Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989–1995. Subsequent studies have supported ...and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.
Polycystic Ovary Syndrome Ehrmann, David A
The New England journal of medicine,
03/2005, Letnik:
352, Številka:
12
Journal Article
Recenzirano
The polycystic ovary syndrome is one of the most common hormonal disorders affecting women. It has multiple components — reproductive, metabolic, and cardiovascular — with health implications for the ...patient's entire life span. This review addresses current concepts regarding the diagnosis, cause, and treatment of the condition.
The polycystic ovary syndrome is one of the most common hormonal disorders affecting women. This review addresses current concepts regarding the diagnosis, cause, and treatment of the condition.
In 1935, Stein and Leventhal published a paper on their findings in seven women with amenorrhea, hirsutism, obesity, and a characteristic polycystic appearance to their ovaries — one of the first descriptions of a complex phenotype today known as the polycystic ovary syndrome.
1
Insight into the pathogenesis and treatment of the polycystic ovary syndrome has increased substantially in the decade since this topic was last addressed in the
Journal
.
2
The condition is now well recognized as having a major effect throughout life on the reproductive, metabolic, and cardiovascular health of affected women. This review addresses current knowledge regarding the . . .
Objective:
The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome (PCOS).
Participants:
An Endocrine Society-appointed Task Force of experts, a ...methodologist, and a medical writer developed the guideline.
Evidence:
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence.
Consensus Process:
One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence.
Conclusions:
We suggest using the Rotterdam criteria for diagnosing PCOS (presence of two of the following criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women. Hyperandrogenism is central to the presentation in adolescents, whereas there is no consistent phenotype in postmenopausal women. Evaluation of women with PCOS should exclude alternate androgen-excess disorders and risk factors for endometrial cancer, mood disorders, obstructive sleep apnea, diabetes, and cardiovascular disease. Hormonal contraceptives are the first-line management for menstrual abnormalities and hirsutism/acne in PCOS. Clomiphene is currently the first-line therapy for infertility; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility. Hormonal contraceptives and metformin are the treatment options in adolescents with PCOS. The role of weight loss in improving PCOS status per se is uncertain, but lifestyle intervention is beneficial in overweight/obese patients for other health benefits. Thiazolidinediones have an unfavorable risk-benefit ratio overall, and statins require further study.
Polycystic ovary syndrome (PCOS), the most common hormonal disorder among women of reproductive age, has various metabolic and reproductive consequences. Metformin was originally shown to lower ...testosterone levels in women with PCOS in the 1990s, an effect presumably related to its insulin sensitising actions. However, the precise mechanisms of metformin action in PCOS remain unclear and there is considerable heterogeneity in the clinical response to this therapy in women with PCOS. Recent evidence indicates that genetic factors may play a significant role in predicting response to metformin therapy in PCOS and future studies are needed to further identify women who are most likely to benefit from this therapy. At present, there is no clear evidence to support broad metformin use in PCOS. Well-designed prospective trials are needed to establish clear benefit for metformin use in the treatment of the reproductive and metabolic consequences associated with PCOS.
Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea are frequently associated with polycystic ovary syndrome (PCOS) but remain underrecognized. Women with PCOS have a 2-4 times ...higher risk of NAFLD independent of body mass index than healthy weight-matched controls. Insulin resistance and hyperandrogenemia together play a central role in the pathogenesis of NAFLD. Timely diagnosis of NAFLD is important because its progression can lead to nonalcoholic steatohepatitis and/or advanced liver fibrosis that can eventually result in liver-related mortality. The presence of NAFLD has also been associated with increased risks of type 2 diabetes, cardiovascular events, overall mortality, and extrahepatic cancers. The treatment of NAFLD in PCOS should include lifestyle interventions. Glucagon-like peptide 1 receptor agonists have shown promising results in patients with PCOS and NAFLD, but future randomized trails are needed to confirm this benefit. Likewise, the use of combined oral estrogen-progestin contraceptives may provide a benefit by decreasing hyperandrogenemia. Sleep disordered breathing is common among women with PCOS and is responsible for a number of cardiometabolic derangements. Obstructive sleep apnea is most often found in overweight and obese women with PCOS, but as is the case with NAFLD, its prevalence exceeds that of women who are of similar weight without PCOS. Left untreated, obstructive sleep apnea can precipitate or exacerbate insulin resistance, glucose intolerance, and hypertension.
