Understanding Gonadotropin Pulsatility in Functional Hypothalamic Amenorrhea

‘Tackling menstrual problems’ is the top priority of the Department of Health and Social Care ‘2022 Women’s Health Strategy’. Functional hypothalamic amenorrhea (FHA) is one of the most common causes of menstrual disturbance in women of reproductive age. It is the result of decreased energy availability due to a combination of excessive exercise and insufficient energy intake. FHA leads to significant psychological distress, subfertility, and adverse effects on bone. It also places affected women at increased risk of cardiometabolic disease. However, the mechanistic basis for FHA is not fully understood, and there is no effective pharmacological therapy available for affected women. Context Recent research has established the role of the neuropeptide kisspeptin in regulating the female reproductive axis. Kisspeptin-neurons in the hypothalamus exhibit intrinsic activity, and their episodic release of kisspeptin onto GnRH neurons generates the pulses of luteinising hormone (LH) that are essential for female fertility. In FHA, kisspeptin neurons become largely unresponsive to oestrogen, leading to the suppression of their episodic activity. While the molecular basis for this effect is unknown, it is likely responsible for the reduction in LH pulses and the associated infertility in women with FHA. Therefore, using kisspeptin to restore LH pulses in women with FHA has been proposed as a valid therapeutic approach. Promisingly, data from our research team has shown that a short-term infusion of kisspeptin can induce LH pulses in a woman with FHA. This finding raises important questions about hypothalamic LH pulse generation, and whether chronic kisspeptin infusion might also restore ovulation in many/all women with FHA. This proposal aims to understand the mechanistic basis for the loss of LH pulses in women with FHA, determine how these pulses are restored by kisspeptin infusion, and test whether kisspeptin-induced pulses can be maintained over a chronic time scale in women with FHA. Hypothesis Understanding the mechanistic basis for the suppression of LH pulses in women with FHA will facilitate the development of a novel and testable therapeutic strategy for the condition. Aims Understand the molecular mechanism of kisspeptin neuron pulse suppression in a mouse model of FHA (Applicants: BMO and AH) Recent mechanistic work by the applicants has demonstrated that the oestrogen receptor (ESR1 or ERa) in kisspeptin neurons plays an essential role in normal LH pulse generation. This aim will utilize a validated mouse model of FHA to investigate how the condition affects ERa gene-regulation and kisspeptin neuron activity. Understand the mechanisms that re-establish pulses upon continuous infusion of kisspeptin (Applicant: AH) It is not known how a continuous infusion of kisspeptin can induce LH pulses in some women with hypothalamic amenorrhea. Understanding this process is crucial, as it will inform which women are likely to benefit from this future therapy. The team will employ state-of-the-art imaging techniques, already validated in the lab, to address this question using a mouse model of FHA. Determine the potential utility of kisspeptin infusion in women with FHA (Applicants: AA and WSD) The team will investigate whether a chronic infusion of kisspeptin is sufficient to restore LH pulses in women with FHA. Overall, this project addresses the top priority of the 2022 Women’s Health Strategy by providing mechanistic insight into an understudied disease, and a rational pathway to clinical translation.