Studying the mechanisms for the complex pathogenesis of polycystic ovary syndrome (PCOS) requires animal models with endocrine, reproductive, and metabolic features of the syndrome. Hyperandrogenism seems to be a central factor in PCOS, leading to anovulation and insulin resistance. In female rats, continuous administration of letrozole, a nonsteroidal inhibitor of P450 aromatase, at 400 μg/d starting before puberty induces hyperandrogenemia and reproductive abnormalities similar to those in women with PCOS. However, despite high circulating testosterone levels, these rats do not develop metabolic abnormalities, perhaps because of their supraphysiological testosterone concentrations or because estrogen synthesis is completely blocked in insulin-sensitive tissues. To test the hypothesis that continuous administration of lower doses of letrozole starting before puberty would result in both metabolic and reproductive phenotypes of PCOS, we performed a 12-wk dose-response study. At 21 d of age, 46 female Wistar rats were divided into two letrozole groups (100 or 200 μg/d) and a control group (placebo). Both letrozole doses resulted in increased body weight, inguinal fat accumulation, anovulation, larger ovaries with follicular atresia and multiples cysts, endogenous hyperandrogemia, and lower estrogen levels. Moreover, rats that received 200 μg/d had insulin resistance and enlarged adipocytes in inguinal and mesenteric fat depots, increased circulating levels of LH, decreased levels of FSH, and increased ovarian expression of Cyp17a1 mRNA. Thus, continuous administration of letrozole, 200 μg/d, to female rats for 90 d starting before puberty results in a PCOS model with reproductive and metabolic features of the syndrome.

-Victorin E. Maternal androgen excess reduces placental and fetal weights, increases placental steroidogenesis, and leads to long-term health effects in their female offspring. Am J Physiol Endocrinol Metab 303: E1373-E1385, 2012. First published October 9, 2012 doi:10.1152/ajpendo.00421.2012.-Here, we tested the hypothesis that excess maternal androgen in late pregnancy reduces placental and fetal growth, increases placental steroidogenesis, and adversely affects glucose and lipid metabolism in adult female offspring. Pregnant Wistar rats were randomly assigned to treatment with testosterone (daily injections of 5 mg of free testosterone from gestational days 16 to 19) or vehicle alone. In experiment 1, fetal and placental weights, circulating maternal testosterone, estradiol, and corticosterone levels, and placental protein expression and distribution of estrogen receptor-␣ and -␤, androgen receptor, and 17␤-hydroxysteroid dehydrogenase 2 were determined. In experiment 2, birth weights, postnatal growth rates, circulating testosterone, estradiol, and corticosterone levels, insulin sensitivity, adipocyte size, lipid profiles, and the presence of nonalcoholic fatty liver were assessed in female adult offspring. Treatment with testosterone reduced placental and fetal weights and increased placental expression of all four proteins. The offspring of testosterone-treated dams were born with intrauterine growth restriction; however, at 6 wk of age there was no difference in body weight between the offspring of testosterone-and control-treated rats. At 10 -11 wk of age, the offspring of the testosterone-treated dams had less fat mass and smaller adipocyte size than those born to control rats and had no difference in insulin sensitivity. Circulating triglyceride levels were higher in the offspring of testosterone-treated dams, and they developed nonalcoholic fatty liver as adults. We demonstrate for the first time that prenatal testosterone exposure alters placental steroidogenesis and leads to dysregulation of lipid metabolism in their adult female offspring. testosterone; prenatal; maternal; placenta; polycystic ovary syndrome; insulin sensitivity; steroidogenesis; estrogen receptor; androgen receptor THE MATERNAL ENVIRONMENT may influence epigenetic processes during placental and fetal development that have long-lasting effects and lead to diseases such as hypertension, obesity, type 2 diabetes, and endocrine and reproductive dysfunction in adult offspring (6,24). Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and is associated with hyperandrogenism, oligo/anovulation (infertility), and polycystic ovaries (5, 26). PCOS is also associated with metabolic disturbances such as hyperinsulinemia and type 2 diabetes and dysfunctional lipid profile, symptoms that are aggravated by obesity (5). Women with PCOS are at a higher risk of delivering prematurely, developing gestational diabetes and preeclampsia (33), and having both small-for-gestational-age (40) and large-for-...

