The Effects of Reproductive Hormones on Mood and Behavior

Sponsor
National Institute of Mental Health (NIMH) (NIH)
Overall Status
Completed
CT.gov ID
NCT00001322
Collaborator
(none)
100
1
3
308.8
0.3

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
100 participants
Allocation:
Non-Randomized
Intervention Model:
Crossover Assignment
Primary Purpose:
Basic Science
Official Title:
The Central Nervous System Effects of Pharmacologically Induced Hypogonadotropic Hypogonadism With and Without Estrogen and Progesterone Replacement
Actual Study Start Date :
Jun 9, 1994
Actual Primary Completion Date :
Mar 3, 2020
Actual Study Completion Date :
Mar 3, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase 1 - Lupron

Eight to 12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly.

Drug: Leuprolide Acetate 3.75
Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly

Experimental: Phase 2, Arm 1 - Estradiol, then progesterone

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
Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly

Drug: Estradiol
Transdermal Estradiol, 100mcg/day by skin patch

Drug: Progesterone
Progesterone suppository, 200mg vaginally twice/day

Drug: Placebo suppository
Placebo suppository twice daily

Drug: Placebo patch
Placebo by skin patch

Experimental: Phase 2, Arm 2 - Progesterone, then estradiol

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
Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly

Drug: Estradiol
Transdermal Estradiol, 100mcg/day by skin patch

Drug: Progesterone
Progesterone suppository, 200mg vaginally twice/day

Drug: Placebo suppository
Placebo suppository twice daily

Drug: Placebo patch
Placebo by skin patch

Outcome Measures

Primary Outcome Measures

  1. 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).

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 50 Years
Sexes Eligible for Study:
Female
Accepts Healthy Volunteers:
Yes
  • 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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland United States 20892

Sponsors and Collaborators

  • National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Peter J Schmidt, M.D., National Institute of Mental Health (NIMH)

Study Documents (Full-Text)

More Information

Additional Information:

Publications

Responsible Party:
National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier:
NCT00001322
Other Study ID Numbers:
  • 920174
  • 92-M-0174
First Posted:
Nov 4, 1999
Last Update Posted:
Mar 22, 2022
Last Verified:
Feb 25, 2021
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by National Institute of Mental Health (NIMH)
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail 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.
Arm/Group Title Phase 1 - Lupron Phase 2, Arm 1 - Estradiol, Then Progesterone Phase 2, Arm 2 - Progesterone, Then Estradiol
Arm/Group Description Eight to 12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly. 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. 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).
Period Title: Phase 1 - Lupron Only
STARTED 92 0 0
COMPLETED 92 0 0
NOT COMPLETED 0 0 0
Period Title: Phase 1 - Lupron Only
STARTED 0 42 40
COMPLETED 0 42 40
NOT COMPLETED 0 0 0
Period Title: Phase 1 - Lupron Only
STARTED 0 42 40
COMPLETED 0 42 40
NOT COMPLETED 0 0 0

Baseline Characteristics

Arm/Group Title Phase 1 - Lupron
Arm/Group Description 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.
Overall Participants 92
Age (Count of Participants)
<=18 years
0
0%
Between 18 and 65 years
92
100%
>=65 years
0
0%
Sex: Female, Male (Count of Participants)
Female
92
100%
Male
0
0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
6
6.5%
Not Hispanic or Latino
82
89.1%
Unknown or Not Reported
4
4.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
Asian
3
3.3%
Native Hawaiian or Other Pacific Islander
0
0%
Black or African American
27
29.3%
White
55
59.8%
More than one race
1
1.1%
Unknown or Not Reported
6
6.5%

Outcome Measures

1. Primary Outcome
Title Mean Beck Depression Inventory Score
Description 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

Outcome Measure Data

Analysis Population Description
Analyses included comparison of mean BDI scores during each phase of the study
Arm/Group Title Phase 1 - Lupron Phase 2 - Estradiol Phase 2 - Progesterone
Arm/Group Description Eight to 12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly. 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). 5 weeks of Progesterone suppositories (200mg vaginally twice/day) and placebo patches.
Measure Participants 92 82 82
Mean (Standard Deviation) [Units on a scale]
1.4
(2.1)
1
(2)
1.1
(1.8)

Adverse Events

Time Frame 6 months
Adverse Event Reporting Description
Arm/Group Title Lupron Phase 2 - Estradiol Phase 2 - Progesterone
Arm/Group Description Eight to 12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly. 4 weeks of transdermal Estradiol (100mcg/day by skin patch) 5 weeks of Progesterone suppositories (200mg vaginally twice/day)
All Cause Mortality
Lupron Phase 2 - Estradiol Phase 2 - Progesterone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/92 (0%) 0/82 (0%) 0/82 (0%)
Serious Adverse Events
Lupron Phase 2 - Estradiol Phase 2 - Progesterone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1/92 (1.1%) 0/82 (0%) 0/82 (0%)
Reproductive system and breast disorders
Breast fibroma 1/92 (1.1%) 0/82 (0%) 0/82 (0%)
Other (Not Including Serious) Adverse Events
Lupron Phase 2 - Estradiol Phase 2 - Progesterone
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 1/92 (1.1%) 1/82 (1.2%) 0/82 (0%)
Gastrointestinal disorders
Epigastric discomfort 1/92 (1.1%) 0/82 (0%) 0/82 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity 0/92 (0%) 1/82 (1.2%) 0/82 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Schmidt, Peter
Organization National Institute of Mental Health
Phone +1 301 496 6120
Email peterschmidt@mail.nih.gov
Responsible Party:
National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier:
NCT00001322
Other Study ID Numbers:
  • 920174
  • 92-M-0174
First Posted:
Nov 4, 1999
Last Update Posted:
Mar 22, 2022
Last Verified:
Feb 25, 2021