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PubMed2006

Isolated scrotal hair in infancy.

Nine male infants who developed scrotal hair with no other signs of virilization were evaluated. Median age for the development of scrotal hair was 4.5 months, and median age at presentation was 7.5 months. Endocrinologic investigations performed in 6 of the infants yielded normal findings. The scrotal hair receded at a mean age of 12 months, suggesting a transient benign event. The development of genital hair in boys under age 9 years is considered precocious, suggesting a possible pathological condition (eg, precocious puberty, congenital adrenal hyperplasia, adrenal or genital tumors), or may be due to premature adrenarche.

Hirsutism↗
PubMed2003

Photoaffinity labeling identification of thyroid hormone-regulated glucocorticoid-binding peptides in rat liver endoplasmic reticulum: an oligomeric protein with high affinity for 16beta-hydroxylated stanozolol.

Steroid-binding proteins unrelated to the classical nuclear receptors have been proposed to play a role in non-genomic actions of the17alpha-alkylated testosterone derivative (17alpha-AA) stanozolol (ST). We have previously reported that male rat liver endoplasmic reticulum contains two steroid-binding sites associated with high molecular mass oligomeric proteins: (1) the ST-binding protein (STBP); and (2) the low-affinity glucocorticoid-binding protein (LAGS). To further explore the role of LAGS on the mechanism of action of ST, we have now studied: (1) the interaction of ST and its hydroxylated metabolites with solubilized LAGS and the cytosolic glucocorticoid receptor (GR); and (2) the effects of hormones on the capability of STBP to bind ST. We found that, unlike 17alpha-methyltestosterone, neither ST nor its hydroxylated metabolites bind to GR. However, the 16beta-hydroxylation of ST significantly increases the capability of LAGS to bind ST. Interestingly, 3'-hydroxylation of ST abrogates the capability of LAGS to bind ST. ST (k(i)=30 nM) and 16beta-hydroxystanozolol (k(i)=13 nM) bind with high affinity to LAGS, and are capable of accelerating the rate of dissociation of previously bound dexamethasone from the LAGS. STBP and LAGS are strongly induced by ethinylestradiol. However, unlike STBP, LAGS is regulated by thyroid hormones and growth hormone, which proves that these steroid-binding activities are associated with different binding sites. These findings seem to suggest a novel mechanism for ST whereby membrane-associated glucocorticoid-binding activity is targeted by the 16beta-hydroxylated metabolite of ST. ST and its 16beta-hydroxylated metabolite modulate glucocorticoid activity in the liver through negative allosteric modulation of LAGS, with the result of this interaction an effective increase in classical GR-signaling by increasing glucocorticoid availability to the cytosolic GR.

Allosteric Regulation↗
PubMed2006

Association between the dihydrotestosterone level in the prostate and prostate cancer aggressiveness using the Gleason score.

PURPOSE: To our knowledge the association between dihydrotestosterone in the prostate and prostate cancer aggressiveness has not yet been elucidated. We analyzed dihydrotestosterone levels in the prostate and Gleason score in patients diagnosed with clinically localized prostate cancer. MATERIALS AND METHODS: A total of 81 patients with suspected prostate cancer underwent prostate biopsy. Serum samples were collected before biopsy. Dihydrotestosterone levels in prostatic tissue and serum were analyzed using liquid chromatography/electrospray ionization-mass spectrometry after polar derivatization. RESULTS: A total of 47 patients were diagnosed with stages T1 to T3N0M0 prostate cancer and 34 were diagnosed with no malignancy. Of the 47 patients 32 had a Gleason score of 6 or less and 15 had a score of 7 to 10. Dihydrotestosterone in prostatic tissue in patients with Gleason score 7 to 10 disease was significantly lower than in those with Gleason score 6 or less disease (p = 0.025). Gleason score correlated with the testosterone-to-serum dihydrotestosterone ratio (rs = 0.329, p = 0.038). CONCLUSIONS: Patients with Gleason score 7 to 10 prostate cancer have low dihydrotestosterone in the prostate, although there were no significant differences between patients with Gleason score 7 to 10 vs 6 or less prostate cancer with respect to serum androgens. Low dihydrotestosterone in cases of aggressive prostate cancer is probably sufficient to activate androgen receptor expression and propagate tumor growth.

