Decoding the role of follicle stimulating hormone in ovarian ageing

卵巢老化是一个自然发生的过程，导致产生的荷尔蒙发生变化，最终导致卵巢功能停止，称为更年期。卵巢老化不仅导致生育力下降，还增加了患上几种改变生活的疾病的风险，例如脆性骨骼疾病、心脏病和认知功能受损。这不仅影响了生活质量，而且给NHS带来了巨大的成本负担。尽管如此，我们目前对卵巢如何衰老以及决定卵巢寿命的因素的了解仍然有限。目前只有一种治疗方法可用于缓解更年期症状和预防相关疾病，即激素替代疗法(HRT)。然而，出于安全考虑，HRT的签约率很低，根据目前的指导方针，由于长期HRT的不利健康风险，最多只能服用10年。延长卵巢寿命的能力为预防/延缓这种改变生命的疾病提供了一种新的治疗策略，消除了围绕HRT的问题，并支持了该项目的长期目标。卵巢功能下降可以通过检测血液样本中的激素-卵泡刺激素(FSH)来检测。卵泡刺激素是卵巢功能的主要控制者，促进卵泡的生长和健康，卵泡是含有球形细胞结构的卵母细胞，为正在生长的卵母细胞提供激素支持和信号。FSH通过与其受体FSHR结合来调节其功能，FSHR位于卵泡内颗粒细胞表面，在细胞内产生不同的信号来控制发育中的卵泡的功能和命运。在细胞表面，FSHR被证明是相互关联的。对于与FSHR属于同一家族的其他受体，称为G蛋白偶联受体，这是在细胞内产生不同信号以调节不同生理反应的重要途径。支持这一应用的数据表明，FSH也是如此，FSHR-FSHR关联的变化可能会改变细胞内激活的信号，从而调节卵巢功能。在体内，卵泡刺激素不是以单一形式产生的。根据FSH结构上形成的不同的糖附着物，FSH被鉴定为两种形式。这些形式的卵泡刺激素被称为‘高糖基化卵泡刺激素’(FSH24)和‘低糖基化卵泡刺激素’(FSH21)。FSH21和FSH24具有不同的效力，在激活细胞信号和结合FSHR方面，FSH21比FSH24更有效。有趣的是，检测到的FSH21：FSH24的比值随年龄变化，年轻女性FSH21：24较高，更年期女性FSH21：FSH24较低。我们使用从小鼠卵巢分离的颗粒细胞进行的研究表明，对FSH21和FSH24的信号反应在生殖旺盛的小鼠和更年期小鼠中不同。因此，我们怀疑，随着年龄的增长，FSH21：FSH24的比例发生变化，可能在一定程度上导致更年期前卵巢功能的下降。这项应用将探索FSH21和FSH24如何调节从青春期到更年期的卵泡功能和信号激活。我们还将介绍随着年龄的增长，基因变化如何影响FSH21和FSH24的产生。这将决定这些随年龄变化的关键荷尔蒙因素如何影响卵巢功能，并最终导致延长卵巢功能以提高生活质量和促进健康老龄化的治疗策略。

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.