Exercise decreases anti-müllerian hormone in anovulatory overweight women with polycystic ovary syndrome: a pilot study

Polycystic ovary syndrome (PCOS) is a common condition in women associated with menstrual irregularity and anovulation. While obesity worsens and weight loss or exercise improves reproduction function in PCOS, the mechanism for this is unclear. The aim of this study was to examine the effect of exercise on ovarian hormones [anti-Müllerian hormone (AMH)] and menstrual and ovulatory function in women with and without PCOS. Overweight women with (n=7) and without (n=8) PCOS of comparable age, weight and BMI undertook a 12-week intensified endurance exercise training program (1?h 3 times/week) with no structured energy restriction. Primary outcomes were AMH, ovulation (weekly urinary pregnanediol) and menstrual regularity. Secondary outcomes were insulin resistance (euglycemic hyperinsulinemic clamp) and body composition (computed tomography and dual X-ray absorptiometry). Exercise decreased BMI, total and android fat mass and improved insulin sensitivity for all women. AMH was significantly higher in women with PCOS compared to controls before (p<0.001) and after exercise (p=0.001). There was a significant interaction between AMH changes with exercise and PCOS status (p=0.007) such that women without PCOS had no change in AMH (+1.4±5.2?pmol/l, p=0.48) while women with PCOS had a decrease in AMH (-?13.2±11.7?pmol/l, p=0.025). Exercise is associated with improvements in ovarian hormones in women with abnormal ovarian function. This suggests that mechanisms associated with ovarian dysfunction can be improved by exercise in PCOS.     

Current and future aspects of several adjunctive treatment strategies in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age. PCOS is characterized by hyperandrogenism, menstrual disorders, and polycystic ovarian morphology. PCOS patients have an increased risk of type 2 diabetes, cardiovascular disease, and infertility. The mechanism of PCOS is not yet fully understood, but insulin resistance and genetic factors may play distinct roles in the pathomechanism.There is ongoing research on new therapeutic modalities for women with PCOS. In this minireview, we assessed the evidence for the effectiveness and safety of selected adjunctive agents (metformin, statins, resveratrol, melatonin, and inositols) for the treatment of women with PCOS. Metformin is a safe medication used in PCOS for 25 years that is currently recommended in select PCOS subpopulations, such as adolescents, women with metabolic disorders, and infertility infertile women undergoing ovarian hyperstimulation. Statins are also suggested in PCOS therapy, as these compounds decrease testosterone concentrations, improve lipid profiles, and ameliorate inflammatory reactions. Despite promising results, the role of statins in PCOS management needs to be further validated. Dietary supplements have also been tested in PCOS patients. Resveratrol was shown to decrease total testosterone production and improve fasting insulin but, until recently, only in one randomized study. Data on the therapeutic efficacy of melatonin and inositols on endocrine and metabolic abnormalities are limited and inconclusive. The multifactorial etiology of PCOS makes tailoring of its treatment more demanding, and there is a constant need for causative and effective modes of PCOS therapy.     

Association of insulin resistance with hyperandrogenia in women

In humans, the skin is a target tissue for androgen action; hair growth and sebum secretion are under active androgen control. An increased production or metabolism of testosterone, the main active androgen, shows up clinically in dermatological symptoms such as hirsutism, hyperseborrheic acne and alopecia. Polycystic ovary syndrome (PCOS) is the most frequent androgen disorder of ovarian function. PCOS patients have amenorrhea or severe oligomenorrhea, increased testosterone levels and most often enlarged polycystic ovaries on ultrasound examination. In addition, many PCOS patients have a tendency to accumulate abdominal fat and/or to develop obesity. Some also display a particular metabolic pattern including an atherogenic lipid profile, glucose intolerance and an increased fasting insulin level, which is known to be closely linked with an insulin resistant state. Several studies have now reported that PCOS patients show increased incidence of type 2 diabetes and cardiovascular disease. In addition to being a target for androgens the skin has abundant insulin receptors on the keratinocyte surface membrane and acanthosis nigricans is a common symptom of severe insulin resistance among patients with insulin receptor disorders. However, acanthosis nigricans could also be present in PCOS women given evidence of the intensity of their insulin resistance. This presentation will review the mutual relationship between hyperandrogenia and insulin resistance, with particular attention paid to: (1) insulin secretion and insulin sensitivity in PCOS; (2) the complexity of the molecular mechanisms involved in insulin resistance; (3) the paradoxical relationship between insulin resistance and hyperandrogenia; (4) the current genetic studies; and (5) new avenues for long-term treatment of PCOS women.     

