Aromatase Inhibitor Effects on Ovarian Function During the Follicular and Early Luteal Phase in Women
Condition: Fertility
Study type: Interventional
Phase: Phase 4

Summary: 
      A single center, open label randomized clinical trial designed to examine ovarian follicular
      dynamics following attempted atresia induction during the late follicular and early luteal
      phase of the menstrual cycle using an aromatase inhibitor.

      We hypothesize that administration of an aromatase inhibitor (AI) at biologically important
      times of the natural menstrual cycle will cause ovulatory failure in women with preovulatory
      follicles and failure of luteogenesis in women who have recently ovulated. It is proposed
      that atresia of the dominant follicle and formation of anovulatory structures will be
      associated with arrested endometrial development and a shortened interval to menstrual
      bleeding (3 days). We anticipate that this will provide us with information to facilitate the
      development of a new method for emergency contraception and a greater understanding of human
      folliculogenesis.

      The rationale for the proposed research project is based on the ovarian synchronization
      concepts developed and documented in the bovine model in the Reproductive Science and
      Medicine Research group at the University of Saskatchewan combined with novel human ovarian
      wave concepts of folliculogenesis first elucidated in the Women's Health Imaging Research
      Laboratory (WHIRL) in the Department of Obstetrics, Gynecology and Reproductive Sciences.
    

Detailed description: 
      In clinical practice emergency contraception (EC) intends to suppress follicular development,
      ovulation, or the ability of a conceptus to implant. Exogenous steroids, estrogen and
      progestin, are used in various formulations to accomplish the suppression. Though EC are now
      available 'over-the-counter' in Canada and many countries around the world; the ovarian
      response is unpredictable and EC do not inhibit ovulation at the most critical times of the
      menstrual cycle. In 2002 approximately 120,000 of 450,000 pregnancies in Canada ended in
      elective pregnancy termination. In the US 49% of the 3.5 million annual pregnancies were
      unintended and 54% of the unintended pregnancies resulted in elective termination.

      Current hormonal contraceptive regimens, pre and post coital, are based on the traditional
      theory of follicular development that states that a single group of antral follicles is
      recruited in the late luteal phase for growth. Recent documentation has show that human
      ovarian folliculogenesis occurs in a 2-3 wave like pattern during a menstrual cycle. Wave
      emergence has been documented to occur in the early luteal phase with the final wave being
      ovulatory. The new model of follicular wave dynamics is well established and supported by
      experimental evidence in the bovine and equine models.

      Traditionally these hormonal medications are taken 72 to 120 hours after known or suspected
      barrier contraception failure or unprotected intercourse. The two standard steroidal EC
      methods are Plan BTM, containing of 0.75 mg levonorgestrel (LNG), and the Yuzpe method,
      containing 0.1 mg ethinyl estradiol (EE) and 0.5 mg LNG. Ovarian follicular development and
      ovulation in women have been studied after EC use; however, the mechanisms underlying
      follicular growth, regression, and ovulation during EC use remain poorly elucidated. The
      mechanism of action differs with each EC regimen as well as being dependent upon the relative
      timing between dosing, intercourse, and ovulation. Previous studies have shown that EC are
      most effective if used when the dominant follicle diameter is small (4 to 5 days prior to
      ovulation), however, during this time interval intercourse is less likely to result in
      pregnancy whether or not EC were administered.

      All current emergency contraception (EC) options are guided by the traditional theory of
      follicular development. Based on the findings of an unpredictable response of the ovaries to
      EC treatment, the occurrence of ovulation after treatment with EC, and findings of follicle
      growth in a 2-3 wave pattern, we need to reconsider the phase of the menstrual cycle and the
      treatment given for emergency contraception.

      Aromatase inhibitors (AI) prevent the enzymatic conversion of androgens to estrogens. This
      significantly lowers serum estrogen levels. AI have been administered around the time of
      menses for ovulation induction and ovulation was seen to follow 10 to 12 days later. The
      rationale for inducing atresia of dominant follicles stems from this observation. Acute
      estradiol deprivation should theoretically initiate atresia of all viable follicles in the
      cohort resulting in the emergence of a new follicle wave without an ovulation event
      occurring.
    

Intervention name(s): Letrozole; Letrozole; Letrozole; Letrozole; Letrozole; Letrozole
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 20 mg, one tablet a day for one day, starting on the day the dominant follicle reaches 12 mm in diameter; 20 mg, one tablet a day for one day, starting on the day the dominant follicle reaches 18 mm in diameter; 20 mg, one tablet a day for one day, starting 24-48 hours after ovulation of the dominant follicle is observed; 2.5 mg, one tablet a day for five days, starting 24-48 hours after ovulation of the dominant follicle is observed; 2.5 mg, one tablet a day for five days, starting on the day the dominant follicle reaches 18 mm in diameter; 2.5 mg, one tablet a day for five days, starting on the day the dominant follicle reaches 18 mm in diameter
Other intervention name(s): Femara (TM); Femara (TM); Femara (TM); Femara (TM); Femara (TM); Femara (TM)
Intervention MeSH terms: Letrozole
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Folliculogenesis; Letrozole; Aromatase Inhibitor; Estrogen