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Postmenopausal Women Estrogen and Progesterone Infusion

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ClinicalTrials.gov Identifier: NCT00455741
Recruitment Status : Completed
First Posted : April 4, 2007
Results First Posted : May 18, 2018
Last Update Posted : May 18, 2018
Sponsor:
Collaborator:
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Janet E. Hall, MD, Massachusetts General Hospital

Brief Summary:
The purpose of the study is to study the effects of aging, estrogen and progesterone on the brain. Specifically, we want to look at how the hypothalamus and pituitary (two small glands in the brain) respond to estrogen. The pituitary gland is controlled by the hypothalamus. The hypothalamus secretes GnRH (Gonadotropin-Releasing Hormone) that signals the pituitary to secrete the reproductive hormones, LH (Luteinizing Hormone) and FSH (Follicle Stimulating Hormone). These hormones act on the ovaries and signal the ovaries to produce estrogen and progesterone. Estrogen in the bloodstream then acts on the brain to modulate this system with changes in LH and FSH. Early changes associated with low levels of estrogen are inhibitory (estrogen negative feedback) while higher levels of estrogen (such as those present when a follicle in the ovary is ready to ovulate) stimulate LH to cause ovulation (positive feedback). This study will determine: 1) hypothalamic and pituitary levels of glucose uptake (as a measure of brain metabolic activity) at baseline and in association with estrogen negative feedback on LH (24 hr) and estrogen positive feedback on LH (72 hr); and 2) the effect of aging on estrogen feedback on LH, assessing negative feedback (nadir ~ 24 hr) and positive feedback (peak between 72 and 96 hr).

Condition or disease Intervention/treatment Phase
Postmenopause Aging Drug: Estradiol infusion Drug: Progesterone infusion Phase 1 Phase 2

Detailed Description:
The transition to menopause is characterized by a decline in the numbers of functional ovarian follicles followed by a decrease in levels of inhibin A and B and complex changes in estradiol, which include an initial increase followed by an inevitable decrease. Therefore, there are dynamic changes in the hypothalamic-pituitary feedback from the aging ovary, prior to the ultimate loss of feedback that occurs with the complete cessation of ovarian function. While there is ample evidence that the loss of ovarian function is a major contributor to the menopause, there is evidence from animal models that primary age-related neuroendocrine changes may also contribute to reproductive aging. Specifically, there is evidence for changes in the hypothalamic and pituitary responses to estrogen negative and positive feedback. An understanding of the age-related changes in the physiology of the hypothalamic and pituitary responsiveness to gonadal steroid feedback is critical in determining whether hypothalamic and pituitary changes per se contribute to the menopause and the impact of the loss of reproductive function on the brain.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Estradiol and progesterone infusion to assess negative and positive feedback on the hypothalamus and pituitary in young and older postmenopausal women.
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Effect of Age on Gonadotropin Responses to Short-Term Negative and Positive Feedback Effects of Gonadal Steroids Using PET Scanning
Study Start Date : November 2000
Actual Primary Completion Date : February 2007
Actual Study Completion Date : August 22, 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Young postmenopausal women
Graded estradiol infusion to young postmenopausal women. Graded progesterone infusion to young postmenopausal women.
Drug: Estradiol infusion
Graded estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr.

Drug: Progesterone infusion
Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr of the 5-day study.

Active Comparator: Older postmenopausal women
Graded estradiol infusion to young postmenopausal women. Graded progesterone infusion to young postmenopausal women..
Drug: Estradiol infusion
Graded estradiol infusion of 0.1 mcg/kg/hr for 12 hr, 0.135 mcg/kg/hr for 12 hr, 0.165 mcg/kg/hr for 12 hr and 0.2 mcg/kg/hr for 60 hr.

Drug: Progesterone infusion
Progesterone infusion of 4.77 nmol/kg/hr (1.5 mcg/kg/hr) for 24 hr and 6.36 nmol/kg/hr (2 mcg/kg/hr) for the final 24 hr of the 5-day study.




