Normal Androgen Levels Research Articles

Lipid profile parameters in men with coronary heart disease in different age categories in connection with sex hormone level

Aim of the study was to investigate the main components of the lipid spectrum of blood serum in patients with coronary artery disease, depending on the level of estradiol (E2), testosterone (T) and age.Material and methods. We examined 161 men aged 35–65 years (median [lower quartile; upper quartile] 53.1 [40.1; 59.4] years) with a history of myocardial infarction more than 30 days before inclusion in the study. Patients were divided into groups by age (35–55 and 56–65 years), as well as according to the content of sex hormones: T ≥ 12 nmol/l and T < 12 nmol/l, E2 ≥ 0.194 nmol/l and E2 < 0.194 nmol/l with double determination.Results. Of the studied components of the lipid profile, the greatest number of significant changes in men with coronary artery disease in different groups, depending on age and levels of sex steroids, had triglyceride (TG) level. In men aged 35–55 and 56–65 years with hypogonadism, TG concentration was higher compared to peers with normal androgen levels. In the older age group, relatively younger male patients, both when comparing a cohort of men with low T and with its normal values, TG content was also higher. In groups of patients with T level > 12 nmol/l and ≤ 12 nmol, when controlling for height and body weight, there is a statistically significant direct association of age in men of 56–65 years with TG concentration (r = 0.483, p = 0.023 and r = 0.549, p = 0.008, respectively). It was found that in patients with coronary artery disease in the age groups of 35–55 years and 56–65 years with E2 content ≥ 0.194 nmol/l, the TG level was higher than in men with normal estrogen concentration (p = 0.008 and p = 0.033, respectively). In a partial correlation analysis with control of height and body weight in men aged 35–55 years with coronary artery disease, a statistically significant relationship was found between the level of E2 ≥ 0.194 nmol/l and TG content (r = 0.566, p = 0.009), a similar relationship independent of anthropometric parameters was verified and in the older age group (r = 0.316, p = 0.011). In a multivariate analysis, the level of TG was determined by E2 concentration, the other variables under consideration did not statistically significantly affect it.Conclusions. Hypogonadism in men in each age group studied is associated with elevated TG content. A significant role in the development of hypertriglyceridemia in men is played by hyperestrogenemia in both age groups, being an independent, independent of androgenic status, proatherogenic factor.

Mitoguardin2 Is Associated With Hyperandrogenism and Regulates Steroidogenesis in Human Ovarian Granulosa Cells.

Polycystic ovary syndrome (PCOS) is an endocrinopathy characterized by hyperandrogenism, anovulation, and polycystic ovaries, in which hyperandrogenism manifests by excess androgen and other steroid hormone abnormalities. Mitochondrial fusion is essential in steroidogenesis, while the role of mitochondrial fusion in granulosa cells of hyperandrogenic PCOS patients remains unclear. In this study, mRNA expression of mitochondrial fusion genes mitoguardin1, -2 (MIGA 1, -2) was significantly increased in granulosa cells of hyperandrogenic PCOS but not PCOS with normal androgen levels, their mRNA expression positively correlated with testosterone levels. Dihydrotestosterone (DHT) treatment in mice led to high expression of MIGA2 in granulosa cells of ovulating follicles. Testosterone or forskolin/ phorbol 12-myristate 13-acetate treatments increased expression of MIGA2 and the steroidogenic acute regulatory protein (StAR) in KGN cells. MIGA2 interacted with StAR and induced StAR localization on mitochondria. Furthermore, MIGA2 overexpression significantly increased cAMP-activated protein kinase A (PKA) and phosphorylation of AMP-activated protein kinase (pAMPK) at T172 but inhibited StAR protein expression. However, MIGA2 overexpression increased CYP11A1, HSD3B2, and CYP19A1 mRNA expression. As a result, MIGA2 overexpression decreased progesterone but increased estradiol synthesis. Besides the androgen receptor, testosterone or DHT might also regulate MIGA2 and pAMPK (T172) through LH/choriogonadotropin receptor-mediated PKA signaling. Taken together, these findings indicate that testosterone regulates MIGA2 via PKA/AMP-activated protein kinase signaling in ovarian granulosa cells. It is suggested mitochondrial fusion in ovarian granulosa cells is associated with hyperandrogenism and potentially leads to abnormal steroidogenesis in PCOS.

