Polycystic Ovary Syndrome, Insulin Resistance, and Cardiovascular Disease.

PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. It has been associated with metabolic, reproductive, and psychiatric disorders. Despite its association with insulin resistance (IR) and cardiovascular disease (CVD) risk factors, the association between PCOS and CVD outcomes has been conflicting. This review reports the updated evidence between PCOS, insulin resistance, and CVD events. RECENT FINDINGS: IR is highly prevalent occurring in 50 to 95% of general and obese PCOS women. The etiology of PCOS involves IR and hyperandrogenism, which lead to CVD risk factors, subclinical CVD, and CVD outcomes. Multiple studies including meta-analysis confirmed a strong association between PCOS and CVD events including ischemic heart disease, stroke, atrial fibrillation, and diabetes, particularly among premenopausal women, and these associations were mediated by metabolic abnormalities. PCOS is highly familial and has substantial CVD risk and transgenerational effects regardless of obesity. A personalized approach to the CVD risk assessment and management of symptom manifestations should be conducted according to its phenotypes. Lifestyle modifications and reduction in environmental stressors should be encouraged for CVD prevention among PCOS women.

Polycystic ovarian syndrome: signs and feedback effects of hyperandrogenism and insulin resistance.

Polycystic ovary syndrome (PCOS) is a disease whose diagnosis is based on the detection of hyperandrogenism (HA) and ovulatory dysfunction. Women with PCOS frequently develop insulin resistance (IR), which generates a metabolic condition that involves a decrease in the action of insulin at the cellular level and is linked to compensatory hyperinsulinemia (HI). In PCOS, the ovary remains sensitive to the action of insulin. Additionally, it has been observed that the main effect of insulin in the ovary is the stimulation of androgen synthesis, resulting in HA, one of the fundamental characteristics of the PCOS. In this sense, the excess of androgens favors the development of IR, thus perpetuating the cycle of IR-HI-HA, and therefore PCOS. Moreover, mitochondrial dysfunction is present in PCOS patients and is a common feature in both IR and HA. This review places electron transfer as a key element in HA and IR development, with emphasis on the relationship between androgen biosynthesis and mitochondrial function. Indeed, metformin has been involved in repair mitochondrial dysfunction, decrease of oxidative stress, reduction of androgens levels and the enhancing of insulin sensitivity. Therefore, we propose that treatment with metformin could decrease HI and consequently HA, restoring, at least in part, the metabolic and hormonal disorders of PCOS.

Steroid hormone analysis of adolescents and young women with polycystic ovarian syndrome and adrenocortical dysfunction using UPC2-MS/MS.

BACKGROUND: We recently identified 35 women with polycystic ovarian syndrome (PCOS) who exhibited features of micronodular adrenocortical hyperplasia. Steroid hormone analysis can be more accurate using state-of-the-art ultra-performance convergence chromatography-tandem mass spectrometry (UPC2-MS/MS). We hypothesized that UPC2-MS/MS may be used to better define hormonally this distinct subgroup of patients with PCOS. METHODS: Plasma from PCOS patients (n = 35) and healthy volunteers (HVs, n = 19) who all received dexamethasone testing was analyzed. Samples were grouped per dexamethasone responses and followed by UPC2-MS/MS analysis. When insufficient, samples were pooled from patients with similar responses to allow quantification over the low end of the assay. RESULTS: The C11-oxy C19 (11ß-hydroxyandrostenedione, 11keto-androstenedione, 11ß-hydroxytestosterone, 11keto-testosterone):C19 (androstenedione, testosterone) steroid ratio was decreased by 1.75-fold in PCOS patients compared to HVs. Downstream steroid metabolites 11ß-hydroxyandrosterone and 11keto-androsterone were also measurable. The C11-oxy C21 steroids, 11-hydroxyprogesterone and 11keto-dihydroprogesterone levels, were 1.2- and 1.7-fold higher in PCOS patients compared to HVs, respectively. CONCLUSIONS: We hypothesized that UPC2-MS/MS may accurately quantify steroids, in vivo, and identify novel metabolites in a subgroup of patients with PCOS and adrenal abnormalities. Indeed, it appears that adrenal C11-oxy steroids have the potential of being used diagnostically to identify younger women and adolescents with PCOS who also have some evidence of micronodular adrenocortical hyperplasia. IMPACT: Adrenal C11-oxy steroids may be clinically important in identifying young patients with PCOS and adrenal abnormalities. The steroids presented in our manuscript have not yet been considered in the clinical setting so far, and we believe that this study could represent a first focused step towards the characterization of a distinct subgroup of women with PCOS who may in fact be treated differently than the average patient with PCOS. This paper can change the understanding of PCOS as one disorder: it is in fact a heterogeneous condition. In addition, for the subgroup of patients with PCOS associated with adrenocortical dysfunction, our paper provides novel hormonal markers that can be used diagnostically. Finally, the paper also adds to the basic pathophysiological understanding of adrenocortical-ovarian interactions in steroidogenesis of young women and adolescent girls with PCOS.

