Resistance of hypogonadic patients with mutated GnRH receptor genes to pulsatile GnRH administration

We have studied a kindred with three siblings with isolated hypogonadotropi c hypogonadism caused by compound heterozygote mutations in the GnRH recept or gene. The disorder was transmitted as an autosomal recessive trait. The R262Q mutation in intracellular loop 3 of the receptor was associated with a mutation in the third transmembrane domain of the receptor, A129D, that h as never been described before. This A129D mutation results in a complete l oss of function, indicated by the lack of inositol triphosphate (TP3) 3 pro duction by transfected Chinese hamster ovary (CHO) cells after GnRH stimula tion. The two brothers had microphallus and bilateral cryptorchidism and we re referred for lack of puberty, whereas their sister had primary amenorrhe a and a complete lack of puberty. Their basal gonadotropin concentrations w ere below the reference range, and their endogenous LH secretory patterns w ere abnormal, with a low-normal frequency of small pulses or no apparent LI I pulse. Pulsatile GnRH administration (10 mu g/pulse every 90 min for 40 h ) resulted in increased mean LH without any significant changes in testoste rone levels in the two brothers, whereas the LH secretory profile of their sister remained apulsatile. Larger pulses of exogenous GnRH (20 mu g every 90 min for 24 h) caused the sister to produce recognizable low amplitude LH pulses. The concentrations of free a-subunit significantly increased in al l patients during the pulsatile GnRR administration. Thus, these hypogonada l patients are partially resistant to pulsatile GnRR administration, sugges ting that they should be treated with gonadotropins to induce spermatogenes is or ovulation rather than with pulsatile GnRH.