Letrozole Treatment in Normal and GnRH Deficient Women - Full Text View

Sponsors and Collaborators:	Massachusetts General Hospital National Institutes of Health (NIH)
Information provided by:	Massachusetts General Hospital
ClinicalTrials.gov Identifier:	NCT00351416

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 II Phase III

Genetics Home Reference related topics: Kallmann syndrome

Drug Information available for: Letrozole Gonadorelin Gonadorelin hydrochloride LH-RH Glutamic acid

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Non-Randomized, Open Label, Active Control, Parallel Assignment
Official Title:	Letrozole Treatment in Normal and GnRH Deficient Women

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 Primary Completion Date:	July 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

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

Contacts

Contact: Teresa Alati

617-726-8484

talati@partners.org

Locations

United States, Massachusetts
Reproductive Endocrine Unit, Massachusetts General Hospital	Recruiting
Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

National Institutes of Health (NIH)

Investigators

Principal Investigator:

Janet E Hall, M.D.

Massachusetts General Hospital

More Information

Responsible Party:	Massachusetts General Hospital ( Janet E. Hall, MD )
Study ID Numbers:	2003-P-001895, R01HD42708
Study First Received:	July 10, 2006
Last Updated:	August 12, 2008
ClinicalTrials.gov Identifier:	NCT00351416
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

Study placed in the following topic categories:

LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-
Gonadal Disorders
Nervous System Malformations
Endocrine System Diseases
Letrozole
Kallmann Syndrome
Septo-optic dysplasia
Healthy

Sex Differentiation Disorders
Hypogonadism
Urogenital Abnormalities
Genetic Diseases, Inborn
Endocrinopathy
Congenital Abnormalities
Septo-Optic Dysplasia

Additional relevant MeSH terms:

Disease
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Hormone Antagonists
Nervous System Diseases
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists

Enzyme Inhibitors
Pharmacologic Actions
Pathologic Processes
Syndrome
Therapeutic Uses
Aromatase Inhibitors

ClinicalTrials.gov processed this record on January 14, 2009