Aging, Postmenopause
Conditions
Keywords
menopause, estrogen, progesterone, hormone replacement, aging, PET
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).
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.
Interventions
DRUGEstradiol 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.
DRUGProgesterone 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.
Sponsors
National Institute on Aging (NIA)
Massachusetts General Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Intervention model description
Estradiol and progesterone infusion to assess negative and positive feedback on the hypothalamus and pituitary in young and older postmenopausal women.
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 80 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Aging on Estrogen Negative Feedback on LH | 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). |
| Effect of Aging on Estrogen Positive Feedback on LH | 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
| Measure | Time frame | Description |
|---|---|---|
| 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Negative Feedback | 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. |
| 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Negative Feedback | 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. |
| 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Positive Feedback | 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. |
| 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Positive Feedback | 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. |
Countries
United States
Participant flow
Recruitment details
36 subjects consented; 6 failed screening, 2 decided not to participate.
Pre-assignment details
1 subject terminated during study (hemoglobin drop) for a total of 24 completed.
Participants by arm
| Arm | Count |
|---|---|
| Younger PMW Postmenopausal women (PMW) ages 45-55 receiving the following hormone infusions.
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.
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. | 13 |
| Older PMW Postmenopausal women (PMW) ages 70-80 receiving the following hormone infusions.
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.
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. | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Younger PMW | Total | Older PMW |
|---|---|---|---|
| Age, Customized | 49.9 years STANDARD_DEVIATION 3.8 | 61.3 years STANDARD_DEVIATION 13.4 | 75.2 years STANDARD_DEVIATION 3.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 5 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 20 Participants | 12 Participants |
| Region of Enrollment United States | 13 participants | 20 participants | 12 participants |
| Sex: Female, Male Female | 13 Participants | 25 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 0 / 12 |
| other Total, other adverse events | 2 / 13 | 1 / 12 |
| serious Total, serious adverse events | 0 / 13 | 0 / 12 |
Outcome results
Primary
Effect of Aging on Estrogen Negative Feedback on LH
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).
Time frame: Baseline at 0 time before infusion, nadir occurred between 8 and 60 hr (mean 24 hr)
Population: NOTE: 2 older and 2 younger postmenopausal women excluded from this analysis as estradiol levels exceeded physiological exposure levels
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger PMW | Effect of Aging on Estrogen Negative Feedback on LH | -52.8 % change from baseline | Standard Error 3 |
| Older PMW | Effect of Aging on Estrogen Negative Feedback on LH | -53.2 % change from baseline | Standard Error 2.3 |
Comparison: effect of age on estrogen negative feedback ( nadir LH as % of baseline LH)p-value: 0.9ANOVA
Comparison: positive feedbackp-value: <0.03ANOVA
Primary
Effect of Aging on Estrogen Positive Feedback on LH
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.
Time frame: Onset of surge (average of 61 hr from beginnning of infusion until the end of the study (120 hr)
Population: NOTE: 2 older and 2 younger postmenopausal women excluded from this analysis as estradiol levels exceeded physiological exposure levels
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger PMW | Effect of Aging on Estrogen Positive Feedback on LH | 4544.6 IU*hr/L | Standard Error 636.3 |
| Older PMW | Effect of Aging on Estrogen Positive Feedback on LH | 2885.5 IU*hr/L | Standard Error 316.7 |
p-value: =0.03ANOVA
Secondary
18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Negative Feedback
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.
Time frame: 0 vs 24 hr
Population: postmenopausal women
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger PMW | 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Negative Feedback | 69.0 units | Standard Error 3.3 |
| Older PMW | 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Negative Feedback | 63.1 units | Standard Error 2.8 |
p-value: <0.02t-test, 2 sided
Secondary
18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Positive Feedback
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.
Time frame: 24 vs 72 hr
Population: postmenopausal women
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger PMW | 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Positive Feedback | 63.1 unit | Standard Error 2.8 |
| Older PMW | 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Positive Feedback | 66.2 unit | Standard Error 3.7 |
p-value: 0.07t-test, 2 sided
Secondary
18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Negative Feedback
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.
Time frame: Baseline vs 24 hr after the onset of steroid infusion
Population: postmenopausal women
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger PMW | 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Negative Feedback | 45.8 units | Standard Error 4.5 |
| Older PMW | 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Negative Feedback | 48.4 units | Standard Error 4 |
p-value: 0.49t-test, 2 sided
Secondary
18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Positive Feedback
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.
Time frame: 24 hr vs 72 hr
Population: postmenopausal women
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Younger PMW | 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Positive Feedback | 48.0 units | Standard Error 4 |
| Older PMW | 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Positive Feedback | 54.3 units | Standard Error 4.4 |
p-value: <0.03t-test, 2 sided