Urinary DENND1A.V2 as a Predictor of Pubertal Hyperandrogenemia

NCT02611128 | Suspended DMC

• 2 other identifiers: 17633P50HD028934
• Study Type: observational
• Target: 65
• Locations: 1 country
• Sites: 1

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).

Conditions

Polycystic Ovary Syndrome; Hyperandrogenism; Puberty

Outcome Measures

Primary Outcomes (2)

• Urinary exosomal DENND1A.V2

  Urinary exosomal DENND1A.V2

  Day 1 of study (the study involves one outpatient visit)

• Serum free testosterone

  Calculated free testosterone

  Day 1 of study (the study involves one outpatient visit)

Secondary Outcomes (4)

• Bone age

  Day 1 of study (the study involves one outpatient visit)

• BMI z-score

  Day 1 of study (the study involves one outpatient visit)

• Morning luteinizing hormone

  Day 1 of study (the study involves one outpatient visit)

• Fasting insulin

  Day 1 of study (the study involves one outpatient visit)

Study Arms (1)

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

Interventions

Phenotype/genotype assessment OTHER

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

Peripubertal girls

Eligibility Criteria

• Age: 8 Years - 17 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Probability Sample

Study Population

Peripubertal girls, Tanner breast stages 1-5

You may qualify if:

• Peripubertal girls, Tanner breast stages 1-5

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Virginia: lead
• Penn State University: collaborator
• Virginia Commonwealth University: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Center for Research in Reproduction

Charlottesville, Virginia, 22908, United States

Location

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).

MeSH Terms

Conditions

Polycystic Ovary Syndrome; Hyperandrogenism

Interventions

Phenotype

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; 46, XX Disorders of Sex Development; Disorders of Sex Development; Urogenital Abnormalities; Adrenogenital Syndrome; Male Urogenital Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Genetic Phenomena

Study Officials

• Christopher McCartney, MD

  University of Virginia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: November 12, 2015
• First Posted: November 20, 2015
• Study Start: May 29, 2015
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: November 2, 2023

Record last verified: 2023-11

Locations

US (1)