Excess androgen production in overweight pubertal girls--precursor to PCOS

描述（由申请人提供）：该研究奖将支持弗吉尼亚大学（UVA）的Christine M. Burt Solorzano医学博士的发展，因为她将在生殖神经内分泌学和多囊卵巢综合征（PCOS）的知名研究者John C. Marshall医学博士的指导下继续进行以患者为导向的研究培训。Solorzano博士是一名儿科内分泌学家，之前的研究经验主要集中在肥胖方面。她的直接目标是了解多囊卵巢综合征的起源，并确定新的治疗策略。她的长期目标是成为儿科多囊卵巢综合征研究的领导者，评估干预措施预防多囊卵巢综合征的疗效。这项培训将使Solorzano博士获得成为一名独立临床研究者所需的技能。该申请概述了一个职业发展计划，包括临床试验方法学、生物统计学、流行病学、研究伦理、分析方法学和研究设计方面的综合指导，部分通过临床研究硕士学位。Solorzano博士的研究计划旨在确定超重女孩雄激素过量的来源和时间，并确定减少这一人群雄激素产生的潜在策略。青春期雄激素过多是多囊卵巢综合征的先兆，多囊卵巢综合征是一种常见的慢性内分泌紊乱，与女性不孕症、代谢紊乱和多毛症有关。儿童期肥胖是一个国际问题，它使女孩面临雄激素过量的风险，甚至在青春期早期。需要确定青春期雄激素过量的来源，以阐明预防多囊卵巢综合征的目标。患有多囊卵巢综合征的妇女和年龄较大的青少年主要是卵巢雄激素分泌过多。然而，目前尚不清楚是肾上腺、卵巢还是两者都导致了超重女孩在发展为完全多囊卵巢综合征之前雄激素过量。尤其是在青春期早期，卵巢功能被认为是最小的。目的1将使用肾上腺抑制/刺激试验和卵巢刺激试验来检查正常和超重女孩整个青春期雄激素产生的来源。Aim 2将使用低剂量氢化可的松和leuprolide治疗来测试短期抑制促肾上腺皮质激素或促性腺激素的产生是否可以降低雄激素过量的超重女孩的雄激素水平。目的3将研究长期治疗（例如，低剂量氢化可的松、二甲双胍或螺内酯）在青春期所有阶段减少与肥胖相关的雄激素过量的潜在疗效。这项研究将在弗吉尼亚大学临床研究中心进行，并将扩展诊断工具，以检查年轻女孩的肾上腺和卵巢雄激素分泌。它可以确定治疗策略的目标，以治疗或预防青春期雄激素过量-青春期是多囊卵巢综合征发展的关键阶段。

DESCRIPTION (provided by applicant): This research award will support the development of Christine M. Burt Solorzano, M.D., of the University of Virginia (UVA), as she continues to train in patient-oriented research under the mentorship of John C. Marshall, M.D., Ph.D., an established investigator in reproductive neuroendocrinology and the polycystic ovary syndrome (PCOS). Dr. Solorzano is a pediatric endocrinologist with previous research experience focusing on aspects of obesity. Her immediate goal is to understand the origins of PCOS and identify new treatment strategies. Her long-term goal is to become a leader in pediatric PCOS research, assessing the efficacy of interventions to prevent PCOS. This training will allow Dr. Solorzano to acquire skills needed to become an independent clinical investigator. The application outlines a career development plan that includes comprehensive instruction in clinical trials methodology, biostatistics, epidemiology, research ethics, assay methodology, and study design, partly via a Masters of Clinical Research. Dr. Solorzano's research proposal is designed to determine the source and timing of androgen excess in overweight girls and to identify potential strategies to reduce androgen production in this population. Androgen excess during puberty is a forerunner to PCOS-a common chronic endocrine disorder associated with infertility, metabolic disorders, and hirsutism in women. Childhood obesity - an international problem -puts girls at risk for androgen excess, even in early puberty. Identifying sources of androgen excess during puberty is needed to elucidate targets for preventing PCOS. Women and older adolescents with PCOS have predominantly ovarian overproduction of androgens. However, it is unknown whether the adrenal gland, ovary, or both are responsible for androgen excess in overweight girls prior to developing the full PCOS syndrome. This is especially true during early puberty when ovarian function is thought to be minimal. Aim 1 will use adrenal suppression/stimulation testing and ovarian stimulation testing to examine sources of androgen production in normal and overweight girls throughout puberty. Aim 2 will use low-dose hydrocortisone and leuprolide therapy to test whether short-term suppression of adrenocorticotropin or gonadotropin production can reduce androgen levels in overweight girls with androgen excess. Aim 3 will examine the potential efficacy of longer-term therapies (e.g., low-dose hydrocortisone, metformin, or spironolactone) to reduce obesity-related androgen excess in girls during all stages of puberty. The research will be performed in the Clinical Research Center at UVA and would extend diagnostic tools to examine adrenal and ovarian androgen production to young girls. It may identify targets for therapeutic strategies to treat or prevent androgen excess during puberty - a critical stage for the development of PCOS. PUBLIC HEALTH RELEVANCE: Childhood obesity - an international problem - puts girls at risk for excess male hormone (androgen) production and polycystic ovary syndrome (PCOS). PCOS leads to infertility, metabolic problems, and male-pattern hair growth in women and adolescents. This project would identify sources of obesity-related androgen excess during puberty and examine the efficacy of potential therapies in reducing androgen levels in girls during all stages of puberty, with the goal of preventing PCOS.