Effects of weight and insulin sensitivity on reproductive function in PCOS

描述（由申请人提供）：K99/R00奖的目标是完成女性生殖内分泌学的进一步培训，特别是多囊卵巢综合征（PCOS）女性原代细胞肌肉培养的转化研究，分析，发表和展示在2个试点研究中收集的数据，并完成杜兰大学临床研究项目理科硕士课程所需的课程。在R00（独立期）期间，PI将对患有多囊卵巢综合征的肥胖女性进行随机对照试验，以确定：a)运动训练，b) 25%饮食限制，c)二甲双胍和d)不干预（对照组）对神经内分泌功能（搏动性LH分泌），生殖功能（排卵率），卵巢形态/功能和胰岛素敏感性的影响。多囊卵巢综合征是一种以雄激素分泌过多和生殖功能障碍为特征的内分泌疾病，是育龄妇女最常见的生殖疾病。多囊卵巢综合征的病因尚不清楚；然而，异常的神经内分泌功能和高胰岛素血症被认为是PCOS发展的主要候选因素。减肥被认为是超重妇女不孕不育的首选治疗方法。然而，尚不清楚生殖功能是否会因改善胰岛素敏感性和/或减轻体重而得到改善。PI进行的初步研究表明，运动与减肥无关，可诱导多囊卵巢综合征女性的月经周期。由于运动不会导致体重减轻，我们现在假设观察到的胰岛素敏感性的增加可能介导了生殖功能的改善，而不是体重减轻。为了支持这一假设，我们为期16周的有氧运动研究降低了空腹胰岛素，增加了胰岛素刺激下的葡萄糖处理。此外，胰岛素增敏剂治疗多囊卵巢综合征患者可以改善雄激素过剩和排卵功能，而不会改变体重。拟议的随机对照试验将提供数据，以表明生活方式改变可以影响多囊卵巢综合征妇女生殖功能的可能机制。希望进一步的研究将导致基于证据的多囊卵巢综合征超重妇女不孕不育治疗方案的发展。

DESCRIPTION (provided by applicant): The objective of this K99/R00 award is to complete further training in female reproductive endocrinology, particularly translational studies in primary cell muscle cultures from women with polycystic ovary syndrome (PCOS), analyze, publish and present data collected during 2 pilot studies and complete the coursework required for the Masters of Science in Clinical Research program at Tulane University. During the R00 (independent phase) the PI will conduct a randomized controlled trial in obese women with PCOS to determine the effect of: a) exercise training, b) 25% dietary restriction, c) metformin and d) no intervention (control group) on neuroendocrine function (pulsatile LH secretion), reproductive function (ovulation rate), ovarian morphology/function and insulin sensitivity. PCOS, an endocrinopathy characterized by excessive androgen production and reproductive dysfunction is the most common reproductive disorder in women of reproductive age. The etiology of PCOS is unclear; however, abnormal neuroendocrine function and hyperinsulinemia are considered primary candidates involved in the development in PCOS. Weight loss is regarded as the choice treatment of infertility in overweight women with the condition. However, it is not known if reproductive function is improved as a result of improving insulin sensitivity and/or reducing body weight. Preliminary studies conducted by the PI indicate that exercise, independent of weight loss, induces menstrual cyclicity in women with PCOS. Since exercise did not cause weight loss, we now hypothesize that the observed increase in insulin sensitivity may mediate the improvement in reproductive function rather than weight loss. In support of this hypothesis, our 16-week aerobic exercise study reduced fasting insulin and increased insulin-stimulated glucose disposal during a hyperinsulinemic euglycemic clamp. Furthermore, treatment of PCOS patients with insulin sensitizers improves both androgen excess and ovulatory function without weight change. The proposed randomized controlled trial will provide data to indicate possible mechanisms by which lifestyle modification can influence reproductive function in women with PCOS. It is hoped that further studies will then lead to the development of evidence based treatment programs for infertility in overweight women with PCOS. PUBLIC HEALTH RELEVANCE: Polycystic ovary syndrome (PCOS) is the most common reproductive abnormality in premenopausal women. The prevalence of PCOS in the community is increasing in parallel with the rise in obesity. Weight loss by regular exercise and dieting is currently recommended in the treatment of the syndrome. The ability of these treatments to restore menstrual function and fertility in some women is not known.