Idiopathic hirsutism: Is it really idiopathic or is it misnomer?

Hirsutism, which is characterized by excessive growth of terminal hair in a male pattern, may result from various causes including polycystic ovary syndrome (PCOS), non-classic congenital adrenal hyperplasia, adrenal or ovarian tumors or it may be idiopathic. Idiopathic hirsutism is currently defined as hirsutism associated with normal ovulatory function, normal serum androgen levels and normal ovarian morphology, however, the pathogenesis of idiopathic hirsutism is not clear. The androgens are the main hormones to stimulate growth of body hair, therefore, there should be any form of increased androgen effect irrespective of normal serum androgen levels in any patient with hirsutism. In accordance to this scientific truth, we have previously shown that, although within normal limits, patients with idiopathic hirsutism have relatively higher serum androgen levels (relative hyperandrogenemia) in comparison to healthy subjects which let as to think that is idiopathic hirsutism really idiopathic? In addition to relative hyperandrogenemia, we have previously shown that, in comparison to healthy subjects, women with idiopathic hirsutism demonstrated higher expression of steroid sulphatase and 17-beta hydroxysteroid dehydrogenase mRNA both in the subumbilical region and arm skin, which contributes to local androgen metabolism. Those results support the idea that, in some patients, although the adrenals or ovaries do not secrete increased amount of androgens leading to hyperandrogenemia, pilocebaceous unit locally produce increased amount of androgens leading to hirsutism without ovulatory dysfunction. Upon the demonstration of relative hyperandrogenemia and possible increase in local androgen synthesis in patients with idiopathic hirsutism, we think that idiopathic hirsutism is not idiopathic and it may be named as "normoandrogenic hirsutism". Furthermore, it may not be a different entity but may be an early stage of hyperandrogenic disorders such as PCOS. Clinically, this can be find out by following-up patients with idiopathic hirsutism prospectively.

A Surgical and Clinical Approach to Persistent Müllerian Duct Syndrome: Laparoscopic, Histological, and Molecular Findings

Background: Persistent müllerian duct syndrome (PMDS) is characterized by the persistence of müllerian duct derivatives in otherwise normally virilized 46,XY males. Biallelic mutations of the anti-müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) genes lead to PMDS type 1 and 2, respectively. Aim: The aims of the study were to report the clinical, hormonal, and genetic findings in a patient with PMDS and discuss surgical strategies to achieve successful orchidopexy. Results: A 4-year-old boy was evaluated after the incidental finding of müllerian derivates during laparoscopy for nonpalpable gonads. Karyotype was 46,XY and laboratory tests revealed normal serum gonadotropin and androgen levels but undetectable serum AMH levels. PMDS was suspected. Molecular analysis revealed a novel variant c.902_929del in exon 5 and a previously reported mutation (c.367C>T) in exon 1 of the AMH gene. Successful orchidopexy was performed in two sequential surgeries in which the müllerian duct structure was preserved and divided to protect the vascular supply to the gonads. Histological evaluation of the testicular biopsy showed mild signs of dysgenesis. Doppler ultrasound showed blood flow in both testes positioned in the scrotum 1.5 years after surgery. Conclusion: PMDS is a rare entity that requires a high index of suspicion (from surgeons) when evaluating a patient with bilateral cryptorchidism. Surgical treatment is challenging and long-term follow-up is essential. Histological evaluation of the testis deserves further investigation.

Androgen dysfunction in non-alcoholic fatty liver disease: Role of sex hormone binding globulin.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the world. It is linked mainly to insulin resistance and metabolic syndrome including obesity and dyslipidemia. In addition, various endocrine dysfunctions including polycystic ovary syndrome (PCOS) and hypogonadism are involved in the development and progression of NAFLD. We need to know the disease pathophysiology more accurately due to the heterogeneity of clinical presentation of fatty liver disease. The liver is the major metabolic organ with sexual dimorphism. Sexual dimorphism is associated not only with behavioral differences between men and women, but also with physiological differences reflected in liver metabolism. In men, normal androgen levels prevent hepatic fat accumulation, whereas androgen deficiency induce hepatic steatosis. In women, higher androgens can increase the risk of NAFLD in PCOS. Sex hormone binding globulin (SHBG) is involved in androgen regulation. Recently, SHBG may be reported as a surrogate marker for NAFLD. Therefore, this review will focus on the mechanism of androgen dysfunction in the regulation of hepatic metabolism, the risk of developing NAFLD, and the potential role of SHBG in the course of NAFLD.; Keywords: Non-alcoholic fatty liver disease, insulin resistance, sexual dimorphism, androgen, sex hormone binding globulin.

