Gonadotropin resistance

Pituitary gonadotropins are essential for normal reproductive function. LH and FSH exert their effects by acting on G protein-coupled receptors. Pituitary LH and placental hCG share the same receptor (LHCGR). Homozygous or compound heterozygous inactivating mutations of LHCGR are associated with a phenotypic spectrum from female or ambiguous external genitalia due to Leydig cell hypoplasia to micropenis, hypergonadotropic hypogonadism and delayed puberty in genetic males. Testes size is slightly reduced, and testosterone levels are low in affected males. Interestingly, the clinical phenotypes are closely correlated with the severity of the mutation. In females, the phenotype is also variable and can range from primary amenorrhea to oligoamenorrhea, associated with constant infertility. Estradiol and progesterone levels remain in the early to mid-follicular phase, whereas the ovaries are normal or enlarged with cysts. In both sexes, LH levels are increased, whereas FSH is usually normal. Inactivating mutations of FSH receptor are associated with partial to complete premature ovarian failure in women and variable impairment of spermatogenesis and small testes in men. Mutations of the human gonadotropin receptors provide natural models for elucidating the differential effects of LH and FSH on the gonads.