Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Pharmacokinetic Evaluation of Bioidentical Compounded Estrogen Cream and Natural Progesterone
Brief Summary: Bioidentical compounded hormone therapy (BCHT) is considered a 'safer' option to the conventional hormones (HT) by its proponents. However, there is limited research data to support their claims. Our group at the Women's Health Clinic, in collaboration with the Departments of Endocrinology, Complementary Medicine and Laboratory Medicine, is interested in developing a line of research to test the safety and efficacy of BCHT. In the present study, we aim to find the dose of BCHT that is bioequivalent to conventional HT, in a randomized, blinded, four-arm, phase I clinical trial. We will estimate the levels of estrone (E1), estradiol (E2) and estriol (E3) at baseline and at steady state with two-weeks of administration of three commonly used doses of bioidentical compounded estrogen cream (Biest) and a standard dose conventional estrogen patch (Vivelle-Dot). E1, E2, and E3 values will be summarized using point estimates and 95% confidence intervals. Two-sample t-test will be used to compare each Biest group to the Vivelle-Dot group. Healthy postmenopausal women, with no contraindications for hormone use, who are able to fully understand and participate in the trial, will be enrolled. We will utilize the resources of Mayo CRU to conduct this study.


Options:
A: Inclusion Criteria:

1. Be a female between the ages of 40 and 65 years (at the time of randomization) who is willing to participate in the study, as documented by signing the informed consent form.
2. Be a postmenopausal woman with an intact uterus and a Screening serum estradiol level of ≤50 pg/mL. Postmenopausal is defined herein as:

   1. ≥ 12 months of spontaneous amenorrhea, or
   2. at least 6 months of spontaneous amenorrhea with a Screening serum FSH level of \>40 mIU/ml, or
   3. ≥ 6 weeks postsurgical bilateral oophorectomy.
3. Be seeking treatment or relief for vasomotor symptoms associated with menopause.
4. To participate in the VMS Substudy, a subject must also report ≥7 moderate to severe hot flushes per day, or ≥50 per week, at the baseline assessment during Screening (subjects whose hot flushes are less frequent may still participate as non-Substudy subjects.

   Note: A minimum of 14 consecutive days of complete hot flush diary data are required during the baseline assessment at Screening, and these consecutive days must occur within the last 14 days prior to the Randomization visit (not counting the Randomization visit day itself). The most recent 7 consecutive days of data prior to randomization (Day -7 to Day -1) will be used to determine the baseline number of mild, moderate and severe hot flushes for each subject.
5. Have a Body Mass Index (BMI) less than or equal to 34 kg/mP2P. (BMI values should be rounded to the nearest integer \[e.g., 34.4 rounds down to 34, while 26.5 rounds up to 27\]).
6. Be willing to abstain from using products (other than study medication) that contain estrogen, progestin, or progesterone throughout study participation.
7. Be judged by the principal or sub-investigator physician as being in otherwise generally good health based on a medical evaluation performed during the Screening period prior to the initial dose of study medication. The medical evaluation findings must include:

   1. a normal or non-clinically significant physical examination, including vital signs (sitting blood pressure, heart rate, respiratory rate and temperature). Sitting systolic blood pressure is ≤140 mmHg and diastolic blood pressure ≤90 mmHg at Screening. A subject may be taking up to two antihypertensive medications.
   2. a normal or non-clinically significant pelvic examination.
   3. a mammogram that shows no sign of significant disease (can be performed within previous 6 months prior to initial dose of study medication). Subjects must have a BI-RADS 1 or 2 to enroll in the study. An incomplete mammogram result, i.e. BI-RADS 0, is not acceptable. The site must obtain a copy of the official report for the subject's study file, and it must be verified that the mammogram itself is available if needed for additional assessment.
   4. a normal or non-clinically significant clinical breast examination. An acceptable breast examination is defined as no masses or other findings identified that are suspicious of malignancy.
   5. a normal Screening Papanicolaou ("Pap") smear. (Subjects with findings of atypical glandular cells \[AGC\], AGUS, ASCUS with high risk HPV type upon reflex testing, LSIL, ASC-H, HSIL, dysplastic cells, or malignant cells must be excluded from randomization.)
   6. an acceptable result from an evaluable Screening endometrial biopsy. The endometrial biopsy reports by the two central pathologists at Screening must each specify one of the following: proliferative endometrium; weakly proliferative endometrium; disordered proliferative pattern; secretory endometrium; endometrial tissue other (including benign, inactive or atrophic fragments of endometrial epithelium, glands, stroma, etc); endometrial tissue insufficient for diagnosis; no endometrium identified; or no tissue identified. However, at least one pathologist must identify sufficient tissue to evaluate the biopsy. Additionally, the endometrial biopsy reports by the two central pathologists of Other Findings at Screening must each specify one of the following: endometrial polyp not present; benign endometrial polyp; or polyp other. (See Exclusion criterion #27)
   7. a normal or non-clinically significant 12-lead ECG.