The influence of ESR1 polymorphisms on selected hormonal, metabolic and mineral balance markers in women with hyperandrogenism

Hyperandrogenism is the most common endocrine disorder in women, characterized by an imbalance in normal estrogen and androgen levels in the blood. Androgens influence bone mineral density, body mass composition, muscle mass, mental state, and the regulation of sexual function.. The aim of the study was to assess the effect of estrogen receptor α gene (ESR1) polymorphisms on selected markers of bone metabolism and hormonal parameters in women with hyperandrogenism. The study group included 80 young women with hyperandrogenism who underwent measurements of bone mineral density (BMD), and determination of hormonal and metabolic parameters. Enzyme immunoassays were used to measure leptin, sRANKL (soluble receptor activator of nuclear factor-kB ligand), osteoprotegerin and 25-OH vitamin D total levels. An analysis of ESR1 gene polymorphisms was performed using the real-time PCR method. A relationship was demonstrated between the concentration of free estradiol (FEI) and the concentration of 17-OH-progesterone, and the ESR1 gene polymorphisms: rs3020314 (p = 0.031, p = 0.026 respectively) and rs1884051 (p = 0.033, p = 0.026 respectively). In conclusion, the ESR gene polymorphisms may be associated with hormonal disturbances in the concentration of estrogens and androgens, in hyperandrogenism in young women which may indirectly affect bone mineral density. However, no statistically significant relationships between the studied polymorphisms and the selected parameters of mineral metabolism have been demonstrated..

Hirsutism, Normal Androgens and Diagnosis of PCOS.

Hirsutism is defined as the presence of terminal hair with male pattern distribution in women. While in the general population, hirsutism affects around 4–11% of women, it is the main manifestation of hyperandrogenism in women with polycystic ovary syndrome (PCOS), with a prevalence estimated at 65–75%. Hirsutism in PCOS is associated with both androgen excess and individual response of the pilosebaceous unit to androgens. The modified Ferriman–Gallwey (mFG) scoring system has been widely used in clinical practice to visually score excessive terminal hair, thus standardizing hirsutism evaluation and facilitating data comparison. Although a universal mFG score cutoff would be useful for comparisons, ethnic variations, as well as skin type and other factors, should be considered when evaluating hirsutism in distinct populations. In turn, androgen levels, measured by conventional techniques, have been shown to correlate poorly with the severity of hirsutism. Indeed, while most women with PCOS and hirsutism also have higher than reference values for serum androgen levels, some of them may not present with biochemical hyperandrogenism, representing a challenge to the diagnosis of PCOS. In this article, we critically review this not uncommon condition in women with PCOS presenting with hirsutism but normal androgen levels.

Association of the CYP19A1 rs700518 Polymorphism with Selected Markers of Bone Metabolism in Women with Hyperandrogenism.

Hyperandrogenism is the most common endocrine disorder in women, characterized by an imbalance of normal estrogen and androgen levels in the blood. Androgens play an important role in the female body because they influence bone mineral density (BMD), body mass composition, muscle mass, mental state, and the regulation of sexual function. The reduced activity of aromatase, due to mutations in the CYP19A1 gene, reduces the estrogen pool in favor of androgens. Clinically, aromatase deficiency causes hyperandrogenism in women. Therefore, the aim of the study was to assess the effect of the CYP19A1 gene polymorphism on selected markers of bone metabolism and hormonal parameters in women with hyperandrogenism. The study group was comprised of 80 young women with hyperandrogenism who underwent measurements of bone mineral density (BMD), and determination of hormonal and metabolic parameters. Enzyme immunoassays were used to measure leptin, total sRANKL (free and bound RANKL), osteoprotegerin, and total 25-OH Vitamin D. An analysis of the CYP19A1 gene polymorphisms was performed using the real-time PCR method. The GG genotype of the CYP19A1 rs700518 polymorphism turned out to be associated with: FEI (Free Estradiol Index), SHGB concentration, estradiol concentration, and insulin concentration determined in the glucose tolerance test 60’ compared to AG and AA genotypes. Patients with the AG genotype had a higher ratio of android to gynoid fat and a greater content of visceral adipose tissue. Higher visceral tissue content may reduce BMD. In conclusion, the study showed that the CYP19A1 rs700518 polymorphism may be associated with the distribution of adipose tissue in young women with hyperandrogenism. These results suggest that patients with the AG genotype may develop osteoporosis.

