Marshall and Dunaif Page 3

pulse frequency can be corrected by prior androgen receptor blockade (33), but may not
simply reflect the degree or duration of HA. The only significant difference between HA
girls resistant to and those who remained sensitive to progesterone feedback, was that
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fasting insulin levels were elevated in progesterone resistant girls (9, 10). It remains
unknown whether blockade of androgen action or reduction in plasma insulin or androgen
levels during pubertal maturation will correct these hypothalamic feedback abnormalities.
However metformin for 3 months improved glucose intolerance, decreased testosterone and
fasting insulin values, and reduced the exaggerated adrenal androgen responses to ACTH
stimulation in obese adolescents (34). Additional evidence shows that low sex hormone
binding globulin (SHBG) levels, HA and elevated insulin in the early teen years, predict
subsequent development of the metabolic syndrome and class 3 obesity by the middle of the
third decade (35). This in turn provides support to the concept that adolescent girls with this
disorder should receive the earliest possible treatment.

In sum, a majority of women and adolescent girls with PCOS have insulin resistance and
consequent hyperinsulinemia. The latter commonly leads to hyperandrogenemia with
negative effects on reproductive function, impairing normal regulation of GnRH secretion
by steroids during pubertal maturation. Together, the increased LH drive and co-
gonadotropin action of insulin on the ovary maintain hyperandrogenemia. The majority of
evidence in adult women indicate that treatment of insulin resistance, either by lifestyle
changes or metformin, leads to improvement in reproductive and metabolic abnormalities
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and probably reduces future development of diabetes and arterial disease. It remains
unknown whether reducing insulin and thus androgen excess over a period of months to
years, will allow reversal of abnormal hypothalamic steroid feedback and restoration of
normal LH secretion. However present evidence would support every effort to reduce
hyperinsulinemia and its consequences both before and during puberty in
hyperandrogenemic girls. In addition to treating adults perhaps we should be more
aggressive and take the lead of our pediatric colleagues, many of whom have already
adopted metformin as a standard treatment in light of the difficulties of maintaining diet and
life style restrictions in the younger age group.

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Fertil Steril. Author manuscript; available in PMC 2013 January 1.