Premenstrual Syndrome, Menstruation Disturbances
Conditions
Keywords
Depression, Menstrual Cycle, Gonadal Steroids, Estradiol, Progesterone, Mood Disorders
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.
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.
Interventions
DRUGLeuprolide
Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly
Transdermal Estradiol, 100mcg/day by skin patch
DRUGProgesterone
Progesterone suppository, 200mg vaginally twice/day
DRUGPlacebo patch
Placebo by skin patch
DRUGPlacebo injection
Placebo given intramuscularly monthly
Placebo vaginal suppository
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: 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: 1. 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; 2. symptoms should have a sudden onset and offset; 3. age 18-50; 4. not pregnant and in good medical health; 5. 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.
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 * 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. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Beck Depression Inventory Score | Placebo: Weeks 6 and 8 of Placebo; Lupron only: Weeks 6 and 8 or 10 and 12; Estradiol or progesterone: Weeks 2 and 4 | 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). |
Countries
United States
Participant flow
Recruitment details
One participant signed consent but withdrew prior to study start
Pre-assignment details
8 of 46 participants who completed Study 2, Phase 1 did not proceed to Study 2, Phase 2.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 8 weeks of placebo (P) injections (one injection per month) | 10 |
| GnRH Agonist Injections (Lupron-L Only) 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 | 49 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Study 2 | Adverse Event | 0 | 0 | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | GnRH Agonist Injections (Lupron-L Only) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 49 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 47 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 15 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 10 Participants | 29 Participants | 39 Participants |
| Sex: Female, Male Female | 10 Participants | 49 Participants | 59 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 58 | 0 / 48 | 0 / 48 |
| other Total, other adverse events | 0 / 10 | 2 / 58 | 3 / 48 | 0 / 48 |
| serious Total, serious adverse events | 0 / 10 | 0 / 58 | 0 / 48 | 0 / 48 |
Outcome results
Primary
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).
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
Population: Analyses included comparison of participants mean BDI scores during each phase of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Beck Depression Inventory Score | 2.6 score on a scale | Standard Deviation 2.6 |
| GnRH Agonist Injections (Lupron-L Only) | Mean Beck Depression Inventory Score | 3.0 score on a scale | Standard Deviation 3.8 |
| Estradiol | Mean Beck Depression Inventory Score | 5.3 score on a scale | Standard Deviation 5.3 |
| Progesterone | Mean Beck Depression Inventory Score | 3.6 score on a scale | Standard Deviation 5.7 |