Basic research to determine normal levels of androgens (testosterone, free testosterone, DHEA-S) in Japanese middle-aged women

ABSTRACT Introduction We surveyed the age distribution (30-80s) of blood androgen levels (testosterone, free testosterone, DHEA-S) in healthy Japanese women at the testing center currently used by general clinicians measure by method for creating androgen reference values ​​of Japanese women. In addition, the major female hormones estradiol, the gonadotropins LH and FSH, and IGF-1, which reflected growth hormone were measured at the same time. Objective & Methods We collected the bloods of 160 healthy volunteer women who visited the Women's Clinic LUNA JAPAN, Sapporo Toho Hospital, and Caress Sapporo Clock Tower Memorial Hospital between Oct. 2020 and Feb.2021 and measured testosterone, free testosterone, DHEA-S, estradiol, LH, FSH and IGF-1. The measurement was outsourced to the Biochemical Blood Testing Department of LSI Medience Corporation, and the androgen level was collectively measured by the CLIA method. The survey was conducted with the approval of the medical corporation LEADING GIERLS Ethics Committee and with the written consent of all patients. Results The average age of volunteer women was 45, the median was 41, the maximum was 87, and the minimum was 20. The number distribution was 16 in their 20’s, 52 in their 30’s, 43 in their 40’s, 17 in their 50’s, 15 in their 60’s, 10 in their 70’s, and 7 in their 80’s. Table 1 shows the mean ± standard deviation of testosterone, free testosterone, DHEA-S, LH, FSH, estradiol, and IGF-1 for each age group. (Table 1) Conclusions In this group, regarding male hormones, DHEA and free testosterone decreased with age. In addition, IGF-1 also decreased with age. On the other hand, with regard to testosterone, the level of decrease is smaller than those of the other two androgens. Regarding estradiol, it decreased rapidly after menopause, but it is maintained at 10 to 20 pg / ml even after menopause. Healthy middle-aged women in Japan may maintain the lowest levels of testosterone and estradiol by eating a diet rich in sex hormone-like flavonoids such as soy isoflavones. However, the sexual function of healthy middle-aged and elderly people in Japan is said to be lower in both men and women than in Europe and the United States, and further research is needed on the relationship between Japanese sex hormone levels and sexual function and culture. Disclosure Work supported by industry: no.

A Proper Increasing in the Testosterone Level May Be Associated With Better Pregnancy Outcomes for Patients With Tubal or Male Infertility During in vitro Fertilization/Intracytoplasmic Sperm Injection.

We aimed to investigate the relationship between testosterone (T) levels and pregnancy outcomes in patients with tubal or male infertility at different times during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Patients with tubal or male infertility and normal androgen levels undergoing IVF/ICSI were consecutively recruited. We performed a longitudinal analysis of T levels at three time points (i.e., T0: baseline, T1: trigger day, and T2: day after the trigger day) in three groups with different pregnancy outcomes (i.e., group 1: no pregnancy; group 2: clinical pregnancy but no live birth; and group 3: live birth) as repeated measurement data using linear mixed-effects models. We also plotted fitted curves depicting the relationship between T levels and a number of oocytes retrieved at different time points and identified the inflection points of the curves. In total, 3,012 patients were recruited. Groups 1 and 3 had improvements in T levels at the three time points. After refitting, the slope in group 3 was significantly higher than that in group 1 (P = 0.000). Curves that reflected the association between T levels and numbers of retrieved oocytes presented an upward trend before a certain inflection point, after which the curves had no obvious changes or fell with increasing T levels. The inflection points for T0, T1, and T2 were calculated as 0.45, 0.94, and 1.09, respectively. A faster upward trend in T levels might be associated with better pregnancy outcomes. Within a range lower than a T level inflection point, more oocytes and embryos could be obtained with increasing T levels.

Understanding Pattern Hair Loss-Hair Biology Impacted by Genes, Androgens, Prostaglandins and Epigenetic Factors.

Pattern hair loss (PHL) is the most frequent cause of hair loss in men and women, accounting for 65% of consultations in a hair referral center. PHL is understood to represent a hereditary, age-dependent progressive thinning of the scalp hair, which follows distinct clinical patterns with notable differences depending on sex and age of onset. Clinical and investigative advances have helped us to understand some of the pathogenic steps, leading to PHL. Besides genetic factors and peculiarities of androgen metabolism, additional pathogenic factors that are suspected include microbiomata, oxidative stress, and microinflammation. While further suspects are likely to be exposed, individual diversity of causal agents, as well as of the sequence of events, or combined factors, must be kept in mind. A large number of therapeutic molecules claimed to be active and patented in this field, and their limited efficacy in offering a definitive cure of PHL confirm the complexity of PHL. The aim of therapy is to retard progression of hair thinning and increase hair coverage of the scalp. As yet, two FDA-approved drugs are available for this purpose, oral finasteride, and topical solution of minoxidil. Variations in posology and formulation allow for an enhancement of patient comfort and treatment efficacy. Antiandrogen treatments in women with normal androgen levels have questionable efficacy while having health risks.

VALIDATION OF DIAGNOSTIC CRITERIA AND ANDROGEN SUPPLEMENTATION AS TREATMENT IN WOMEN WITH THE HYPOANDROGENIC PCOS-LIKE PHENOTYPE (H-PCOS)

The H-PCOS-like phenotype, representing ontogenically at ages over 35 the lean PCOS-phenotype D by Rotterdam criteria, has been demonstrated to be relatively resistant to standard fertility treatments, including IVF.1,2 The objective of this study was to determine whether reconstitution of normal androgen levels reverses this treatment resistance.

Interaction between Renal Sodium‐Glucose Cotransporter 2 and Renin‐Angiotensin System in a PCOS Rat Model

Introduction : Polycystic Ovary Syndrome (PCOS) is characterized by androgen excess, oligo/anovulation, and polycystic ovaries. PCOS is co-prevalent with insulin resistance (IR), increased blood pressure (BP), and a dysfunctional renin-angiotensin system (RAS). The RAS has both a vasoconstrictive arm with angiotensin-converting enzyme (ACE) and a vasodilatory arm with ACE2. While PCOS patients require multiple medications to control their comorbidities, it is unknown how these medications interact with each other. ACE inhibitors (ACEi) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) seem to influence each other in male rodents. However, how androgens influence these interactions in females is unknown. We have a well-established rat model that mimics PCOS, including IR, increased BP, and overactive RAS. Using this model, we tested the hypothesis that SGLT2i would attenuate the RAS and that ACEi would decrease renal SGLT2 expression in a rat model of PCOS. Methods : In Experiment 1, four-week old female Sprague Dawley (SD) rats implanted with DHT pellets (7.5mg/90 days) or control were randomized to drinking water with and without the SGLT2i empagliflozin at a dose of 10 mg/kg/day during the last 3 weeks of the study (n=10/group). At 3 months of DHT, fasting plasma was collected for the homeostatic model assessment of IR (HOMA-IR). BP was measured by radiotelemetry. Renal cortex and medulla were collected for quantitative real-time polymerase chain reaction (qRT-PCR) and western blot for ACE and ACE2. In Experiment 2, four-week old female SD rats implanted with DHT pellets (7.5mg/90 days) or control were randomized to drinking water with and without the ACEi enalapril at a dose of 250 mg/mL throughout the study (n=10/group). At 3 months of DHT, kidneys were collected for qRT-PCR for SGLT2. Results : PCOS rats had increased IR, BP, and renal expression of ACE and ACE2 compared to controls. SGLT2i had no impact on IR while causing a small reduction in BP in both groups. SGLT2i decreased cortical ACE mRNA and protein (1.03 ± 0.08 vs 1.37 ± 0.04, P<0.05) in PCOS, and had no impact in controls. SGLT2i also decreased cortical ACE2 protein (1.02 ± 0.05 vs 1.18 ± 0.03, P<0.05) in PCOS, but not in controls. SGLT2i decreased mRNA and protein of medullar ACE and ACE2 in both groups. In Experiment 2, cortical SGLT2 mRNA was increased in PCOS compared to controls. ACEi increased SGLT2 mRNA in controls (30.32 ± 8.03 vs 1.00 ± 0.32, P<0.01) with no effect in PCOS. Conclusions In summary, PCOS rats had increased IR, BP, and intrarenal ACE. Without impacting IR, SGLT2i attenuated both intrarenal ACE and ACE2 expression in PCOS. This suggests ACEi could work synergistically with SGLT2i to reduce BP. PCOS rats have increased SGLT2 mRNA, suggesting a differential response to SGLT2i between PCOS rats and controls, such as shown with cortical ACE. ACEi also increased cortical SGLT2 mRNA in controls, but androgen excess appeared to blunt this effect. Overall, this suggests that there could be a differential response in hyperandrogenemic women taking both SGLT2i and ACEi compared to a woman with normal androgen levels.