Endocrine characteristics of polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is probably the most prevalent endocrinopathy in women and the most common cause of anovulatory infertility. Patients with PCOS have clinical and biochemical features consistent with the ultrasound diagnosis and they are likely to face the problems of hyperandrogenism, subfertility and recurrent miscarriage. The aim of the present review is to summarize our present knowledge on the hormonal background of this very prevalent syndrome and to give some clinical examples how the present knowledge can be applied to treat PCOS patients according to their current problem, such as menstrual cycle disorder, hirsutism, infertility or to prevent late consequences as diabetes mellitus. The etiology and pathogenesis of PCOS is still a matter of controversies, but it is apparent that inappropriate gonadotropin secretion, obesity, hyperinsulinism and insulin resistance are the major determining factors in the development of ovarian hyperandrogenism an chronic anovulation. Reversal of insulin resistance in PCOS constitutes the fundamental goal in the management of hyperandrogenic anovulatory infertility and in the prevention of long-term consequences. The value of the insulin sensitizer metformin therapy awaits further evaluation and it should be integrated in the spectrum of therapeutical options that include the discussed surgical methods and GnRH analogues as well.     

多囊卵巢综合征伴胰岛素抵抗的研究进展

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是国内外研究者、医患人员非常关心的育龄期妇女常见的内分泌代谢疾病,其主要表现为闭经、月经量减少、肥胖、不孕、体多毛等。多数伴有胰岛素抵抗（insulin resistance,IR）的发生,胰岛素抵抗（insulin resistance,IR）是指正常水平的胰岛素促进葡萄糖摄取及利用能力下降,机体各组织、器官代偿性分泌胰岛素以维持机体血糖稳定的一种代谢状态。近年来的研究不断证实PCOS患者2型糖尿病、血脂代谢紊乱及代谢综合征（metabolicsyndrome,MS）等并发症的发病率明显增高。运动能够改善2型糖尿病患者胰岛素抵抗的说法已经得到了共识,其分子机制也逐渐分明。PCOS患者胰岛素抵抗的研究目前仍处于进一步探讨阶段,但是经过近几年的努力已经有了新的进展,若在PCOS胰岛素抵抗患者的治疗过程中给予一定的运动干预,相信一定能够有新的突破。本文就PCOS患者胰岛素抵抗研究的机制、诊断及治疗方法的新进展简单做一综述。     

Pathophysiological roles of chronic low‐grade inflammation mediators in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common hormonal imbalance disease in reproductive‐aged women. Its basic characteristics are ovulatory dysfunction and ovarian overproduction of androgens that lead to severe symptoms such as insulin resistance, hirsutism, infertility, and acne. Notwithstanding the disease burden, its underlying mechanisms remain unknown, and no causal therapeutic exists. In recent years, further studies showed that inflammation processes are involved in ovulation and play a key role in ovarian follicular dynamics. Visceral adipose tissue can cause inflammatory response and maintenance of the inflammation state in adipocytes by augmented production of inflammatory cytokines, monocyte chemoattractant proteins, and recruitment of the immune cell. Therefore, the PCOS can be related to a low‐grade inflammation state and inflammatory markers. Investigating the inflammatory processes and mediators that contribute to the commencement and development of PCOS can be a critical step for better understanding the pathophysiology of the disease and its treatment through inhibition or control of related pathways. In the present review, we discuss the pathophysiological roles of chronic low‐grade inflammation mediators including inflammasome‐related cytokines, interleukin‐1β (IL‐1β), and IL‐18 in PCOS development.     

