Decrease In Dihydrotestosterone Research Articles

Genistein prevents the production of hypospadias induced by Di-(2-ethylhexyl) phthalate through androgen signaling and antioxidant response in rats

Environmental estrogen exposure has increased dramatically over the past 50 years. In particular, prenatal exposure to estrogen causes many congenital diseases, among which reproductive system development disorders are extremely serious. In this study, the molecular mechanism of hypospadias and the therapeutic effect of genistein (GEN) were investigated through in vivo models prepared by Di-(2-ethylhexyl) phthalate (DEHP) exposure between 12 and 19 days of gestation. With increased DEHP concentrations, the incidence of hypospadias increased gradually. DEHP inhibited the key enzymes involved in steroid synthesis, resulting in decreasing testosterone synthesis. At the same time, DEHP increased reactive oxygen species (ROS) and produced inflammatory factors via NADPH oxidase-1 (NOX1) and NADPH oxidase-4 (NOX4) pathways. It also inhibited Steroid 5 α Reductase 2 (Srd5α2) and decreased dihydrotestosterone (DHT) synthesis. Additionally, DEHP inhibited the androgen receptor (AR), resulting in reduced DHT binding to the AR that ultimately retarded the development of the external reproductive system. GEN, a phytoestrogen, competes with DEHP for binding to estrogen receptor β (ERβ). This competition, along with GEN's antiestrogen and antioxidant properties, could potentially reverse impairments. The findings of this study provide valuable insights into the role of phytoestrogens in alleviating environmental estrogen-induced congenital diseases.

Trazodone by epigenetic mechanism can reverse the post finasteride syndrome

The action mechanism of finasteride as inhibitor of the 5alpha-reductase enzyme in the brain could cause an epigenetic change imbalance in the messenger RNA of androgen receptor. The decrease of dihydrotestosterone (DHT) followed by an increase of free testosterone in the brain could in theory cause an imbalance in acetylation and methylation of histones in neurons. So, the post finasteride syndrome would be caused by an epigenetic change in androgen receptors of neurons circuits. Thus, the alpha-adrenergic antagonist properties of trazodone, for example cause priapism, and could change the epigenetic expression of androgen receptors in neuronal circuits responsible for erection and libido. Therefore, through this mechanism, the trazodone could reverse the effect of finasteride on the brain.

Postnatal Dynamics of Circulating Steroid Hormones in Mule and Equine Neonates.

It is necessary to study hormonal patterns from mules to recognize alterations and neonatal maladaptation. Our objective was to evaluate concentrations of hormones in mule (n = 6) and equine foals (n = 6). Blood was collected at T0, 1, 6 and 12 h after birth. Hormone concentrations were evaluated using liquid chromatography tandem mass spectrometry. Effects of time, group and interactions and regression analysis were evaluated (p < 0.05). There was a cubic and quadratic decline in mule and equine foals, respectively, for 3β,20α-dihydroxy-DHP. Mule foals were born with lower circulating 3β,20α-dihydroxy-DHP concentrations, which might be related to progestogen concentrations in mares with a hybrid placenta. Corticosterone and cortisol concentrations remained unchanged for the first hour post-foaling then declined in mule and equine foals (p < 0.0001). Dehydroepiandrosterone was the main androgen present. There was a decrease in dihydrotestosterone at 12 h (p = 0.002). Differences in the temporal patterns of secretion within each steroid class, pregnanes, corticoids, and androgens, suggest they were derived from different tissue sources, presumptively the placenta, adrenals and gonads of the fetus/neonate, respectively. Mule and horse foals were born without evidence of testosterone secretion. For the first time, steroid hormone levels were measured in neonatal mules, and this will provide insight into neonatal physiology that differs from equine and allow us to gain an understanding of mules that have rarely been studied. Further studies are needed to elucidate the effects of hybrid pregnancies in the steroid endocrinology of neonates.

Efficacy and safety of topical finasteride spray solution for male androgenetic alopecia: a phase III, randomized, controlled clinical trial.

