[On the tolerance of the liver for 1-alpha-methyl-5-alpha-androstan-17-beta-ol-3-one (mesterolone)].
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Adult↗
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[Effect of 1-alpha-methyl-5-alpha-androstane-17-beta-ol-3-one (mesterolone) on the excretion of steroids in man].
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17-Hydroxycorticosteroids↗
Action of steroids on LH-RH provoked gonadotropin release.
The action of mesterolone (1 alpha-methyl-17-beta-hydroxy-5 alpha-androsten-3-one) mesterolone cipionate, testosterone, 17 alpha-methyl-testosterone, 17 beta-hydroxy-5 alpha-androstane-3-one, cyproterone actetate and D-norgestrel on basal and LH-RH stimulated, gonadotropin release was studied in vitro. Hemi-gland preparation of the anterior pituitary were incubated in the presence or absence of steroids and/or LH-RH. Steroid hormones were added at a concentration of 25, 5 and 1 mug per ml medium. Basal levels of LH and FSH discharge were not influenced by mesterolone, whereas inhibition of LH-RH stimulated gonadotropin release was noted at 25 mug mesterolone/ml medium. The addition of mesterolone cipionate to the incubation medium did not significantly change basal FSH levels, whereas an inhibition of LH-RH provoked FSH discharge was noted. Basal LH release was stimulated by the presence of 1 mug mesterolone cipionate per 1 ml medium. LH-RH stimulated LH release in the presence of 25, 5 and 1 mug mesterolone cipionate per 1 ml medium was indistinguishable from control levels. Basal levels of LH and FSH were not affected by testosterone, whereas an impaired gonadotropin response to LH-RH was observed in the presence of testosterone. At 1 mug testosterone per 1 ml medium only LH response to LH-RH was found. Basal gonadotropin levels in the presence of 17 alpha-methyl-testosterone were indistinguishable from control values. The only inhibition of LH-RH action was found for stimulation of LH release at 25 mug 17 alpha-methyl-testosterone/ml medium. On the other hand, 17 beta-hydroxy-5 alpha-androstane-3-one stimulated basal LH and FSH discharge, and LH-RH actions were not impaired. Results of our studies with cyproterone acetate indicate that this steroid stimulates basal pituitary gonadotropin discharge at high concentration, without blunting responses to LH-RH. No action of D-norgestrel on basal and LH-RH stimulated gonadotropin release was observed. These experiments add further evidence that steroids modulate LH-RH actions at the pituitary level. It is concluded that the fine control of gonadotropin release resides at the adenohypophysis whereas the coarse control of LH and FSH discharge is at the hypothalamus and/or other centers of the central nervous system.
Androstenes↗
The medical treatment of male infertility.
Mesterolone, HCG and PMS, clomiphene and various other drugs were administered to 236 subfertile patients with disturbed spermatogenesis. Most of the patients received mesterolone. The effects of the various therapeutic regimes are discussed. Improvement of the sperm count and spermatozoal motility was more frequent after mesterolone treatment than after HCG and PMS or after clomiphene. 14 wives of patients in the mesterolone group became pregnant and gave birth to normal children. There were two pregnancies in the gonadotropin group and 3 in the clomiphene group. Specific treatment of the few patients with varicocele or epididymitis led to improved findings in the spermiogram.
Adult↗
Effect of non aromatizable androgens on LHRH and TRH responses in primary testicular failure.
