Insight on the Intracrinology of Menopause: Androgen Production within the Human Vagina.

In this study, we investigated steroidogenic gene mRNA expression in human vaginas and verified the ability of human vagina smooth muscle cells (hvSMCs) to synthesize androgens from upstream precursor dehydroepiandrosterone (DHEA). As a readout for androgen receptor (AR) activation, we evaluated the mRNA expression of various androgen-dependent markers. hvSMCs were isolated from vagina tissues of women undergoing surgery for benign gynecological diseases. In these cells, we evaluated mRNA expression of several steroidogenic enzymes and sex steroid receptors using real time reverse transcription-polymerase chain reaction. Androgen production was quantified with liquid chromatography tandem-mass spectrometry (LC-MS/MS). In vaginal tissues, AR mRNA was significantly less expressed than estrogen receptor α, whereas in hvSMCs, its mRNA expression was higher than progestin and both estrogen receptors. In hvSMCs and in vaginal tissue, when compared to ovaries, the mRNA expression of proandrogenic steroidogenic enzymes (HSD3ß1/ß2, HSD17ß3/ß5), along with 5α-reductase isoforms and sulfotransferase, resulted as being more abundant. In addition, enzymes involved in androgen inactivation were less expressed than in the ovaries. The LC-MS/MS analysis revealed that, in hvSMCs, short-term DHEA supplementation increased Δ4-androstenedione levels in spent medium, while increasing testosterone and DHT secretion after longer incubation. Finally, androgenic signaling activation was evaluated through AR-dependent marker mRNA expression, after DHEA and T stimulation. This study confirmed that the human vagina is an androgen-target organ with the ability to synthesize androgens, thus providing support for the use of androgens for local symptoms of genitourinary syndrome in menopause.

Metformin in vitro and in vivo increases adenosine signaling in rabbit corpora cavernosa.

INTRODUCTION: In subjects with erectile dysfunction responding poorly to sildenafil, metformin was reported to improve erections. AIMS: The aim of this study is to investigate metformin's mechanism of action on erectile function, particularly focusing on adenosine (ADO) and nitric oxide (NO) signaling in an animal model of high-fat diet (HFD)-induced metabolic syndrome. METHODS: In vitro contractility studies of penile strips. Penile expression of genes related to ADO or NO signaling was also evaluated. MAIN OUTCOME MEASURE: In vitro contractility studies were used to investigate the effect of in vivo and ex vivo metformin administration on ADO- or acetylcholine (Ach)-induced relaxation of penile strips from HFD as compared with animals fed a regular diet (RD). RESULTS: Expression of ADO receptor type 3 (A3 R), ADO deaminase (ADA), AMP deaminase type 1 (AMPD1), and 2 (AMPD2) was decreased in HFD as compared with RD. Accordingly, in HFD the ADO relaxant effect was potentiated as compared with RD (P < 0.02). In vivo metformin treatment in both RD and HFD significantly increased the ADO relaxing effect (P < 0.0001 and P < 0.01, respectively, vs. relative untreated groups) although to a different extent. In fact, the half-maximal inhibitory concentration (IC50 )/IC50 ratio in RD increased fourfold vs. HFD (RD IC50 ratio = 13.75 ± 2.96; HFD IC50 ratio = 2.85 ± 0.52). In corpora cavernosa (CC) from HFD, in vivo metformin (i) normalized A3 R, ADA, and AMPD1; (ii) further decreased AMPD2; (iii) increased dimethylarginine dimethylamino-hydrolase; and (iv) partially restored impaired Ach-induced relaxation. Ex vivo metformin time and dose dependently increased the relaxant effect of ADO in RD. The potentiating effect of metformin on ADO-induced relaxation was significantly reduced by preincubation with NO synthase inhibitor N(ω) -Nitro-L-arginine methyl ester hydrochloride (L-NAME). Interestingly, in vivo testosterone supplementation in HFD rabbits (i) increased penile expression of endothelial NO synthase and AMPD2 and (ii) restored metformin's potentiating effect on ADO-induced relaxation up to RD level. CONCLUSION: Metformin in vivo and ex vivo increases ADO signaling in CC, most probably interfering with NO formation and ADO breakdown.

Testosterone supplementation and sexual function: a meta-analysis study.

