Clinical trial NCT00455741: Postmenopausal Women Estrogen and Progesterone Infusion
Official title: Effect of Age on Gonadotropin Responses to Short-Term Negative and Positive Feedback Effects of Gonadal Steroids Using PET Scanning
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Postmenopause
Aging
Keywords: menopause
estrogen
progesterone
hormone replacement
aging
PET
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2007-04-04
Enrollment: 20
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Estradiol and progesterone infusion to assess negative and positive feedback on the hypothalamus and pituitary in young and older postmenopausal women.
Primary purpose: OTHER

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.

Eligibility 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

Primary outcomes:
measure: Effect of Aging on Estrogen Negative Feedback on LH
timeFrame: Baseline at 0 time before infusion, nadir occurred between 8 and 60 hr (mean 24 hr)
measure: Effect of Aging on Estrogen Positive Feedback on LH
timeFrame: Onset of surge (average of 61 hr from beginnning of infusion until the end of the study (120 hr)
Secondary outcomes:
measure: 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Negative Feedback
timeFrame: Baseline vs 24 hr after the onset of steroid infusion
measure: 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Negative Feedback
timeFrame: 0 vs 24 hr
measure: 18 FDG Uptake at the Pituitary During Estrogen Infusion: LH Positive Feedback
timeFrame: 24 hr vs 72 hr
measure: 18 FDG Uptake at the Hypothalamus During Estrogen Infusion: LH Positive Feedback
timeFrame: 24 vs 72 hr
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Janet E Hall, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shaw ND, Srouji SS, Histed SN, Hall JE. Differential effects of aging on estrogen negative and positive feedback. Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E351-5. doi: 10.1152/ajpendo.00150.2011. Epub 2011 May 10.
citation: Ottowitz WE, Derro D, Dougherty DD, Lindquist MA, Fischman AJ, Hall JE. FDG-PET analysis of amygdalar-cortical network covariance during pre- versus post-menopausal estrogen levels: potential relevance to resting state networks, mood, and cognition. Neuro Endocrinol Lett. 2008 Aug;29(4):467-74.
citation: Ottowitz WE, Dougherty DD, Fischman AJ, Hall JE. [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography demonstration of estrogen negative and positive feedback on luteinizing hormone secretion in women. J Clin Endocrinol Metab. 2008 Aug;93(8):3208-14. doi: 10.1210/jc.2008-0203. Epub 2008 Jun 3.
citation: Ottowitz WE, Siedlecki KL, Lindquist MA, Dougherty DD, Fischman AJ, Hall JE. Evaluation of prefrontal-hippocampal effective connectivity following 24 hours of estrogen infusion: an FDG-PET study. Psychoneuroendocrinology. 2008 Nov;33(10):1419-25. doi: 10.1016/j.psyneuen.2008.09.013. Epub 2008 Oct 31.