The Genetic Backdrop of Hypogonadotropic Hypogonadism

Int J Mol Sci. 2021 Dec 8;22(24):13241. doi: 10.3390/ijms222413241.


The pituitary is an organ of dual provenance: the anterior lobe is epithelial in origin, whereas the posterior lobe derives from the neural ectoderm. The pituitary gland is a pivotal element of the axis regulating reproductive function in mammals. It collects signals from the hypothalamus, and by secreting gonadotropins (FSH and LH) it stimulates the ovary into cyclic activity resulting in a menstrual cycle and in ovulation. Pituitary organogenesis is comprised of three main stages controlled by different signaling molecules: first, the initiation of pituitary organogenesis and subsequent formation of Rathke's pouch; second, the migration of Rathke's pouch cells and their proliferation; and third, lineage determination and cellular differentiation. Any disruption of this sequence, e.g., gene mutation, can lead to numerous developmental disorders. Gene mutations contributing to disordered pituitary development can themselves be classified: mutations affecting transcriptional determinants of pituitary development, mutations related to gonadotropin deficiency, mutations concerning the beta subunit of FSH and LH, and mutations in the DAX-1 gene as a cause of adrenal hypoplasia and disturbed responsiveness of the pituitary to GnRH. All these mutations lead to disruption in the hypothalamic-pituitary-ovarian axis and contribute to the development of primary amenorrhea.

Keywords: DAX-1; FGFR-1; GPR54; HESX1; pituitary amenorhhea.

Publication types

  • Review

MeSH terms

  • DAX-1 Orphan Nuclear Receptor / genetics
  • Follicle Stimulating Hormone, beta Subunit / genetics
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Hypogonadism / genetics*
  • Luteinizing Hormone, beta Subunit / genetics
  • Mutation*


  • DAX-1 Orphan Nuclear Receptor
  • Follicle Stimulating Hormone, beta Subunit
  • Luteinizing Hormone, beta Subunit
  • NR0B1 protein, human