Aged↗
PubMed2006

The benefits of androgens combined with hormone replacement therapy regarding to patients with postmenopausal sexual symptoms.

OBJECTIVE: To evaluate the benefits and risks of hormone replacement therapy (HRT) combined with methyltestosterone (MT) in postmenopausal women with sexual dysfunction. DESIGN: This study was a randomized, double-blind, placebo-controlled and crossover trial. Eighty-five women using HRT were divided into four treatment groups: GI-HRT plus placebo for 4 months; GII-HRT plus MT 2.5mg/day for 4 months; GIII-HRT plus placebo for 2 months and then replaced with HRT plus MT 2.5mg/day for 2 months; GIV-HRT plus MT 2.5mg/day and then replaced with HRT plus placebo for 2 months. Blood was collected at baseline, after 2 months (T1) and 4 months (T2) of treatment for hormone determinations of estradiol, FSH, total and free testosterone, GOT, GPT, glucose, total and fractions of cholesterol and triglycerides. All participants answered clinical questions and a validated questionnaire of modified McCoy's sex scale. RESULTS: The association of HRT with MT 2.5mg/day did not significantly change liver enzymes or increase cardiovascular risk factors. The patients of GII, GIIII and GIV when using MT presented amelioration of sex symptoms, mainly satisfaction and desire (p<0.01); however, GIII at T1 (1.3+/-0.3) presented similar problem score results as compared to GIII at T2 (1.5+/-0.6). CONCLUSION: All data suggest that combined HRT-androgen therapy may be beneficial for postmenopausal women receiving HRT who continue to complain of sexual difficulties or for postmenopausal women with sexual complaints who are not undergoing estrogen therapy.

Cross-Over Studies↗
PubMed2004

Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells.

Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines. GHR mRNA levels were 80% higher and GHR(tr) only 25% higher, in the carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3 cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was further characterized, on the basis of its M(r) of 120kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to (125)I-hGH and its ability to secrete GH binding protein, all characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. No effect of GH (72h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2-12h) though transient striking increase in immunoreactive androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h) reduction (< or = 80%), with only modest parallel changes in serine-phosphorylated AR. In conclusion, the GH-induced activation of signaling pathways, its effects on AR protein in LNCaP cells and the isoform-specific regulation of GHR in prostate cancer patient tissues, suggest that GH, most likely in concert with other hormones and growth factors, may play an important role in progression of human prostate cancer.

Animals↗
PubMed2005

Role of the alpha subunit in the modulation of GABA(A) receptors by anabolic androgenic steroids.

Neural transmission mediated by circuits expressing alpha2 subunit-containing gamma-aminobutyric acid type A (GABA(A)) receptors is critical for the expression of behaviors known to be altered by anabolic androgenic steroids (AAS). Here we show that micromolar concentrations of AAS, which reflect levels found in steroid abusers, induce positive modulation of currents from alpha2beta3 gamma2L recombinant receptors elicited by pulses of GABA that mimic synaptic conditions in a manner that is mechanistically distinct from modulation induced at alpha1beta3 gamma2L receptors. Specifically, at alpha2-containing receptors, the AAS, 17alpha-methyltestosterone (17alpha-MeT) enhanced peak current, slowed deactivation, diminished desensitization, and promoted entry of receptors into more distal states along the activation pathway. Analysis of GABA(A) receptor-mediated synaptic currents in primary cortical neurons followed by single cell real-time RT-PCR demonstrated that 17alpha-MeT enhancement of synaptic currents is proportional to the ratio of alpha2 to alpha1 subunit mRNA. Finally, we show that the modulation elicited by AAS is not comparable to that produced by micromolar concentrations of other positive allosteric modulators at alpha2-containing receptors. In sum, these data indicate that AAS elicit effects on GABA(A) receptor function that depend significantly on alpha subunit composition and that the mechanism of AAS modulation of GABA(A) receptors is distinct from that of other positive allosteric modulators.

