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Androgen receptor immunoreactivity of male rat cervical motor neurons is increased by chronic pharmacologic testosterone treatment.

Chronic pharmacologic testosterone treatment of adult male rats decreases neuromuscular transmission failure (NTF) in the rat diaphragm muscle and increases choline acetyltransferase (ChAT) mRNA levels in cervical motor neurons. These testosterone-induced changes in NTF and ChAT mRNA levels may be mediated through the activation of the androgen receptor (AR). The purpose of this study was to determine if the AR expression of cervical motor neurons is modulated by chronic pharmacologic testosterone treatment of gonadally intact male rats with testosterone propionate (TP). Serum testosterone levels were elevated by a subcutaneous implant of capsules containing crystalline TP for 28 days. The proportion of motor neurons containing AR-I positive nuclei was increased from 14.8 +/- 10.8% among the control group to 81.7 +/- 12.6% in the TP-treated animals (p<0.05). These results imply that anabolic-androgenic steroid effects on neuromuscular function may be mediated through AR dependent regulation of gene expression in motor neurons.

Animals↗

Effects of neonatally administered chlorpromazine and reserpine on the responsiveness of rat hepatic drug-metabolising enzymes to testosterone in adult life.

The effects of neonatally administered chlorpromazine and reserpine on the response of rat hepatic drug-metabolising enzymes to testosterone in adult life have been investigated using the chlorinated cyclodiene substrate DME. Neonatal treatment with chlorpromazine and reserpine had effects on the metabolism of DME similar to, but not as pronounced as, those of castration when adult. The effects of adult castration of male rats on hepatic microsomal metabolism of DME were fully reversed by treatment with testosterone propionate, with metabolism being restored to that of a control intact male. However, testosterone propionate treatment of either intact or castrated adult males that had received neonatal reserpine or chlorpromazine did not restore levels of metabolism to those characteristic of control adult male rats. These results suggest that neonatally administered chlorpromazine and reserpine alter the sensitivity of hepatic drug-metabolising enzymes to the actions of testosterone in adult life.

Aging↗

Sites of action of testosterone in the brain of the female primate.

Thaw-mount autoradiography was used to map target neurons for tritiated steroids in the brains of ovariectomized rhesus monkeys. In five females, studies were performed 60 min after the administration of 3H-estradiol. Of these, two females were pretreated for five days with daily injections of 2 mg testosterone propionate, one female was pretreated with daily injections of 2 mg dihydrotestosterone propionate, and two females were pretreated with oil vehicle. For comparison, two additional females were administered 3H-testosterone and were killed 30 min later. Following 3H-estradiol administration in females pretreated with oil, there were numerous labeled neurons in the medial preoptic nucleus (n.), anterior hypothalamic area, ventromedial hypothalamic n., arcuate n., bed n. of stria terminalis, lateral septal n., and regions of the amygdala. In females pretreated with testosterone propionate, labeling was virtually abolished in all these areas with the exceptions of the lateral septal n. and arcuate n., presumably because estradiol formed from testosterone competed with 3H-estradiol for estrogen-binding sites. Pretreatment with dihydrotestosterone propionate had no effect on the labeling following the administration of 3H-estradiol. Areas where labeling was blocked, therefore, represent regions where testosterone acted as an estrogen, and it would appear that regional differences in the activity of aromatizing enzymes determine which estrogen target sites in the brain can interact with estrogenic metabolites of testosterone in female primates.

Androgens↗

Postnatal masculinization alters the HPA axis phenotype in the adult female rat.

The ability of postnatal testosterone propionate (TP) to masculinize both behaviour and gonadal cyclicity in the female rat is well documented. We have investigated whether postnatal androgen also has an organizational effect on another sexually dimorphic neuroendocrine system--the hypothalamo-pituitary-adrenal (HPA) axis. Female rats were exposed to a single injection of testosterone propionate (TP) or oil within 24 h of birth. As adults, rats were either ovariectomized and given 17beta-oestradiol replacement (OVXE2) or sham ovariectomized with cholesterol implants (SHOVX). An automated sampling system collected blood from unanaesthetized adult female rats every 10 min over a 24-h period, during a mild psychological stress (noise) and following an immunological lipopolysaccharide stress (LPS). Neonatal TP-treated SHOVX rats had a significant reduction in the number, height, frequency and amplitude of corticosterone pulses over the basal 24-h period, compared to both the neonatal oil-treated and TP-treated OVXE2 animals. The corticosterone response to both noise and LPS was also significantly decreased for the TP-treated SHOVX females. Three hours post-LPS administration, TP females had significantly lower values of paraventricular nucleus (PVN) corticotrophin releasing hormone (CRH), arginine vasopressin (AVP) and anterior pituitary proopiomelanocortin (POMC) mRNAs and greater PVN glucocorticoid receptor (GR) mRNA expression compared to the oil-treated controls. E2 replacement in adult TP rats normalized all the mRNA levels, except for PVN GR mRNA which did fall towards the levels of the oil-control animals. A single injection of TP within 24 h of birth disrupts the development of the characteristic female pattern of corticosterone secretion and the normal female HPA response to stress, resulting in a pattern similar to that seen in males. These effects can be reversed by E2 treatment in the adult TP female rat.

