Decoding the role of follicle stimulating hormone in ovarian ageing

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Ageing of the ovary is a naturally occurring process that results in changes in the hormones produced and ultimately in the cessation of ovarian function, termed menopause. Ovarian ageing not only results in declining fertility, but also increases the risk of developing several life-changing diseases, e.g., brittle bone disease, heart disease and impaired cognitive functions. This not only impacts on quality of life, but also results in a significant cost burden to the NHS. Despite this, our current understanding of how the ovary ages and what determines the lifespan of the ovary remains limited. Currently there is only one treatment option available for alleviating menopausal symptoms and preventing related diseases, hormone replacement therapy (HRT). However, HRT has a poor sign-up rate due to safety concerns, and according to current guidelines, can only be taken for a maximum of 10 years, due to adverse health risks of long-term HRT. The ability to extend ovarian lifespan offers a new treatment strategy for preventing/delaying such life-changing diseases, eliminating the problems surrounding HRT, and underpins the long-term goal of this project. Declining ovarian function can be detected by measuring the hormone, follicle stimulating hormone (FSH) in blood samples. FSH is a master controller of ovarian function, promoting the growth and health of ovarian follicles, the oocyte containing spherical cellular structures that provide hormonal support and signals to the growing oocyte. FSH mediates its function by binding to its receptor, FSHR, located on the surface of granulosa cells within the follicles , which generates different signals inside the cell to control the function and fate of the growing ovarian follicle. On the cell surface, FSHR have been shown to associate with each other. For other receptors belonging to the same family as FSHR, termed G protein-coupled receptors, this is an important way of generating different signals inside cells to mediate different physiological responses. Our data supporting this application suggests that this is also the case for FSH, and that changes in FSHR-FSHR association may alter the signals activated inside cells, to modulate ovarian function. Within the body, FSH is not produced as a single form. Two forms of FSH have been identified, based on the different sugar attachments formed to the structure of FSH. These forms of FSH are termed 'hyper-glycosylated FSH' (FSH24) and 'hypo-glycosylated FSH' (FSH21). FSH21 and FSH24 have been shown to have different potencies, with FSH21 more potent than FSH24 at activated cell signals and at binding to FSHR. Interestingly, the ratios of FSH21:FSH24 detected have been shown to change with age, with high FSH21:24 in young women, and low FSH21:FSH24 in menopausal women. Our studies using granulosa cells isolated from mouse ovaries suggest that the signal responses to FSH21 and FSH24 differ in mice in their reproductive prime versus menopausal mice. We therefore suspect that changes in the ratio of FSH21:FSH24 that occurs with ageing may in part cause the decline in ovarian function observed in the lead up to menopause. This application will explore how FSH21 and FSH24 regulate ovarian follicle function and signal activation from puberty to menopause. We will also how changes in genes effect the production of FSH21 and FSH24 with age. This will determine how these key hormonal factors that change with age affect ovarian function and ultimately lead to therapeutic strategies to extend ovarian function to improve quality of life and promote healthy ageing.