Gonadotropin Hormones: Disorders

Abstract

Abnormalities in gonadotropin hormone release and function can arise from changes in a variety of genes expressed throughout the hypothalamic–pituitary (gonadotrope)–gonadal (HPG) axis. Alterations in these genes can disrupt proteins that are involved in many different biological processes such as neuronal migration, gonadotropin‐releasing hormone (GnRH) release and action, and pituitary development, as well as affecting synthesis and function of the gonadotropin hormones (follicle‐stimulating hormone and luteinising hormone) themselves. The identification and characterisation of these factors is providing important insight into the reproductive axis in humans and may result in improved treatment and counselling for patients with infertility problems. However, the underlying cause of GnRH deficiency or altered gonadotropin action is not currently known in most cases, and it is emerging that digenic or oligogenic inheritance patterns are important in some situations. Therefore, the molecular basis of disorders of gonadotropin hormones may be more complex than originally thought. Key Concepts: The gonadotropins, FSH and LH, are heterodimeric glycoprotein hormones released in pulses from the pituitary gonadotrope cells. FSH and LH secretion is regulated by hypothalamic GnRH, which itself is pulsatile. GnRH‐secreting neurons originate in the olfactory placode and migrate to the hypothalamus during development; defects affecting neuronal migration can be associated with a lack of smell (anosmia). Gonadotropes develop within the anterior pituitary gland, which originates from the oral ectoderm; defects affecting gonadotrope function can be associated with other pituitary hormone deficiencies. FSH and LH act through peripheral G protein‐coupled receptors to stimulate gonad development and function. Some factors can influence the hypothalamic–pituitary–gonadal axis at multiple levels. More than 30 single gene disorders affecting gonadotropin function have now been described, often affecting receptor‐ligand pairs. Phenotypic penetrance can be variable, even within families and may reflect the influence of modifier genes, epigenetic factors or environmental stimuli. In some situations, changes in two genes can result in a clinical phenotype (digenic inheritance). In many cases the underlying molecular basis of hypogonadism is still unknown.