NCT03440359

Vaginal Progesterone Supplementation in Women With PCOS Undergoing Ovulation Induction With Letrozole

"Supplementation of the Luteal Phase With Vaginal Progesterone (Crinone 8%) in Women With Polycystic Ovary Syndrome Undergoing Ovulation Induction With Letrozole: A Prospective and Randomized Controlled Trial

• Status: Completed
• Phase: Phase 2 / Phase 3
• Study type: Interventional
• Enrollment: 52 (actual)
• Sponsor: Eastern Virginia Medical School · Academic / Other
• Sex: Female
• Age: 20 Years – 40 Years
• Healthy volunteers: Not accepted

Summary

Aromatase inhibitors such as letrozole are hypothesized to maintain normal hypothalamic/ pituitary feedback mechanisms and in the case of OI (ovulation induction) in women with PCOS, may act to increase follicular sensitivity to FSH by increasing intrafollicular androgen levels. Letrozole also may act to increase midluteal P levels presumably by induction of follicles and corpora lutea. The investigators are asking the question whether P supplementation with Crinone (8%) may have an additive beneficial effect on endometrial development in those women taking letrozole. Progesterone levels in the endometrium (tissue levels) have been documented to be significantly higher than serum levels after vaginal administration which may lead to higher pregnancy rates. In addition P has been shown to decrease LH pulse frequency which is elevated in PCOS and has been shown to down regulate endometrial androgen receptors. There have been retrospective studies showing progesterone supplementation seems to benefit both CC and letrozole treatment groups. In fact, this study showed the only pregnancies in the letrozole group were those in women who took P supplementation. However the number of cycles studied was small. There is a place for a randomized controlled trial (RCT) to determine if luteal phase P supplementation with Crinone should be used in all women using letrozole for Ovulation Induction (OI) in combination with Intrauterine Insemination (IUI) or Timed Intercourse (TI). This is currently not done in all clinical practices.

Detailed description

Approval of the study was obtained from the local IRB. Prospective volunteers had had an infertility workup including blood hormone levels (FSH, LH, E2, Progesterone, Prolactin, and Thyroid), partner's semen analysis, HSG, laparoscopy or hydrosonogram, plus a baseline evaluation including ultrasound of ovaries and uterus performed as standard of care. If the results of these tests and the remaining Inclusion/Exclusion criteria were met, the study consent was reviewed with participants and signatures were obtained. Participants contacted the clinic at the start of their menses (spontaneous or progesterone-induced) to start the treatment cycle. Eligibility criteria was reviewed, and Letrozole 2.5-7.5 mg day 3-7 was initiated based on BMI and prior response. An ultrasound was performed on cycle day 11 or 12 and repeated if needed to determine response until at least 1 follicle with mean diameter \> 17mm in size was observed. When the appropriate follicle size was reached, participants were randomized into one of the two treatment groups as determined by a randomization table, and Ovidrel (250mcg) was administered. If there was no response identified by follicle growth on day 21, the participant was considered a letrozole failure, the cycle was stopped, and the participant was dropped from the study and was not included in subsequent cycles. IUI/TI was performed at 24-48 hours after the Ovidrel (hCG) injection. If the participant was randomized to progesterone (Crinone), the luteal phase was supplemented once daily with vaginal progesterone (Crinone 8%) starting the second day after the IUI or TI and continued for 14 days. A urine or serum pregnancy test was performed as standard of care 16 days after the IUI/TI. If the test was positive, a confirmatory blood level (βhCG) was performed as standard of care X2 (1 week apart) and an ultrasound on post-hCG day 35-42 was done. Any pregnancies occurring in either treatment group were followed for delivery outcomes. Information regarding the delivery (induced, vaginal, cesarean section), date of birth, infant measurements (weight and length) and other important information regarding the infant's condition was obtained. Participants were allowed to undergo up to 3 cycles of letrozole as the pregnancy rates for the first 3 cycles have been shown to be similar. The participants were re-randomized each cycle. If the participant was pregnant, Crinone (8%) was continued until 10 weeks gestation in both groups. Each participant was able to proceed with up to 3 cycles (consecutively, if desired) of OI over the next 6 months and was re-randomized each cycle.

Conditions

• Polycystic Ovary Syndrome

Interventions

Type	Name	Description
DRUG	Progesterone Vaginal Gel 8%	progesterone supplementation for luteal phase support administered with vaginal applicators and used instead of progesterone intramuscular injections or progesterone vaginal suppositories.
DRUG	Letrozole Oral Tablet	letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction
DIAGNOSTIC_TEST	pelvic ultrasound	pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is \>17 mm in diameter
DRUG	Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe	ovidrel 250 mcg given when leading follicle size is \> 17 mm in diameter
OTHER	Intrauterine insemination or timed intercourse	Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel

Timeline

• Start date: 2012-07-06
• Primary completion: 2016-11-02
• Completion: 2017-12-30
• First posted: 2018-02-22
• Last updated: 2018-02-26

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study