An Inactivating Mutation of the Receptor Causes Amenorrhea in a 46,XX Female*

Hypergonadotropic hypogonadism is characterized by decreased gonadal function due to the inability of the gonads to respond to pituitary gonadotropins. Hypergonadotropic hypogonadism in fe­ males has many causes, among which are ovarian dysgenesis and abnormalities of the ovarian receptors for the pituitary gonadotro­ pins. We evaluated a woman who presented with amenorrhea due to hypergonadotropic hypogonadism, but who had structurally normal ovaries* She is a sister of two previously identified 46fXY male pseudohermaphrodites with Ley dig cell hypoplasia. Injection of hCG did not cause any change in plasma levels of estradiol or progesterone, suggesting complete ovarian resistance to LH. Analysis of the DNA sequence of the LH receptor gene revealed that the patient is ho­ mozygous for the same single base change as her two brothers. This mutation causes substitution of an alanine residue by a proline at position 593. In vitro analysis of the mutant LH receptor in cultured human embryonic kidney 293 cells documented that the receptor is unable to stimulate adenylyl cyclase in response to hCG. Plasma levels of estradiol and progesterone were low, whereas LH and FSH levels were increased. On histological analysis of the ovary, follicles were seen at all developmental stages. Nonetheless, primary amen­ orrhea had been present for 5 yr, and repeated measurements of plasma estradiol and progesterone indicate that ovulation does not occur. These results document the existence of inherited LH resis­ tance as a cause of primary amenorrhea in women. The combined clinical and molecular observations are consistent with previous ex­ perimental data suggesting that in humans, LH is necessary for ovulation but follicular maturation can occur in the presence of FSH alone. (J Clin Endocrinol Metab 81: 3850-3854, 1996)