The Effects of Reproductive Hormones on Mood and Behavior

NCT00001322 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 92017492-M-0174
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteers

Keywords

Behavior; Brain Function; Progesterone; Central Nervous System Function; gonadotropin-releasing hormone (GnRH) Agonist

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (3)

Phase 1 - Lupron

EXPERIMENTAL

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

Drug: Leuprolide Acetate 3.75

Phase 2, Arm 1 - Estradiol, then progesterone

EXPERIMENTAL

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; Drug: Estradiol; Drug: Progesterone; Drug: Placebo suppository; Drug: Placebo patch

Phase 2, Arm 2 - Progesterone, then estradiol

EXPERIMENTAL

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; Drug: Estradiol; Drug: Progesterone; Drug: Placebo suppository; Drug: Placebo patch

Interventions

Leuprolide Acetate 3.75 DRUG

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

Phase 1 - Lupron; Phase 2, Arm 1 - Estradiol, then progesterone; Phase 2, Arm 2 - Progesterone, then estradiol

Estradiol DRUG

Transdermal Estradiol, 100mcg/day by skin patch

Phase 2, Arm 1 - Estradiol, then progesterone; Phase 2, Arm 2 - Progesterone, then estradiol

Progesterone DRUG

Progesterone suppository, 200mg vaginally twice/day

Phase 2, Arm 1 - Estradiol, then progesterone; Phase 2, Arm 2 - Progesterone, then estradiol

Placebo suppository DRUG

Placebo suppository twice daily

Phase 2, Arm 1 - Estradiol, then progesterone; Phase 2, Arm 2 - Progesterone, then estradiol

Placebo patch DRUG

Placebo by skin patch

Phase 2, Arm 1 - Estradiol, then progesterone; Phase 2, Arm 2 - Progesterone, then estradiol

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (8)

• Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998 Jan 22;338(4):209-16. doi: 10.1056/NEJM199801223380401.

  PMID: 9435325 BACKGROUND

• Burgess LH, Handa RJ. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology. 1992 Sep;131(3):1261-9. doi: 10.1210/endo.131.3.1324155.

  PMID: 1324155 BACKGROUND

• Berman KF, Schmidt PJ, Rubinow DR, Danaceau MA, Van Horn JD, Esposito G, Ostrem JL, Weinberger DR. Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8836-41. doi: 10.1073/pnas.94.16.8836.

  PMID: 9238064 BACKGROUND

• Li HJ, Goff A, Rudzinskas SA, Jung Y, Dubey N, Hoffman J, Hipolito D, Mazzu M, Rubinow DR, Schmidt PJ, Goldman D. Altered estradiol-dependent cellular Ca2+ homeostasis and endoplasmic reticulum stress response in Premenstrual Dysphoric Disorder. Mol Psychiatry. 2021 Nov;26(11):6963-6974. doi: 10.1038/s41380-021-01144-8. Epub 2021 May 25.

  PMID: 34035477 DERIVED

• Di Florio A, Alexander D, Schmidt PJ, Rubinow DR. Progesterone and plasma metabolites in women with and in those without premenstrual dysphoric disorder. Depress Anxiety. 2018 Dec;35(12):1168-1177. doi: 10.1002/da.22827. Epub 2018 Sep 5.

  PMID: 30184299 DERIVED

• Nguyen TV, Reuter JM, Gaikwad NW, Rotroff DM, Kucera HR, Motsinger-Reif A, Smith CP, Nieman LK, Rubinow DR, Kaddurah-Daouk R, Schmidt PJ. The steroid metabolome in women with premenstrual dysphoric disorder during GnRH agonist-induced ovarian suppression: effects of estradiol and progesterone addback. Transl Psychiatry. 2017 Aug 8;7(8):e1193. doi: 10.1038/tp.2017.146.

  PMID: 28786978 DERIVED

• Wei SM, Baller EB, Kohn PD, Kippenhan JS, Kolachana B, Soldin SJ, Rubinow DR, Schmidt PJ, Berman KF. Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study. Mol Psychiatry. 2018 Apr;23(4):1066-1075. doi: 10.1038/mp.2017.72. Epub 2017 Apr 18.

  PMID: 28416813 DERIVED

• Dubey N, Hoffman JF, Schuebel K, Yuan Q, Martinez PE, Nieman LK, Rubinow DR, Schmidt PJ, Goldman D. The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder. Mol Psychiatry. 2017 Aug;22(8):1172-1184. doi: 10.1038/mp.2016.229. Epub 2017 Jan 3.

  PMID: 28044059 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Behavior

Interventions

Estradiol; Progesterone

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnenediones; Pregnenes; Pregnanes; Corpus Luteum Hormones; Progesterone Congeners

Results Point of Contact

• Title: Schmidt, Peter
• Organization: National Institute of Mental Health

peterschmidt@mail.nih.gov

+1 301 496 6120

Study Officials

• Peter J Schmidt, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 1999
• First Posted: November 4, 1999
• Study Start: June 9, 1994
• Primary Completion: March 3, 2020
• Study Completion: March 3, 2020
• Last Updated: March 22, 2022
• Results First Posted: February 24, 2022

Record last verified: 2021-02-25

Locations

US (1)