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The Effects of Aging and Estrogen on the Pituitary

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ClinicalTrials.gov Identifier: NCT00386022
Recruitment Status : Unknown
Verified April 2017 by Janet E. Hall, MD, Massachusetts General Hospital.
Recruitment status was:  Active, not recruiting
First Posted : October 11, 2006
Results First Posted : April 13, 2017
Last Update Posted : April 13, 2017
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Janet E. Hall, MD, Massachusetts General Hospital

Study Description
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Brief Summary:
The purpose of this study is to study the effects of aging and estrogen on the brain. Specifically, this study will examine how the hypothalamus signals the pituitary gland to secrete reproductive hormones and how that changes with aging.

Condition or disease Intervention/treatment Phase
Healthy Drug: GnRH Drug: NAL-GLU GnRH antagonist Drug: Estrogen patch Phase 2 Phase 3

Detailed Description:

Although it is clear that loss of ovarian function plays a major role in the menopause in women, there is evidence from animal studies that primary age-related hypothalamic and pituitary changes may also contribute to reproductive aging. Complete cessation of ovarian function results in the loss of negative feedback of ovarian steroids and inhibin on the hypothalamic and pituitary components of the reproductive axis. An increase in serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) occurs in postmenopausal women with removal of negative ovarian feedback. However, levels of LH and FSH after menopause decline steadily as a function of age in most though not all studies.

The current study is designed to determine: 1) whether negative feedback on LH and FSH occurs at the pituitary; and 2) whether there is an effect of aging on estrogen negative feedback at the pituitary. Younger and older postmenopausal women underwent a baseline study and a second identical study after a month of low dose estrogen replacement. The study protocol consisted of the following: 1) administration of a GnRH antagonist (Nal-Glu at 150 mg/kg that blocks endogenous GnRH so that the dose and interval of pituitary exposure to GnRH are precisely controlled; 2) beginning 8 hours following GnRH antagonist administration (at a time when LH had reached its nadir following GnRH receptor blockade), administration of 4 graded doses of GnRH (25, 75, 250 and 750 ng/kg every 2 hours with 2 hours of blood draws following each dose). Blood was sampled every 30 min for 4 hours before antagonist administration, every 30 min for the following 7 hours and then every 10 min until the completion of the study.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 19 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: The study will is considered sequential as participants were studied at baseline and after one month of low-dose estrogen. Randomization refers to randomization of the order of doses of GnRH between participants.
Masking: None (Open Label)
Primary Purpose: Other
Official Title: The Effect of Aging on the Isolated Pituitary Response to Gonadotropin Releasing Hormone at Baseline and With Low Dose Estrogen Administration
Study Start Date : January 2002
Actual Primary Completion Date : January 2012
Estimated Study Completion Date : January 2018

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Young postmenopausal women
intervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch
 Drug: GnRH
GnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr at baseline and after transdermal estradiol
Other Names:
  • gonadotropin-releasing hormone
  • Factryl

Drug: NAL-GLU GnRH antagonist
A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg before and after transdermal estradiol
Other Name: GnRH antagonist

Drug: Estrogen patch
transdermal estrogen patches 0.05mg/day, changing the patch every 86 hr in second part of sequential study
Other Names:
  • Climara
  • Estraderm
Experimental: Older postmenopausal women
intervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch
 Drug: GnRH
GnRH doses of 25, 75, 250 and 750 ng/kg will be given IV every 4 hr at baseline and after transdermal estradiol
Other Names:
  • gonadotropin-releasing hormone
  • Factryl

Drug: NAL-GLU GnRH antagonist
A single subcutaneous injection of the NAL-GLU GnRH antagonist at a dose of 150 mcg/kg before and after transdermal estradiol
Other Name: GnRH antagonist

Drug: Estrogen patch
transdermal estrogen patches 0.05mg/day, changing the patch every 86 hr in second part of sequential study
Other Names:
  • Climara
  • Estraderm


Outcome Measures
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Primary Outcome Measures :
  1. Pituitary Response to GnRH [ Time Frame: Peak hormone level within 2 hours post GnRH doses ]
    Baseline LH and FSH responses to each of 4 GnRH doses - peak to nadir amplitude expressed as percent (%) change from nadir

  2. Effect of Estrogen on Pituitary Response to GnRH [ Time Frame: Peak hormone level within 2 hours post GnRH doses ]
    LH and FSH responses to each of 4 GnRH doses, expressed as change in amplitude [amp] from peak to nadir between plus estrogen and baseline conditions


Eligibility Criteria
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Ages Eligible for Study:   45 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • 45-55 or 70-80 years old
  • History of natural menopause defined by the absence of menses for at least 12 months (or history of surgical menopause defined as bilateral oophorectomy) and a FSH level >26 IU/L
  • On no hormonal medication or herbal supplements and/or over the counter menopause therapy for a minimum of 2 months prior to study
  • Normal thyroid stimulating hormone, prolactin, factor V Leiden, and complete blood count - Normal blood urea nitrogen and creatinine (< 2 times the upper limit of normal)
  • basal metabolic index ≤ 30
  • Non-smokers or smoke less than 10 cigarettes/day

Exclusion Criteria:

  • Absolute contraindications to the use of physiologic replacement doses of estrogen, including a negative screening mammogram within the past 24 months
  • History of coronary artery disease
  • On medications thought to act centrally on the GnRH pulse generator
  • Past history of hypersensitivity or allergy to narcotics, vancomycin, muscle relaxants, aspirin, and/or anaphylactic reaction(s) to other drugs
  • Prior history of breast cancer and/or blood clots
Contacts and Locations
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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): NCT00386022


Locations
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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Janet E Hall, M.D. Massachusetts General Hospital
More Information
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Publications of Results:

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Responsible Party: Janet E. Hall, MD, Associate Physician, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00386022    
Other Study ID Numbers: 2000-P-002498
R01AG013241 ( U.S. NIH Grant/Contract )
First Posted: October 11, 2006    Key Record Dates
Results First Posted: April 13, 2017
Last Update Posted: April 13, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Coded data with identifying information can be requested by contacting the PI.
Keywords provided by Janet E. Hall, MD, Massachusetts General Hospital:
Gonadotropin-releasing hormone
Estrogens
postmenopausal women
Pituitary hormones
Additional relevant MeSH terms:
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Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases
Prolactin Release-Inhibiting Factors
 Estrogens
LHRH, N-Ac-2-Nal(1)-4-Cl-Phe(2)-3-Pal(3)-Arg(5)-Glu(6)-AlaNH2(10)-
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Hormone Antagonists