BackgroundOral finasteride is a well‐established treatment for men with androgenetic alopecia (AGA), but long‐term therapy is not always acceptable to patients. A topical finasteride formulation has been developed to minimize systemic exposure by acting specifically on hair follicles.ObjectivesTo evaluate the efficacy and safety of topical finasteride compared with placebo, and to analyse systemic exposure and overall benefit compared with oral finasteride.MethodsThis randomized, double‐blind, double dummy, parallel‐group, 24‐week study was conducted in adult male outpatients with AGA at 45 sites in Europe. Efficacy and safety were evaluated. Finasteride, testosterone and dihydrotestosterone (DHT) concentrations were measured.ResultsOf 458 randomized patients, 323 completed the study and 446 were evaluated for safety. Change from baseline in target area hair count (TAHC) at week 24 (primary efficacy endpoint) was significantly greater with topical finasteride than placebo (adjusted mean change 20.2 vs. 6.7 hairs; P < 0.001), and numerically similar between topical and oral finasteride. Statistically significant differences favouring topical finasteride over placebo were observed for change from baseline in TAHC at week 12 and investigator‐assessed change from baseline in patient hair growth/loss at week 24. Incidence and type of adverse events, and cause of discontinuation, did not differ meaningfully between topical finasteride and placebo. No serious adverse events were treatment related. As maximum plasma finasteride concentrations were >100 times lower, and reduction from baseline in mean serum DHT concentration was lower (34.5 vs. 55.6%), with topical vs. oral finasteride, there is less likelihood of systemic adverse reactions of a sexual nature related to a decrease in DHT with topical finasteride.ConclusionTopical finasteride significantly improves hair count compared to placebo and is well tolerated. Its effect is similar to that of oral finasteride, but with markedly lower systemic exposure and less impact on serum DHT concentrations.

Genetic Analysis of 25 Patients with 5α-Reductase Deficiency in Chinese Population.

Background A deficiency in steroid 5α-reductase type 2 is an autosomal recessive disorder. Affected individuals manifested ambiguous genitalia, which is caused by decreased dihydrotestosterone (DHT) synthesis in the fetus. Methods We analyzed 25 patients with 5α-reductase deficiency in China. Seventeen of the 25 patients (68%) were initially raised as females. Sixteen patients changed their social gender from female to male after puberty. Results Eighteen mutations were identified in these patients. p.Gly203Ser and p.Gln6∗ were found to be the most prevalent mutations. On the basis of the genotype of these patients, we divided them into different groups. There was no significant difference in hormone levels and external masculinization score (EMS) in patients with or without these prevalent mutations. Twelve common single-nucleotide polymorphisms (SNPs) near the p.Gln6∗ mutation were chosen for haplotype analysis. Three haplotypes were observed in 6 patients who had the p.Gln6∗ mutation (12 alleles). Conclusion We analyzed mutations of the SRD5A2 gene in Chinese patients with 5α-reductase deficiency. Although hotspot mutations exist, no founder effect of prevalent mutations in the SRD5A2 gene was detected in the Chinese population.

Segmental Electrical Stimulation and Basic Pharmacotherapy in the Treatment of Chronic Prostatitis/chronic Pelvic Pain Syndrome

