The Role of Estrogen in Luteinizing Hormone Surge and Ovulation

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Completed
• CT.gov ID: NCT01999569
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arms: 2
• Duration (Months): 13
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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; 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group 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: Apr 1, 2007
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

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 Names: Femara

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Progesterone Level Greater Than 1.5 ng/mL [Cycle days 12-22]

   Serum progesterone ng/mL drawn during cycle days twelve through 22

Secondary Outcome Measures

1. Number of Participants With a Positive LH Test [Cycle days 10-18]

   Urine ovulation tests assessed

2. Number of Participants With Follicular Development [Cycle day 12]

   Ovulation; elevated progesterone

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Women's Institute at Carolinas Medical Center	Charlotte	North Carolina	United States	28204

Sponsors and Collaborators

• Wake Forest University Health Sciences

Investigators

• Principal Investigator: Brad S Hurst, MD, Wake Forest University Health Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

• Burstein HJ, Griggs JJ, Prestrud AA, Temin S. American society of clinical oncology clinical practice guideline update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Oncol Pract. 2010 Sep;6(5):243-6. doi: 10.1200/JOP.000082. Epub 2010 Aug 6.
• Casper RF, Mitwally MF. Review: aromatase inhibitors for ovulation induction. J Clin Endocrinol Metab. 2006 Mar;91(3):760-71. doi: 10.1210/jc.2005-1923. Epub 2005 Dec 29.
• Christensen A, Bentley GE, Cabrera R, Ortega HH, Perfito N, Wu TJ, Micevych P. Hormonal regulation of female reproduction. Horm Metab Res. 2012 Jul;44(8):587-91. doi: 10.1055/s-0032-1306301. Epub 2012 Mar 21.
• Goh HH, Ratnam SS. The LH surge in humans: its mechanism and sex difference. Gynecol Endocrinol. 1988 Jun;2(2):165-82. doi: 10.3109/09513598809023624.
• Laven JS, Fauser BC. What role of estrogens in ovarian stimulation. Maturitas. 2006 Jul 20;54(4):356-62. doi: 10.1016/j.maturitas.2006.04.022. Epub 2006 Jun 19.
• Mitwally MF, Casper RF. Aromatase inhibition reduces the dose of gonadotropin required for controlled ovarian hyperstimulation. J Soc Gynecol Investig. 2004 Sep;11(6):406-15. doi: 10.1016/j.jsgi.2004.03.006.
• Morioka N, Zhu C, Brannstrom M, Woessner JF, LeMaire WJ. Mechanism of mammalian ovulation. Prog Clin Biol Res. 1989;294:65-85.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT01999569
• Other Study ID Numbers: LH-2013
• First Posted: Dec 3, 2013
• Last Update Posted: Apr 22, 2022
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Ovarian Cysts; Letrozole

Study Results

Participant Flow

Recruitment Details	Ovulatory volunteers

Arm/Group Title	Control Then Letrozole
Arm/Group Description	Control cycle. Then letrozole cycle
Period Title: Control Cycle
STARTED	10
COMPLETED	10
NOT COMPLETED	0
Period Title: Control Cycle
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Control
Arm/Group Description	Control cycle. Then letrozole cycle
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	10 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	0 0%
Unknown or Not Reported	10 100%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Progesterone Level Greater Than 1.5 ng/mL
Description	Serum progesterone ng/mL drawn during cycle days twelve through 22
Time Frame	Cycle days 12-22

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Letrozole Treatment Cycle
Arm/Group Description	Control cycle
Measure Participants	10	10
Count of Participants [Participants]	9 90%	10 NaN

2. Secondary Outcome

Title	Number of Participants With a Positive LH Test
Description	Urine ovulation tests assessed
Time Frame	Cycle days 10-18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Letrozole Treatment Cycle
Arm/Group Description	Control cycle
Measure Participants	10	10
Count of Participants [Participants]	9 90%	10 NaN

3. Secondary Outcome

Title	Number of Participants With Follicular Development
Description	Ovulation; elevated progesterone
Time Frame	Cycle day 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Control	Letrozole Treatment Cycle
Arm/Group Description	Control cycle.
Measure Participants	10	10
Count of Participants [Participants]	10 100%	10 NaN

Adverse Events

Time Frame	two ovulation cycles (2 months)
Arm/Group Title	Control		Letrozole
Arm/Group Description	Control cycle. No intervention.		5mg daily Letrozole: Letrozole administered daily through the time of ovulation.
All Cause Mortality
	Control		Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Control		Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Control		Letrozole
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.