Anabolic Agents↗
PubMed2005

Specific modulation of nongenomic androgen signaling in the ovary.

Maturation, or meiotic progression, of amphibian oocytes is one of the few physiologically relevant steroid-mediated processes that occurs in the complete absence of transcription from beginning to end. As such, frog oocyte maturation has served as a useful model of nongenomic steroid signaling for many years. Earlier work in Xenopus laevis demonstrated that, although several steroids promoted oocyte maturation in vitro, androgens were the most abundant and potent steroids detected in the serum and ovaries of ovulating frogs. Thus, androgens were likely the primary physiologic regulators of Xenopus oocyte maturation, mediating their actions at least in part via classical androgen receptors expressed in oocytes. The importance of androgens for Xenopus oocyte maturation and ovulation has now been confirmed, as inhibition of androgen production in vivo by blocking CYP17 activity reduced hCG-triggered oocyte maturation and delayed ovulation in female frogs. Taking advantage of the absolute transcription-independence of this androgen-mediated response, selective androgen receptor modulators (SARMs) have been characterized that specifically promote genomic versus nongenomic androgen responses. These include androstenediol and estren, which preferentially promote nongenomic signals, as well as R1881 and 19-nortestosterone, which preferentially promote genomic signaling. Interestingly, the SARMs androstenediol and R1881 signal similarly in mouse oocytes, demonstrating the conserved nature of androgen-mediated maturation in vertebrates. These results suggest that SARMs may serve as useful tools for specifically regulating nongenomic androgen signaling both in vitro and in vivo.

Androgens↗
PubMed2004

Effect of organochlorine pesticides on human androgen receptor activation in vitro.

Many persistent organochlorine pesticides (OCs) have been implicated in adverse effects, that is, reproductive and developmental effects, in man and in wildlife alike. It has been hypothesized that these so-called xeno-hormones could be responsible for the increased incidence in various male sexual differentiation disorders such as hypospadias, cryptorchidism, low sperm counts and quality. In this report, OCs, called endocrine disrupters, were tested for their interaction with the androgen receptor. The stable prostatic cell line PALM, which contains a human androgen receptor (hAR) expression vector and the reporter MMTV-luciferase, was used to characterize the response of hAR to OC and was compared with synthetic androgen compound R1881. We found that all the OC pesticides tested were able to shift the agonist [(3)H]-R1881 from its binding site to the AR in competitive binding assays. In addition, these compounds antagonize-in a dose-dependent manner-the AR-mediated transcription by synthetic AR ligand R1881. None of the pesticides reacted as agonists. These results demonstrate that OC endocrine activities in vivo probably result from direct and specific binding to the AR ligand-binding domain. Although the antagonistic potential of OC pesticides is lower than that of hydroxyflutamide, they are capable of disrupting the male hormone signaling pathway. Because these chemicals are extremely persistent and tend to bioaccumulate, these results support the hypothesis that the recent increase in the incidence of male sexual disorders could be due to long exposure to ubiquitous OC pesticides found in the environment.

Androgen Antagonists↗
PubMed2005

Screening for androgen receptor activities in 253 industrial chemicals by in vitro reporter gene assays using AR-EcoScreen cells.

