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Premenstrual SyndromePhase 1NCT00001259

A Treatment Study for Premenstrual Syndrome (PMS)

A Phase 1 study testing Leuprolide, Estradiol Patches and Progesterone in people with Premenstrual Syndrome and Menstruation Disturbances, run by National Institute of Mental Health (NIMH) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 45 years, women only
What is being tested?
Leuprolide, Estradiol Patches and Progesterone
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
60 participants
Where
1 siteUnited States
Study dates
11 Aug 1992to 6 Feb 2020
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 45 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.
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  • 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:
  • Blood
  • Complete blood count; thyroid function tests; cortisol; renal function tests, such as blood urea nitrogen (BUN) and creatinine; electrolytes; glucose; liver function tests.
  • 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.

Who cannot join

  • 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,
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  • 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.
  • 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
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: The Treatment of Menstrually-Related Mood Disorders With the Gonadotropin Releasing Hormone (GnRH) Agonist, Depot Leuprolide Acetate (Lupron)

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.

Read more

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.

Read the detailed description

This protocol is designed to accompany Clinical Protocol # 81-M-0126, The Phenomenology and Biophysiology of Menstrually-Related Mood and Behavioral Disorders. Its original purposes were as follows: 1) to evaluate the efficacy of the gonadotropin releasing hormone (GnRH) agonist depot leuprolide acetate (Lupron) in the treatment of menstrually-related mood disorders (MRMD) by determining whether mood and behavioral symptoms are eliminated when the cyclic secretion of both gonadotropic hormones and gonadal steroids is suppressed, and 2) to determine the possible relevance of gonadal steroids to affective state by sequentially replacing estradiol and progesterone during continued GnRH suppression in those patients whose premenstrual symptoms remit following administration of the GnRH agonist. We observed that GnRH agonist induced ovarian suppression was an effective treatment compared to placebo in women with MRMD. Additionally, women with MRMD but not asymptomatic controls (participating in companion protocol 92-M-0174) experienced a recurrence of mood and behavioral symptoms when either estradiol or progesterone (but not placebo) was added back. These data suggest that women with MRMD have a differential sensitivity to the mood destabilizing effects of gonadal steroids.

Having established that women with MRMD show a differential behavioral response to estrogen and progesterone, we now hope to identify the underlying mechanisms and physiologic concomitants of the differential behavioral sensitivity by performing studies (described in companion protocols) under the three hormonal conditions created by this protocol, and comparing results obtained with those seen in normal controls (Protocol #92-M-0174). Planned studies include the following: cognitive testing, brain imaging [(3D-positron emission tomography (PET), functional magnetic resonance imaging (FMRI), magnetic resonance spectroscopy (MRS)] and genetic studies including induced pluripotent cells.

Being tested
Leuprolide, Estradiol Patches, Progesterone, Placebo patch, Placebo injection
Keywords
Depression, Menstrual Cycle, Gonadal Steroids, Estradiol, Progesterone, Mood Disorders
Medical subject headings
Premenstrual Syndrome, Menstruation Disturbances, Depression, Mood Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LeuprolideDrug

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

  • Estradiol PatchesDrug

    Transdermal Estradiol, 100mcg/day by skin patch

  • ProgesteroneDrug

    Progesterone suppository, 200mg vaginally twice/day

  • Placebo patchDrug

    Placebo by skin patch

  • Placebo injectionDrug

    Placebo given intramuscularly monthly

  • Placebo suppositoryDrug

    Placebo vaginal suppository

Study groups in NCT00001259
Study groupRoleWhat they receive
Study 1, Phase 1, Assignment 1 - PlaceboPlacebo comparatorAs 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.
Receives: Drug: Placebo injection
Study 1, Phase 1, Assignment 2 - GnRH agonist injections (Lupron-L only)ExperimentalAs 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.
Receives: Drug: Leuprolide
Study 1, Phase 2, Arm 1 - Estradiol, then progesteroneExperimental12 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.
Receives: Drug: Leuprolide; Drug: Estradiol Patches; Drug: Progesterone; Drug: Placebo patch; Drug: Placebo suppository
Study 1, Phase 2, Arm 2 - Progesterone, then estradiolExperimental12 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).
Receives: Drug: Leuprolide; Drug: Estradiol Patches; Drug: Progesterone; Drug: Placebo patch; Drug: Placebo suppository
Study 2, Phase 1 - GnRH agonist injections (Lupron-L only)ExperimentalEight to 12 weeks of GnRH agonist treatment 3.75 mg given intramuscularly monthly.
Receives: Drug: Leuprolide
Study 2, Phase 2, Arm 1 - Estradiol, then progesteroneExperimental12 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.
Receives: Drug: Leuprolide; Drug: Estradiol Patches; Drug: Progesterone; Drug: Placebo patch; Drug: Placebo suppository
Study 2, Phase 2, Arm 2 - Progesterone, then estradiolExperimental12 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).
Receives: Drug: Leuprolide; Drug: Estradiol Patches; Drug: Progesterone; Drug: Placebo patch; Drug: Placebo suppository

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Nov 1999 (estimated)
  2. Study start11 Aug 1992
  3. Primary completion6 Feb 2020
  4. Study completion6 Feb 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Crossover
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
60 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00001259
Sponsor's protocol ID
900088
Other IDs
90-M-0088
Status last verified
4 Jan 2021
First submitted
3 Nov 1999
Last updated
2 Mar 2023
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 2962499

  • 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.

    PubMed 2011161

  • 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.

    PubMed 9435325

  • 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.

    PubMed 34035477

  • 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.

    PubMed 30184299

  • 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.

    PubMed 28786978

  • 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.

    PubMed 28044059

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Leuprolide, Estradiol Patches and Progesterone in people with Premenstrual Syndrome and Menstruation Disturbances, run by National Institute of Mental Health (NIMH) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 2 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean Beck Depression Inventory Score (time frame: Placebo: Weeks 6 and 8 of Placebo; Lupron only: Weeks 6 and 8 or 10 and 12; Estradiol or progesterone: Weeks 2 and 4). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00001259, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Mar 2023.

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