There is convincing evidence that, in humans, discrete sleep stages are important for daytime brain function, but whether any particular sleep stage has functional significance for the rest of the ...body is not known. Deep non-rapid eye movement (NREM) sleep, also known as slow-wave sleep (SWS), is thought to be the most "restorative" sleep stage, but beneficial effects of SWS for physical well being have not been demonstrated. The initiation of SWS coincides with hormonal changes that affect glucose regulation, suggesting that SWS may be important for normal glucose tolerance. If this were so, selective suppression of SWS should adversely affect glucose homeostasis and increase the risk of type 2 diabetes. Here we show that, in young healthy adults, all-night selective suppression of SWS, without any change in total sleep time, results in marked decreases in insulin sensitivity without adequate compensatory increase in insulin release, leading to reduced glucose tolerance and increased diabetes risk. SWS suppression reduced delta spectral power, the dominant EEG frequency range in SWS, and left other EEG frequency bands unchanged. Importantly, the magnitude of the decrease in insulin sensitivity was strongly correlated with the magnitude of the reduction in SWS. These findings demonstrate a clear role for SWS in the maintenance of normal glucose homeostasis. Furthermore, our data suggest that reduced sleep quality with low levels of SWS, as occurs in aging and in many obese individuals, may contribute to increase the risk of type 2 diabetes.
Abstract
Objective
To update the “Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline,” published by the Endocrine Society in 2008.
...Participants
The participants include an Endocrine Society–appointed task force of seven medical experts and a methodologist.
Evidence
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies.
Consensus Process
Group meetings, conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees, members, and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines.
Conclusion
We suggest testing for elevated androgen levels in all women with an abnormal hirsutism score. We suggest against testing for elevated androgen levels in eumenorrheic women with unwanted local hair growth (i.e., in the absence of an abnormal hirsutism score). For most women with patient-important hirsutism despite cosmetic measures (shaving, plucking, waxing), we suggest starting with pharmacological therapy and adding direct hair removal methods (electrolysis, photoepilation) for those who desire additional cosmetic benefit. For women with mild hirsutism and no evidence of an endocrine disorder, we suggest either pharmacological therapy or direct hair removal methods. For pharmacological therapy, we suggest oral combined estrogen–progestin contraceptives for the majority of women, adding an antiandrogen after 6 months if the response is suboptimal. We recommend against antiandrogen monotherapy unless adequate contraception is used. We suggest against using insulin-lowering drugs. For most women who choose hair removal therapy, we suggest laser/photoepilation.
An update of the “Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Practice Guideline,” published by the Endocrine Society in 2008.
Insufficient sleep increases the risk for insulin resistance, type 2 diabetes, and obesity, suggesting that sleep restriction may impair peripheral metabolic pathways. Yet, a direct link between ...sleep restriction and alterations in molecular metabolic pathways in any peripheral human tissue has not been shown.
To determine whether sleep restriction results in reduced insulin sensitivity in subcutaneous fat, a peripheral tissue that plays a pivotal role in energy metabolism and balance.
Randomized, 2-period, 2-condition, crossover clinical study.
University of Chicago Clinical Resource Center.
Seven healthy adults (1 woman, 6 men) with a mean age of 23.7 years (SD, 3.8) and mean body mass index of 22.8 kg/m(2) (SD, 1.6).
Four days of 4.5 hours in bed or 8.5 hours in bed under controlled conditions of caloric intake and physical activity.
Adipocytes collected from subcutaneous fat biopsy samples after normal and restricted sleep conditions were exposed to incremental insulin concentrations. The ability of insulin to increase levels of phosphorylated Akt (pAkt), a crucial step in the insulin-signaling pathway, was assessed. Total Akt (tAkt) served as a loading control. The insulin concentration for the half-maximal stimulation of the pAkt-tAkt ratio was used as a measure of cellular insulin sensitivity. Total body insulin sensitivity was assessed using a frequently sampled intravenous glucose tolerance test.
