Acute Effects of Progesterone on LH Pulses During the Follicular Phase (CRM006)
Condition: Female Reproductive Physiology
Intervention: oral micronized progesterone suspension; Placebo
Intervention description: oral micronized progesterone (100 mg p.o.) suspension; Placebo contains only inert ingredients and is not expected to exert any direct physiological effects
Intervention MeSH terms: Progesterone
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized, placebo-controlled, crossover study
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 12.0
Sex: Female
Minimum age: 18 Years
Maximum age: 30 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      The rapidity with which progesterone slows LH (and by inference GnRH) pulse frequency in
      women is unclear. The investigators hypothesize that progesterone slows LH pulse frequency
      within 10 hours. The investigators propose to assess this further with a randomized,
      cross-over, placebo-controlled study. Regularly cycling women without hyperandrogenism will
      be admitted to the Clinical Research Unit on cycle day 5-9 (mid-follicular phase) for a 10
      hour frequent sampling study to observe LH, FSH, estradiol, progesterone, and testosterone.
      Either oral micronized progesterone suspension or placebo will be administered at 0900 h.
      During a subsequent menstrual cycle, subjects will undergo another study identical to the
      first except that oral progesterone will be exchanged for placebo or vice versa in accordance
      with a crossover design.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects will be healthy women with regular menstrual cycles and no evidence of
             hyperandrogenism.

          -  Subjects will be 18-30 years old; the investigators use a cutoff age of 30 years
             because age-related alterations in the hypothalamic-pituitary-ovarian axis is uncommon
             before age 30 years.

          -  Subjects will be willing to strictly avoid pregnancy (using non-hormonal methods)
             during the time of study and must be willing and able to provide informed consent.

        Exclusion Criteria:

          -  Pregnancy

          -  Lactation

          -  History of allergy to progesterone

          -  BMI < 18 kg/m2 or > 30 kg/m2 (underweight and obesity can affect
             hypothalamic-pituitary-ovarian function)

          -  Excessive exercise, defined as routine and current engagement in either (a) moderate
             exercise (e.g., brisk walking) exceeding 14 hours per week or (a) vigorous exercise
             exceeding 7 hours a week.

          -  Clinical hyperandrogenism (primarily hirsutism)

          -  Abnormally elevated free testosterone or DHEAS concentration

          -  A previous diagnosis of diabetes, a fasting glucose ≥ 126 mg/dl

          -  Abnormal TSH (subjects with adequately treated hypothyroidism, reflected by normal TSH
             values, will not be excluded; or, for a new diagnosis of hypothyroidism, further study
             will at the least be delayed pending appropriate treatment) (confirmed on repeat)

          -  Abnormal prolactin (confirmed on repeat)

          -  Evidence of Cushing's syndrome by history or physical exam

          -  History of venous thromboembolism, breast/ovarian/endometrial cancer

          -  The investigators will exclude women with any other cancer diagnosis and/or treatment
             (with the exception of basal cell or squamous skin carcinoma) unless they have
             remained clinically disease free (based on appropriate surveillance) for five years.

          -  Women with anemia (hematocrit < 36% and hemoglobin level < 12 g/dl) will be treated
             with iron for a maximum of 2 sequential months before the 1st admission and/or before
             the 2nd admission. If they remain anemic after 2 sequential months of ferrous
             gluconate (325 mg bid), they will then be excluded from further participation in the
             study.

          -  Women with a significant history of cardiac or pulmonary dysfunction (e.g., known or
             suspected congestive heart failure; known or suspected coronary atherosclerosis;
             asthma requiring systemic intermittent corticosteroids; etc.) will be excluded.

          -  Women with liver enzymes, alkaline phosphatase, or bilirubin > 1.5 times upper limit
             of normal (confirmed on repeat) will be excluded, with the exception that mild
             bilirubin elevations will be accepted in the setting of known Gilbert's syndrome.

          -  Abnormal sodium or potassium concentrations (confirmed on repeat); bicarbonate
             concentrations <20 or >30 (confirmed on repeat)

          -  Women with abnormal renal function (i.e., serum creatinine > 1.4) will be excluded
             (confirmed on repeat)

          -  Due to the amount of blood being drawn in the study, subjects with body weight < 110
             pounds will be excluded from the study

          -  Being a study of the acute effects of progesterone on the hypothalamic-pituitary unit,
             subjects must not take hormonal medications (e.g., oral contraceptives) or other
             medications known to affect the reproductive axis for 60 days prior to the study and
             during the study.