Differential Effects of Various Androgens on Polycystic Ovary Syndrome.

The hyperandrogenism in polycystic ovary syndrome (PCOS) is associated with the risk for the future development of the cardiovascular disease. The objective of the study is to verify whether different androgens have the same harmful effect. This cross-sectional study enrolled 823 women with PCOS: 627 (76.2%) with biochemical hyperandrogenism and 196 (23.8%) with normal androgen levels. The role of individual androgen was evaluated using univariate and multivariate logistic regression. In normoandrogenemic PCOS (NA-PCOS), free androgen index (FAI) predicted significant abnormality in visceral adipose index (VAI, OR=9.2, p=0.002) and dehydroepiandrosterone (DHEA) predicted against alteration in β-cell function (OR=0.5, p=0.007). In hyperandrogenemic PCOS (HA-PCOS), FAI predicted derangements in waist triglyceride index (WTI), VAI, and lipid accumulation product (LAP) (OR ranging from 1.6 to 5.8, p<0.05). DHEA weakly predicted against VAI (OR 0.7, p=0.018), dehydroepiandrosterone sulfate (DHEAS) tended to predict against the conicity index (OR=0.7, p=0.037). After multiple regression, FAI retained significant strength to predict various anthropometric and metabolic abnormalities (OR ranging from 1.1 to 3.0, p<0.01), DHEA was kept as a protector factor against WTI, LAP, and VAI (OR ranging from 0.6 to 0.9; p<0.01) and DHEAS against the conicity index (OR=0.5, p<0.001). In conclusion, the free androgen index was the most powerful predictor of anthropometric and metabolic abnormalities of polycystic ovary syndrome. Conversely, DHEA and DHEAS demonstrated protective effects against disorders in some markers of obesity and abnormal metabolism.

Association between hyperandrogenism and adverse pregnancy outcomes in patients with different polycystic ovary syndrome phenotypes undergoing in vitro fertilization/intracytoplasmic sperm injection: a systematic review and meta-analysis

Objective To study the association between hyperandrogenism (HA) and adverse pregnancy outcomes in patients with different polycystic ovary syndrome phenotypes undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Methods We reviewed all eligible articles published up to October 2020 after searching in PubMed, Embase, Cochrane Library, Web of Science, Wanfang Data, and CNKI databases. The primary outcomes were the clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR), whereas the secondary outcomes were the number of retrieved oocytes and endometrial thickness. Risk ratios (RRs) or mean differences with 95% confidence intervals (CIs) were calculated to estimate the HA impact on IVF/ICSI outcomes in patients with polycystic ovary syndrome (PCOS) phenotypes. Results Of the 789 trials identified, nine retrospective studies involving 3037 patients with PCOS were included. Compared to the PCOS group with normal androgen levels, the PCOS group with HA exhibited increased MR (RR: 1.56, 95% CI: 1.13, 2.16); the CPR (RR: 0.88, 95% CI: 0.77, 1.01) and LBR (RR: 0.79, 95% CI: 0.55, 1.11) were not significantly different between these groups. Subgroup analysis revealed that the CPR was lower in the polycystic ovarian (PCO)-morphology + HA + oligo-anovulation (AO) group than in the PCO + AO group (RR: 0.81, 95% CI: 0.67, 0.99). Among Asians, the PCOS/HA group had increased MR (RR: 1.56, 95% CI: 1.06, 2.31) and showed thinner endometrial thickness. However, among Caucasians, no differences were observed between the two groups. Conclusions HA may have adverse effects on clinical pregnancy and miscarriage outcomes in different PCOS phenotypes, particularly among Asians.

