Polycystic ovary syndrome: Ovaries no longer controlled by the brain

Source: "BTIT Club" official account

Polycystic ovary syndrome (PCOS) is the most common endocrine disease in women of childbearing age, with a prevalence of 10%-13%. The etiology of PCOS is complex, and the clinical manifestations are heterogeneous, affecting reproduction, metabolism, cardiovascular and mental health. Rebecca E. Campbell from the University of Otago in New Zealand published an article titled Beyond the ovary: rewiring our perspective on polycystic ovary syndrome in Nature Reviews Endocrinology, reviewing the process of understanding the pathogenesis of PCOS.

Hypothalamic-pituitary-gonadal axis (HPG)

Polycystic ovary syndrome is a complex endocrine disorder defined as ovarian dysfunction characterized by disturbed gonadotropin secretion, androgen excess, chronic anovulation, and polycystic ovarian morphology. Two seminal studies in the late 1990s challenged the primary role of the ovaries in the pathogenesis of PCOS and found that intrinsic features in the brain, particularly the gonadotropin-releasing hormone (GnRH) neuronal network, are central to the pathology of PCOS. Feedback regulation is a fundamental feature of the endocrine system, and the hypothalamic-pituitary-gonadal axis (HPG) refers to the mutual feedback between the gonadotropin-releasing hormone neuronal network in the brain and the gonads. Hormones released from the hypothalamus, pituitary, and gonads are a key part of this feedback communication. Pulsatile release of gonadotropin-releasing hormone in the hypothalamus promotes the release of pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which together regulate ovarian function. Gonadal hormones secreted by the ovaries, in turn, provide the necessary feedback signals to the hypothalamus and pituitary to regulate the release of gonadotropin-releasing hormone and luteinizing hormone.

Figure: Research history of the pathophysiological manifestations of polycystic ovary syndrome

In certain phenotypes of PCOS, signaling pathways along the hypothalamic-pituitary-gonadal axis are disrupted, resulting in persistently elevated luteinizing hormone secretion, leading to downstream ovarian dysfunction manifested by anovulation and excess androgen production. Although elevated levels of gonadotropin-releasing hormone and luteinizing hormone are an expected consequence of reduced ovarian gonadal hormone feedback, two independent research groups have suggested that the brain, rather than the ovaries, may be responsible for this hormonal feedback disorder.

Sarah L. Berga and John C. Marshall's research groups both used continuous blood sampling to measure luteinizing hormone, which can reflect the dynamic changes in gonadotropin-releasing hormone secretion, and believed that the hypersecretion of luteinizing hormone in patients with polycystic ovary syndrome is caused by the impaired sensitivity of hypothalamic gonadotropin-releasing hormone pulse release to the negative feedback of gonadal hormones. Daniels and Berga found that during the period of taking oral contraceptives containing estradiol and progesterone, the luteinizing hormone of women with normal menstrual cycles decreased significantly, but the luteinizing hormone pulse of women with no ovulation and elevated androgens was still elevated. These research data show that the increase in luteinizing hormone and gonadotropin-releasing hormone associated with androgen excess is due to the resistance of gonadotropin-releasing hormone to the negative feedback of gonadal hormones.

Pastor and colleagues supported this theory with another series of experiments. They found that women with PCOS had slower and weaker suppression of LH when taking exogenous estradiol and progesterone and required higher doses of progesterone than women without PCOS. Importantly, women with and without PCOS had similar LH responses to exogenous GnRH, suggesting that pituitary function was normal and that dysfunction occurred in the central nervous system. These studies highlighted the role of brain networks regulating GnRH release in the etiology of PCOS. Subsequent studies have shown that elevated androgen levels participate in and contribute to the impaired negative feedback of gonadal hormones and overactivation of the hypothalamic-pituitary-gonadal axis associated with PCOS. Investigators have also used transgenic animal models and a growing number of neuroscience tools to identify specific mechanisms of the syndrome.

Sue Moenter's research group discovered modified neurotransmission in the gonadotropin-releasing hormone neuronal network in a developing androgenized mouse model with PCOS-like features. Since then, an increasing number of studies have identified key cell types and specific neuronal circuits involved in PCOS-like pathogenesis. In a paper published in 2023, Paolo Giacobini's research group found that short-term overactivation of gonadotropin-releasing hormone neurons alone was sufficient to induce persistent PCOS-like features, including excess androgen and abnormally high luteinizing hormone pulse secretion. The research evidence supports the central role of the gonadotropin-releasing hormone neuronal network in the pathogenesis of PCOS and further demonstrates that gonadotropin-releasing hormone antagonism is a potential targeted therapy.

Future Directions

The etiology of PCOS remains largely unknown, and the groundbreaking research by Berga and Marshall's groups has helped us focus our attention on the importance of factors beyond the ovaries and into the brain. The health impacts of PCOS continue throughout the lifespan from adolescence to postmenopause. Current treatments are primarily directed at hyperandrogenism, the consequences of ovarian dysfunction, and/or related metabolic disorders, but specific treatments are lacking. More research is needed to uncover the pathogenesis and treatment of neuroendocrine dysfunction in PCOS.

References:

[1] Teede HJ, Tay CT, Laven JJE, Dokras A, Moran LJ, Piltonen TT, Costello MF, Boivin J, Redman LM, Boyle JA, Norman RJ, Mousa A, Joham AE. Recommendations From the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2023 Sep 18;108(10):2447-2469. doi: 10.1210/clinem/dgad463. PMID: 37580314; PMCID: PMC10505534.

[2] Campbell RE. Beyond the ovary: rewiring our perspective on polycystic ovary syndrome. Nat Rev Endocrinol. 2024 Feb 20. doi: 10.1038/s41574-024-00963-3. Epub ahead of print. PMID: 38378986.

[3] Dapas M, Dunaif A. Deconstructing a Syndrome: Genomic Insights Into PCOS Causal Mechanisms and Classification. Endocr Rev. 2022 Nov 25;43(6):927-965. doi: 10.1210/endrev/bnac001. PMID: 35026001; PMCID: PMC9695127.

[4] Silva MSB, Decoster L, Delpouve G, Lhomme T, Ternier G, Prevot V, Giacobini P. Overactivation of GnRH neurons is sufficient to trigger polycystic ovary syndrome-like traits in female mice. EBioMedicine. 2023 Nov;97:104850. doi: 10.1016/j.ebiom.2023.104850. Epub 2023 Oct 27. PMID: 37898094; PMCID: PMC10630624.