This study evaluates the effects of estrogen and progesterone on mood, the stress response, and brain function in healthy women.

The 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 healthy volunteer women without PMS.

This study will investigate effects of reproductive hormones by temporarily stopping the menstrual cycle with leuprolide acetate and then giving, in sequence, the menstrual cycle hormones progesterone and estrogen. Tests (such as brain imaging or stress testing, etc.) will be performed during the different hormonal conditions (low estrogen and progesterone, progesterone add-back, estrogen add-back). The results of these studies will be compared between women without PMS and women with PMS (see also protocol 90-M-0088).

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.

Evidence suggests that the gonadal steroids may exert clinically significant effects on central nervous system function. For example, the menstrual cycle may influence the occurrence of seizures in some female epileptics and the performance on certain cognitive tests. Central nervous system effects of gonadal steroids have been inferred largely from changes in behavior occurring in association with presumed changes in gonadal steroids during the normal menstrual cycle, during the administration of ovarian hormones, or in a gender-specific context. These inferences are, by definition, indirect and associational in nature and further are incapable of disentangling the effects of hormones which are simultaneously present in women of reproductive age. This study is designed to address those problems by comparing measures during Lupron-induced hypogonadism with those during replacement with estrogen or progesterone. On the basis of prior findings from our group and from others, we will be asking the following questions: 1) Does cognitive function differ as a function of gender (in concert with protocol # 94-M-0037) or of hormonal condition; 2) Is the decreased r-CBF that we observed in the prefrontal cortex during the hypogonadal state confirmed in individual women using new imaging techniques; 3) Will the mental rotation task, a sexually dimorphic cognitive task, better identify gonadal steroid related differences in brain r-CBF than tests of working memory; and 4) Do measures of hypothalamic-pituitary-adrenal axis responsivity differ as a function of hormonal condition. Additionally, this protocol will serve as a control study for protocol # 90-M-0088 and a companion protocol for 94-M-0037.

• Schmidt PJ, Nieman LK, Danaceau MA, Adams LF, Rubinow DR. Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med. 1998 Jan 22;338(4):209-16.
• Burgess LH, Handa RJ. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology. 1992 Sep;131(3):1261-9.
• Berman KF, Schmidt PJ, Rubinow DR, Danaceau MA, Van Horn JD, Esposito G, Ostrem JL, Weinberger DR. Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8836-41.

• ELIGIBILITY CRITERIA:

Volunteers participating in this study will be women between the ages of 18 and 55 years, not pregnant, in good medical health, medication free, and who have no history of menstrual-related mood or behavioral disturbances. The absence of menstrual-related mood disorders will be prospectively confirmed during a two month period prior to the study entry when subjects will complete daily visual analogue rating scales monitoring both mood and behavior as outlined in NIMH protocol # 81-M-0126. Additionally, we will recruit a subsample of 20 asymptomatic women who will meet all inclusion and exclusion criteria in this protocol except they will have a history of a past major depressive episode.

The Structured Clinical Interview for DSM-IV will be administered to controls prior to study entry. Any control with a current or past axis I psychiatric diagnosis will be excluded from participating in this protocol (except in the subgroup of asymptomatic women with a past major depressive episode who participate in this protocol).

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

The following conditions will constitute contraindications to treatment with hormonal therapy and will preclude a subject's participation in this protocol: 1) history consistent with endometriosis; 2) diagnosis of ill-defined, obscure pelvic lesions, particularly undiagnosed ovarian enlargement; 3) hepatic disease as manifested by abnormal liver function tests; 4) history of mammary carcinoma; 5) history of pulmonary embolism or phlebothrombosis; 6) undiagnosed vaginal bleeding; 7) porphyria; 8) diabetes mellitus; 9) history of malignant melanoma; 10) cholecystitis or pancreatitis; 11) cardiovascular or renal disease; 12) pregnancy; and 13) a past or current Axis I psychiatric illness (with the exception of those women with a past major depression who will be studied in this protocol). Further, subjects will be warned not to become pregnant during the study and will be required to employ barrier contraceptive methods. Finally, participants who have an active condition that places them at an increased risk for osteoporosis will be excluded from this protocol.