Genetic abnormalities in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a very common endocrinopathy and is the major cause of anovulatory infertility. It is also associated with an increased risk of non insulin dependent diabetes (NIDDM) in later life. Despite the importance of PCOS to women's health, little is known about its aetiology. Because of the well-known familial clustering of cases of PCOS, recent studies in our department have focused on clinical and molecular genetic studies in an attempt to identify key genes which may be involved in its aetiology. We have found evidence that a polymorphism in the regulatory region of CYP11a (encoding P450 cholesterol side chain cleavage, also an important enzyme in the steroidogenic pathway) is associated with and linked to PCOS. In examination of the insulin gene (INS), we have shown, in three separate populations, that class III alleles in the INS-VNTR (the minisatellite in the regulatory region of the insulin gene) are associated with PCOS. Variation in this element has also been implicated in the aetiology of NIDDM. We propose that PCOS is an oligogenic disorder in which a small number of key genes interact with environmental factors (notably dietary), the balance of which factors determine, the typically heterogeneous, clinical and biochemical phenotype.     

Pituitary-ovarian relationships in polycystic ovary syndrome.

The spontaneous pattern of pituitary gonadotropins and ovarian steroids and their response to dynamic tests were measured in 12 women with polycystic ovarian syndrome (PCO) and the results compared to those from 6 normal women during the early follicllar phase of the cycle (controls). As judged by serial measurements of urinary total estrogen and pregnanediol over a 12-week period, in PCO patients 75% of cycles were anovulatory (anovulatory PCO) as compared to 100% ovulatory in controls. The basal concentrations of LH, androstenedione and estrone were significantly higher and the concentration os FSH significantly lower in anovulatory PCO than in the controls (P less than .05). In PCO patients the concentration of LH was lower following an ovulatory cycle than that following a period of anovulation. Negative and positive feedback responses to an estrogen provocation test (200 microgram ethinyl estradiol per day for 3 days) were normal in anovulatory PCO although the LH peak occurred 24 h earlier than in the controls. The amplitude of the pulses of LH was significantly greater in anovulatory PCO than in the controls and was suppressed in both groups after ethinyl estradiol. The peak release of LH in response to 56 microgram LRF in ovulatory PCO was similar in controls but LH responses in anovulatory PCO were significantly greater. It is suggested that the abnormalities in gonadotropin secretion in PCO are secondary to excessive and prolonged extraglandular production of estrogen from androstenedione.     

New perspectives in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is, perhaps, the most common endocrinopathy affecting premenopausal women. Of such women, 5%-10% have the classic endocrine syndrome of hyperandrogenism and chronic anovulation. The syndrome not only has these long-appreciated reproductive morbidities, but it also has more recently recognized important metabolic consequences related to insulin resistance. This article reviews the current state of the field with respect to the pathogenesis of PCOS and the insulin resistance associated with it.     

Hypertension in polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is associated with multiple cardiovascular risk factors. The aims of this study are to investigate the prevalence of hypertension in a female population with PCOS and to correlate hypertension with her clinical and hormonal profile. MATERIALS AND METHODS: it is a transversal study of 79 PCOS patients with mean age of 25 +/- 7 years (range 13-44). PCOS diagnosis is made by Rotterdam consensus criteria's (2003). WHO definition of hypertension is used (BP 140/90 mmHg). Blood pressure is measured three times in each patient. Ovarian echography and biochemical assays (GnRH test, androgens, cholesterol, triglycerides, and oral glucose tolerance test) are made before the 5th day of the menstrual cycle. RESULTS: 12% of PCOS women have hypertension. Family history of hypertension is not a predictive factor of hypertension in our study. PCOS patients with hypertension are not significantly older than those without hypertension (28.4 +/- 6.5 vs. 25.2 +/- 7; p = 0.12). If compared to PCOS women without hypertension, those with hypertension have a significantly higher BMI (39.2 +/- 7 vs. 29.6; p = 0.0004). PCOS patients with and without hypertension do not differ significantly in their level of androgens and total cholesterol. Triglycerides level is higher in PCOS patients with hypertension (p = 0.06). In oral glucose tolerance test, areas under the curve of insulin and glucose are significantly higher in PCOS patients with hypertension (respectively p = 0.06 and 0.02). The area under the curve of LH during GnRH test is lower in PCOS patients with hypertension (p = 0.04).     

