A Phase 1/2 interventional study of Estradiol infusion and Progesterone infusion in Postmenopause and Aging, sponsored by Massachusetts General Hospital. Completed at 1 site in United States. Open to female participants aged 45 Years to 80 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-05-18.
Sponsored by Massachusetts General Hospital · Phase 1/2, Interventional, and Other
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).
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.
Massachusetts General Hospital is the lead sponsor of 2,536 studies on the registry; 446 are open to participants now.
Of its 214 completed or terminated interventional studies of FDA-regulated products, 161 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
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
Graded estradiol infusion to young postmenopausal women. Graded progesterone infusion to young postmenopausal women.
Drug: Estradiol infusion · Drug: Progesterone infusion
Graded estradiol infusion to young postmenopausal women. Graded progesterone infusion to young postmenopausal women..
Drug: Estradiol infusion · Drug: Progesterone 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 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.
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)
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)
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
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
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
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
36 subjects consented; 6 failed screening, 2 decided not to participate.
| Milestone | Younger PMW | Older PMW |
|---|---|---|
| Started | 13 | 12 |
| Completed | 13 | 11 |
| Not completed | 0 | 1 |
| Withdrew: Physician decision | 0 | 1 |
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).
| % change from baseline | Younger PMW | Older PMW |
|---|---|---|
| Effect of Aging on Estrogen Negative Feedback on LH | -52.8 ± 3.0 | -53.2 ± 2.3 |
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.
| IU*hr/L | Young Postmenopausal Women | Older Postmenopausal Women |
|---|---|---|
| Effect of Aging on Estrogen Positive Feedback on LH | 4544.6 ± 636.3 | 2885.5 ± 316.7 |
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.
| units | Baseline Pituitary | Negative Feedback Pituitary |
|---|---|---|
| 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Negative Feedback | 45.8 ± 4.5 | 48.4 ± 4.0 |
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.
| units | Baseline Hypothalamus | Negative Feedback Hypothalamus |
|---|---|---|
| 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Negative Feedback | 69.0 ± 3.3 | 63.1 ± 2.8 |
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.
| units | Pituitary at 24 hr | Pituitary at 72 hr |
|---|---|---|
| 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Positive Feedback | 48.0 ± 4.0 | 54.3 ± 4.4 |
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.
| unit | Hypothalamus at 24 hr | Hypothalamus 72 hr |
|---|---|---|
| 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Positive Feedback | 63.1 ± 2.8 | 66.2 ± 3.7 |
Collected over 60 days for each subject; 4 years in total. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Younger PMW | 0/13 (0%) | 0/13 (0%) | 2/13 (15.4%) |
| Older PMW | 0/12 (0%) | 0/12 (0%) | 1/12 (8.3%) |
| Event | Younger PMW | Older PMW |
|---|---|---|
| vasomotor symptomsVascular disorders | 2/13 | 0/12 |
| anemiaBlood and lymphatic system disorders | 0/13 | 1/12 |
All subjects were healthy and had experienced their last menstrual period 18 mo previously. Subjects were not on any medications known to interact with the neuroendocrine reproductive axis, including over-the-counter medications or herbal remedies. Factor V Leiden mutations were absent in all patients.
| Age, Customized(years) | Younger PMW | Older PMW | Total |
|---|---|---|---|
| Mean | 49.9 ± 3.8 | 75.2 ± 3.6 | 61.3 ± 13.4 |
| Sex: Female, Male(Participants) | Younger PMW | Older PMW | Total |
|---|---|---|---|
| Female | 13 | 12 | 25 |
| Male | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Younger PMW | Older PMW | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 5 | 0 | 5 |
| White | 8 | 12 | 20 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Younger PMW | Older PMW | Total |
|---|---|---|---|
| United States | 13 | 12 | 20 |
Plan to share: Undecided — Requests for sharing coded results without patient identifiers can be made directly to the PI.
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Massachusetts General Hospital