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The standard first-line treatment for normogonadotropic anovulatory infertile patients [referred to as World Health Organization group 2 (WHO 2)] is ovulation induction using clomiphene citrate (CC) in incremental doses. Twenty to 25% of women show clomiphene-resistant anovulation (CRA), that is, they remain anovulatory even after multiple attempts with increased doses of CC. About 50% of the ovulatory CC patients conceive within six CC-induced cycles. Given the heterogeneous nature of the group, the individual prognosis (i.e., the chance of success) will vary considerably between patients. In the event an individual prognosis of each patient would be available before the start of the treatment, the overall efficiency of ovulation induction could be improved. Prognostic evidence at an individual level should use multiple patient variables, including results from previous treatments (if any). When variables are interdependent, a statistical model can be used to relate individual characteristics with the predicted outcome. Such a model will provide estimates of prognosis for individualized patient profiles, allowing new patients to profit from the experience of the cohort of previous patients used to build the model. This paper discusses the prediction of time to pregnancy following induction of ovulation with CC. This prediction was broken down in two steps, leading to two separate prognostic models. The first model predicts an intermediate outcome, the chance that the patient will be CRA (i.e., no ovulation in response to CC medication); the second model predicts the final outcome (time until pregnancy) in women who do ovulate. The CRA model was based on a prospective cohort study of 201 patients with normogonadotropic oligoamenorrheic infertility, 45 of whom were CRA (22%). It contained four predictor variables all related to the diagnosis of PCOS within the group of WHO 2: Increased free androgen index (FAI; hyperandrogenemia), elevated body mass index (BMI; obesity), greater mean ovarian volume (as an ultrasound feature of polycystic ovaries), and amenorrhea were all predictive for CRA. The second model was based on the non-CRA patients and contained two prognostic variables: increased age and oligomenorrhea were predictive for longer time to pregnancy after first ovulation with CC. Using the example of the prediction of time to pregnancy following induction of ovulation with CC, we present and discuss characteristics of good prognostic evidence for clinical use, focusing on study design, statistical analysis, evaluation, and presentation of results.
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PMID:Characteristics of the best prognostic evidence: an example on prediction of outcome after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. 1280 58

Mono-ovulatory cycles for women are optimal because singleton pregnancies have a better outcome than multiples. Multiple births began to increase in the 1950s after the first appearance of effective ovulation induction for the treatment of anovulation. Since the 1980s when ovulation induction and IVF were more broadly applied to the treatment of unexplained and persistent infertility, there has been an unprecedented rise in multiple births. Strategies to achieve mono-ovulation during treatment of anovulatory patients are distinct from those for the treatment of ovulating patients who have unexplained and persistent infertility. Anovulatory patients with hypogonadotrophic hypogonadism can be treated with exogenous pulsatile GnRH, which restores normal gonadotrophin secretion, ovulation rates and conception rates. The multiple pregnancy rate is not increased with GnRH treatment. In patients with normogonadotrophic anovulation, attention should be given to diet and exercise before any other interventions are considered. Pharmacological induction of ovulation can be achieved with antiestrogen, gonadotrophin or pulsatile GnRH treatment; antiestrogen is the first choice with gonadotrophin more widely used for clomiphene citrate (CC)-resistant patients. Obesity and polycystic ovaries are common in this group, so that gonadotrophin and GnRH treatment are associated with lower responses compared with hypogonadotrophic hypogonadism, and higher multiple pregnancy rates. Low dosage protocols are being tested that may lower the multiple birth rates. The role of drugs enhancing sensitivity to insulin, e.g. metformin, remains undetermined. Laparoscopic ovarian diathermy achieves conception rates that are equivalent to gonadotrophin treatment, with fewer multiple births. Augmenting normal ovulation processes for couples with unexplained and persistent infertility is less effective. Pregnancy rates are statistically significantly higher with CC but the size of the increase is not clinically important. CC with intrauterine insemination is associated with a clinically important effect on conception. Achieving mono-ovulation is more difficult in assisted reproductive technology cycles because success depends on maintaining the level of FSH above the threshold level longer than normal in order to increase the number of mature follicles. Milder stimulation for IVF and IVF in the untreated cycle show great potential, however, especially in view of the trend toward transfer of a single embryo in assisted reproductive treatment cycles.
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PMID:Mono-ovulatory cycles: a key goal in profertility programmes. 1285 47

