Estrogen and Serotonin on Changing Brain Chemistry

The overarching purpose of this study is to further our understanding of the individual and
interactive effects of the hormone estrogen and the neurotransmitter serotonin on certain
aspects of cognition and brain activation in menopausal women ages 48 to 60 years. Women will
undergo cognitive testing and fMRI sessions both before and after 6 weeks of either estrogen
or placebo administration. We will recruit women who are across the first 10 years since
their last menstrual period so that the investigators can gather information regarding the
potential impact of time since menopause on our outcomes of interest. We anticipate that
findings from this study will help scientist and clinicians to refine their use of estrogen
therapy in menopausal women. In addition, should the role of serotonin be of utmost
importance for maintenance of healthy cognition, these data aid future drug development to
preserve health cognition and/or to treat dementias in which serotonin is an important
factor. This proposal is both novel and timely as results from this study are likely to
provide information critical to the on-going discussion regarding the risks and benefits of
ET use in menopausal women.

Key Inclusion Criteria:

Women ages 48 to 60 (at the time of enrollment) will be eligible for this study if they:

1. Have no history of major depressive disorder, generalized anxiety disorder, and or
panic disorder within the last three years according to the Structured Clinical
Interview for DSM-IV (Diagnostic and Statistical Manual) Axis I Disorders (SCID-NP)
(First et al., 1995), or a history of major depressive disorder, generalized anxiety
disorder, and or panic disorder greater than 3 years ago, but now resolved according
to the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-NP) (First et
al., 1995);

2. Have no substance abuse disorders (this includes alcohol, prescription, and illicit
substances) within the last three years according to the Structured Clinical Interview
for DSM-IV Axis I Disorders (SCID-NP) (First et al., 1995);

3. Subject has history of substance abuse disorders (this includes alcohol, prescription,
and illicit substances) >3 years ago but the period of abuse did not last more than 5
years according to the Structured Clinical Interview for DSM-IV Axis I Disorders
(SCID-NP) (First et al., 1995);

4. No first-degree relative (excluding children) with a known psychotic disorder or
bi-polar disorder per patient report. Psychotic disorders include schizophrenia,
schizoaffective disorder, psychotic disorder;

5. Have not taken hormonal contraceptives, ET (estrogen therapy) or HT (hormone therapy)
for at least 3 months as per self-report;

6. Are within 10 years and 11 months of LMP (last menstrual period) as per self-report;

7. Have a follicular stimulating hormone level (FSH) of >30 IU/ml as per hormone testing
results; women with an FSH below 30 will have the option to undergo an additional
blood draw between 3-9 months following the initial blood draw (see note 2 below);

8. Are able to give written informed consent;

9. Provide written documentation of having had a normal mammogram and a PAP smear
(Papanicolaou test) within the recommended timeframe as defined by the American
College of Obstetricians and Gynecologists (ACOG) - please visit their website for
current recommendations;

10. Must have clear urine toxicology screen upon recruitment;

11. Are fluent in written and spoken English;

12. Are right-handed.

Key Exclusion Criteria

1. Currently smoking more than 10 cigarettes/day by self report;

2. History of clinical CVD (cardiovascular disease) including myocardial infarction,
angina, or congestive heart failure;

3. History of thromboembolic disease (deep vein thrombosis or pulmonary embolus);

4. History of untreated (no cholecystectomy) gallbladder disease as per self-report
during PE;

5. History of triglyceridemia by subject report;

6. Undiagnosed vaginal bleeding as per self-report;

7. History of estrogen responsive cancers as per self-report;

8. Known hypercoagulable state (thrombophilias) as per self-report;

9. Severe lactose intolerance (sham depletion requires lactose/microcellulose
administration; mild to moderate lactose intolerance is acceptable); Dr. Epperson will
make the final decision whether an individual's lactose intolerance is severe enough
to require exclusion;

10. Use of estrogen- or progestin-containing medication or phytoestrogen containing
supplements (e.g. soy concentrates or extracts) within 3 months of participation as
per self-report; foods containing soy (e.g. tofu, soy milk) will be permissible;
estrogen-based localized treatments such as creams and vaginal inserts will be
permissible, so long as said treatments do not effect systemic estrogen levels (women
using localized treatments must have estrogen levels similar to other women in the
study of their age and menopause status). PI will have final decision about enrollment
(see note 3 below);

11. Have a Mini Mental Status Score of < 25;

12. Hamilton Depression Score > 14;

13. As per self-report, have taken a psychotropic medication within the previous month,
with the exception of sleeping aids if the participant is willing to forgo use during
study participation;

14. Have a metallic implant as per self-report;

15. Are claustrophobic as per self-report;

16. Are pregnant (pertains to peri-menopausal women only).

Note 1: In the case of participants with full or partial hysterectomy, timing of final
menstrual period will be determined by Dr. Epperson (the study PI) or one of the study MDs.
In cases in which final menstrual period cannot be established, subjects will be excluded
from the study.

Note 2: Women who undergo the repeat FSH blood test will be enrolled if their levels are >
30. Women will not be required to repeat all admission procedures unless they report
experiencing a life event which would impact their mental or physical health and
well-being. The PI will make the final determination regarding what, if any, screening
procedures need to be repeated.

Note 3: Women on localized estrogen treatments who show elevated systemic estrogen levels
will not be enrolled. Instead, they will need to discontinue use for 1 month and then have
their estrogen levels retested with an additional blood draw. PI will have the final
decision regarding eligibility.