Gene-environment interaction in functional hypothalamic amenorrhea

Abstract

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea and chronic anovulation in adolescent girls and young women, diagnosed after excluding other organic causes. It is commonly associated with calorie restriction, excessive physical exercise, and psychosocial stress. These stressors alter the pulsatile secretion of gonadotropin-releasing hormone, leading to a chronic condition of hypoestrogenism and significant health consequences. Recent evidence has highlighted a genetic predisposition to FHA that could explain interindividual variability in stress response. Indeed, not all women experience FHA in response to stress. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with FHA, suggesting that these mutations may contribute to an increased susceptibility of women to the trigger of stress exposure. FHA appears today as a complex disease resulting from the combination of genetic predisposition, environmental factors, and epigenetic changes. Furthermore, the genetic background of FHA allows for the hypothesis of a male counterpart. Despite the paucity of data, preliminary findings indicate that an equivalent condition of FHA exists in men, warranting further investigation. This narrative review aims to summarize the recent genetic evidence contributing to the pathophysiology of FHA and to raise awareness on a possible male counterpart.

Keywords: epigenetic; functional hypothalamic amenorrhea (FHA); genetic susceptibility; idiopathic hypogonadotropic hypogonadism; male equivalent of FHA; stress.

Figure 1

New model explaining the etiopathogenesis of functional hypothalamic amenorrhea: a combination of genetic predisposition, environmental factors, and epigenetic changes. This figure illustrates a new model for the etiopathogenesis of functional hypothalamic amenorrhea (FHA), highlighting the interplay between genetic predisposition, environmental factors, and epigenetic changes. Genetic vulnerability: Rare genetic variants in genes associated with idiopathic hypogonadotropic hypogonadism (IHH), which control the migration, development and/or function of GnRH neurons, predispose some women to FHA by impairing GnRH neuron function. Environmental factors: Energy deficiency due to caloric restriction or excessive energy expenditure, intrapersonal characteristics, and life events act as stressors that disrupt normal GnRH secretion. Stressors have a particularly significant impact in genetically predisposed people, leading to decreased LH levels and subsequent menstrual irregularities. Epigenetic changes: Environmental stressors induce epigenetic modifications, such as DNA methylation, histone modification, and miRNA regulation. These changes alter gene expression without changing the DNA sequence, resulting in long-lasting hypothalamic dysfunction. This model highlihghts the importance of personalized approaches in the diagnosis, treatment, and prevention of FHA. GnRH, Gonadotropin Releasing Hormone; FSH, follicle stimulating hormone (FSH); LH, luteinizing hormone.