P-613 Association between basal androgen concentrations and number of follicles on the day of triggering final oocyte maturation in poor responders undergoing IVF; A prospective study

Abstract Study question Are basal androgen concentrations associated with the number of follicles on the day of triggering final oocyte maturation in poor responders undergoing in vitro fertilization (IVF)? Summary answer A significant negative association is present between (dehydroepiandrosterone sulfate) DHEAS concentrations and the number of follicles on the day of triggering final oocyte maturation. What is known already Studies in animals have shown that androgens promote early follicular development and granulosa cell proliferation, by augmenting follicle-stimulating hormone (FSH) receptor expression in granulosa cells. Several retrospective studies have evaluated the association between basal androgen concentrations and follicular development in normal and poor responders undergoing ovarian stimulation for IVF with conflicting results. Study design, size, duration This prospective study was performed between 02/2020 and 01/2022 in 103 poor responders according to the Bologna criteria. Androgens, including total testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), Δ4-androstenedione and 17-OH progesterone (17-OHP), were measured at the initiation of ovarian stimulation, using the automated Elecsys immunoanalyser (Roche Diagnostics, Mannheim, Germany). Ovarian stimulation was performed using a fixed dose of 300 IU of recombinant gonadotrophins and gonadotrophin-releasing hormone (GnRH) analogues. Participants/materials, setting, methods Triggering of final oocyte maturation was performed in the presence of three follicles of ≥ 17mm. The primary outcome measure was the number of follicles ≥11mm on the day of triggering final oocyte maturation. The association between androgen concentrations and the number of follicles ≥11mm on the day of triggering was evaluated using generalized estimating equations, accounting for female age and body mass index (BMI). Values were expressed as coefficient (coef) or mean (95% confidence interval). Main results and the role of chance Female age was 41.9 (41.2-42.6) years, while BMI was 26.1 (24.9-27.3) kg/m2. The duration of ovarian stimulation was 10.3 (9.7-10.8) days and the total dose of gonadotrophins required was 3058 (2903-3213) IU. The number of follicles ≥11 mm on the day of triggering final oocyte maturation was 6.1 (5.3-7.0). The number of COCs retrieved was 3.9 (3.2-4.6), the number of MII oocytes was 3.4 (2.8-3.9) and the number of 2pn oocytes was 2.5 (2.1-2.8). No significant association was found between basal testosterone (coef: -0.008, -0.019 to + 0.003, p = 0.17), 17-OHP (coef: -0.044, -0.391 to + 0.303, p = 0.80), SHBG (coef: -0.002, -0.007 to + 0.002, p = 0.25) Δ4-androstenedione (coef: -0.101, -0.306 to + 0.104, p = 0.33) concentrations and the number of follicles ≥11mm on the day of triggering final oocyte maturation. In contrast, a significant negative association was found between basal DHEAS (coef: -0.011, -0.019 to -0.003, p = 0.007) concentrations and the number of follicles ≥11 mm on the day of triggering final oocyte maturation. Higher DHEAS concentrations were associated with the development of fewer follicles ≥11 mm. Limitations, reasons for caution This prospective study evaluated the association between basal androgen concentrations and the number of follicles on the day of triggering final oocyte maturation in poor responders stimulated with a fixed dose of recombinant FSH. However, the precision of the estimates could be increased by analyzing a larger study population. Wider implications of the findings DHEA supplementation in poor responders undergoing IVF has not been shown to improve ovarian response. Given the significant negative association between DHEAS concentrations and the number of follicles on the day of triggering final oocyte maturation, future studies on DHEA supplementation should consider basal DHEAS concentrations. Trial registration number N/A </jats:sec

Transdermal testosterone pretreatment in poor responders undergoing ICSI: A randomized clinical trial

