Determining How Quickly Progesterone Slows LH Pulse Frequency
Condition: Normal; PCOS
Study type: Interventional
Phase: Phase 1

Summary: 
      The rapidity with which progesterone (P) suppresses daytime lutenizing hormone (LH) (and by
      inference gonadotropin releasing hormone (GnRH)) pulse frequency is unknown. We propose to
      assess this further using a randomized, cross-over, placebo-controlled study. Ovulatory women
      will begin E2 patches on day 4-8 of the cycle, while women with PCOS will begin E2 patches
      either on day 4-8 of the cycle or at least 8 weeks post-menses. After 3 d of E2
      administration, women will undergo a 24-h sampling study in the GCRC. Beginning at 2000 h,
      blood for LH, FSH, E2, P, and T will be obtained over a 24-h period. After 10 h of sampling,
      either oral micronized P (100 mg p.o.) suspension or placebo suspension will be administered
      (according to randomization). At the completion of sampling, E2 patches will be discontinued.
      During a subsequent menstrual cycle (or after at least 3 weeks in oligomenorrheic PCOS),
      subjects will undergo another GCRC study identical to the first (including pretreatment with
      E2) except that oral P will be exchanged for placebo or vice versa in accordance with the
      crossover design. We will assess the acute effects of progesterone on LH frequency, with
      secondary endpoints being mean LH, LH pulse amplitude, and mean follicle-stimulating hormone
      (FSH). We propose two primary hypotheses: (1) administration of P (at 0600 h) to normally
      cycling adult women during the follicular phase will result in a demonstrable suppression of
      daytime LH (and by inference GnRH) pulse frequency within 12 hours; (2) administration of P
      (at 0600 h) to women with PCOS will result in less suppression of daytime LH pulse frequency
      than in ovulatory women without PCOS. A secondary hypothesis is that augmentation of LH
      amplitude after P administration will be less in PCOS compared to normal controls.
    

Detailed description: 
      Studies under this protocol will be performed in normally cycling women and in women with
      PCOS from 18 to 35 years old. Criteria for PCOS will be (a) clinical and/or biochemical
      evidence of hyperandrogenism, (b) oligomenorrhea, and (b) the absence of clinical or
      biochemical evidence of other potential causes of hyperandrogenism and/or oligomenorrhea.
      After informed consent is obtained, all potential subjects will undergo a screening history
      and physical exam. Subjects will need to fast for a minimum of 8 hours prior to screening
      blood draw. After informed consent is obtained, blood tests (~ 16 cc) will be drawn at
      0800-0900 h as follows: LH, FSH, progesterone (P), estradiol (E2), total testosterone, SHBG,
      17-OHP, androstenedione, DHEA-S, beta-hCG, TSH, prolactin, CBC, chemistry and liver panels,
      hemoglobin A1c, fasting insulin, and fasting glucose. Additionally, BOD POD® will be used to
      measure total fat mass, fat free mass, and percent body fat. Waist and hip circumference will
      be measured.

      This study follows a crossover design, with assessment of the acute effects of P and placebo
      (individually) on GnRH pulse frequency; subjects will be randomized to receive either P or
      placebo during the first GCRC admission, with subsequent GCRC study occurring during a
      subsequent cycle.

      Women will begin E2 patches (0.1 mg/d per patch, 2 patches [delivering a total of 0.2 mg/d]
      placed on the abdomen and changed every 2 d) on the evening of day 4-8 of the study cycle
      (controls or PCOS) or >= 8 weeks post-menses (PCOS only). These patches will be continued for
      a total of 4 d, with GCRC admission occurring on day 3 of E2 administration. Exogenous E2
      administration will standardize hypothalamic exposure to E2 and help ensure the presence of
      sufficient hypothalamic P receptors.

      Four to 5 days before a scheduled GCRC admission, subjects will come to the GCRC for an
      outpatient blood draw for P and beta-HCG (2 cc). If 30 days will have elapsed between (a) the
      most recent hemoglobin and hematocrit and (b) the scheduled GCRC admission, a hemoglobin and
      hematocrit will also be drawn at this time (1cc).

      After 3 d of E2 administration, women will undergo a 24-h sampling study in the GCRC.
      Estradiol administration (E2 patches) will continue throughout the GCRC admission. Subjects
      will be admitted to the GCRC at 1800 h (2 h prior to sampling). Beginning at 2000 h, blood
      will be obtained through an indwelling i.v. forearm heparin lock over a 24-h period as
      follows: LH every 10 min (1 ml); P every 30 min (1 ml); FSH, E2, and T every 2 h (assays to
      be run in same samples as LH and P). SHBG, fasting insulin, and fasting glucose (i.e.,
      fasting since 2200 h) will be run on the 0600 h sample (extra 2 cc drawn). (Subjects will
      fast from 2200 to 0600 h.) After 10 h of sampling (i.e., at 0600 h), either oral micronized P
      (100 mg p.o.) suspension or placebo suspension will be administered (according to
      randomization). With exogenous P, we aim to achieve mean plasma P concentrations 4-8 ng/ml.
      Subjects will not be allowed to sleep during the day (i.e., from 0600 to 2200 h). Subjects
      will be encouraged to sleep from 2200 to 0600. Sleep will be formally evaluated
      (extraoculograms, electroencephalograms, wrist actigraphy, etc.). At the completion of
      sampling, E2 patches will be discontinued. Volunteers will be discharged on oral iron (325 mg
      BID). We will ask women to eat only the food provided by the GCRC.

      Subjects will undergo another GCRC study identical to the first (including pretreatment with
      E2, outpatient blood draw 4-5 days before admission, etc.), except that oral P will be
      exchanged for placebo or vice versa in accordance with the crossover design. (Subjects will
      again begin E2 patches on the evening of cycle day 4-8 [controls or PCOS] or >= 8 weeks
      post-menses [PCOS only].) In this way, we will be able to standardize any change in GnRH
      pulse frequency after P administration to any change in GnRH pulse frequency after placebo
      administration.

      The study will end after the second GCRC admission. Subjects will be asked to continue oral
      iron supplementation for at least 30 d after this last GCRC admission.
    

Intervention name(s): oral micronized progesterone suspension; Placebo
Intervention type(s): Drug; Other
Intervention description(s): oral micronized progesterone suspension, single 100 mg oral dose; Placebo contains only inert ingredients and is not expected to exert any direct physiological effects
Other intervention name(s): progesterone
Intervention MeSH terms: Progesterone
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized, placebo-controlled, crossover study
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Other
Keywords: PCOS