The Effects of Aging and Estrogen on the Pituitary

April 12, 2017 updated by: Janet E. Hall, MD, Massachusetts General Hospital

The Effect of Aging on the Isolated Pituitary Response to Gonadotropin Releasing Hormone at Baseline and With Low Dose Estrogen Administration

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

19

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Female

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Peak hormone level within 2 hours post GnRH doses
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
Peak hormone level within 2 hours post GnRH doses

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Collaborators

National Institute on Aging (NIA)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2002

Primary Completion (Actual)

January 1, 2012

Study Completion (Anticipated)

January 1, 2018

Study Registration Dates

First Submitted

October 6, 2006

First Submitted That Met QC Criteria

October 6, 2006

First Posted (Estimate)

October 11, 2006

Study Record Updates

Last Update Posted (Actual)

April 13, 2017

Last Update Submitted That Met QC Criteria

April 12, 2017

Last Verified

April 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2000-P-002498
  • R01AG013241 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Coded data with identifying information can be requested by contacting the PI.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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