Department of Gynecology, Beijing Haidian Hospital of Traditional Chinese Medicine, Beijing, China.
Department of Obstetrics, Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, China.
Reprod Sci. 2022 Apr;29(4):1357-1367. doi: 10.1007/s43032-021-00700-5. Epub 2021 Oct 15.
As one of the most common endocrine disorders affecting women, polycystic ovary syndrome (PCOS) is associated with serious conditions including anovulation, endometrial cancer, infertility, hyperandrogenemia, and an increased risk for obesity and metabolic derangements. One contributing etiology to the pathophysiology of hyperandrogenemia associated with PCOS is an intrinsic alteration in ovarian steroidogenesis, leading to enhanced synthesis of androgens including testosterone. Studies have suggested that the increased testosterone synthesis seen in PCOS is driven in part by increased activity of CYP17A1, the rate-limiting enzyme for the formation of androgens in the gonads and adrenal cortex, which represents a critical factor driving enhanced testosterone secretion in PCOS. In this work, we evaluated the hypothesis that dysregulation of the noncoding RNA H19 results in aberrant CYP17 and testosterone production. To achieve this, we measured Cyp17 in ovarian tissues of H19 knockout mice, and quantified serum testosterone levels, in comparison with wild-type controls. We also evaluated circulating and ovarian H19 expression and correlated results with the presence or absence of PCOS in a group of women undergoing evaluation and treatment for infertility. We found that the loss of H19 in a mouse model results in decreased ovarian Cyp17, along with decreased serum testosterone in female mice. Moreover, utilizing serum samples and cumulus cells from women with PCOS, we showed that circulating and ovarian levels of H19 are increased in women with PCOS compared to controls. Findings from our multimodal experimental strategy, involving both a mouse model of dysregulated H19 expression and clinical serum and ovarian cellular samples from women with PCOS, suggest that the loss of H19 may disrupt androgen production via a Cyp17-mediated mechanism. Conversely, excess H19 may play a role in the pathogenesis of PCOS-associated hyperandrogenemia.
多囊卵巢综合征（PCOS）是一种常见的影响女性的内分泌疾病，与无排卵、子宫内膜癌、不孕、高雄激素血症以及肥胖和代谢紊乱风险增加等严重疾病有关。高雄激素血症与 PCOS 相关的病理生理学的一个病因是卵巢甾体生成的内在改变，导致雄激素（包括睾酮）的合成增强。研究表明，PCOS 中观察到的睾酮合成增加部分是由 CYP17A1 活性增加驱动的，CYP17A1 是性腺和肾上腺皮质中雄激素形成的限速酶，这是 PCOS 中增强的睾酮分泌的关键因素。在这项工作中，我们评估了非编码 RNA H19 失调导致 CYP17 和睾酮产生异常的假设。为了实现这一目标，我们测量了 H19 敲除小鼠卵巢组织中的 Cyp17，并与野生型对照进行比较，量化了血清睾酮水平。我们还评估了循环和卵巢 H19 的表达，并将结果与一组正在接受不孕评估和治疗的女性的 PCOS 存在与否相关联。我们发现，在小鼠模型中 H19 的缺失导致卵巢 Cyp17 减少，同时雌性小鼠的血清睾酮减少。此外，利用 PCOS 女性的血清样本和卵丘细胞，我们表明与对照组相比，PCOS 女性的循环和卵巢 H19 水平升高。涉及失调的 H19 表达的小鼠模型和来自患有 PCOS 的女性的临床血清和卵巢细胞样本的多模式实验策略的研究结果表明，H19 的缺失可能通过 Cyp17 介导的机制破坏雄激素的产生。相反，过量的 H19 可能在 PCOS 相关高雄激素血症的发病机制中起作用。