Recently, there has been great concern about the potential of industrial chemicals to act as endocrine disrupters. In this report, we conducted a pilot study to validate the use of AR-EcoScreen cells for tier 1 screening of androgen receptor (AR) agonist and antagonist activities. From 253 test compounds, we identified two AR agonists and nine antagonists. The two agonists, 2-tert-butylanthraquinone and benzoanthrone, were relatively weak (10% maximal activation of the positive control, 5alpha-dihydrotestosterone, at 2.54x10(-7) and 4.46x10(-6) M, respectively). The most potent antagonist was 3,3'-dichlorobenzidine dihydrochloride (IC50 = 2.28x10(-7) M). The order of the anti-androgenic activities was 3,3'-dichlorobenzidine dihydrochloride>4-diethylaminobenzaldehyde>4,4'-[1-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenyl]ethylidene]bis[phenol]>2,4,6-trichlorophenylhydrazine = 4-(phenylpropyl)pyridine>2-hydroxy-4-methoxybenzophenone>2,2-bis(4-cyanophenyl)propane>4-methoxy-2-methyldiphenylamine = 2,4-diphenyl-4-methylpentene-1. These results suggest that AR-EcoScreen cell line has the potential to be used as a tool for the large scale tier 1 screening of chemicals for androgen receptor agonist and antagonist activity.

Androgen Antagonists↗
PubMed2004

Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging.

OBJECTIVES: To To compare testosterone undecanoate versus propionyl-L-carnitine plus acetyl-L-carnitine and placebo in the treatment of male aging symptoms. METHODS: A total of 120 patients were randomized into three groups. The mean patient age was 66 years (range 60 to 74). Group 1 was given testosterone undecanoate 160 mg/day, the second group was given propionyl-L-carnitine 2 g/day plus acetyl-L-carnitine 2 g/day. The third group was given a placebo (starch). Drugs and placebo were given for 6 months. The assessed variables were total prostate-specific antigen, prostate volume, peak systolic velocity, end-diastolic velocity, resistive index of cavernosal penile arteries, nocturnal penile tumescence, total and free testosterone, prolactin, luteinizing hormone, International Index of Erectile Function score, Depression Melancholia Scale score, fatigue scale score, and incidence of side effects. The assessment was performed at intervals before, during, and after therapy. RESULTS: Testosterone and carnitines significantly improved the peak systolic velocity, end-diastolic velocity, resistive index, nocturnal penile tumescence, International Index of Erectile Function score, Depression Melancholia Scale score, and fatigue scale score. Carnitines proved significantly more active than testosterone in improving nocturnal penile tumescence and International Index of Erectile Function score. Testosterone significantly increased the prostate volume and free and total testosterone levels and significantly lowered serum luteinizing hormone; carnitines did not. No drug significantly modified prostate-specific antigen or prolactin. Carnitines and testosterone proved effective for as long as they were administered, with suspension provoking a reversal to baseline values. Only the group 1 prostate volume proved significantly greater than baseline 6 months after testosterone suspension. Placebo administration proved ineffective. Negligible side effects emerged. CONCLUSIONS: Testosterone and, especially, carnitines proved to be active drugs for the therapy of symptoms associated with male aging.

Aged↗
PubMed1983

Androgen stimulated elevation in androgen receptor levels is inhibited by the synthetic glucocorticoid triamcinolone acetonide.

Two cloned tumor cell lines derived from the rat prostate and hamster ductus deferens contain receptors for androgens and glucocorticoids. Androgens increase both the rate of proliferation in these cells and induce a doubling in the number of androgen receptors within 6 hours. This elevation in androgen receptors is dependent on protein synthesis. The glucocorticoid triamcinolone acetonide specifically inhibits both these androgen mediated events without altering the equilibrium dissociation constant (Kd) of the androgen receptor for either [3H]-methyltrienolone (Kd = 0.46 nM) or [3H]-dihydrotestosterone (Kd = 0.2 nM). These observations infer that androgen receptor up-regulation is an important facet of androgen action which may be modulated by glucocorticoids.

Androgens↗
PubMed2002

Expression of P16(INK4a) in testis of rhesus monkey during heat stress and testosterone undecanoate induced azoospermia or oligozoospermia.