Insulin action in the polycystic ovary syndrome.

Research on insulin action in PCOS has been intensive after the identification of insulin resistance as a feature of the syndrome in 1980. It is now clear that PCOS is a metabolic as well as a reproductive disorder and an important cause of type 2 diabetes mellitus in women. The cellular and molecular mechanisms of insulin resistance in PCOS are distinct from those in other insulin resistance syndromes. Elucidating these mechanisms promises to provide considerable insight into insulin receptor signal specificity. Conversely, insulin resistance is now known to have an important role in the pathogenesis of the reproductive disturbances of PCOS. It is thought that one or several genetic defects may cause both the insulin resistance and reproductive abnormalities characteristic of PCOS.     

Antiandrogen treatment of polycystic ovary syndrome.

Although hirsutism and androgenetic alopecia are cosmetic problems, they can be psychologically devastating for women. Mechanical hair removal may control the cosmetic appearance of hirsutism, but the underlying problem usually continues to progress. Topical therapies for androgenetic alopecia provide for modest improvement at best, and no topical therapy has been shown to be effective for hirsutism. Antiandrogens, combined with ovarian suppression, offer the best hope for the improvement of hirsutism and androgenetic alopecia in women with PCOS. Improvement will occur in most women. Unless the underlying cause of the PCOS is corrected, medical therapy will need to be continued indefinitely.     

Neuroendocrine aspects of polycystic ovary syndrome.

A series of investigations have emphasized the heterogeneous nature of the clinical condition known as PCOS and have delineated several factors that may contribute to the hyperandrogenemia and anovulation in this condition. Currently, it remains unclear whether intrinsic abnormalities of ovarian steroidogenesis, the effects of hyperinsulinemia in augmenting LH stimulation of ovarian androgen production, and the persistent rapid frequency of LH/GnRH secretion are primary factors in all patients. Indeed, these factors may have variable roles in different patients, all of whom present with the clinical syndrome of PCOS. A consensus has emerged that abnormalities in the neuroendocrine control of GnRH secretion exist in a significant subset of patients and lead to persistent hypersecretion of LH, which seems to be an important component of the syndrome, particularly in nonobese patients. The relative frequency of primary abnormalities in the regulation of GnRH secretion versus secondary changes reflecting altered circulating concentrations of ovarian steroid remains uncertain. No clear evidence exists for an underlying neuroendocrine abnormality of GnRH regulation in all patients. The recent data showing insensitivity of the hypothalamic GnRH pulse generator to E2 progesterone feedback have suggested potential mechanisms that may explain the abnormalities of GnRH secretion seen in adolescent girls in whom the clinical syndrome of PCOS is destined to develop. Further studies are required in adolescents to establish whether GnRH regulation is impaired during puberty or whether data in adults simply reflect the long-term effects of elevated androgens, estrogens, or other hormones on the hypothalamus. Studies in carefully delineated subgroups of patients with PCOS are needed to establish these points, with a long-term goal of providing patients with improved methods of inducing ovulation and reducing hyperandrogenemia.     

Secondary forms of polycystic ovary syndrome.

Hyperandrogenism and chronic anovulation are the most common endocrine disorders of premenopausal women. Most patients have polycystic ovary syndrome (PCOS), which is essentially benign, but might be associated with increased cardiovascular morbidity; PCOS is associated with specific endocrine and ultrasonographic features. Some patients exhibiting similar features to PCOS might have other underlying diagnoses, such as adrenal and ovarian steroidogenic deficiencies, adrenal and ovarian androgen-secreting tumours, other medical or endocrine disorders, and/or be on medications thought to cause PCOS, such as anti-epileptics. Unlike PCOS, some of these conditions can occasionally be life threatening and require prompt diagnosis and treatment. Here, we focus on these disorders, including their pathogenesis, and attempt to define the clinical and biochemical features that distinguish them from PCOS.     