STUDY QUESTION: Does pretreatment with transdermal testosterone increase the number of cumulus-oocyte complexes (COCs) retrieved by more than 1.5 in poor responders undergoing intracytoplasmic sperm injection (ICSI), using recombinant follicle stimulating hormone (FSH) and gonadotrophin releasing hormone agonists (GnRHa)? SUMMARY ANSWER: Testosterone pretreatment failed to increase the number of COCs by more than 1.5 as compared with no pretreatment in poor responders undergoing ICSI (difference between medians: 0.0, 95% CI: -1.0 to +1.0). WHAT IS KNOWN ALREADY: Androgens are thought to play an important role in early follicular development by enhancing ovarian sensitivity to FSH. In a recent meta-analysis, testosterone pretreatment resulted in an increase of 1.5 COCs as compared with no pretreatment. However, this effect was based on the analysis of only two randomized controlled trials (RCTs) including 163 patients. Evidently, there is a need for additional RCTs that will allow firmer conclusions to be drawn. STUDY DESIGN, SIZE, DURATION: The present RCT was designed to detect a difference of 1.5 COCs (sample size required = 48 patients). From 02/2014 until 04/2015, 50 poor responders fulfilling the Bologna criteria have been randomized (using a randomization list) to either testosterone pretreatment for 21 days (n = 26) or no pretreatment (n = 24). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients underwent a long follicular GnRHa protocol. Recombinant FSH stimulation was started on Day 22 following GnRHa initiation. In the testosterone pretreatment group, a daily dose of 10 mg of testosterone gel was applied transdermally for 21 days starting from GnRHa initiation. Results are expressed as median (interquartile range). MAIN RESULTS AND THE ROLE OF CHANCE: No differences in baseline characteristics were observed between the two groups compared. Testosterone levels [median (interquartile range)] were significantly higher in the testosterone pretreatment on the day of initiation of FSH stimulation [114 (99.5) ng/dl versus 20 (20) ng/dl, respectively, P < 0.001]. Duration of FSH stimulation [median (interquartile range)] was similar between the groups compared [12.5 (3.0) days versus 12 (3.0) days, respectively, P = 0.52]. The number of COCs retrieved [median (interquartile range)] was not different between the testosterone pretreatment and the no pretreatment groups [3.5 (4.0) versus 3.0 (3.0), 95% CI for the median: 2.0-5.0 versus 2.7-4.3, respectively; difference between medians: 0.0, 95% CI: +1.0 to -1.0). Similarly no differences were observed regarding fertilization rates [median (interquartile range)] [66.7% (32.5) versus 66.7% (42.9), respectively, P = 0.97] and live birth rates per randomized patient (7.7% versus 8.3%, respectively, rate difference: -0.6%, 95% CI: -19.0 to +16.9). LIMITATIONS, REASONS FOR CAUTION: The study was not powered to detect differences less than 1.5 COCs, although it is doubtful whether these differences would be clinically relevant. Moreover, due to sample size restrictions, no conclusions can be drawn regarding the probability of live birth. WIDER IMPLICATIONS OF THE FINDINGS: The results of this randomized clinical trial, suggesting that pretreatment with 10 mg of transdermal testosterone for 21 days does not improve ovarian response by more than 1.5 oocytes, could be used to more accurately consult patients with poor ovarian response. However, an improvement in IVF outcome using a higher dose of testosterone or a longer pretreatment period cannot be excluded. STUDY FUNDING/COMPETING INTEREST: The study was partially funded by a Scholarship from the Academy of Athens. C.A.V. reports personal fees and non-financial support from Merck, Sharp and Dome, personal fees and non-financial support from Merck Serono, personal fees and non-financial support from IPSEN Hellas S.A., outside the submitted work. B.C.T. reports grants from Merck Serono, grants from Merck Sharp & Dohme, personal fees from Merck Serono, personal fees from Merck Sharp & Dohme, personal fees from IBSA & Ferring, outside the submitted work. TRIAL REGISTRATION NUMBER: NCT01961336. TRIAL REGISTRATION DATE: 10 October 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 02/2014. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved