Randomized, assessor-blinded trial comparing highly purified human menotropin and recombinant follicle-stimulating hormone in high responders undergoing intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the efficacy and safety of highly purified human menotropin (HP-hMG) and recombinant follicle-stimulating hormone (rFSH) for controlled ovarian stimulation in a population of patients predicted to be high responders. DESIGN: Randomized, open-label, assessor-blinded, parallel-group, noninferiority trial. SETTING: Fertility centers. PATIENT(S): A total of 620 women with serum antimüllerian hormone (AMH) ≥5 ng/mL. INTERVENTION(S): Controlled ovarian stimulation with HP-hMG or rFSH in a GnRH antagonist assisted reproductive technology (ART) cycle. Fresh transfer of a single blastocyst was performed unless ovarian response was excessive, in which all embryos were cryopreserved. Subjects could undergo subsequent frozen blastocyst transfer within 6 months of randomization. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rate (OPR) after fresh transfer (primary endpoint), as well as cumulative live birth, ovarian hyperstimulation syndrome (OHSS), and pregnancy loss rates. RESULTS: OPR/cycle start after fresh transfer was 35.5% with HP-hMG and 30.7% with rFSH (difference: 4.7%, 95% CI -2.7%, 12.1%); noninferiority was established. Compared to rFSH, HP-hMG was associated with significantly lower OHSS (21.4% vs. 9.7% respectively; difference: -11.7%, 95% CI -17.3%, -6.1%) and cumulative early pregnancy loss rates (25.5% vs. 14.5% respectively; difference: -11.0%, 95% CI -18.8%, -3.14%). Despite 43 more transfers in the rFSH group, cumulative live birth rates were similar with HP-hMG and rFSH at 50.6% and 51.5% respectively (difference: -0.8%, 95% CI -8.7%, 7.1%). CONCLUSION(S): In high responders, HP-hMG provided comparable efficacy to rFSH with fewer adverse events, including pregnancy loss, suggesting its optimized risk/benefit profile in this population. CLINICAL TRIAL REGISTRATION NUMBER: NCT02554279 (clinicaltrials.gov).

Progesterone pharmacokinetics and pharmacodynamics with 3 dosages and 2 regimens of an effervescent micronized progesterone vaginal insert.

CONTEXT: Progesterone vaginal insert (PVI), an effervescent delivery system, dissolves rapidly, is absorbed through the vaginal epithelium, and achieves higher endometrial tissue concentrations than those achieved with progesterone in oil (PIO) given im. OBJECTIVE: Our objective was to examine the pharmacokinetics and pharmacodynamics of PVI compared with PIO. DESIGN, SETTING, AND PARTICIPANTS: Fifty-eight healthy premenopausal women were randomized to 50, 100, or 200 mg PVI once daily; 100 or 200 mg PVI twice daily; or 50 to 100 mg PIO via im injection once daily for 10 days. Serum samples were obtained after the first dose; serum and endometrial tissue were obtained after the last dose. MAIN OUTCOME MEASURES: Maximum observed serum concentration (Cmax), time to Cmax, and area under the serum-concentration time curve over the dosing interval were calculated after correcting for baseline progesterone concentrations. ANOVA and paired t test were used to compare results across and within groups. RESULTS: A higher Cmax was observed after PIO than PVI administration. Endometrial tissue progesterone concentrations were higher for PVI regimens. Time to Cmax was 7.3 hours after PIO and 3.3 to 5.9 hours after PVI. Steady state was achieved within 24 and 48 hours for PVI and PIO regimens, respectively. The area under the curve increased with increasing PVI dosage; however, the increase was not proportional to the increase in dosage. Downregulation of estrogen and progesterone receptors was observed in secretory biopsy specimens. CONCLUSION: The PVI system consistently allowed for rapid progesterone absorption and achieved higher endometrial tissue concentrations and lower systemic exposures than observed after im PIO.

Single and multidose pharmacokinetic study of a vaginal micronized progesterone insert (Endometrin) compared with vaginal gel in healthy reproductive-aged female subjects.

