Suppress Testosterone Production Research Articles

Population pharmacokinetic/pharmacodynamic modeling of cetrorelix, a novel LH-RH antagonist, and testosterone in rats and dogs.

Population models for the pharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasing hormone (LH-RH) antagonist, and the pharmacodynamic response on testosterone production were investigated in rats and dogs. The plasma concentrations of CET and testosterone were determined after intravenous and subcutaneous injections. The population PK/PD-models were developed using P-PHARM software. Absolute bioavailability of cetrorelix was 100% in rats and 97% in dogs. In rats, the pharmacokinetics was explained by a two-compartment model with saturable absorption, while a three-compartment model was used in dogs. Testosterone suppression in both species was described by a sigmoid E(max) model with maximum effect (E(max)) considered as total hormonal suppression. The duration of testosterone suppression in rats was longer at higher doses. The population elimination half-lives after iv-dose were 3.0 h in rats and 9.3 h in dogs. Population mean estimates of IC50 were 1.39 and 1.24 ng/ml in rats and dogs, respectively. A population pharmacokinetic model was developed to explain the dissolution rate limited absorption from the injection site. The suppression of testosterone could be described by an indirect inhibitory sigmoid E(max) model. In both species 1-2 ng/ml CET in plasma was necessary to suppress testosterone production.

Short Communication Tamoxifen exerts testosterone-dependent and independent effects on thymic involution

Circulating testosterone concentrations and seminal vesicles weights, as well as thymus and spleen weights and histology were assessed in male Wistar rats from the infantile to post-pubertal period. The widely used anti-estrogenic agent tamoxifen was then administered in adult intact and castrated male rats and its long-term effects on thymic involution and splenic growth were examined. The results showed that: (1) age-related involution of the male thymus from the juvenile period through puberty to post-puberty depends on the rising testosterone levels and represents mainly a decrease of thymic lymphoid-cell elements; (2) tamoxifen administration reverses thymic involution in intact adult male rats and this effect is related to a dose-dependent, tamoxifen-induced castration and decrease of testosterone levels; (3) the changes of circulating testosterone levels, either resulting from maturity, or induced by tamoxifen or by castration, have a minimal effect on splenic growth and weight; and (4) in contrast to intact animals, administration of tamoxifen at pharmacological doses to adult castrated rats results in thymic regression. Underscoring the critical role of testosterone on thymic involution, these findings show that tamoxifen is able to reverse ageing changes in the thymus by suppressing testosterone production, while conversely, exerts thymolytic effects in the absence of androgens.

Elevated concentrations of ascorbate and normoxia suppress testosterone production in cultured guinea pig leydig cells

In recent years, several metabolic roles have been proposed for vitamin C. Recent information suggests a strong causal relationship between high endogenous levels of ascorbic acid and changes in normal reproductive biology. Using highly enriched populations of guinea pig Leydig cells, we have found that elevated levels (50 to 500 μM) of ascorbate significantly ( P < 0.01) depressed testosterone production in a dose-dependent manner while low levels (0 to 10 μM) were without effect. Leydig cells incubated under hypoxic (3% oxygen) culture conditions produced significantly ( P < 0.01) more testosterone than similar cells cultured under normoxic (19% oxygen) conditions. The results of this study suggest that high concentrations of ascorbate and normoxic culture conditions suppress testosterone production in isolated Leydig cells. Thus, it would seem that there exists a delicate balance between normal metabolic requirements for vitamin C and excessive ascorbate levels that might alter normal gonadal reproductive events.

Reciprocal changes in plasma corticosterone and testosterone in stressed male rats maintained in a visible burrow system: evidence for a mediating role of testicular 11 beta-hydroxysteroid dehydrogenase

The purpose of these studies was to investigate the possible role of rat Leydig cell 11 beta-hydroxysteroid dehydrogenase (11HSD) in mediating the inhibitory effects of corticosterone on testosterone production. In a unique communal environment, the visible burrow system, male Long-Evans rats spontaneously segregated into unstressed dominant and stressed subordinate social relationships. Subordinate animals had elevated plasma corticosterone and diminished circulating testosterone levels relative to the dominant animals. The categories of animals were distinguished by behavioral criteria: weight change, wounds received, offensive and defensive behavior, and freedom of movement. As a result of their persistently elevated corticosterone levels, subordinate animals had smaller thymi and larger adrenals and spleens than dominants. We have postulated that Leydig cells are protected against the inhibitory effects of glucocorticoids on testosterone secretion by the inactivating effects of 11HSD. High corticosterone and low 11HSD are predicted to suppress testosterone production, and normal or diminished corticosterone levels combined with normal or elevated 11HSD should permit undiminished testosterone production. Consistent with these predictions, the testes of subordinate animals contained significantly lower 11HSD activity than those of dominant animals. The 11HSD of livers of subordinate and dominant animals were statistically indistinguishable. The results of this study support the postulated role of 11HSD as a protector of Leydig cell function.

