A Treatment Study for Premenstrual Syndrome (PMS)

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 PET, FMRI, MRS) and
genetic studies including induced pluripotent cells.

- 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
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 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.