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Letrozole Treatment in Normal and GnRH Deficient Women

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ClinicalTrials.gov Identifier: NCT00351416
Recruitment Status : Active, not recruiting
First Posted : July 12, 2006
Results First Posted : April 27, 2017
Last Update Posted : July 27, 2017
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Janet E. Hall, MD, Massachusetts General Hospital

Brief Summary:

This research study involves the use of the drugs Letrozole, GnRH, and NAL-GLU GnRH antagonist. Letrozole is a drug that is approved by the U.S. Food and Drug Administration (FDA) for use in breast cancer treatment that has been found to block the formation of estrogen. The NAL-GLU GnRH antagonist is a drug that temporarily blocks the action of GnRH. GnRH is a hormone that the body makes that stimulates other hormones that then control the function of the ovary.

The purpose is to study the effects of the administration of letrozole in women with GnRH deficiency at the same time that they receive gonadotropin-releasing hormone (GnRH). In addition, administration of letrozole and NAL-GLU GnRH antagonist in healthy women with normal menstrual cycles will be done to evaluate the role of estrogen in the control of the hormone FSH, or Follicle Stimulating Hormone, in the female reproductive cycle. A better understanding of FSH control may help in the development of new treatments for women with difficulty conceiving.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: Letrozole Drug: NAL-GLU GnRH antagonist Phase 1 Phase 2

Detailed Description:

The negative feedback control of FSH is crucial for the precise regulation of follicular development in the female. An important component of this feedback is exerted by estrogen. Letrozole will be used to block aromatase and therefore estradiol production in normal and GnRH deficient females. These studies will dissect the relative roles of estradiol and inhibin on FSH secretion at the pituitary and hypothalamus.

The aromatase inhibitors block aromatization of androgens to estrogens, allowing us to examine the relative contribution of estradiol and the inhibins to FSH regulation. The use of a submaximal dose of a GnRH antagonist will allow us to estimate the overall amount of GnRH secreted (hypothalamic contribution) with and without aromatase inhibition.

A more thorough understanding of estrogen and inhibin feedback on FSH will improve our understanding of the failure of follicle development in subsets of patients with infertility, such as polycystic ovary syndrome, in which FSH levels are normal but follicles fail to develop. Study of FSH control will also help us understand the failure of negative feedback on FSH, which can result in multiple follicular development and multiple gestation and its associated costs and risks. Thus, these studies may afford new therapeutic options for conception in infertile patients while simultaneously providing new methods to avoid the risks of multiple gestations.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: This is a physiologic study designed to investigate the relative roles of estradiol and inhibin A or inhibin B in the control of FSH secretion during normal menstrual cycles using an aromatase inhibitor. Subjects serve as their own control with no intervention in cycle 1 and letrozole administration in cycle 2. Subjects are studied in the early follicular phase or the late follicular phase.
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Letrozole Treatment in Normal and GnRH Deficient Women
Actual Study Start Date : January 21, 2004
Primary Completion Date : June 29, 2009

Resource links provided by the National Library of Medicine

Drug Information available for: Letrozole
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Aromatase inhibitor EFP

Letrozole administration (20 mg) on day 2-4 (EFP; early follicular phase) of cycle 2 and

Nal-Glu GnRH antagonist used to estimate the overall amount of GnRH secreted.

Drug: Letrozole
Letrozole 20 mg orally one time
Other Names:
  • aromatase inhibitor
  • Femara
Drug: NAL-GLU GnRH antagonist
5 mcg/kg of the NAL-GLU GnRH antagonist subcutaneously
Other Name: GnRH antagonist
Experimental: Aromatase inhibitor LFP

Letrozole administration (20 mg daily x 2) at follicle size of > 16 mm (LFP; late follicular phase) in cycle 2.

Nal-Glu GnRH antagonist used to estimate the overall amount of GnRH secreted.

Drug: Letrozole
Letrozole 20 mg orally one time
Other Names:
  • aromatase inhibitor
  • Femara
Drug: NAL-GLU GnRH antagonist
5 mcg/kg of the NAL-GLU GnRH antagonist subcutaneously
Other Name: GnRH antagonist

Primary Outcome Measures :
  1. FSH Level [ Time Frame: EFP: average of menstrual cycle day 6 in the EFP; LFP: average of 2 days after follicle size of 16 mm ]
    Difference in FSH peak following letrozole administration compared with control cycle

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
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

Healthy Normal Subjects will meet the following criteria:

  • 18 to 35 years of age
  • good general health
  • on no medications including any hormonal drug products for at least 3 months before the study
  • regular menstrual cycles every 25-35 days with ovulation documented by a luteal phase progesterone > 3 ng/ml
  • no evidence of androgen excess
  • normal TSH, prolactin and hemoglobin
  • use of double-barrier contraception, permanent sterilization or abstinence during the cycle of study.
  • Negative pregnancy test (serum) at the beginning of each cycle of study
  • Normal Liver Function Test

Exclusion Criteria:

  • History of liver and/or kidney disease
  • Substance or alcohol abuse
  • Hormone dependent neoplasia including breast cancer
  • Women who are trying to become pregnant

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 ClinicalTrials.gov identifier (NCT number): NCT00351416

United States, Massachusetts
Reproductive Endocrine Unit, Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
National Institutes of Health (NIH)
Principal Investigator: Janet E Hall, M.D. Massachusetts General Hospital

Responsible Party: Janet E. Hall, MD, Associate Physician, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00351416     History of Changes
Other Study ID Numbers: 2003-P-001895
Sundry Department Fund ( Other Identifier: MGH-REU Department Fund )
First Posted: July 12, 2006    Key Record Dates
Results First Posted: April 27, 2017
Last Update Posted: July 27, 2017
Last Verified: June 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Once published, de-identified individual level data will be shared upon request to the PI.

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janet E. Hall, MD, Massachusetts General Hospital:
GnRH deficiency
GnRH antagonist

Additional relevant MeSH terms:
Aromatase Inhibitors
LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-
Prolactin Release-Inhibiting Factors
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs