A Treatment Study for Premenstrual Syndrome (PMS)
Condition: Premenstrual Syndrome; Menstruation Disturbances
MeSH terms: Syndrome; Premenstrual Syndrome; Menstruation Disturbances
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Leuprolide; Estradiol Patches; Progesterone; Placebo patch; Placebo injection; Placebo suppository
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Depression; Menstrual Cycle; Gonadal Steroids; Estradiol; Progesterone; Mood Disorders