Polycystic Ovarian Syndrome [keywords]
- Quantifying the mediating effect of body mass index on the relation between a Mediterranean diet and development of maternal pregnancy complications: the Australian Longitudinal Study on Women's Health. [JOURNAL ARTICLE]
- Am J Clin Nutr 2016 Jul 27.
The contribution of body mass index (BMI) to the observed associations between dietary patterns and risk of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP) remains unclear.The objective of this study was to formally quantify the mediating effect of prepregnancy BMI in these associations.Women (aged 25-30 y) participating in the Australian Longitudinal Study on Women's Health were not pregnant at baseline in 2003 and reported ≥1 pregnancy up to 2012. GDM and HDP diagnoses were self-reported for each pregnancy and validated in a subset. A Mediterranean diet score was created by use of a baseline-validated food-frequency questionnaire and dichotomized to reflect low adherence (<25th percentile) and higher adherence (≥25th percentile). A causal inference framework for mediation analysis was used to estimate total, natural direct, and natural indirect effects of the prepregnancy Mediterranean diet on incident GDM and HDP and proportions mediated through prepregnancy BMI.In 3378 women without a history of diabetes, 240 (7.1%) developed GDM. HDP was reported in 273 (8.6%) of 3167 women with no history of hypertension. Low adherence to the Mediterranean diet was associated with higher risk of GDM (OR: 1.35; 95% CI: 1.02, 1.60) and HDP (OR: 1.41; 95% CI: 1.18, 1.56), after adjustment for education, parity, polycystic ovary syndrome, energy intake, and physical activity. Proportions mediated through prepregnancy BMI (per 1-kg/m(2) increase) were 32% and 22% for GDM and HDP, respectively.These findings suggest that prepregnancy BMI as a single mediator contributes substantially to the total effects of the prepregnancy Mediterranean diet on GDM and HDP risk.
- Polycystic Ovary Syndrome as a Proinflammatory State: The Role of Adipokines. [JOURNAL ARTICLE]
- Curr Pharm Des 2016 Jul 26.
Polycystic Ovary Syndrome (PCOS) is a complex heterogeneous disorder and the most common endocrinopathy amongst women of reproductive age. It is characterized by androgen excess, chronic anovulation and an altered cardiometabolic profile. PCOS is linked to impaired adipose tissue (AT) physiology and women with this disorder present with greater risk for insulin resistance (IR), hyperinsulinemia, central adiposity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) than matched for age and body mass index (BMI) women without PCOS. Hyperandrogenaemia appears to be driving adipocyte hypertrophy observed in PCOS under the influence of a hyperinsulinaemic state. Changes in the function of adipocytes have an impact on the secretion of adipokines, adipose tissue-derived proinflammatory factors promoting susceptibility to low grade inflammation.In this article, we review the existing knowledge on the interplay between hyperandrogenaemia, insulin resistance, impaired adipocyte biology, adipokines and chronic low-grade inflammation in PCOS.In PCOS, more than one mechanisms have been suggested in the development of a chronic low-grade inflammation state with the most prevalent being that of a direct effect of the immune system on adipose tissue functions as previously reported in obese women without PCOS. Despite the lack of conclusive evidence regarding a direct mechanism linking hyperandrogenaemia to pro-inflammation in PCOS, there have been recent findings indicating that hyperandrogenaemia might be involved in chronic inflammation by exerting an effect on adipocytes morphology and attributes.Increasing evidence suggests that there is an important connection and interaction between pro-inflammatory pathways, hyperinsulinemia, androgen excess and adipose tissue hypertrophy and, dysfunction in PCOS. While lifestyle changes and individualized prescription of insulin-sensitizing drugs are common in managing PCOS, further studies are warranted to eventually identify an adipokine that could serve as an indirect marker of adipocyte dysfunction in PCOS, used as a reliable and path gnomic sign of metabolic alteration in this syndrome.
- Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus. [Journal Article]
- Sci Rep 2016.:30679.
Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients.
- Neurokinin B Receptor Antagonism in Women with Polycystic Ovary Syndrome: A Randomized, Placebo-Controlled Trial. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2016 Jul 26.:jc20161202.
Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women, is characterized by high levels of secretion of luteinizing hormone (LH) and testosterone. Currently, there is no treatment licensed specifically for PCOS.To investigate whether a targeted therapy would decrease LH pulse frequency in women with PCOS, subsequently reducing serum LH and testosterone concentrations and thereby presenting a novel therapeutic approach to the management of PCOS.Double-blind, double-dummy, placebo-controlled, phase 2 trial.University hospitals and private clinical research centres.Women with PCOS aged 18-45 years.AZD4901 (a specific neurokinin-3 [NK3] receptor antagonist) at a dose of 20, 40, or 80 mg/day or matching placebo for 28 days.Change from baseline in the area under the LH serum concentration-time curve over 8 hours (AUC) on day 7 relative to placebo.Of a total of 67 randomized patients, 65 were evaluable. On day 7, the following baselineadjusted changes relative to placebo were observed in patients receiving AZD4901 80 mg/day: (1) a reduction of 52.0% (95% CI: 29.6-67.3%) in LH AUC; (2) a reduction of 28.7% (95% CI: 13.9-40.9%) in total testosterone concentration; and (3) a reduction of 3.55 LH pulses/8 hours (95% CI: 2.0 -5.1) (all nominal P < .05).The NK3 receptor antagonist AZD4901 specifically reduced LH pulse frequency and subsequently serum LH and testosterone concentrations, thus presenting NK3 receptor antagonism as a potential approach to treating the central neuroendocrine pathophysiology of PCOS.from this phase 2 clinical trial demonstrate the potential for a selective neurokinin-3 receptor antagonist to target the neuroendocrine pathophysiology of luteinizing hormone hypersecretion and hyperandrogenism in PCOS.
- Contributions of the Nurses' Health Studies to Reproductive Health Research. [JOURNAL ARTICLE]
- Am J Public Health 2016 Jul 26.:e1-e8.
To review the Nurses' Health Study's (NHS's) contribution to identifying risk factors and long-term health consequences of reproductive events.We performed a narrative review of the NHS I, NHS II, NHS3, and Growing Up Today Study (GUTS) publications between 1976 and 2016.Collection of detailed reproductive history to identify breast cancer risk factors allowed the NHS to document an association between menstrual irregularities, a proxy for polycystic ovary syndrome (PCOS), and increased risk of diabetes and cardiovascular disease. The NHS II found that infertility associated with ovulation problems and gestational diabetes are largely preventable through diet and lifestyle modification. It also identified developmental and nutritional risk factors for pregnancy loss, endometriosis, and uterine leiomyomata. As women in NHS II age, it has become possible to address questions regarding long-term health consequences of pregnancy complications and benign gynecologic conditions on chronic disease risk. Furthermore, the NHS3 and GUTS are allowing new lines of research into human fertility, PCOS, and transgenerational effects of environmental exposures.The multigenerational resources of the NHSs and GUTS, including linkages of related individuals across cohorts, can improve women's health from preconception through late adulthood and onto the next generation. (Am J Public Health. Published online ahead of print July 26, 2016: e1-e8. doi:10.2105/AJPH.2016.303350).
- Over-expression of Lnk in the ovaries was involved in insulin resistance in the women with polycystic ovary syndrome. [JOURNAL ARTICLE]
- Endocrinology 2016 Jul 26.:en20161234.
Polycystic ovary syndrome (PCOS) progression involves abnormal insulin signaling. Lnk may be an important regulator of the insulin signaling pathway. We investigated whether Lnk was involved in insulin resistance. Thirty-seven women due to receive laparoscopic surgery from June 2011 to February 2012 were included from the gynecologic department of the Sun Yat-Sen Memorial hospital, Sun Yat-Sen University, Guangzhou, China. Samples of polycystic and normal ovary tissues were examined by immunohistochemistry. Ovarian cell lines underwent insulin stimulation and Lnk over-expression. Expressed Lnk underwent co-immunoprecipitation tests with GFP-labeled insulin receptor and His-tagged insulin receptor substrate 1 (IRS1), and their co-localization in HEK293T cells was examined. Ovarian tissues from PCOS patients with insulin resistance exhibited higher expression of Lnk than ovaries from normal control subjects and PCOS patients without insulin resistance; mainly in follicular granulose cells, the follicular fluid and plasma of oocytes in secondary follicles, and atretic follicles. Lnk was co-immunoprecipitated with insulin receptor and IRS1. Lnk and insulin receptor/IRS1 locations overlapped around the nucleus. IR, Akt, and ERK1/2 activities were inhibited by Lnk over-expression and inhibited further after insulin stimulation while IRS1 serine activity was increased. Insulin receptor (Tyr1150/1151), Akt (Thr308) and ERK1/2(Thr202/Tyr204) phosphorylation was decreased while IRS1 (Ser307) phosphorylation was increased with Lnk over-expression. In conclusion, Lnk inhibits the PI3K-AKT and MAPK-ERK signaling response to insulin. Higher expression of Lnk in polycystic ovary syndrome suggests that Lnk probably plays a role in the development of insulin resistance.
- The Pathogenesis of Polycystic Ovary Syndrome (PCOS). [JOURNAL ARTICLE]
- Endocr Rev 2016 Jul 26.:er20151104.
Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-95. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyper-responsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of DENND1A.V2, a protein identified by genome-wide association screening, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, while acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis. The Hypothesis of PCOS as Functional Ovarian Hyperandrogenism Revisited.
- Metabolic Screening in Patients with Polycystic Ovary Syndrome is Largely Underutilized among Obstetrician-Gynecologists. [JOURNAL ARTICLE]
- Am J Obstet Gynecol 2016 Jul 22.
