Chapter 4 Diseases Associated with Mutations of the Human Lutropin Receptor

The human lutropin receptor (LHCGR) plays an integral role in male and female reproductive physiology. In response to either placental hCG or pituitary LH, gonadal LHCGR mediates its effects primarily through Gs activation. Heterozygous mutations leading to constitutive activation of the LHCGR cause gonadotropin-independent precocious puberty in males, but have no detectable effects on prepubertal or postpubertal females. Homozygous or compound heterozygous inactivating mutations of the LHCGR cause gonadal resistance to hCG and LH, where the clinical phenotypes associated with these mutations are closely correlated with the severity of the mutation. Inactivating mutations in 46,XY individuals cause Leydig cell hypoplasia and impairments in the differentiation of male external genitalia, the development of secondary sexual characteristics and sperm production. 46,XX siblings with inactivating LHCGR mutations exhibit infertility and varying degrees of menstrual irregularities.