Acute Effects of Progesterone on LH Pulses During the Follicular Phase (CRM006)

Acute Effects of Progesterone on LH Pulses During the Follicular Phase

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.

Study Overview

• Status: Terminated
• Conditions: Female Reproductive Physiology
• Intervention / Treatment: Drug: oral micronized progesterone suspension; Drug: Placebo

Detailed Description

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 frequent sampling study. Beginning at 0900 h, blood for LH, FSH, estradiol, progesterone, and testosterone will be obtained over a 10-hour period. Either oral micronized progesterone (100 mg p.o.) 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. The primary endpoint of interest is LH pulse frequency; the investigators will compare LH pulse frequency after progesterone administration to LH pulse frequency after placebo administration.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Center for Research in Reproduction

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 30 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: micronized progesterone, then placebo; Participants first received oral micronized progesterone (100 mg p.o.) suspension. After a washout period of approximately 20 days, they then received placebo (matching oral micronized progesterone suspension).	Drug: oral micronized progesterone suspension; oral micronized progesterone (100 mg p.o.) suspension; Other Names: Progesterone; Drug: Placebo; Placebo contains only inert ingredients and is not expected to exert any direct physiological effects
Placebo Comparator: Placebo, then micronized progesterone; Participants first received placebo. After a washout period of approximately 20 days, they then received oral micronized progesterone syrup (100 mg p.o.)Placebo contains only inert ingredients and is not expected to exert any direct physiological effects	Drug: oral micronized progesterone suspension; oral micronized progesterone (100 mg p.o.) suspension; Other Names: Progesterone; Drug: Placebo; Placebo contains only inert ingredients and is not expected to exert any direct physiological effects

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Number of LH Pulses Per Hour	The primary endpoint is the change in the number of LH pulses per hour (over 10 h), comparing (a) number of LH pulses at baseline to (b) number of LH pulses immediately after progesterone or placebo administration	10 hours following administration of micronized progesterone or placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean LH	This secondary endpoint is the change of the mean LH (over 10 h), comparing (a) mean LH at baseline to (b) mean LH immediately after progesterone or placebo administration	10 hours following administration of micronized progesterone or placebo
Change in Mean LH Amplitude	This secondary endpoint is the change in the mean LH amplitude (over 10 h), comparing (a) mean LH amplitude at baseline to (b) mean LH amplitude immediately after progesterone or placebo administration	10 hours following administration of micronized progesterone or placebo

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Christopher R. McCartney, MD, University of Virginia

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): July 31, 2015
• Study Completion (Actual): July 31, 2015

Study Registration Dates

• First Submitted: May 17, 2012
• First Submitted That Met QC Criteria: May 18, 2012
• First Posted (Estimate): May 21, 2012

Study Record Updates

• Last Update Posted (Actual): October 16, 2018
• Last Update Submitted That Met QC Criteria: October 15, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: 16085; R01HD058671 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: We do not have current plans to share IPD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No