The Effects of Reproductive Hormones on Mood and Behavior
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This study evaluates the effects of estrogen and progesterone on mood, the stress response,
      and brain function in healthy women.

      The purpose of this study is to evaluate how low levels of estrogen and progesterone (that
      occur during treatment with leuprolide acetate) compare to menstrual cycle levels of estrogen
      and progesterone (given during individual months of hormone add-back) on a variety of
      physiologic measures (brain imaging, stress testing, etc.) in healthy volunteer women without
      PMS.

      This study will investigate effects of reproductive hormones by temporarily stopping the
      menstrual cycle with leuprolide acetate and then giving, in sequence, the menstrual cycle
      hormones progesterone and estrogen. Tests (such as brain imaging or stress testing, etc.)
      will be performed during the different hormonal conditions (low estrogen and progesterone,
      progesterone add-back, estrogen add-back). The results of these studies will be compared
      between women without PMS and women with PMS (see also protocol 90-M-0088).

      At study entry, participants will undergo a physical examination. Blood, urine, and pregnancy
      tests will be performed. Cognitive functioning and stress response will be evaluated during
      the study along with brain imaging and genetic studies.
    

Detailed description: 
      Evidence suggests that the gonadal steroids may exert clinically significant effects on
      central nervous system function. For example, the menstrual cycle may influence the
      occurrence of seizures in some female epileptics and the performance on certain cognitive
      tests. Central nervous system effects of gonadal steroids have been inferred largely from
      changes in behavior occurring in association with presumed changes in gonadal steroids during
      the normal menstrual cycle, during the administration of ovarian hormones, or in a
      gender-specific context. These inferences are, by definition, indirect and associational in
      nature and further are incapable of disentangling the effects of hormones which are
      simultaneously present in women of reproductive age. This study is designed to address those
      problems by comparing measures during Lupron-induced hypogonadism with those during
      replacement with estrogen or progesterone. On the basis of prior findings from our group and
      from others, we will be asking the following questions: 1) Is the decreased r-CBF that we
      observed in the prefrontal cortex during the hypogonadal state confirmed in individual women
      using new imaging techniques; 2) Will variation in genotype (e.g., COMT val/met, BDNF
      val/met) confer differential sensitivity to ovarian steroids in brain circuitry and 3) Are
      the menstrual cycle phase-related changes in reward systems that we previously observed
      related to estradiol or progesterone actions within the brain (1). Additionally, this
      protocol will serve as a control study for protocol # 90-M-0088.
    

Intervention name(s): Leuprolide Acetate 3.75; Estradiol; Progesterone; Placebo suppository; Placebo patch
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly; Transdermal Estradiol, 100mcg/day by skin patch; Progesterone suppository, 200mg vaginally twice/day; Placebo suppository twice daily; Placebo by skin patch
Intervention MeSH terms: Leuprolide; Estradiol; Progesterone
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Primary purpose: Basic Science
Keywords: Behavior; Brain Function; Progesterone; Central Nervous System Function; gonadotropin-releasing hormone (GnRH) Agonist