Optimizing ovulation induction in women with polycystic ovary syndrome

Recent developments in our understanding of the pathophysiology of polycystic ovary syndrome led to the introduction of new therapeutic approaches. It is apparent that a significant proportion of women with polycystic ovary syndrome have insulin resistance and compensatory hyperinsulinemia. Growing evidence indicates that elevated serum insulin induces hyperandrogenism, which in turn leads to anovulation and infertility. Hyperinsulinemia also contributes to the increased risk for cardiovascular disorders and type 2 diabetes mellitus. These concepts provide rationale for therapies focused on treatments of insulin resistance. In particular, weight loss and exercise have been shown to increase insulin sensitivity and improve ovulatory function. Metformin, an insulin-sensitizing agent, is particularly effective in women with polycystic ovary syndrome who have significant insulin resistance. Metformin use leads to a decrease in serum insulin and androgen levels as well as an improvement in ovulatory function. Moreover, it appears to ameliorate cardiovascular risk factors. Other approaches to ovulation induction in women with polycystic ovary syndrome include traditional therapies using clomiphene citrate or gonadotropins. In clomiphene-resistant subjects, one can consider laparoscopic ovarian drilling and other forms of partial ovarian resection or destruction.     

Visceral adiposity index as a predictor of clinical severity and therapeutic outcome of PCOS

Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disease which often accompany with abnormal fat distribution. Visceral adiposity has association with abnormal lipid metabolic, pro-inflammatory activity, insulin resistance (IR) and hyperandrogenism. Increased visceral adiposity raises the risk of metabolic syndrome, type 2 diabetes and cardiovascular (CV) events, and aggravates ovulatory dysfunction and hyperandrogenism in PCOS women. Visceral adiposity index (VAI), a simple surrogate maker of visceral adipose dysfunction and visceral adiposity, is a predictor of IR, and link hyperinsulinemia, hyperandrogenism and anovulation. This review aims to discuss the visceral adiposity situation in PCOS women, and suggests that VAI may be a useful predictor of clinical severity and therapeutic outcome of PCOS.     

Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity

OBJECTIVE: To assess the role of insulin resistance, independent of obesity, in determining cardiovascular risk among women with the polycystic ovarian syndrome (PCOS). DESIGN: Cross-sectional study examining the relationships between hyperinsulinemia, composite cardiovascular risk scores, and prevalence of individual risk factors among lean and obese women with PCOS and healthy controls. SETTING: University-based tertiary care outpatient endocrinology clinic. PATIENT(S): 57 women with clinically defined PCOS and 45 unselected healthy age-matched controls. INTERVENTION(S): Clinical and anthropomorphic measurements and laboratory determinations of insulin and lipid levels. MAIN OUTCOME MEASURE(S): Fasting serum insulin and a cardiovascular risk score. RESULTS: Hyperinsulinemic women with PCOS carried more cardiovascular risk than their normoinsulinemic counterparts, who in turn had more risk than the control women (P=.004 by analysis of covariance). In addition to the lipid changes expected with insulin resistance (high triglyceride and low HDL cholesterol levels), there was an excess of LDL cholesterol among the women with PCOS (P=.006 by analysis of covariance). Across the range of body mass index, women with PCOS had greater insulin resistance than controls, suggesting that PCOS itself and body mass index both contribute to the observed insulin resistance. CONCLUSIONS: Our data support the hypothesis that insulin resistance in PCOS is a determinant of overall cardiovascular risk independent of obesity. The mechanism of this relationship remains uncertain and is the subject of ongoing research.     

Dyslipidemia involvement in the development of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is widely accepted as the most common endocrine abnormality in women of childbearing age and may be accompanied by dyslipidemia, hyperandrogenism, hyperinsulinemia, oxidative stress and infertility. Dyslipidemia is now known to play an important role in the development of PCOS. Lipid abnormalities, including elevated low-density lipoprotein and triglyceride levels and reduced high-density lipoprotein levels, are often found in women with PCOS and play an important role in PCOS; therefore, we summarize the effect of lipid abnormalities on hyperandrogenism, insulin resistance, oxidative stress and infertility in PCOS and review the effects of common lipid-lowering drugs on patients with PCOS. The purpose of this article is to elucidate the mechanisms of lipid metabolism abnormalities in the development of PCOS.     

Hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome: a common endocrinopathy with distinct pathophysiologic features

The HAIR-AN syndrome that consists of hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) is an underdiagnosed endocrinopathy, because hyperandrogenic women are not commonly screened for insulin resistance or acanthosis nigricans. The distinct pathophysiologic features of the HAIR-AN syndrome are discussed in detail. In this syndrome, the primary pathophysiologic derangements are the insulin resistance and the hyperandrogenism. The acanthosis nigricans is an epiphenomenon of these primary processes. In patients with the HAIR-AN syndrome, the degree of severity of the insulin resistance is positively correlated with the degree of severity of the hyperandrogenism. In patients with adequate pancreatic beta-islet cell reserve, insulin resistance results in a long-term increase in circulating insulin levels. The hyperinsulinemia probably directly stimulates ovarian androgen production. In turn, hyperandrogenism itself produces insulin resistance. This positive feedback loop between insulin resistance and hyperandrogenism propagates the disease, and increases its severity over time. The relationship between insulin resistance and hyperandrogenism may explain the hyperandrogenemia seen in the following disease processes: obesity, acromegaly, lipoatrophic diabetes, leprechaunism, and Kahn types A and B insulin resistance.     

Polycystic ovary syndrome

Women with polycystic ovarian syndrome have chronic anovulation and androgen excess not attributable to another cause. This condition occurs in approximately 4% of women. The fundamental pathophysiologic defect is unknown, but important characteristics include insulin resistance, hyperandrogenism, and altered gonadotropin dynamics. Inadequate follicle-stimulating hormone is hypothesized to be a proximate cause of anovulation. Obesity frequently complicates polycystic ovarian syndrome but is not a defining characteristic. The diagnostic approach should be based largely on history and physical examination, thus avoiding numerous laboratory tests that don't contribute to clinical management. Women with polycystic ovarian syndrome typically present because of irregular bleeding, hirsutism, and/or infertility. These conditions can be treated directly with oral contraceptives, oral contraceptives plus spironolactone, and ovulation induction, respectively. However, women with polycystic ovarian syndrome also have a substantially higher prevalence of diabetes and increased risk factors for cardiovascular disease. They should also be screened, therefore, for these conditions and followed closely if any risk factors are uncovered. For obese women with polycystic ovarian syndrome, behavioral weight management is a central component of the overall treatment strategy.     

Polycystic ovary syndrome and the androgen-insulin connection

The association of hyperandrogenism, insulin resistance, and polycystic ovarian disease is well established. The accompanying hyperinsulinemia results in acanthosis nigricans, an epiphenomenon of this syndrome. The knowledge that states of insulin resistance of diverse causes are associated with ovarian hyperandrogenism makes the argument for insulin-driven ovarian androgen secretion compelling. However, equally compelling evidence suggests that hyperandrogenism may contribute to insulin resistance and hyperinsulinemia. The irreconcilable differences between these two hypotheses have resulted in an array of contradictory studies. In this article a unified concept of polycystic ovary syndrome and its androgen-insulin connection is proposed. The hypothesis incorporates the role of hyperinsulinemia in the androgen excess observed (and vice versa); the key to this connection is the androgen-dependent change in regional body fat distribution and its metabolic consequence. The pathophysiologic features of polycystic ovary syndrome, which has important clinical sequelae, deserve further consideration.     

Metabolic and cardiovascular consequences of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-10% of reproductive aged women, about 1 out of 15 women worldwide. Traditionally it was considered as a reproductive disorder showing hyperandrogenism, chronic anovulation and infertility; it is now well accepted that PCOS represents a 'multifaceted' syndrome with substantial metabolic and cardiovascular long term consequences. Several PCOS women present abdominal adiposity (visceral fat) with a level of peripheral insulin resistance (IR), similar to that present in women with type 2 diabetes, in association with an increased incidence of impaired glucose tolerance. Several cardiovascular risk factors are often related to metabolic alterations, such as dyslipidemia, hypertension, endothelial dysfunction, low grade chronic inflammation, that are present even at early age in PCOS women. Pathogenetic mechanisms of these impairments are not completely clarified yet, but IR appears to play a critical role, such as the key factor linking hypertension, glucose intolerance, obesity, lipid abnormalities and coronary artery disease. In conclusion, although increased incidence of metabolic abnormalities and metabolic disease like type 2 diabetes, and several cardiovascular abnormalities have been widely demonstrated in PCOS women, larger and multicenter trials of long term cardiovascular outcomes are required to better define the incidence of cardiovascular risk and cardiovascular disease in PCOS.     

Insulin resistance and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a frequent disease, characterized by disturbed ovarian function with hyperandrogenism. Anovulation is secondary to an absence of follicular dominance. Apart from a primary ovarian defect, insulin resistance is observed in PCOS women, even in the absence of overweight. This insulin resistance could be secondary to a defect in the insulin transduction pathway, mainly by a defect in receptor phosphorylation. It enhances hyperandrogenism as it increases ovarian androgen production. Therefore treating insulin resistance by weight loss or drugs reducing insulin resistance might improve fertility of PCOS women. Metformin has been shown to reduce ovarian production, enhance ovulatory cycles and in some cases increase fertility. However, there are few randomized studies on large numbers of patients to prove an effect on pregnancies as well as on the occurrence of early pregnancy loss. There are currently no recommendation on dose and duration of metformin treatment. It is noteworthy that metformin has no authorization in France to be prescribed apart from diabetic patients' care. Considering the medical care of PCOS women, the cardiovascular risk needs to be taken into account. Therefore hypertension, dyslipidemia and diabetes must be treated in those women who need to be followed carefully all over their life.     

Insulin resistance in preeclampsia

Contemporary scientific data show that there is a link between insulin resistance and preeclampsia. Many features of the insulin resistance syndrome are common with this condition. These include hypertension, hyperinsulinemia, glucose intolerance, obesity and lipid abnormalities. The women with preeclampsia are more insulin resistant than those with normal pregnancy. The surrogate markers of insulin resistance like leptin, TNF-alpha, tissue plasminogen activator, SHBG etc are also changed in preeclampsia. Whether these changes are connected with etiology or with the pathogenesis of preeclampsia is still not clear.     

Induction of ovulation in infertile women with hyperandrogenism and insulin resistance

The polycystic ovary syndrome is a common cause of anovulatory infertility. Women with severe insulin resistance are a unique subset of polycystic ovary syndrome. The syndrome of hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN syndrome) is one presentation of the insulin-resistant subset of polycystic ovary syndrome. Insulin resistance and hyperandrogenism are caused by genetic and environmental factors. In women with anovulatory infertility caused by hyperandrogenism and insulin resistance, clomiphene citrate treatment often fails to result in pregnancy. For these women, weight loss and insulin sensitizers can be effective methods of inducing ovulation and pregnancy and may reduce the number of clomiphene-resistant women with polycystic ovary syndrome who are treated with gonadotropins, ovarian surgery, or in vitro fertilization-embryo transfer.     

Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion

Six nonobese women with polycystic ovarian disease (PCOD) showed significant hyperinsulinemia, compared with controls after oral glucose (P less than 0.05). As an indicator of insulin sensitivity, in vitro proliferation of erythrocyte progenitor cells of PCOD subjects exposed to physiologic concentrations of insulin was significantly blunted (P less than 0.001). Monocyte insulin receptor binding was not impaired in the PCOD subjects. Three of the PCOD patients were treated with a long-acting gonadotropin-releasing hormone agonist for 6 months, which resulted in marked suppression of ovarian androgen secretion but no demonstrable changes in in vivo or in vitro indicators of insulin resistance. Thus insulin resistance in PCOD subjects appears to be unrelated to ovarian hyperandrogenism (or acanthosis or obesity). Although certain tissues are insulin-resistant in PCOD patients, the ovary may remain sensitive and overproduce androgens in response to high circulating insulin levels.     

PCOS: diagnosis and management of related infertility

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. It is characterised by a combination of hyperandrogenism (either clinical or biochemical), chronic oligo/anovulation, and polycystic ovaries. It is frequently associated with insulin resistance and obesity. PCOS receives considerable attention because of its high prevalence and possible reproductive, metabolic, and cardiovascular consequences. It is the most common cause of anovulatory infertility. Ovulation induction with an aromatase inhibitor or anti-oestrogen is the first-line medical treatment. The aim of ovulation induction is monofollicular growth to avoid multiple pregnancy. The second-line treatments include gonadotrophins and laparoscopic ovarian drilling. The role and benefit of metformin in ovulation induction is uncertain. Woman with PCOS undergoing IVF are at significant risk of ovarian hyperstimulation syndrome. Women with PCOS are also at an increased risk of developing gestational diabetes, pregnancy-induced hypertension, and pre-eclampsia.     

