Konsensusgerechte Therapie des PCOS

Treatment options remain controversial for polycystic ovary syndrome (PCOS), one of the most common endocrinopathies of women of reproductive age. Following the Rotterdam consensus meeting of 2003, which covered diagnostic aspects of PCOS, international experts met again in Thessaloniki (Greece) in 2007 under the patronage of ASRM and ESHRE to work on recommendations for the evidence-based therapy of this heterogeneous disease [36]. These recently published recommendations are attracting increasing interest in the German-speaking countries. The consensus includes detailed comments concerning the key pathogenetic factors obesity, insulin resistance, and hyperandrogenemia and their practical implications for therapy. The central statements are as follows: 1. Lifestyle changes are mandatory for overweight PCOS patients. 2. Clomiphene remains the first-line option for ovulation induction in PCOS patients. 3. The insulin-sensitizer metformin is less effective than clomiphene, and its use is recommended only in case of insulin resistance. Here, we summarize the consensus recommendations concerning overweight, insulin sensitizers and clomiphene for the treatment of PCOS and discuss them in the context of recent research results.     

PCOS: a diagnostic challenge

Useful research and diagnostic criteria for PCOS arose from a conference in 1990, whereby PCOS could be defined by: (i) clinical and/or biochemical hyperandrogenism, (ii) chronic anovulation, and (iii) exclusion of related disorders. The presence of "polycystic ovaries" was not included in this definition, which created significant concern since many women with PCOS have polycystic ovaries on ultrasound, and conversely women with this ovarian morphology have a higher prevalence of androgen excess and insulin resistance. More recently, at an expert meeting in 2003 in Rotterdam, it was recommended that PCOS be defined when at least two of the following three features were present, after exclusion of other aetiologies: (i) oligo- or anovulation, (ii) clinical and/or biochemical hyperandrogenism, or (iii) polycystic ovaries. These newer criteria effectively create additional phenotypes of PCOS (e.g. women with hyperandrogenism and polycystic ovaries but normal ovulatory function, and women with ovulatory dysfunction and polycystic ovaries but no clinical or biochemical evidence of hyperandrogenism). It remains to be demonstrated whether these phenotypes actually represent patients with PCOS. Nonetheless, the trend towards the use of uniform diagnostic criteria in studies of PCOS will increase the comparability and potentially the value of published research.     

Practical Approach to the PCOS Patient

Purpose of Review

The purpose of this review is to provide an overview of polycystic ovary syndrome (PCOS) with a discussion on our current understanding of the pathophysiology and sequela of this syndrome. A diagnostic algorithm, as well as the challenges clinicians may face when evaluating these patients is also included. Clinical treatment strategies for fertility and non-fertility PCOS patients are described in detail.

Recent Findings

Recent discussions on the inaccuracies and lack of standardization for the measurement of androgens, both clinically and chemically, are highlighted. A meta-analysis and a randomized controlled trial evaluating the efficacy of commonly used ovulation induction medications are also included along with recommendations from national committee reports and consensus opinions.

Summary

PCOS is recognized as one of the most common endocrinopathies in women worldwide which continues to attract increased attention and research. Inheritance patterns are multifactorial and may be influenced trans-generationally due to the epigenetic influence of metabolic syndrome. Women with PCOS are at an increased risk of long-term health consequences for which they should be appropriately monitored and treated, in order to decrease the overall morbidity associated with this syndrome. Treatment should be individualized based on the phenotypic presentation of the patient as well as their fertility desires. For some patients, referral to a specialist and multidisciplinary care may be required.

     

PCOS in lesbian and heterosexual women treated with artificial donor insemination

It has been claimed that the prevalence of polycystic ovary syndrome (PCOS) is significantly higher in lesbian compared with heterosexual women. The present study tried to corroborate this finding in a population of lesbian and heterosexual women consulting for artificial insemination with donor spermatozoa (AID) in the authors' infertility centre. Separate Rotterdam criteria were compared, as well as the outcome of AID. Data were collected from patient files and 174 lesbian and 200 heterosexual women were included in this study. The diagnosis of PCOS was made following the Rotterdam PCOS consensus workshop group. A total of 8.0% of the lesbian women had PCOS compared with 8.7% of the heterosexual women. Concerning the presence of polycystic ovaries and cycle length and regularity, no significant differences were found. Conclusions about hirsutism and chemical hyperandrogenism were not made. Statistical analysis did not show any difference for the type and outcome of treatment. This study does not confirm a link between sexual orientation and the diagnosis of PCOS. The absence of a significant difference in therapy type and outcome emphasizes that there is no difference in (in)fertility rates between the study groups.     