Obesity, particularly the abdominal phenotype, is associated with several reproductive disturbances. Whereas mechanisms by which obesity affect fertility are complex and still not completely understood, an important role appears to be played by the presence of a condition of functional hyperandrogenism and hyperinsulinaemia, which accompanies the insulin-resistant state. In women with the polycystic ovary syndrome, abdominal obesity may be co-responsible for the development of hyperandrogenism and associated chronic anovulation, through mechanisms primarily involving the insulin-mediated overstimulation of ovarian steroidogenesis and decreased sex hormone-binding globulin blood concentrations. By these mechanisms, obesity may also favour resistance to clomiphene and gonadotrophin-induced ovulation and reduce outcomes of IVF/ICSI procedures. Due to the beneficial effects of weight loss, lifestyle intervention programmes should represent the first-line approach in the treatment of infertile obese women. Insulin-sensitizing agents may add further benefits, particularly if administered in combination with hypocaloric dieting. Therefore, individualized pharmacological support aimed at favouring weight loss and improving insulin resistance should be widely extended in clinical practice in obese infertile patients. This may be beneficial even during pregnancy, thereby permitting favourable physiological delivery and healthy babies.
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PMID:Obesity and reproductive disorders in women. 1292 29

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic anovulation and hyperandrogenism. PCOS is one of the leading causes of infertility and manifests with hirsutism, acne, and obesity. To investigate its impact on health-related quality of life and sexuality, 50 women with PCOS and 50 controls were evaluated with standardized questionnaires (36-item short-form health survey, symptom checklist revised, and life satisfaction questionnaire). The impact of hirsutism, obesity, and infertility was assessed using five-point rating scales, and sexual satisfaction was analyzed with visual analog scales. Patients showed greater psychological disturbances on the symptom checklist revised dimensions, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, aggression, and psychoticism, along with a lower degree of life satisfaction in the life satisfaction questionnaire scales health, self, and sex. Health-related quality of life measured with the 36-item short-form health survey revealed significantly decreased scores for physical role function, bodily pain, vitality, social function, emotional role function, and mental health in patients with PCOS. Although patients had the same partner status and frequency of sexual intercourse, they were significantly less satisfied with their sex life and found themselves less attractive. Most of the differences were not affected by correction for body weight. In conclusion, PCOS causes a major reduction in the quality of life and severely limits sexual satisfaction.
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PMID:Quality of life, psychosocial well-being, and sexual satisfaction in women with polycystic ovary syndrome. 1467 Nov 72

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.
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PMID:Polycystic ovary syndrome. 1470 63

Polycystic ovary syndrome (PCOS) is the most common endocrine disorders among women in reproductive age, but diagnostic criteria used in clinical practice are still controversial. In 1990 the National Institute of HEALTH (NIH) conference on PCOS recommended that diagnostic criteria should include biochemical evidence of hyperandrogenism and ovarian dysfunction (in the absence of non-classical adrenal hyperplasia) without considering the morphological diagnosis of polycystic ovary by ultrasound as an essential part of the diagnosis. In the Rotterdam PCOS workshop of May 2003, however, PCOS is diagnosed when 2 of the following criteria are recognized: oligomenorrhea and/or anovulation, clinical or biochemical signs of hyperandrogenism, ultrasound findings of polycystic ovary. Further-more, it is underlined that the metabolic study is not necessary for PCOS diagnosis, while it is suggested for "at risk patients" (obesity, diabetes, familiar and obstetrical history) with an oral glucose tolerance test (OGTT). A recent study carried out by our group underlined the role of ultrasound parameter, in particular suggesting a ratio between ovarian stroma area and total area of the ovarian section (S/A), with a cut-off of 0.34, as "gold parameter" for PCOS diagnosis, because it shows high sensitivity and specificity (96.3%, 97.0% for the S/A).
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PMID:[Diagnosis of polycystic ovary syndrome]. 1497 6