Cardio-metabolic risk factors among young infertile women: a systematic review and meta-analysis.

BACKGROUND: There is currently no concise systematic review or meta-analysis addressing cardio-metabolic risk factors in women experiencing infertility. OBJECTIVES: To determine whether infertile women have higher levels of cardiovascular risk factors compared with fertile women. SEARCH STRATEGY: We performed a systematic literature search using PubMed, Embase and CINAHL, Scopus and additional manual and bibliographic searches for relevant articles (end search date 6 November 2019). SELECTION CRITERIA: We selected studies that compared cardio-metabolic risk factors in fertile and infertile women of reproductive age. DATA COLLECTION AND ANALYSIS: At least two authors independently screened potentially eligible studies. MAIN RESULTS: There was an increased presence of several cardio-metabolic risk factors in infertile women compared with fertile women. Infertile women had statistically significant higher body mass index (BMI), increased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) compared with fertile women. Fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and mean arterial pressure were not found to be different between fertile and infertile women. A subgroup analysis revealed that TC, fasting glucose and fasting insulin were increased, and high-density lipoprotein was decreased only in women with polycystic ovarian syndrome compared with fertile women, whereas BMI, TG and LDL-C were statistically significantly increased in women with any indication of infertility compared with fertile women. CONCLUSIONS: Infertile women have a higher level of cardio-metabolic risk factors compared with fertile women. This finding has clinical implications for infertile women in general, and those attempting to conceive through medically assisted reproduction. TWEETABLE ABSTRACT: Infertile women appear to have a higher level of cardio-metabolic risk factors compared with fertile women.

PCOS without hyperandrogenism is associated with higher plasma Trimethylamine N-oxide levels.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder, and its pathogenesis is still under debate. Trimethylamine-N-oxide (TMAO) is a small, organic compound generated by the gut microbiome with a hypothesized relation to insulin resistance (IR) and low-grade inflammation in PCOS. By comparing plasma TMAO levels in non-PCOS participants and PCOS patients without hyperandrogenism (HA), we aimed to determine whether plasma TMAO levels correlate with PCOS without HA and to analyze their relationship with low-grade inflammation and IR. METHODS: A total of 27 PCOS patients without HA and 23 non-PCOS participants were enrolled in this study and subdivided into "nonobese" and "obese" arms for each group. Levels of plasma TMAO were quantified, and basic clinical characteristics and plasma biomarkers of inflammation were assessed. RESULTS: First, plasma TMAO levels, insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) values were higher in PCOS patients without HA, especially in the obese subgroup. Second, the levels of the inflammatory factors interleukin (IL)-17A, IL-18 and interferon gamma (IFN-γ) were significantly increased in obese PCOS patients without HA. Third, plasma TMAO levels were associated with body mass index (BMI) in the normal-weight groups, and the obese groups had higher fasting plasma insulin (FINS) and HOMA-IR values. Finally, logistic regression showed that the plasma levels of TMAO and luteinizing hormone/follicle-stimulating hormone (LH/FSH) were independent predictors of PCOS and indicated an increased risk of PCOS. CONCLUSIONS: Elevated plasma TMAO levels may be associated with the pathogenesis of PCOS without HA and correlated with increased systemic inflammation. Further studies are needed to determine the suitability of TMAO as a predictive biomarker and to identify possible therapies for PCOS.

Comparing pregnancy, childbirth, and neonatal outcomes in women with different phenotypes of polycystic ovary syndrome and healthy women: a prospective cohort study.

The aim of this study was to compare pregnancy, childbirth, and neonatal outcomes in women with different phenotypes of polycystic ovary syndrome (PCOS) with healthy women. A prospective cohort study from the beginning to the end of pregnancy for 41 pregnant women with PCOS (case) and 49 healthy pregnant women (control) was completed. Based on the presence or absence of menstrual dysfunction (M), hyperandrogenism (HA), and polycystic ovaries (PCO) on ultrasound, the PCOS (case) group were divided into three phenotypes (HA + PCO (n = 22), M + PCO (n = 9), HA + M+PCO (n = 10). Pre-eclampsia, gestational diabetes, and lower birth weight among newborns were significantly higher in the PCOS case group compared to the control group especially in the phenotype HA + M+PCO (p < .05). High BMI (ß = 2.40; p=.03) was the strongest predictor of pre-eclampsia in patients with PCOS. High androgen levels (free androgen index) (ß = 13.71, 3.02; p < .05), was the strongest predictor of developing diabetes during pregnancy and reduced birth weight baby, respectively.These results suggest that PCOS, particularly in phenotype HA + M+PCO (p < .05), is a risk factor for adverse pregnancy and neonatal outcomes including gestational diabetes, pre-eclampsia, and reduced weight babies.