Medical management of metabolic dysfunction in PCOS

Polycystic ovary syndrome (PCOS) is associated with metabolic derangements including insulin resistance, dyslipidemia, systemic inflammation and endothelial dysfunction. There is a growing need to develop pharmacologic interventions to improve metabolic function in women with PCOS. Medications that have been tested in patients with PCOS include metformin, thiazolidinediones, acarbose, naltrexone, orlistat, vitamin D and statins. Metformin decreases hepatic gluconeogenesis and free fatty acid oxidation while increasing peripheral glucose uptake. Early studies in PCOS suggested that metformin indirectly reduces insulin level, dyslipidemia and systemic inflammation; however, recent placebo-controlled trials failed to demonstrate significant metabolic benefit. Thiazolidinediones act primarily by increasing peripheral glucose uptake. Most studies in PCOS have demonstrated that thiazolidinediones reduce insulin resistance; however, effects on dyslipidemia were disappointing. Use of thiazolidinediones is associated with weight gain and major complications. Acarbose reduces digestion of polysaccharides. Studies in PCOS yielded inconsistent effects of acarbose on insulin sensitivity and no significant improvement of dyslipidemia. Naltrexone reduces appetite and modulates insulin release; its use in PCOS may reduce hyperinsulinemia. Orlistat decreases absorption of dietary fats; studies in PCOS suggest beneficial effects on insulin sensitivity. Vitamin D may improve insulin sensitivity but mixed results on lipid profile in PCOS have been reported. Statins are competitive inhibitors of the key enzyme regulating the mevalonate pathway; their effects are related to reduced cholesterol production as well as anti-inflammatory and anti-oxidant properties. In women with PCOS, statins reduce hyperandrogenism, improve lipid profile and reduce systemic inflammation while the effects on insulin sensitivity are variable. Use of statins is contraindicated in pregnancy.     

Altered Trace Mineral Milieu Might Play An Aetiological Role in the Pathogenesis of Polycystic Ovary Syndrome

Insulin resistance is a very common associate of polycystic ovary syndrome (PCOS). Pathophysiology in relation with the essential elements including copper, magnesium, zinc, manganese, chromium, and calcium has been reported in women with insulin resistance. This prospective study was designed to explore whether the women with PCOS do exhibit altered serum element levels in association with/without insulin resistance. One hundred and thirty-two women with PCOS and forty-six control women were studied. Women with PCOS were further divided based on the presence of insulin resistance (insulin resistant: n?=?50; non-insulin resistant: n?=?82). In all women, basal levels of gonadotropins, prolactin, testosterone, insulin, glucose, and the six different elements were measured. Serum levels of testosterone (p?<?0.001), luteinizing hormone (p?<?0.05), and fasting insulin (p?<?0.004) were significantly higher in the PCOS population compared to controls as well as PCOS women without insulin resistance. Women with PCOS exhibited a significantly high calcium (p?<?0.04) and lower manganese levels (p?<?0.002) when compared to controls. However, the PCOS women with insulin resistance exhibited significantly lower serum levels of magnesium and chromium (p?<?0.04), in addition to higher levels of zinc and copper (p?<?0.04). The differences in calcium (p?<?0.03) and manganese levels (p?<?0.0001) became aggravated with the presence of insulin resistance when compared to control as well as PCOS women without insulin resistance. In PCOS-associated insulin resistance, circulating serum magnesium (r?=??0.31; p?<?0.03) and chromium (r?=??0.38; p?<?0.006) status significantly correlated with fasting insulin levels. We conclude that imbalanced element status may be a key foundation for insulin resistance in PCOS. The findings in this study should be investigated with further trials in order to obtain new insights into PCOS.     