We have assessed the gonadotropin, TSH and PRL responses to the non aromatizable androgens, mesterolone and fluoxymestrone, in 27 patients with primary testicular failure. All patients were given a bolus of LHRH (100 micrograms) and TRH (200 micrograms) at zero time. Nine subjects received a further bolus of TRH at 30 mins. The latter were then given mesterolone 150 mg daily for 6 weeks. The remaining subjects received fluoxymesterone 5 mg daily for 4 weeks and 10 mg daily for 2 weeks. On the last day of the androgen administration, the subjects were re-challenged with LHRH and TRH according to the identical protocol. When compared to controls, the patients had normal circulating levels of testosterone, estradiol, PRL and thyroid hormones. However, basal LH, FSH and TSH levels, as well as gonadotropin responses to LHRH and TSH and PRL responses to TRH, were increased. Mesterolone administration produced no changes in steroids, thyroid hormones, gonadotropins nor PRL. There was, however, a reduction in the integrated and incremental TSH secretion after TRH. Fluoxymesterone administration was accompanied by a reduction in thyroid binding globulin (with associated decreases in T3 and increases in T3 resin uptake). The free T4 index was unaltered, which implies that thyroid function was unchanged. In addition, during fluoxymesterone administration, there was a reduction in testosterone, gonadotropins and LH response to LHRH. Basal TSH did not vary, but there was a reduction in the peak and integrated TSH response to TRH. PRL levels were unaltered during fluoxymesterone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Are hormones psychoactive? Evoked potential investigations in man.
The somatosensory evoked potential (SEP) of physically and mentally healthy male subjects was recorded before as well as 4 hours after administration of one single dose of placebo, cyproterone acetate (an antiandrogen), and mesterolone (an androgen). Quantitative evaluation of drug-induced changes in SEP latencies and amplitudes, which, when plotted in terms of t-values, result in the so-called "SEP profiles", did not demonstrate any significant alterations after placebo. Contrary to this, cyproterone acetate induced systematic and significant changes characterized by a latency increase in the early peaks and latency decrease in the late peaks of the SEP. Apart from the non-significant amplitude changes, such alterations were previously described by us as typical for drugs of the anxiolytic class. Mesterolone on the other hand, produced a significant latency decrease in the early part and a latency increase in the late part of the evoked response which was found to be typical for the SEP profiles of tricyclic antidepressants. The amplitude did not show any systematic changes. Based on step-wise discriminant analysis of these data we could significantly differentiate both hormones from placebo as well as from each other. A comparative analysis of low and high doses did not yield any significant differences between the two levels. It was concluded that both test substances have psychoactive properties; whereas cyproterone acetate reveals anxiolytic qualities, mesterolone exhibits antidepressant ones. These findings are discussed from the clinical as well as from the neurophysiological point of view.
Administration, Oral↗
Androgens versus placebo or no treatment for idiopathic oligo/asthenospermia.
BACKGROUND: Oligo-astheno-teratospermia (sperm of low concentration, reduced motility and increased abnormal morphology) of unknown cause is common and the need for treatment is felt by patients and doctors alike. As a result, a variety of empirical, non-specific treatments have been used in an attempt to improve semen characteristics and fertility. Androgens have been suggested as a treatment because its binding proteins maintain a maintain a high intratesticular level testosterone essential for spermatogenesis and because the epididymis and seminal vesicles affect the seminal constitution and sperm motility and are also androgen-dependent. However exogenous testosterone was found to exert negative feedback on the pituitary-gonadal axis and thereby to suppress FSH and LH secretion. Spermatogenesis was thus adversely affected. Nevertheless androgens are used for the treatment of male infertility either for a putative direct "stimulatory" or "rebound" therapy. The stimulatory androgens used are mesterolone and testosterone undecanoate which, it is postulated, in a form and dosage that does not influence pituitary gonadotrophin secretion, either have a direct stimulatory effect on spermatogenesis or influence sperm transport and maturation though an effect on the epididymis, ductus deferens and seminal vesicles. Other androgens have been used to produce a rebound effect. These androgens are administered to suppress gonadotrophin secretion and spermatogenesis. After androgen therapy is discontinued there is a surge of FSH and LH and spermatogenesis is recommenced. Because of their different proposed mechanisms of action, stimulatory and rebound androgen therapy are analysed separately in the comparisons. This review considers the available evidence of the effect of androgens for idiopathic oligo and/or asthenospermia. OBJECTIVES: The objective of this review was to assess the effect of androgen treatment of men among couples where failure to conceive has been attributed to idiopathic oligo- and/or asthenospermia. SEARCH STRATEGY: The Cochrane Subfertility Review Group specialised register of controlled trials was searched". SELECTION CRITERIA: Randomised trials of mesterolone or testosterone undecanoate versus placebo or no treatment (stimulatory therapy), or testosterone enanthate or testosterone undecanoate versus placebo or no treatment (rebound therapy) in couples where subfertility is attributed to male factor. DATA COLLECTION AND ANALYSIS: Eligibility and trial quality were assessed. MAIN RESULTS: Eleven trials involving 930 patients were included. For stimulatory therapy, androgens had little effect on endocrinal outcomes and sperm parameters. The rate of pregnancy after androgens with stimulatory effect compared to no treatment or placebo was also similar (odds ratio 1.10, 95% confidence interval 0.75 to 1.61). In rebound therapy, no difference was found in sperm parameters. The pregnancy rate after androgens with rebound effect also showed no difference compared to no treatment or placebo (odds ratio 1.60, 95% confidence interval 0.42 to 6.16). Adverse effects such as headaches and exanthema were reported. REVIEWER'S CONCLUSIONS: There is not enough evidence to evaluate the use of androgens for male subfertility. [This abstract has been prepared centrally.]
