Healthy Volunteers
Conditions
Keywords
Behavior, Brain Function, Progesterone, Central Nervous System Function, gonadotropin-releasing hormone (GnRH) Agonist
Brief 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.
Interventions
DRUGLeuprolide Acetate 3.75
Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly
DRUGEstradiol
Transdermal Estradiol, 100mcg/day by skin patch
DRUGProgesterone
Progesterone suppository, 200mg vaginally twice/day
Placebo suppository twice daily
DRUGPlacebo patch
Placebo by skin patch
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Beck Depression Inventory Score | Phase 1: Weeks 6 and 8 or 10 and 12; Phase 2: Weeks 2 and 4 of estradiol or progesterone | 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). |
Countries
United States
Participant flow
Pre-assignment details
4 participants were screen failures, 4 withdrew prior to start of study and 92 started and completed phase 1 the study. 10 participants did not proceed to phase 2 (crossover arm) of the study.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 - Lupron Eight to 12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly before randomization to estradiol or progesterone arm in the crossover phase of the study. | 92 |
| Total | 92 |
Baseline characteristics
| Characteristic | Phase 1 - Lupron |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 92 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 82 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 27 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 55 Participants |
| Sex: Female, Male Female | 92 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 92 | 0 / 82 | 0 / 82 |
| other Total, other adverse events | 1 / 92 | 1 / 82 | 0 / 82 |
| serious Total, serious adverse events | 1 / 92 | 0 / 82 | 0 / 82 |
Outcome results
Primary
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).
Time frame: Phase 1: Weeks 6 and 8 or 10 and 12; Phase 2: Weeks 2 and 4 of estradiol or progesterone
Population: Analyses included comparison of mean BDI scores during each phase of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1 - Lupron | Mean Beck Depression Inventory Score | 1.4 Units on a scale | Standard Deviation 2.1 |
| Phase 2 - Estradiol | Mean Beck Depression Inventory Score | 1 Units on a scale | Standard Deviation 2 |
| Phase 2 - Progesterone | Mean Beck Depression Inventory Score | 1.1 Units on a scale | Standard Deviation 1.8 |