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting women in reproductive age, characterized by chronic anovulation and hyperandrogenism. The etiology of PCOS is still unknown. However, several studies have suggested that insulin resistance plays an important role in the pathogenesis of the syndrome. As a consequence of insulin-resistance, women affected by PCOS often present abnormalities of glucose metabolism and lipid profile, and have an increased risk of type 2 diabetes and cardiovascular disease over-time. Besides insulin-resistance, it has been demonstrated that some of these women also have alterations in beta-cell-function. Both disorders (insulin-resistance and beta-cell-dysfunction) are recognized as major risk factors for the development of type 2 diabetes. Long-term studies, evaluating the glucose-insulin system in women affected by PCOS, have shown a higher incidence of glucose intolerance, including both impaired glucose tolerance and type 2 diabetes, compared to age and weight matched control populations. The risk of glucose intolerance among PCOS subjects seems to be approximately 5 to 10 fold higher than normal and appears not limited to a single ethnic group. Moreover, the onset of glucose intolerance in PCOS women has been reported to occur at an earlier age than in the normal population (approximately by the 3rd-4th decade of life). However, other risk factors such as obesity, a positive family history of type 2 diabetes and hyperandrogenism may contribute to increasing the diabetes risk in PCOS.
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PMID:Type 2 diabetes and the polycystic ovary syndrome. 1497 9

Aim of this study was to test the hypothesis that obesity promotes the insulin-sensitivity and ovarian hyperandrogenism in anovulating women independently of the polycystic ovary syndrome (PCOS). We examined 80 women of reproductive age (19-38 years, mean 28.5 +/- 0.6 years) with anovulary cycles. 45 subjects had PCOS and 35 had chronic anovulation without hormonal and ultrasound criteria of PCOS. The control group consisted of 12 healthy females with normal ovulary menstrual cycle (age 26.4 +/- 0.6 years). We evaluated plasma insulin level baselines (I0); 120 min after oral administration of 75g of glucose (I120), we examined FSH, LH, prolactin, testosterone, 17 OH progesterone and DHEAS and calculated indexes of insulin sensitivity, i.e. FIRI and G/I. Women with anovulary cycles yielded a significant increase in I0 (p < 0.01), I120 (p < 0.01), FIRI (p < 0.01), FSH, LH (both p < 0.05) and testosterone (p < 0.01), and a significantly decrease in G/I (p < 0.01) in comparison to controls with normal weight. There was a significant correlation between BMI and insulin levels, BMI and FIRI, and between WHR or waist circumference and FIRI, or G/I. The highest levels of insulinemia and the highest degree of insulin resistance were found in obese women (BMI > 30 kg/m2). In the group of obese anovulating women we found a positive correlation between I0 and testosterone (p < 0.01). In PCOS group, we found a negative correlation between I0 and LH (p < 0.01), and FIRI and LH (p < 0.01). In the group of obese PCOS women there were significantly higher levels of plasma insulin, and lower insulin sensitivity as compared to lean PCOS patients. However, lean PCOS women were more hyperinsulinemic and insulin resistant than the control group of lean women. Our results indicate, that obesity is the important factor determinating the insulin sensitivity and hyperinsulinemia in PCOS women. Moreover, the body weight is the major determinant of insulinemia, insulin sensitivity and ovarian hyperandrogenism, independently of PCOS. (Tab. 5, Fig. 4, Ref. 23.).
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PMID:Obesity is the major factor determining an insulin sensitivity and androgen production in women with anovulary cycles. 1505 31