The metabolic syndrome in polycystic ovary syndrome

Much overlap is present between the polycystic ovary syndrome (PCOS) and the metabolic syndrome. This article reviews the existing data regarding the prevalence, characteristics, and treatment of the metabolic syndrome in women with PCOS. The prevalence of the metabolic syndrome in PCOS is approximately 43-47%, a rate 2-fold higher than that for women in the general population. High body mass index and low serum HDL cholesterol are the most frequently occurring components of the metabolic syndrome in PCOS. The pathogenic link between the metabolic syndrome and PCOS is most likely insulin resistance. Therefore, the presence of the metabolic syndrome in PCOS suggests a greater degree of insulin resistance compared to PCOS without the metabolic syndrome. Obesity, atherogenic dyslipidemia, hypertension, impaired fasting glucose/impaired glucose tolerance, and vascular abnormalities are all common metabolic abnormalities present in PCOS. Lifestyle modification has proven benefit and pharmacological therapy with insulin-sensitizing agents has potential benefit in the treatment of the metabolic syndrome in women with PCOS.     

Insulin-sensitizing agents in polycystic ovary syndrome

Insulin-sensitizing agents have been recently proposed as the therapy of choice for polycystic ovary syndrome (PCOS), since insulin resistance and associated hyperinsulinemia are recognized as important pathogenetic factors of the syndrome. Moreover, since almost all obese PCOS women and more than half of those of normal weight are insulin resistant, and therefore present some degree of hyperinsulinemia, the use of insulin sensitizers should be suggested in most patients with PCOS. Insulin sensitizer treatment has been associated with a reduction in serum androgen levels and gonadotropins, and with an improvement in serum lipids and in prothrombotic factor plasminogen-activator inhibitor type 1, whatever the insulin sensitizer used. This therapy has also been associated with a decrease in hirsutism and acne, and with a regulation of menses and an improvement of ovulation and fertility. Notable improvements in all these parameters have also been described after a change in lifestyle approach, particularly in the presence of obesity. Lifestyle interventions should therefore be combined with insulin sensitizers in PCOS when obesity is present.     

Adrenal abnormalities in polycystic ovary syndrome

This study was undertaken to examine the role of adrenal androgen excess in the pathogenesis of polycystic ovary syndrome (PCOS) and, if such was present, to assess its reversibility using dexamethasone given in physiological dosage at night. Mean plasma testosterone (T), T/sex-hormone binding globulin (T/SHBG) ratio, androstenedione, and 17-OH-progesterone levels were elevated in the 19 patients studied. Plasma estrone values were elevated, whereas estradiol levels were normal. Plasma FSH was decreased and LH responsiveness to LHRH was exaggerated. Metyrapone, an 11-hydroxylase inhibitor, was administered at 2400 h to induce hypocortisolemia and compensatory ACTH secretion so that adrenal androgen and glucocorticoid responsiveness to endogenous stimulation could be examined. Plasma T, androstenedione, and 11-deoxycortisol responses to metyrapone were excessive in PCOS patients, thus indicating a specific adrenal abnormality. After 3 months treatment with dexamethasone, 0.5 mg at night, mean plasma T/SHBG and androstenedione declined to normal, and mean plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate declined to below normal. The mean estrone value was slightly lower during dexamethasone. Plasma LH responsiveness to LHRH was no longer significantly different from normal, but FSH was suppressed. During treatment androgen responsiveness to metyrapone stimulation was normal, whereas 11-deoxycortisol responsiveness was suppressed. Fifteen patients completed 3 months of treatment with dexamethasone. Of these, 10 resumed regular menstruation. The latter group had suppression of plasma T, T/SHBG, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Only plasma androstenedione fell significantly in the remainder. These observations support the hypothesis that, in at least some patients, PCOS develops in response to abnormal gonadotropin secretion induced by hyperestronemia occurring as a consequence of excessive adrenal androgen secretion.     