The objective: assessment of the efficacy and safety of the segmental effects of sinusoidal electric current alone and in combination with basic pharmacotherapy in treatment of chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS).Materials and methods. The study involved 64 patients with CP/CPPS who were equally randomized into 2 groups. Patients filled out questionnaires NIH-CPSI, PHQ-9, GAD-7. An enzyme immunoassay revealed changes in the concentration of testosterone, dihydrotestosterone (DHT) and prostate-specific antigen (PSA) in the blood, as well as ejaculate cytokines. All patients received segmental electrical stimulation, which was performed using the «Amplipulse» apparatus, 10 sessions of 15 minutes. Group 2 patients additionally received basic pharmacotherapy. The latter included diclofenac sodium (Dicloberl® retard, 100 mg/day, oral, 2 weeks), modified release tamsulosin (Flosin®, 0.4 mg/day, oral, 1 month), extract from the fruit of the Serenoa repens palm tree (Prostamol® Uno, 320 mg/day, orally, 6 months). Treatment was prescribed regardless of the presence and severity of symptoms of CP / CPS. The reduction in NIH-CPSI by 6 points, PHQ-9 by 6 points, GAD-7 by 5 points were considered clinically significant.Results. A significant decrease in prostatitis symptoms was observed in both groups after 2 weeks and persisted throughout the observation period (6 months). In group 2 patients, unlike group 1, there was a statistically significant increase in testosterone level, a decrease in DHT and PSA blood, a significant decrease in the pro-inflammatory cytokine in the ejaculate (interleukin-1β), along with an increase in the content of the anti-inflammatory cytokine (interleukin-10), a significant improvement depression and anxiety. The clinical efficacy of electrotherapy was 47 % and 34 % (at 2 weeks and 6 months of treatment, respectively). The combination ofelectrotherapy with basic pharmacotherapy reduced the intensity of the symptoms of prostatitis significantly more (p&lt;0.05). Its clinical efficacy was 85 % and 69 %, respectively. A significant link between the duration of the disease and the effectiveness of treatment was revealed: the greatest effectiveness and the minimum risk of relapse were observed with a disease duration of up to 1 year. Treatment tolerance was good in both groups of patients, especially in the electrotherapy group, in which no side effects were detected.Conclusion. The use of segmental electrotherapy and its combination with basic pharmacotherapy in the treatment of CP/CPPS is quite effective and safe. Using a combination of these techniques is significantly more effective, especially with a disease duration of up to 1 year. The advantage of electrotherapy is the safety of the technique.

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

The enzymatic conversion of progesterone and testosterone by the enzyme 5alpha-reductase exerts a crucial role in the control of nervous function. The effects of finasteride in the brain, an inhibitor of this enzyme used for the treatment of human benign prostatic hyperplasia and androgenic alopecia, have been poorly explored. Therefore, the effects of a subchronic treatment with finasteride at low doses (3 mg/kg/day) and the consequences of its withdrawal on neuroactive steroid levels in plasma, cerebrospinal fluid and some brain regions as well as on the expression of classical and non-classical steroid receptors have been evaluated in male rats. After subchronic treatment (i.e., for 20 days) the following effects were detected: (i) depending on the compartment considered, alteration in the levels of neuroactive steroids, not only in 5alpha-reduced metabolites but also in its precursors and in neuroactive steroids from other steroidogenic pathways and (ii) an upregulation of the androgen receptor in the cerebral cortex and beta3 subunit of the GABA-A receptor in the cerebellum. One month after the last treatment (i.e., withdrawal period), some of these effects persisted (i.e., the upregulation of the androgen receptor in the cerebral cortex, an increase of dihydroprogesterone in the cerebellum, a decrease of dihydrotestosterone in plasma). Moreover, other changes in neuroactive steroid levels, steroid receptors (i.e., an upregulation of the estrogen receptor alpha and a downregulation of the estrogen receptor beta in the cerebral cortex) and GABA-A receptor subunits (i.e., a decrease of alpha 4 and beta 3 mRNA levels in the cerebral cortex) were detected. These findings suggest that finasteride treatment may have broad consequences for brain function.

Effect of Finasteride on Serum Androstenedione and Risk of Prostate Cancer Within the Prostate Cancer Prevention Trial: Differential Effect on High- and Low-grade Disease

To evaluate the effect of finasteride on serum androst-4-ene-3,17-dione (androstenedione) and its association with prostate cancer risk among subjects who participated in the Prostate Cancer Prevention Trial. We analyzed serum androstenedione levels in 317 prostate cancer cases and 353 controls, nested in the Prostate Cancer Prevention Trial, a randomized placebo-controlled trial that found finasteride decreased prostate cancer risk. Androstenedione is the second most important circulating androgen in men besides testosterone and also a substrate for 5α-reductase enzyme. We observed a 22% increase in androstenedione levels compared with the baseline values in subjects who were treated with finasteride for 3 years. This significant increase did not vary by case-control status. Adjusted odds ratio and 95% confidence interval for the third tertile of absolute change in androstenedione levels compared with the first tertile were 0.42 (95% confidence interval, 0.19-0.94) for low-grade (Gleason score <7) cases. Similar results were observed when analyzed using percent change. There were no significant associations between serum androstenedione levels and the risk of high-grade disease. The results of this nested case-control study confirm that finasteride blocks the conversion of testosterone to dihydrotestosterone (DHT) and of androstenedione to 5α-androstanedione-3,17-dione, which also leads to the reduction of DHT formation. This decrease in DHT may help reduce the risk of low-grade prostate cancer in men. Our data on a differential effect of androstenedione also suggest that some high-grade prostate cancers may not require androgen for progression.

