Letrozole Treatment in Normal and GnRH Deficient Women

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Janet E. Hall, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT00351416
First received: July 10, 2006
Last updated: November 5, 2013
Last verified: November 2013
  Purpose

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 Intervention Phase
Kallmann's Syndrome
Hypogonadotropic Hypogonadism
Healthy Volunteers
Drug: Letrozole
Drug: NAL-GLU GnRH antagonist
Drug: GnRH
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: Letrozole Treatment in Normal and GnRH Deficient Women

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • In healthy subjects, the acute changes in FSH, inhibin A, inhibin B and estradiol between the Letrozole and control cycles at each cycle stage [ Time Frame: end of control and treatment cycles ] [ Designated as safety issue: No ]
  • The average LH, FSH, inhibin A, inhibin B, estradiol and progesterone in the control and treatment cycles [ Time Frame: end of control and treatment cycles ] [ Designated as safety issue: No ]
  • The number of pulses in 8 hrs and LH pulse amplitude will be compared in the control and treatment cycle [ Time Frame: after each 16-hour admission ] [ Designated as safety issue: No ]
  • The percent suppression of LH will be compared in the control and Letrozole cycles [ Time Frame: after each 16-hour admission ] [ Designated as safety issue: No ]

Estimated Enrollment: 70
Study Start Date: July 2004
Estimated Study Completion Date: December 2018
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1
Early-follicular phase of the menstrual cycle
Drug: Letrozole
Letrozole 20mg orally one time
Drug: NAL-GLU GnRH antagonist
5 mcg/kg of the NAL-GLU GnRH antagonist subcutaneously
Drug: GnRH
For GnRH-deficient subjects only: 75 ng/kg GnRH IV
2
Late follicular phase of the menstrual cycle
Drug: Letrozole
Letrozole 20mg orally one time
Drug: NAL-GLU GnRH antagonist
5 mcg/kg of the NAL-GLU GnRH antagonist subcutaneously
Drug: GnRH
For GnRH-deficient subjects only: 75 ng/kg GnRH IV
3
Luteal phase of the menstrual cycle
Drug: Letrozole
Letrozole 20mg orally one time
Drug: NAL-GLU GnRH antagonist
5 mcg/kg of the NAL-GLU GnRH antagonist subcutaneously
Drug: GnRH
For GnRH-deficient subjects only: 75 ng/kg GnRH IV

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 inhibin to FSH regulation. Using normal subjects and GnRH-deficient subjects receiving replacement GnRH allows us to compare the effect of relative estradiol blockade at the pituitary (GnRH deficient subjects) vs the pituitary and hypothalamus (normal subjects), thus determining the direct site of estradiol action.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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

GnRH Deficient Subjects will meet the following criteria:

  • 18 to 40 years of age
  • good general health
  • on no gonadal replacement for at least 1 month before the study
  • GnRH deficiency (idiopathic hypogonadotropic hypogonadism or Kallmann's Syndrome, secondary hypothalamic amenorrhea, acquired hypogonadotropic hypogonadism)
  • normal TSH, prolactin and hemoglobin
  • use of double-barrier contraception or abstinence during the cycle of Letrozole administration
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00351416

Locations
United States, Massachusetts
Reproductive Endocrine Unit, Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Investigators
Principal Investigator: Janet E Hall, M.D. Massachusetts General Hospital
  More Information

No publications provided

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
Study First Received: July 10, 2006
Last Updated: November 5, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Massachusetts General Hospital:
GnRH deficiency
GnRH antagonist
Letrozole
GnRH
FSH
LH
Inhibins

Additional relevant MeSH terms:
Kallmann Syndrome
Hypogonadism
Gonadal Disorders
Endocrine System Diseases
46, XY Disorders of Sex Development
Disorders of Sex Development
Urogenital Abnormalities
Congenital Abnormalities
Genetic Diseases, Inborn
Letrozole
LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Aromatase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 14, 2014