Clinical features of women with resistance to luteinizing hormone

OBJECTIVE To review clinical and hormonal characteristics of new and published females with LH resistance. PATIENTS Seven sisters of patients with male pseudohermaphroditism due to LH resistance. MEASUREMENTS Clinical characteristics, hormonal levels, pelvic ultrasound and molecular studies. RESULTS Patients had: (1) normal female external genitalia; (2) spontaneous breast and pubic hair development at ages 9-13 years; (3) menarche at 12-20 years, followed by irregular menstrual cycles (3 weeks to 15 months); (4) infertility; (5) withdrawal bleeding after progesterone administration; (6) elevated serum LH levels (10-38 IU/I, normal 0.9-8.4) and elevated LH/FSH ratio with normal androgen levels; (7) low or normal oestradiol levels for the follicular phase; and (8) normal or small uterus and normal or increased ovary size with one or more cysts at ultrasound examination. Ovarian biopsy showed antral follicles and confirmed lack of ovulation. One homozygous mutation in exon 11 of the LH receptor gene was found in each of 4 patients: 1 nonsense (Arg554Stop) and 2 missense mutations (Glu354Lys and Ala593Pro) and 1 microdeletion (Leu-608, Val-609) were found. In 3 patients (1 family) with the same phenotypic characteristics, no mutations in the coding sequence of the LH receptor gene were found. CONCLUSIONS We conclude that women with LH resistance have spontaneous breast development, primary or secondary amenorrhoea, infertility, elevated serum LH levels and LH/FSH ratio with normal androgen levels and normal or enlarged cystic ovaries. Therefore, in females, primary and secondary sexual characteristics develop independently of LH action. However, LH stimulation is necessary for normal ovarian steroidogenesis and ovulation.