Reciprocal changes in plasma corticosterone and testosterone in stressed male rats maintained in a visible burrow system: evidence for a mediating role of testicular 11 beta-hydroxysteroid dehydrogenase.

The purpose of these studies was to investigate the possible role of rat Leydig cell 11 beta-hydroxysteroid dehydrogenase (11HSD) in mediating the inhibitory effects of corticosterone on testosterone production. In a unique communal environment, the visible burrow system, male Long-Evans rats spontaneously segregated into unstressed dominant and stressed subordinate social relationships. Subordinate animals had elevated plasma corticosterone and diminished circulating testosterone levels relative to the dominant animals. The categories of animals were distinguished by behavioral criteria: weight change, wounds received, offensive and defensive behavior, and freedom of movement. As a result of their persistently elevated corticosterone levels, subordinate animals had smaller thymi and larger adrenals and spleens than dominants. We have postulated that Leydig cells are protected against the inhibitory effects of glucocorticoids on testosterone secretion by the inactivating effects of 11HSD. High corticosterone and low 11HSD are predicted to suppress testosterone production, and normal or diminished corticosterone levels combined with normal or elevated 11HSD should permit undiminished testosterone production. Consistent with these predictions, the testes of subordinate animals contained significantly lower 11HSD activity than those of dominant animals. The 11HSD of livers of subordinate and dominant animals were statistically indistinguishable. The results of this study support the postulated role of 11HSD as a protector of Leydig cell function.

The effects of opioid receptor antagonists suggest that testicular opiates regulate Sertoli and Leydig cell function in the neonatal rat.

beta-Endorphin and other peptides derived from proopiomelanocortin are synthesized in testicular Leydig cells. To better understand the possible function of these and other endogenous opioid peptides in the testis, the opioid antagonists naloxone and nalmefene were administered intratesticularly to hemicastrated 5-day-old rats. Both naloxone and nalmefene potentiated testicular hypertrophy induced by unilateral orchidectomy at 11 days of age. Unexpectedly, at least a 100-fold lower dose of nalmefene was required to produce maximal hypertrophy than that previously reported for naloxone. Leydig and Sertoli cell functions were evaluated, respectively, by measurement of basal testosterone production in vitro and rat androgen-binding protein (rABP) in serum. The optimal dose of naloxone for hypertrophy (1 microgram/testis) suppressed testosterone production and had a nonuniform effect on rABP secretion (either had no effect or produced a slight increase). By contrast, the optimal dose of nalmefene for hypertrophy (0.01 microgram/testis) not only suppressed basal testosterone secretion, but also uniformly increased rABP levels in serum. Larger doses of this opioid antagonist, up to 1 microgram/testis, were not as effective on the three parameters measured (hypertrophy, testosterone secretion, and rABP levels). These results suggest that this agent has both antagonistic and agonistic activities in the testis. At the doses that produced optimal effects on hypertrophy, systemic administration of these antagonists produced no effects. The results of these studies suggest that intratesticular opiates exert a suppressive effect on Sertoli cell growth and rABP secretion. In addition, these peptides may modulate testosterone secretion by Leydig cells.

Effect of ketoconazole and other imidazole fungicides on testosterone biosynthesis.

A single oral dose of 400 mg ketoconazole, a broad-spectrum antifungal drug, administered orally to 5 young men induced a drop in serum and saliva testosterone into the range of hypogonadism, while LH, FSH and prolactin levels remained unchanged. In vitro studies with mouse Leydig cells demonstrated a direct reversible inhibition of testosterone biosynthesis by ketoconazole. Comparative studies with chemically related compounds showed similar effects on testosterone production of mouse Leydig cells by isoconazole, miconazole, econazole and clotrimazole, while metronidazole and levamisole were without influence on testosterone biosynthesis. Since all tested imidazoles which suppress testosterone production have as a common feature a phenylated side chain of the imidazole molecule, this indicates a structure/activity relationship for the effects observed.