Androgens↗
Osteoporosis in male hypogonadism: responses to androgen substitution differ among men with primary and secondary hypogonadism.
BACKGROUND: No randomized study exists comparing the effects of different modes of androgen substitution on bone mineral density (BMD). METHODS: We performed a prospective, randomized, trial assigning 53 hypogonadal men to the following treatment groups: mesterolone 100 mg p.o. daily, testosterone undecanoate 160 mg p.o. daily, testosterone enanthate 250 mg i.m. every 21 days, or a single subcutaneous implantation of 1,200 mg crystalline testosterone. The BMD was determined by peripheral quantitative computed tomography. RESULTS: At baseline, men with secondary hypogonadism (n = 33) had a lower BMD (-1.52 +/- 0.23 SDS; Z-scores) than men with primary hypogonadism (n = 20, -0.87 +/- 0.23 SDS, p < 0.01). In men with primary hypogonadism, the BMD increased dose dependently (crystalline testosterone +7.0 +/- 1.3%, testosterone enanthate +4.8 +/- 0.2%, testosterone undecanoate +3.4 +/- 2.5%, mesterolone +0.8 +/- 1.6%) after 6 months of therapy. Only secondary hypogonadal men treated with testosterone enanthate experienced an increase of the BMD. CONCLUSIONS: In primary hypogonadal men the BMD responds dose dependently to testosterone substitution, whereas in secondary hypogonadism only testosterone enanthate treatment significantly increased the BMD.
Adult↗
Human androgen receptor mutation disrupts ternary interactions between ligand, receptor domains, and the coactivator TIF2 (transcription intermediary factor 2).
The androgen receptor (AR) is a ligand-dependent X-linked nuclear transcription factor regulating male sexual development and spermatogenesis. The receptor is activated when androgen binds to the C-terminal ligand-binding domain (LBD), triggering a cascade of molecular events, including interactions between the LBD and the N-terminal transactivation domain (TAD), and the recruitment of transcriptional coactivators. A nonconservative asparagine to lysine substitution in AR residue 727 was encountered in a phenotypically normal man with subfertility and depressed spermatogenesis. This N727K mutation, although located in the LBD, did not alter any ligand-binding characteristic of the AR in the patient's fibroblasts or when expressed in heterologous cells. Nonetheless, the mutant AR displayed only half of wild-type transactivation capacity when exposed to physiological or synthetic androgens. This transactivation defect was consistently present when examined with two different reporter systems in three cell lines, using three androgen-driven promoters (including the complex human prostate-specific antigen promoter), confirming the pathogenicity of the mutation. In mammalian two-hybrid assays, N727K disrupted LBD interactions with the AR TAD and with the coactivator, transcription intermediary factor 2 (TIF2). Strikingly, the transactivation defect of the mutant AR can be rectified in vitro with mesterolone, consistent with the ability of this androgen analog to restore sperm production in vivo. Mesterolone, but not the physiological androgen dihydrotestosterone, restored mutant LBD interactions with the TAD and with TIF2, when expressed as fusion proteins in the two-hybrid assay. Our data support an emerging paradigm with respect to AR mutations in the LBD and male infertility: pathogenicity is transmitted through reduced interdomain and coactivator interactions, and androgen analogs that are corrective in vitro may indicate hormonal therapy.
