Intervention: Duavee
Trial phase: Phase 2
SMILES: CC12CCC3C(=CCc4cc(OS(=O)(=O)O)ccc43)C1CCC2=O.CC12CCC3c4ccc(OS(=O)(=O)O)cc4CCC3C1CCC2=O.CC12CCc3c(ccc4cc(OS(=O)(=O)O)ccc34)C1CCC2=O.Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12
Sex: Female
Age groups: Adult
Healthy volunteers: No
Participants at risk: 24
Group description: 1 Tablet of 0.45mg conjugated estrogens/20 mg bazedoxifene daily for 8 weeks

Tissue Selective Estrogen Complex: Once-daily dosing of Duavee for 8 weeks.
Eligibility criteria:
Inclusion Criteria:

Women aged 40-62 years.
Perimenopausal: 6 months of amenorrhea; women who had a bi-lateral oophorectomy; women without a uterus and who still have one or both ovaries, with FSH level > 20 mIU/mL and estradiol ≤ 50 pg/mL; women with a uterus who have skipped 2 or more menstrual cycles with an amenorrhea interval; women who are using the Mirena IUD or who have had an endometrial ablation and who still have one or both ovaries, with FSH level > 20 mIU/mL and estradiol ≤ 50 pg/mL
Bothersome MS symptoms: Mean of two or more hot flashes/night sweats per 24 hrs; Hot flashes/night sweats rated as bothersome ('moderately' to 'a lot') and/or severe ('moderate' to 'severe') on 4 or more 12 hour (day/night) blocks of times
In general good health (determined by medical history, blood pressure, and heart rate)
No history of endometrial, ovarian, or breast cancer; No abnormal mammogram in the last 2 years; Absence of any current severe or unstable medical illness

MS considerations:

If using psychotropic medications: no change in the past 3 months
If on DMT, no change in past 6 months Normal vitamin D levels (20-50 ng/mL)

Exclusion Criteria:

BMI >35 kg/m2 as higher BMI may affect PK/PD
Use of hormone therapy or hormonal contraceptives 2 months prior to enrollment
Use of any prescribed therapy that is taken specifically for hot flashes in the past 1 month.
Use of any over-the-counter or herbal therapies that are taken specifically for hot flashes in the past 2 weeks.
Use of selective estrogen receptor modulators (SERMs) or aromatase inhibitors during the 2 months before enrollment.
Known hypersensitivity or contraindications to estrogen.
Drug or alcohol abuse in the past 1 year
Depression: moderate or severe (HAD score > 8) Other psychiatric disease meeting DSM-IV criteria
Lifetime diagnosis of psychosis or bipolar disorder.
Pregnancy, intending pregnancy, or breast feeding

History of any of the following, as determined by clinician review of the potential participant's medical history:

Pre-breast cancer or high-risk breast cancer condition;
Abnormal bleeding suggestive of endometrial pre-cancer;
Endometrial hyperplasia;
Asthma, diabetes mellitus, epilepsy, and migraine disorders that are not stable or under medical management;
Active or past history of venous or arterial thromboembolism
History of gallstones IF gallbladder intact
Known or suspected estrogen-dependent neoplasia
History of coronary artery disease
Hypersensitivity (angioedema, anaphylaxis) to estrogens, bazedoxifene, or any ingredients
Known hepatic impairment or disease
Thyroid dysfunction on thyroid medications
Known hypoparathyroidism
Blood test results indicating:
Liver function tests: AST >2.5 times upper limit of normal; ALT >2.5 times upper limit of normal; total bilirubin 1.5 times upper limit of normal;
Kidney test: creatinine >1.5 mg/dL;
Blood count: hematocrit <30%;
Hemoglobin <8 g/dL.
Current participation in another drug trial or intervention study.
Inability or unwillingness to complete the study procedures.

MS considerations:

Clinical relapse within the last three months (to ensure disease stability)
Steroid treatment in prior 1 month
Evidence of other structural brain disease (e.g. prior stroke)

MRI considerations:

Metal implants
Prior head trauma
Claustrophobia requiring anxiolytic or sedation, or other contraindication to MRI.