Exclusion Criteria:

* To participate in the study, a subject must NOT:

  1. Be currently hospitalized.
  2. Have a history of thrombosis of deep veins or arteries or a thromboembolic disorder.
  3. Have a history of coronary artery or cerebrovascular disease (e.g., myocardial infarction, angina, stroke, TIA).
  4. Have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure).
  5. Have a history of a malabsorption disorder (e.g., gastric bypass, Crohn's disease).
  6. Have a history of gallbladder dysfunction/disorders (e.g., cholangitis, cholecystitis), unless gallbladder has been removed.
  7. Have a history of diabetes, thyroid disease or any other endocrinological disease. (Subjects with diet-controlled diabetes or controlled hypothyroid disease at Screening are not excluded.)
  8. Have a history of estrogen-dependent neoplasia.
  9. Have a history of atypical ductal hyperplasia of the breast.
  10. Have a finding of clinically significant uterine fibroids at Screening.
  11. Have had a uterine ablation.
  12. Have a history of undiagnosed vaginal bleeding.
  13. Have any history of endometrial hyperplasia, melanoma, or uterine/endometrial, breast or ovarian cancer.
  14. Have any history of other malignancy within the last 5 years, with the exception of basal cell (excluded if within 1 year) or non-invasive squamous cell (excluded if within 1 year) carcinoma of the skin.
  15. Have a history of any other cardiovascular, hepatic, renal, pulmonary, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychological (e.g., bipolar disorder, schizophrenia, major depressive disorder), or musculoskeletal disease or disorder that is clinically significant in the opinion of the Principal Investigator or Medical Sub-Investigator.
  16. Have any of the following clinical laboratory values at Screening:

      1. fasting triglyceride of ≥300 mg/dL and/or total cholesterol of ≥300mg/dL
      2. positive laboratory finding for Factor V Leiden mutation
      3. AST or ALT ≥1.5 times the upper limit of normal (ULN)
      4. fasting glucose \>125 mg/dL
  17. Be known to be pregnant or have a positive urine pregnancy test. (Note: A pregnancy test is not required for subjects who have had bilateral tubal ligation, bilateral oophorectomy, or are 55 years old or greater and have experienced cessation of menses for at least 1 year.)
  18. Have contraindication to estrogen and/or progestin therapy or allergy to the use of estradiol and/or progesterone or any components of the investigational drugs.
  19. Use 15 or more cigarettes per day or currently use any electronic cigarettes.
  20. Have a history of drug and/or alcohol abuse within one year of start of study.
  21. Have used, within 28 days prior to the initial dose of study medication at Visit 1, any medication known to induce or inhibit CYP3A4 enzyme activity that may affect estrogen and/or progestin drug metabolism. (See 48TUSection 4.3U48T)
  22. Have used, within 28 days prior to Screening, or plan to use during the study, any prescription or over-the-counter (OTC) medications (including herbal products, such as St. John's Wort) that would be expected to alter progesterone or estrogen activity or is being used to treat vasomotor symptoms. (See Section 4.3U48T)
  23. Have used estrogen alone or estrogen/progestin, SERM (selective estrogen receptor modulator), testosterone, or estrogen/testosterone for any of the following time periods:

      1. Vaginal nonsystemic hormonal products (rings, creams, gels) within 7 days prior to Screening, or vaginal systemic products (e.g., FemRing) within 28 days prior to Screening.
      2. Transdermal estrogen alone or estrogen/progestin products within 8 weeks prior to Screening.
      3. Oral estrogen and/or progestin and/or SERM therapy within 8 weeks prior to Screening.
      4. Progestational implants, estrogen or estrogen/progestational injectable drug therapy within 3 months prior to Screening.
      5. Estrogen pellet therapy or progestational injectable drug therapy within 6 months prior to Screening.
      6. Percutaneous estrogen lotions/gels within 8 weeks prior to Screening.
      7. Oral, topical, vaginal, patch, implantable or injectable androgen therapy within 8 weeks prior to Screening.
  24. Have used an intrauterine device (IUD) within the 12 weeks prior to Screening.
  25. For subjects in the VMS Substudy only: use of medication that may affect the outcome of the vasomotor symptom endpoints within 28 days prior to Screening (e.g. SSRIs \[selective serotonin reuptake inhibitors\], SNRIs \[serotonin and norepinephrine reuptake inhibitors\], aldomet, dopaminergic or antidopaminergic drugs, gabapentin, clonidine, or bellergal.)
  26. Have any reason which, in the opinion of the Principal Investigator or Medical Sub-Investigator, would prevent the subject from safely participating in the study or complying with protocol requirements.
  27. Have a Screening endometrial biopsy sample that is found by both primary pathologists to have endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified. (With the approval of the Medical Monitor, the Screening endometrial biopsy may be repeated once.)
  28. Endometrial polyps with atypical nuclei reported by at least 1 central pathologist.
  29. Have contraindication to any planned study assessments (e.g., endometrial biopsy).
  30. Have participated in another clinical trial within 30 days prior to Screening, have received an investigational drug within the three months prior to the initial dose of study medication, or be likely to participate in a clinical trial or receive another investigational medication during the study.
  31. Currently use marijuana.
B: Inclusion Criteria:

* Postmenopausal women
* serum estradiol level less than or equal to 20 pg per mL
* serum FSH greater than 40 mIU per mL

Exclusion Criteria:

* Pathological cancer findings on screening
* abnormal endometrium
* serious hepatic, renal or cardiac disease
C: Inclusion Criteria:

1. Women 40-60 years old;
2. Postmenopausal status, as documented by absence of periods for ≥ 1 year or amenorrhea for ≥ 6 months along with FSH ≥ 40 IU/L;
3. Surgical menopause;
4. History of a normal mammogram within the last 11 months;
5. Normal screening labs (within 20% of upper limit of lab normal);
6. Able to understand and sign informed consent; and
7. Able and willing to be in a monitored CRU setting and provide blood samples as requested.

Exclusion Criteria:

1. Contraindications to the use of hormones because of personal history of coronary artery disease, stroke, breast cancer, DVT/PE, active liver or gall bladder disease, hormone dependent migraine headaches, endometrial, ovarian or other hormone dependent cancers;
2. Medical conditions increasing the risk of complications from hormone replacement such as uncontrolled hypertension (\>160/100 mmHg), smoking, diabetes and lupus;
3. Current use of estrogen, progesterone or testosterone;Depending on the drug, it could be 7 days to 6 months.
4. Current use of isoflavone containing products;
5. Current use of protein binding medications like rifampin, warfarin, antiepileptic drugs (effect on estrogen bioavailability);
6. Family history of premenopausal breast cancer in a first degree relative, two or more premenopausal breast cancers in second degree relatives, male breast cancer, ovarian cancer in two or more relatives and; and
7. Women with alcohol or substance abuse or dementia (compliance issues).
8. Women who are more than ten years from their last menstrual period (unfavorable risk : benefit ratio)
9. Women with peanut allergy (Prometrium has peanut oil)
10. Women who are found to have premenopausal estrogen levels, as confirmed by a baseline Estradiol level of \>35 pg/ml and vaginal ultrasound suggesting ovarian activity.
D: Inclusion Criteria:

* Post menopausal women,
* Ages 35 or older,
* Frequent moderate to severe hot flushes,
* Qualifying general medical health

Exclusion Criteria:

* Disqualifying gynecological disorders,
* Disqualifying dermatological disorders,
* Disqualifying concurrent conditions

Answer: C