The purpose of this study is to examine the influence of estrogen and progesterone on mood 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.

Condition	Treatment or Intervention	Phase
Depressive Disorder Mood Disorder	Drug: Luprolide Acetate 3.75 mg	Phase II

Further Study Details: 

Expected Total Enrollment:  100

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, HPA axis function evaluation with social stress testing, brain imaging (3D PET, FMRI, MRS) and genetic studies.

Genders Eligible for Study:  Female

Criteria

INCLUSION CRITERIA:
Criteria for Patient Selection
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 18-40; 4) not pregnant and in good 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 symptoms 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 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.
EXCLUSION CRITERIA:
Results of Pap smear performed within one year of the onset of treatment will be obtained. 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.

Maryland
      National Institute of Mental Health (NIMH), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  900088; 90-M-0088
Record last reviewed:  February 27, 2004
Last Updated:  March 29, 2005
Record first received:  November 3, 1999
ClinicalTrials.gov Identifier:  NCT00001259
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08