Hyperhomocysteinaemia is associated with biochemical hyperandrogenaemia in women with reproductive age

Objective

Hyperhomocysteinaemia is a well-established risk factor for cardiovascular disease. This study investigated the relationship between hyperhomocysteinaemia and factors related to polycystic ovary syndrome (PCOS).

Study design

Case–control study. Three hundred and thirty-nine women were included; of these, 84 had hyperhomocysteinaemia (homocysteine >12.4 μmol/l) and 255 had normal homocysteine levels. Homocysteine, high-sensitivity C-reactive protein, insulin resistance, metabolic disturbance and PCOS-related disturbance were evaluated. The clinical and biochemical characteristics of women with hyperhomocysteinaemia and normal homocysteine levels, including insulin resistance, metabolic disturbance and PCOS-related disturbance, were compared.

Results

Correlation was found between serum homocysteine level and serum total testosterone level and diastolic blood pressure. No correlation was found between serum homocysteine level and age, body mass index, insulin resistance and lipid profile. Women with hyperhomocysteinaemia had a significantly higher risk for biochemical hyperandrogenaemia and higher serum total testosterone levels than women with normal homocysteine levels. The prevalence rates of PCOS, oligo-amenorrhoea, polycystic ovary morphology and metabolic disturbance did not differ between the two groups. The parameters of insulin resistance and lipid profiles were similar between the two groups, and signs of clinical hyperandrogenism (hirsutism and the modified Ferriman–Gallwey score) did not differ between the two groups. Logistic regression analysis found a significant association between hyperandrogenaemia and hyperhomocysteinaemia (odds ratio 2.24, 95% confidence interval 1.26–4.01).

Conclusions

For women with PCOS, an elevated serum total testosterone level is the main factor associated with hyperhomocysteinaemia. The association between biochemical hyperandrogenism and hyperhomocysteinaemia may contribute to cardiovascular risk for women with PCOS.     

Apolipoprotein E-containing HDL-associated platelet-activating factor acetylhydrolase activities and malondialdehyde concentrations in patients with PCOS

PAF and PAF-like oxidized phospholipids hydrolysed by platelet-activating factor (PAF) acetylhydrolase (AH) are potent lipid mediators involved in inflammation and atherosclerosis. Apolipoprotein (apo) E-containing high-density lipoprotein (HDL) has antioxidant, anti-inflammatory and anti-atherogenic properties. The study investigated apoE-containing HDL-associated PAF-AH (HDL-PAF-AH) and total (apoE-containing+apoE-poor) HDL-PAF-AH activities as well as malondialdehyde (MDA) concentration in 291 patients with polycystic ovary syndrome (PCOS) using the Rotterdam consensus criteria and 281 control women. Compared with the control women, patients with hyperandrogenism+oligo/anovulation+polycystic ovaries (PCO) or hyperandrogenism+PCO had lower total, apoE-containing and apoE-poor HDL-PAF-AH activities, while those with oligo/anovulation+PCO showed decreased total and apoE-poor HDL-PAF-AH activities. Other factors including insulin resistance and obesity in PCOS had the adverse effects associated with the HDL-PAF-AH activities. Serum MDA concentration was associated with PCOS, hyperandrogenism, insulin resistance and hypertriglyceridaemia in patients with PCOS. Decreased total and apoE-containing HDL-PAF-AH activities and increased serum MDA concentration may contribute to the pathogenesis of PCOS and potentially link to related complications responsible for oxidative stress and inflammation such as an increased risk for type 2 diabetes mellitus and/or future cardiovascular diseases in PCOS patients.     

Polycystic ovary syndrome: clinical perspectives and management.

The polycystic ovary syndrome (PCOS) is a common hyperandrogenic disorder and is characterized by a constellation of signs and symptoms often in association with a family history of hyperandrogenism and/or PCOS. It is often associated with hyperinsulinism and insulin resistance, which puts patients at risk for possible potential complications including type 2 diabetes mellitus and cardiovascular disease. Clinical signs may be subtle, and biochemical markers most often include an elevation of free testosterone (T) and possibly dehydroepiandrosterone sulfate (DHEAS). The diagnosis should be sought in any woman with hyperandrogenic features so that appropriate treatment may be used. There is often a good therapeutic response of the hirsutism, acne, or oligomenorrhea associated with PCOS. The new modalities that increase insulin sensitivity as well as weight reduction in the obese woman with PCOS may potentially be useful in modifying the potential later complications of this common endocrinopathy of young adult women.     