OBJECTIVE: To determine pharmacokinetic profiles of two times a day and three times a day dosage regimens of Endometrin, a micronized progesterone vaginal insert for luteal support in assisted reproductive technology, compared with a gel. DESIGN: A single-center, randomized, open-label, single-day, and multiple-day (5 days) parallel design pharmacokinetic study. SETTING: University clinical research unit. PATIENT(S): Three groups of six healthy subjects, ages 18 to 40 years. INTERVENTION(S): Endometrin vaginal inserts two times a day or three times a day, or gel daily. MAIN OUTCOME MEASURE(S): Pharmacokinetic profiles. RESULT(S): Progesterone serum concentrations increased rapidly following administration of Endometrin vaginal insert, producing higher peak concentrations (Cmax) and clearing faster than gel. On the single day of dosing, mean Cmax was 17.0+/-2.7 ng/mL in the two times a day group, 19.8+/-2.9 ng/mL in the three times a day group, and 6.82+/-1.69 ng/mL in the gel group. Endometrin treatments reached steady state within the first 2 days (24-36 hours), much more rapidly than the gel, which had not reached steady state by 5 days. At 5 days, the Endometrin treatments produced sustained progesterone concentrations exceeding 10 mg/mL across 24 hours. CONCLUSIONS: Endometrin vaginal inserts reached higher Cmax, produced greater systemic exposure (area under the curve 0-24), achieved steady state more rapidly, and cleared more rapidly after termination of therapy than the comparator.

Matched-samples comparison of intramuscular versus vaginal progesterone for luteal phase support after in vitro fertilization and embryo transfer.

OBJECTIVE: To evaluate vaginal compared to intramuscular (IM) progesterone supplementation for luteal phase support after in vitro fertilization and embryo transfer (IVF-ET). DESIGN: Retrospective matched-samples comparative study. SETTING: Private infertility center. PATIENTS(S): Two hundred forty patients undergoing IVF-ET. INTERVENTION(S): Patients received either vaginal progesterone supplementation in the form of Endometrin 100 mg twice a day (n = 12), Endometrin 100 mg three times a day (n = 11), or Crinone 8% gel 90 mg every day (n = 17), or 50 mg every day IM progesterone in oil (n = 200). MAIN OUTCOME MEASURE(S): Clinical intrauterine pregnancy rates, pregnancy loss, and live birth rates. RESULT(S): Among patients using vaginal progesterone, there were no statistically significant differences in patient characteristics and clinical outcomes, regardless of the type of vaginal progesterone used. There were no differences in outcomes between the vaginal and IM progesterone treatment groups. There were 20 pregnancies (50.0%) among patients treated with vaginal progesterone and 103 pregnancies (51.5%) among matched IM progesterone patients. The live birth rates were 47% in the IM versus 47.5% in the vaginal progesterone groups. There were no statistically significant differences in miscarriage rates between groups. CONCLUSION(S): There are no significant differences in treatment outcomes between vaginal and IM progesterone supplementation, yielding similar clinical pregnancy, miscarriage, and live birth rates.

Endometrin for luteal phase support in a randomized, controlled, open-label, prospective in-vitro fertilization trial using a combination of Menopur and Bravelle for controlled ovarian hyperstimulation.

OBJECTIVE: To assess the efficacy and safety of a vaginal progesterone (P(4)) insert (Endometrin) for luteal support for assisted reproductive technology (ART). DESIGN: Multicenter, randomized, open-label (assessor-blinded) phase III clinical trial. SETTING: Twenty-five U.S. ART centers. PATIENT(S): A total of 1,211 ART patients randomized to three groups: Endometrin 100 mg twice daily (n = 404), Endometrin 100 mg three times daily (n = 404), and P(4) 90 mg 8% gel daily (n = 403). INTERVENTION(S): In vitro fertilization and ET were performed according to site-specific protocols. The day after oocyte retrieval, Endometrin or vaginal P(4) gel was begun for luteal support and continued for up to 10 weeks of pregnancy. MAIN OUTCOME MEASURE(S): Biochemical, clinical, and ongoing pregnancy and live birth rates. RESULT(S): Pregnancy rates were high and similar in all treatment groups, with biochemical rates exceeding 50%, clinical and ongoing rates >or=40%, and live birth rates at 35%-38%. The adverse event profiles were similar across groups. CONCLUSION(S): Pregnancy rates and live birth rates for Endometrin (twice daily and three times daily) were high and similar to those for P(4) gel. The adverse event profiles for both were similar to that for P(4) gel and primarily due to IVF stimulation and oocyte retrieval. Endometrin was safe and well tolerated.