Testosterone, level of the lesion and age are independently associated with prostate volume in men with chronic spinal cord injury.

Although men with spinal cord injury (SCI) exhibit a prostate volume significantly smaller compared to age-matched able-bodied men, the independent association of lower prostate volume withits putative determinants has never been analyzed in this population. This study was designed to identify variables independently associated with prostate volume in men with chronic SCI. In this cross-sectional study, prostate volume of 138 men with chronic (> 1years) SCI, aged 54.5 (25th-75th percentile: 36.0-66.0) years, was evaluated with trans-rectal ultrasonography. All patients underwent a complete neurological exam, as well as biochemical and hormonal assessment, including total testosterone (TT) levels. Free testosterone levels were calculated (cFT) by the Vermeulen formula. The median prostate volume was 23.4mL. At the univariate analysis, a larger prostate volume was associated with higher TT (p = 0.00001) and cFT (p = 0.001), SCI level below T12 (p = 0.007), more advanced age (p = 0.04), lower body mass index (p = 0.04), higher functional independence score (p = 0.06), higher values of prostate-specific antigen (p = 0.12) and shorter duration of the injury (p = 0.21). However, at the multiple regression analyses, an independent and positive association only persisted between the prostate volume with either TT or cFT levels, and, to a lesser extent, with age and a level of spinal lesion below T12. A prostate volume below the median value was observed in 91.4% (32/35) of patients with both androgen deficiency (TT < 264ng/dL) and spinal lesion level ≥ T12, but only in 16.5% (2/12) of patients with both normal androgen levels and spinal lesion level below T12 (p < 0.001). Our data indicate that lower testosterone levels and, to a lesser extent, a younger age and a spinal lesion level ≥ T12 represent the only variables exhibiting an independent association with a smaller prostate volume in men with SCI.

Female hyperandrogenism and elite sport.

Emerging evidence indicates that testosterone, which can increase muscle mass and strength, stimulates erythropoiesis, promotes competitive behaviour, and enhances the physical performance of women. Indeed, the levels of testosterone within the normal female range are related to muscle mass and athletic performance in female athletes. Furthermore, among these athletes, the prevalence of hyperandrogenic conditions, including both polycystic ovary syndrome and rare differences/disorders of sex development (DSD), which may greatly increase testosterone production, are elevated. Thus, if the androgen receptors of an individual with XY DSD are functional, her muscle mass will develop like that of a man. These findings have led to the proposal that essential hyperandrogenism is beneficial for athletic performance and plays a role in the choice by women to compete in athletic activities. Moreover, a recent randomized controlled trial demonstrated a significant increase in the lean mass and aerobic performance by young exercising women when their testosterone levels were enhanced moderately. Circulating testosterone is considered the strongest factor to explain the male advantage in sport performance, ranging between 10 and 20%. It appears to be unfair to allow female athletes with endogenous testosterone levels in the male range (i.e. 10–20 times higher than normal) to compete against those with normal female androgen levels. In 2012, this consideration led international organizations to establish eligibility regulations for the female classification in order to ensure fair and meaningful competition, but the regulations are controversial and have been challenged in court.

Phase II trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer.

94 Background: Monoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer. Methods: An open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by: PSA ≥ 0.4 ng/ml (post-prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline. Results: Characteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥ 30% and ≥ 50% were observed in 25% (n=5/20) and 10% (n=2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥ 30% and ≥ 50% of 24% (n=4/17) and 6% (n=1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2= 35%), hypertension (grade ≥ 2 =30%), and edema (grade 1=25%, grade 2=10%). There was 1 episode of grade 4 hypertension (cycle 4) and 2 episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment. Conclusions: Phenelzine demonstrated efficacy in patients with biochemical recurrent castrate sensitive prostate cancer. Most treatment related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer. Clinical trial information: NCT02217709.

