transforming-growth-factor-beta and Polycystic-Ovary-Syndrome

To analyze whether metformin treatment in patients with polycystic ovary syndrome (PCOS) results in a decrease of anti-Müllerian hormone (AMH) levels, we reviewed and analyzed PCOS studies which evaluated serum AMH levels before and after metformin treatment.. This is a systematic review and meta-analysis of self-controlled clinical trials. Databases including PubMed, Embase, and Web of Science library were searched to identify eligible studies published before February 2023. Random-effects models were applied to assess standardized mean differences (SMDs) with 95% confidence intervals (95% CI).. The electronic-based search retrieved 167 articles of which 14 studies (12 publications) involving 257 women with PCOS were included. In general, AMH levels decreased significantly after metformin treatment [SMD (95% CI) of -0.70 (-1.13 to -0.28); P = 0.001]. Metformin exhibited a strong inhibitory effect on AMH levels for PCOS patients with age less than 28 [SMD - 1.24, 95% CI - 2.15 to - 0.32, P = 0.008]. Additionally, AMH levels significantly slid down in PCOS patients with no more than 6 months metformin treatment [SMD - 1.38, 95% CI - 2.18 to - 0.58, P = 0.0007], or with no more than a dose of 2000 mg/day [SMD -0.70, 95% CI -1.11 to -0.28; P = 0.001]. Notably, suppressive effects of metformin treatment were merely observed in patients with AMH levels at baseline higher than 4.7 ng/ml [SMD - 0.66, 95% CI - 1.02 to - 0.31, P = 0.0003].. This meta-analysis provided quantitative evidence demonstrating that metformin significantly decreased AMH levels, especially for young patients and those with AMH levels at baseline higher than 4.7 ng/ml.. PROSPERO CRD42020149182.

Topics: Anti-Mullerian Hormone; Databases, Factual; Female; Humans; Metformin; Polycystic Ovary Syndrome; PubMed; Transforming Growth Factor beta

Polycystic Ovary Syndrome (PCOS) is a metabolic condition that affects women in their reproductive age by altering the ovarian hormone levels, leading to infertility. Increased inflammation, insulin resistance, hyperandrogenism, irregular menses, and infertility are the causes of morbidity when PCOS is the disease in question. PCOS is considered a multifactorial disease resulting from the disruption of multiple signalling pathways. Hence, the mono-targeted drugs are hardly adequate and conventional therapeutic strategies provide only palliative care. Studies show that the consumption of polyunsaturated fatty acids (PUFAs) regulates menstrual cycle, decrease testosterone and insulin levels, and improve metabolic health. This could favourably affect diabetes and infertility. In recent years, the fibrillin-3 gene has been linked to PCOS. Fibrillins along with the molecules in the extracellular matrix modulate the Transforming Growth Factor-β (TGF-β) signalling. So, mutations in the fibrillin-3 gene could cause TGF-β dysregulation, which might further contribute to PCOS pathogenesis. Therefore, the current study aimed to understand whether PUFAs could manage PCOS via the TGF-β pathway and function as a therapeutic agent for PCOS and its complications. To understand this, we have focused on the involvement of TGF-β in PCOS pathogenesis, discussed the effect of PUFA on hormones, insulin resistance, inflammation, obesity, adiponectin, and cardiovascular conditions. Using PUFAs to target TGF-β or its receptor molecules to modulate the TGF-β production might function as a treatment option for PCOS. PUFA therapy could be a good alternative, supportive medication for PCOS.

Topics: Animals; Fatty Acids, Unsaturated; Female; Humans; Polycystic Ovary Syndrome; Transforming Growth Factor beta

Research on polycystic ovarian syndrome (PCOS) remains intense due to its evolving impact on metabolism, reproduction and cardiovascular function. Changes in metabolic pathways can also significantly impact renal function including the development of Focal Segmental Glomerulosclerosis (FSGS), one of the most highly investigated renal diseases. In FSGS, scarring of the glomerulus vascular tuft damages the kidneys. Onset of FSGS may either be congenital or due to other disorders that affect the metabolism and normal kidney function. Both PCOS and FSGS appear to be associated with Transforming Growth Factor-β (TGF-β) signalling. Over-expression of TGF-β may be due to the activation of the thrombospondin 1 (TSP1) gene, which increases the probability of developing renal disorders. Higher androgen levels in PCOS may also cause podocyte damage thus directly impacting development of FSGS. This article reviews the role of TGF-β's in PCOS and FSGS and explores the inter-relationship between these two disorders.

Topics: Female; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Podocytes; Polycystic Ovary Syndrome; Transforming Growth Factor beta

Thyroid disorders, especially Hashimoto's thyroiditis (HT), are observed significantly more often in patients with polycystic ovary syndrome (PCOS) than in the general population - approximately 27% and 8%, respectively. This is extremely important in young women, because both disorders are connected with fertility problems. As HT and PCOS occur together, fertility problems may become a serious clinical issue in these patients.. A systematic literature review in PubMed of PCOS- and HT-related articles in English, published until December 2015 was conducted.. The reasons for joint prevalence still remain unclear. Genetic and autoimmune backgrounds are recognized to be possible common etiological factors. Three genetic polymorphisms have been described to play a role in PCOS as well as in HT. They are polymorphism of the gene for fibrillin 3 (FBN3) regulating the activity of transforming growth factor-b (TGF-b) and regulatory T cell levels, gonadotropin-releasing hormone receptor (GnRHR) polymorphism and CYP1B1 polymorphism standing for estradiol hydroxylation. High estrogen-to-progesterone ratios owing to anovulatory cycles, as well as high estrogen levels during prenatal life, disrupt development of the thymus and its function in maintaining immune tolerance, and are suspected to enhance autoimmune response in PCOS. Vitamin D deficiency could be also involved in the pathogenesis of HT and PCOS.. The above-mentioned common etiological factors associated with fertility problems in HT and PCOS require further research.

Topics: Cytochrome P-450 CYP1B1; Female; Fibrillins; Hashimoto Disease; Humans; Polycystic Ovary Syndrome; Receptors, LHRH; Transforming Growth Factor beta

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in reproductive age affecting 5 to 7% of women. It is characterized by anovulatory infertility, hyperandrogenism, and polycystic ovaries. Angiogenesis in the ovary is critical for follicular growth, ovulation, and the subsequent development and regression of the corpus luteum. Accumulating evidence suggests that multiple angiogenic factors are dysregulated in PCOS, including vascular endothelial growth factor, angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. This angiogenic factor imbalance likely underlies the increased stromal vascularity observed in PCOS. Angiogenic factor dysregulation may play an important role in the pathophysiology of PCOS and may contribute to ovulatory dysfunction, subfertility, and ovarian hyperstimulation syndrome, which are commonly seen in women with PCOS. Further experimental studies are needed to gain a better understanding of the growth factors that are involved in normal and pathological ovarian angiogenesis, and to assess the potential of angiogenesis-based treatment strategies in PCOS.

