Hormonal Causes of Menstrual-Related Mood Disorders
Condition: Mood Disorders; Depression
MeSH terms: Depression; Mood Disorders
Study type: Observational

Summary: 
      This study will explore possible hormonal causes of menstrual-related mood disorders (MRMD)
      by stopping the menstrual cycle with a drug called Lupron and then giving in sequence two
      menstrual cycle hormones, progesterone and estrogen. The study will first evaluate Lupron's
      effectiveness in treating MRMD and will then examine the effects of giving estrogen and
      progesterone on mood and behavior. In addition, positron emission tomography (PET) and
      magnetic resonance imaging (MRI) will be used to study serotonin receptors and transporters -
      molecules in the brain that are thought to play a major role in mood changes related to the
      menstrual cycle.

      Menstruating women between 18 and 50 years of age who are in good health, not pregnant, and
      not taking medications may be eligible for this study. Women with MRMD must have had at least
      moderately severe MRMD or behavioral disturbances for at least 6 months within 2 years of
      entering the study. Healthy controls must have no history of MRMD or behavioral disturbances.
      Candidates undergo physical and neurological examinations, chest x-ray, electrocardiogram,
      and blood and urine tests. Results of a recent Pap smear (no longer than 12 months before
      beginning the study) must be available.

      Participants undergo the following tests and procedures:

        -  Drug treatment: Lupron is injected into a muscle once a month for 5 months. After the
           second month, participants receive estrogen or progesterone, or both, daily. Estrogen is
           delivered through a skin patch (20 micrograms per day) and the progesterone is taken as
           a rectal or vaginal suppository twice a day for the remaining 12 weeks of the study.
           Every day, all participants wear a skin patch and insert two suppositories, but at some
           point during the 12 weeks, active medication is replaced with placebo to allow the drugs
           to wash out of the body.

        -  Physical examination and blood draw: A physical examination and blood tests are done at
           the start of the study and several times during the study to assess general health,
           evaluate liver and kidney function, and measure blood cell counts.

        -  Response to treatment drugs: Responses to Lupron, estrogen, and progesterone are
           evaluated periodically with interviews and symptoms self-rating scales. Control subjects
           also take paper and pencil psychological tests.

        -  PET imaging: A total of six PET scans are done at three time points during hormone
           treatment. PET uses small amounts of a radioactive chemical called a tracer that
           "labels" active areas of the brain. For the procedure, the subject lies on the scanner
           bed. A special mask is fitted to the head and attached to the bed to help keep the
           subject's head still during the scan so the images will be clear. A brief scan is done
           just before the radioactive tracer is injected to help in analyzing the PET data. After
           the tracer is injected through a catheter (plastic tube) placed in the arm, pictures are
           taken for about 2 hours, during which the subject lies still on the scanner bed.

        -  MRI scan: MRI uses a magnetic field and radio waves to produce images of body tissues
           and organs. For this procedure, the patient lies on a table that is moved into the
           scanner (a narrow cylinder) and wears earplugs to muffle loud knocking and thumping
           sounds that occur during the scanning process. The procedure lasts about 1 hour.
    

Detailed description: 
      The central serotonergic (5HT) system is one of the candidate systems that may mediate the
      abnormal mood and behavioral response to ovarian steroids observed in women with
      menstrual-related mood disorders (MRMD). Numerous studies have attempted to measure 5HT
      system function in women with MRMD and controls; however, previous studies were restricted to
      the evaluation of indirect measures of 5HT function (e.g., platelet 5HT uptake or responses
      to serotonergic pharmacologic challenges). Radioligand imaging of specific components of the
      5HT system currently represents the most direct measure of central serotonergic function
      available. In this study we will image serotonergic measures during pharmacological
      conditions previously demonstrated to induce a remission and a subsequent provocation of mood
      symptoms in women with MRMD but not controls.

      This protocol has two outcome measures (5HT(1A) binding and SERT binding), two groups of
      subjects (women with MRMD and controls), and three distinct hormonal conditions
      (hypogonadism, estrogen replacement, and progesterone replacement). Our principal aim in this
      study is to investigate differences in the outcome measures in women with MRMD compared to
      controls. Our primary hypothesis is that 5HT(1A) binding will be decreased and SERT binding
      will be increased in women with MRMD. A secondary hypothesis is that women with MRMD, but not
      controls, will display reproductive steroid modulation of 5HT(1A) and SERT binding. This
      study will help test existing hypotheses about the pathophysiologic relevance of serotonin
      function in MRMD and the role of reproductive steroids in serotonergic regulation. First, we
      selected 5HT(1A) receptor binding as an outcome measure for the following reasons: 5HT(1A)
      function is modulated by both estradiol and progesterone, abnormalities of 5HT(1A) binding
      have been reported in both depressive and anxiety disorders as well as possibly MRMD, 5HT(1A)
      receptors have been identified as potential mediators of estradiol's antidepressant-like
      effects in the forced swim test, and the 5HT(1A) system is involved in the regulation of GABA
      activity abnormalities of which have been implicated in MRMD. Second, we selected SERT
      binding as an outcome measure for the following reasons: selective serotonin reuptake
      inhibitors, but not traditional antidepressants, are effective treatments for MRMD;
      abnormalities of SERT binding have been reported in depressive disorders in women,
      preliminary data suggest that women with MRMD are characterized by an elevated frequency of
      the long, more transcriptionally active polymorphism of the serotonin transporter (5HTTLPR)
      (Roca et al); women with MRMD have altered imipramine binding and platelet 5HT uptake
      compared to controls as well as altered platelet paroxetine binding (which normalize with
      successful treatment with GnRH agonist); and, finally, SERT message, binding and protein have
      been reported to be changed by ovarian steroids in preclinical studies.

      We hypothesize that the effects of hormonal condition on 5HT(1A) (receptor) binding will
      differ in patients and controls. Specifically, we anticipate that 5HT1A binding will be
      decreased in hippocampus and prefrontal cortex in patients with MRMD but not controls. Such a
      decrease, if a trait characteristic, will be demonstrable irrespective of hormonal state.
      However, as symptoms of MRMD are directly precipitated by estradiol or progesterone (see
      below), it is possible that symptoms are accompanied by state and steroid-dependent changes
      in 5HT(1A) binding and function. Consequently, our secondary hypothesis is that estradiol or
      progesterone induces changes in 5HT(1A) (receptor) binding in women with MRMD but not in
      control women.

      Similarly, we hypothesize that women with MRMD will have increased SERT binding activity
      compared to controls, consistent with the therapeutic efficacy of selective serotonin
      reuptake inhibitors in this condition. However, a secondary hypothesis is that estradiol or
      progesterone-induced changes in SERT binding will occur in a hormone-dependent and mood
      state-dependent manner. Specifically, consistent with the literature in rodents, acute
      changes in ovarian steroids will increase SERT binding in association with the induction of
      symptoms in women with MRMD but not controls.
    

Keywords: Gonadal Steroids; GnRH Agonist; Depression; Menstrual Cycle; Menstrually Related Mood Disorder; MRMD; Healthy Volunteer; HV