Etiological Factors of Obesity-Associated Hyperandrogenemia in Peripubertal Girls
A number of pathophysiological mechanisms underlie the polycystic ovary syndrome (PCOS).
Neuroendocrine abnormalities play a significant role in most women with PCOS, and PCOS is
associated with relative resistance of the gonadotropin releasing hormone (GnRH) pulse
generator to negative feedback by progesterone and estradiol. This hypothalamic resistance
to negative feedback appears to be a result of hyperandrogenemia (HA), and can also occur in
adolescents with HA. We have hypothesized that peripubertal HA (which can represent a
forerunner of adult PCOS) can promote the development of PCOS in part via induction of
hypothalamic resistance to negative feedback. However, the cause of peripubertal HA remains
largely unknown. Obesity is a well-recognized pathophysiological factor in the HA of adult
PCOS; and recent data demonstrate that peripubertal obesity is associated with HA. However,
the mechanisms underlying the relationship between peripubertal obesity and HA—and the
marked variability of androgen levels observed among obese girls—are unknown. We have
gathered preliminary data that suggests that obese pre- and early pubertal girls with high
androgen levels also exhibit greater degrees of insulin resistance compared to obese girls
with lower androgens.
The primary goal of this pilot project is to begin to establish the relationship between
insulin resistance (as determined by insulin clamp studies) and free testosterone
concentrations in obese peripubertal girls. Secondarily, the aim is to assess the
contributions of elevated luteinizing hormone (determined by frequent blood sampling for LH)
in obesity-associated HA across puberty.
Subjects will be admitted to the General Clinical Research Center at 1600 h after 4 hours of
fasting. We will measure luteinizing hormone every 10 minutes from 1800 h to 0900 h; other
hormones (e.g., testosterone) will be assessed as well. Measurements of insulin and glucose
will occur before and after a standardized mixed meal (eaten at 1900 h) and while fasting
the following morning. A standard hyperinsulinemic euglycemic clamp procedure will be
performed from 0900-1100 h.
Characterization of the factors underlying peripubertal HA may permit prediction of which
pre- and early pubertal girls will subsequently go on to develop symptoms of PCOS. Data
generated by this project will prompt novel future studies to investigate the complex
interactions among metabolic and classical endocrine pathways that lead to PCOS.
Observational Model: Case-Only, Time Perspective: Prospective
Morning free testosterone
0700 to 0900 hours
Christopher McCartney, MD
University of Virginia
United States: Institutional Review Board
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