects of low doses of cortisone as well as those of high doses of testosterone (drop in the total number of rosette- and plaque-forming cells: RFC and PFC) were conditioned by the involution of the thymic cortex provoked by such hormonal doses, since these changes did not occur in thymectomized rats. The effects of high doses of cortisone were partly not influenced by thymectomy (drop in the RFC and PFC levels) but partly thymus-dependent (drop in the serum antibody titers). The latter were apparently related to advanced lesions of the thymic medulla.

Contraceptives for Males

Recent work regarding male contraception is reviewed and methods that may become available for general use are considered. The main methods of contraception that have been available to the male have been coitus interruptus condoms and vasectomy. The pituitary gland secretes follicle stimulating hormone (FSH) and luteinizing hormone (LH). The secretion of these hormones is stimulated by the LH-releasing hormone (LH-RH) secreted by the hypothalamus. LH carried by the blood stream to the testes stimulates production of testosterone and FSH facilitates the production of sperm. Sperm maturation occurs during their transit through the epididymis and vas. Potential male contraceptives may be effective through inhibition of FSH and LH production by the pituitary either directly or by suppression of LH-RH secretion. High doses of testosterone taken orally or by injection will suppress LH and FSH causing infertility. However these doses produce other undesirable effects. With lower dosages a 2-3 month interval is required to achieve infertility and a similar period to regain fertility after treatment. Attempts to suppress LH-RH have not been successful. A protein substance that blocks FSH secretion but not LH secretion has been extracted from testicular tissues and seminal fluids of animals but has not been available for clinical trials. Drugs acting directly on the testes to inhibit formation have been accompanied by unacceptable side effects. Drugs affecting the function of the epididymis have been used in experiments on rats but in humans decreased libido and potency have been reported. The principle disadvantage of vasectomy has been the usually irreversible result. Freezing or sperm banking has been very successful in animals but is considered unreliable at present in humans. Immunizing the male against some component of his own reproductive system has been tried but a satisfactory technique has not been developed. Presently available methods do not seem likely to be more widely used in the future. New and more efficient techniques are anticipated.

Histological observations of inhibitory effect of testosterone on lymphoid regeneration in the thymus-independent areas of B mice.

High doses of testosterone were subcutaneously given to B mice, neonatally thymectomized, lethally irradiated and reconstituted with syngeneic bone marrow cells. Histological observations of the peripheral lymphoid tissues revealed that testosterone inhibited the regeneration of the thymus-independent areas which were considered to be composed mainly of B lymphocytes. This result suggests that testosterone would inhibit the differentiation of B lymphocytes.

Hormone metabolism and action: Testosterone and metabolites in prostate organ culture

Summary Explants of ventral prostate glands from intact rats were incubated for 24 hours in culture medium with 3H-testosterone and the radioactive metabolites in the medium and tissue analysed. At all testosterone concentrations (50-0.1 M), 4 metabolites averaging 22 p. 100 of incubated testosterone were identified. Among them, the main compound was 17β-hydroxy-5α-androstan-3-one (androstanolone). Androstanolone formed the greatest proportion of total radioactivity in the nuclei and was also the most abundant identified metabolite in the cytoplasmic fraction and in the medium. The highest androstanolone/testosterone ratio was observed in the cytoplasm. 5α-androstane-3α,17β-diol (androstanediol), 5α-androstane-3β,17β-diol (3β-androstanediol) were also identified, but neither 5β-derivatives nor 19-nor- compounds or estrogens were observed. Unknown non-polar radioactive compounds were found and partially characterized. The metabolism of metabolites prepared in radioactive form was also studied. Androstanolone was not converted to testosterone, but otherwise the pattern of metabolites in cytoplasm and nuclei was similar to that of testosterone. Androstanediol was largely converted to androstanolone and androsterone and to a smaller extent to 3β-androstanediol. In contrast, 3β-androstanediol was not converted to androstanolone, androsterone or androstanediol; its only metabolite identified in cytoplasma and nuclei was 3β-hydroxy-5α-androstan-17-one (epiandrosterone). The activity of testosterone and its metabolites was tested in organ cultures grown for 6 days in the presence of these compounds at concentrations ranging from 3.5 to 70 M. Testosterone maintained epithelial height and secretory activity, and kept the stroma at a minimum. Androstanolone was more active than testosterone and also provoked epithelial hyperplasia which was seen only after high doses of testosterone. Androstanediol was less active in preserving epithelial differentiation and increased epithelial proliferation to a slight degree. 3β-androstanediol fully maintained epithelial height and stimulated secretory activity but there was no hyperplasia. The corresponding 17-oxo-steroids showed weak activity, and 5β-androstane steroids were inactive. The results indicate that testosterone action may be related to its conversion to different active metabolites, and particularly to androstanolone and 3β-androstanediol.

Nuclear DNA estimations in the Hooker and Forbes test with sex hormones.