Primary Outcome Measures :
  1. Effect of Aging on Estrogen Negative Feedback on LH [ Time Frame: Baseline at 0 time before infusion, nadir occurred between 8 and 60 hr (mean 24 hr) ]
    Difference between baseline LH (average of 3 samples drawn 15 min apart) and nadir LH based on a 3-point moving average of blood samples drawn every 4 hours over 120 hr, expressed as a percent of baseline (% baseline).

  2. Effect of Aging on Estrogen Positive Feedback on LH [ Time Frame: Onset of surge (average of 61 hr from beginnning of infusion until the end of the study (120 hr) ]
    LH area under the curve in response to estrogen positive feedback. Area under the curve was calculated from blood samples drawn every 4 hours from the onset of positive feedback until the end of the study (120 min). The onset of positive feedback is defined as the time when LH first exceeds mean + 2SD of the previous three time points and shows a sustained rise.


Secondary Outcome Measures :
  1. 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Negative Feedback [ Time Frame: Baseline vs 24 hr after the onset of steroid infusion ]
    Regional cerebral glucose metabolism (rCMRglu) is used as a measure of neuronal metabolic activity and calculated as average uptake (voxels) of 18 flurodeoxyglucose within the region of interest (ROI) and expressed simply as units. Normalized uptake refers to co-registration of the PET with the MRI to provide more accurate anatomic correlates.

  2. 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Negative Feedback [ Time Frame: 0 vs 24 hr ]
    Regional cerebral glucose metabolism (rCMRglu) is used as a measure of neuronal metabolic activity and calculated as average uptake (voxels) of 18 flurodeoxyglucose within the region of interest (ROI) and expressed simply as units. Normalized uptake refers to co-registration of the PET with the MRI to provide more accurate anatomic correlates.

  3. 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Positive Feedback [ Time Frame: 24 hr vs 72 hr ]
    Regional cerebral glucose metabolism (rCMRglu) is used as a measure of neuronal metabolic activity and calculated as average uptake (voxels) of 18 flurodeoxyglucose within the region of interest (ROI) and expressed simply as units. Normalized uptake refers to co-registration of the PET with the MRI to provide more accurate anatomic correlates.

  4. 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Positive Feedback [ Time Frame: 24 vs 72 hr ]
    Regional cerebral glucose metabolism (rCMRglu) is used as a measure of neuronal metabolic activity and calculated as average uptake (voxels) of 18 flurodeoxyglucose within the region of interest (ROI) and expressed simply as units. Normalized uptake refers to co-registration of the PET with the MRI to provide more accurate anatomic correlates.



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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:

postmenopausal women young (age 45-55) or old (age 70-80) History of natural menopause defined by the absence of menses for at least 12 months (or history of surgical menopause defined as bilateral oophorectomy) Normal TSH, PRL and CBC, and Factor V activity Normal BUN and Creatinine (< 2 times the upper limit of normal) BMI between 18 to 30 kg/m2 An increased FSH measured at the screening visit will be consistent with menopause. If the initial determination is low, a repeat sample may be drawn.

Exclusion criteria:

Hormonal medication or herbal supplements and/or over the counter menopause therapy in the 2 months prior to study Any absolute contraindications to the use of physiologic replacement doses of estrogen and/or progesterone History of coronary artery disease Medications thought to act centrally on the GnRH pulse generator History of breast cancer or blood clots Smoking more than 10 cigarettes/day Prior history of allergic reaction to any dyes used with x-rays or scans and/ or any other contraindications to PET scans No metal implants, pacemakers, aneurysm clips, implanted hearing aids and/or any other contraindications to MRI scan


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): NCT00455741


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

Publications of Results:
Responsible Party: Janet E. Hall, MD, Associate Physician, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00455741     History of Changes
Other Study ID Numbers: 2000P-002496
R01AG013241 ( U.S. NIH Grant/Contract )
First Posted: April 4, 2007    Key Record Dates
Results First Posted: May 18, 2018
Last Update Posted: May 18, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Requests for sharing coded results without patient identifiers can be made directly to the PI.

Keywords provided by Janet E. Hall, MD, Massachusetts General Hospital:
menopause
estrogen
progesterone
hormone replacement
aging
PET

Additional relevant MeSH terms:
Estradiol
Polyestradiol phosphate
Estrogens
Progesterone
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Estradiol valerate
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Progestins