Consensus on infertility treatment related to polycystic ovary syndrome

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. On the basis of the currently available evidence, a group of experts reached a consensus regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counseling should be provided emphasizing the importance of lifestyle, especially weight reduction and exercise in overweight women, smoking, and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotropins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotropins is associated with increased chances for multiple pregnancy, and, therefore, intense monitoring of ovarian response is required. Laparoscopic ovarian surgery alone is usually effective in less than 50% of women, and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC-gonadotropin paradigm) is reported to be highly effective with a cumulative singleton live-birth rate of 72%. Recommended third-line treatment is in vitro fertilization (IVF). More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-line, second-line, or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.     

PCOS

Polycystic ovarian syndrome (PCOS) is the most frequent endocrinopathy in women of reproductive age. The pathophysiology remains unexplained. The two most significant illustrative models refer to gonadotropin secretion and metabolic aberrations. Insulin-sensitizing drugs offer new treatment options. This substance group, however, is not approved for the treatment of infertility in PCOS and is currently tested only in clinical trials. Classic therapy employs increasing doses of clomiphene for ovulation induction in PCOS. If ovulation cannot be induced, the patient is considered resistant to clomiphene, and combined treatment with metformin is initiated, which leads to higher ovulation rates.     

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.     

Developmental origins of polycystic ovary syndrome (PCOS), a case control study comparing birth weight in women with PCOS and control group

Evidence from various epidemiological studies and experimental animal studies has linked adverse intrauterine circumstances with health problems in adult life. This field of investigation is known as Developmental Origins of Health and Disease (DOHaD). Studies investigating the relation between developing polycystic ovary syndrome (PCOS) in adulthood and birth weight have yielded inconsistent results: PCOS is described more often in women with low birth weight and high birth weight, while other studies have failed to establish any relation. In this retrospective case–control study, we evaluated whether women diagnosed with PCOS had lower birth weight compared to women with a regular menstrual cycle (controls). Binary logistic regression models were used to analyze the data and correct for known confounders. About 65 women with PCOS and 96 controls were recruited for this purpose. The average birth weight of PCOS women (3357?g) did not differ from the average birth weight of controls (3409?g). Mean age at menarche differed significantly between groups, 13.7 years and 12.8 years (p?=?0.006), respectively, for PCOS women and controls. In conclusion, we could not confirm the effect of adverse intrauterine conditions, reflected in birth weight, on developing 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.     

Exercise and sedentary habits among adolescents with PCOS

Study ObjectiveThe purpose of this study was the recording of physical activity and sedentary habits of adolescents with polycystic ovarian syndrome (PCOS).MethodsWe performed a structured interview to assess the level of physical activity and sedentary habits of girls with PCOS. We used a group of healthy adolescents as controls. All girls had their age, height, weight, hip and waist circumference measured and their BMI calculated.Results81 girls (35 with PCOS and 46 controls) participated in the study. Girls with PCOS engaged in physical activities less than controls. Even when they did, the frequency and intensity of exercise was less. Also, girls with PCOS were less likely to be aware of the positive effects of exercise on their health. Girls in both groups were sedentary in excess of the 4 hours per day limit, which has been linked with obesity.ConclusionHealthy teenagers were involved in a sporting activity more often and more frequently than the PCOS group. Athletic and sedentary habits of adolescents with PCOS may interact with other factors leading to obesity.     