Sex hormones in allergic conjunctivitis: altered levels of circulating androgens and estrogens in children and adolescents with vernal keratoconjunctivitis.

Purpose. Vernal keratoconjunctivitis (VKC) is a chronic allergic disease mainly affecting boys in prepubertal age and usually recovering after puberty. To evaluate a possible role of sex hormones in VKC, serum levels of sex hormones in children and adolescents with VKC were assessed. Methods. 12 prepubertal and 7 early pubertal boys with active VKC and 6 male patients with VKC in remission phase at late pubertal age and 48 healthy age and sex-matched subjects were included. Serum concentration of estrone, 17 beta-estradiol, dehydroepiandrosterone-sulfate, total testosterone and free testosterone, dihydrotestosterone (DHT), cortisol, delta-4-androstenedione, follicle-stimulating hormone, luteinizing hormone, and sex-hormones binding globuline (SHBG) were evaluated. Results. Serum levels of Estrone were significantly increased in all groups of patients with VKC when compared to healthy controls (P < 0.001). Prepubertal and early pubertal VKC showed a significant decrease in DHT (P = 0.007 and P = 0.028, resp.) and SHBG (P = 0.01 and P = 0.002, resp.) when compared to controls and serum levels of SHBG were increased in late pubertal VKC in remission phase (P = 0.007). Conclusions and Relevance. VKC patients have different circulating sex hormone levels in different phases of the disease and when compared to nonallergic subjects. These findings suggest a role played by sex hormones in the pathogenesis and/or activity of VKC.

Antiandrogenic mechanisms of pesticides in human LNCaP prostate and H295R adrenocortical carcinoma cells.

Several pesticides suspected or known to have endocrine disrupting effects were screened for pro- or antiandrogenic properties by determining their effects on proliferation, prostatic-specific antigen (PSA) secretion and androgen receptor (AR) expression, and AR phosphorylation in androgen-dependent LNCaP human prostate cancer cells, as well as on the expression and catalytic activity of the enzyme CYP17 in H295R human adrenocortical carcinoma cells, an in vitro model of steroidogenesis. Effects on SRD5A gene expression were determined in both cell lines. Benomyl, vinclozolin, and prochloraz, but not atrazine, concentration dependently (1-30 μM) decreased dihydrotestosterone (DHT)-stimulated proliferation of LNCaP cells. All pesticides except atrazine decreased DHT-stimulated PSA secretion, AR nuclear accumulation, and AR phosphorylation on serines 81 and 213 in LNCaP cells. Benomyl and prochloraz, but not vinclozolin or atrazine, decreased levels of CYP17 gene and protein expression, as well as catalytic activity in H295R cells. In the case of prochloraz, some of these effects corresponded with cytotoxicity. H295R cells expressed AR protein and SRD5A1, but not SRD5A2 transcripts. SRD5A1 gene expression in H295R cells was increased by 10 nM DHT, whereas in LNCaP cells significant induction was observed by 0.1 nM DHT. AR protein expression in H295R cells was not increased by DHT. Vinclozolin decreased DHT-induced SRD5A1 gene expression in LNCaP, but not H295R cells, indicating a functional difference of AR between the cell lines. In conclusion, pesticides may exert antiandrogenic effects through several mechanisms that are cell type-specific, including AR antagonism and down-regulation or catalytic inhibition of androgen biosynthetic enzymes, such as CYP17 and SRD5A1.

