Management of infertility in women with hypothalamic hypogonadotropic hypogonadism: an expert opinion

Hypothalamic gonadotropin-releasing hormone (GnRH) plays a central role in regulating the pituitary-gonadal axis. The pulsatility of GnRH release is critical for maintaining the function of GnRH receptors and the secretion pattern of gonadotropins, namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which regulate endocrine function and follicular growth and maturation. During the luteal phase, LH is crucial for supporting a functional corpus luteum and stimulating it to produce progesterone, estradiol and relaxin.Hypothalamic hypogonadotropic hypogonadism originates from a deficiency in GnRH secretion. Low circulating gonadotropin levels subsequently lead to reduced ovarian function and anovulation. This condition may be congenital or acquired, for example through functional hypothalamic amenorrhoea (FHA) or FHA combined with polycystic ovarian morphology (PCOM). Pulsatile GnRH therapy plays a pivotal role in restoring the physiological menstrual cycle and selecting a dominant follicle in these women, thereby inducing ovulation and achieving fertility. There is extensive literature accounting for a high ovulation rate and consequently high pregnancy and birth rates per cycle, with a lower risk of adverse outcomes.

In this review, based on clinical evidence and published studies, we provide recommendations for the alternative treatment of infertility in women with congenital hypothalamic hypogonadotropic hypogonadism (CHH) and FHA (with or without PCOM), until pulsatile GnRH therapy becomes available again or in countries where this device is not marketed. Starting doses and adjustments should be made according to the aetiology of hypothalamic hypogonadotropic hypogonadism and other patient parameters. In all cases, luteal phase support is imperative and should ideally be provided by hCG injections to optimize corpus luteum functions.

When pulsatile GnRH therapy is not available, and to ensure the effective treatment of female infertility due to FHA (with or without PCOS) or hypothalamic CHH, we advise physicians to optimise stimulation with exogenous gonadotropins according to the cause of hypothalamic hypogonadotropic hypogonadism. In all cases, providing luteal phase support by optimising corpus luteum function is mandatory.