Women with polycystic ovary syndrome have substantially higher rates of insulin resistance, impaired glucose tolerance, type 2 diabetes, dyslipidemia, and metabolic syndrome, when compared to women without the disease. Given the high prevalence of these comorbidities, guidelines issued by the American College of Obstetricians and Gynecologists (ACOG) and Endocrine Society recommend that all women with polycystic ovary syndrome undergo screening for impaired glucose tolerance and dyslipidemia with a 2-hour 75-gram oral glucose tolerance test and fasting lipid profile upon diagnosis, and undergo repeat screening every 2-5 years and every 2 years, respectively. Although a hemoglobin A1C and/or fasting glucose are widely used screening tests for diabetes, both ACOG and Endocrine Society preferentially recommend the 2-hour oral glucose tolerance test in women with polycystic ovary syndrome as a superior indicator of impaired glucose tolerance/diabetes mellitus. However, we found that gynecologists underutilize current recommendations for metabolic screening in women with polycystic ovarian syndrome. In an online survey study targeting ACOG fellows and junior fellows, 22.3% of respondents would not order any screening test at the initial visit for at least 50% of their patients with polycystic ovary syndrome. The most common tests used to screen for impaired glucose tolerance in women with polycystic ovary syndrome were hemoglobin A1C (51.0%) and fasting glucose (42.7%). Whereas 54.1% would order a fasting lipid profile in at least 50% of their polycystic ovary syndrome patients, only 7% of respondents order a 2-hr oral glucose tolerance test. We therefore call for increased efforts to encourage obstetrician-gynecologists to address metabolic abnormalities in their patients with polycystic ovary syndrome. Such efforts should include education of physicians early in their careers, at the medical student and resident level. Efforts should also include implementation of continuing medical education activities, both locally and at the national level, to improve understanding of the metabolic implications of polycystic ovary syndrome. Electronic medical record systems should be utilized to generate prompts for appropriate screening tests in patients with a diagnosis of polycystic ovary syndrome. Since obstetrician-gynecologists may be the only physicians seen by many polycystic ovary syndrome patients, particularly those in their young reproductive years, such interventions could effectively promote optimal preventative health care and early diagnosis of metabolic comorbidities in these at-risk women.
- Polycystic ovary syndrome in type 2 diabetes: does it predict a more severe phenotype? [JOURNAL ARTICLE]
- Fertil Steril 2016 Jul 22.
To examine the prevalence of a history of polycystic ovary syndrome (PCOS) in women with type 2 diabetes (DM2) and to compare metabolic and reproductive outcomes between women with and without PCOS.Cross-sectional study.Tertiary hospital.Female inpatients age 18-75 years with DM2.A face-to-face questionnaire was administered.Age at diagnosis of diabetes, history of gestational diabetes, family history of diabetes, and reproductive history, fertility history, number of miscarriages, and morbidity in pregnancy.One hundred seventy-one inpatients with DM2 participated. The prevalence of a history of PCOS was 37%. Women with PCOS had an earlier mean age of diagnosis of DM2 (44.2 vs. 48.8 years), higher recalled peak body mass index (BMI; 43.1 kg/m(2) vs. 36.8 kg/m(2)), higher rate of gestational diabetes (28% vs. 18%), and higher rate of hypertension in pregnancy (40% vs. 22%). Women with PCOS were less likely to have a family history of DM2 than those without PCOS (45% vs. 67%).A history of PCOS in women with DM2 is associated with earlier onset of DM2, higher BMI, and a more severe phenotype. Since PCOS subjects were less likely to have a family history of DM2, lack of a family history of DM2 in women with PCOS is not reassuring for DM2 risk. We recommend identifying PCOS in early life and intervening to reduce the risk of diabetes and its comorbidities and suboptimal reproductive outcomes.
- Interrelationships with Metabolic Syndrome, Obesity and Cardiovascular. [JOURNAL ARTICLE]
- Curr Vasc Pharmacol 2016 Jul 22.
Cardiovascular (CV) disease is the most common cause of morbidity and mortality worldwide, particularly in the presence of the metabolic syndrome (MetS). Classifications and treatment of the MetS have recently been redefined. While the majority of the cardiac components such as hypertension, diabetes mellitus (DM) and dyslipidemia are objectively measurable elements, a few disparities among the definitions have to be considered that can variably modify diagnosis, treatment and prevention. Noncardiac factors such as liver disease (including, but not limited to, alcoholic and non-alcoholic steatosis/hepatitis), renal disease, severe obesity, polycystic ovarian syndrome and obstructive sleep apnea, may have independent or synergistic relationship with complementary cardiac MetS elements, and these additional risk factors may have an incremental adverse impact on CV outcome. The combination of all these factors potentiates the adverse significance on CV events. MetS not only increases morbidity and mortality but also has economic ramifications for the healthcare system. Prevention of CV disease includes primary and secondary aspects. Besides overall advances to provide optimal care for hypertension, diabetes, and dyslipidemia, early-targeted inventions to diagnose, treat and prevent obstructive sleep apnea, and severe obesity, are needed.