Protocol Number: 05-M-0059

Title:

5HT1A and SERT Imaging During Pharmacologically Induced Hypogonadotropic Hypogonadism With and Without Estrogen and Progesterone Replacement

Number:

05-M-0059

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 45 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.

Sponsoring Institute:

National Institute of Mental Health (NIMH)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Female

Referral Letter Required: No

Population Exclusion(s): Male

Eligibility Criteria:

INCLUSION CRITERIA:

Women who meet the criteria for MRMD will have participated in Protocol No. 81-M-0126, The Phenomenology and Biophysiology of Menstrually-related Mood and Behavioral Disorders". In brief, these criteria include:

-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.

-Symptoms should have a sudden onset and offset.

-age 18-45.

-Not pregnant and in good medical health.

-Medication free.

-No prior DSM-IV Axis I disorder.

-No prior history of treatment with antidepressant medications

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.

Asymptomatic controls participating in this study will be women between the ages of 18 and 45 years, not pregnant, in good medical health, medication free, and who have no history of menstrual-related mood or behavioral disturbances.

All subjects will be required to use non-hormonal forms of birth control (e.g., barrier methods) to avoid pregnancy during this study.

EXCLUSION CRITERIA:

The following conditions will constitute contraindications to treatment with hormonal therapy and will preclude a subject's participation in this protocol.

-History consistent with endometriosis.

-Diagnosis of ill-defined, obscure pelvic lesions, particularly undiagnosed ovarian enlargement.

-Hepatic disease as manifested by abnormal liver function test.

-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.

Further, subjects will be warned not to become pregnant during the study and will be required to employ barrier contraceptive methods.

Any patient or control with a current and any control with a past Axis I psychiatric diagnosis will be excluded from participating in this protocol.

Subjects taking birth control pills or diuretics will be excluded from the study.

Special Instructions:

Currently Not Provided

Keywords:

PMS

PMDD

Gonadal Steroids

Serotonin 1A Receptor

Serotonin Transporter Protein

GnRH

Estradiol

Progesterone

GnRH Agonist

Recruitment Keyword(s):

Menstrually Related Mood Disorder

MRMD

Healthy Volunteer

HV

Condition(s):

Mood Disorders

Premenstrual syndrome

PMS

PMDD

Depression

Healthy

Investigational Drug(s):

(F18) FCWAY

Investigational Device(s):

None

Intervention(s):

None

Supporting Site:

National Institute of Mental Health

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

McEwen BS, Alves SE. Estrogen actions in the central nervous system. Endocr Rev. 1999 Jun;20(3):279-307. Review. No abstract available.

Osterlund MK, Halldin C, Hurd YL. Effects of chronic 17beta-estradiol treatment on the serotonin 5-HT(1A) receptor mRNA and binding levels in the rat brain. Synapse. 2000 Jan;35(1):39-44.

Lu NZ, Bethea CL.Ovarian steroid regulation of 5-HT1A receptor binding and G protein activation in female monkeys, Neuropsychopharmacology. 2002 Jul;27(1):12-24.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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