Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations

GnRH receptor mutations have recently been identified in a small number of familial cases of nonanosmic hypogonadotropic hypogonadism. In the present report we studied a kindred in which two sisters with primary amenorrhea we re affected with GnRH deficiency due to a compound heterozygote mutation (G ln(106)Arg, Arg(262)Gln) and performed extensive phenotyping studies. Baseline patterns of gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the proband. Low amplitude pu lses of both LH and free alpha-subunit (FAS) were detected during 24 h of e very 10 min blood sampling. The proband then received exogenous pulsatile G nRH iv for ovulation induction, and daily blood samples for gonadotropins a nd sex steroids were monitored. At the conventional GnRH replacement dose f or women with hypogonadotropic hypogonadism (75 ng/kg), no follicular devel opment occurred. At a GnRH dose of 100 ng/kg, the level and pattern of gona dotropin secretion more closely mimicked the follicular phase of normal wom en; a single dominant follicle was recruited, and an endogenous LH surge wa s elicited. However, the luteal phase was inadequate, as assessed by proges terone levels. At a GnRH dose of 250 ng/kg, the gonadotropin and sex steroi d dynamics reproduced those of normal ovulatory women in both the follicula r and luteal phases, and the proband conceived. The FAS responses to both c onventional and high dose GnRH were within the normal range. The following conclusions were made: 1) Increased doses of GnRH may be used effectively for ovulation induction in same patients with GnRH receptor mu tations. 2) Higher doses of GnRH are required for normal luteal phase dynam ics than for normal follicular phase function. 3) Hypersecretion of FAS in response to exogenous GnRH, which is a feature of congenital hypogonadotrop ic hypogonadism, was not seen in this patient with a GnRH receptor mutation .