STUDY QUESTIONIs oral dydrogesterone 30 mg daily non-inferior to 8% micronized vaginal progesterone (MVP) gel 90 mg daily for luteal phase support in IVF?SUMMARY ANSWEROral dydrogesterone demonstrated non-inferiority to MVP gel for the presence of fetal heartbeats at 12 weeks of gestation (non-inferiority margin 10%).WHAT IS KNOWN ALREADYThe standard of care for luteal phase support in IVF is the use of MVP; however, it is associated with vaginal irritation, discharge and poor patient compliance. Oral dydrogesterone may replace MVP as the standard of care if it is found to be efficacious with an acceptable safety profile.STUDY DESIGN, SIZE, DURATIONLotus II was a randomized, open-label, multicenter, Phase III, non-inferiority study conducted at 37 IVF centers in 10 countries worldwide, from August 2015 until May 2017. In total, 1034 premenopausal women (>18 to <42 years of age) undergoing IVF were randomized 1:1 (stratified by country and age group), using an Interactive Web Response System, to receive oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily.PARTICIPANTS/MATERIALS, SETTING, METHODSSubjects received either oral dydrogesterone (n = 520) or MVP gel (n = 514) on the day of oocyte retrieval, and luteal phase support continued until 12 weeks of gestation. The primary outcome measure was the presence of fetal heartbeats at 12 weeks of gestation, as determined by transvaginal ultrasound.MAIN RESULTS AND THE ROLE OF CHANCENon-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates in the full analysis sample (FAS) at 12 weeks of gestation of 38.7% (191/494) and 35.0% (171/489) in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 3.7%; 95% CI: −2.3 to 9.7). Live birth rates in the FAS of 34.4% (170/494) and 32.5% (159/489) were obtained for the oral dydrogesterone and MVP gel groups, respectively (adjusted difference 1.9%; 95% CI: −4.0 to 7.8). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP gel.LIMITATIONS, REASONS FOR CAUTIONThe analysis of the results was powered to consider the ongoing pregnancy rate, but a primary objective of greater clinical interest may have been the live birth rate. This study was open-label as it was not technically feasible to make a placebo applicator for MVP gel, which may have increased the risk of bias for the subjective endpoints reported in this study. While the use of oral dydrogesterone in fresh-cycle IVF was investigated in this study, further research is needed to investigate its efficacy in programmed frozen-thawed cycles where corpora lutea do not exist.WIDER IMPLICATIONS OF THE FINDINGSThis study demonstrates that oral dydrogesterone is a viable alternative to MVP gel, due to its comparable efficacy and tolerability profiles. Owing to its patient-friendly oral administration route, dydrogesterone may replace MVP as the standard of care for luteal phase support in fresh-cycle IVF.STUDY FUNDING/COMPETING INTERESTS(S)This study was sponsored and supported by Abbott. G.G. has received inves...

Luteinizing hormone (LH) in synergy with follicle stimulating hormone (FSH) stimulates normal follicular growth and ovulation. FSH is frequently used in assisted reproductive technology (ART). Recent studies have facilitated better understanding on the complementary role of the LH to FSH in regulation of the follicle; however, role of LH in stimulation of follicle, optimal dosage of LH in stimulation and its importance in advanced aged patients has been a topic of discussion among medical fraternity. Though the administration of exogenous LH with FSH is obligatory for controlled ovarian stimulation in patients with hypogonadotropic hypogonadism, there is still a paucity of information of its usage in other patient population. In this review we looked in to the multiple roles that LH plays complementary to FSH to better understand the LH requirement in patients undergoing ART.

The aim of the present study was to evaluate dydrogesterone for luteal-phase support in assisted reproductive technologies (ART) and to compare it with micronized vaginal progesterone. All patients underwent long-term downregulation with gonadotropin-releasing hormone agonists. In phase I, 498 patients were divided into three groups: long protocol and not at risk of ovarian hyperstimulation syndrome (OHSS) (group A); long protocol and at risk of OHSS (group B); and those in a donor oocyte program (group C). All patients received micronized progesterone 600 mg/day, vaginally. They were also randomized to dydrogesterone 20 mg/day (n = 218) or placebo (n = 280). The pregnancy rate was higher with dydrogesterone than with placebo in group A (33.0% vs. 23.6%), group B (36.8% vs. 28.1%) and group C (42.9% vs. 15.6%; p < 0.001). In phase II, 675 patients were divided into the same three groups (groups D, E and F) and were randomized to dydrogesterone 30 mg/day (n = 366) or micronized progesterone 600 mg/day (n = 309). The pregnancy rate was significantly higher with dydrogesterone than with progesterone in group D (39.1% vs. 26.7%; p < 0.01), group E (41.2% vs. 35.6%; p < 0.01) and group F (48.2% vs. 33.9%; p < 0.001). In conclusion, dydrogesterone is effective in luteal-phase support in ART.

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Successful oocyte implantation and a favorable pregnancy outcome rely on optimal progesterone levels. Therefore, progesterone deficiencies associated with infertility and miscarriage have commonly been treated with progestogens that mimic the activity of progesterone. Among those is dydrogesterone, an oral retrosteroid with a structure closely related to that of progesterone yet with a greater bioavailability and higher selectivity for the progesterone receptor. This review describes the efficacy of dydrogesterone for the treatment of threatened and recurrent miscarriage, and infertility due to luteal phase insufficiency. Data from clinical trials evaluating dydrogesterone in assisted reproductive technology are also discussed. Prospective clinical trials, systematic reviews and meta-analyses have demonstrated that dydrogesterone significantly improves pregnancy outcomes in women with threatened miscarriage or with a history of miscarriage. Although this is not yet a registered indication, dydrogesterone was as effective as vaginal micronized progesterone for luteal phase support in the setting of assisted reproductive technology. The safety and tolerability of dydrogesterone treatment in pregnant women are also briefly addressed and the data support a well-established and favorable benefit-risk profile.