Clinical management of PCOS

The polycystic ovary syndrome (PCOS) is a heterogeneous condition with genetic predisposition. It is characterized by a myriad of symptoms including oligomenorrhea or amenorrhea, anovulation or infertility, hirsutism or acne. Insulin resistance appears to be an important factor in PCOS though the lack of an etiology has led to symptom oriented therapy which includes lifestyle modification, the use of cyclical progestagens and antiandrogens. Ovulation induction by drug therapy and ovarian drilling aims to treat subfertility in women with PCOS. Therapeutic approaches to PCOS remain an ongoing source of debate. Insulin sensitizing agents may bring new hope in therapy. Future research is aimed at shedding light on the pathophysiology so as to optimize treatment of women with PCOS.     

Adolescent PCOS

Adolescent PCOS is characterized by menstrual cycle irregularities, usually less than 6 per year and with clinical or/and biochemical features of hyperandrogenism. Metabolic syndrome is seen in more than 50% of the cases with PCOS. It includes obesity, insulin resistance, dyslipidemia and hypertension. There is described a correlation between PCOS, precocious puberty and low birth weight. An important fact is that although PCOS is a very well known condition, its diagnosis in puberty is quite complicated. This is due to the heterogeneity of the syndrome in complex with the mild differences between PCOS and some physiologic processes in adolescence. The precise diagnosis is crucial for the exact therapy.     

Knowledge of PCOS in physicians-in-training: identifying gaps and educational opportunities

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. A recent study found that many obstetrics and gynecology (ObGyn) practicing physicians are unaware of the Rotterdam criteria recommended for diagnosis. Our objective was to identify gaps in trainee knowledge of PCOS diagnostic criteria and management. An online survey was sent out to US ObGyn physicians-in-training in 2018. The primary outcomes were identification of at least one component of each Rotterdam criteria (Rot-3): (1) oligomenorrhea/amenorrhea, (2) clinical or biochemical hyperandrogenism, and (3) ovarian volume or antral follicle count, and identification of all five components (Rot-5). Secondary outcomes were identification of comorbidities and management of PCOS. Multivariable logistic regression was used controlling for gender, seniority (PGY) status, program type, completion of an REI rotation, and number of PCOS patients seen. 85.4% of 347 trainees completing the survey reported using Rotterdam criteria to diagnose PCOS. However, only 55% identified Rot-3 and less than 10% identified Rot-5. Seniority (PGY4 OR 2.2; 95% CI: 1.2–4.1; p?=?.01) and completion of REI rotation (OR 1.8 95% CI: 1.2, 1.8; p?=?.006) were associated with identifying Rot-3. Similar findings were noted with identifying Rot-5. Our study identified significant gaps in knowledge regarding PCOS, suggesting an urgent need for improving strategies for trainee education to increase patient satisfaction and provide comprehensive care.     

Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS

OBJECTIVE: To determine the rate of clinically evident polycystic ovary syndrome (PCOS) among first-degree female relatives within families with a proband affected by PCOS. DESIGN: Clinical and biochemical evaluation of the mothers and sisters of 93 patients with PCOS. The diagnosis of PCOS was established by: [1] a history of oligomenorrhea, [2] clinical evidence (i.e., hirsutism) or biochemical evidence (i.e., elevated total or free T) of hyperandrogenism, and [3] the exclusion of related disorders. SETTING: Tertiary care university. PATIENT(S): Patients with PCOS and their mothers and sisters. INTERVENTION(S): Interview, physical examination, and hormonal testing on blood samples were performed for all subjects. MAIN OUTCOME MEASURE(S): The presence of hirsutism and hyperandrogenemia was determined in the mothers and sisters of the patients with PCOS. RESULT(S): Of the 78 mothers and 50 sisters evaluated clinically, 19 (24%) and 16 (32%) were affected with PCOS, respectively. A higher rate of PCOS was observed when only premenopausal women not taking hormones (i.e., untreated) were considered (i.e., 35% of mothers and 40% of sisters), consistent with amelioration of symptoms with hormonal therapy or aging. These rates of PCOS are significantly higher than that observed in our general population (approximately 4%) and suggest the involvement of a major genetic component in the disorder. CONCLUSION(S): The rates of PCOS in mothers and sisters of patients with PCOS were 24% and 32%, respectively, although the risk was higher when considering untreated premenopausal women only.     