INTRODUCTION: The role of testosterone supplementation (TS) as a treatment for male sexual dysfunction remains questionable. AIM: The aim of this study was to attempt a meta-analysis on the effect of TS on male sexual function and its synergism with the use of phosphodiesterase type 5 inhibitor (PDE5i). METHODS: An extensive Medline, Embase, and Cochrane search was performed. MAIN OUTCOME MEASURES: All randomized controlled trials (RCTs) comparing the effect of TS vs. placebo or the effect of TS as add on to PDE5is on sexual function were included. Data extraction was performed independently by two of the authors (A. M. Isidori and G. Corona), and conflicts resolved by the third investigator (M. Maggi). RESULTS: Out of 1,702 retrieved articles, 41 were included in the study. In particular, 29 compared TS vs. placebo, whereas 12 trials evaluated the effect of TS as add on to PDE5is. TS is able to significantly ameliorate erectile function and to improve other aspects of male sexual response in hypogonadal patients. However, the presence of possible publication bias was detected. After applying "trim and fill" method, the positive effect of TS on erectile function and libido components retained significance only in RCTs partially or completely supported by pharmaceutical companies (confidence interval [0.04-0.53] and [0.12; 0.52], respectively). In addition, we also report that TS could be associated with an improvement in PDE5i outcome. These results were not confirmed in placebo-controlled studies. The majority of studies, however, included mixed eugonadal/hypogonadal subjects, thus imparting uncertainty to the statistical analyses. CONCLUSIONS: TS plays positive effects on male sexual function in hypogonadal subjects. The role of TS is uncertain in men who are not clearly hypogonadal. The apparent difference between industry-supported and independent studies could depend on trial design more than on publication bias. New RCTs exploring the effect of TS in selected cases of PDE5i failure that persistently retain low testosterone levels are advisable.

Dehydroepiandrosterone supplementation in elderly men: a meta-analysis study of placebo-controlled trials.

CONTEXT: Age-related dehydroepiandrosterone (DHEA) deficiency has been associated with a broad range of biological abnormalities in males. OBJECT: Our objective was to meta-analyze all double-blind, placebo-controlled randomized trials (RCTs) investigating the effect of oral DHEA (DHEA supplementation) in comparison with placebo on sexual and metabolic outcomes in elderly men. DATA SOURCE: An extensive Medline Embase and Cochrane search was performed including the following words: DHEA, RCTs, and males. STUDY SELECTION: Only double-blind placebo-controlled trials performed in elderly men were included. DATA EXTRACTION: Data extraction was performed independently by 2 of the authors (A.S. and V.G.), and conflicts were resolved by the third investigator (G.C.). The quality of RCTs was assessed using the Cochrane criteria. RESULTS: Of 220 retrieved articles, 25 were included in the study. The available RCTs enrolled 1353 elderly men, with a mean follow-up of 36 weeks. DHEA supplementation was associated with a reduction of fat mass (standardized mean difference of -0.35 [-0.65 to -0.05]; P = .02). However, the association with fat mass disappeared in a multivariate regression model after adjusting for DHEA-related metabolite increases such as total testosterone and estradiol. In contrast to what was observed for fat mass, no effect of DHEA supplementation in comparison with placebo was observed for various clinical parameters including lipid and glycemic metabolism, bone health, sexual function, and quality of life. CONCLUSIONS: The present meta-analysis of intervention studies shows that DHEA supplementation in elderly men can induce a small but significant positive effect on body composition that is strictly dependent on DHEA conversion into its bioactive metabolites such as androgens or estrogens.

Emerging medication for the treatment of male hypogonadism.

INTRODUCTION: Since the phenotype and clinical need of the hypogonadal individuals changes dramatically over time, versatile therapies are needed. AREAS COVERED: The authors review the available evidence on possible therapies. EXPERT OPINION: In the case of primary hypogonadism starting early in life, substitution with testosterone (T) is the only choice. For secondary congenital hypogonadism, we recommend starting with gonadotrophins to allow the testes to reach pubertal size. Thereafter, T replacement therapy can be administered until fertility is desired. At that time, gonadotrophins should be employed until fathering occurs. Antiestrogens are an alternative, however, their efficacy has not been adequately tested. In the presence of increased estrogen production symptoms (breast tenderness and gynecomastia), a short-term trial with non-aromatizable androgens (dihydrotestosterone mesterolone or oxandrolone) could be advisable. However, after a few months of therapy, switching to other aromatizable preparations is recommended, to prevent bone loss. When prostate safety is concerned, the use of steroidal or non-steroidal selective androgen receptor modulators that are less susceptible to 5α reduction might be advisable. An attractive possibility is the combined use of testosterone with 5α inhibitors. Theoretically, also estrogen receptor-beta ligands could be employed, however the development of these compounds, although promising, is still in its infancy.