Successful Use of Pulsatile Gonadotropin-Releasing Hormone (GnRH) for Ovulation Induction and Pregnancy in a Patient with GnRH Receptor Mutations¹

Abstract

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 were affected with GnRH deficiency due to a compound heterozygote mutation (Gln(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 pulses of both LH and free alpha-subunit (FAS) were detected during 24 h of every 10 min blood sampling. The proband then received exogenous pulsatile GnRH i.v. for ovulation induction, and daily blood samples for gonadotropins and sex steroids were monitored. At the conventional GnRH replacement dose for women with hypogonadotropic hypogonadism (75 ng/kg), no follicular development occurred. At a GnRH dose of 100 ng/kg, the level and pattern of gonadotropin secretion more closely mimicked the follicular phase of normal women; a single dominant follicle was recruited, and an endogenous LH surge was elicited. However, the luteal phase was inadequate, as assessed by progesterone levels. At a GnRH dose of 250 ng/kg, the gonadotropin and sex steroid dynamics reproduced those of normal ovulatory women in both the follicular and luteal phases, and the proband conceived. The FAS responses to both conventional 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 some patients with GnRH receptor mutations. 2) Higher doses of GnRH are required for normal luteal phase dynamics than for normal follicular phase function. 3) Hypersecretion of FAS in response to exogenous GnRH, which is a feature of congenital hypogonadotropic hypogonadism, was not seen in this patient with a GnRH receptor mutation.

High Population Frequency of GNRHR p.Q106R in Malta: An Evaluation of Fertility and Hormone Profiles in Heterozygotes

“…There are multiple reports of compound GNRHR heterozygous patients in whom IHH can be explained by the presence of 2 different GNRHR variant alleles [ 23 , 53 , 54 ]. However, the presence of the monoallelic GNRHR p.Q106R in multiple individuals from the MAMI cohort with normal hormone levels, puberty, and fertility reinforces the premise that additional deleterious variants in other genes must be present in IHH patients in whom only a single GNRHR variant allele is identified.…”

Familial case of normosmic hypogonadotropic hypogonadism with polydactyly, associated with defect of FGFR1 gene

“…S. Seminara и соавт. [10] исследовали 2 сестер с нормосмическим ГГ, и у обеих имелось сочетание гетерозиготной миссенс-мутации в гене FGFR1 с ранее выявленными гетерозиготными мутациями в гене GNRHR. Аналогичный дефект FGFR1 был выявлен у отца девочек, имевшего поздний пубертат в анамнезе.…”

Molecular genetics and phenotypic features of congenital isolated hypogonadotropic hypogonadism

“…и Abel и соавт. также доказывают, что резистентность рецептора у данной когорты пациенток может быть успешно преодолена [ 50 ][ 51 ]. Пульсовая терапия ГнРГ подтвердила свою эффективность и у мужчин с гипогонадизмом вследствие мутаций в гене GNRHR [ 52 ].…”