Urinary DENND1A.V2 as a Predictor of Pubertal Hyperandrogenemia

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).

Sex

Female

Minimum age

8 Years

Maximum age

17 Years

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.