A Treatment Study for Premenstrual Syndrome (PMS)
Condition: Premenstrual Syndrome; Menstruation Disturbances
MeSH terms: Syndrome; Premenstrual Syndrome; Menstruation Disturbances
Intervention: Leuprolide; Estradiol Patches; Progesterone; Placebo patch; Placebo injection; Placebo suppository
Intervention description: Eight to 12 weeks of GnRH agonist, Leuprolide Acetate 3.75 mg given intramuscularly monthly; Transdermal Estradiol, 100mcg/day by skin patch; Progesterone suppository, 200mg vaginally twice/day; Placebo by skin patch; Placebo given intramuscularly monthly; Placebo vaginal suppository
Intervention MeSH terms: Leuprolide; Estradiol; Progesterone
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 60.0
Sex: Female
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: No
Keywords: Depression; Menstrual Cycle; Gonadal Steroids; Estradiol; Progesterone; Mood Disorders

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.
    

Eligibility 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.