Topics: Angiopoietins; Female; Fibroblast Growth Factors; Humans; Infertility, Female; Neovascularization, Pathologic; Ovarian Hyperstimulation Syndrome; Ovary; Platelet-Derived Growth Factor; Polycystic Ovary Syndrome; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic oligoanovulation and hyperandrogenism and associated with insulin resistance, type 2 diabetes, and cardiovascular risk. In recent years, genetic studies have linked PCOS to a dinucleotide marker D19S884 in the fibrillin 3 gene. Fibrillins make up the major component of microfibrils in the extracellular matrix (ECM) and interact with molecules in the ECM to regulate transforming growth factor β (TGF-β) signaling. Therefore, variations in fibrillin 3 and subsequent dysregulation of TGF-β may contribute to the pathogenesis of PCOS. Here, we review the evidence from genetic studies supporting the role of TGF-β in PCOS and describe how TGF-β dysregulation may contribute to (1) the fetal origins of PCOS, (2) reproductive abnormalities in PCOS, and (3) cardiovascular and metabolic abnormalities in PCOS.

Topics: Animals; Female; Fertility; Fibrillins; Genetic Predisposition to Disease; Genetic Variation; Humans; Infertility, Female; Microfilament Proteins; Ovary; Phenotype; Polycystic Ovary Syndrome; Signal Transduction; Transforming Growth Factor beta

Folliculogenesis is a complex process, in which multiple endocrine and intraovarian paracrine interactions create a changing intrafollicular microenvironment for appropriate oocyte development. Within this microenvironment, bidirectional cumulus cell-oocyte signaling governs the gradual acquisition of developmental competence by the oocyte, defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. These regulatory mechanisms of follicle growth, controlled in part by the oocyte itself, are susceptible to derangement in polycystic ovary syndrome (PCOS), a heterogeneous syndrome characterized by ovarian hyperandrogenism, insulin resistance, and paracrine dysregulation of follicle development. Consequently, only a subset of PCOS patients experience reduced pregnancy outcome after ovarian stimulation for in vitro fertilization. Recent data implicate functional associations between endocrine/paracrine abnormalities, metabolic dysfunction, and altered oocyte gene expression with impaired oocyte developmental competence in women with PCOS. Therefore, an understanding of how developmentally relevant endocrine/paracrine factors interact to promote optimal oocyte developmental is crucial to identify those PCOS patients who might benefit from long-term correction of follicle growth to improve fertility, optimize follicular responsiveness to gonadotropin therapy, and enhance pregnancy outcome by in vitro fertilization.

Topics: Female; Humans; Meiosis; Oocytes; Oogenesis; Ovarian Follicle; Polycystic Ovary Syndrome; Transforming Growth Factor beta

Human follicle development requires the recruitment of primordial follicles into a cohort of growing follicles from which one follicle is selected to ovulate a mature oocyte. During this developmental process, complex endocrine and intraovarian paracrine signals create a changing intrafollicular hormonal milieu. With this microenvironment, appropriate cumulus cell-oocyte signaling governs oocyte developmental competence, defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. Many of these mechanisms are perturbed in polycystic ovary syndrome (PCOS), a heterogeneous syndrome characterized by ovarian hyperandrogenism, hyperinsulinemia from insulin resistance, and reduced fecundity. In addition to these endocrinopathies, PCOS also is characterized by paracrine dysregulation of follicle development by intraovarian proteins of the transforming growth factor-beta family. Consequently, PCOS patients undergoing ovarian stimulation for in vitro fertilization are at increased risks of impaired oocyte developmental competence, implantation failure, and pregnancy loss. Recent data demonstrate links between endocrine/paracrine factors and oocyte gene expression in PCOS and suggest that new clinical strategies to optimize developmental competence of PCOS oocytes should target correction of the entire follicle growth and oocyte development process.

Topics: Female; Humans; Hyperandrogenism; Hyperinsulinism; Luteinization; Oocytes; Oogenesis; Ovarian Follicle; Polycystic Ovary Syndrome; Transforming Growth Factor beta

To examine the effects of common treatments for polycystic ovary syndrome (PCOS) on a panel of hormones (reproductive/metabolic).. Secondary analysis of blood from a randomized controlled trial of three 16-week preconception interventions designed to improve PCOS-related abnormalities: continuous oral contraceptive pills (OCPs, N = 34 subjects), intensive lifestyle modification (Lifestyle, N = 31), or a combination of both (Combined, N = 29).. Post-treatment levels of activin A and B, inhibin B, and follistatin (FST), as well as Insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 2 (IGFBP-2), glucagon, glucagon-like peptide 1 (GLP-1) and 2, and oxyntomodulin were compared to baseline, and the change from baseline in these parameters were correlated with outcomes.. Oral contraceptive pill use was associated with a significant suppression in activin A, inhibin A, and anti-mullerian hormone (AMH), but a significant increase in FST. IGF-1, IGFBP-2, glucagon, and GLP-2 levels were significantly decreased. Oxyntomodulin was profoundly suppressed by OCPs (ratio of geometric means: 0.09, 95% confidence interval [CI]: 0.05, 0.18, P < 0.001). None of the analytes were significantly affected by Lifestyle, whereas the effects of Combined were similar to OCPs alone, although attenuated. Oxyntomodulin was significantly positively associated with the change in total ovarian volume (rs = 0.27; 95% CI: 0.03, 0.48; P = 0.03) and insulin sensitivity index (rs = 0.48; 95% CI: 0.27, 0.64; P < 0.001), and it was inversely correlated with change in area under the curve (AUC) glucose [rs = -0.38; 95% CI: -0.57, -0.16; P = 0.001]. None of the hormonal changes were associated with live birth, only Activin A was associated with ovulation (risk ratio per 1 ng/mL increase in change in Activin A: 6.0 [2.2, 16.2]; P < 0.001).. In women with PCOS, OCPs (and not Lifestyle) affect a wide variety of reproductive/metabolic hormones, but their treatment response does not correlate with live birth.