Selective insulin resistance in the polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia that is amplified by insulin in the presence of resistance to insulin's action to stimulate glucose uptake in muscle and fat. To explore the mechanisms for this paradox, we examined the metabolic and mitogenic actions of insulin and insulin-like growth factor I (IGF-I) in cultured skin fibroblasts from PCOS (n = 16) and control (n = 11) women. There were no significant decreases in the number or affinity of insulin- or IGF-I-binding sites in PCOS compared to control fibroblasts. Basal rates were similar, but there were significant decreases in insulin-stimulated (control, 51.8 +/- 7.0; PCOS, 29.5 +/- 2.9 nmol/10(6) cells x 2 h at 1,000,000 pmol/L; P < 0.005) and IGF-I-stimulated (control, 48.9 +/- 6.7; PCOS, 33.0 +/- 3.2 PCOS nmol/10(6) cells x 2 h at 100,000 pmol/L IGF-I; P < 0.05) glucose incorporation into glycogen in PCOS fibroblasts, a metabolic action of insulin. Stimulation of thymidine incorporation, a mitogenic action of insulin, was similar in PCOS and control fibroblasts in response to both insulin and IGF-I. There were also no significant differences in insulin- or IGF-I-stimulated insulin receptor substrate-1-associated phosphatidylinositol-3-kinase activity in PCOS compared to control fibroblast cells. We conclude that 1) there is a selective defect in insulin action in PCOS fibroblasts that affects metabolic, but not mitogenic, signaling pathways; 2) there is a similar defect in IGF-I action, suggesting that insulin and IGF-I stimulate glycogen synthesis by the same postreceptor pathways; and 3) insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activation by insulin and IGF-I is similar to the control value, suggesting that the metabolic signaling defect is in another pathway or downstream of this signaling step in PCOS fibroblasts.     

Ovarian and adrenal function in polycystic ovary syndrome.

Androgens are secreted by both the ovaries and adrenal glands in response to their respective trophic hormones LH and ACTH. Androgens in women are not specifically under negative feedback control by these pituitary hormones because they are by-products of estradiol and cortisol secretion. Rather, androgen secretion seems to be regulated mostly by intraglandular mechanisms. Functional ovarian hyperandrogenism is found in about 70% of patients with PCOS. It is characterized by excessive secretion of 17-hydroxyprogesterone in response to GnRH agonist or hCG stimulation. Failure of dexamethasone to suppress plasma free testosterone normally in the presence of normal adrenocortical suppression is also typical. Functional adrenal hyperandrogenism is found in about half of patients with PCOS. It is most often characterized by moderately increased secretion of the 17-ketosteroid DHEA in response to ACTH. The most likely cause of the excessive androgen secretion by both glands seems to be abnormal regulation (dysregulation) of the 17-hydroxylase and 17,20-lyase activities of P-450c17, the rate-limiting step in androgen biosynthesis. There are also subtle generalized disturbances of steroid metabolism, including tendencies toward excessive estrogen and cortisol secretion. The cause of dysregulation of steroidogenesis is unknown. The hyperinsulinemia that is compensatory for resistance to the glucose-metabolic effect of insulin seems to have a role in many cases. In most cases, intrinsic intraovarian or intra-adrenal autocrine or paracrine regulatory mechanisms are most likely malfunctioning.     

多囊卵巢综合征的药物治疗

多囊卵巢综合征是一种涉及多系统的内分泌疾病,常伴有代谢紊乱和心血管疾患.传统的治疗药物包括口服避孕药、促排卵药、抗雄激素药等,新的治疗药物包括双胍类、噻唑烷二酮类、他汀类、芳香化酶抑制剂等.本文就多囊卵巢综合征药物治疗的研究进展作一综述.     

Obesity and polycystic ovary syndrome

The aetiology of Polycystic Ovary Syndrome (PCOS) is complex and multifactorial. There is much evidence, however, to suggest that adipose tissue plays an important role in the development and maintenance of PCOS pathology. There is a close correlation between adiposity and symptom severity in women with PCOS, and even modest reductions in weight generally translate into significant improvements in menstrual regularity, fertility and hyperandrogenic features. This review article considers the various mechanisms that might underlie this link between excess adiposity and PCOS - including the effects of differential insulin sensitivity, abnormal steroid hormone metabolism and adipocytokine secretion. Greater attention to the therapeutic options available to reduce the impact of excess adiposity on ovarian and metabolic function is essential to the management of PCOS.