Insulin resistance is associated with hirsutism in unselected reproductive-aged women.

OBJECTIVE: Hirsutism affects 5%-10% of reproductive-aged women worldwide and exhibits clinical importance as a cutaneous manifestation of underlying hyperandrogenism. Racial and genetic factors play roles in manifestation of hirsutism, and the prevalence of hirsutism seems to be low in East Asians. However, the reference value of the modified Ferriman-Gallwey (mFG) score to diagnose hirsutism and the prevalence of hirsutism have not been determined in Korean populations to date. We aimed to investigate the distribution of the mFG score and establish its reference value for defining hirsutism and to examine its relationship with metabolic and reproductive traits in reproductive-aged Korean women. DESIGN, PATIENTS AND MEASUREMENTS: We enrolled 2139 female volunteers of reproductive age (15-39 years). We recorded mFG scores from 0 to 4 on 9 different body locations (upper lip, chin, chest, arm, upper abdomen, lower abdomen, upper back, lower back and thighs). Hirsutism was defined as >95th percentile of mFG score. In addition, a 75-g oral glucose tolerance test was performed, and the homoeostasis model assessment of insulin resistance (HOMA-IR) was calculated. RESULTS: The mFG values of the 50th, 75th, 90th and 95th percentiles were 0, 1, 4 and 6, respectively. Therefore, the mFG score was indicative of hirsutism when the score was 6 or greater, which represents the 95th percentile. In the correlation analysis, total testosterone, free testosterone, fasting plasma insulin and HOMA-IR were positively correlated with mFG score (all Ps <0.05). Multiple linear regression analysis revealed that HOMA-IR (ß = 0.081) was positively associated with mFG score after adjustments for age, body mass index, total testosterone and the number of menses per year (P < 0.001). CONCLUSIONS: In conclusion, setting the 95th percentile of the mFG score as normal, the reference value to define hirsutism was 6 in reproductive-aged Korean women. HOMA-IR was positively associated with the mFG score even after adjustment for biochemical hyperandrogenism.

Geometric, elastic and contractile-relaxation changes in coronary arterioles induced by Vitamin D deficiency in normal and hyperandrogenic female rats.

Vitamin D (VitD) hypovitaminosis and androgen excess (AE) are both risk factors for cardiovascular diseases in fertile women. However, the possible early interaction between AE and VitD status is not clear. Our goal was to describe how VitD status influences early changes in the biomechanical reactivity of small coronary arterioles in adult female rats after transdermal testosterone treatment. Forty-six adolescent, 90-110-gram-weighed female Wistar rats were randomly grouped into 4 groups. Twenty-four animals received an optimal VitD-supplemented diet, from which 12 animals underwent transdermal testosterone treatment. Twenty-two animals received a VitD-deficient diet, from which 11 were treated with testosterone. At 8 weeks of treatment, invasive arterial blood pressure was registered after in vivo cannulation of carotid artery. Arteriolar end and side branches (200 µm diameter) of the left anterior descendent coronary artery (LAD) were obtained and examined with pressure arteriography in vitro. Similar segments were removed for histological examination. The inner and outer radii of the arterioles were measured using video-microscopy. Normal myogenic tone, maximal passive vasorelaxation and vasoconstriction of the arterioles were measured and statistically analyzed. The vessels' maximal smooth muscle relaxant potential, thromboxane-induced contraction capacity and normal myogenic tone were significantly influenced by actual VitD status. A lower relaxation capacity and increased wall thickness were observed in VitD-deficient groups, which could cause rigidity of the coronary arterioles and elevate cardiovascular risk. Supplementation of VitD could improve myogenic tone and relaxation and hold cardiovascular benefits.

Relationship of Biological Markers of Body Fat Distribution and Corticosteroidogenic Enzyme Activities in Women with Polycystic Ovary Syndrome.

The aim of the study is to determine the impact of different anthropometric measurements of fat distribution on baseline sex-steroid concentrations and corticosteroidogenic enzyme activity in women with polycystic ovary syndrome compared to those with regular menstrual cycles. The current cross-sectional study included 106 normal cycling controls and 268 polycystic ovary syndrome patients. Patients with polycystic ovary syndrome, diagnosed by Rotterdam criteria, were divided in normoandrogenemic (n=91) and hyperandrogenemic (n=177). Anthropometric, biochemical, and hormone parameters were assessed and correlated with corticosteroidogenic enzyme activities in all three groups. Corticosteroidogenic enzyme activities were calculated using product-to-precursor ratios. Regarding sex-steroids individually, anthropometric parameters correlated with the concentrations of several androgens in polycystic ovary syndrome patients, most of them in patients with biochemical hyperandrogenism. The androgen precursors androstenedione, 17-hydroxyprogesterone, and dehydroepiandrosterone were less correlated with anthropometric parameters. The 17,20 lyase activity, in both Δ4 and Δ5 pathways, correlated with several anthropometric measurements in normo- and hyperandrogenemic polycystic ovary syndrome patients. The 17,20 lyase enzyme activity (Δ4 pathway) also correlated with conicity index, visceral adiposity index, and lipid accumulation product in the control group. 17-Hydroxylase activity positively correlated with waist-height ratio in both polycystic ovary syndrome groups. In contrast, 17-hydroxilase negatively correlated with the conicity index. Anthropometric markers of adiposity are associated with androgen levels and their precursors in blood. Body fat distribution correlates with the activities of some steroidogenic enzyme in both normo-and hyperandrogenemic polycystic ovary syndrome phenotypes. The molecular mechanisms involved in these associations are largely unclear and more investigations are required.

Relationships Between Biochemical Markers of Hyperandrogenism and Metabolic Parameters in Women with Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

While several studies have documented an increased risk of metabolic disorders in patients with polycystic ovary syndrome (PCOS), associations between androgenic and metabolic parameters in these patients are unclear. We aimed to investigate the relationships between biochemical markers of hyperandrogenism (HA) and metabolic parameters in women with PCOS. In this systematic review and meta-analysis, a literature search was performed in the PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science from 2000 to 2018 for assessing androgenic and metabolic parameters in PCOS patients. To assess the relationships between androgenic and metabolic parameters, meta-regression analysis was used. A total number of 33 studies involving 9905 patients with PCOS were included in this analysis. The associations of total testosterone (tT) with metabolic parameters were not significant; after adjustment for age and BMI, we detected associations of this androgen with low-density lipoproteins cholesterol (LDL-C) (ß=0.006; 95% CI: 0.002, 0.01), high-density lipoproteins cholesterol (HDL-C) (ß=-0.009; 95% CI: -0.02, -0.001), and systolic blood pressure (SBP) (ß=-0.01; 95% CI: -0.03, -0.00). We observed a positive significant association between free testosterone (fT) and fasting insulin (ß=0.49; 95% CI: 0.05, 0.91); this association remained significant after adjustment for confounders. We also detected a reverse association between fT and HDL-C (ß=-0.41; 95% CI: -0.70, -0.12). There was a positive significant association between A4 and TG (ß=0.02; 95% CI: 0.00, 0.04) after adjustment for PCOS diagnosis criteria. We also found significant negative associations between A4, TC, and LDL-C. Dehydroepiandrosterone sulfate (DHEAS) had a positive association with LDL-C (ß=0.02; 95% CI: 0.001, 0.03) and a reverse significant association with HDL-C (ß=-0.03; 95% CI: -0.06, -0.001). This meta-analysis confirmed the associations of some androgenic and metabolic parameters, indicating that measurement of these parameters may be useful for predicting metabolic risk in PCOS patients.

When does an advantage become unfair? Empirical and normative concerns in Semenya's case.

There is a fundamental tension in many sports: human sex is not binary, but there are only two categories in which people can compete: male and female. Over the past 10 years, the International Association of Athletics Federations (IAAF) regulations have been at the centre of two notable legal disputes. The Court of Arbitration for Sport (CAS) reached two contradictory rulings: in the first case (Dutee Chand vs Athletics Federation India and IAAF), the IAAF regulations for the eligibility of athletes to compete in the female category were suspended (24 July 2015) on grounds of "discrimination against the female category"; in the latter (Caster Semenya and Athletics South Africa vs IAAF), the regulations were reaffirmed (1 May 2019) on grounds that although discriminatory, they are necessary to maintain a "level playing field" and to "protect" the female category. Although Semenya's case has paved the way for questioning existing gender norms in sport, a new stable norm has yet to emerge from her case. The pharmacological solution put forward by IAAF to the tension between fairness and inclusivity of bodies non-conforming to two sexes is not, however, the only possible solution/resolution to the case, as I aim to show in this paper. Here I present some reflections on this topic and suggest how CAS should approach the case if it hopes to resolve it.

Close correlation between hyperandrogenism and insulin resistance in women with polycystic ovary syndrome-Based on liquid chromatography with tandem mass spectrometry measurements.