Polycystic ovary syndrome: recent genetic contributions

Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. It is characterized by hyperandrogenism, chronic anovulation and it is often associated with hyperinsulinemia, insulin resistance and dyslipidaemia. The pathophysiology of polycystic ovary syndrome seems to implicate primary defects in ovarian steroidogenesis, influenced by environment, insulin action and obesity. Polycystic ovary syndrome is probably both a multigenetic and environmental disease. Knowing the genes of polycystic ovary syndrome would be helpful to develop therapeutics and prevention. Genes of gonadotrophins, steroid hormone synthesis and insulin resistance seem not to be directly involved, except perhaps the CYP 11 a gene. On the other hand, identification of the signal transduction pathways involved in these genes may provide valuable information that can be applied to other clinical manifestations of polycystic ovary syndrome (follicular growth arrest, insulin resistance, obesity and endometrial cancer...).     

Syndrom der polyzystischen Ovarien (PCOS)

Polycystic ovary syndrome (PCOS), including chronic anovulation, hyperandrogenism and polycystic ovaries, is the most common endocrine disorder in women of reproductive age, affecting around 5–10% with familial clustering. Although the pathophysiology of PCOS is not fully understood, insulin resistance with consecutive hyperinsulinemia plays a central role. Among obese women the observed insulin resistance is at least partially explained by excess adipose tissue, but lean women are affected as well. The symptoms of PCOS range from the cutaneous stigmata of hyperandrogenism and sterility to metabolic syndrome. Because of the severe health implications of the metabolic syndrome, the diagnosis of PCOS should include all facets, especially disturbed glucose metabolism. An optimal form of treatment that targets all symptoms does not exist. This review sheds light on some important aspects of PCOS with the aim of raising awareness about its complexity and its consequences.     

Insulin-lowering medications in polycystic ovary syndrome

A growing body of evidence suggests that serum hyperinsulinemia contributes to the excess ovarian androgen secretion observed in women with PCOS. As a group, women with PCOS are hyperinsulinemic and insulin resistant when compared with weight-matched normal women, but not all PCOS subjects display clear metabolic defects. The small studies using insulin-sensitizing drugs have demonstrated conclusively that a reduction in serum insulin levels is associated with a reduction of ovarian androgen secretion in PCOS, providing further evidence that hyperinsulinemia contributes to hyperandrogenism by increasing ovarian androgen secretion and reducing SHBG. The improvement of serum androgen levels with multiple different drug classes with different mechanisms of actions suggests an effect mediated by reduction in circulating insulin levels rather than a direct ovarian effect of the drugs. Although the studies published to date have increased understanding of the pathophysiologic mechanisms of PCOS, before these drugs can be recommended as first-line therapy for women, longer term clinical trials are needed to compare their safety and efficacy with other established therapies, such as oral contraceptive pills and antiandrogens. Because of the potential direct and unique beneficial effects of these medications on metabolism, studies must be performed to evaluate their efficacy in combination with other therapies, especially oral contraceptives. It is likely that subsets of patients who cannot tolerate traditional medications will be better managed with insulin sensitizers as first-line therapy; however, to date, the optimal way to identify these subjects is unknown. Whether therapy should be limited to subjects with documented hyperinsulinemia also remains unknown.     

多囊卵巢综合征胰岛素抵抗的新进展

多囊卵巢综合征（PCOS）是青春期及育龄妇女最常见的内分泌和代谢紊乱性疾病,其发病率占育龄妇女的5%～10%。PCOS的基本特征为长期不排卵或稀发排卵、卵巢多囊性增大和高雄激素血症等,此外还表现有胰岛素抵抗（IR）及胰岛β细胞功能失调。PCOS患者妊娠率降低,妊娠期自然流产、妊娠期糖尿病的患病率亦较普通人群高,同时子宫内膜癌发病风险增高。PCOS患者代谢综合征的发病率升高,后者与心血管疾病风险紧密相连,并与IR有密切关系。目前许多学者对PCOS患者的IR做了大量的研究,提示改善PCOS的IR可改善内分泌及生殖功能,而改善生活方式是改善患者IR的有效手段。口服降糖药已成为治疗PCOS的IR的有效方法之一。