Neuroactive steroid levels in plasma and cerebrospinal fluid of male multiple sclerosis patients

Neuroactive steroid family includes molecules synthesized in peripheral glands (i.e., hormonal steroids) and directly in the nervous system (i.e., neurosteroids) which are key regulators of the nervous function. As already reported in clinical and experimental studies, neurodegenerative diseases affect the levels of neuroactive steroids. However, a careful analysis comparing the levels of these molecules in cerebrospinal fluid (CSF) and in plasma of multiple sclerosis (MS) patients is still missing. To this aim, the levels of neuroactive steroids were evaluated by liquid chromatography-tandem mass spectrometry in CSF and plasma of male adults affected by Relapsing-Remitting MS and compared with those collected in control patients. An increase in pregnenolone and isopregnanolone levels associated with a decrease in progesterone metabolites, dihydroprogesterone, and tetrahydroprogesterone was observed in CSF of MS patients. Moreover, an increase of 5α-androstane-3α,17β-diol and of 17β-estradiol levels associated with a decrease of dihydrotestosterone also occurred. In plasma, an increase in pregnenolone, progesterone, and dihydrotestosterone and a decrease in dihydroprogesterone and tetrahydroprogesterone levels were reported. This study shows for the first time that the levels of several neuroactive steroids, and particularly those of progesterone and testosterone metabolites, are deeply affected in CSF of relapsing-remitting MS male patients. We here demonstrated that, the cerebrospinal fluid and plasma levels of several neuroactive steroids are modified in relapsing remitting multiple sclerosis male patients. Interestingly, we reported for the first time that, the levels of progesterone and testosterone metabolites are deeply affected in cerebrospinal fluid. These findings may have an important relevance in therapeutic and/or diagnostic field of multiple sclerosis.

Preventive Effects of Monascus on Androgen-Related Diseases: Androgenetic Alopecia, Benign Prostatic Hyperplasia, and Prostate Cancer

Androgen-related diseases impair the well-being of many aging men. Unfortunately, the medications used to treat these diseases have many side effects. Therefore, there is a significant need for the development of novel drugs to treat androgen-related diseases. In this study, we investigated the effects of Monascus cursory extraction (M-CE) on androgen-related diseases, including androgenetic alopecia (AGA), benign prostatic hyperplasia (BPH) and prostate cancer. We found that M-CE suppressed baldness in male B6CBAF1/j mice. Furthermore, M-CE decreased PSA levels, indicating a protective effect of M-CE on testosterone-induced hyperplasia. M-CE also significantly decreased tumor volume and tumor incidence in an N-methyl-N-nitrosourea (MNU)/testosterone-induced rat prostate cancer model and markedly decreased dihydrotestosterone (DHT) but not testosterone. Additionally, PCNA expression was decreased in the prostate of rats treated with M-CE. These results suggest that M-CE could be a new potential therapeutic candidate for the treatment of androgen-related diseases.

The IVS1- 2A&gt;G mutation in the SRD5A2 gene predominates in Cypriot patients with 5α reductase deficiency

5α steroid reductase deficiency (5αSRD) is an autosomal recessive enzymatic deficiency and mutations in the 5α steroid reductase type 2 gene (SRD5A2) result in male pseudohermaphrodism caused by decreased dihydrotestosterone (DHT) synthesis. To identify the specific mutations of the SRD5A2 gene in Cypriot patients with 5αSRD. Five unrelated patients with 46,XY karyotype were examined. Four of them were born with ambiguous genitalia and 1 patient, who was raised as girl, presented with primary amenorrhea. The hCG test was informative (elevated testosterone/DHT) of 5αSRD in 3 out of 4 subjects. Sequencing of the SRD5A2 gene was completed for all patients. Genomic DNA was also isolated from a total of 204 healthy unrelated Cypriot subjects. Screening for the IVS1-2A>G mutation was performed by using direct sequencing and restriction enzyme analysis. The IVS1-2A>G was identified in homozygosity in 3 patients and in a compound heterozygote state in the other 2 patients, in combination with p.P181L and p.R171S in exon 3, respectively. The carrier frequency in the Cypriot population for the IVS1-2A>G mutation was estimated to be 0.98% or 2 in 204. The same IVS1-2A>G mutation in the SRD5A2 gene seems to characterize all Cypriot patients with 5αSRD diagnosed so far. Furthermore this relatively rare genetic defect, which has only been reported previously in a single case in the Eastern Mediterranean region, is very likely to be the result of a founder effect.