Topics: Adolescent; Adult; Behavior Therapy; Combined Modality Therapy; Contraceptives, Oral; Female; Hormones; Humans; Incretins; Life Style; Obesity; Polycystic Ovary Syndrome; Retrospective Studies; Transforming Growth Factor beta; Treatment Outcome; United States; Young Adult

Recently, rare heterozygous AMH protein-altering variants were identified in women with polycystic ovary syndrome (PCOS), causing reduced anti-Müllerian hormone (AMH) signaling. However, the exact functional mechanism remains unknown. Here, we analyzed the processing, secretion, and signaling of these AMH variants. Functional analysis of six PCOS-specific AMH variants (V12G, P151S, P270S, P352S, P362S, H506Q) and one control-specific variant (A519V) was performed in the mouse granulosa cell-line KK-1. Human (h) AMH-151S and hAMH-506Q have ∼90% decreased AMH signaling compared to wild-type (wt) AMH signaling. Coexpression of hAMH-151S or hAMH-506Q with wt-hAMH dose-dependently inhibited wt-hAMH signaling. Western blotting revealed that hAMH-151S and hAMH-506Q proteins were detected in the cell lysate but not in the supernatant. Confocal microscopy showed that HEK293 cells expressing hAMH-151S and hAMH-506Q had higher cellular AMH protein levels with endoplasmic reticulum (ER) retention compared to cells expressing wt-hAMH. Using two AMH ELISA kits, hAMH-151S was detected in the cell lysate, while only very low levels were detected in the supernatant. Both hAMH-362S and hAMH-519V were detectable using the automated AMH ELISA but showed severely reduced immunoactivity in the manual ELISA. Surprisingly, hAMH-506Q was undetectable in both the cell lysate and supernatant using either ELISA. However, in PCOS cases, heterozygous carriers of the P151S and H506Q variants still had detectable AMH in both assays. Thus, P151S and H506Q disrupt normal processing and secretion of AMH, causing ER retention. Additionally, AMH variants can impair the AMH immunoactivity. An AMH variant may be considered when serum AMH levels are relatively low in PCOS cases.

Topics: Animals; Anti-Mullerian Hormone; Female; Follicle Stimulating Hormone; HEK293 Cells; Humans; Luteinizing Hormone; Mice; Polycystic Ovary Syndrome; Transforming Growth Factor beta

Phytoestrogens can act as natural estrogens owing to their structural similarity to human estrogens. Biochanin-A (BCA) is a well-studied phytoestrogen with a wide variety of pharmacological activities, whereas not reported in the most frequently encountered endocrinopathy called polycystic ovary syndrome (PCOS) in women.. This study aimed to investigate the therapeutic effect of BCA on dehydroepiandrosterone (DHEA) induced PCOS in mice.. Thirty-six female C57BL6/J mice were divided into six groups: sesame oil, DHEA-induced PCOS, DHEA + BCA (10 mg/kg/day), DHEA + BCA (20 mg/kg/day), DHEA + BCA (40 mg/kg/day), and metformin (50 mg/kg/day).. The results showed a decrease in obesity, elevated lipid parameters, restoration of hormonal imbalances (testosterone, progesterone, estradiol, adiponectin, insulin, luteinizing hormone, and follicle-stimulating hormone), estrus irregular cyclicity, and pathological changes in the ovary, fat pad, and liver.. In conclusion, BCA supplementation inhibited the over secretion of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and upregulated TGFβ superfamily markers such as GDF9, BMP15, TGFβR1, and BMPR2 in the ovarian milieu of PCOS mice. Furthermore, BCA reversed insulin resistance by increasing circulating adiponectin levels through a negative correlation with insulin levels. Our results indicate that BCA attenuated DHEA-induced PCOS ovarian derangements, which could be mediated by the TGFβ superfamily signaling pathway via GDF9 and BMP15 and associated receptors as first evidenced in this study.

Topics: Adiponectin; Animals; Bone Morphogenetic Protein 15; Dehydroepiandrosterone; Estrogens; Female; Growth Differentiation Factor 9; Insulin; Mice; Polycystic Ovary Syndrome; Signal Transduction; Transforming Growth Factor beta; Up-Regulation

The ratio of the anti-Müllerian hormone (AMH) precursor (proAMH) to active AMH (AMH. Total AMH and proAMH were measured by immunoassay in a single-centre, cross-sectional observational study; 61 controls and 29 girls with PCOS were included in the study (age range 8-21 years). The API was calculated as proAMH as a percentage of total AMH. Differences in API between control and PCOS subjects and across age-groups were examined by Welch's ANOVA. The relationship between API and a range of metabolic parameters was examined by Pearson correlation.. The API in healthy females increased between the ages of 10~15 years and declined from 15~20 years (p < 0.001). The API was negatively correlated with body mass index in the control (p = 0.04) and PCOS groups (p = 0.007). The API was associated with factors related to adiposity and lipid metabolism. The API was not significantly different in control girls and girls with PCOS.. Higher API during adolescence suggests that proteolytic activation of proAMH is suppressed during this life stage. API was not different between control girls and girls with PCOS indicating that it is not useful in diagnosis of PCOS during adolescence.

Topics: Adolescent; Adult; Anti-Mullerian Hormone; Biomarkers; Body Mass Index; Child; Cross-Sectional Studies; Female; Humans; Peptide Hormones; Polycystic Ovary Syndrome; Transforming Growth Factor beta; Young Adult

