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The Effects of Reproductive Hormones on Mood and Behavior

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00001322
Recruitment Status : Completed
First Posted : November 4, 1999
Results First Posted : February 24, 2022
Last Update Posted : March 22, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

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
Healthy Volunteers Drug: Leuprolide Acetate 3.75 Drug: Estradiol Drug: Progesterone Drug: Placebo suppository Drug: Placebo patch 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.

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Study Type : Interventional  (Clinical Trial)
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 : June 9, 1994
Actual Primary Completion Date : March 3, 2020
Actual Study Completion Date : March 3, 2020

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Mean Beck Depression Inventory Score [ Time Frame: 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).




Information from the National Library of Medicine

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00001322


Locations
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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Peter J Schmidt, M.D. National Institute of Mental Health (NIMH)
  Study Documents (Full-Text)

Documents provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT00001322    
Other Study ID Numbers: 920174
92-M-0174
First Posted: November 4, 1999    Key Record Dates
Results First Posted: February 24, 2022
Last Update Posted: March 22, 2022
Last Verified: February 25, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Behavior
Brain Function
Progesterone
Central Nervous System Function
gonadotropin-releasing hormone (GnRH) Agonist
Additional relevant MeSH terms:
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Leuprolide
Estradiol
Progesterone
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Reproductive Control Agents
Progestins
Fertility Agents, Female
Fertility Agents
Antineoplastic Agents, Hormonal
Antineoplastic Agents