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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

Tracking Information
First Submitted Date  ICMJE October 6, 2006
First Posted Date  ICMJE October 11, 2006
Results First Submitted Date  ICMJE May 22, 2014
Results First Posted Date  ICMJE April 13, 2017
Last Update Posted Date April 13, 2017
Study Start Date  ICMJE January 2002
Actual Primary Completion Date January 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 12, 2017)
  • 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
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: October 6, 2006)
pituitary response after GnRH stimulation; LH, FSH and FAS, the peak amplitude, and area under the curve for each GnRH dose per study group
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effects of Aging and Estrogen on the Pituitary
Official Title  ICMJE The Effect of Aging on the Isolated Pituitary Response to Gonadotropin Releasing Hormone at Baseline and With Low Dose Estrogen Administration
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE 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
Condition  ICMJE Healthy
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Young postmenopausal women
    intervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch
    Interventions:
    • Drug: GnRH
    • Drug: NAL-GLU GnRH antagonist
    • Drug: Estrogen patch
  • Experimental: Older postmenopausal women
    intervention: graded doses of GnRH following NAL-GLU GnRH antagonist administration with or without transdermal estrogen patch
    Interventions:
    • Drug: GnRH
    • Drug: NAL-GLU GnRH antagonist
    • Drug: Estrogen patch
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Actual Enrollment  ICMJE
 (submitted: April 12, 2017)
19
Original Enrollment  ICMJE
 (submitted: October 6, 2006)
40
Estimated Study Completion Date  ICMJE January 2018
Actual Primary Completion Date January 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 45 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00386022
Other Study ID Numbers  ICMJE 2000-P-002498
R01AG013241 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Coded data with identifying information can be requested by contacting the PI.
Responsible Party Janet E. Hall, MD, Massachusetts General Hospital
Study Sponsor  ICMJE Massachusetts General Hospital
Collaborators  ICMJE National Institute on Aging (NIA)
Investigators  ICMJE
Principal Investigator: Janet E Hall, M.D. Massachusetts General Hospital
PRS Account Massachusetts General Hospital
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP