Prenatal hyperandrogenism induces alterations that affect liver lipid metabolism

Prenatal hyperandrogenism is hypothesized as one of the main factors contributing to26 the development of polycystic ovary syndrome (PCOS). PCOS patients have high risk27 of developing fatty liver and steatosis. This study aimed to evaluate the role of prenatal28 hyperandrogenism in liver lipid metabolism and fatty liver development. Pregnant rats29 were hyperandrogenized with testosterone. At pubertal age, the prenatally30 hyperandrogenized (PH) female offspring displayed both ovulatory (PHov) and31 anovulatory (PHanov) phenotypes that mimic human PCOS features. We evaluated32 hepatic transferases, liver lipid content, the balance between lipogenesis and fatty acid33 oxidation pathway, oxidant/antioxidant balance and pro-inflammatory status. We also34 evaluated the general metabolic status through growth rate curve, basal glucose and35 insulin levels, glucose tolerance test, HOMA-IR index and serum lipid profile.36 Although neither PH group showed signs of liver lipid content, the lipogenesis and fatty37 oxidation pathways were altered. The PH groups also showed impaired38 oxidant/antioxidant balance, a decrease in the pro-inflammatory pathway (measured by39 prostaglandin E2 and cyclooxygenase-2 levels), decreased glucose tolerance, imbalance40 of circulating lipids and increased risk of metabolic syndrome. We conclude that41 prenatal hyperandrogenism generates both PHov and PHanov phenotypes with signs of42 liver alterations, imbalance in lipid metabolism and increased risk of developing43 metabolic syndrome. The anovulatory phenotype showed more alterations in liver44 lipogenesis and a more impaired balance of insulin and glucose metabolism, being more45 susceptible to the development of steatosis.Fil: Abruzzese, Giselle Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Heber, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Ferreira, Silvana Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Velez, Leandro Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Reynoso, Roxana María. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Endocrinología; ArgentinaFil: Pignataro, Omar Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Motta, Alicia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Salivary testosterone measurement in women with and without polycystic ovary syndrome

Clinical and/or biochemical hyperandrogenism is one of the diagnostic criteria for PCOS. An evaluation of the role of salivary testosterone (salT) and androstenedione (salA) for the diagnosis of PCOS was undertaken in a cross sectional study involving 65 women without PCOS and 110 women with PCOS fulfilling all 3 diagnostic Rotterdam criteria. Serum and salivary androgen measurements were determined by LC-MS/MS. salT and salA were significantly elevated in PCOS compared to controls (P<001). No androgen marker was more predictive than another using ROC curves, but multiple logistic regression suggested salT was more predictive than free androgen index (FAI)(p<0.01). The combination of salT or FAI identified 100% of PCOS women. PCOS women with both biochemical and clinical hyperandrogenism as opposed to clinical hyperandrogenism alone showed a metabolic phenotype (p<0.05) and insulin resistance(p<0.001). PCOS patients with an isolated elevated FAI showed increased insulin resistance compared to those with an isolated salT(P<0.05). salT appeared to be at least as predictive as FAI for the diagnosis of the classical PCOS phenotype, and the combination of salT or FAI identified 100% of PCOS patients. This suggests that salT measurement by LC-MS/MS holds the promise of complementing existing laboratory tests as a means of assessing hyperandrogenemia

Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome

Context/Objective: Current diagnostic criteria for polycystic ovary syndrome (PCOS) have generated distinct PCOS phenotypes, based on the different combinations of diagnostic features found in each patient. Our aim was to assess whether either each single diagnostic feature or their combinations into the PCOS phenotypes may predict insulin resistance in these women. Patients/Design: A total of 137 consecutive Caucasian women with PCOS, diagnosed by the Rotterdam criteria, underwent accurate assessment of diagnostic and metabolic features. Insulin sensitivity was measured by the glucose clamp technique. Results: Among women with PCOS, 84.7% had hyperandrogenism, 84.7% had chronic oligoanovulation, and 89% had polycystic ovaries. According to the individual combinations of these features, 69.4% of women had the classic phenotype, 15.3% had the ovulatory phenotype, and 15.3% had the normoandrogenic phenotype. Most subjects (71.4%) were insulin resistant. However, insulin resistance frequency differed among phenotypes, being 80.4%, 65.0%, and 38.1%, respectively, in the 3 subgroups (P < .001). Although none of the PCOS diagnostic features per se was associated with the impairment in insulin action, after adjustment for covariates, the classic phenotype and, to a lesser extent, the ovulatory phenotype were independently associated with insulin resistance, whereas the normoandrogenic phenotype was not. Metabolic syndrome frequency was also different among phenotypes (P = .030). Conclusions: There is a scale of metabolic risk among women with PCOS. Although no single diagnostic features of PCOS are independently associated with insulin resistance, their combinations, which define PCOS phenotypes, may allow physicians to establish which women should undergo metabolic screening. In metabolic terms, women belonging to the normoandrogenic phenotype behave as a separate group

Polycystic Ovary Syndrome: Pathogenesis, health consequences, and treatment of PCOS in relation to insulin resistance

