Pulsatile
GnRH acts at the
GnRH receptor on gonadotropes to stimulate
gonadotropin gene expression,
hormone synthesis and secretion. The
pituitary gonadotropins, LH and FSH, stimulate
steroid production and gametogenesis in males and in females.
Gonadotropin production thus requires the normal development and function of hypothalamic
GnRH-producing neurons and pituitary gonadotrope cells. Genes involved in gonadotrope development and/or gene expression include SF1, DAX1, KAL, GNRHR, PC1, HESX1, LHX3, PROP1,
LH beta, and
FSH beta. Given the complex control of
gonadotropin biosynthesis and secretion, it is not surprising that genetic abnormalities have been identified at several of these steps. Some of the mutations that will be reviewed include: (1) SF1 and DAX1-orphan
nuclear receptors that are expressed at multiple levels throughout the reproductive axis; (2) KAL-X-linked
Kallmann syndrome, where there is abnormal development of hypothalamic
GnRH-producing neurons; (3) PC1-causing abnormal processing of
GnRH and GNRHR mutations that impair action at the
GnRH receptor; (4) HESX1, LHX3, PROP1-abnormal development/function of the gonadotrope cell lineage; (5)
LH beta and
FSH beta-mutations in the
gonadotropin genes that cause structural abnormalities in the
hormones. Although all of these gene defects lead to
gonadotropin deficiency, each disorder is associated with unique phenotypic or hormonal features. Characterization of the molecular basis of
gonadotropin deficiency is useful for directing
therapy and for genetic counseling. Identification of these mutations also provides insight into the pathways that govern reproduction.