Hypergonadotropic hypogonadism is characterized by decreased gonadal function due to the inability of the gonads to respond to
pituitary gonadotropins.
Hypergonadotropic hypogonadism in females has many causes, among which are ovarian dysgenesis and abnormalities of the ovarian receptors for the
pituitary gonadotropins. 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 46,XY male pseudohermaphrodites with Leydig 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 homozygous 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
amenorrhea 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 resistance as a cause of primary
amenorrhea in women. The combined clinical and molecular observations are consistent with previous experimental data suggesting that in humans, LH is necessary for ovulation but follicular maturation can occur in the presence of FSH alone.