The effect of polymorphisms in FSHR gene on late follicular phase progesterone and estradiol serum levels in predicted normoresponders.

STUDY QUESTION: Does the presence of FSHR single-nucleotide polymorphisms (SNPs) affect late follicular phase progesterone and estradiol serum levels in predicted normoresponders treated with rFSH? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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. TRIAL REGISTRATION NUMBER: NCT03007043.

Effect of GnRHa ovulation trigger dose on follicular fluid characteristics and granulosa cell gene expression profiles.

PURPOSE: A recent dose-finding study showed no significant differences in number of mature oocytes, embryos and top-quality embryos when triptorelin doses of 0.2, 0.3 or 0.4 mg were used to trigger final oocyte maturation in oocyte donors co-treated with a gonadotropin-releasing hormone (GnRH) antagonist. This analysis investigated whether triptorelin dosing for triggering final oocyte maturation in oocyte donors induced differences in follicular fluid (FF) hormone levels and granulosa cell gene expression. METHODS: This single-centre, randomised, parallel, investigator-blinded trial was conducted in oocyte donors undergoing a single stimulation cycle at IVFMD, My Duc Hospital, Ho Chi Minh City, Vietnam, from August 2014 to March 2015. A total of 165 women aged 18-35 years with body mass index <28 kg/m2, anti-Müllerian hormone >1.25 ng/mL, and antral follicle count ≥6 were randomised to three different triptorelin doses for trigger. The main outcome was concentration of steroid hormones in FF collected from the first punctured follicle on each side. Moreover, luteinising hormone receptor (LHR), 3ß-hydroxy-steroid-dehydrogenase (3ßHSD) and inhibin-Ba (INHB-A) gene expression in cumulus and mural granulosa cells were investigated in a subset of women from each group. RESULTS: Progesterone and oestradiol levels in FF did not differ significantly by trigger doses; findings were similar for 3ßHSD, LHR and INHB-A gene expression in both cumulus and mural granulosa cells. CONCLUSIONS: In women co-treated with a GnRH antagonist, no significant differences in FF steroid levels and granulosa cell gene expression were seen when different triptorelin doses were used to trigger final oocyte maturation.

Recombinant follicle-stimulating hormone and recombinant luteinizing hormone versus recombinant follicle-stimulating hormone alone during GnRH antagonist ovarian stimulation in patients aged ≥35 years: a randomized controlled trial.

STUDY QUESTION: Does luteinizing hormone (LH) supplementation improve live birth rate after in vitro fertilization (IVF) in patients aged ≥35 years receiving a gonadotrophin-releasing hormone (GnRH) antagonist protocol? SUMMARY ANSWER: There was no difference in live birth rate with use of LH during IVF in patients aged ≥35 years undergoing IVF treatment using a GnRH antagonist protocol. WHAT IS KNOWN ALREADY: Use of GnRH analogues as part of a controlled ovarian hyperstimulation protocol during IVF treatment cycles decreases the amount of LH available to developing follicles. The role of LH supplementation for improving outcomes in patients undergoing controlled ovarian hyperstimulation as part of assisted reproduction treatments, particularly those involving a GnRH antagonist protocol, is unclear. It has been suggested that higher risk patients (e.g. age ≥35 years, poor ovarian reserve) may benefit from LH supplementation. STUDY DESIGN, SIZE, DURATION: This single-centre, randomized controlled trial was conducted from 1 October 2012 to 30 June 2014. A total of 240 women aged ≥35 years undergoing IVF received ovarian stimulation using a GnRH antagonist protocol, with recombinant follicle-stimulating hormone (r-FSH; Gonal-F(®)) starting from cycle day 2 or 3. GnRH antagonist (Cetrotide(®)) was administered on Day 5 of r-FSH administration. On Day 6, patients in the LH supplementation group were switched to r-FSH/r-LH (Pergoveris(®)) 150/75 IU/day. Randomization to study treatments was performed in blocks of 4 via a computer-generated random number list. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the 240 patients randomized to treatment, 120 received r-FSH/r-LH and 120 received r-FSH. Patients were recruited from the IVFAS, An Sinh Hospital, Ho Chi Minh City, Vietnam. MAIN RESULTS AND THE ROLE OF CHANCE: Live birth rate did not differ significantly (P > 0.05) between r-FSH/r-LH and r-FSH recipients (16.7 versus 17.5%; between-group difference 0.8, 95% confidence interval [CI] -9.5, 11.2). In addition, there were no significant differences between the r-FSH/r-LH and r-FSH groups with respect to the number of oocytes retrieved, implantation rate, miscarriage rate and clinical pregnancy rate. LIMITATIONS, REASONS FOR CAUTION: The open-label design could have introduced bias, and the relatively small sample size may have allowed detection of only the most common adverse events. In addition, the study was likely to be underpowered based on differences between the response rate assumptions used in the sample size calculation and the actual response rate during the study. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study found no additional benefit from adding LH supplementation to ovarian stimulation with a GnRH antagonist protocol in women aged ≥35 years, and add to the body of evidence in this area. However, findings across studies are still inconsistent and additional research is needed before any clear recommendations for clinical practice can be made. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Research Center for Genetics and Reproductive Health, School of Medicine, Vietnam National University HCMC. The authors state that they have no financial or commercial conflicts of interest. TRIAL REGISTRATION NUMBER: The trial was registered with clinicaltrials.gov (NCT02244866).

Characteristics of black patients admitted to coronary care units in metropolitan Seattle: results from the Myocardial Infarction Triage and Intervention Registry (MITI).

Since 1988, 641 black and 11,892 white patients with chest pain of presumed cardiac origin have been admitted to coronary care units in 19 hospitals in metropolitan Seattle. Black men and women were younger (58 vs 66, p less than 0.0001), more often admitted to central city hospitals (p less than 0.0001), and developed evidence of acute myocardial infarction (AMI) less often (19 vs 23%, p = 0.01). In the subset of 2,870 AMI patients, blacks (n = 121) were younger (59 vs 67, p less than 0.0001) and had less prior coronary artery bypass graft surgery (2 vs 10%, p = 0.005) and more prior hypertension (67 vs 46%, p less than 0.0001). During hospitalization, whites (n = 2,749) had higher rates of coronary angioplasty (18 vs 10%, p = 0.03) and coronary artery bypass graft surgery (10 vs 4%, p = 0.04), although thrombolytic therapy and cardiac catheterization were used equally in the 2 groups. Hospital mortality was 7.4% for black and 13.1% for white patients (p = 0.07). However, after adjustment for key demographic and clinical variables by logistic regression, this difference was not as apparent (p = 0.38). Questions about the premature onset of coronary artery disease, excess systemic hypertension, and the differential use of interventions in black persons have been raised by other investigators. Despite differences in age, referral patterns and the use of coronary angioplasty and bypass surgery, black and white patients with AMI in metropolitan Seattle had similar outcomes.