Could changes in transforming growth factor β (TGFβ) signalling during foetal ovary development alter the expression of polycystic ovary syndrome (PCOS) candidate genes leading to a predisposition to PCOS?. TGFβ signalling molecules are dynamically expressed during foetal ovary development and TGFβ1 inhibits expression of the androgen receptor (AR) and 7 (INSR, C8H9orf3, RAD50, ERBB3, NEIL2, IRF1 and ZBTB16) of the 25 PCOS candidate genes in foetal ovarian fibroblasts in vitro, whilst increasing expression of the AR cofactor TGFβ-induced transcript 1 (TGFB1I1 or Hic5).. The ovarian stroma arises from the mesonephros during foetal ovary development. Changes in the morphology of the ovarian stroma are cardinal features of PCOS. The ovary is more fibrous and has more tunica and cortical and subcortical stroma. It is not known why this is and when this arises. PCOS has a foetal origin and perhaps ovarian stroma development is altered during foetal life to determine the formation of a polycystic ovary later in life. PCOS also has a genetic origin with 19 loci containing 25 PCOS candidate genes. In many adult tissues, TGFβ is known to stimulate fibroblast replication and collagen deposition in stroma, though it has the opposite effect in the non-scaring foetal tissues. Our previous studies showed that TGFβ signalling molecules [TGFβs and their receptors, latent TGFβ binding proteins (LTBPs) and fibrillins, which are extracellular matrix proteins that bind LTBPs] are expressed in foetal ovaries. Also, we previously showed that TGFβ1 inhibited expression of AR and 3 PCOS candidate genes (INSR, C8H9orf3 and RAD50) and stimulated expression of TGFB1I1 in cultured foetal ovarian fibroblasts.. We used Bos taurus for this study as we can ethically collect foetal ovaries from across the full 9-month gestational period. Foetal ovaries (62-276 days, n = 19) from across gestation were collected from pregnant B. taurus cows for RNA-sequencing (RNA-seq) analyses. Foetal ovaries from B. taurus cows were collected (160-198 days, n = 6) for culture of ovarian fibroblasts.. RNA-seq transcriptome profiling was performed on foetal ovaries and the data on genes involved in TGFβ signalling were extracted. Cells were dispersed from foetal ovaries and fibroblasts cultured and treated with TGFβ1. The effects of TGFβ regulation on the remaining eight PCOS candidate genes not previously studied (ERBB3, MAPRE1, FDFT1, NEIL2, ARL14EP, PLGRKT, IRF1 and ZBTB16) were examined.. Many TGFβ signalling molecules are expressed in the foetal ovary, and for most, their expression levels increased accross gestation (LTBP1/2/3/4, FBN1, TGFB2/3, TGFBR2/3 and TGFB1I1), while a few decreased (FBN3, TGFBR3L, TGFBI and TGFB1) and others remained relatively constant (TGFBRAP1, TGFBR1 and FBN2). TGFβ1 significantly decreased expression of PCOS candidate genes ERBB3, NEIL2, IRF1 and ZBTB16 in cultured foetal ovarian fibroblasts.. The FASTQ files, normalized data and experimental information have been deposited in the Gene Expression Omnibus (GEO) accessible by accession number GSE178450.. Regulation of PCOS candidate genes by TGFβ was carried out in vitro and further studies in vivo are required. This study was carried out in bovine where foetal ovaries from across all of the 9-month gestational period were available, unlike in the human where it is not ethically possible to obtain ovaries from the second half of gestation.. From our current and previous results we speculate that inhibition of TGFβ signalling in the foetal ovary is likely to (i) increase androgen sensitivity by enhancing expression of AR, (ii) increase stromal activity by stimulating expression of COL1A1 and COL3A1 and (iii) increase the expression of 7 of the 25 PCOS candidate genes. Thus inhibition of TGFβ signalling could be part of the aetiology of PCOS or at least the aetiology of polycystic ovaries.. Funding was received from Adelaide University China Fee Scholarship (M.L.), Australian Research Training Program (R.A.) and the Faculty of Health and Medical Science Divisional Scholarship (R.A.), Adelaide Graduate Research Scholarships (R.A. and N.A.B.), Australia Awards Scholarship (M.D.H.), Robinson Research Institute Career Development Fellowship (K.H.) and Building On Ideas Grant (K.H.), National Health and Medical Research Council of Australia Centre for Research Excellence in the Evaluation, Management and Health Care Needs of Polycystic Ovary Syndrome (N.A.B., M.D.H. and R.J.R.; GTN1078444) and the Centre for Research Excellence on Women's Health in Reproductive life (R.A., R.J.R. and K.H.; GTN1171592) and the UK Medical Research Council (R.A.A.; grant no. G1100357). The funders did not play any role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. The authors of this manuscript have nothing to declare and no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Topics: Animals; Australia; Cattle; Female; Fetus; Humans; Polycystic Ovary Syndrome; Pregnancy; Transforming Growth Factor beta

The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome.. Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)?. Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation.. Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size.. Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays.. The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ± 189 pg/mL [mean ± SEM], n = 188; non-PCO: 3498 ± 199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ± 40 pg/mL, n = 125; non-PCO: 573 ± 55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO.. Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO.

Topics: Anti-Mullerian Hormone; Biomarkers; Bone Morphogenetic Protein 15; Female; Follicular Fluid; Growth Differentiation Factor 9; Humans; Inhibins; Oocytes; Polycystic Ovary Syndrome; Transforming Growth Factor beta

HAS2 antisense RNA 1 (HAS2-AS1) is a long noncoding RNA that has increased expression in mature granulosa cells (GCs) and contributes to cumulus expansion by regulating HAS2 expression. However, the roles of HAS2-AS1 during the pathological process of polycystic ovary syndrome (PCOS) are still unclear. This study investigated the roles of HAS2-AS1 in patients with PCOS. Here, a significant upregulation of HAS2-AS1 was found in the primary GCs from patients with PCOS, which was positively correlated with the level of the protein HAS2. The knockdown of HAS2 restored the upregulation of HAS2-AS1 in promoting migration but could not restore the effects of HAS2-AS1 overexpression in promoting proliferation and repressing apoptosis. Transforming growth factor β (TGF-β) upregulated HAS2-AS1 levels, while HAS2-AS1 functioned as a feedback inhibition factor repressing TGF-β signaling by inhibiting TGF-β receptor type 2 (TGFBR2) expression. HAS2-AS1 bonded with EZH2 and guided the polycomb complex 2 to the TGFBR2 promoter region. HAS2-AS1 overexpression induced H3K27 hypermethylation in the TGFBR2 promoter region and then repressed TGFBR2 transcription in KGN cells and primary GCs. In conclusion, we identified for the first time that HAS2-AS1 is upregulated in patients with PCOS and represses TGF-β signaling via inducing TGFBR2 promoter region hypermethylation, which allowed us to explore the pathological processes of PCOS.

Topics: Cell Proliferation; Female; Granulosa Cells; Humans; Hyaluronan Synthases; MicroRNAs; Polycystic Ovary Syndrome; Receptor, Transforming Growth Factor-beta Type II; RNA, Long Noncoding; Transforming Growth Factor beta; Up-Regulation

To evaluate the relationship between the size of endometrioma and serum Anti-mullerian hormone (AMH).. A Descriptive study.. This study was conducted at the Bagcilar Training and Research Hospital, Istanbul, Turkey, from January 2015 to January 2020.. Healthy women of reproductive age, who were found to have unilateral endometrioma in ultrasonography, were included in the study group. There were 82 female patients with unilateral endometrioma in the study group and 96 healthy female patients with male factor infertility in the control group. Women with autoimmune disease, a history of pelvic infection or surgery, polycystic ovary syndrome, pregnancy, those undergoing infertility treatment, family history of premature ovarian failure, and those with atypical or suspected endometrioma were excluded. Age, gravida, serum AMH value, and endometrioma size of the study and control groups were recorded. In addition, the endometrioma group was divided into 2 groups with a cut-off size of greater or less than 40 mm. AMH values ​​were evaluated in these two groups.. AMH values ​​of women with endometrioma were significantly lower than the control group (2.03 ng/ml and 3.87 ng/ml, respectively, p<0.001). When the relationship between endometrioma size (greater than 40 mm and less than 40 mm) and AMH was examined, no statistically significant difference was found among serum AMH values (1.89 ng/ml and 2.07 ng/ml, respectively, p=0.65).. The presence of endometrioma was associated with lower AMH suggesting lower ovarian reserve, but endometrioma size was not associated with significant difference in the AMH values.. Endometrioma, AMH, Ovarian reserve, Endometrioma size.

