The aim of this study is to examine the effects of estrogen and serotonin on cognition, emotional processing, and brain activation. The investigators will study the effects of acute tryptophan (TRP) depletion on cognition and mood in healthy menopausal women before and after estrogen replacement treatment (ERT). Using functional magnetic resonance imaging (fMRI), the investigators will identify differences in brain activation during memory tasks with and without TRP depletion and before and after estrogen therapy in order to determine which brain regions and cognitive functions are affected by each manipulation.

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.

The participants that were analyzed completed all 4 test days. The study team was not permitted to collect or use the information collected from the 6 participants who did not complete up to test day 4, and so those participants are excluded from the baseline analysis population.

Adverse event data was at each test day visit, of which there were 4 and over the course of the 10-week patch treatment (either Estradiol or placebo).