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) T HE PITUITARY hormones FSH and LH have an es­ sential role in the regulation of gonadal function (1 , 2). In the cycling ovary, the growth of small follicles is dependent on FSH. Some small antral follicles develop into preovulatory (or Graafian) follicles. Ovulation is sub­ sequently induced by a peak in the level of circulating LH. The pituitary secretion of LH and FSH is negatively con­ trolled by the gonadal hormones estradiol and progester­ one. In hypergonadotropic hypogonadal patients, the ovary does not respond to LH or FSH with the secretion of steroid hormones, and the absence of the negative feed­ back results in elevated levels of these gonadotropins (3). In this report we describe a patient with amenorrhea and infertility due to hypergonadotropic hypogonadism. She is a sister of two 46,XY male pseudohermaphrodites in a pedigree (Fig. 1) that was previously analyzed by us (4). The two male pseudohermaphrodites have Leydig cell hypoplasia due to a homozygous inactivating mutation in the LH receptor gene. This suggested that the primary amenorrhea and infertility in the present patient might Received February 26,1996. Revision received July 17,1996. Accepted July 23, 1996. Address all correspondence and requests for reprints to: Dr. A. P. N. Themmen, Department of Endocrinology and Reproduction, Erasmus University Rotterdam, P.O. Box 1738y 3000 DR Rotterdam, The Neth­ erlands. E-mail: [email protected]. * This work was supported by the Sao Paulo State Foundation for Research and the National Research Council of Brazil. also be caused by this mutation. Indeed, plasma levels of estradiol and progesterone were low, suggesting the ab­ sence or hypofunction of ovarian follicles with regard to LH-dependent hormone production. Histological exami­ nation of ovarian tissues revealed complete follicular de­ velopment, suggesting uncompromised response to FSH, The subject was, therefore, evaluated for an inherited de­ fect of the ovarian receptor for LH. DNA analysis revealed a homozygous nucleotide change in the LH receptor gene, rendering the LH receptor molecule unable to stimulate cAMP production upon stimulation with hCG. We con­ clude that inherited complete ovarian resistance to LH causes anovulation in the presence of normal follicular maturation. Subjects and Methods