Changes of metabolic profile in men treated for androgenetic alopecia with 1 mg finasteride

Androgenetic alopecia is recognized as a risk factor for cardiovascular diseases, glucose metabolism disorders, and benign prostate hyperplasia and/or carcinoma. Finasteride, used for treatment of androgenetic alopecia at a dose of 1mg/day, is an effective inhibitor of type II 5alpha-reductase, the enzyme responsible for the reduction of testosterone to dihydrotestosterone. Recent studies reported that dihydrotestosterone, among other activities, might play some role in visceral fat metabolism. It thus seemed reasonable to examine whether finasteride treatment of androgenetic alopecia ameliorates some features of metabolic syndrome frequently seen associated with this condition. We examined 12 men with premature balding (defined as frontoparietal and vertex hair loss before age 30 with alopecia defined as grade 3 vertex or more on the Norwood-modified Hamilton alopecia classification). Hormonal levels and metabolic parameters were determined and insulin tolerance tests performed for all individuals. Finasteride (1 mg/day) was administrated for 12 months. The hormonal profile and lipid spectrum were monitored after 4, 8 and 12 months of treatment and insulin tolerance tests were repeated after 12 months of the treatment. After treatment with finasteride the expected changes in the steroid spectrum were seen, namely a decrease in dihydrotestosterone and increase in testosterone, androstenedione and free testosterone index. We observed an initial increase in total cholesterol and HDL- and LDL-cholesterol, which stabilized with prolonged treatment. We founded a significant decrease in glycated hemoglobin HbA1c and insulin resistance measured using rate constant for plasma glucose disappearance (kITT) showed only a borderline decrease. Finasteride is an efficient 5alpha-reductase inhibitor even at low doses of 1 mg/day. In men treated with this dose for 12 months, we observed mild differences in metabolic profile with slight amelioration of glucose metabolism regulation.

An open label, dose response study to determine the effect of a dietary supplement on dihydrotestosterone, testosterone and estradiol levels in healthy males

BackgroundMaintaining endogenous testosterone (T) levels as men age may slow the symptoms of sarcopenia, andropause and decline in physical performance. Drugs inhibiting the enzyme 5α-reductase (5AR) produce increased blood levels of T and decreased levels of dihydrotestosterone (DHT). However, symptoms of gynecomastia have been reported due to the aromatase (AER) enzyme converting excess T to estradiol (ES). The carotenoid astaxanthin (AX) from Haematococcus pluvialis, Saw Palmetto berry lipid extract (SPLE) from Serenoa repens and the precise combination of these dietary supplements, Alphastat® (Mytosterone(™)), have been reported to have inhibitory effects on both 5AR and AER in-vitro. Concomitant regulation of both enzymes in-vivo would cause DHT and ES blood levels to decrease and T levels to increase. The purpose of this clinical study was to determine if patented Alphastat® (Mytosterone(™)) could produce these effects in a dose dependent manner.MethodsTo investigate this clinically, 42 healthy males ages 37 to 70 years were divided into two groups of twenty-one and dosed with either 800 mg/day or 2000 mg/day of Alphastat® (Mytosterone(™)) for fourteen days. Blood samples were collected on days 0, 3, 7 and 14 and assayed for T, DHT and ES. Body weight and blood pressure data were collected prior to blood collection. One-way, repeated measures analysis of variance (ANOVA-RM) was performed at a significance level of alpha = 0.05 to determine differences from baseline within each group. Two-way analysis of variance (ANOVA-2) was performed after baseline subtraction, at a significance level of alpha = 0.05 to determine differences between dose groups. Results are expressed as means ± SEM.ResultsANOVA-RM showed significant within group increases in serum total T and significant decreases in serum DHT from baseline in both dose groups at a significance level of alpha = 0.05. Significant decreases in serum ES are reported for the 2000 mg/day dose group and not the 800 mg/day dose group. Significant within group effects were confirmed using ANOVA-2 analyses after baseline subtraction. ANOVA-2 analyses also showed no significant difference between dose groups with regard to the increase of T or the decrease of DHT. It did show a significant dose dependant decrease in serum ES levels.ConclusionBoth dose groups showed significant (p = 0.05) increases in T and decreases in DHT within three days of treatment with Alphastat® (Mytosterone(™)). Between group statistical analysis showed no significant (p = 0.05) difference, indicating the effect was not dose dependent and that 800 mg/per day is equally effective as 2000 mg/day for increasing T and lowering DHT. Blood levels of ES however, decreased significantly (p = 0.05) in the 2000 mg/day dose group but not in the 800 mg/day dose group indicating a dose dependant decrease in E levels.