Amino Acid Sequence↗
[Varicocele: spermiogram, testicular biopsy, plasma testosterone. Results of therapy (author's transl)].
In 73 patients with unilateral (70 patients) and bilateral (3 patients) varicocele and subfertility as a clinical finding, spermiograms, testicular biopsies, and plasma testosterone levels were examined for their prognostic evaluation, and therapeutic conclusions were drawn. The high ligature of the internal spermatic vein in the presence of a normal plasma testosterone level resulted, without accompanying therapy, in an improvement of normalization of the spermiogram in 23.3% of cases, and only in 7% did a pregnancy occur. A significant improvement of these results could be achieved through additional combined therapy with Mesterolone and Clomiphene. In primary testosterone deficiency, a combination of surgical correction and chemotheraphy (Mesterolone and Clomiphene) gave relatively satisfactory results. Primary sperm counts below 10(6)/ml, a motility index under 30%, and histologically proven desquamation of the germ epithelium in the testicular biopsy are to be regarded as extremely grave prognostic criteria.
Biopsy↗
Effects of serotonin antagonists in sexually impotent men.
Thirty-one men affected with sexual impotence were studied. Since sexual function in the male seems to be controlled by both dopaminergic stimulatory and serotoninergic inhibitory mechanisms, the patients were treated with serotonin antagonists. In basal conditions mean serum LH, FSH, PRL and testosterone did not significantly differ from those found in normal subjects; no significant variations, except for PRL reduction, were observed after treatment. Both methysergide, in association with bromocriptine or mesterolone, and metergoline, either alone or in association with mesterolone, were ineffective in significantly improving sexual activity.
Adult↗
Effects of androgen treatment on expression of macrophage Fcgamma receptors.
Macrophage Fcgamma receptors (FcgammaRs) play an important role in the host defense against infection and in the pathophysiology of immune cytopenias. Modulation of macrophage FcgammaR expression is a potential therapeutic approach to immune disorders. Glucocorticoids and progesterones decrease macrophage FcgammaR expression. We assessed the effect of treatment with androgens and antiandrogens on the expression of macrophage FcgammaRs using an experimental guinea pig model. Four androgens (testosterone, dihydrotestosterone, mesterolone, and danazol) and five antiandrogens (flutamide, nilutamide, cyproterone acetate, spironolactone, and finasteride) were studied. Following in vivo treatment of guinea pigs, we determined the clearance of immunoglobulin G (IgG)-sensitized erythrocytes in vivo, the binding of IgG-sensitized erythrocytes by isolated splenic macrophages, and splenic macrophage FcgammaR cell surface expression. All of the androgens impaired the clearance of IgG-sensitized erythrocytes by decreasing splenic macrophage FcgammaR expression. Dihydrotestosterone and mesterolone were more effective than testosterone or dihydrotestosterone. Flow cytometry and fluorescence microscopy with monoclonal antibodies demonstrated that the androgens decreased the cell surface expression of FcgammaR1,2 more than that of FcgammaR2. Antiandrogens did not significantly alter macrophage FcgammaR expression. Nevertheless, antiandrogens counteracted the effects of androgens on macrophage FcgammaR expression. These data indicate that androgens impair the clearance of IgG-coated cells by decreasing splenic macrophage FcgammaR expression. Thus, androgens other than danazol are candidate drugs for the treatment of immune disorders.
Androgens↗
[Androgen therapy of impotentia coeundi in elderly men. Psychological and endocrinological investigations (author's transl)].
The aim of the present investigation was to assess impotence in elderly men by clinical, endocrinological and psychological examinations. Altogether 17 patients were treated in a double-blind study with placebo or 75 mg mesterolone per day over 8 weeks. The subjects were aged between 45 and 60 years and suffered from impotentia coeundi. No differences in serum LH and testosterone levels were noted between the start and end of therapy. Similarly, serum LH and testosterone levels in these patients did not differ from those in a control group. These results suggest that the "male climacteric" need not necessarily the associated with alterations in hormone parameters. On the other hand, mesterolone therapy resulted in an improvement in potency and other psychosomatic parameters.
