Charlottesville, Virginia 22908

  • PCOS

Purpose:

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.


Study summary:

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.


Criteria:

Inclusion Criteria: - Subjects will be healthy women in two groups: (1) women with regular menstrual cycles and no evidence of hyperandrogenism, and (2) women with PCOS (defined as clinical/biochemical evidence of hyperandrogenism plus oligomenorrhea, but with no evidence for other endocrinopathies). - Subjects will be 18-35 years old. - 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: - We will exclude women with a history of any disorders that may potentially be complicated by hormonal treatment, such as DVT and breast, ovarian, or endometrial cancer. - We 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/or a 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 history of any disorders that may potentially be complicated by long-term iron supplementation, such as hemochromatosis and polycythemia vera, will be excluded. - 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) - Pregnant and breast-feeding women will be excluded. - A history of allergy to progesterone or estradiol will constitute grounds for exclusion. - Women with a BMI greater or equal to 40 kg/m2. - Virilization - A total testosterone > 150 ng/dl in women with PCOS (which suggests the possibility of a virilizing neoplasm) (confirmed on repeat) - Elevated DHEAS (mild elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal will be accepted in PCOS) (confirmed on repeat) - Follicular 17-hydroxyprogesterone > 300 ng/dl, which suggests the possibility of congenital adrenal hyperplasia (if elevated during the luteal phase and there is a concern about the possibility of congenital adrenal hyperplasia, the 17-hydroxyprogesterone may be collected during the follicular phase, or >60 if oligomenorrheic). NOTE: If a 17-hydroxyprogesterone > 300 ng/dl is confirmed on repeat testing, an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl will be required for study participation. - A previous diagnosis of diabetes, a fasting glucose ≥ 126 mg/dl, or a hemoglobin A1c > 6.5% - 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 (mild elevations may be seen in PCOS, and elevations < 1.5 times the upper limit of normal will be accepted in this group) (confirmed on repeat) - Evidence of Cushing's syndrome by history or physical exam - Due to the amount of blood being drawn in the study, subjects with body weight < 110 lbs. will be excluded from the study


Study is Available At:


Original ID:

13368


NCT ID:

NCT00594217


Secondary ID:

R01HD058671


Study Acronym:

CRM001


Brief Title:

Determining How Quickly Progesterone Slows LH Pulse Frequency


Official Title:

Determining the Rapidity With Which Exogenous P Suppresses Daytime LH (GnRH) Pulse Frequency in Women During the Follicular Phase of the Menstrual Cycle


Overall Status:

Recruiting


Study Phase:

Phase 1


Genders:

Female


Minimum Age:

18 Years


Maximum Age:

35 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

University of Virginia


Oversight Authority:

United States: Food and Drug Administration


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

2


Number of Groups:

0


Total Enrollment:

72


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Christopher McCartney, MD
Principal Investigator
University of Virginia
Primary Contact:Christopher McCartney, MD
434-243-6911
cm2hq@virginia.edu
Backup Contact:Melissa Gilrain
434-243-6911
pcos@virginia.edu

Study Dates

Start Date:November 2007
Completion Date:July 2021
Completion Type:Anticipated
Primary Completion Date:December 2020
Primary Completion Type:Anticipated
Verification Date:October 2019
Last Changed Date:October 9, 2019
First Received Date:January 4, 2008

Study Outcomes

Outcome Type:Primary Outcome
Measure:The primary endpoint is the change in the number of LH pulses (over 10 h) attributable to Progesterone.
Time Frame:10 hours before and after administration of micronized progesterone and placebo
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:acute effects of P on mean LH
Time Frame:10 hours before and after administration of micronized progesterone and placebo
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:acute effects of P on mean LH pulse amplitude
Time Frame:10 hours before and after administration of micronized progesterone and placebo
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:acute effects of P on mean FSH
Time Frame:10 hours before and after administration of micronized progesterone and placebo
Safety Issues:False

Study Interventions

Intervention Type:Drug
Name:oral micronized progesterone suspension
Description:oral micronized progesterone suspension, single 100 mg oral dose
Arm Name:Progesterone
Other Name:progesterone
Intervention Type:Other
Name:Placebo
Description:Placebo contains only inert ingredients and is not expected to exert any direct physiological effects
Arm Name:Placebo

Study Arms

Study Arm Type:Experimental
Arm Name:Progesterone
Description:oral micronized progesterone suspension, single 100 mg oral dose
Study Arm Type:Placebo Comparator
Arm Name:Placebo
Description:Placebo contains only inert ingredients and is not expected to exert any direct physiological effects

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:University of Virginia
Agency Class:NIH
Agency Type:Collaborator
Agency Name:Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: April 03, 2020

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