The Effect of 5α-Reductase Inhibition with Dutasteride and Finasteride on Semen Parameters and Serum Hormones in Healthy Men

Dutasteride and finasteride are 5alpha-reductase inhibitors (5ARIs) that dramatically reduce serum levels of dihydrotestosterone (DHT). Because androgens are essential for fertility, we sought to determine the impact of 5ARI administration on serum testosterone (T), DHT, and spermatogenesis. DESIGN, SETTING, SUBJECTS, AND INTERVENTION: We conducted a randomized, double-blinded, placebo-controlled trial in 99 healthy men randomly assigned to receive dutasteride (D; 0.5 mg) (n = 33), finasteride (F; 5 mg) (n = 34), or placebo (n = 32) once daily for 1 yr. Blood and semen samples were collected at baseline and 26 and 52 wk of treatment and 24 wk after treatment and were assessed for T, DHT, and semen parameters. D and F significantly (P < 0.001) suppressed serum DHT, compared with placebo (D, 94%; F, 73%) and transiently increased serum T. In both treatment groups, total sperm count, compared with baseline, was significantly decreased at 26 wk (D, -28.6%; F, -34.3%) but not at 52 wk (D, -24.9%; F, -16.2%) or the 24-wk follow-up (D, -23.3%; F, -6.2%). At 52 wk, semen volume was decreased (D, -29.7%; F, -14.5%, significantly for D) as was sperm concentration (D, -3.2%; [corrected] F, -7.4%, neither significant). There was a significant reduction of -6 to 12% in sperm motility during treatment with both D and F and at follow-up. Neither treatment had any effect on sperm morphology. This study demonstrates that the decrease in DHT induced by 5ARIs is associated with mild decreases in semen parameters that appear reversible after discontinuation.

5α-Reductase 2 Gene Mutations in Three Unrelated Patients of Greek Cypriot Origin: Identification of an Ancestral Founder Effect

5alpha-Steroid reductase deficiency (5alphaSRD) is an autosomal recessive enzymatic deficiency. Mutations in the 5alpha-steroid reductase type 2 gene (SRD5A2) result in male pseudohermaphroditism caused by decreased dihydrotestosterone (DHT) synthesis--a key hormone of virilization of male external genitalia. To study for the first time patients from the Greek Cypriot population, describe their clinical characteristics, and identify the genetic mutations of the SRD5A2 gene. Three unrelated patients with 46,XY karyotype born with ambiguous genitalia were examined. Patient 1 was raised as a girl and was diagnosed with partial androgen insensitivity syndrome, based on the clinical picture and incomplete laboratory investigation at the age of 4 years, and underwent gonadectomy. For this patient sequencing analysis of all five exons of the SRD5A2 gene and exons 2 to 8 of the androgen receptor (AR) gene was performed. Patients 2 and 3 were also born with ambiguous genitalia. The hCG test for these two patients was informative of 5alphaSRD, as it showed elevated T/DHT ratio after stimulation. Despite genetic counseling, both families decided to raise their infants as females because of severe under-virilization. Sequencing of the SRD5A2 gene was also completed for both patients. No mutations were found in the AR sequence for patient 1. Patients 1 and 3 were found homozygous for the mutation A/G at splice junction intron 1/exon 2 and patient 2 was found heterozygous for the same A/G substitution and also heterozygous for an additional mutation, Pro181Leu, in exon 3. The same mutation in the SRD5A2 gene was identified in three unrelated patients, in both homozygous and heterozygous form. This splice mutation was previously reported in Turkish patients. This underlying genetic abnormality may be characteristic for the Eastern Mediterranean region and is likely due to an ancestor effect.

5alpha-reductase-2 deficiency and complete androgen insensitivity: lessons from nature.

The importance of the hormones testosterone and dihydrotestosterone in the male is best illustrated by studies of the inherited condition of male pseudohermaphroditism due to 5a—reductase-2 deficiency (Imperato-McGinley et al, 1974,1976;Fratianni and Imperato-McGInley, 1994; Walsh et al, 1974). Testosterone is converted to dihydrotestosterone by two known 5a—reductase isoenzymes 5a—reductase-1 and 5a—reductase-2. It is defects in the 5a—recluctase-2 gene that cause male pseudohermaphroditism. The syndrome of 5a-reductase-2 deficiency results in a selective decrease in dihydrotestosterone. The clinical and laboratory findings of this syndrome have defined specific roles for testosterone and dihydrotestosterone in male sexual differentiation and development. The unusual psychosexual aspects of this clinical entity have helped to define the role of androgens in gender identity formation.

