在接受rFSH治疗的预测正常反应者中,FSHR单核苷酸多态性(SNP)的存在是否会影响晚期卵泡期孕酮和雌二醇的血清水平?
FSHRSNP(rs6165,rs6166,rs1394205)的存在对接受GnSH每日剂量固定的GnRH方案的预测正常反应者的晚期卵泡期血清孕酮和雌二醇水平没有临床显着影响
先前的研究表明,晚期卵泡期血清孕酮和雌二醇水平与卵巢反应程度显著相关。几位作者提出,对卵巢刺激(OS)反应的个体差异可以通过FSHR的变体来解释。然而,到目前为止,关于这种遗传变异对卵泡晚期类固醇生成反应的影响,文献很少。我们的目的是确定FSHR基因的遗传变异是否可以调节卵泡后期血清孕酮和雌二醇水平。
在2016年11月至2019年6月进行的这项多中心跨国前瞻性研究中,来自越南的366名患者,比利时和西班牙(来自欧洲的166和来自亚洲的200)接受了OS,然后在GnRH拮抗剂方案中以150IUrFSH的固定日剂量进行卵母细胞取回。所有患者均对3个FSHRSNP(rs6165,rs6166,rs1394205)进行基因分型,并在触发当天进行血清孕酮和雌二醇测量。
纳入的患者为预测的正常反应女性,<38岁,正在经历第一个或第二个OS周期。晚期卵泡期孕酮升高(PE)的患病率,以及触发当天的平均血清孕酮和雌二醇水平在不同的FSHRSNP基因型之间进行了比较.PE定义为>1.50ng/ml。
PE的总患病率为15.8%(n=58)。在高加索和亚洲患者中,PE的患病率没有显着差异(17.5%对14.5%)。PE患者在触发当天的雌二醇水平和取回的卵母细胞数量显着升高(4779±6236.2对3261±3974.5pg/ml,P=0.003,分别为16.1±8.02和13.5±6.66,P=0.011)。遗传模型分析,根据患者年龄调整,身体质量指数,检索到的卵母细胞数量和大陆(亚洲与欧洲),揭示了在共显性中类似的PE患病率,变体FSHRrs6166,rs6165和rs1394205的显性和隐性模型。根据FSHRrs6166的基因型,卵泡晚期孕酮血清水平的平均差异无统计学意义(P=0.941),双变量分析中rs6165(P=0.637)和rs1394205(P=0.114)。此外,在遗传模型分析中,不同基因型的卵泡晚期孕酮平均水平没有差异.遗传模型分析还显示,在共显性触发当天,平均雌二醇水平没有统计学上的显着差异,变体FSHRrs6166,rs6165和rs1394205的显性和隐性模型。单倍型分析显示,rs6166/rs6165单倍型GA触发当天雌二醇水平显著降低,AA和GG与AG相比(分别为估计平均差(EMD)-441.46pg/ml(95%CI-442.47;-440.45),EMD-673.46pg/ml(95%CI-674.26;-672.67)和EMD-582.10pg/ml(95%CI-584.92;-579.28))。根据rs6166/rs6165单倍型,关于PE的患病率或晚期卵泡期孕酮水平没有发现统计学上的显着差异。
结果是指在整个OS期间用150IUrFSH的正常/低固定剂量治疗的预测的正常应答者群体。因此,在将我们的结果推广到所有患者类别之前,需要谨慎。
根据我们的结果,FSHRSNPrs6165,rs6166和rs1394205对预测的正常反应者的晚期卵泡期血清孕酮或雌二醇水平均无任何临床显着影响。这些发现增加了文献中关于个体遗传易感性对该人群中OS响应的影响的争议。
这项研究得到了默克夏普和多姆公司(MSD,IISP56222).N.P.P.报告MSD的赠款和/或个人费用,默克·塞罗诺,罗氏诊断,FerringInternational,BesinsHealthcare,GedeonRichter,Organon,Theramex和研究所BiochimiqueSA(IBSA)。C.A.报告MerckSerono的会议费用,美狄亚和事件星球。A.R.N.,C.B.,C.S.,P.Q.M.M.,H.T.,C.B.,N.L.V.,M.T.H.和S.G.报告没有与本文内容相关的利益冲突。
NCT03007043。
Does the presence of FSHR single-nucleotide polymorphisms (SNPs) affect late follicular phase progesterone and estradiol serum levels in predicted normoresponders treated with rFSH?