SUMMARY The DNA content of individual nuclei has been estimated histophotometrically in uteri of spayed mice submitted to intrauterine injections of progesterone, oestradiol, oestradiol plus progesterone and testosterone according to the method of Hooker and Forbes. The endometrial reaction to progesterone is shown to be correlated with a significant increase (20%) of DNA in the nuclei. Oestradiol promoted DNA synthesis to a lesser extent (11%). When a mixture of oestradiol and progesterone was used, the hormones acted antagonistically. High doses of testosterone did not affect DNA synthesis in the stromal nuclei.

Effects of gonadectomy and sex hormone administration on accessory reproductive organs of protein-deficient rats.

SummaryInvolution of accessory reproductive organs of male rats fed a 0% protein diet was accentuated by gonadectomy, attesting to residual testis function in intact protein-depleted rats. Sex accessories of gonadectomized protein-deficient rats responded to the same low levels of estradiol benzoate or testosterone propionate effective in gonadectomized control animals, indicating that sensitivity of these organs to exogenous hormone was unaffected by the diet. A subnormal response of accessory organs to high doses of testosterone was noted, however, in male protein-deficient rats.

Influence of testosterone on the secretion of thyrotrophin in the rat.

ABSTRACT Castration of male rats decreases both pituitary and serum TSH-levels. Administration of testosterone propionate increases serum TSH-levels in castrated males, but its effect on pituitary TSH-content appears to be complex: whereas treatment with physiological amounts of testosterone prevents the decrease induced by castration, administration of high doses of testosterone results in low pituitary TSH-contents not unlike those seen in untreated castrated rats. Testosterone administered to thyroxine-maintained thyroidectomized rats had the same effects as mentioned above, but if thyroxine treatment was omitted, no effect of testosterone on pituitary and serum TSH-levels could be observed. It is thought that testosterone interferes with the effect of thyroid hormone on the secretion of TSH.

Hormonal basis of sex skin in male rhesus monkeys

Observations of seasonal changes in sex skin of free-ranging male monkeys and the absence of adequate information on the hormonal basis of sex skin stimulated a study to determine which of the sex hormones could produce the changes noted, and to duplicate the changes seen in the field by experimental manipulation of dose levels. Castration causes a decline in sex skin coloration and edema. Both testosterone and estrogen produce the return of redness and edema sex skin produced by estrogen is female-like, sex skin produced by low doses of testosterone resembles the sex skin of nonbreeding males, and sex skin produced by high doses of testosterone resembles the sex skin seen during the breeding season.

Gonad-brain relationship: effects of castration and testosterone on electroshock convulsions in male rats.

The effects of castration and testosterone on brain excitability were investigated in male rats by measuring the minimal electroshock seizure threshold and the maximal electroshock seizure pattern. The principal results were: (a) Castration. Postpuberally castrated rats demonstrated less excitability than intact controls, as shown by changes in the maximal seizure pattern. However, excitability, measured by seizure thresholds, appeared slightly increased when castration was performed prepuberally. (b) Testosterone. The daily administration of high doses of testosterone to castrated rats increased the seizure threshold, whereas low and moderate doses had no effect. This decrease in excitability was further evidenced by an anticonvulsant effect on the maximal seizure pattern at 74 days of age after 2 weeks of testosterone injections. On the other hand, continued administration of the androgen reversed the anticonvulsant pattern to a convulsant one at 95 and 109 days of age, even though seizure thresholds we...

SOME BIOLOGICAL ACTIVITIES OF CERTAIN PROGESTOGENS: I. 17?-HYDROXYPROGESTERONE 17-n-CAPROATE

Immature virgin female rabbits were injected for 6 days with 5 mcg of estradiol and then treated with 4 daily doses of progesterone 17alpha-hydroxyprogesterone caproate (HPC) or 17alpha-hydroxyprogesterone (17alpha-OHP). Segments of uteri were taken on the fifth day for histological evaluation. The decrease in progestational efficacy of progesterone following 17alpha-hydroxylation was completely reversed by subsequent esterification with caproic acid which led to a potentiation of progesterone. 17alpha-OHP HPC and testosterone were administered subcutaneously daily for 20 days to immature castrated male rats. The animals were autopsied on Day 21 and organ weights were recorded. High doses of testosterone (1 mg) proved thymolytic but neither 17alpha-OHP nor HPC showed such activity. In contrast both 17alpha OHP and HPC tended to increase adrenal weights. Prostatic hypertrophy was evident following 17alpha-OHP but no androgenic activity was noted with comparable doses of HPC. Measurements of urinary sodium excretion were made in intact and adrenalectomized male rats. Animals treated with .3 mg progesterone daily for 3 days excreted more sodium than did rats given comparable doses of HPC. Pretreatment with progesteone for 3 days or 1 hour prior to the sodium load resulted in sodium retention in adrenalectomized rats. combinations of estradiol with progesterone 9alpha-fluoro-11beta-hydroxyprogesterone (FHP) 17alpha-OHP or HPC were administered to immature female mice daily for 3 days. FHP was the most potent antagonist of estradiol. Antiuterotrophic and progestational activities were virtually abolished when progesterone was hydroxylated in the 17alpha position.