Previous studies on azoospermia or oligozoospermia induced by heat stress or high doses of testosterone mainly focused on germ cell apoptosis; no data regarding their possible effect on spermatogonia mitosis are available. We have established unilateral cryptorchid and testosterone undecanoate (TU)-treated monkey models and examined expression of P16(INK4a) in the testis to look at its possible role in azoospermia or oligozoospermia induced by the heat stress or the TU treatment. The results showed that both heat stress and TU were capable of inducing expression of P16(INK4a) mainly in spermatogonia and other types of germ cells as well as Sertoli cells at the later stage of germ cell apoptosis, namely on Day 10 after operation or on Day 60 after TU injection. It is, therefore, suggested for the first time that P16(INK4a) protein may inhibit the spermatogonia mitosis in the testis at the later stage of the germ cell apoptosis, resulting in arrest of spermatogenesis.

Animals↗
PubMed1997

Androgen regulation of ornithine decarboxylase in human prostatic cells identified using differential display.

Androgens are essential for normal prostate physiology and have a permissive role in the development and progression of prostate cancer. Using the mRNA differential display technique, ornithine decarboxylase (ODC) was identified to be up-regulated by androgens in human prostatic LNCaP cells. On Northern analysis, the induction of ODC expression by 10 nM androgen was rapid and continued up to 48 h exposure with a maximum 6.3-fold up-regulation. The anti-androgen Casodex inhibited the androgen-induced up-regulation of ODC, whereas the protein synthesis inhibitor cycloheximide did not. Together these data suggest that regulation is mediated through the androgen receptor protein and does require secondary protein synthesis, respectively. The kinetics of induction of ODC were almost identical to those of prostate specific antigen. Taken together these data suggest that ODC is directly regulated by androgens in LNCaP cells.

Base Sequence↗
PubMed2001

Effects of androgen supplementation of hormone replacement therapy on the vascular reactivity of cerebral arteries.

OBJECTIVE: To determine the effect of the androgen supplementation of hormone replacement therapy (HRT) on the vascular reactivity of cerebral arteries. DESIGN: Open randomized study. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Forty postmenopausal women who were treated with sequential HRT (transdermal E2 50 microg/d + medroxyprogesterone acetate 10 mg/d for 12 days every other month) for > or =1 year and < or =5 years. INTERVENTION(S): Testosterone undecanoate (40 mg/d, p.o.) was randomly administered to 20 patients during ongoing HRT; the other 20 served as controls. Doppler evaluations of the internal carotid and middle cerebral arteries were performed together with lipid levels assessments. A visual analogue scale (VAS) was used to evaluate various parameters relating to sexual life and well-being. MAIN OUTCOME MEASURE(S): Pulsatility index (PI) of the arteries, VAS assessment of psychophysical well-being. RESULT(S): The administration of testosterone undecanoate during HRT induced an increase in the PI of the middle cerebral artery and a reduction of high-density lipoprotein cholesterol. Sexual desire and satisfaction were greatly improved. CONCLUSION(S): In postmenopausal women, androgen supplementation during HRT can partially counteract the beneficial effects of estrogens on cerebral vascular reactivity and lipid profiles, but sexual desire and satisfaction are greatly improved.

Administration, Cutaneous↗
PubMed2003

Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia.