The presence of FSHR SNPs (rs6165, rs6166, rs1394205) had no clinically significant impact on late follicular phase serum progesterone and estradiol levels in predicted normoresponders undergoing a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH.
Previous studies have shown that late follicular phase serum progesterone and estradiol levels are significantly correlated with the magnitude of ovarian response. Several authors have proposed that individual variability in the response to ovarian stimulation (OS) could be explained by variants in FSHR. However, so far, the literature is scarce on the influence of this genetic variability on late follicular phase steroidogenic response. Our aim is to determine whether genetic variants in the FSHR gene could modulate late follicular phase serum progesterone and estradiol levels.
In this multicenter multinational prospective study conducted from November 2016 to June 2019, 366 patients from Vietnam, Belgium and Spain (166 from Europe and 200 from Asia) underwent OS followed by oocyte retrieval in a GnRH antagonist protocol with a fixed daily dose of 150 IU rFSH. All patients were genotyped for 3 FSHR SNPs (rs6165, rs6166, rs1394205) and had a serum progesterone and estradiol measurement on the day of trigger.
Included patients were predicted normal responder women <38 years old undergoing their first or second OS cycle. The prevalence of late follicular phase progesterone elevation (PE), as well as mean serum progesterone and estradiol levels on the day of trigger were compared between the different FSHR SNPs genotypes. PE was defined as >1.50 ng/ml.
The overall prevalence of PE was 15.8% (n = 58). No significant difference was found in the prevalence of PE in Caucasian and Asian patients (17.5% versus 14.5%). Estradiol levels on the day of trigger and the number of retrieved oocytes were significantly higher in patients with PE (4779 ± 6236.2 versus 3261 ± 3974.5 pg/ml, P = 0.003, and 16.1 ± 8.02 versus 13.5 ± 6.66, P = 0.011, respectively). Genetic model analysis, adjusted for patient age, body mass index, number of retrieved oocytes and continent (Asia versus Europe), revealed a similar prevalence of PE in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. No statistically significant difference was observed in the mean late follicular phase progesterone serum levels according to the genotypes of FSHR rs6166 (P = 0.941), rs6165 (P = 0.637) and rs1394205 (P = 0.114) in the bivariate analysis. Also, no difference was found in the genetic model analysis regarding mean late follicular phase progesterone levels across the different genotypes. Genetic model analysis has also revealed no statistically significant difference regarding mean estradiol levels on the day of trigger in co-dominant, dominant and recessive models for variants FSHR rs6166, rs6165 and rs1394205. Haplotype analysis revealed a statistically significant lower estradiol level on the day of trigger for rs6166/rs6165 haplotypes GA, AA and GG when compared to AG (respectively, estimated mean difference (EMD) -441.46 pg/ml (95% CI -442.47; -440.45), EMD -673.46 pg/ml (95% CI -674.26; -672.67) and EMD -582.10 pg/ml (95% CI -584.92; -579.28)). No statistically significant differences were found regarding the prevalence of PE nor late follicular phase progesterone levels according to rs6166/rs6165 haplotypes.
Results refer to a population of predicted normal responders treated with a normal/low fixed dose of 150 IU rFSH throughout the whole OS. Consequently, caution is needed before generalizing our results to all patient categories.
Based on our results, FSHR SNPs rs6165, rs6166 and rs1394205 do not have any clinically significant impact neither on late follicular phase serum progesterone nor on estradiol levels in predicted normal responders. These findings add to the controversy in the literature regarding the impact of individual genetic susceptibility in response to OS in this population.
This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD, IISP56222). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Organon, Theramex and Institut Biochimique SA (IBSA). C.A. reports conference fees from Merck Serono, Medea and Event Planet. A.R.N., C.B., C.S., P.Q.M.M., H.T., C.B., N.L.V., M.T.H. and S.G. report no conflict of interests related to the content of this article.
NCT03007043.