Androgens↗
Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema.
Treatment with 17 alpha-methyltestosterone and with some synthetic androgens prevents attacks of hereditary angioedema (HAE). However, the potential hepatotoxicity of 17 alpha-alkylated androgens raises the problem of long-term prophylactic use of these agents. Therefore we compared the efficacy in preventing HAE attacks of 17 alpha-alkylated steroids (danazol and stanozolol) with non-17 alpha-alkylated derivatives (quinbolone, nandrolone decanoate and mesterolone). As the latter group proved ineffective, it seems that a drug's efficacy in preventing HAE attacks is connected to its 17 alpha-alkylation. Moreover, our long-term observations with the minimum effective dose of danazol seem to indicate the absence of important collateral effects.
Adult↗
The discovery of antidepressant drugs by computer-analyzed human cerebral bio-electrical potentials (CEEG).
Antidepressant properties of six compounds were predicted based on their computer-analyzed human electroencephalographical (CEEG) profiles. The clinical investigations with mianserin (GB-94) confirmed the CEEG prediction. This compound has now been marketed as the first antidepressant of which the clinical effects were discovered solely by the quantitative pharmaco-EEG method. As predicted by the CEEG, clinical antidepressant properties of GC-46, mesterolone, and estradiol valerate were observed in preliminary investigations. No extensive studies with definite statistical results were yet carried out with these compounds. No systematic large studies could be conducted with cyclozocine and cyproterone acetate because of the intolerable side effects with these compounds. The optical isomers of mianserin, GF-59 and GF-60, both predicted as antidepressant by the computer EEG data base, have not yet been tested in depressive patients. None of these compounds possess the "typical" pharmacological and/or biochemical profiles of marketed antidepressants. Thus, the discovery of the established antidepressant properties of mianserin (GB-94) by computer analyzed EEG method challenges the well-known biochemical hypotheses of depression and the "classical" development of antidepressant drugs.
Animals↗
The role of antiandrogenic action in cyproterone acetate-induced morphologic and biochemical changes in human semen.
Following the daily administration of 10 mg of cyproterone acetate to three normal fertile human volunteers for 12 to 16 weeks, there was a marked decrease in the count, motility, and cervical mucus-penetrating ability of spermatozoa, with a concomitant increase in abnormal and immature forms. The levels of seminal acid phosphatase and glycerylphosphoryl choline were also significantly decreased. Subsequently, concurrent daily administration of 75 mg of mesterolone increased the count, motility, and cervical mucus-penetrating ability of spermatozoa and stimulated the seminal biochemical constituents. The results indicate that the effects of a low dose of cyproterone acetate are due mainly to peripheral androgen deprivation.
Acid Phosphatase↗
Influence of various modes of androgen substitution on serum lipids and lipoproteins in hypogonadal men.
We investigated whether the androgen type or application mode or testosterone (T) serum levels influence serum lipids and lipoprotein levels differentially in 55 hypogonadal men randomly assigned to the following treatment groups: mesterolone 100 mg orally daily ([MES] n = 12), testosterone undecanoate 160 mg orally daily ([TU] n = 13), testosterone enanthate 250 mg intramuscularly every 21 days ([TE] n = 15), or a single subcutaneous implantation of crystalline T 1,200 mg ([TPEL] n = 15). The dosages were based on standard treatment regimens. Previous androgen substitution was suspended for at least 3 months. Only metabolically healthy men with serum T less than 3.6 nmol/L and total cholesterol (TC) and triglyceride (TG) less than 200 mg/dL were included. After a screening period of 2 weeks, the study medication was taken from days 0 to 189, with follow-up visits on days 246 and 300. Before substitution, all men were clearly hypogonadal, with mean serum T less than 3 nmol/L in all groups. Androgen substitution led to no significant increase of serum T in the MES group, subnormal T in the TU group (5.7 +/- 0.3 nmol/L), normal T in the TE group (13.5 +/- 0.7 nmol/L), and high-normal T in the TPEL group (23.2 +/- 1.1 nmol/L). 