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CLINICAL-MOLECULAR CORRELATES IN A MOTHER AND 2 SONS WITH A CONSTITUTIVELY ACTIVATING MUTATION OF THE LUTEINIZING HORMONE (LH) RECEPTOR (LHR). † 569

Thorough studies of ovarian function have not been reported in females with activating mutations of the LHR. We studied the function of the pituitary-gonadal axis, spontaneously and in response to acute challenge with the gonadotropin releasing hormone (GnRH) agonist nafarelin in a family with two half brothers with familial pseudoprecocious puberty (testotoxicosis). These half brothers and their mother were found to have the same constitutively activating mutation of the LHR. Genotyping revealed that each had a mutation in one of the two alleles, a substitution of Gly for Asp 578 in the 6th transmembrane segment of LHR. This is the most common mutation in testotoxicosis. The mother was studied at age 36 years. Ovarian function was normal as assessed by LH levels including pulse analysis, FSH and androgen levels throughout the menstrual cycle. Hormonal responses to acute nafarelin challenge were normal. Ovarian steroids were suppressed to prepubertal levels when LH was suppressed by chronic GnRH agonist and dexamethasone. The boys, studied on presentation at 2.4 and 3.7 years of age, revealed acute LH responses to nafarelin in the hypogonadotropic range. FSH responses were prepubertal despite late pubertal testosterone blood levels. At 11 years of age, true puberty occurred in the older brother, and gonadotropin responses were normal for the stage of sexual development. Thus, the activating LHR mutation does not cause ovarian hyperandrogenism and causes only incomplete pubertal activation of Leydig cells. These results are compatible with this LHR structural abnormality having relatively low constitutive activity. This is sufficient to stimulate androgen secretion by Leydig cells but not thecal cells.

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Rosenfield, R., Rosenthal, I., Refetoff, S. et al. CLINICAL-MOLECULAR CORRELATES IN A MOTHER AND 2 SONS WITH A CONSTITUTIVELY ACTIVATING MUTATION OF THE LUTEINIZING HORMONE (LH) RECEPTOR (LHR). † 569. Pediatr Res 39, 97 (1996). https://doi.org/10.1203/00006450-199604001-00590

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