Steroidogenic enzymes of adipose tissue in modulation of trivalent chromium in a mouse model of PCOS

Polycystic ovary syndrome (PCOS) is a type of endocrine metabolic disorder with many different consequences to health, most commonly infertility, obesity and insulin resistance. Trivalent chromium (Cr³⁺) was previously found to improve the metabolic profiles of patients with PCOS. The aim of this study was to explore the effect of Cr on regulating steroidogenic enzymes in adipose tissue. Female BALB/c mice were divided into three groups (n?=?6 per group): the control group, PCOS?+?placebo milk group and PCOS?+?Cr-containing milk group. The dietary intake of Cr significantly decreased fasting blood sugar (FBS) and homeostasis model assessment of insulin resistance levels in the murine model of PCOS. Importantly, we found significant correlations among the levels of Cr, insulin and dehydroepiandrosterone (DHEA). In adipose tissue, decreases in the enzyme expressions of 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase, but not of aromatase, were observed. By understanding the role of steroidogenic enzymes in PCOS in normal and pathological states, trace elements may be used as a form of adjunctive therapy in the management of patients with PCOS.     

Associations of preconception Body Mass Index in women with PCOS and BMI and blood pressure of their offspring

Women with polycystic ovary syndrome (PCOS) have unfavorable metabolic profiles. Their offspring may be affected by such risks. The objective of the current study was to disclose associations between preconception health of these women and health of their offspring. 74 women diagnosed with PCOS according to the Rotterdam criteria were screened systematically before conception. Cardiovascular health of their offspring was assessed at 2.5–4 (n?=?42) or at 6–8?years of age (n?=?32). Multivariate linear regression analysis was performed with adjustments for potential confounders. In the primary analyses the association between preconception Body Mass index (BMI) and offspring BMI was evaluated. Secondly associations between preconception blood pressure, androgens, insulin-resistance (HOMA-IR), and LDL-cholesterol in women with PCOS and BMI and blood pressure of offspring were assessed. Results show that preconception BMI of women with PCOS was positively associated with sex- and age-adjusted BMI of their offspring at 6–8?years of age (β?=?0.55 (95% CI: 0.12 to 0.97), p?=?.012). No other significant associations were found. In conclusion, our data suggest that preconception BMI in PCOS is significantly associated with offspring BMI at 6–8?year of age. If this suggestion could be confirmed this may provide an opportunity for improving the future health of these children.     

Cardiovascular and metabolic characteristics of infertile Chinese women with PCOS diagnosed according to the Rotterdam consensus criteria

Polycystic ovary syndrome (PCOS) is strongly associated with metabolic abnormalities in Western women. However, data from other populations and geographical regions are scarce. This study evaluated cardiovascular and metabolic risk factors in Chinese infertile women diagnosed with PCOS using the 2003 Rotterdam consensus criteria. A total of 615 women representing the four PCOS phenotypes (oligo- or anovulation (AO) + hyperandrogenism (HA) + polycystic ovaries (PCO), AO + HA, AO + PCO and HA + PCO) underwent standardized metabolic screening including a 75 g oral glucose tolerance test. All groups presented with similar reproductive characteristics, with the only difference being a significantly higher Ferriman–Gallwey score for hirsutism (P = 0.01) in the subgroup characterized by HA + PCO. Overall, the prevalence of metabolic syndrome was 6.4%, with no difference among the four groups (range of 2.3–12.2%). Metabolic syndrome was associated with body mass index (P < 0.001), waist/hip ratio (P = 0.002), index of insulin resistance (P = 0.005) and fasting insulin (P = 0.009) in multivariate analysis. Compared with Caucasians and Chinese women in Westernized societies, mainland Chinese women with PCOS have a low risk of metabolic syndrome and its presence does not vary across the specific PCOS phenotypes.Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is diagnosed if at least two of three of the following characteristics are present: lack of ovulation (oligo- or anovulation), specific ultrasound characteristics of the ovaries (enlarged ovary and/or increased number of antral follicles), and increased production of androgen hormones and/or its clinical manifestations such as hirsutism and acne. Therefore, four presentations of PCOS can be distinguished. PCOS is also associated with the metabolic syndrome, a clustering of from three to five risk factors of cardiovascular disease. Unfortunately, knowledge about PCOS and its metabolic associations for the Asian region is scarce. The objective of this study was to evaluate cardiovascular and metabolic risk factors in a group of 615 Chinese infertile women with PCOS representing the four PCOS subgroups, from mainland China. Overall, women in the four PCOS subgroups had similar physical, hormonal and biochemical characteristics, with only more hirsutism in the subgroup characterized by overproduction of androgen hormones and ovarian ultrasound characteristics. Of the total group, 6.4% had metabolic syndrome with no differences among subgroups (range 2.3–12.2%). We found that the presence of metabolic syndrome was associated with higher body mass index, higher waist/hip ratio, and a higher index of insulin resistance (HOMA-IR) and higher fasting insulin concentrations. We conclude that in contrast to Caucasians and Chinese women in Westernized societies, mainland Chinese women with PCOS have a low risk of metabolic syndrome and that its presence does not vary among the four PCOS phenotypes.     