Effects of long-term treatment with Serenoa repens (Permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia.

The n-hexane lipido-sterol extract of Serenoa repens (LSESr, Permixon, Pierre Fabre Medicament, Castres, France), a phytotherapeutic agent used in the treatment of benign prostatic hyperplasia (BPH), has a multisite mechanism of action including inhibition of types 1 and 2 5alpha-reductase and competitive binding to androgen receptors in prostatic cells. Here, the response of testosterone (T), dihydrotestosterone (DHT), and epidermal growth factor (EGF) in BPH tissue of patients treated with LSESr (320 mg/day for 3 months) is analyzed. BPH samples were sectioned in periurethral, subcapsular, and intermediate regions: in each region T, DHT, and EGF were determined by radioimmunoassay after purification on celite columns or Sep-pak C18 cartridges. In the untreated group, T, DHT, and EGF presented the highest concentrations in the periurethral region (615 +/- 62 (SE) pg/g tissue, 7,317 +/- 551 pg/g tissue, and 20.9 +/- 3.3 ng/g tissue, respectively) with respect to the peripheral subcapsular region (425 +/- 45 pg/g tissue, 4,215 +/- 561 pg/g tissue, and 10.8 +/- 1.4 ng/g tissue, respectively). In the LSESr-treated group, a statistically significant reduction was observed, mainly in the periurethral region of DHT (2,363 +/- 553 pg/g tissue, P < 0.001) and EGF (6.98 +/- 2.48 ng/g tissue, P < 0.01), with increased T values (1,023 +/- 101 pg/g tissue, P < 0.001). The decrease of DHT and the rise of T in BPH tissue of patients treated with Permixon confirms the capacity of this drug to inhibit in vivo 5alpha-reductase in human pathological prostate. A marked decrease of EGF, associated with DHT reduction, was also observed. These biochemical effects, similar to those obtained with finasteride, are particularly evident in the periurethral region, whose enlargement is responsible for urinary obstruction, with respect to the subcapsular region. A possible speculation is that the preferential reduction of DHT and EGF content in the periurethral region is involved in the clinical improvement of the obstructive symptoms in BPH during LSESr therapy.

Interleukin‐6 inhibits the potent stimulatory action of androgens, glucocorticoids and interleukin‐1α on apolipoprotein D and GCDFP‐15 expression in human breast cancer cells

Our study was designed to investigate the potential interaction between steroid hormones and interleukin-6 (IL-6) in the regulation of apolipoprotein D (apo-D) and gross cystic disease fluid protein 15 (GCDFP-15) expression in ZR-75-1 human breast cancer cells. We first observed that exposure to IL-6 for 6-14 days decreased basal apo-D and GCDFP-15 secretion by 50% and 23%, respectively. In the same experiment, such treatment with IL-6 decreased cell proliferation by approximately 40% after 6 and 14 days of incubation. Exposure to IL-6 markedly decreased dihydrotestosterone (DHT)-induced apo-D and GCDFP-15 release, with a half-maximal effect measured at 13 U/ml. A similar inhibitory action of IL-6 was observed on the glucocorticoid dexamethasone (DEX)-induced apo-D and GC-DFP-15 secretion. The sensitivity of the apo-D and GCDFP-15 response to the stimulatory action of DHT or DEX was, however, not changed by concomitant exposure to IL-6. The inhibitory effect of IL-6 on the secretion of these two biochemical markers was additive to that of 17 beta-estradiol. In addition, IL-6 blocked the stimulatory effect of interleukin-1 alpha (IL-1 alpha) on apo-D and GCDFP-15 secretion. Our results show that IL-6 is a potent inhibitory of basal as well as androgen-, glucocorticoid- and IL-1 alpha-induced apo-D and GCDFP-15 secretion in ZR-75-1 human breast cancer cells, while cell proliferation is inhibited by this cytokine.