Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries

Several studies have demonstrated an association between polycystic ovary syndrome (PCOS) and the dinucleotide repeat microsatellite marker D19S884, which is located in intron 55 of the fibrillin-3 (FBN3) gene. Fibrillins, including FBN1 and 2, interact with latent transforming growth factor (TGF)-β-binding proteins (LTBP) and thereby control the bioactivity of TGFβs. TGFβs stimulate fibroblast replication and collagen production. The PCOS ovarian phenotype includes increased stromal collagen and expansion of the ovarian cortex, features feasibly influenced by abnormal fibrillin expression. To examine a possible role of fibrillins in PCOS, particularly FBN3, we undertook tagging and functional single nucleotide polymorphism (SNP) analysis (32 SNPs including 10 that generate non-synonymous amino acid changes) using DNA from 173 PCOS patients and 194 controls. No SNP showed a significant association with PCOS and alleles of most SNPs showed almost identical population frequencies between PCOS and control subjects. No significant differences were observed for microsatellite D19S884. In human PCO stroma/cortex (n = 4) and non-PCO ovarian stroma (n = 9), follicles (n = 3) and corpora lutea (n = 3) and in human ovarian cancer cell lines (KGN, SKOV-3, OVCAR-3, OVCAR-5), FBN1 mRNA levels were approximately 100 times greater than FBN2 and 200–1000-fold greater than FBN3. Expression of LTBP-1 mRNA was 3-fold greater than LTBP-2. We conclude that FBN3 appears to have little involvement in PCOS but cannot rule out that other markers in the region of chromosome 19p13.2 are associated with PCOS or that FBN3 expression occurs in other organs and that this may be influencing the PCOS phenotype.

Pancreatic and adrenal development and function in an ovine model of polycystic ovary syndrome.

Polycystic Ovary Syndrome (PCOS) is a complex disorder encompassing reproductive and metabolic dysfunction. Ovarian hyperandrogenism is an endocrine hallmark of human PCOS. In animal models, PCOS-like abnormalities can be recreated by in utero over-exposure to androgenic steroid hormones. This thesis investigated pancreatic and adrenal development and function in a unique model of PCOS. Fetal sheep were directly exposed (day 62 and day 82 of gestation) to steroidal excesses - androgen excess (testosterone propionate - TP), estrogen excess (diethylstilbestrol - DES) or glucocorticoid excess (dexamethasone - DEX). At d90 gestation there was elevated expression of genes involved in β- cell development and function: PDX-1 (P<0.001), and INS (P<0.05), INSR (P<0.05) driven by androgenic excess only in the female fetal pancreas. β- cell numbers (P<0.001) and in vitro insulin secretion (P<0.05) were also elevated in androgen exposed female fetuses. There was a significant increase in insulin secreting β-cell numbers (P<0.001) and in vivo insulin secretion (glucose stimulated) (P<0.01) in adult female offspring, specifically associated with prenatal androgen excess. At d90 gestation, female fetal adrenal gene expression was perturbed by fetal estrogenic exposure. Male fetal adrenal gene expression was altered more dramatically by fetal glucocorticoid exposure. In female adult offspring from androgen exposed pregnancies there was increased adrenal steroidogenic gene expression and in vivo testosterone secretion (P<0.01). This highlights that the adrenal glands may contribute towards excess androgen secretion in PCOS, but such effects might be secondary to other metabolic alterations driven by prenatal androgen exposure, such as excess insulin secretion Thus there may be dialogue between the pancreas and adrenal gland, programmed during early life, with implications for adult health Given both hyperinsulinaemia and hyperandrogenism are common features in PCOS, we suggest that their origins may be at least partially due to altered fetal steroidal environments, specifically excess androgenic stimulation

Oxidative stress and inflammation in lean and obese subjects with polycystic ovary syndrome

To determine whether polycystic ovary syndrome (PCOS) independently influences oxidative stress and inflammation or if the culprit is the comorbidities of obesity and/or insulin resistance common to this condition.

Polycystic ovary syndrome influences the level of serum amyloid A and activity of phospholipid transfer protein in HDL2 and HDL3

The suitability of polycystic ovary syndrome-specific questionnaires for measuring the impact of PCOS on quality of life in clinical trials

Objectives: Generic patient-reported outcome (PRO) measures underestimate the impact of polycystic ovary syndrome (PCOS) on quality of life (QoL). The aim of this review was to identify PCOS-specific QoL measures and establish whether their development history and measurement properties support their use in clinical trials.

Methods: A systematic search was conducted using terms synonymous with “PCOS” and “QoL.” Following identification of measures, further searches were undertaken using the questionnaire name and abbreviation to explore its use, development history, and demonstrated measurement properties.

Results: Of 56 abstracts screened, 21 reported using PRO measures. One PCOS-specific QoL measure was identified: the PolyCystic Ovary Syndrome Questionnaire (PCOSQ). Nine papers show that the PCOSQ’s development history is somewhat incomplete, and that it does not have good content validity. The PCOSQ subscales demonstrate acceptable levels of reliability (0.70–0.97) and partial known-groups validity as well as convergent/divergent validity with other PRO instruments. Responsiveness
to change is variable and minimally important differences have not been established.

Conclusions: The PCOSQ is the only condition-specific measure of the impact of PCOS on QoL. Additional research is required to ensure its comprehensiveness, sensitivity, and to guide interpretation prior to including in clinical trials.

The effect of obesity on polycystic ovary syndrome : a systematic review and meta-analysis

While many women with polycystic ovary syndrome (PCOS) are overweight, obese or centrally obese, the effect of excess weight on the outcomes of PCOS is inconsistent. The review aimed to assess the effects of overweight, obesity and central obesity on the reproductive, metabolic and psychological features of PCOS. MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL) and PSYCINFO were searched for studies reporting outcomes according to body mass index categories or body fat distribution. Data were presented as mean difference or risk ratio (95% confidence interval). This review included 30 eligible studies. Overweight or obese women with PCOS had decreased sex hormone-binding globulin (SHBG), increased total testosterone, free androgen index, hirsutism, fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance index and worsened lipid profile. Obesity significantly worsened all metabolic and reproductive outcomes measured except for hirsutism when compared to normal weight women with PCOS. Overweight women had no differences in total testosterone, hirsutism, total-cholesterol and low-density lipoprotein-cholesterol compared to normal weight women and no differences in SHBG and total testosterone compared to obese women. Central obesity was associated with higher fasting insulin levels. These results suggest that prevention and treatment of obesity is important for the management of PCOS.

Prevalence of the metabolic syndrome and its components in Brazilian women with polycystic ovary syndrome

SOARES, Elvira Maria Mafaldo et al. Prevalence of the metabolic syndrome and its components in Brazilian women with polycystic ovary syndrome. Fertility and Sterility, v.89, n.3, p.649-655, mar. 2008

Genetic polymorphisms associated with steroids metabolism and insulin action in polycystic ovary syndrome

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)