Topics: Anti-Mullerian Hormone; Endometriosis; Female; Humans; Infertility; Male; Polycystic Ovary Syndrome; Pregnancy; Transforming Growth Factor beta

Polycystic ovary syndrome (PCOS) is a disease with chronic nonspecific low-grade inflammation. The imbalance of immune cells exists in PCOS. Several studies have found that heat shock protein 70 (HSP70) may be involved in the immunological pathogenesis of PCOS, but the relationship between HSP70 and Regulatory T cell (Treg)/T helper cell 17(Th17) ratio remains unclear. This study aims to explore the correlation between HSP70 and Treg/Th17 ratio and to provide evidence for the role of HSP70 in the immunological etiology of PCOS.. The abnormal level of HSP70 is correlated with Treg/Th17 imbalance and corresponding cytokines, which indicates that HSP70 may play an important role in PCOS immunologic pathogenesis.

Topics: Adult; Blood Glucose; Female; HSP70 Heat-Shock Proteins; Humans; Insulin; Interleukin-10; Interleukin-17; Interleukin-23; Interleukin-6; Luteinizing Hormone; Lymphocyte Count; Polycystic Ovary Syndrome; T-Lymphocytes, Regulatory; Testosterone; Th17 Cells; Transforming Growth Factor beta; Young Adult

In recent years, female infertility from Polycystic Ovary Syndrome (PCOS) has gained scientific interest. PCOS alters the metabolic and endocrine functioning in females. The elevation in androgens can damage the androgen receptors present on the kidney giving rise to renal disorders like Focal Segmental Glomerulosclerosis (FSGS). Transforming Growth Factor Beta (TGF-β) in the ovary is activated by activin for Follicle Stimulating Hormone (FSH) secretion and in the kidney by thrombospondin 1 (TSP1) for cell growth and apoptosis. Studies show that gamma-linolenic acid (GLA) effectively treats breast cancer, eczema, inflammatory conditions and PCOS.. The study aimed to find out the possibility of FSGS development in PCOS and to understand the effect of GLA on FSGS via the TGF-β pathway.. To carry out the study, the dehydroepiandrosterone (DHEA) induced PCOS model was used. Three groups namely vehicle control, DHEA, and DHEA+GLA, were used with six animals in each. TGF-β1, TGF-β2, and TSP1 genes were studied using real-time PCR.. The study showed an increase in the level of renal fibrosis biomarker, TSP1, in the DHEA group, which was further decreased by an anti-inflammatory agent, GLA. The TGF-β1 and TGF-β2 genes associated with the TGF-β pathway were seen to be increased in DHEA-induced PCOS rats which showed a possible relation between the two conditions.. The study shows a possible development of renal fibrosis in the DHEA-induced PCOS model. The GLA might act as a ligand to regulate TGF-β signaling in glomerulosclerosis in a DHEA-induced PCOS model.

Topics: Adjuvants, Immunologic; Animals; Dehydroepiandrosterone; Female; gamma-Linolenic Acid; Glomerulosclerosis, Focal Segmental; Polycystic Ovary Syndrome; Rats; Rats, Wistar; Signal Transduction; Transforming Growth Factor beta

Polycystic ovary syndrome (PCOS) is an endocrine disorder, the etiology of which is complex and unclear. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a conserved long non-coding RNA which has been found to play a role in the pathophysiological process of reproductive system diseases, such as endometriosis and pregnancy loss. However, the role of MALAT1 in PCOS is still unknown. In this study, reduced MALAT1 expression was found in granulosa cells (GCs) from 68 patients with PCOS and 30 healthy controls, which relates to upregulated cell proliferation and downregulated apoptosis. Using phosphorylation pathway profiling array, MALAT1 reduction was identified to contribute to the repression of transforming growth factor beta (TGFβ) signaling in GCs. Subsequently, MALAT1 was confirmed to function as a competing endogenous RNA (ceRNA), interacting with miR-125b and miR-203a. Meanwhile, miR-125b and miR-203a was identified as two novel TGFβ signaling negative regulators by targeting TGFBR1 and TGFBR2. Finally, MALAT1 knockdown was found to induce the upregulation of miR-125b and miR-203a, which further repressed TGFβ signaling, changed some downstream gene expression, and resulted in a disordered cell cycle. In conclusion, MALAT1 reduction was identified in GCs, which may contribute to the pathophysiological processes of PCOS by regulating TGFβ signaling through sponging miR-125b and miR-203a.

Topics: Adult; Case-Control Studies; Cell Proliferation; Cells, Cultured; Down-Regulation; Female; Granulosa Cells; Humans; MicroRNAs; Phosphorylation; Polycystic Ovary Syndrome; Pregnancy; RNA, Long Noncoding; Signal Transduction; Transforming Growth Factor beta

Normal-weight women with polycystic ovary syndrome (PCOS) may have adipose tissue insulin resistance (adipose-IR).. To examine whether adipose-IR and subcutaneous (SC) abdominal adipose stem cell (ASC) gene expression are altered in normal-weight women with PCOS and correlated with hyperandrogenemia and/or whole-body IR.. Prospective cohort study.. Academic medical center.. Ten normal-weight women with PCOS and 18 control subjects matched for age and body mass index.. Women underwent circulating hormone and metabolic measurements, IV glucose tolerance testing, total-body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy.. Adipose-IR (fasting insulin × total fatty acid levels) and SC abdominal ASC gene expression were compared between groups and correlated with clinical outcomes.. Adipose-IR was greater in women with PCOS than in control subjects (P < 0.01), with 29 pmol/L × mmol/L providing 94% specificity and 80% sensitivity in discriminating the two groups (P < 0.001). Adipose-IR positively correlated with serum androgen and log of fasting triglyceride (TG) levels, percentage of small adipocytes (P < 0.01, all correlations), and acute insulin response to glucose (P < 0.05); and negatively correlated with insulin sensitivity (Si; P < 0.025) and serum adiponectin levels (P < 0.05). Adjusting for serum androgens, adipose-IR correlations with Si and log TG levels remained significant. ASC genes were differentially expressed by the two groups. Expression of functionally critical genes was associated with serum testosterone and/or fasting insulin levels.. Normal-weight women with PCOS have increased adipose-IR and altered ASC gene expression related to hyperandrogenism and IR.