Steroidogenic alterations and adrenal androgen excess in PCOS

BACKGROUND: This cross-sectional study was undertaken to improve our understanding of the steroidogenic alterations leading to adrenal hyperandrogenism in polycystic ovarian syndrome (PCOS). METHODS: Two-hundred and thirty-four women with clinical and biochemical features suggestive of PCOS underwent metabolic and hormonal evaluation. We used the androstenedione/DHEAS ratio as a surrogate for the level of ovarian 3betaHSD activity. We then selected the 90th percentile for the ratio in those with elevated DHEAS (>9 micromol/l) as the cut-off level beyond which excess DHEAS production will be minimized by excess ovarian 3betaHSD activity. This cut-off level was at a ratio of 1.5 and all PCOS women were then divided into two groups, the higher (>1.5) being the group with excess ovarian 3betaHSD activity. We hypothesized that women with a high ratio would be unlikely to have DHEAS excess due to the rapid conversion of DHEA to androstenedione. Those with a low ratio (concordant ovarian and adrenal steroidogenesis) could then either have high DHEAS or normal DHEAS, depending on whether CYP17 activity was higher or lower respectively. RESULTS: Insulin resistance was found to be associated with decreased CYP17 activity while irregular cycles and neuroendocrine dysfunction were determined to be associated with higher ovarian 3betaHSD activity. CONCLUSION: Adrenal androgen excess in PCOS seems to be related to insulin sensitivity as well as decreased activity of 3betaHSD, the latter being preferentially present in those women with regular cycles or without neuroendocrine dysfunction.     

Identifying genes associated with the development of human polycystic ovary syndrome

The pathophysiology of polycystic ovary syndrome (PCOS) is confusing until today as it is a multifactorial endocrine disorder. It is presented with altered gonadotropin levels, bulky multi-follicular ovaries, infertility, and obesity. This complex pathophysiology is linked with insulin resistance and hyperandrogenism. Hyperandrogenemia significantly contributes towards cosmetic anomalies including hirsutism, acne, and alopecia in the PCOS women. The preexisting insulin resistance in women with PCOS is likely to aggravate the increased levels of androgen. The review findings have shown that in the steroidogenic pathway, ovarian steroidogenesis patterns classify mainly towards the hypertrophy of theca cells along with alteration in the expression of key enzymes. The association of polymorphisms in genes encoding the process of an intricate cascade of steroidogenesis is delineated. The emergence of an unanimously accepted genetic marker for susceptible PCOS was affected based on inconsistent findings. The present study has provided a comprehensive summary of the impact of polymorphisms among the common androgen-related genes to govern the genetic predisposition.     

Elevated ghrelin plasma levels in patients with polycystic ovary syndrome.

Polycystic ovary syndrome is a common endocrine disorder in women. It is associated with hirsuitism, obesity, insulin resistance, abnormality in the growth hormone/insulin-like growth factor I (IGF-1) axis and polycystic ovaries. The etiology of PCOS has not been clarified. Ghrelin is an endogenous ligand of the growth hormone secretagogue receptor. It is mainly secreted by stomach cells but has also been shown to be present in hypothalamus, pituitary, pancreas and gonads. Ghrelin is a regulator of energy homeostasis and GH secretion. The influence of ghrelin on insulin secretion and gonadal function is known. Since ghrelin may play an important role in pathophysiology of PCOS, we studied ghrelin levels in a group of 52 women with PCOS and in 16 women in a control group. Plasma levels of insulin, total testosterone, SHBG, LH, and FSH were also measured. In conclusion, PCOS women have higher ghrelin levels than controls. Ghrelin negatively correlates with BMI and insulin levels in PCOS group. A relation between ghrelin and SHBG was observed. Our data suggest that ghrelin could be the possible link in PCOS etiology.     

Molecular mechanisms of insulin resistance in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of unknown aetiology that affects women of reproductive age. During the past ten years, defective insulin activity in PCOS has been demonstrated in target tissues and causes insulin resistance and hyperinsulinaemia. Furthermore, presence of insulin receptors in the ovarian tissue and overproduction of androgens by theca cells leads to characteristic hyperandrogenaemia. Recent data suggest a divergence in post-receptor signalling pathways for insulin in its target tissues (muscle, adipocytes and ovarian tissue), where the metabolic pathway of insulin activity is defective, whereas the activation of steroidogenesis is maintained. Investigators are still searching for clues to understand the cause of this enigmatic syndrome, despite great advances in molecular medicine and genetics.     

Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS)

The polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age today. Women with PCOS often demonstrate defective ovarian steroid biosynthesis and present with hyperandrogenemia. Moreover, 50-70% of PCOS women are insulin resistant and hyperinsulinemic. Insulin acts on the ovary via its own receptor and interacts with gonadotrophins, modulating steroidogenesis. The precise role of insulin and the molecular mechanisms that take place are not yet completely explicated. This review will be focused on insulin's action on the ovary and other target tissues, describing the intracellular signaling pathways implicated in steroidogenesis and their defects in women with PCOS.     

Inflammation in Polycystic Ovary Syndrome: underpinning of insulin resistance and ovarian dysfunction

Chronic low-grade inflammation has emerged as a key contributor to the pathogenesis of Polycystic Ovary Syndrome (PCOS). A dietary trigger such as glucose is capable of inciting oxidative stress and an inflammatory response from mononuclear cells (MNC) of women with PCOS, and this phenomenon is independent of obesity. This is important because MNC-derived macrophages are the primary source of cytokine production in excess adipose tissue, and also promote adipocyte cytokine production in a paracrine fashion. The proinflammatory cytokine tumor necrosis factor-α (TNFα) is a known mediator of insulin resistance. Glucose-stimulated TNFα release from MNC along with molecular markers of inflammation are associated with insulin resistance in PCOS. Hyperandrogenism is capable of activating MNC in the fasting state, thereby increasing MNC sensitivity to glucose; and this may be a potential mechanism for promoting diet-induced inflammation in PCOS. Increased abdominal adiposity is prevalent across all weight classes in PCOS, and this inflamed adipose tissue contributes to the inflammatory load in the disorder. Nevertheless, glucose ingestion incites oxidative stress in normal weight women with PCOS even in the absence of increased abdominal adiposity. In PCOS, markers of oxidative stress and inflammation are highly correlated with circulating androgens. Chronic suppression of ovarian androgen production does not ameliorate inflammation in normal weight women with the disorder. Furthermore, in vitro studies have demonstrated the ability of pro-inflammatory stimuli to upregulate the ovarian theca cell steroidogenic enzyme responsible for androgen production. These findings support the contention that inflammation directly stimulates the polycystic ovary to produce androgens.     

Dyslipidemia in PCOS

Life-long apolipoprotein lipid metabolic dysfunction in women with PCOS exaggerates the risk for cardiovascular disease (CVD) with aging. The dysfunction has involved insulin resistance (IR), which occurs in most women with PCOS. Women with PCOS have androgen excess, IR, variable amounts of estrogen exposure, and many environmental factors, all of which can influence lipid metabolism. On average, women with PCOS were higher triglyceride [26.39 95% CI (17.24, 35.54)], lower HDL-cholesterol [6.41 95% CI (3.69, 9.14)], and higher non HDL cholesterol levels [18.82 95% CI (15.53, 22.11)] than their non-PCOS counterparts. They have higher ApoCIII/ApoCII ratios and higher ApoCI even if they are not obese. ApoC1 elevation in women with PCOS needs to be further evaluated as a marker of dysfunction and potential CVD risk. ApoB measurements track with non-HDL cholesterol as a surrogate for increased atherogenic circulating small LDL particles. Elevated triglycerides and waist circumference predict CVD risk and women with PCOS often have these phenotypes. Diet and exercise interventions followed by selective lipid lowering medications are encouraged to normalize the dyslipidemia.     