Animals↗

Synergistic effect of estrogen and androgen on induction of uterine thymidine kinase activities in immature rats.

Estradiol-17 beta induced a significant increase in the uterine thymidine kinase activity with a characteristic isozyme pattern 30 h after injection into immature rats. Testosterone propionate also revealed a similar increase. Following combined injection of estradiol-17 beta and testosterone propionate, the overall and separate isozyme activities of thymidine kinase increased to nearly the total amount of those when each hormone was injected separately.

Animals↗

[Effect of the male sex hormone and its 5 alpha-reduced metabolites on the function of the thyroid in vivo and in vitro].

The administration of testosterone propionate, dihydrotestosterone and androstandiol to male rats was followed by different changes in thyroid function. Testosterone propionate exerted a stimulating effect, whereas its metabolites induced marked depression of thyroid functional activity in the experiments in vivo. In vitro both sex hormones and 5-alpha-reduced metabolites inhibited radioactive iodine absorption by rat thyroid slices and human thyrotoxic struma. The data demonstrate that testosterone may produce a direct effect on the thyroid without the hypophysis.

Androstenediol↗

[An experimental study(II) on the inhibition of prostatic hyperplasia by extract of seeds of Brassica alba].

OBJECTIVE: To study the active components and their functionary mechanism of the extract of Brassica alba seeds, which inhibits experimental mice prostatic hyperplasia. METHOD: Prostatic hyperplasia of castrated male mice induced by testosterone propionate, the penetrability of capillary vessel of mice skin induced by histamine and the endermic flesh bud of rat induced by filter paper were used as experimental models. Sinalbin and beta-sitosterol separated from seeds of Brassica alba were used to test the activities. RESULT: Sinalbin and beta-sitosterol(16.0 mg.kg-1.d-1 and 8.0 mg.kg-1.d-1) could significantly inhibit mice prostatic hyperplasia induced by testosterone propionate and activity of serum acid phosphatase(P < 0.01 or P < 0.05), Sinalbin(16.0 mg.kg-1.d-1)could significantly inhibit the hyperplasia of endermic flesh bud in rat induced by filter paper(P < 0.05), beta-sitosterol(16.0 mg.kg-1.d-1 and 8.0 mg.kg-1.d-1) could significantly decrease the penetrability of capillary vessel of mice skin induced by histamine. CONCLUSION: Sinalbin and beta-sitosterol have anti-androgen and anti-inflammation activities.

Androgen Antagonists↗

Regulation of the pituitary 5 alpha-reductase activity by gonadotropin releasing hormone and testosterone in the adult male rat.

Intact or castrated adult male rats were treated for nine days with GnRH (10 micrograms/day), the synthetic GnRH goserelin (100 micrograms/day) or the GnRH-antagonist Org 30276 (250 or 500 micrograms/day). In some series, 1 mg testosterone propionate was administered alone, or in combination with goserelin or Org 30276. The in vitro metabolism of [1 alpha,2 alpha-3H]testosterone by pituitary and hypothalamic homogenates was investigated in combination with the estimation of plasma concentrations of testosterone and gonadotropins. No qualitative or quantitative differences were observed in hypothalamic testosterone metabolism or in the pituitary 17 beta-hydroxysteroid dehydrogenase activity. Testosterone administration to intact male rats decreased the pituitary 5 alpha-reductase activity and LH, while administered to castrated rats, it was able to suppress totally the castration-induced increase of the 5 alpha-reductase activity and of the gonadotropin secretion. The drastic decrease of the plasma levels of testosterone, observed after a prolonged treatment with GnRH, goserelin or Org 30276 was not accompanied by an increased pituitary 5 alpha-reductase activity. Injected to castrated rats, it was observed that the castration-induced increase of the pituitary 5 alpha-reductase was further stimulated by GnRH, totally suppressed by goserelin and partially suppressed by Org 30276. Concomitant administration of goserelin or Org 30276 and testosterone propionate to castrated rats resulted in a further decrease of the pituitary 5 alpha-reductase activity, compared to the castrated, GnRH-analogue treated rats. These data indicate that the pituitary 5 alpha-reductase enzyme system is controlled by both direct steroidal and indirect GnRH-mediated mechanisms.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Antidopaminergic-induced hypothalamic LHRH release and pituitary gonadotrophin secretion in 12 day-old female and male rats.