Sex-determined differences in drug susceptibility

not received. EFFECT OF ALCOHOL ON GONADAL FUNCTION DAVID H. VAN THIEL*, JUDITH S. GAVALER, PATRIC’IA K. EAGON and ROGER LESTER Departments of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15621, and Unioersity of Texas, Houston, TX 77025 (rr.S.A.) During the past decade there has been an increasing appreciation of the fact that ethanol is a tissue toxin which adversely effects multiple organs including the endocrine system. In particular it has been recognized that ethanol impairs the functioning of the hypothalamic-pituitary-gonadal axis. Thus, hypogonadism is seen commonly in alcoholic men. Such hypogonadism is manifested by a high prevalence of decreased libido and/or impotence (70 to 80%) and testicular atrophy with infertility (70 to 80%). Histologic examination of testicular tissues obtained from such individuals show seminiferous tubular atrophy with a marked loss of normal germ cells and a high prevalence of grossly abnormal germ cells. In addition to demonstrating evidence of hypogonadism, chronic alcoholic men also are hyperestrogenizied. Thus, a female escutcheon develops in 50%, gynecomastia in 2096, spider angiomata and palmer erythema in 40 to 50%. Unlike impotence, which commonly is experienced with acute alcohol abuse, these signs suggest irreversible hepatic disease (cirrhosis). In contrast, considerable evidence has accrued to suggest that sexual dysfunction is an early finding in alcoholabusing men and animals and can occur in the absence of histologic liver disease. Recent clinical studies have provided evidence that alcohol and/or its principal metabolite, acetaldehyde, are testicular toxins. Thus, testosterone concentrations have been shown to fall transiently in normal men after alcohol ingestion. Similarly, a dose-dependent fall in testosterone has been reported in mice given ethanol. Moreover, histologic and biochemical testicular damage has been reported in alcohol-fed rats. Most recently, perfusion of the isolated perfused rat testes with ethanol over a dose range of 50 to 300 mg/dl has been shown to suppress testosterone production and secretion by as much as 75%. The specific mechanisms by which alcohol adversely effects Leydig cell and/or seminiferous tubular function are, as yet, unknown. It is possible that vitamin A bioactivation is altered as a result of alcohol metabolism. Alcohol metabolism also may shift the balance between NAD and NADH, thus limiting synthesis. Evidence also is accumulating to

Effects of 15(S)-15-Methyl Prostaglandin F2α Methyl Ester-Containing Silastic Discs in Male Rats

Silicone rubber discs containing 15(S)-15-methyl prostaglandin F2 alpha ester (15-Me-PGF2 alpha) in the matrix were implanted in the left side of the scrotums of Sprague-Dawley rats. The effect of 1% and 2% drug concentration was examined for 10, 20, or 28 days and compared with the effects of Silastic discs containing no prostaglandin. The discs containing prostaglandin reduced mean testicular and accessory gland weights. Histologically the testes and epididymides showed decreased or absent spermatogenic elements and hypertrophy of the interstitial cell masses in comparison with other cells. Implanted prostaglandin significantly depressed serum testosterone, luteinizing hormone, and follicle-stimulating hormone (FSH) concentrations when 15-Me-PGF2 alpha plasma concentrations exceeded 2 ng/ml. Hormone concentrations returned to control values as drug concentrations declined. FSH concentrations significantly exceeded control values 10 and 20 days after implantation, when prostaglandin concentration was nondetectable. The acute suppression of all three hormones suggest that 15-Me-PGF2 alpha either may act directly on the tests to suppress testosterone production or may suppress testosterone production or may suppress gonadotropin secretion, resulting in depressed testosterone output.

Androgen production in boys with sexual precocity and congenital adrenal hyperplasia

Plasma testosterone and testosterone production rates were studied in young boys with idiopathic sexual precocity and congenital adrenal hyperplasia (CAH). Four males with CAH and one with idiopathic sexual precocity underwent physiologic studies to delineate the source of testosterone. In young boys with idiopathic sexual precocity and CAH, plasma testosterone was increased over prepubertal levels although the increase was greater in the one patient with idiopathic sexual precocity than in those with CAH. Testosterone production rates (TPR) were increased to the same degree in both conditions. Physiologic studies of stimulation and suppression of gonads and adrenals delineate the glandular source of testosterone and provide a means of defining therapeutic measures of suppressing testosterone production.

Conversion of pregnenolone and 4-androstene-3β,17β-diol to testosterone by mouse testes [formula omitted

The in vitro conversion of pregnenolone-7-H 3 to testosterone by a mouse testis mince preparation has been demonstrated. Human chorionic gonadotrophin administered in vitro had a stimulatory effect on the in vitro conversion. The addition to the incubation medium of SU-4885 at 10-3 M and 10 −4 M suppressed testosterone production. 4-Androstene-3β,17β-diol-4C 14 was converted primarily to testosterone and only minor amounts of 4-androstene-3,17-dione were formed.