Clinical Trial: Urinary DENND1A.V2 as a Predictor of Pubertal Hyperandrogenemia

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational

Official Title: Urinary DENND1A.V2 as a Predictor of Pubertal Hyperandrogenemia

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

Detailed Summary:

To date, the mechanisms underlying excess androgen production from steroid producing tissues have been unclear, but recent Genome Wide Association Studies (GWAS) have provided additional data in this regard. Initial GWAS data in a Han Chinese population identified some 12 loci as potential PCOS susceptibility gene candidates. One of these loci, the DENND1A locus at 9q22.32, has been replicated in GWAS studies in both Asian and European populations. Strauss and colleagues recently demonstrated DENND1A expression in testes, ovarian theca cells, and H295 adrenal carcinoma cells — all androgen producing tissues/cells. DENND1A is therefore an exceedingly strong PCOS susceptibility gene candidate. However, it remains unclear how DENND1A may contribute to the PCOS phenotype.

Importantly, there are two transcriptional forms of the DENND1A gene — a consequence of alternate splicing. The larger transcript (DENND1A Variant 1, or DENND1A.V1) encodes a 1009 amino acid protein, while the smaller transcript DENND1A.V2 encodes a truncated 559 amino acid. The product of DENND1A.V2 contains the DENN domain and a clathrin-binding domain, but differs from the product of DENND1A.V1 in two ways: (1) it does not contain the proline-rich C-terminal domain present in Variant 1, and (2) DENND1A.V2 results from differential splicing and contains a unique 33 amino acid C-terminal sequence. Of significant interest, published studies by Drs. McAllister and Strauss (McAllister JM, et al. Proc Natl Acad Sci USA. 2014;111:E1519-27) strongly implicate the DENND1A.V2 splice variant as a contributor to excessive theca cell androgen production in PCOS:

• Expression of DENND1A.V2 protein in cultured theca cells isolated from women with PCOS was over 3-fold elevated compared to normal ovarian theca cells. Similarly, DEN
  Sponsor: University of Virginia
  

  Current Primary Outcome:

  • Urinary exosomal DENND1A.V2 [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    Urinary exosomal DENND1A.V2
  • Serum free testosterone [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    Calculated free testosterone
  
  
  

  Original Primary Outcome: Same as current
  
  

  Current Secondary Outcome:

  • Bone age [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    A measure of maturational stage
  • BMI z-score [ Time Frame: Day 1 of study (the study involves one outpatient visit) ]
    Body mass index normalized for age and gender
  • 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
  • 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
  
  
  

  Original Secondary Outcome: Same as current
  
  Information By: University of Virginia
  

  Dates:
  Date Received: November 12, 2015
  Date Started: August 2014
  Date Completion: December 2019
  Last Updated: February 21, 2017
  Last Verified: February 2017