5 alpha-Dihydrotestosterone significantly increased in all treatment groups compared with baseline. Compared with presubstitution levels, a significant increase of TC was observed in all treatment groups (TU, 14.4% +/- 3.0%; MES, 18.8% +/- 2.5%; TE, 20.4% +/- 3.0%; TPEL, 20.2% +/- 2.6%). Low-density lipoprotein cholesterol (LDL-C) also increased significantly by 34.3% +/- 5.5% (TU), 46.4% +/- 4.1% (MES), 65.2% +/- 5.7% (TE), and 47.5% +/- 4.3% (TPEL). High-density lipoprotein cholesterol (HDL-C) showed a significant decrease by -30.9% +/- 2.8% (TU), -34.9% +/- 2.5% (MES), -35.7% +/- 2.6% (TE), and -32.5% +/- 3.5% (TPEL). Serum TG significantly increased by 37.3% +/- 11.3% (TU), 46.4% +/- 10.3% (MES), 29.4% +/- 6.5% (TE), and 22.9% +/- 6.7% (TPEL). TU caused a smaller increase of TC than TE and TPEL, whereas the parenteral treatment modes showed a lower increase of TG. There was no correlation between serum T and lipid concentrations. Despite the return of serum T to pretreatment levels, serum lipid and lipoprotein levels did not return to baseline during follow-up evaluation. In summary, androgen substitution in hypogonadal men increases TC, LDL-C, and TG and decreases HDL-C independently of the androgen type and application made and the serum androgen levels achieved. Due to the extended washout period for previous androgen medication and the exclusion of men with preexisting hyperlipidemia, this investigation demonstrates more clearly than previous studies the impact of androgen effects on serum lipids and lipoproteins. It is concluded that preexisting low serum androgens induce a "male-type" serum lipid profile, and increasing serum androgens further within the male normal range does not exert any additional effects. The threshold appears to be above the normal female androgen serum levels and far below the lower limit of normal serum T levels in adult men. These findings may have considerable implications for the use of androgens as a male contraceptive and for androgen therapy in elderly men.
Adult↗
Human chorionic gonadotropin free beta-subunit in the human seminal plasma: a new marker for spermatogenesis?
UNLABELLED: In the past 20 years, several factors were detected in the human seminal plasma and proposed as markers for spermatogenesis. Human chorionic gonadotropin (hCG) and its beta-subunit were therefore investigated, and their seminal levels were found to be higher than those detected in the serum and to correlate with sperm parameters. OBJECTIVE: We designed a retrospective study to determine the suitability of hCG free beta-subunit concentration in the seminal plasma of fertile and infertile male patients as marker of spermatogenesis. STUDY DESIGN: A total of 79 infertile male patients were divided into four groups by their semen analysis results (group 1 [n=8]: azoospermia; group 2 [n=21]: severe oligozoospermia; group 3 [n=40]: oligoasthenospermia (OAS); group 4 [n=10]: asthenospermia) and 10 healthy volunteers of proven fertility were evaluated. RESULTS: The hCG free beta-subunit levels in the seminal plasma were found to be significantly higher (P<0.0001) in the control group in respect to those assayed in the infertile patients and showed a correlation with sperm count (r=0.5) and total motile sperm density (r=0.5). Twenty-five patients were on treatment with oral Mesterolone (100mg daily) plus Tamoxifen (20mg daily) for 3-6 months. Apart from a significant improvement (P<0.05) in sperm morphology, no significant changes in sperm count and motility were observed after the treatment in all the patients. In the seminal plasma of 10 patients who showed a significant increase in sperm count, hCG free beta-subunit levels were found to be significantly higher compared to those detected in the remaining patients (P<0.01). In all patients, these levels remained unchanged after the treatment. CONCLUSIONS: The evidence regarding the positive correlation between hCG free beta-subunit levels in the seminal plasma and sperm concentration is consistent with the previous results regarding hCG levels. A previous study demonstrated that testosterone levels in seminal plasma correlated with sperm concentrations; from the same evidence regarding hCG we hypothesize that seminal plasma testosterone and hCG levels are correlated. Thus, hCG may play a paracrine role in the intratesticular regulation of testosterone secretion.
Adult↗