Postmenopausal Women Estrogen and Progesterone Infusion
Condition: Postmenopause; Aging
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Estradiol infusion; Progesterone infusion
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Intervention MeSH terms: Estradiol; Progesterone
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
Keywords: menopause; estrogen; progesterone; hormone replacement; aging; PET