Topics: Adiponectin; Adult; Female; Gene Expression Regulation; Humans; Insulin Resistance; Polycystic Ovary Syndrome; Subcutaneous Fat, Abdominal; Testosterone; Transforming Growth Factor beta; Triglycerides

Members of the TGF-β family have been implicated in aberrant follicle development in women with polycystic ovaries (PCO).. Are there quantitative differences in the concentrations of TGF-β family members in fluid from human small antral follicles (hSAFs) in women with or without PCO?. Follicle fluids (FFs) were collected from 4- to 11-mm hSAFs obtained from women undergoing ovarian tissue cryopreservation for fertility preservation.. FFs from 16 women with PCO (FF = 93) and 33 women without PCO (FF = 92).. Intrafollicular concentrations of growth differentiation factor-9 (GDF9); anti-Müllerian hormone (AMH); inhibin-A and inhibin-B; total inhibin; activin-A, activin-B, and activin-AB; follistatin; follistatin-like-3; estradiol; and testosterone.. Activin-B concentrations were reported in hSAFs, and concentrations were 10 times higher than activin-A and activin-AB concentrations. Activin-B showed significant associations with other growth factors. Concentrations of inhibin-A and inhibin-B were significantly lower in FFs from women with PCO, especially in hSAFs <8 mm in diameter. AMH concentrations did not differ between the groups in hSAFs <8 mm; however, AMH remained high in hSAFs >8 mm in women with PCO but decreased in women without PCO. Estradiol was significantly lower in FFs from women with PCO and showed significant associations with AMH. Concentrations of GDF9 showed significantly higher concentrations in PCO FFs of follicles >6 mm.. Altered concentrations of TGF-β family members in hSAFs from women with PCO highlight altered growth factor signaling as a potential mechanism for follicle growth arrest.

Topics: Activins; Adolescent; Adult; Anti-Mullerian Hormone; Biomarkers; Case-Control Studies; Female; Follicular Fluid; Follistatin; Follow-Up Studies; Gene Expression Regulation; Growth Differentiation Factor 9; Humans; Inhibins; Ovarian Follicle; Ovary; Polycystic Ovary Syndrome; Prognosis; Transforming Growth Factor beta; Young Adult

The polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder with pathological mechanisms remain unclear. The following study investigates the ovarian hyperfibrosis forming via transforming growth factor-β (TGF-β) signaling pathway in Dehydroepiandrosterone (DHEA)- induced polycystic ovary syndrome (PCOS) rat model. We furthermore explored whether TGF-βRI inhibitor (SB431542) decreases ovarian fibrosis by counterbalancing the expression of fibrotic biomarkers.. Thirty female Sprague-Dawley rats were randomly divided into Blank group (n = 6), Oil group (n = 6), and Oil + DHEA-induced model group (n = 6 + 12). The model groups were established by subcutaneous injection of DHEA for 35 consecutive days. The 12 successful model rats were additionally divided in vehicle group (n = 6) and SB431542-treated group (n = 6). Vehicle group and SB431542-treated group, served as administration group and were intraperitoneally injected with DMSO and SB431542 for additional 14 consecutive days. Ovarian morphology, fibrin and collagen localization and expression in ovaries were detected using H&E staining, immunohistochemistry and Sirius red staining. The ovarian protein and RNA were examined using Western blot and RT-PCR.. In DHEA-induced ovary in rat, fibrin and collagen had significantly higher levels, while the main fibrosis markers (TGF-β, CTGF, fibronectin, a-SMA) were obviously upregulated. SB431542 significantly reduced the expression of pro-fibrotic molecules (TGF-β, Smad3, Smad2, a-SMA) and increased anti-fibrotic factor MMP2.. TGF-βRI inhibitor (SB431542) inhibits the downstream signaling molecules of TGF-β and upregulates MMP2, which in turn prevent collagen deposition. Moreover, ovarian hyperfibrosis in DHEA-induced PCOS rat model could be improved by TGF-βRI inhibitor (SB431542) restraining the transcription of accelerating fibrosis genes and modulating EMT mediator.

Topics: Animals; Biomarkers; Dehydroepiandrosterone; Disease Models, Animal; Estrous Cycle; Female; Fibrosis; Flow Cytometry; Gene Expression Profiling; Gene Expression Regulation; Hormones; Immunohistochemistry; Polycystic Ovary Syndrome; Rats; Signal Transduction; Transforming Growth Factor beta

Plasminogen activator inhibitor-1 (PAI-1) is elevated in women with polycystic ovary syndrome (PCOS), but the regulation in granulosa cells (GCs) is unclear.. PAI-1 expression in PCOS ovaries was investigated immunohistologically. PAI-1 expressions in HGrC1, a human GC cell line, were investigated at mRNA and activity levels. The expressions of TGF-β and TNF-α in peritoneal fluid mononuclear cells (PFMCs) were measured with quantitative PCR.. Little PAI-1 expression is observed in healthy GCs, whereas GCs of PCOS and atretic follicle exhibit distinct expression in vivo. In vitro study using HGrC1 shows that TGF-β and TNF-α increase PAI-1 mRNA and its activity, and both together exhibit a synergistic effect. The expression of PAI-1 mRNA is suppressed by simvastatin. Moreover, insulin-sensitizing drugs (metformin, pioglitazone, and rosiglitazone) suppress LPS-induced TGF-β and TNF-α mRNA expression in PFMC.. Statin and insulin-sensitizing drugs may provide a potential therapy for PCOS via down-regulation of PAI-1 expression in GCs and down-regulation of TGF-β and TNF-α expression in PFMC, respectively.

Topics: Ascitic Fluid; Cell Line; Female; Granulosa Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Leukocytes, Mononuclear; Lipopolysaccharides; Ovarian Follicle; Plasminogen Activator Inhibitor 1; Polycystic Ovary Syndrome; Protein Kinase Inhibitors; RNA, Messenger; Simvastatin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Aberrant signaling between germ cells and somatic cells can lead to reproductive disease and depends on diffusible signals, including transforming growth factor-beta (TGFB) -family proteins. The TGFB-family protein Gsdf (gonadal soma derived factor) controls sex determination in some fish and is a candidate for mediating germ cell/soma signaling.. Zebrafish expressed gsdf in somatic cells of bipotential gonads and expression continued in ovarian granulosa cells and testicular Sertoli cells. Homozygous gsdf knockout mutants delayed leaving the bipotential gonad state, but then became a male or a female. Mutant females ovulated a few oocytes, then became sterile, accumulating immature follicles. Female mutants stored excess lipid and down-regulated aromatase, gata4, insulin receptor, estrogen receptor, and genes for lipid metabolism, vitellogenin, and steroid biosynthesis. Mutant females contained less estrogen and more androgen than wild-types. Mutant males were fertile. Genomic analysis suggests that Gsdf, Bmp15, and Gdf9, originated as paralogs in vertebrate genome duplication events.. In zebrafish, gsdf regulates ovarian follicle maturation and expression of genes for steroid biosynthesis, obesity, diabetes, and female fertility, leading to ovarian and extra-ovarian phenotypes that mimic human polycystic ovarian syndrome (PCOS), suggesting a role for a related TGFB signaling molecule in the etiology of PCOS. Developmental Dynamics 246:925-945, 2017. © 2017 Wiley Periodicals, Inc.

