A Treatment Study for Premenstrual Syndrome (PMS)

NCT00001259 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 90008890-M-0088
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

This study examines the effects of estrogen and progesterone on mood, the stress response, and brain function and behavior in women with premenstrual syndrome. Previously this study has demonstrated leuprolide acetate (Lupron (Registered Trademark)) to be an effective treatment for PMS. The current 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 women with PMS. PMS is a condition characterized by changes in mood and behavior that occur during the second phase of the normal menstrual cycle (luteal phase). This study will investigate possible hormonal causes of PMS by temporarily stopping the menstrual cycle with leuprolide acetate and then giving, in sequence, the menstrual cycle hormones progesterone and estrogen. The results of these hormonal studies will be compared between women with PMS and healthy volunteers without PMS (see also protocol 92-M-0174). 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

Premenstrual Syndrome; Menstruation Disturbances

Keywords

Depression; Menstrual Cycle; Gonadal Steroids; Estradiol; Progesterone; Mood Disorders

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 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; weeks 6 and 8 of placebo alone; during the 4-week long estradiol phase (weeks 2 and 4 of estradiol) and the 4-week long progesterone phase (weeks 2 and 4 of progesterone).

  Placebo: Weeks 6 and 8 of Placebo; Lupron only: Weeks 6 and 8 or 10 and 12; Estradiol or progesterone: Weeks 2 and 4

Study Arms (7)

Study 1, Phase 1, Assignment 1 - Placebo

PLACEBO COMPARATOR

As part of double Blind randomized trial, participants in Assignment 1 were randomized to 8 weeks of placebo (P) injections (1 injection per month). These participants then continued on to Study 2 after completion of 8 weeks of placebo injections.

Drug: Placebo injection

Study 1, Phase 1, Assignment 2 - GnRH agonist injections (Lupron-L only)

EXPERIMENTAL

As part of double Blind randomized trial, participants in Assignment 2 were randomized to 8 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly. Those who exhibited a remission of symptoms after 8 weeks continued on to receive one more month of GnRH agonist treatment (12 weeks total) and then entered Study 1, Phase 2.

Drug: Leuprolide

Study 1, 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; Drug: Estradiol Patches; Drug: Progesterone; Drug: Placebo patch; Drug: Placebo suppository

Study 1, 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; Drug: Estradiol Patches; Drug: Progesterone; Drug: Placebo patch; Drug: Placebo suppository

Study 2, Phase 1 - GnRH agonist injections (Lupron-L only)

EXPERIMENTAL

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

Drug: Leuprolide

Study 2, 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; Drug: Estradiol Patches; Drug: Progesterone; Drug: Placebo patch; Drug: Placebo suppository

Study 2, 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; Drug: Estradiol Patches; Drug: Progesterone; Drug: Placebo patch; Drug: Placebo suppository

Interventions

Leuprolide DRUG

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

Study 1, Phase 1, Assignment 2 - GnRH agonist injections (Lupron-L only); Study 1, Phase 2, Arm 1 - Estradiol, then progesterone; Study 1, Phase 2, Arm 2 - Progesterone, then estradiol; Study 2, Phase 1 - GnRH agonist injections (Lupron-L only); Study 2, Phase 2, Arm 1 - Estradiol, then progesterone; Study 2, Phase 2, Arm 2 - Progesterone, then estradiol

Estradiol Patches DRUG

Transdermal Estradiol, 100mcg/day by skin patch

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

Progesterone DRUG

Progesterone suppository, 200mg vaginally twice/day

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

Placebo patch DRUG

Placebo by skin patch

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

Placebo injection DRUG

Placebo given intramuscularly monthly

Study 1, Phase 1, Assignment 1 - Placebo

Placebo suppository DRUG

Placebo vaginal suppository

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

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• The subjects of this study will be women who meet the criteria for MRMD as described in Protocol No. 81-M-0126, 'The Phenomenology and Biophysiology of Menstrually-related Mood and Behavioral Disorders.' In brief, these criteria include:
• history within the last two years of at least six months with menstrually-related mood or behavioral disturbances of at least moderate severity--i.e., disturbances that are distinct in appearance and associated with a notable degree of subjective distress;
• symptoms should have a sudden onset and offset;
• age 18-50;
• not pregnant and in good medical health;
• medication free.
• All patients participating in this protocol will have already participated in Protocol No. 81-M-0126 and will have a prospectively confirmed and predictable relationship between their mood disorder and the premenstrual phase of the menstrual cycle, i.e., a 30% change in severity of symptom self rating scales, relative to the range of the scale employed, during the seven days premenstrually compared with the seven days post-menstrually in two out of three months of study.
• The Schedule for Affective Disorders and Schizophrenia will be administered to all patients prior to study entry. Any patient with a current axis I psychiatric diagnosis will be excluded from participating in this protocol.
• Prior to treatment, a complete physical and neurological examination will have been performed and the following routine laboratory data obtained:
• A. Blood
• Complete blood count; thyroid function tests; cortisol; renal function tests, such as blood urea nitrogen (BUN) and creatinine; electrolytes; glucose; liver function tests.
• B. Urine
• Routine urinalysis; urine pregnancy test.
• GnRH agonist will not be administered to any subject with significant clinical or laboratory abnormalities. The blood tests and urinalysis will be repeated 2 weeks after GnRH agonist administration to rule out any evidence of acute renal, hepatic or hematologic toxicity.
• Results of Pap smear performed within one year of the onset of treatment will be obtained.

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
• 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. Specifically, we will exclude any woman with an elevated plasma follicle stimulating hormone (FSH) level (\>= 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 (7)

• Rubinow DR, Hoban MC, Grover GN, Galloway DS, Roy-Byrne P, Andersen R, Merriam GR. Changes in plasma hormones across the menstrual cycle in patients with menstrually related mood disorder and in control subjects. Am J Obstet Gynecol. 1988 Jan;158(1):5-11. doi: 10.1016/0002-9378(88)90765-x.

  PMID: 2962499 BACKGROUND

• Schmidt PJ, Nieman LK, Grover GN, Muller KL, Merriam GR, Rubinow DR. Lack of effect of induced menses on symptoms in women with premenstrual syndrome. N Engl J Med. 1991 Apr 25;324(17):1174-9. doi: 10.1056/NEJM199104253241705.

  PMID: 2011161 BACKGROUND

• 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

• 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

• 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

Premenstrual Syndrome; Menstruation Disturbances; Depression; Mood Disorders

Interventions

Leuprolide; Progesterone

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Behavioral Symptoms; Behavior; Mental Disorders

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Progesterone Congeners; Gonadal Steroid Hormones

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
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 3, 1999
• First Posted: November 4, 1999
• Study Start: August 11, 1992
• Primary Completion: February 6, 2020
• Study Completion: February 6, 2020
• Last Updated: March 2, 2023
• Results First Posted: March 2, 2023

Record last verified: 2021-01-04

Locations

US (1)