Urinary DENND1A.V2 as a Predictor of Pubertal Hyperandrogenemia

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).

Conditions

• Polycystic Ovary Syndrome
• Hyperandrogenism
• Puberty

Interventions

OTHER

Phenotype/genotype assessment

The investigators will perform careful phenotyping in addition to hormonal assessments and assessments of DENND1A

Sponsors & Collaborators

• Penn State University

  collaborator OTHER

• Virginia Commonwealth University

  collaborator OTHER

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

  collaborator NIH

• University of Virginia

  lead OTHER

Principal Investigators

• Christopher McCartney, MD · University of Virginia

Eligibility

Min Age

8 Years

Max Age

17 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2015-05-29

Primary Completion

2024-12-31

Completion

2024-12-31

Countries

• United States

Study Locations