Topics: Adult Stem Cells; Animals; Female; Gene Expression Regulation, Developmental; Gonads; Humans; Male; Ovarian Follicle; Polycystic Ovary Syndrome; Transforming Growth Factor beta; Zebrafish Proteins

Do dehydroepiandrosterone (DHEA)-treated rats with polycystic ovary syndrome (PCOS) demonstrate a high level of fibrosis in ovarian and uterine tissues?. DHEA induces ovarian and uterine hyperfibrosis in rats, probably involving a transforming growth factor-β (TGF-β)-dependent mechanism.. Chronic inflammation is the typical cause of fibrosis and is involved in the pathophysiological process of PCOS. Patients with PCOS are reported to have a higher serum level of TGF-β, a well-characterized key pro-fibrotic factor. Fibrillin-3, a protein capable of interacting with TGF-β, has been reported to be partially responsible for the fetal origin of PCOS.. Female Sprague-Dawley rats were treated with a vehicle control or DHEA for 35 days, with subsequent analyses of changes in morphology and gene expression in ovarian and uterine tissues. Rescue groups treated with metformin or simvastatin and their corresponding controls were also analyzed. A total of 80 rats were included.. The PCOS model was induced by daily administration of DHEA s.c. to 3-week-old female rats, and the rescue groups were injected daily with either metformin or simvastatin in addition to DHEA. Serum steroid hormone levels were measured by enzyme-linked immunosorbent assay. Samples were stained with hematoxylin and eosin for histological morphology, and Sirius Red and immunohistochemistry for revealing collagens. The expression of fibrosis-related genes was analyzed both at mRNA (real-time RT-PCR) and protein (western blot) levels.. DHEA-induced rats with PCOS exhibited significantly higher levels of fibrosis (collagen IV) in both ovarian and uterine tissues. In ovarian tissue, the expression of connective tissue growth factor (CTGF) increased following DHEA treatment at both mRNA and protein levels (P < 0.05, P < 0.001 versus controls, respectively). Similar results versus controls were obtained at a protein level for TGF-β (P < 0.01) and mRNA level for fibronectin (P < 0.05) and angiotensin-II (P < 0.05). Likewise, in uterine tissue, the protein levels of both CTGF and TGF-β were higher than controls following DHEA treatment (P < 0.05). Treatment with either metformin or simvastatin attenuated the fibrosis progression induced by DHEA exposure, as evidenced by a reduction of TGF-β, plus CTGF or not, in both ovarian and uterine tissues.. The particular mechanism involved in the DHEA-induced fibrosis was not fully revealed.. Ovarian and uterine hyperfibrosis may occur in patients with PCOS and result in anovulation or other PCOS-related phenotypes. Anti-fibrotic therapy, for example metformin treatment, may be beneficial for patients with PCOS.. This study was supported by the National Natural Science Foundation of China (81170541) and the Natural Basic Research Program of China (973 program 2010CB945103). The authors declare no conflicts of interest.

Topics: Animals; Dehydroepiandrosterone; Female; Fibrosis; Hypoglycemic Agents; Hypolipidemic Agents; Metformin; Ovarian Diseases; Polycystic Ovary Syndrome; Rats; Rats, Sprague-Dawley; Simvastatin; Transforming Growth Factor beta; Uterine Diseases

To explore the Intervention effect of Rosiglitozone in ovarian fibrosis of PCOS rats.. 60 female SD rats were randomly divided into 3 groups: control group, model group and treatment group. The model and treatment groups were established by subcutaneous injection of DHEA, while the treatment group was given RGZ. The serum hormone values, pathohistology of ovarian structure of rats, ovarian ultrastructure and the expressions of TGF-β(1) and CTGF were detected.. The PCOS model was established successfully. The expression intensity of TGF-β(1) and CTGF in Oocytes of the PCOS groups was 9.545±2.954 and 9.665±2.400, respectively and was significantly higher than that of the control group 6.636±2.264 and 7.036±2.133; after treatment with rosiglitazone, the expression was significantly decreased 6.980±2.421 and 6.642±2.721 as compared with that of the model group (P<0.05, P<0.001). The values in serum of the PCOS groups were 3.749±2.054 and 0.265±0.129, and 1.914±1.801 and 0.096±0.088 in the control group which had statistically significant difference (P<0.05, P<0.001). After treatment with rosiglitazone, the values were 2.3100±1.825 and 0.112±0.187 and were significantly different with those of the model group (P<0.05, P<0.001).. TGF-β(1) and CTGF play an important role in the development of ovary fibrosis in PCOS. However, RGZ may postpone the development of fibrosis by decreasing the levels of TGF-β(1) and CTGF.

Topics: Animals; Connective Tissue Growth Factor; Female; Fibrosis; Hypoglycemic Agents; Ovary; Polycystic Ovary Syndrome; Random Allocation; Rats; Rats, Sprague-Dawley; Rosiglitazone; Thiazolidinediones; Transforming Growth Factor beta

Although not often discussed, the ovaries of women with polycystic ovary syndrome (PCOS) show all the hallmarks of increased TGF-β activity, with increased amounts of fibrous tissue and collagen in the ovarian capsule or tunica albuginea and ovarian stroma. Recent studies suggest that PCOS could have fetal origins. Genetic studies of PCOS have also found linkage with a microsatellite located in intron 55 of the extracellular matrix protein fibrillin 3. Fibrillins regulate TGF-β bioactivity in tissues by binding latent TGF-β binding proteins. We therefore examined expression of fibrillins 1-3, latent TGF-β binding proteins 1-4, and TGF-β 1-3 in bovine and human fetal ovaries at different stages of gestation and in adult ovaries. We also immunolocalized fibrillins 1 and 3. The results indicate that TGF-β pathways operate during ovarian fetal development, but most important, we show fibrillin 3 is present in the stromal compartments of fetal ovaries and is highly expressed at a critical stage early in developing human and bovine fetal ovaries when stroma is expanding and follicles are forming. These changes in expression of fibrillin 3 in the fetal ovary could lead to a predisposition to develop PCOS in later life.

Topics: Animals; Cattle; Female; Fibrillins; Gene Expression Regulation, Developmental; Humans; Immunohistochemistry; Latent TGF-beta Binding Proteins; Microfilament Proteins; Ovarian Follicle; Ovary; Polycystic Ovary Syndrome; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Transforming Growth Factor beta3

The pathogenesis of polycystic ovary syndrome (PCOS) is poorly understood. PCOS-like phenotypes are produced by prenatal androgenization (PA) of female rhesus monkeys. We hypothesize that perturbation of the epigenome, through altered DNA methylation, is one of the mechanisms whereby PA reprograms monkeys to develop PCOS. Infant and adult visceral adipose tissues (VAT) harvested from 15 PA and 10 control monkeys were studied. Bisulfite treated samples were subjected to genome-wide CpG methylation analysis, designed to simultaneously measure methylation levels at 27,578 CpG sites. Analysis was carried out using Bayesian Classification with Singular Value Decomposition (BCSVD), testing all probes simultaneously in a single test. Stringent criteria were then applied to filter out invalid probes due to sequence dissimilarities between human probes and monkey DNA, and then mapped to the rhesus genome. This yielded differentially methylated loci between PA and control monkeys, 163 in infant VAT, and 325 in adult VAT (BCSVD P<0.05). Among these two sets of genes, we identified several significant pathways, including the antiproliferative role of TOB in T cell signaling and transforming growth factor-β (TGF-β) signaling. Our results suggest PA may modify DNA methylation patterns in both infant and adult VAT. This pilot study suggests that excess fetal androgen exposure in female nonhuman primates may predispose to PCOS via alteration of the epigenome, providing a novel avenue to understand PCOS in humans.

