Speaker Khushboo Goel
The speaker discussed a multicentric randomized control trial comparing neutral phase pretreatment with estradiol versus follicular Gonadotropin-releasing hormone (GnRH) antagonists for follicular synchronization in poor responders. In poor responders, achieving follicular synchrony is crucial, as asynchrony can lead to low oocyte retrieval, low maturation rates, high cycle cancellation rates, and the need for additional cycles. In the late luteal phase of a natural cycle, the fall in estrogen and progesterone levels leads to a rise in Follicle-stimulating hormone (FSH), which recruits another cohort of follicles. Due to different sensitivities to FSH, some follicles grow faster, causing heterogeneity. Two common approaches to achieve synchronization are luteal estradiol and follicular GnRH antagonists. Estradiol in the luteal phase maintains negative feedback on the Hypothalamic-pituitary-ovarian (HPO) axis, helping recruit a synchronous cohort of follicles for the next cycle. GnRH antagonists in the follicular phase act on already recruited follicles, attenuating the growth of larger follicles and promoting homogeneity in size.
The European Society of Human Reproduction and Embryology (ESHRE) recommendations regarding these two pretreatments were conditional, emphasizing the need for more robust and high-quality studies. The primary objective of the randomized controlled trial (RCT) was to evaluate several outcomes, including the follicular output rate and the ratio of pre-ovulatory follicles (measuring more than 14 mm) to the antral follicle count. Additionally, the trial examined the follicle-to-oocyte index, which calculates the ratio of oocytes retrieved to the antral follicle count, and the ovarian sensitivity index, measuring the ratio of oocytes retrieved per thousand units of gonadotropin dose. The oocyte retrieval rate, representing the ratio of oocytes retrieved to pre-ovulatory follicles measuring more than 14 mm, and the maturation rate, quantifying the ratio of mature oocytes to the total number retrieved, were also examined. Secondary objectives included assessing cycle cancellation, fertilization, cleavage, and blastulation rates.
The study, registered with the Clinical Trials Registry of India, was conducted over one year at seven Oocyte Synchronization & Stimulation (OSS) fertility centers. Out of 196 randomized patients, 145 completed the study. The inclusion criteria were poor responders (Poseidon criteria, Groups 1-4), while exclusions included conditions affecting ovarian function, gonadotropin or sex steroid pharmacokinetics, hypogonadotropic hypogonadism, and premature ovarian insufficiency. Patients were randomized using computer-generated block randomization into two arms. Arm A received oral estradiol valerate 4 mg daily for 7 days before expected menses, followed by antagonist protocol stimulation, dual trigger Oocyte pick-up (OPU) at 35 hours, and Embryo transfer (ET). Arm B received subcutaneous GnRH 0.25 mg daily from day 1 of menses for 5 days, followed by antagonist protocol stimulation as in Arm A.
Most of the 145 patients completing the study (80 luteal estradiol, 65 follicular antigens) were Poseidon 3 group. Baseline variables were similar between groups. Luteal estradiol yielded a 72% maturation rate versus 63% with follicular antigens (p = 0.04), the only significant finding. No differences were observed in other outcomes: oocytes retrieved, mature oocytes, Follicle-to-oocyte index (FOI), Follicle-to-oocyte ratio (FOT), Ovarian sensitivity index (OSI), cycle cancellation rate, blastulation rate, cleavage rate, fertilization rate, or fertilized oocytes. Subgroup analyses, excluding endometriosis or severe male factor infertility, showed consistent results. No significant difference was found among expected poor responders, even after excluding patients with endometriosis or severe male factor infertility. Luteal estradiol is cost-effective and patient-friendly. The RCT is the first to directly compare luteal estradiol with follicular GnRH antagonists in poor responders. The study's limitations contributed to a higher dropout rate, including a lack of blinding, short-term focus, small sample size, and the absence of randomization in the previous cycle. A future RCT will compare follicular estradiol versus GnRH antagonists administered in the same phase to address these issues.
During the discussion, questions about the rationale behind increased maturation rates with estradiol were raised. It was explained that estradiol, administered in the luteal phase, maybe more physiologically effective in achieving follicular synchrony compared to antagonists given in the follicular phase. Regarding differences in gonadotropin duration and dose between the studies, it was clarified that there were no statistically significant differences. A flexible antagonist protocol was used in both arms without alteration. The choice between recombinant FSH and Human Menopausal Gonadotropin (HMG) depended on individual patient factors rather than treatment type (estrogen vs. antagonist). Regarding optimal estradiol duration and dose, the decision to use 4 mg of estradiol valerate daily for seven days was based on an extensive literature review, aiming to avoid profound suppression in subsequent cycles and maintain efficacy.
European Society of Human Reproduction and Embryology, July 7-10, Amsterdam, The Netherlands