BACKGROUND: To investigate the correlation between hyperandrogenism (HA) and insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) by measuring serum total testosterone (TT) using a liquid chromatography and tandem mass spectrometry assay (LC-MS/MS). METHODS: This cohort study included 332 patients with PCOS, 63 patients with IR and 276 with controls. TT levels were measured by LC-MS/MS and chemiluminescent immunoassay (CLIA); glucose and insulin levels were determined by an oral glucose tolerance test (OGTT). RESULTS: Compared with CLIA, LC-MS/MS differentiated more cases with high TT levels among the non-PCOS subjects with IR In patients with PCOS, LC-MS/MS-based TT levels or a combination with the mFG score detected a significantly higher incidence of HA in subjects with IR identified by hyperinsulinemia (HIN), HOMA-IR or impaired fasting glucose (IFG) than in those without IR Conversely, the IR rates demonstrated by HIN, HOMA-IR, or IFG were remarkably higher in the LC-MS/MS-defined high TT subgroup than in the normal TT subgroup. However, the CLIA platform could not discern a difference in HA incidence between IR and non-IR subgroups or in IR rate between high and normal TT populations. ROC curves also proved that HIN, HOMA-IR, and IFG were positive contributors to HA as measured by LC-MS/MS CONCLUSIONS: The correlation between HA and IR has always been underestimated, partly owing to the less accurate methods previously used to measure TT. HIN, HOMA-IR, and IFG are likely to contribute to the development of HA from a clinical perspective.

The diagnosis of androgenetic alopecia in children: Considerations of pathophysiological plausibility.

Androgenetic alopecia (AGA), one of the most common causes of hair loss in men and women, is an infrequent cause of alopecia in children. In AGA, patients generally start noticing hair thinning after the onset of puberty due to progressive miniaturisation of the hair follicle which leads to vellus transformation of terminal hair. However, the occurrence of prepubertal AGA has rarely been reported in the literature. The pathophysiology of AGA is tightly linked to androgen hormones; prepubertal children do not usually produce significant amounts of adrenal or gonadal androgens. When it does occur, an underlying abnormality should be suspected. Secondary causes of AGA must be excluded when evaluating a patient before the appearance of puberty. Premature puberty, polycystic ovarian syndrome and other causes of hyperandrogenism can present with hair loss in an androgenetic pattern. This article reviews the normal physiology of androgen hormones and their role in the pathophysiology of childhood AGA.

Influence of androgen levels on conception probability in patients undergoing fertility treatment: a retrospective cohort study.

PURPOSE: Primary and secondary sterility have become an issue of increasing importance due to demographic and social changes in society. Data regarding the association between female androgen levels and the probability of successful conception after fertility treatment are sparse and contradictive. This study was designed to assess this clinical question. METHODS: In this retrospective single-center cohort study concentrations of androgens androstenedione, dehydroepiandrosteronsulfat (DHEAS) and testosterone (ng/ml) were investigated in the serum of patients presenting for sterility at the department of reproductive medicine of Saarland University hospital Homburg between January 2015 and December 2017. Androgen levels were correlated with reproductive outcomes. Statistical analysis was performed with the aid of SPSS version 24. Significance for conception rates in dependence of androgen concentration was assessed using Kruskal-Wallis test (significance was estimated with p < 0.05). RESULTS: The laboratory values of a total of 301 patients were examined (64% primary, 36% secondary sterility). Median age at first visit at the fertility department was 32.7 years (range 20-47 years). 64 pregnancies were observed during the study period (conception rate 21.3%). 23 out of 301 patients (7.6%) suffered from hypoandrogenaemia, 248 (82.4%) had normal androgen levels and 30 (10%) showed hyperandrogenaemia (p = 0.25). Regarding patients in whom fertility treatment was successful 3 (4.7%) showed hypoandrogenaemia, 54 (84.4%) were normoandrogenaemic and 7 (10.9%) had hyperandrogenaemia (p = 0.40 Kruskal-Wallis test). CONCLUSIONS: We found no association between female androgen levels and sterility and reproductive outcomes.

La esteroidogénesis en el síndrome de ovarios poliquísticos.

Polycystic ovary syndrome is the most common endocrine disease in reproductive age, characterized by menstrual alterations, clinical or biochemical hyperandrogenism, and ultrasound-identified ovarian cysts. The neuroendocrine and metabolic alterations that accompany this condition involve the desensitization of the hypothalamus-pituitary-ovary axis, steroidogenesis and hyperandrogenism; recently, the role of insulin resistance has been explored. Hyperandrogenism has been established to be the main cause of polycystic ovary syndrome, due to enzymatic alterations in the steroidogenic pathway that cause luteinizing hormone over-stimulation because of quick pulses generated by gonadotropin-releasing hormones. Various growth factors of and cytokines inhibit the conversion of androgens into estrogens; activin and prostaglandins are also involved, even high levels of insulin participate in the characteristic deregulation of this syndrome.

