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Urinary DENND1A.V2 as a Predictor of Pubertal Hyperandrogenemia (DENND1A)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02611128
Recruitment Status : Recruiting
First Posted : November 20, 2015
Last Update Posted : April 16, 2019
Penn State University
Virginia Commonwealth University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
Chris McCartney, University of Virginia

Brief Summary:
Polycystic ovary syndrome (PCOS) is a common disorder marked by hyperandrogenism, oligo-/anovulation, and subfertility. The precise causes of PCOS are unclear, but the pathophysiology involves complex genetic and environmental influences. Importantly, not all girls with obesity have HA, and free testosterone (T) concentrations are highly variable in this group. Luteinizing hormone (LH) and insulin concentrations are significant but only partial predictors of free T in girls with obesity; significant unexplained variability in free T suggests that additional factors contribute to HA in this population. Abnormalities of ovarian and adrenal steroidogenesis are likely contributors in this regard, but such abnormalities are difficult to quantify. Recent Genome Wide Association Studies have identified DENND1A as a PCOS susceptibility gene candidate. Preliminary in vitro data strongly implicate a DENND1A splice variant called DENND1A Variant 2 (DENND1A.V2) as a contributor to excessive theca cell androgen production in PCOS. The investigators' primary goal with the proposed pilot study is to determine the relationship between urinary exosomal DENND1A.V2 mRNA and free T concentrations in peripubertal girls. The investigators hypothesize that urinary exosomal DENND1A.V2 mRNA quantity is a significant and independent predictor of peripubertal hyperandrogenemia. In this study, the investigators will carefully phenotype peripubertal girls with and without hyperandrogenemia (primarily in the form of hormonal, maturational, and anthropometric measurements) in addition to measuring urinary exosomal DENND1A.V2 mRNA. As a primary analysis, the investigators will examine the relationship between morning free testosterone and urinary exosomal DENND1A.V2, controlling for previously-described partial predictors of free testosterone (LH, insulin) in addition to potential confounders (BMI z-score, bone age). These studies will provide important information regarding the etiology of HA in peripubertal girls. Ultimately, these data may lead to a non-invasive test of ovarian/adrenal steroidogenic activity and support the development of a diagnostic test for PCOS in high-risk peripubertal girls (e.g., those with obesity).

Condition or disease Intervention/treatment
Polycystic Ovary Syndrome Hyperandrogenism Puberty Other: Phenotype/genotype assessment

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Study Type : Observational
Estimated Enrollment : 65 participants
Observational Model: Other
Time Perspective: Cross-Sectional
Official Title: Urinary DENND1A.V2 as a Predictor of Pubertal Hyperandrogenemia
Study Start Date : August 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Group/Cohort Intervention/treatment
Peripubertal girls
Peripubertal girls with varying androgen concentrations will have careful phenotype/genotype assessment, primarily to assess the relationship between urinary exosomal DENND1A.V2 and serum free testosterone concentrations.
Other: Phenotype/genotype assessment
The investigators will perform careful phenotyping in addition to hormonal assessments and assessments of DENND1A

Primary Outcome Measures :
  1. Urinary exosomal DENND1A.V2 [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    Urinary exosomal DENND1A.V2

  2. Serum free testosterone [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    Calculated free testosterone

Secondary Outcome Measures :
  1. Bone age [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    A measure of maturational stage

  2. BMI z-score [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    Body mass index normalized for age and gender

  3. Morning luteinizing hormone [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    Serum luteinizing hormone (LH) measured at same time as free testosterone and fasting insulin

  4. Fasting insulin [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    Serum insulin measured at same time as free testosterone and morning LH

Biospecimen Retention:   Samples With DNA
Optional sample banking for later genetic analysis: At the time of study, the investigators will request consent/assent to bank saliva samples for later genetic analysis (e.g., if additional highly-promising gene candidates for adolescent hyperandrogenemia/PCOS are identified). If subjects and parents do not provide assent/consent that would allow specimens to be banked for later genetic analysis, the samples and the means of linking specimens to data will be destroyed (once analysis for all participants is completed).

Information from the National Library of Medicine

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Ages Eligible for Study:   8 Years to 17 Years   (Child)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Peripubertal girls, Tanner breast stages 1-5

List of Inclusion Criteria

• Peripubertal girls, Tanner breast stages 1-5

List of Exclusion Criteria

  • Age < 8 or > 17 y
  • Men and boys are excluded
  • Inability to obtain proper consent/assent
  • Atypical obesity
  • Underweight: Underweight is defined as a BMI-for-age percentile < 5
  • Positive pregnancy test or lactation
  • Assessment during the luteal phase as suggested by a serum progesterone ≥ 1.5 ng/ml
  • Virilization or a total testosterone > 150 ng/dl
  • Excessively elevated DHEA-S: This will be defined as a DHEA-S > 1.5 times the age-appropriate upper limit of normal
  • Congenital adrenal hyperplasia (CAH)
  • Cortisol deficiency/excess
  • Inadequately-treated or unstable thyroid dysfunction
  • Significant hyperprolactinemia: Since mild elevations may be seen in girls with hyperandrogenemia or PCOS, elevations up to 30 (i.e., 1.5 times the upper limit of normal) will be accepted in such girls
  • Significant chronic medical history: This includes a significant history of cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure; asthma requiring intermittent systemic corticosteroids; etc.); history of renal insufficiency or durable electrolyte abnormalities; or a history of substantial liver disease. A history of liver test abnormalities will be allowed in two circumstances: (1) mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome; (2) mild transaminase (ALT, AST) elevations may be seen in obese girls, so stable elevations < 1.5 times the upper limit of normal will be accepted in this group.
  • Uncontrolled type 2 diabetes mellitus: This will be reflected by a hemoglobin A1c > 7.0%. Subjects with impaired glucose tolerance or a diagnosis of type 2 diabetes that is well-controlled with lifestyle management alone will be allowed to participate.
  • Type 1 diabetes mellitus: Since subjects with type 1 diabetes invariably require exogenous insulin, they will not be allowed to participate.

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 identifier (NCT number): NCT02611128

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Contact: Melissa Gilrain 434-243-6911
Contact: Christopher McCartney, MD

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United States, Virginia
Center for Research in Reproduction Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Melissa Gilrain    434-243-6911   
Principal Investigator: Christopher R McCartney, MD         
Sub-Investigator: John C Marshall, MD, PhD         
Sub-Investigator: Jan McAllister, PhD (Penn State)         
Sub-Investigator: Jerome Strauss, MD, PhD (VCU)         
Sponsors and Collaborators
University of Virginia
Penn State University
Virginia Commonwealth University
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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Principal Investigator: Christopher McCartney, MD University of Virginia

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Responsible Party: Chris McCartney, Associate Professor of Medicine, University of Virginia Identifier: NCT02611128    
Other Study ID Numbers: 17633
P50HD028934 ( U.S. NIH Grant/Contract )
First Posted: November 20, 2015    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: April 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
Additional relevant MeSH terms:
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Polycystic Ovary Syndrome
Ovarian Cysts
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
46, XX Disorders of Sex Development
Disorders of Sex Development
Urogenital Abnormalities
Adrenogenital Syndrome
Congenital Abnormalities