Polycystic ovary syndrome (PCOS) is a common heterogeneous disorder characterized by hyperandrogenism and chronic anovulation. The syndrome is frequently associated with an increased risk for insulin resistance and type 2 diabetes mellitus; obesity exacerbates insulin resistance and favors the progression from impaired glucose tolerance to diabetes in these patients. In young women, precocious pubarche and hyperinsulinemia are early manifestations of PCOS. The familial clustering of women with PCOS suggests that heredity is implicated in the origin of the syndrome. However, genetic approaches to its pathogenesis have been hampered by the heterogeneity of phenotypic features within families, and the lack of uniform criteria for diagnosis. Currently, PCOS is considered a polygenic trait that might result from the interaction of susceptibility and protective genomic variants under the influence of environmental factors. Both linkage analysis and association studies are valid tools for the study of the genetics of PCOS. Candidate genes for PCOS include those related to androgenic pathways and metabolic associations of the syndrome. More recently, genes encoding inflammatory cytokines have been identified as target genes for PCOS, as proinflammatory genotypes and phenotypes are also associated with obesity, insulin resistance, type 2 diabetes, PCOS, and increased cardiovascular risk. This paper reviews the candidate genes involved in the metabolic pathways that are altered in patients with PCOS. Despite a significant amount of research in this area, none of the genes studied so far has been identified as the PCOS susceptibility gene for the majority of cases. PCOS is the first component of the metabolic syndrome to be detected in many women, so the identification and correct diagnosis of PCOS has important preventive and therapeutic implications for the affected women and their families. In the future, new therapeutic approaches to PCOS will rely on knowing the genes, environmental influences, and etiologic mechanisms associated with the disorder.
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PMID:Genetic basis of metabolic abnormalities in polycystic ovary syndrome: implications for therapy. 1505 32

Hyperinsulinemic hyperandrogenism with anovulation, the so-called polycystic ovary syndrome (PCOS), is the most frequent endocrine disorder of young women. One of the stigmata of PCOS is a deficit of lean mass and an excess of fat, in particular, abdominal fat, even in the absence of obesity. Adiponectin and IL-6 are among the adipocytokines that have recently been related to abdominal fat excess, insulin resistance states, and cardiovascular disease risk. We studied the effects of two new treatment options, ethinylestradiol-drospirenone and flutamide-metformin, and of their combination on adipocytokinemia and body adiposity in adolescents and women with PCOS. Adolescents with PCOS (n = 32; age, approximately 15 yr; body mass index, approximately 22 kg/m(2)) were randomly assigned to receive the oral contraceptive (OC) ethinylestradiol-drospirenone, or the low-dose generic duo of flutamide (62.5 mg/d) plus metformin (850 mg/d). Young women with PCOS (n = 22; age, approximately 19 yr; body mass index, approximately 22 kg/m(2)) were randomized to receive the same OC, either alone or with flutamide-metformin. Fasting blood glucose, serum insulin, lipids, androgens, IL-6, adiponectin, and body composition (by absorptiometry) were assessed at the start, and after 3 and/or 9 months. At the start, serum concentrations of the proinflammatory IL-6 were high, and those of the antiinflammatory adiponectin were low; body composition was adipose in each subpopulation. Abnormal adipocytokine levels, hypertriglyceridemia, and body adiposity diverged further from the norm in adolescents on OC; in contrast, girls on flutamide-metformin reverted all study indices toward normal, lost part of their fat excess, and reduced their lean mass deficit. In comparison to the girls on OC, those on flutamide-metformin lost a mean of approximately 4 kg of fat and gained approximately 4 kg of lean mass. Similarly, abnormal adipocytokine levels and adiposity were aggravated in women on OC alone and improved in women on OC plus flutamide-metformin; within 9 months, the latter subgroup lost a mean of approximately 3 kg of fat and gained approximately 3 kg of lean mass, in comparison to women on OC alone. In conclusion, young and nonobese PCOS patients were found to be in a low-grade, chronic inflammation state, and to have a body adiposity that evolves according to the balance of circulating adipocytokines and lipids, rather than to androgen excess or fasting hyperinsulinemia. Monotherapy with ethinylestradiol-drospirenone may not be a prime choice for PCOS, given its inefficacy to attenuate abnormal adipocytokine levels and body adiposity; ethinylestradiol-drospirenone plus flutamide-metformin, however, is a first OC combination that was found capable of reverting both the adipocytokine balance and the body composition toward normal, and that may therefore improve the long-term cardiovascular perspectives of women with PCOS.
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PMID:Ethinylestradiol-drospirenone, flutamide-metformin, or both for adolescents and women with hyperinsulinemic hyperandrogenism: opposite effects on adipocytokines and body adiposity. 1507 Sep 17


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