The Effects of Reproductive Hormones on Mood and Behavior

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Central Nervous System Effects of Pharmacologically Induced Hypogonadotropic Hypogonadism With and Without Estrogen and Progesterone Replacement

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Leuprolide Acetate 3.75
* Drug: Estradiol
* Drug: Progesterone
* Drug: Placebo suppository
* Drug: Placebo patch


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Volunteers participating in this study will be women meeting the following criteria: Between the ages of 18 and 50 years, Not pregnant, In good medical health, Medication free, No history of menstrual-related mood or behavioral disturbances. Additionally, we will recruit a subsample of 20 asymptomatic women who will meet all inclusion and exclusion criteria in this protocol except they will have a history of a past major depressive episode. Finally, a third sample of 10 women who meet all the inclusion and exclusion criteria listed above for this protocol will be recruited to establish the dose range of transdermal estrogen gel for this and related protocols (i.e., 90-M-0088 and 05-M-0059). EXCLUSION CRITERIA: The following conditions will constitute contraindications to treatment with hormonal therapy and will preclude a subject's participation in this protocol: Current Axis I psychiatric diagnosis (with the exception of this women with a past major depression who will be studied on this protocol); History consistent with endometriosis; Diagnosis of ill-defined, obscure pelvic lesions, particularly undiagnosed ovarian enlargement; Hepatic disease as manifested by abnormal liver function tests; History of mammary carcinoma; History of pulmonary embolism or phlebothrombosis; Undiagnosed vaginal bleeding; Porphyria; Diabetes mellitus; History of malignant melanoma; Cholecystitis or pancreatitis; Cardiovascular or renal disease; Pregnancy; Any woman meeting the Stages of Reproductive Aging Workshop Criteria (STRAW) for the perimenopause (129). Specifically, we will exclude any woman with an elevated plasma follicle stimulating hormone (FSH) level (greater than or equal to 14 IU/L) and with menstrual cycle variability of > 7 days different from their normal cycle length. National Institute of Mental Health (NIMH) employees/staff and their immediate family members will be excluded from the study per NIMH policy. Subjects taking birth control pills will be excluded from the study. Subjects taking diuretics, prostaglandin inhibitors, or pyridoxine (putative treatments for MRMD) will similarly be excluded from the study, as will patients taking psychotropic agents (e.g., lithium carbonate, tricyclic antidepressants). All subjects will be required to use non-hormonal forms of birth control (e.g., barrier methods) to avoid pregnancy during this study. Participants who have an active condition that places them at an increased risk for osteoporosis will be excluded from this protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 - Lupron<br>Eight to 12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly. | Drug: Leuprolide Acetate 3.75<br>* Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly<br>|
| Experimental: Phase 2, Arm 1 - Estradiol, then progesterone<br>12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly. Additionally, 4 weeks of transdermal Estradiol (100mcg/day by skin patch) and placebo suppositories. Week 5 involves 100mcg/day transdermal Estradiol and active Progesterone suppositories (200mg vaginally twice/day). Followed by 1-2 weeks (weeks 6-7) washout period. Then crossover to 5 weeks (week 8-12) of Progesterone suppositories (200mg vaginally twice/day) and placebo patches. | Drug: Leuprolide Acetate 3.75<br>* Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly<br>Drug: Estradiol<br>* Transdermal Estradiol, 100mcg/day by skin patch<br>Drug: Progesterone<br>* Progesterone suppository, 200mg vaginally twice/day<br>Drug: Placebo suppository<br>* Placebo suppository twice daily<br>Drug: Placebo patch<br>* Placebo by skin patch<br>|
| Experimental: Phase 2, Arm 2 - Progesterone, then estradiol<br>12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly. Additionally, 5 weeks of Progesterone suppositories (200mg vaginally twice/day) and placebo patches. Followed by 1-2 weeks (weeks 6-7) washout period. Then crossover to 4 weeks (weeks 8-11) of transdermal Estradiol (100mcg/day by skin patch) and placebo suppositories. Week 12 involves 100mcg/day transdermal Estradiol and active Progesterone suppositories (200mg vaginally twice/day). | Drug: Leuprolide Acetate 3.75<br>* Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly<br>Drug: Estradiol<br>* Transdermal Estradiol, 100mcg/day by skin patch<br>Drug: Progesterone<br>* Progesterone suppository, 200mg vaginally twice/day<br>Drug: Placebo suppository<br>* Placebo suppository twice daily<br>Drug: Placebo patch<br>* Placebo by skin patch<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Beck Depression Inventory Score | The Beck Depression Inventory (BDI) is a 21-item, self-report rating inventory that measures the severity of symptoms accompanying depression. Each item has a minimum score of 0 and a maximum score of 3, with higher numbers consistent with more severe symptoms. The score of each item is summed to amount the overall BDI score, with a minimum score of 0 and a maximum score of 63. Higher BDI scores are consistent with more severe depression. Score of 16 or greater is consistent with clinical depression. Each participant completed the BDI every 2 weeks during each of the study phases (i.e., GnRH agonist alone, estradiol and progesterone) throughout the 6-month study. Outcome measures reported consist of the average of two BDI scores from each phase of the study: the last 4 weeks of the GnRH agonist alone (phase 1), during the 4-week long estradiol phase (phase 2: weeks 2 and 4 of estradiol) and the 4-week long progesterone phase (phase 2: weeks 2 and 4 of progesterone). | Phase 1: Weeks 6 and 8 or 10 and 12; Phase 2: Weeks 2 and 4 of estradiol or progesterone | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Behavior, Brain Function, Progesterone, Central Nervous System Function, gonadotropin-releasing hormone (GnRH) Agonist