In previous studies we have shown that the developing rat provides an interesting physiologic model in which the dopaminergic control of both LH and FSH is well defined in contrast to the controversial results obtained in adult rats. We wished to establish the role of testosterone in antidopaminergic induced gonadotrophins release in 12 day-old male and female rats, and evaluate the effect of antidopaminergic drugs at the hypothalamic level during this developmental stage. Haloperidol, an antidopaminergic drug, increased both LH and FSH in female 12 day-old rats but not in male littermates. The effect was blocked by bromocriptine and not by phentolamine indicating that haloperidol acted on the dopaminergic receptor, and that unspecific stimulation of the noradrenergic system was not involved. Haloperidol was ineffective when female rats were previously ovariectomized and injected with testosterone propionate at 9 days of age. If females were treated on the day of birth with testosterone propionate, haloperidol-induced FSH and LH release was also abolished. In control males haloperidol had no effect on the release of LH or FSH. But if males were orchidectomized at birth or at 9 days of age, haloperidol released both LH and FSH during the infantile period. In an attempt to establish the site of action of antidopaminergic drugs on gonadotrophin release, hypothalami (mediobasal and preoptic-suprachiasmatic area) from 12 day-old infant female rats were perifused with either haloperidol or domperidone (2*10(-6) M). Both drugs increased LHRH release into the perifusate. Besides haloperidol did not modify the release of LH or FSH from adenohypophyseal cells incubated in vitro. We therefore conclude that antidopaminergic-induced gonadotrophins release is modulated by serum testosterone concentrations, and that the site of action is probably the LHRH-secreting neuron of the hypothalamus.

Adrenergic alpha-Antagonists↗

Administration of gonadal steroids to the castrated male rat prevents a decrease in the release of gonadotropin-releasing hormone from the incubated hypothalamus.

The influence of testosterone on gonadotropin-releasing hormone (GnRH) secretion was assessed indirectly by altering the serum testosterone concentration of male rats and measuring GnRH release from their incubated hypothalami 1 wk later.GnRH release from hypothalami of castrated rats was 13.4+/-1.2 (SE) pg/h, compared to 35.3+/-3.8 pg/h from hypothalami of intact rats (P < 0.001). GnRH release from the hypothalami of castrated rats treated with testosterone propionate, 100 or 500 mug daily, was 25.0+/-3.4 pg/h and 27.9+/-3.6 pg/h, which is significantly greater (P < 0.05 and P < 0.01, respectively) than that from hypothalami of castrated rats treated only with sesame oil.A similar decrease in GnRH release from hypothalami of hypophysectomized rats and prevention of this decrease by treating the hypophysectomized rats with testosterone propionate is evidence that the observed effects of testosterone are not mediated via luteinizing hormone and(or) follicle-stimulating hormone secretion. Treatment of castrated rats with either dihydrotestosterone propionate or estradiol benzoate also prevented the decrease in GnRH release from the hypothalami of castrated rats. We conclude that testosterone, dihydrotestosterone, and estradiol all prevent the decrease in GnRH release from hypothalami of castrated rats treated with these steroids. The possibility exists that these steroids may also maintain GnRH secretion in vivo.

Animals↗

Formation of behaviorally effective 17 beta-estradiol in the dove brain: steroid control of preoptic aromatase.

The preoptic area (POA) of the male dove is a known target area for separable behavioral actions of testosterone and 17 beta-estradiol (E2) and contains an active aromatase system. We have examined the regulatory influence of gonadal hormones on aromatase using an in vitro microassay that measures conversion of [1 alpha, 2 alpha-3H]testosterone to E2 in anatomically defined brain samples of individual animals. Preoptic aromatase activity, which is higher in males than females, is decreased (77%) in both short (30 day) and long term (180 day) castrates, indicating that gonadal hormones maintain POA aromatase activity. Basal levels of POA activity are not influenced by the period of hormonal deficit. Low levels of aromatase activity detected in area basalis are also unaffected by castration. Intramuscular testosterone propionate rapidly increases aromatase activity (within 12 h) specifically in POA of castrated males. The inductive effect of testosterone propionate in castrated doves is not increased by limited behavioral interactions in a test situation with sexually active females. A nonaromatizable androgen, 5 alpha-dihydrotestosterone, has no effect on POA aromatase activity, whereas the activity of this enzyme is restored to levels of sexually active males by systemic E2. Diethylstilbestrol has a similar, though less potent effect, indicating an estrogenic action on the enzyme. We conclude that circulating androgen modulates preoptic aromatase activity. The product of the reaction, E2, is also likely to be involved as part of a positive feedback system.

Animals↗

Hormonal influences on sexual dimorphism in rate of extinction of a conditioned taste aversion in rats.

The hormonal influences on the slow extinction rate of a conditioned taste aversion shown by male rats and the fast extinction rate shown by female rats were investigated. When males were castrated, they extinguished as quickly as females. When castrated males were given testosterone propionate replacement, they had a slow extinction rate. Castration had no effect on the extinction rate of females. But when testosterone propionate was administered to castrated or intact females, they had a slow, malelike extinction rate. Thus, sexual dimorphism in the extinction rate of a conditioned taste aversion seems to be due to the activational effects of testosterone.

Animals↗

Effect of actinomycin D or puromycin on microsomal testosterone hydroxylase activity enhanced by testosterone in female rat liver.

The injection of testosterone propionate for 4 successive days into female rats resulted in an increase of the in vitro conversion of the hydroxylated testosterones from testosterone by the hepatic microsomal fraction, but no change in the content of microsomal cytochrome P-450 occurred. Actinomycin D or puromycin, which was administered for 4 days with injections of testosterone propionate, prevented the enzyme induction.

Animals↗

Steroid hormones retard aflatoxin-induced cytotoxicity.

Protective effect of sex steroid hormones on aflatoxin-induced cytotoxicity on RBC (hemolysis) was examined in vitro. Addition of aflatoxin (2 micrograms/ml) in RBC suspension caused significant increase in hemolysis. Concurrent addition of aflatoxin (2 micrograms/ml) and estradiolbenzoate (100-1200 pg/ml) in RBC suspension significantly retarded aflatoxin-induced hemolysis. Similarly, addition of aflatoxin (2 micrograms/ml) along with testosterone propionate (5-60 ng/ml) in RBC suspension retarded aflatoxin-induced hemolysis. Among the two synthetic hormones studied estradiolbenzoate was more potent than testosterone propionate.

Adult↗

The involvement of androgens in the control of epididymal protein synthesis and amino acid transport in the rat.

The effect of androgen withdrawal upon different parameters of the rat epididymis has been investigated, as well as the early response of these to the readministration of testosterone. The weight, protein and RNA content of the epididymides decreased after castration. However, their response to a single injection of 6 mg testosterone propionate in oil administered 24 hr before sacrifice, varied according to the parameter examined. Epididymal weight increased after androgen was given to rats castrated for 3 days or less. The protein content was moderately elevated when testosterone was administered to rats castrated for 3, 6 or 13 days. The RNA content increased sharply after androgen, the magnitude of the response being proportional to the duration of castration. These changes in epididymal trophism were dramatically illustrated by the 50% decrease in amino acid incorporation into acid insoluble material already measurable 24 hr after castration. This effect was reverted by testosterone propionate administered 24 hr before sacrifice. The free alcohol form of testosterone given at the same dose induced a significant increase in this parameter as early as 12 hr after its intraperitoneal injection. Finally, we could demonstrate the existence of active transport of amino acids into the epididymal cells and the stimulatory effect of testosterone upon this function.

Amino Acids↗

Steroid hormone receptors and their relevance for sebum production in the sebaceous gland ear model of the Syrian hamster.