The insulin concentration for the half-maximal pAkt-tAkt response was nearly 3-fold higher (mean, 0.71 nM SD, 0.27 vs. 0.24 nM SD, 0.24; P = 0.01; mean difference, 0.47 nM SD, 0.33; P = 0.01), and the total area under the receiver-operating characteristic curve of the pAkt-tAkt response was 30% lower (P = 0.01) during sleep restriction than during normal sleep. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity.
This was a single-center study with a small sample size.
Sleep restriction results in an insulin-resistant state in human adipocytes. Sleep may be an important regulator of energy metabolism in peripheral tissues.
National Institutes of Health.
► PCOS is among the most common endocrine disorders in women. ► Women with PCOS are highly predisposed to develop impaired glucose tolerance and type 2 diabetes. ► Obstructive sleep apnea (OSA) ...contributes to the metabolic disturbances associated with PCOS. ► Correction of OSA is associated with amelioration of metabolic dysfunction in PCOS.
Polycystic ovary syndrome (PCOS) affects between 5% and 8% of women, making it one of the most common endocrinopathies in women. The disorder typically has its onset at puberty with evidence of excessive androgen production, obesity, and insulin resistance. Women with PCOS are more insulin resistant than weight-matched controls and have an exceptionally high prevalence of early-onset impaired glucose tolerance (30–40%), and type 2 diabetes (up to 10%). Over the past several years, chronic decreases in sleep duration and/or quality have been identified as a risk for the development of a number of metabolic derangements that are strikingly similar to those seen in PCOS. Specifically, decreased sleep quality due to obstructive sleep apnea (OSA) has been causally linked to insulin resistance, glucose intolerance, dyslipidemia and hypertension independent of body mass index (BMI). Until recently, however, it had not been recognized that OSA is present in a disproportionate number of women with PCOS: the risk for OSA is at least 5- to 10-fold higher compared to the risk in similarly obese women without PCOS. The causes and consequences of OSA in women with PCOS are addressed in this manuscript.
Context:
Questionnaire studies linked symptoms of obstructive sleep apnea (OSA) to the risk of gestational diabetes mellitus (GDM). Whether this association is present when OSA is assessed ...objectively by polysomnography is not known.
Objective:
The objective of the study was to assess the relationship between pregnancy, OSA, and GDM.
Design, Setting, and Participants:
We conducted observational case-control studies using polysomnography in 15 nonpregnant, nondiabetic women (NP-NGT), 15 pregnant women with normal glucose tolerance (P-NGT), and 15 pregnant women with GDM (P-GDM). The groups were frequency matched for age and race/ethnicity. Pregnant women were studied during the late second to early third trimester.
Main Outcome Measures:
Comparisons of OSA diagnosis and sleep parameters between NP-NGT and P-NGT to assess the impact of pregnancy and between P-NGT and P-GDM to explore the association between GDM and OSA were measured.
Results:
Compared with NP-NGT, P-NGT women had a higher apnea hypopnea index (AHI) (median 2.0 vs 0.5, P = .03) and more disrupted sleep as reflected by a higher wake time after sleep onset (median 66 vs 21 min, P < .01) and a higher microarousal index (median 16.4 vs 10.6, P = .01). Among the pregnant women, P-GDM had markedly lower total sleep time (median 397 vs 464 min, P = .02) and a higher AHI (median 8.2 vs 2.0, P = .05) than P-NGT women. OSA was more prevalent in P-GDM than in P-NGT women (73% vs 27%, P = .01). After adjustment for prepregnancy body mass index, the diagnosis of GDM was associated with a diagnosis of OSA odds ratio 6.60 (95% confidence interval 1.15–37.96). In pregnancy, after adjusting for prepregnancy body mass index, higher microarousal index significantly associated with higher hemoglobin A1c and fasting glucose levels. Higher oxygen desaturation index was associated with higher fasting glucose levels.
Conclusion:
Pregnancy is associated with sleep disturbances. Sleep is more disturbed in GDM than in P-NGT women. There is a strong association between GDM and OSA.
PDF
