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The Role of Estrogen in Luteinizing Hormone Surge and Ovulation

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01999569
Recruitment Status : Completed
First Posted : December 3, 2013
Last Update Posted : August 6, 2014
Information provided by (Responsible Party):
Brad Hurst, Atrium Health

Brief 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.

Condition or disease Intervention/treatment Phase
Ovulation Disorder ESTROGENS/RIFAMPIN [VA Drug Interaction] Ovarian Cysts Drug: Letrozole Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
Official Title: The Role of Estrogen in Luteinizing Hormone Surge and Ovulation
Study Start Date : April 2007
Actual Primary Completion Date : May 2008
Actual Study Completion Date : May 2008

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones

Arm Intervention/treatment
No Intervention: Control
Control cycle. No intervention.
Experimental: Letrozole
5mg daily
Drug: Letrozole
Letrozole administered daily through the time of ovulation.
Other Name: Femara

Primary Outcome Measures :
  1. Increase in Progesterone level [ Time Frame: Cycle days 12-22 ]

Secondary Outcome Measures :
  1. Change in LH level [ Time Frame: Cycle days 10-18 ]
  2. Follicular Development [ Time Frame: Cycle day 12 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Patient having regular menstrual cycles between 26-30 days
  • Ages 18-40
  • Patient must not be sexually active during the study period, or if so must be using a reliable form of non-hormonal birth control including tubal ligation or vasectomy, non-hormonal intrauterine contraceptive device (IUD), or condoms with spermicide.
  • Willing to participate in study and available for all monitoring visits.
  • IRB consent

Exclusion Criteria:

  • Patient must NOT have used hormonal contraception three months or less prior to study.
  • Irregular menstrual cycles (<26 days or >30 days within the last 6 months.
  • Untreated thyroid dysfunction or hyperprolactinemia
  • Pregnancy (current or within 3 months) or breastfeeding
  • Allergy or contraindication to letrozole

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01999569

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United States, North Carolina
Women's Institute at Carolinas Medical Center
Charlotte, North Carolina, United States, 28204
Sponsors and Collaborators
Atrium Health
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Principal Investigator: Brad S Hurst, MD Atrium Health

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Responsible Party: Brad Hurst, Director of Assisted Reproduction, Atrium Health Identifier: NCT01999569     History of Changes
Other Study ID Numbers: LH-2013
First Posted: December 3, 2013    Key Record Dates
Last Update Posted: August 6, 2014
Last Verified: August 2014

Additional relevant MeSH terms:
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Ovarian Cysts
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists