Intervention: Estradiol
Trial phase: Phase 3
ATC code: G02BB01 | G03AA14 | G03AA17 | G03AB08 | G03CA03 | G03CA53 | G03EA01 | G03EA02 | G03EA03 | G03FA01 | G03FA02 | G03FA03 | G03FA04 | G03FA05 | G03FA06 | G03FA07 | G03FA08 | G03FA09 | G03FA10 | G03FA11 | G03FA12 | G03FA13 | G03FA14 | G03FA15 | G03FA16 | G03FA17 | G03FB01 | G03FB02 | G03FB03 | G03FB04 | G03FB05 | G03FB06 | G03FB07 | G03FB08 | G03FB09 | G03FB10 | G03FB11 | G03FB12 | G03HB01 | H01CC53 | H01CC54
SMILES: [H][C@@]12CCc3cc(O)ccc3[C@@]1([H])CC[C@]1(C)[C@@H](O)CC[C@@]21[H]
Sex: Female
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 102
Group description: One hundred participants will be randomized into the Vagifem® 'active' arm. These women will receive a bottle of Vagifem® tablets (estradiol 10 mcg). One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.

Vagifem® tablets contain 10.3 mcg of estradiol hemihydrate equivalent to 10 mcg of estradiol. The excipient (inactive) ingredients are hypromellose, lactose monohydrate, maize starch, and magnesium stearate. Vagifem® comes as a small white film-coated tablet. The coating is made of hypromellose and polyethylene glycol.

A placebo vaginal gel visually identical composed of inert hydroxyethylcellulose gel (pH adjusted) applied every 3 days over entire 12 weeks.

Vagifem: One tablet is to be inserted vaginally daily for 2 weeks, then 2 days/week for the remaining 10 weeks of the study.
Eligibility criteria:
Inclusion Criteria

Females aged 45-70 years
2 or more years since last natural menstrual period, or surgical menopause (bilateral oophorectomy)

At least 1 vaginal symptom (inside or outside the vagina) reported from the following list, experienced in the past 30 days which is moderate or severe:

Dryness at least once a week
Itching at least once a week
Irritation at least once a week
Soreness/Pain at least once a week
Pain associated with sexual activity at least once
Signed informed consent

Exclusion Criteria

Current unexplained abnormal genital bleeding (or any unevaluated bleeding since menopause)
Currently pregnant, attempting pregnancy or breast feeding
Current acute vaginal infection (as indicated by wet mount at V1)
Pelvic or vaginal surgery in prior 60 days
Antibiotic use in the past 30 days
Women under age 55 with endometrial ablation
Women under age 55 with hysterectomy and at least one ovary
Current cancer treatment (exception basal or squamous skin cell cancers)
Current or past thromboembolic disease (pulmonary embolus or deep vein thrombosis, not including thrombophlebitis), myocardial infarction or stroke
Current severe liver disease
Current or past breast or endometrial cancer or pre-cancer
Blood clotting disorder (e.g., Factor V Leiden, prothrombin mutation, protein C, protein or antithrombin deficiency)
Porphyria
Current or past lichen sclerosus or lichen planus
History of adverse reaction to vaginal estrogen or Replens
Use of any systemic reproductive hormones (hormonal contraception, postmenopausal hormone therapies, SERMS) in the past 2 months
Use of hormonal contraception in the past year
Use of any type of vaginal estrogen product (however interested women will be allowed to join the study if they abstain from use during the month preceding enrollment)
Use of any type of vaginal moisturizer, douche, vaginal prebiotic or probiotic, or soap in the vagina in the past month (however interested women will be allowed to join the study if they abstain from use during the month preceding enrollment)
Unwilling to abstain from use of any non-study vaginal moisturizer, vaginal estrogen, douche, or soap in the vagina throughout the trial
Unable to follow instructions, complete questionnaires, or physically unable to place product in the vagina
Current participation in another drug trial or intervention study
Chronic vulvo-vaginal symptoms in the 5 years before menopause (defined as a vaginal or vulvar condition requiring more than 4 visits to a health care provider in a given year)