Marshall and Dunaif Page 2
maintaining changes over a prolonged period of time, and recedivism is unfortunately all to
common in the absence of ongoing organized programs. The thiazolidinediones,
(pioglitazone and rosiglitazone are presently available) have been shown to be effective in
NIH-PA Author Manuscript
controlled trials, reducing plasma androgens and improving insulin sensitivity and glucose
tolerance (17,18). While effective, TZDs have significant practical limitations in that they
induce weight gain, and more recently have been associated with increased coronary artery
disease and myocardial infarction. World wide, we have over 40 years experience using the
biguanide metformin, which is FDA approved for managing type 2 diabetes mellitus.
Present understanding of the mechanism of metformin action is incomplete, but it activates
the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway (19).
AMPK activation appears to be a mechanism reducing hepatic glucose production and
increasing insulin sensitivity in peripheral tissues, with additional effects of lowering plasma
free fatty acids.
Metformin has been demonstrated to be effective in normalizing several parameters in
women with PCOS. Meta analyses (21,22) reviewed some 30 trials and revealed that
ovulation was enhanced compared to placebo alone, and resulted in fewer multiple
pregnancies while being less effective than clomiphene citrate per se. Other data suggest that
metformin is effective in improving ovulation rates in women with clomiphene resistance.
Further support for the effectiveness of metformin is seen from a large meta analysis of
subjects at risk for diabetes mellitus, including those with and without PCOS and those with
NIH-PA Author Manuscript
and without obesity (23). Overall, treatment with metformin for at least 8 weeks reduced
weight, fasting glucose, triglycerides and LDL by 4.5–5.6%, fasting insulin by 14%,
calculated insulin resistance (HOMA-IR) by 22% and reduced new onset diabetes by 40%.
Importantly in PCOS metformin for up to 6 months reduced hirsutism and in most studies
significantly reduced androgen levels, with reductions in testosterone being between 25–
50% (24,25). Other studies have not revealed as great a reduction in testosterone and
metformin alone is not as effective as a combined oral contraceptive, though the
combination may enhance responses (26).
Thus in women without evidence of renal or hepatic disease, metformin appears effective in
reducing the negative effects of PCOS on both reproductive and metabolic health. A main
limitation can be side effects, which are predominantly gastroenterological consisting of
bloating, abdominal discomfort, nausea and diarrhea. The latter is usually dose dependant
and can be minimized by gradually building up the dose of metformin, starting at 250–
500mg per day taken just before the main meal and increasing over a period of 1–2 months,
reaching doses of 2,000–2,500mg per day. If GI side effects intervene, reducing the dose to
the prior symptom free level for a period of 7–10 days, can often be followed by a
resumption of the dosage increase.
NIH-PA Author Manuscript
The above sections emphasize the overall positive action of metformin in reducing signs and
symptoms of PCOS. They also bring to mind the question of whether we should be more
aggressive in treating younger subjects who are obese and have hyperandrogenemia (HA).
Paralleling the marked increase in obesity in the last 30–40 years, HA is relatively common
being present in 60–70% of pre and post pubertal girls with marked obesity (BMI >90–
95%ile for age) (27,28, 29). Given that hyperandrogenemic syndromes prior to puberty are a
risk factor for subsequent development of PCOS (30), and approximately half of HA
adolescents have already developed resistance to progesterone inhibition of the GnRH pulse
generator (9), efforts to ameliorate the excess androgen production would seem appropriate.
Indeed abnormal regulation of GnRH/LH secretion with persistently rapid GnRH pulse
secretion is already present in premenarchal adolescent girls with HA (31), suggesting that
prepubertal androgen excess may modify hypothalamic set points for steroid feedback
during pubertal maturation (32). In adults impairment of progesterone inhibition of GnRH
Fertil Steril. Author manuscript; available in PMC 2013 January 1.