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Etiological Factors of Obesity-Associated Hyperandrogenemia in Peripubertal Girls (CRM002)

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ClinicalTrials.gov Identifier: NCT00928759
Recruitment Status : Recruiting
First Posted : June 26, 2009
Last Update Posted : October 11, 2019
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Chris McCartney, University of Virginia

Brief Summary:
The purpose of this study is to learn if obese pre- and early pubertal girls with hyperandrogenemia (HA) are more insulin resistant (i.e., have lower insulin-stimulated glucose disposal) compared to obese peripubertal girls without HA; and that overnight mean luteinizing hormone (LH) concentration is also an independent predictor of free testosterone concentrations, especially in mid- to late pubertal girls.

Condition or disease
Obesity Hyperandrogenemia Polycystic Ovary Syndrome

Detailed Description:

A number of pathophysiological mechanisms underlie the polycystic ovary syndrome (PCOS). Neuroendocrine abnormalities play a significant role in most women with PCOS, and PCOS is associated with relative resistance of the gonadotropin releasing hormone (GnRH) pulse generator to negative feedback by progesterone and estradiol. This hypothalamic resistance to negative feedback appears to be a result of hyperandrogenemia (HA), and can also occur in adolescents with HA. We have hypothesized that peripubertal HA (which can represent a forerunner of adult PCOS) can promote the development of PCOS in part via induction of hypothalamic resistance to negative feedback. However, the cause of peripubertal HA remains largely unknown. Obesity is a well-recognized pathophysiological factor in the HA of adult PCOS; and recent data demonstrate that peripubertal obesity is associated with HA. However, the mechanisms underlying the relationship between peripubertal obesity and HA—and the marked variability of androgen levels observed among obese girls—are unknown. We have gathered preliminary data that suggests that obese pre- and early pubertal girls with high androgen levels also exhibit greater degrees of insulin resistance compared to obese girls with lower androgens.

The primary goal of this pilot project is to begin to establish the relationship between insulin resistance (as determined by insulin clamp studies) and free testosterone concentrations in obese peripubertal girls. Secondarily, the aim is to assess the contributions of elevated luteinizing hormone (determined by frequent blood sampling for LH) in obesity-associated HA across puberty.

Subjects will be admitted to the General Clinical Research Center at 1600 h after 4 hours of fasting. We will measure luteinizing hormone every 10 minutes from 1800 h to 0900 h; other hormones (e.g., testosterone) will be assessed as well. Measurements of insulin and glucose will occur before and after a standardized mixed meal (eaten at 1900 h) and while fasting the following morning. A standard hyperinsulinemic euglycemic clamp procedure will be performed from 0900-1100 h.

Characterization of the factors underlying peripubertal HA may permit prediction of which pre- and early pubertal girls will subsequently go on to develop symptoms of PCOS. Data generated by this project will prompt novel future studies to investigate the complex interactions among metabolic and classical endocrine pathways that lead to PCOS.


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Study Type : Observational
Estimated Enrollment : 40 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Etiological Factors of Obesity-Associated Hyperandrogenemia in Peripubertal Girls
Study Start Date : March 2008
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : July 2021

Resource links provided by the National Library of Medicine


Group/Cohort
peripubertal obese girls
Peripubertal obese girls, aged 8 - 16 years, who are obese (BMI-for-age percentile greater or equal to 95)



Primary Outcome Measures :
  1. Morning free testosterone [ Time Frame: 0700 to 0900 hours ]
  2. Insulin-stimulated glucose disposal [ Time Frame: 0900 to 1100 hours ]

Secondary Outcome Measures :
  1. Estimated 24-hour mean insulin concentration [ Time Frame: 24 hours ]
  2. Luteinizing hormone pulse frequency [ Time Frame: 1800 to 0900 hours ]
  3. Mean luteinizing hormone concentration [ Time Frame: 1800 to 0900 hours ]


Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years to 16 Years   (Child)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Generally healthy peripubertal girls ages 8 - 16 years with a BMI of > or = to 95th percentile will be recruited from the general population of the surrounding area.
Criteria

Inclusion Criteria:

  • Peripubertal (Tanner stage 1 to 5) girl, age 8-16 years
  • Obesity (BMI-for-age ≥ 95th percentile)
  • Generally healthy (save for exogenous obesity)
  • Ability and willingness of subject/parents to provide informed assent/consent

Exclusion Criteria:

  • Age < 8 or > 16 y
  • Greater than 4 y post-menarche
  • Obesity associated with a diagnosed (genetic) syndrome (e.g., Prader-Willi syndrome, leptin deficiency), obesity related to medications (e.g., glucocorticoids), etc.
  • Pregnancy or lactation
  • Virilization
  • Total testosterone > 150 ng/dl, which suggests the possibility of a virilizing neoplasm
  • DHEAS greater than twice upper limit of age-appropriate normal range
  • 17-OHP greater than 250 ng/dl, which suggests the possibility of congenital adrenal hyperplasia (if postmenarcheal, the 17-OHP will be collected during the follicular phase, or > 60 if oligomenorrheic) NOTE: If a 17-OHP > 250 ng/dl is confirmed on repeat testing, an ACTH stimulation test will be offered, with a post-ACTH 17-OHP < 1000 ng/dl being required for study participation
  • History of premature adrenarche (i.e., appearance of pubic and/or axillary hair before age 8)
  • Fasting glucose > 125 mg/dl or hemoglobin A1c > 7.0%
  • Abnormal TSH or prolactin
  • Evidence of Cushing's syndrome by history or physical exam (e.g., history of impaired growth, striae)
  • Hematocrit < 36% or hemoglobin < 12 g/dl
  • Significant and current cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure; asthma requiring systemic intermittent corticosteroids; etc.)
  • Abnormal liver enzymes, age-specific alkaline phosphatase, or a bilirubin > 1.5 times upper limit of normal
  • Abnormal sodium, potassium, bicarbonate concentrations, or elevated creatinine concentration
  • Weight less than 34 kg is an exclusion criterion (to ensure safe blood withdrawal)
  • Subjects using restricted medication (see restrictions below) are excluded unless the subject's primary care provider approves stopping the medication

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00928759


Contacts
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Contact: Melissa Gilrain 434-243-6911 pcos@virginia.edu
Contact: Christopher McCartney, MD 434-243-6911 cm2hq@virginia.edu

Locations
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United States, Virginia
University of Virginia Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Melissa Gilrain    434-243-6911    pcos@virginia.edu   
Principal Investigator: Christopher McCartney, MD         
Sponsors and Collaborators
University of Virginia
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Christopher McCartney, MD University of Virginia

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Chris McCartney, Associate Professor of Medicine, University of Virginia
ClinicalTrials.gov Identifier: NCT00928759     History of Changes
Other Study ID Numbers: 13552
P50HD028934 ( U.S. NIH Grant/Contract )
First Posted: June 26, 2009    Key Record Dates
Last Update Posted: October 11, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: We do not have current plans to share IPD

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chris McCartney, University of Virginia:
Obesity
Polycystic Ovary Syndrome
Additional relevant MeSH terms:
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Obesity
Nutrition Disorders
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
Polycystic Ovary Syndrome
Overnutrition
Overweight
Body Weight
Signs and Symptoms
Ovarian Cysts
Cysts
Neoplasms