Genetic and functional analyses of polymorphisms in the human FSH receptor gene

Abstract

To determine the influence of FSH receptor variants Thr307-Asn680 (TN) and Ala307-Ser680 (AS) on ovarian function, we investigated the frequency of these gene polymorphisms by using restriction fragment length polymorphism analysis and observed their effects on clinical manifestations. In a population of 522 Japanese women, the overall frequency of TN/TN (NN), TN/AS (NS), and AS/AS (SS) was 41.0, 46.9 and 12.1% respectively. In polycystic ovary patients, the NS population was significantly larger when compared with the spontaneously ovulating group (66.7 versus 43.5%, P < 0.05). In the SS group, a significantly higher (46%) basal level of serum FSH was observed as compared with that in the NS group (P < 0.05). A higher dose of the exogenous gonadotrophin was required to achieve ovulation induction in the SS group as compared with the NS group (P < 0.05). At the time of hCG administration, estradiol levels per oocyte retrieved for IVF in the SS group were significantly lower as compared with the levels in the NS and NN groups (P < 0.05). There were no significant differences in FSH-stimulated cAMP production and PI turnover as well as ligand-binding affinity between the two receptor isoforms when overexpressed in transfected 293T cells. These results suggest that although FSH receptor polymorphisms have no discernible effect on FSH receptor function in vitro, there are associations between the genotype and some aspects of patient status.

Follicle stimulating hormone receptor gene variants in women with primary and secondary amenorrhea

“…Our results are in accordance with the earlier study, where no association of genotypes with gynaecological diseases was observed when the frequency distribution of the genotypes at position 2039 was compared in hypothalamic primary amenorrhea, secondary amenorrhea and POF subjects [18]. Another study has failed to observe differences in the prevalence of FSHR genotype in fertile and infertile women [13].…”

“…G −29 A, A 919 G (Thr 307 Ala) and A 2039 G (Asn 680 Ser) polymorphisms have been extensively studied by different investigators. It was reported that the polymorphism A 2039 G is associated with high basal FSH levels in women undergoing Assisted Reproductive Technology (ART) programme [17][18][19][20][21][22]. Recently, we have reported association of FSHR gene polymorphism (A 919 G, G −29 A) with altered ovarian response in subjects undergoing gonadotropin treatment during ART programme [23,24].…”

FSH-receptor Ala307Thr polymorphism is associated to polycystic ovary syndrome and to a higher responsiveness to exogenous FSH in Italian women

“…This was evident also when PCOS and women with normal ovary were considered as separate subgroups, indicating that the higher percentage of "bestresponders" among heterozygotes in the whole group was not due to a higher prevalence of PCOS among heterozygotes. Interestingly enough, results similar to ours were reported by another study [10], in which heterozygotes required a lower total hMG dose and had more retrieved oocytes. Our data suggest that heterozygosis at position 307 gives a better responsiveness to FSH: this could affect the outcome of the whole IVF treatment, as the "bestresponders" are known to have a high pregnancy chance.…”

“…Sudo [10] reported a significant increase in the Ala307Thr frequency among Japanese women with PCOS, 66.7% of which had such allelic variant in comparison to 43.5% of normally ovulating women. In European normogonadotropic anovulatory women (including PCOS), Laven [9] showed a significantly uneven frequency distribution: 20% homozygote Ala307, 57% Ala307Thr and 23% homozygote Thr307.…”

“…A couple of studies have been published, one showing that normo-ovulatory women with homozygous Ala307 have the best responsiveness to exogenous FSH [8], the other showing no 307 variant-linked changes in the responsiveness to FSH in chronic anovulatory subjects [9]. A significant increase in the Ala307Thr genotype frequency among women with PCOS was also reported [9][10][11], but not confirmed by other studies [12,13].…”