We determined the capacity of steroid hormone receptors in the sebaceous glands of intact nontreated, castrated, with testosterone substituted castrated male, intact female, and intact with testosterone substituted female animals using the animal ear model of the Syrian hamster. The steroid hormone binding capacity was compared with the sebaceous gland areas and sebogenesis. Intact male animals showed large sebaceous follicles, a high sebogenesis rate, and high capacity for sexual hormone binding proteins. In castrated males, the sebaceous gland areas and sebogenesis were both diminished, and androgen and estrogen receptors were decreased. When the castrated males were substituted with testosterone propionate, the sebaceous glands showed large volumes, high sebum production, and androgen binding activity again. In female animals having small sebaceous follicles and a low rate of sebogenesis, testosterone propionate enlarged the sebaceous glands and increased sebogenesis and the capacity of androgen binding. One can conclude from these data that testosterone is not only the main hormone for sebum production but also induces the synthesis of its own receptor.

Animals↗

[Changes in the biological activity of androgens after the exposure of cockerels to lindane].

A biological test was performed to study the changes in the effectiveness of androgens after the administration of different doses of lindane to sexually immature cockerels. Testosterone-propionate and Stenolon were used as reference hormones. The results indicate that the administration of lindane increases the biological effectiveness of testosterone-propionate expressed through the stimulation of the growth of comb. On the other hand, the effect of the insecticide caused a statistically highly significant reduction of androgenic activity when Stenolon was used as a reference preparation. The causes leading to different manifestations of the interactions of lindane with the two hormones tested are analyzed. The paper gives further proofs that the exposure of poultry to relatively low doses of chlorinated insecticides interferes with the biological effectiveness of sex hromones.

Animals↗

Effects of various drugs on insulin antibodies.

1. Insulin antibodies were induced in young guinea-pigs of both sexes weighing 300-400 g and housed in a room maintained at 28 degrees C+/-2 degrees C, by subcutaneous injection of 2 ml of freshly prepared insulin antigen emulsion between the shoulders once every month.2. To estimate the titre of serum antibody the serum was incubated with a known concentration of insulin for 90 min at 37 degrees C and the insulin not bound to antibody was estimated by the rat hemidiaphragm method.3. No significant (P>0.5) development of insulin antibody could be detected in the serum samples collected 1 month after the first and 15 days after the second monthly injections in groups of ten male guinea-pigs and six female guinea-pigs. However, the titre of insulin antibody in the serum of these groups of guinea-pigs 15 days after the third monthly injection of insulin antigen emulsion was significantly (P<0.01) raised. There was no further increase in the titre of insulin antibody in the sera 15 days after the fourth and fifth monthly injections of insulin antigen emulsion. Thus the peak titre was reached 15 days after the third monthly injection of the antigen.4. Two groups of ten male guinea-pigs each received testosterone propionate or diethylstilboestrol daily for 1 week after each monthly injection of insulin antigen emulsion. Two other groups of six female guinea-pigs each received testosterone propionate or diethylstilboestrol in a similar manner. One more group of ten female guinea-pigs received both sex hormones for 1 week after each monthly injection of insulin antigen emulsion. Testosterone facilitated the induction of insulin antibody in the serum of males but did not affect the antibody titre in the female guinea-pigs. Diethylstilboestrol facilitated the induction of insulin antibody in the serum of groups of either sex, the peak titre being attained after the second monthly injection of insulin antigen emulsion. The response of the females which received both sex hormones was similar to that of females which received diethylstilboestrol alone.5. Fifteen days after the third monthly injection of insulin antigen emulsion a group of ten guinea-pigs received hydrocortisone subcutaneously each day for 1 month. The serum antibody titre was estimated at the end of the drug treatment, and was significantly (P<0.01) reduced.6. Fifteen days after the third monthly injection of insulin antigen emulsion three different groups of five-six guinea-pigs each received tolbutamide, chlorpropamide or phenformin orally every day for a month. Antibody titres of the serum were estimated at the end of this period; there was no significant (P>0.05) reduction in groups receiving chlorpropamide or phenformin, but the serum antibody titre of the group receiving tolbutamide was significantly (P<0.01) raised.7. Fifteen days after the third monthly injection of insulin antigen emulsion different groups of five-six guinea-pigs received one of the following: 5-bromouracil, 5-fluorouracil, 6-mercaptopurine, methotrexate, 6-azauridine, busulphan, chlorambucil, cyclophosphamide, actinomycin-D or mytomycin-C intraperitoneally each day for 5 days. The serum antibody titre of all the groups of guinea-pigs was significantly (P<0.01) reduced. On the other hand the serum antibody titre of a control group of six guinea-pigs receiving normal saline intraperitoneally each day for 5 days was not significantly (P>0.5) affected.

Animals↗