The Role of Estrogen in Luteinizing Hormone Surge and Ovulation
Condition: Ovulation Disorder; Ovarian Cysts
MeSH terms: Ovarian Cysts
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of the study is to establish that sustained estrogen levels are the driving force
      for the LH surge, and are thereby necessary for ovulation to occur. We predict that by
      reducing levels of circulating estrogen, letrozole, an aromatase inhibitor, will inhibit
      ovulation from occurring.
    

Detailed description: 
      Sine the common understanding of ovulation in a natural cycle suggests that a sustained,
      elevated estradiol level is required to trigger the LH surge, administration of letrozole
      throughout the cycle should lower estradiol levels and prevent the LH surge from occurring.
      In this study, we sought to determine if the LH surge, ovulation and luteinization occurs in
      spite of low estradiol levels by daily administration of letrozole in a group of normal
      ovulatory volunteers in a prospective study.

      After IRB approval and informed consent were obtained, ten willing volunteers that met
      inclusion criteria (no hormonal contraception within 3 months, regular menstrual cycles 26 -
      30 days, normal thyroid function and normal prolactin, and no pregnancy currently or within 3
      months) were monitored for one month without treatment for evaluation of normal ovulation.

      Natural control cycle The subjects used home urine LH tests (Clearblue® Easy, SPD Swiss
      Precision Diagnostics, Switzerland) on days 10-18 to monitor for the LH surge in both the
      initial natural cycle and the letrozole cycle. Blood was drawn every other day starting on
      day 12 of the cycle through day 22 to measure estradiol and progesterone levels, and
      follicular development was monitored using transvaginal ultrasound on cycle day 12-14.

      Letrozole cycle In the next cycle, all ten subjects were administered oral letrozole 5 mg
      daily (Femara®, Novartis Pharmaceuticals Corporation, East Hanover, NJ ) starting on cycle
      day 1-3 and continuing through the completion of the study (cycle day 22). Once again, serum
      estradiol and progesterone levels were measured every other day on days 12-22. The
      development of the ovarian follicles was monitored by transvaginal ultrasound once in each
      cycle between days 12-14, and LH surge was monitored with home urine ovulation tests on days
      10-18. Table 1 illustrates protocols for both the natural control cycle and the letrozole
      study cycle.

      The primary outcome, assessment of ovulation in letrozole cycles, was determined by the
      presence or absence of progesterone elevation (>1.5 ng/mL) and the presence or absence of a
      positive urinary LH test. The bioequivalence evaluation of two cycles (before and after
      letrozole administration) was based on pharmacokinetic parameters such as area under the
      serum concentration-time curve (AUC), the peak serum concentration (Cmax) and the time of
      peak serum concentration (Tmax). Cmax and Tmax were determined by visual inspection from each
      volunteer's serum concentration-time curve for estradiol and progesterone. AUC was calculated
      by the linear trapezoidal method from day 12 through day 22 in both the initial natural cycle
      and the letrozole cycle.

      Paired t-tests, or Wilcoxon Signed Rank tests if non-normally distributed, were used to
      evaluate the statistical significance of the mean values of the pharmacokinetic parameters.
      The McNemar test was used to assess the difference in LH surge and follicular development
      before and after letrozole administration. A standard of statistical significance (alpha) of
      0.05 was used in all cases. The SAS System (SAS Institute, Cary, NC) was used for all
      analyses.
    

Intervention name(s): Letrozole
Intervention type(s): Drug
Intervention description(s): Letrozole administered daily through the time of ovulation.
Other intervention name(s): Femara
Intervention MeSH terms: Letrozole
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Diagnostic