El síndrome de ovarios poliquísticos es la enfermedad endocrina más frecuente en la edad reproductiva; se caracteriza por alteraciones menstruales, hiperandrogenismo clínico o bioquímico e identificación ultrasonográfica de quistes ováricos. Las alteraciones neuroendocrinas y metabólicas que lo acompañan implican desensibilización del eje hipotálamo-hipófisis-ovario, esteroidogénesis e hiperandrogenismo. Recientemente se ha explorado el papel de la resistencia a la insulina. Se ha establecido que la principal causa del síndrome de ovarios poliquísticos es el hiperandrogenismo, debido a alteraciones enzimáticas en la vía esteroidogénica, por lo que existe sobreestimulación por parte de la hormona luteinizante a causa de los pulsos rápidos generados por la hormona liberadora de gonadotropinas. Diversos factores de crecimiento y citocinas inhiben la conversión de andrógenos a estrógenos. En la desregulación característica de este síndrome también están involucradas la activina y las prostaglandinas e, incluso, altos niveles de insulina.

Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic inflammation in PCOS.

OBJECTIVE: Insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic low-grade inflammation may act together in a vicious cycle in the pathophysiology of PCOS. However, the inter-relationships of these components are not fully understood. We aimed to study these mechanisms in the pathophysiology of PCOS. PARTICIPANTS AND METHODS: Premenopausal women with PCOS (Rotterdam diagnostic criteria) and without PCOS were recruited from a community setting into a cross-sectional substudy within a randomized control trial. Insulin resistance (fasting insulin and glucose), hyperandrogenism (testosterone, sex hormone-binding globulin [SHBG] and Free Androgen Index [FAI]), muscle sympathetic nerve activity (MSNA) and markers of chronic low-grade inflammation (high sensitivity C-reactive protein [hs-CRP] and high molecular weight adiponectin [HMW-adiponectin]) were measured. RESULTS: Forty-nine women with PCOS (mean age 30 ± 6 mean BMI 29 ± 5) and 23 controls (mean age 29 ± 8 mean BMI 33 ± 7) with included in this analysis. MSNA and testosterone level were most significantly associated with PCOS status, after adjustment for age and BMI. In women with PCOS, markers of sympathetic activity correlated inversely with HMW-adiponectin and HMW-adiponectin correlated inversely with FAI. Testosterone and FAI both correlated positively with insulin resistance in women PCOS. CONCLUSION: Sympathetic dysfunction and hyperandrogenism are significantly associated with PCOS. Chronic low-grade inflammation potentially mediates the effect of sympathetic dysfunction on hyperandrogenism and insulin resistance.

Chronic hyperandrogenemia and western-style diet beginning at puberty reduces fertility and increases metabolic dysfunction during pregnancy in young adult, female macaques.

STUDY QUESTION: What are the impacts of elevated testosterone (T) and an obesogenic western-style diet (WSD), either independently or together, on fertility and metabolic adaptations of pregnancy in primates? SUMMARY ANSWER: Testosterone increases the time to achieve pregnancy, while a WSD reduces overall fertility, and the combination of testosterone and WSD additionally impairs glucose tolerance and causes pregnancy loss. WHAT IS KNOWN ALREADY: Both hyperandrogenemia and obesity are hallmarks of polycystic ovary syndrome, which is a leading cause of infertility among women worldwide. Female macaques receiving T and WSD beginning at puberty show increased metabolic, ovarian and uterine dysfunction in the non-pregnant state by 3 years of treatment. STUDY DESIGN, SIZE, DURATION: The same cohort of female rhesus macaques continued treatments from the time of puberty (2.5 years) to 4 years, including this fertility trial. There were four groups (n = 9-10/group): controls (C), T-treated (T; average total serum level 1.35 ng/ml), WSD-treated, and combined T and WSD-treated (T + WSD) females. PARTICIPANTS/MATERIALS, SETTING, METHODS: Females, which were typically having menstrual cycles, were paired for 4 days with a proven male breeder following the late follicular rise in circulating estradiol (≥100 pg/ml). The presence of sperm in the reproductive tract was used to confirm mating. Animals went through up to three successive rounds of mating until they became pregnant, as confirmed by a rise in circulating mCG during the late luteal phase and ultrasound evidence of a gestational sac at Day 30 post-mating (GD30). Placental vascular parameters were also measured at GD30. Metabolic measurements consisted of fasting levels of blood glucose and insulin at approximately GD30, 60, 90 and 115, as well as an intravenous (iv) glucose tolerance test (GTT) at GD115. MAIN RESULTS AND THE ROLE OF CHANCE: While all animals in the C and T groups eventually became pregnant, T-treated females on average had a greater interval to achieve pregnancy (P < 0.05). However, only ~70% of animals in the WSD and T + WSD groups became pregnant (P < 0.004). One pregnancy in T + WSD group resulted in an anembryonic pregnancy which miscarried around GD60, while another T + WSD female conceived with a rare identical twin pregnancy which required cessation due to impending fetal loss at GD106. Thus, the number of viable fetuses was less in the T + WSD group, compared to C, T or WSD. Placental blood volume at GD30 was reduced in all treatments compared to the C group (P < 0.05). Maternal P4 levels were elevated in the WSD (P < 0.03) group and E2 levels were elevated in T + WSD animals (P < 0.05). An increase in serum A4 levels throughout gestation was observed in all groups (P < 0.03) except WSD (P = 0.3). All groups displayed increased insulin resistance with pregnancy, as measured from the ivGTT during pregnancy. However, only the T + WSD group had a significant increase in fasting glucose levels and glucose clearance during the GTT indicating a worsened glucose tolerance. WSD treatment decreased female fetuses third trimester weights, but there was an interaction between WSD and T to increase female fetal weight when normalized to maternal weight. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The small number of pregnancies in the WSD and T + WSD groups hampers the ability to make definitive conclusions on effects during gestation. Also, the high fertility rate in the controls indicates the cohort was at their breeding prime age, which may impair the ability to observe subtle fertility defects. The low number of fetuses used for male and female analysis requires additional studies. WIDER IMPLICATIONS OF THE FINDINGS: The current findings strongly suggest that both hyperandrogenemia and obesity have detrimental effects on fertility and gestation in primates, which may be directly relevant to women with polycystic ovary syndrome. STUDY FUNDING/COMPETING INTEREST(S): All ONPRC Cores and Units were supported by NIH Grant P51 OD011092 awarded to ONPRC. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) under Award Number P50HD071836 (to R.L.S.). The authors have no competing conflict of interests to disclose.

Chronic hyperandrogenemia in the presence and absence of a western-style diet impairs ovarian and uterine structure/function in young adult rhesus monkeys.

STUDY QUESTION: Does chronic hyperandrogenemia beginning at menarche, in the absence and presence of a western-style diet (WSD), alter ovarian and uterine structure-function in young adult rhesus monkeys? SUMMARY ANSWER: Phenotypic alterations in ovarian and uterine structure/function were induced by exogenous testosterone (T), and compounded in the presence of a WSD (T+WSD). WHAT IS KNOWN ALREADY: Hyperandrogenemia is a well-established component of PCOS and is observed in adolescent girls, indicating a potential pubertal onset of disease symptoms. Obesity is often associated with hyperandrogenemia and it is hypothesized that metabolic dysfunction exacerbates PCOS symptoms. STUDY DESIGN, SIZE, DURATION: Macaque females (n = 40) near the onset of menarche (~2.5 years of age) were assigned to a 2 by 2 factorial cohort design. Effects on reproductive characteristics were evaluated after 3 years of treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Rhesus macaques (Macaca mulatta) were fed either a normal balanced diet (n = 20) or a WSD (n = 20). Additionally, implants containing cholesterol (n = 20) or T (n = 20) were implanted subcutaneously to elevate serum T approximately 5-fold. This resulted in treatment groups of controls (C), T, WSD and T+WSD (n = 10/group). Vaginal swabbing was performed daily to detect menses. After 3 years of treatment, daily serum samples from one menstrual cycle were assayed for hormone levels. Ovarian structure was evaluated in the early follicular phase by 3D/4D ultrasound. Uterine endometrial size and ovarian/luteal vascular function was also evaluated in subgroups (n = 6/group) in the late follicular and mid-luteal phases by 3D/4D ultrasound and contrast-enhanced ultrasound, respectively. Expression of steroid hormone receptors and markers of decidualization and endometrial receptivity were assessed in endometrial biopsies at mid-luteal phase. MAIN RESULTS AND THE ROLE OF CHANCE: Approximately 90% of menstrual cycles appeared ovulatory with no differences in frequency or duration between groups. Serum estradiol (E2) levels during the early follicular phase were greatest in the T alone group, but reduced in T+WSD (P < 0.02). Serum LH was elevated in the T group (P < 0.04); however, there were no differences among groups in FSH levels (P > 0.13). Ovarian size at menses tended to be greater in the WSD groups (P < 0.07) and antral follicles ≥1 mm were more numerous in the T+WSD group (P < 0.05). Also, females in T and T+WSD groups displayed polycystic ovarian morphology (PCOM) at greater frequency than C or WSD groups (P < 0.01). Progesterone (P4) levels during the luteal phase were reduced in the T+WSD group compared to C and T groups (P < 0.05). Blood volume (BV) and vascular flow (VF) within the corpus luteum was reduced in all treatment groups compared to C (P < 0.01, P = 0.03), with the WSD alone group displaying the slowest BV and VF (P < 0.05). C and WSD groups displayed endometrial glands at mid-luteal phase with low estrogen receptor 1 (ESR1) and progesterone receptor (PGR) mRNA and immunohistochemical staining in the functionalis zone, but appreciable PGR in the stroma. In contrast, T and T+WSD treatment resulted in glands with less secretory morphology, high ESR1 expression in the glandular epithelium and low PGR in the stroma. Endometrial levels of TIMP3 and MMP26 mRNA and immunostaining were also decreased in the T and T+WSD groups, whereas AR expression was unchanged. LARGE SCALE DATA: None. LIMITATIONS, REASONS FOR CAUTION: Females are young adults, so effects could change as they reach prime reproductive age. The T level generated for hyperandrogenemia may be somewhat greater than the 3-4-fold increase observed in adolescent girls, but markedly less than those observed in male monkeys or adolescent boys. WIDER IMPLICATIONS OF THE FINDINGS: Alterations to ovarian and uterine structure-function observed in T and, in particular, T+WSD-treated female macaques are consistent with some of the features observed in women diagnosed with polycystic ovary syndrome (PCOS), and suggest impaired fertility. STUDY FUNDING/COMPETING INTEREST(S): Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) under Award Number P50HD071836 (to RLS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional funding was provided by Office of the Director, NIH under Award Number P51OD011092 (Support for National Primate Research Center). Authors declare no competing interests.

Sport, doping and female fertility.

This article is a review that addresses the following topics, divided by paragraphs. The first paragraph investigates the effects of physical activity on ovarian function, analyzing in particular the changes concerning the serum concentrations of follicle-stimulating hormone, luteinizing hormone, prolactin, growth hormone, thyroid hormones, leptin, ghrelin, neuropeptide Y. The second paragraph analyzes the effects of doping on the hypothalamic-pituitary-ovarian axis. Finally, the last paragraph analyzes the PCOS category, evaluating the effects of hyperandrogenism in relation to athletic performance.

Body mass index and basal androstenedione are independent risk factors for miscarriage in polycystic ovary syndrome.

BACKGROUND: There is limited literature investigating the effects of body mass index (BMI) and androgen level on in vitro fertilization (IVF) outcomes with a gonadotropin-releasing hormone (GnRH)-antagonist protocol in polycystic ovary syndrome (PCOS). Androgen-related variation in the effect of body mass index (BMI) on IVF outcomes remains unknown. METHODS: In this retrospective study, 583 infertile women with PCOS who underwent IVF using the conventional GnRH-antagonist protocol were included. Patients were divided into four groups according to BMI and androgen level: overweight- hyperandrogenism(HA) group, n = 96, overweight-non-HA group, n = 117, non-overweight-HA group, n = 152, and non-overweight-non-HA group, n = 218. RESULTS: A significantly higher number of oocytes were retrieved, and the total Gn consumption as well Gn consumption per day was significantly lower, in the non-overweight groups than in the overweight groups. The number of available embryos was significantly higher in the HA groups than in the non-HA groups. Clinical pregnancy rate was of no significant difference among four groups. Live-birth rates in the overweight groups were significantly lower than those in non-overweight-non-HA group (23.9, 28.4% vs. 42.5%, P<0.05). The miscarriage rate in overweight-HA group was significantly higher than that in non-overweight-non-HA group (45.2% vs. 14.5%, P<0.05). Multivariate logistic regression analysis revealed that BMI and basal androstenedione (AND) both acted as significantly influent factors on miscarriage rate. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis for BMI and basal AND on miscarriage rate were 0.607 (P = 0.029) and 0.657 (P = 0.001), respectively, and the cut-off values of BMI and basal AND were 25.335 kg/m2 and 10.95 nmol/L, respectively. CONCLUSIONS: In IVF cycles with GnRH-antagonist protocol, economic benefits were seen in non-overweight patients with PCOS, with less Gn cost and more retrieved oocytes. BMI and basal AND were both significantly influential factors with moderate predictive ability on the miscarriage rate. The predictive value of basal AND on miscarriage was slightly stronger than BMI.