Polycystic ovary syndrome (PCOS) is a reproductive and metabolic disorder associated with obesity and insulin resistance that often precedes the development of type-2 diabetes. Rats continuously exposed to dihydrotestosterone from prepuberty display typical reproductive and metabolic PCOS characteristics including anovulation, polycystic ovaries, insulin resistance, and obesity. Our aim was to investigate if resveratrol improves reproductive and metabolic functions in PCOS rats. The effect was compared to exercise. Control and PCOS rats were treated with vehicle or resveratrol (400 mg · kg−1  · day−1) for 5-6 weeks. Another group of PCOS rats received vehicle treatment and exercised for 5-6 weeks. Insulin sensitivity was determined by euglycemic-hyperinsulinemic clamp. The glucose infusion rate was lower in the PCOS-vehicle group compared to control-vehicle rats (P < 0.05). Exercise increased insulin sensitivity compared with PCOS-vehicle rats (P < 0.05), but resveratrol did not. Resveratrol treatment and exercise resulted in smaller adipocytes, upregulated estrogen-related receptor α gene expression in subcutaneous fat, and improved estrus cyclicity in the previously acyclic PCOS rats. Although resveratrol had positive effects on adiposity and cyclicity in a similar manner to exercise, resveratrol does not seem to be a good candidate for treating insulin resistance associated with PCOS because no improvement in insulin sensitivity was observed in PCOS rats on normal chow.

One acupuncture session with electrical stimulation improves insulin sensitivity and modulates skeletal muscle gene and protein expression more than manual stimulation. Although electrical stimulation is superior to manual in enhancing insulin sensitivity during stimulation, they are equally effective after stimulation indicating that it is activation of sensory afferents rather than muscle contraction per se leading to the observed changes.

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Edited by: Paula Brunton New Findings r What is the central question of this study?The effectiveness of low-frequency electroacupuncture in the treatment of metabolic disorders associated with polycystic ovary syndrome (PCOS), an endocrine-metabolic disorder characterized by an imbalance in sex steroid production, is controversial. r What is the main finding and its importance?In a rat model of PCOS induced by the inhibition of P450 aromatase, low-frequency electroacupuncture increased low-density lipoprotein-cholesterol but did not improve the insulin resistance or the adipose tissue dysfunction, suggesting that a balance of sex steroids is needed to restore the metabolic function in this rat model of PCOS.Low-frequency electroacupuncture restores sex steroid synthesis and sympathetic activity in women with polycystic ovary syndrome, which may ameliorate its metabolic disturbances, probably by modulating sympathetic nerve activity or sex steroid synthesis. We investigated whether low-frequency electroacupuncture regulates the metabolic function to the same extent as treatment with estradiol or β-adrenergic blocking in a rat model of polycystic ovary syndrome induced by a P450 aromatase inhibitor (letrozole). Letrozole (200 μg day −1 ) or placebo pellets were implanted in prepubertal Wistar rats. Six weeks thereafter, rats were treated for 5-6 weeks with the following: low-frequency electroacupuncture (5 days per week); a β-adrenergic blocker (propranolol hydrochloride, 0.1 mg kg −1 , 5 days per week); or 17β-estradiol (2.0 μg) every fourth day. Body weight development, body composition, locomotor activity, insulin sensitivity, tissue-specific glucose uptake, lipid profile, adipocyte size, serum concentrations of adiponectin and insulin, and gene expression in inguinal fat were measured. All treatments increased circulating levels of low-density lipoprotein-cholesterol. Estradiol treatment restored locomotor activity and increased insulin sensitivity but did not modify the glucose uptake in muscle and fat. An upregulation of genes related to insulin sensitivity and downregulation of genes related to adipogenesis were observed in subcutaneous adipose tissue from rats exposed to letrozole. Only

IntroductionApproximately 5%–20% of reproductive women suffer from polycystic ovary syndrome (PCOS). Auricular points acupressure (AA) may serve as alternative management for PCOS for its benefits in both physical and psychological well-being. However, the effects of AA for insulin resistance (IR) in overweight/obese PCOS women have not been confirmed.Methods and analysisThe present study is designed as a randomised, placebo-controlled pilot trial to evaluate the effectiveness and safety of AA in treating IR in women with PCOS. A total of 60 eligible PCOS subjects will be randomised into an intervention group (AA group) and a control group (sham AA group) in a ratio of 1:1. Magnetic beads will be taped to the auricular points by the same senior acupuncture specialist from the First Affiliated Hospital, Heilongjiang University of Chinese Medicine. The treatment will last for 12 weeks. Primary outcome measure will be changes in homeostasis model assessment of IR between baseline and after 3 months of AA/sham AA treatment. Secondary outcomes include hormonal profile, weight, waist/hip circumference, body mass index, blood pressure, Ferriman-Gallwey score, acne and the assessment of health-related quality of life. Outcome measures are collected at baseline and the end of treatment visit.Ethics and disseminationThe protocol has been approved by the ethics committee of the First Affiliated Hospital of Heilongjiang University of Chinese Medicine (HZYLLKY201800301). Written informed consent will be obtained from all participants. The results will be disseminated through peer-reviewed journals for publications.Trial registration numberNCT03546595; Pre-results.