Vaginal Progesterone Supplementation in Women With PCOS Undergoing Ovulation Induction With Letrozole
Condition: Polycystic Ovary Syndrome
MeSH terms: Polycystic Ovary Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Progesterone Vaginal Gel 8%; Letrozole Oral Tablet; pelvic ultrasound; Ovidrel 250 MCG Per 0.5 ML Prefilled Syringe; Intrauterine insemination or timed intercourse
Intervention type(s): Drug; Drug; Diagnostic Test; Drug; Other
Intervention description(s): progesterone supplementation for luteal phase support administered with vaginal applicators and used instead of progesterone intramuscular injections or progesterone vaginal suppositories.; letrozole oral tablet 2.5 mg or 5 mg administered cycle day 3-7 for ovulation induction; pelvic ultrasound performed at cycle day 11 or 12 and repeated as necessary until leading follicle size is >17 mm in diameter; ovidrel 250 mcg given when leading follicle size is > 17 mm in diameter; Intrauterine insemination or timed intercourse (depending on semen parameters) performed 36-40 hours after Ovidrel
Other intervention name(s): Crinone 8% vaginal gel; recombinant hCG 250 mcg
Intervention MeSH terms: Letrozole; Progesterone
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants who met criteria were randomized to either Crinone vaginal therapy versus no therapy in the luteal phase of an ovulation induction cycle. Participants who did not achieve a pregnancy were able to participate in up to 3 cycles, and were re-randomized with each cycle.
Masking: Single (Outcomes Assessor)
Primary purpose: Other
Keywords: PCOS, crinone, vaginal progesterone, ovulation induction