The p.N680S sequence variation of the follicle-stimulating hormone (FSH) receptor gene was previously shown to influence the ovarian response to FSH in normo-ovulatory women undergoing controlled ovarian hyperstimulation. In this prospective, randomized, controlled study, we tested whether the same daily dose of FSH results in lower levels of oestradiol in women homozygous for the p.N680S sequence variation, and whether the difference can be overcome by higher FSH doses. Women undergoing controlled ovarian hyperstimulation for in vitro fertilization or intracytoplasmic sperm injection and homozygous for the wild-type or for the p.N680S FSH receptor were randomly assigned to group I (Ser/Ser, n=24), receiving an FSH dose of 150 U/day, or group II (Ser/Ser, n=25), receiving an FSH dose of 225 U/day. In group III (Asn/Asn, n=44), the FSH dose was 150 U/day. Age and basal FSH levels were not different between groups. At ovulation induction, total FSH doses were comparable in group I (1631+/-96 U) and group III (1640+/-57 U) but significantly higher in group II (2421+/-112 U) (P<0.001). Peak oestradiol levels on the day of human chorionic gonadotrophin (hCG) administration were significantly lower in group I (5680+/-675 pmol/l) compared to group III (8679+/-804 pmol/l) (P=0.028). Increasing the FSH dose from 150 to 225 U/day overcame the lower oestradiol response in women with Ser/Ser (group II, 7804+/-983 pmol/l). In women undergoing controlled ovarian hyperstimulation, the p.N680S sequence variation results in lower oestradiol levels following FSH stimulation. This lower FSH receptor sensitivity can be overcome by higher FSH doses.
The Premature Ovarian Failure (POF) syndrome is a very heterogeneous clinical disorder due probably to the complex genetic networks controlling human folliculogenesis. Clinical subgroups of POF patients whose aetiology of ovarian failure is based on the same genetic factors are therefore difficult to establish. Some experimental evidence suggests that these genes might be clustered on the female sex chromosome in the POF1 and POF2 loci. This review is aimed to present an overview of the actual structural changes of the X chromosome causing POF, and to present a number of X and autosomal female fertility genes which are probably key genes in human folliculogenesis and are therefore prominent POF candidate genes. Towards the molecular analysis of their functional contribution to the genetic aetiology of POF in the clinic, an interdisciplinary scheme for their diagnostic analysis is presented in a pilot study focussed on chromosome analyses and the expression analysis of some major POF candidate genes (DAZL, DBX, FOXL2, INHalpha, GDF9, USP9X) in the leukocytes of 101 POF patients. It starts with a comprehensive and significantly improved clinical diagnostic program for this large and heterogeneous patient group.
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