OBJECTIVE: To assess the effect of treatment with a combination of the antiestrogen tamoxifen citrate and the androgen testosterone undecanoate on sperm variables and pregnancy incidence in men with idiopathic oligozoospermia and couple subfertility. DESIGN: Prospective, randomized, placebo-controlled trial. SETTING: Clinical research in a tertiary care academic hospital. PATIENT(S): Two hundred twelve men with idiopathic oligozoospermia and 82 normozoospermic men with female factor subfertility. INTERVENTION(S): Oligozoospermic patients were randomly assigned to two treatment groups with tamoxifen citrate, 20 mg/d, and testosterone undecanoate, 120 mg/d (n = 106) or placebo treatment (n = 106) for 6 months. Normozoospermic men were followed for the same period. Couple counseling was part of the intervention in all groups. MAIN OUTCOME MEASURE(S): Pregnancy incidence and sperm characteristics after 3 and 6 months on medication and 3 months after the end of the trial. RESULT(S): In the active treatment group, total sperm count (median [25th, 75th percentile], 27.1 x 10(6) cells/mL [9.4, 54.0 x 10(6) cells/mL] at baseline and 61.5 x 10(6) cells/mL [28.2, 119.6 x 10(6) cells/mL] at 6 months), progressive motility (mean [+/-SD], 29.7% +/- 12.0% at baseline and 41.6% +/- 13.1% at 6 months), and normal morphology (mean, 41.2% +/- 14.0% at baseline and 56.6% +/- 11.5% at 6 months) were noted. No marked changes were observed in placebo recipients or normozoospermic men. The incidence of spontaneous pregnancy was 33.9% in the active treatment group and 10.3% in the placebo group (36 vs. 11 pregnancies), with a relative risk of 3.195 (95% CI, 2.615 to 3.765). CONCLUSION(S): Treatment with tamoxifen citrate and testosterone undecanoate improved sperm variables and led to a higher incidence of pregnancy in couples with subfertility related to idiopathic oligozoospermia.

Adult↗
PubMed1997

An oral regimen of cyproterone acetate and testosterone undecanoate for spermatogenic suppression in men.

OBJECTIVE: To test the effectiveness, safety, and reversibility of the combined administration of cyproterone acetate and T undecanoate. DESIGN: Open clinical trial. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Eight healthy men, aged 25-42 years were selected. INTERVENTION(S): Cyproterone acetate, 12.5 mg, and T undecanoate, 80 mg, were administered orally twice daily for 16 weeks. MAIN OUTCOME MEASURE(S): Semen analyses every 2 weeks; physical examination, chemistries, hematology, prostatic-specific antigen, gonadotropins and T levels, and a questionnaire on sexual and behavioral function every 4 weeks. RESULT(S): In all subjects a profound suppression of spermatogenesis occurred; one subject became azoospermic, five subjects had sperm counts of < or = 3 x 10(6)/mL, and in two subjects sperm counts were 4 and 6 x 10(6)/mL in week 16. Sperm counts returned to baseline in all men after hormone administration was discontinued. No changes in metabolic parameters and total prostatic-specific antigen were detected. Hemoglobin and hematocrit decreased statistically significantly at week 16 of treatment and returned to baseline by week 12 of recovery. There was no change in sexual function or behavior. CONCLUSION(S): The oral administration of T undecanoate plus cyproterone acetate induces a profound suppression of spermatogenesis with no major adverse effects. These data suggest the feasibility of oral contraception in men.

Adult↗
PubMed1997

The combination of testosterone undecanoate with tamoxifen citrate enhances the effects of each agent given independently on seminal parameters in men with idiopathic oligozoospermia.

OBJECTIVE: To evaluate the effects of combined tamoxifen citrate and T undecanoate treatment on seminal parameters in men with idiopathic oligozoospermia. DESIGN: Prospective randomized clinical study. SETTING: A state hospital tertiary clinic. PATIENT(S): Eighty oligozoospermic men were included in the protocol. INTERVENTION(S): Patients were randomized to receive placebo, T undecanoate (40 mg three times per day), tamoxifen citrate (10 mg two times per day), or T undecanoate plus tamoxifen citrate. RESULT(S): Tamoxifen citrate plus T undecanoate treatment produced a satisfactory improvement of total sperm number, motility, and functional sperm fraction after 3 and 6 months. Comparisons with other active treatment groups showed significantly higher increment values for motility and functional fraction, whereas aniline, acrosine, and free L-carnitine also were markedly better in the combination treatment group. CONCLUSION(S): These results indicate that the combination of tamoxifen citrate with T undecanoate not only improves significantly important seminal parameters but also compares favorably with the single treatments used. Therefore, this combination deserves a place as a first line of treatment in idiopathic oligozoospermia.

Acrosin↗