Topics: Androgens; Animals; Animals, Newborn; Bayes Theorem; DNA Methylation; Epigenesis, Genetic; Female; Intra-Abdominal Fat; Macaca mulatta; Pilot Projects; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Complications, Neoplastic; Prenatal Exposure Delayed Effects; Signal Transduction; Transforming Growth Factor beta; Virilism

Endocrine factors appear to play an important part in arrest of antral follicle maturation in polycystic ovary syndrome (PCOS) but are unlikely to have an impact on early, preantral follicle development, which is clearly abnormal in PCOS. Disordered early folliculogenesis in PCOS is characterised by a higher proportion of follicles entering the growing phase and more prolonged survival of small follicles than in normal ovarian tissue. The factors responsible for aberrant preantral follicle development remain to be determined but IGFs, growth factors of the TGFbeta family and androgens may all have a role.

Topics: Anovulation; Anti-Mullerian Hormone; Female; Growth Substances; Humans; Ovarian Follicle; Ovulation Induction; Polycystic Ovary Syndrome; Transforming Growth Factor beta

In an attempt to evaluate the association between allele 8 (A8) of D19S884 in the fibrillin-3 gene and circulating transforming growth factor (TGF) β and inhibin levels in women with polycystic ovary syndrome (PCOS), we studied 120 similarly aged women from families with PCOS and compared 40 women with PCOS who did not have A8 (A8- PCOS) with 40 women with PCOS who had A8 (A8+ PCOS) and 40 normally menstruating women who did not have either PCOS or A8 (A8- Non-PCOS). A8- PCOS is associated with higher levels of TGF-β1 compared with A8+ PCOS or A8- Non-PCOS, similar levels of TGF-β2 compared with A8+ PCOS but lower levels of TGF-β2 compared with A8- Non-PCOS, and lower levels of inhibin B and aldosterone compared with A8+ PCOS.

Topics: Adult; Alleles; Case-Control Studies; Female; Fibrillins; Genetic Predisposition to Disease; Genotype; Humans; Inhibins; Microfilament Proteins; Polycystic Ovary Syndrome; Polymorphism, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta2; Young Adult

Recent genome-wide association (GWA) studies have identified several novel genetic loci associated with age at menarche and age at natural menopause. However, the stringent significance threshold used in GWA studies potentially led to false negatives and true associations may have been overlooked. Incorporating biologically relevant information, we examined whether common genetic polymorphisms in candidate genes of nine groups of biologically plausible pathways and related phenotypes are associated with age at menarche and age at natural menopause. A total of 18,862 genotyped and imputed single nucleotide polymorphisms (SNPs) in 278 genes were assessed for their associations with these two traits among a total of 24,341 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 22,054). Linear regression was used to assess the marginal association of each SNP with each phenotype. We adjusted for multiple testing within each gene to identify statistically significant SNP associations at the gene level. To evaluate the overall evidence for an excess of statistically significant gene associations over the proportion expected by chance, we applied a one-sample test of proportion to each group of candidate genes. The steroid-hormone metabolism and biosynthesis pathway was found significantly associated with both age at menarche and age at natural menopause (P = 0.040 and 0.011, respectively). In addition, the group of genes associated with precocious or delayed puberty was found significantly associated with age at menarche (P = 0.013), and the group of genes involved in premature ovarian failure with age at menopause (P = 0.025).

Topics: Adolescent; Age Factors; Age of Onset; Child; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Gonadal Steroid Hormones; Humans; Linear Models; Menarche; Menopause; Middle Aged; Nurses; Obesity; Phenotype; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Primary Ovarian Insufficiency; Puberty, Delayed; Puberty, Precocious; Signal Transduction; Smoking; Somatomedins; Thrombophilia; Tobacco Use Disorder; Transforming Growth Factor beta; Women's Health

Production of transforming growth factor-beta(2)mRNA in the endometrium of women with polycystic ovary syndrome decreased compared to normal and this decrease directly depends on the duration of anovulatory period (from 3 weeks to 4 months). Low production of transforming growth factor-beta(2)mRNA probably contributes to the development of endometrial hyperplasia in women with polycystic ovary syndrome.

Topics: Base Sequence; DNA Primers; Endometrium; Female; Humans; Polycystic Ovary Syndrome; RNA, Messenger; Transforming Growth Factor beta

To investigate intrafollicular insulin-like growth factor II (IGF-II) in patients affected with polycystic ovary syndrome (PCOS) in comparison with normal women.. Insulin-like growth factor-II was determined in 103 follicular fluids (FF) from normally ovulating women and in 102 FF from patients with PCOS. Ribonucleic acid was extracted from granulosa cells of follicles obtained from control and PCOS patients and from tissue from polycystic ovaries.. Procedures were performed in a university laboratory.. Twenty-nine normally ovulating women and 19 patients with PCOS underwent ovulation induction for IVF-ET with LH-releasing hormone (LH-RH) analog and gonadotropins. Eleven of them, 4 to 8 months later, underwent ovulation induction with approximately the same dosage of gonadotropins plus a standard dosage of GH.. Intrafollicular IGF-II, IGF-I, epidermal growth factor (EGF), transforming growth factor beta 2, (TGF-beta 2), inhibin, and steroids were evaluated by appropriate RIA, immunoenzymatic assay (EIA), and ELISA assays. The expression of the gene encoding IGF-II was analyzed by Northern blot.. Intrafollicular IGF-II was lower in PCOS than in controls. Accordingly, IGF-II messenger RNA expression was lower in PCO than in normal granulosa cells. Several differences in FF IGF-I, EGF, inhibin, and TGF-beta 2 concentrations were observed between PCOS and controls.. Both IGF-II and IGF-I were reduced in PCOS, confirming a possible role of an IGF imbalance in the development of this disease.

Topics: Adult; Case-Control Studies; Epidermal Growth Factor; Estradiol; Female; Follicular Fluid; Granulosa Cells; Humans; Inhibins; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Ovulation; Polycystic Ovary Syndrome; Progesterone; RNA, Messenger; Transforming Growth Factor beta