Female hyperandrogenism and elite sport

Emerging evidence indicates that testosterone, which can increase muscle mass and strength, stimulates erythropoiesis, promotes competitive behaviour, and enhances the physical performance of women. Indeed, the levels of testosterone within the normal female range are related to muscle mass and athletic performance in female athletes. Furthermore, among these athletes, the prevalence of hyperandrogenic conditions, including both polycystic ovary syndrome and rare differences/disorders of sex development (DSD), which may greatly increase testosterone production, are elevated. Thus, if the androgen receptors of an individual with XY DSD are functional, her muscle mass will develop like that of a man. These findings have led to the proposal that essential hyperandrogenism is beneficial for athletic performance and plays a role in the choice by women to compete in athletic activities. Moreover, a recent randomized controlled trial demonstrated a significant increase in the lean mass and aerobic performance by young exercising women when their testosterone levels were enhanced moderately. Circulating testosterone is considered the strongest factor to explain the male advantage in sport performance, ranging between 10 and 20%. It appears to be unfair to allow female athletes with endogenous testosterone levels in the male range (i.e. 10-20 times higher than normal) to compete against those with normal female androgen levels. In 2012, this consideration led international organizations to establish eligibility regulations for the female classification in order to ensure fair and meaningful competition, but the regulations are controversial and have been challenged in court.

MON-207 Identification of Monogenic Causes of Polycystic Ovary Syndrome by High Throughput Sequencing

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common complex endocrine disorder, whose etiology remains to be elucidated. PCOS has a strong heritable component. Genome-wide association studies have identified several risk loci for PCOS; however, the identified candidate genes could explain less than 5% of PCOS heritability. This missing heritability might be explained by the presence of rare genetic variants with larger biological impact. High throughput sequencing (HTS) could be an interesting tool to identify these rare variants. OBJECTIVE: To identify rare genetic variants through HTS in a selection of patients with PCOS clinical relevant phenotypes or familial PCOS clusters. METHODS: Among a cohort of 130 PCOS patients, we selected 32 women presenting one or more of the following phenotypes: 1. adrenal hyperandrogenism (DHEA and/or DHEAS levels 1.5 higher the upper limit of the normal range); 2. primary amenorrhea; 3. severe insulin resistance (IR) (basal insulin >50 mUi/mL and/or after OGTT >300 mUI/mL); 4. normal androgen levels (total and free testosterone, androstenedione, DHEA and DHEAS in the normal range measured by gold standard methods). This group was studied through targeted gene sequencing panels (Miseq Illumina) including 50 genes involved in ovarian folliculogenesis, steroid hormone synthesis, gonadotropin action and insulin-signaling pathway, and genes suggested by monogenic/dygenic PCOS causes. Additional 2 families, with two PCOS sisters and their unaffected mother, were studied by exome sequencing (Hiseq Illumina). Allelic variants were considered pathogenic/potential pathogenic if they had a MAF<0.01 (Gnom AD and ExAC databases), were classified deleterious/probably deleterious by several prediction sites (i.e. SIFT, PolyPhen 2, Mutation Taster) and affect amino acids that are highly conserved among homologues (GERP scores). RESULTS: Among the 34 PCOS index patients studied, the phenotype was distributed as following: 15 with severe IR, 10 with adrenal hyperandrogenism, 2 normoandrogenic, 3 with primary amenorrhea and 4 familial cases. Twelve variants were identified in 10 patients (29.4%), affecting 6 genes: INSR, LMNA, POMC, GATA4, FSHR, H6PD, DLK1 and SCN1A. All genes were found once, except LMNA that was found in 4 different PCOS patients with severe IR. The variants in INSR, POMC and FSHR genes were found in the severe IR group, and in GATA4 in the adrenal hyperandrogenism group. The DLK1 and SCN1A variants were found in the two families studied through exome. CONCLUSION: High throughput sequencing allowed the identification of monogenic forms of PCOS, especially in patients with severe insulin resistance. The identification of rare genetic variants in PCOS patients might increase our comprehension of the pathogenesis of this disease, with positive clinical implications in patient’s treatment and genetic counseling.