Endometrial progesterone resistance and PCOS

Polycystic ovary syndrome (PCOS) is a state of altered steroid hormone production and activity. Chronic estrogen exposure or lack of progesterone due to ovarian dysfunction can result in endometrial hyperplasia and carcinoma. A key contributor to our understanding of progesterone as a critical regulator for normal uterine function has been the elucidation of progesterone receptor (PR) expression, regulation, and signaling pathways. Several human studies indicate that PR-mediated signaling pathways in the nucleus are associated with progesterone resistance in women with PCOS. The aim of this review is to provide an overview of endometrial progesterone resistance in women with PCOS; to present the PR structure, its different isoforms, and their expression in the endometrium; to illustrate the possible regulation of PR and PR-mediated signaling in progesterone resistance in women with PCOS; and to discuss current clinical treatments for atypical endometrial hyperplasia and endometrial carcinoma in women with PCOS and accompanying progesterone resistance.     

Programmed cell death 4: A novel player in the pathogenesis of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a pathological condition recognized by menstrual cycle irregularities, androgen excess, and polycystic ovarian morphology, affecting a significant proportion of women of childbearing age and accounting for the most prevalent cause of anovulatory sterility. In addition, PCOS is frequently accompanied by metabolic and endocrine disturbances such as obesity, dyslipidemia, insulin resistance, and hyperinsulinemia, indicating the multiplicity of mechanisms implicated in the progression of PCOS. However, the exact pathogenesis of PCOS is yet to be elucidated. Programmed cell death 4 (PDCD4) is a ubiquitously expressed protein that contributes to the regulation of various cellular processes, including gene expression, cell cycle progression, proliferation, and apoptosis. Despite some disparities concerning its exact cellular effects, PDCD4 is generally characterized as a protein that inhibits cell cycle progression and proliferation and instead drives the cell into apoptosis. The apoptosis of granulosa cells (GCs) is speculated to take a major part in the occurrence and progression of PCOS by ceasing antral follicle development and compromising oocyte competence. Given the possible involvement of GC apoptosis in the progression of PCOS, as well as the contribution of PDCD4 to the regulation of cell apoptosis and the development of metabolic diseases, the current review aimed to discuss whether or how PDCD4 can play a role in the pathogenesis of PCOS by affecting GC apoptosis.     

Metabolic syndrome in polycystic ovary syndrome

Both metabolic syndrome (MS) and polycystic ovary syndrome (PCOS) are common among women. The exact prevalence of MS in women with PCOS is dependent upon the diagnostic criteria used for each. However, the frequent co-occurrence of both MS and PCOS in women is suggestive of a common aetiology. In this short review article we argue that insulin resistance, as a consequence of abdominal obesity, may represent such a common aetiology. We also review the literature on the prevalence of MS in women with PCOS and consider the impact that the particular criteria used to diagnose both MS and PCOS may have had on these estimates of prevalence.     

Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome

The polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, is one of the most common hormonal disorders among premenopausal women and is associated with infertility, obesity, and insulin resistance. Accumulating evidence suggests a role of the blood coagulation factor gene F13A1 in obesity (GeneBank ID: NM_000129.3). The aim of this study was to investigate the association of intronic allelic variants of the F13A1 gene with PCOS susceptibility and metabolic parameters in lean and obese PCOS women. In a case-control study, we determined an intronic F13A1 single nucleotide polymorphism (SNP) (dbSNP ID: rs7766109) in 585 PCOS and 171 control women and tested for PCOS susceptibility and associations with anthropometric, metabolic and hormonal parameters. Genotype frequencies of the F13A1 SNP rs7766109 were equivalent in PCOS and control women. In PCOS women, F13A1 gene variants were significantly associated with body mass index (BMI) (p=0.013), systolic blood pressure (p=0.042), insulin response (AUCins) (p=0.015), triglycerides (TG) (p=0.001), and high density lipoprotein cholesterol (HDL) (p=0.012). In the subgroup of obese PCOS women free androgen index (FAI), free testosterone and sex hormone binding globulin (SHBG) as well as glucose measurements showed a significantly different pattern across F13A1 gene variants (p=0.043; p=0.039 and p=0.013, respectively). We report for the first time an association of the F13A1 SNP rs7766109 with BMI, androgens, and insulin resistance in PCOS women. Further studies are needed to confirm our findings and to evaluate whether F13A1 is causally involved in the pathogenesis of PCOS related metabolic and hormonal disturbances.