Postmenopausal Women Estrogen and Progesterone Infusion

Phase 1

Completed

Conditions: Postmenopause
Aging

Interventions: Drug: Estradiol infusion
Drug: Progesterone infusion

Registration Number: NCT00455741

Lead Sponsor: 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).

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 20

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Older postmenopausal women	Progesterone infusion	Graded estradiol infusion to young postmenopausal women. Graded progesterone infusion to young postmenopausal women..
Young postmenopausal women	Estradiol infusion	Graded estradiol infusion to young postmenopausal women. Graded progesterone infusion to young postmenopausal women.
Young postmenopausal women	Progesterone infusion	Graded estradiol infusion to young postmenopausal women. Graded progesterone infusion to young postmenopausal women.
Older postmenopausal women	Estradiol infusion	Graded estradiol infusion to young postmenopausal women. Graded progesterone infusion to young postmenopausal women..

Primary Outcome Measures

Name	Time	Method
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.
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).

Secondary Outcome Measures

Name	Time	Method
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 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 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.
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.