Letrozole Treatment in Normal and GnRH Deficient Women
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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 |
- 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 2011 |
| Estimated 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 |
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| United States, Massachusetts | |
| Reproductive Endocrine Unit, Massachusetts General Hospital | |
| Boston, Massachusetts, United States, 02114 | |
| 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: | October 4, 2011 |
| 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:
|
Hypogonadism Kallmann Syndrome 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 May 23, 2013