The purpose of this paper is to present a review of the current research on polycystic ovary syndrome (PCOS). PCOS is one of the most common endocrine disorders in women of reproductive age, affecting 5-10% of the population. Despite its prevalence, PCOS remains largely under unknown. This review has been broken down into two separate chapters. The first is the pathogenesis and related health consequences of PCOS. This chapter focuses on the diagnosis of PCOS as well as the prevalence and incidence of the disease. It then delves into the pathogenesis with a focus on genetics, obesity, insulin resistance and birth weight. Lastly, the health consequences related to PCOS are discussed, with a focus on insulin resistance. The health outcomes reviewed include the metabolic syndrome, cardiovascular disease, and type II diabetes mellitus. The second chapter is a comparison of drug therapies and lifestyle modifications used to treat polycystic ovary syndrome. A short discussion on combination therapy is also included. By focusing on insulin resistance in treatment, it is possible to manage many of the symptoms of PCOS solely through lifestyle modifications. Although many questions remain surrounding polycystic ovary syndrome, this article provides a summary of the current research

Psychiatric characterization of children with genetic causes of hyperandrogenism

Objective: Very little is known about the mental health status in children with genetic causes of hyperandrogenism. This study sought to characterize psychiatric morbidity in this group. Design/methods: Children (8-18 years) with the diagnosis of classic congenital adrenal hyperplasia (CAH) or familial male precocious puberty (FMPP) underwent a semi-structured psychiatric interview, the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. According to sex and the literature, incidence of identified psychopathology was compared between the two endocrinological groups. We evaluated 72 patients: 54 CAH (21 females) and 18 FMPP. Results: Twenty-four (44.4%) CAH patients and 10 (55.6%) FMPP patients met the criteria for at least one lifetime psychiatric diagnosis. Attention-deficit hyperactivity disorder (ADHD) was present in 18.2% of CAH males, 44.4% of FMPP males, and one case (4.8%) in CAH females. A high rate of anxiety disorders was also found in all the three groups (17-21%). Relative to females with CAH, the FMPP patients exhibited higher rates of ADHD. Age at diagnosis and the treatment modalities were not associated with psychopathology. Rates of psychiatric disorder, specifically ADHD and anxiety disorders, were higher than in the general population. Conclusion: Although anxiety disorders may occur at an increased rate in children with chronic illness, androgens may contribute to higher risk for psychopathology in pediatric patients with genetic cause of excess androgen. Early diagnosis and treatment of childhood hyperandrogenism is essential for optimal development. The results suggest that assessment for psychiatric disorders should be part of the routine evaluation of these patients

Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo- or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty

The IAAF’s hyperandrogenism regulations suspended

On 27 July, the Court of Arbitration for Sport (‘CAS’) delivered a landmark ruling on the regulation of gender in sport. The decision explores how the categorisation of sport on the basis of sex can be best reconciled with the “biological reality” that human sex cannot necessarily be divided so clearly. Dr. Seema Patel, Senior Lecturer at Nottingham Trent University, Deputy Director of the Centre for Sports Law and author of ‘Inclusion and Exclusion in Competitive Sport: Socio-Legal and Regulatory Perspectives,’ reviews the case and suggests that sport regulation must be cautious of traditional criteria to determine eligibility in sports

Androsterone glucuronide to dehydroepiandrosterone sulphate ratio is discriminatory for obese Caucasian women with polycystic ovary syndrome

BACKGROUND: Androsterone glucuronide (ADTG) concentrations have been suggested as a marker of the effects of androgens at the target tissue level. As the mechanism for hyperandrogenemia in obese and nonobese polycystic ovary syndrome (PCOS) may differ, this study compared the different androgen parameters in non-obese compared to obese women with PCOS, and in normal subjects. METHODS: Eleven non-obese and 14 obese women with PCOS were recruited and compared to 11 control women without PCOS. Total testosterone, dehydroepiandrosterone sulphate (DHEAS), ADTG, and androstenedione were analysed using gold standard tandem mass spectrometry, and the free androgen index (FAI) was calculated. RESULTS: Total testosterone, ADTG and androstendione levels did not differ between non-obese (body mass index (BMI) ≤25 kg/m2) and obese PCOS (BMI >25 kg/m2) but all were significantly higher than for controls (p &lt; 0.01). The ADTG to DHEAS ratio was significantly elevated 39 ± 6 (p &lt; 0.01) in obese PCOS in comparison to non-obese PCOS and controls (28 ± 5 and 29 ± 4, respectively). The free androgen index (FAI) and insulin resistance (HOMA-IR) were significantly higher in obese PCOS compared to non-obese PCOS and controls (p &lt; 0.01). DHEAS was significantly higher in the non-obese versus obese PCOS (p &lt; 0.01). All androgen parameters were significantly lower and sex hormone binding globulin (SHBG) significantly higher in normal subjects compared to those with obese and non-obese PCOS. CONCLUSIONS: The ADTG:DHEAS ratio was significantly elevated in obese PCOS compared to non-obese PCOS and controls suggesting that this may be a novel biomarker discriminatory for obese PCOS subjects, perhaps being driven by higher hepatic 5α reductase activity increasing ADTG formation in these women