The central role of ovulatory disturbances in the etiology of androgenic polycystic ovary syndrome (PCOS)—Evidence for treatment with cyclic progesterone

Abstract Purpose To examine the pathophysiology of androgenic PCOS as a model of androgen excess with estradiol (E2) - progesterone (P4) imbalance; to assess therapy with Cyclic P4. Major sources of information Brain or hypothalamic origins of PCOS were drawn from basic science, animal, and clinical data, with a focus on the pulse rate of gonadotrophin releasing hormone (GnRH) and effects on luteinizing hormone (LH) pulsatility and ovarian androgen production. Synthesis of data PCOS occurs for 10% of reproductive-aged women from a myriad of potential etiologies, including the central pathophysiology of rapidly pulsing GnRH consequent to increased kisspeptin and GABAA. The inhibitory progesterone feedback that normally slows LH is decreased or absent with PCOS, resulting in chronic LH stimulation of ovarian theca cells and hyperandrogenism. Standard PCOS therapy with combined hormonal contraceptives (CHC) induces predictable flow and lower androgens but does not correct neuroendocrine disturbances and increases already tonically high E2 levels. In contrast, Cyclic P4 provides predictable withdrawal flow and symptom relief but also decreases LH and androgens. Vaginal progesterone with other therapies appears to improve fertility outcomes. Incorporating new data into clinical practice and research Although non-randomized controlled studies of single-cycle progesterone therapy are available, there is no evidence that longer-duration Cyclic P4 reverses the clinical and/or metabolic PCOS disturbances. Longer studies and RCTs are needed. Conclusion Ovulatory disturbances, androgen excess, and E2 > P4 imbalance are central to androgenic PCOS. Cyclic P4 therapy, by slowing GnRH pulse rate, may improve both PCOS symptoms and fertility.