Family-based analysis of INSR polymorphisms in Chinese PCOS

The insulin receptor (INSR), which is an indispensable component of the insulin-signalling pathway, could be a plausible candidate gene for polycystic ovary syndrome (PCOS). This study was designed to determine whether an association exists between three SNP variants (rs3786681, rs17253937 and rs2252673) of the INSR gene and PCOS in Han Chinese. A total of 224 family trios (672 participants in total) were enrolled in this family-based transmission disequilibrium test. Genotypes were obtained by sequencing. A weak association was detected in rs2252673 (P = 0.027), which indicated that INSR may confer an increased susceptibility to PCOS in Chinese. Additionally, the association between INSR gene variants and clinical and metabolic characteristics of women with PCOS was investigated. Carriers of the CG and GG genotypes in women with PCOS were slightly associated with higher cholesterol concentration (t = 2.072, P = 0.048) and lower high-density lipoprotein cholesterol concentration (t = 2.274, P = 0.026). The minor allele conferred increased odds of PCOS independently of body mass index. The present data may provide a basis for further studies of the role of the INSR in the aetiology of PCOS.     

The role of plasma renin activity in distinguishing patients with polycystic ovary syndrome (PCOS) from oligomenorrheic patients without PCOS

All the components of the renin-angiotensin system have been identified in the human ovary. Renin plays a major role in folliculogenesis, and possibly in follicular atresia. Polycystic ovary syndrome (PCOS) is characterized by early follicular atresia. We studied whether assessment of plasma renin activity would be useful for diagnosing PCOS and distinguishing PCOS and non-PCOS in oligomenorrheic patients. Patients were divided into three groups: PCOS group (group 1, n = 40), non-PCOS oligomenorrheic group (group 2, n = 30) and ovulatory control group (group 3, n = 30). Plasma renin activity was determined in the early follicular phase of the menstrual cycle. Baseline serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, insulin, aldosterone and androgens (total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate and 17α hydroxyprogesterone) were determined in all groups. The mean LH level was lower (4.94 ± 4.65 mIU/ml) in control patients than in PCOS patients (12.9 ± 1.75 mIU/ml) and non-PCOS oligomenorrheic patients (10.8 ± 1.65 mIU/ml). There was no statistically significant difference between the groups regarding FSH levels. The mean plasma renin activity was 3.47 ± 0.29 ng/ml in the PCOS group. The mean plasma renin activity was 1.59 ± 0.21 ng/ml the non-PCOS oligomenorrheic group (statistically significiant differrence). There was no statistically significant difference between the non-PCOS oligomenorrheic (1.59 ± 0.21 ng/ml) and control groups (1.2 ± 0.16 ng/ml). Use of plasma renin activity alone as a diagnostic marker in PCOS is not useful, because the clinical findings of PCOS are heterogeneous and the pathogenesis is unclear. However, it can be used together with other variables to diagnose women with PCOS and to distinguish non-PCOS oligomenorrheic women from those with PCOS.