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There is evidence
that girls with low birth weight (LBW) and precocious pubarche (prior to 8
years of age) are at high risk of polycystic ovarian syndrome (PCOS) even if
not obese. Inbáñez and colleagues performed a randomized early prevention study
in 24 such girls 6 to 12 months post-menarche. In each, precocious pubarche was
diagnosed by high serum androstenedione and/or DHEAS levels. To be included in
the study, girls had to have a birth weight for gestational age <–1.5 SD,
BMI <26%, hyperinsulinemia on a 2-hour OGTT (peak serum insulin >150
µU/mL or mean serum insulin >84 mU/L), and subclinical ovarian
hyperandrogenism (17-HO progesterone response >160ng/dL to GnRH agonist).
They were randomized to receive either metformin 850 mg once daily or no
treatment for 12 months. Serial clinical and biochemical measurements were made
throughout the study.
There were no differences
in any parameter between the treated and untreated groups at baseline. All
subjects had increased androgen levels, abnormal lipid profiles, increased
total body fat and reduced lean body mass. By 12 months, the treated group
showed significant decreases in androgen levels, LDL cholesterol, and total
body and truncal fat mass, and increases in HDL cholesterol and lean body mass.
In addition, insulin resistance was normalized. Most of these effects were seen
between 3 and 6 months of treatment. The untreated group had significant
worsening of each of these parameters. The authors conclude that the early
post-menarchal years are an important period in the evolution of PCOS in girls
with the predisposing clinical criteria. The authors also noted that the
intervention was effective although limited to a once-daily medication without
any other lifestyle change.
Ibáñez L, Ferrer A, Ong K, Amin R, Dunger D, de Zegher F. Insulin sensitization early after menarche prevents progression from precocious pubarche to polycystic ovary syndrome. J Pediatr. 2004;144:23–29
Editor’s Comment: This is an important and well-designed
study performed by a group of investigators with significant research
experience in this area. Their suggested pathophysiologic schema for the
development of PCOS consists of girls with LBW but normal catch-up growth who
maintain reduced muscle mass and become insulin resistant. This predisposes
them to central obesity and excessive fat mass despite appearing lean, as well
as to PCOS. Ibáñez and colleagues also suggest that their data provided
evidence that the endocrine-metabolic state is primary rather than secondary in
this process. These are provocative conclusions and, if applicable to other
patient populations, suggest an important role for insulin sensitizers, such as
metformin, in the prevention of PCOS. Most pediatric endocrinologists are
encountering more patients with PCOS. Therapy often includes metformin, an
androgen-receptor blocker, and/or oral contraceptives, but the results are
rarely satisfactory. Clearly, there is a need to prevent the development of
this syndrome. The etiology may not be the same in all cases, but close
follow-up is merited in all girls born with LBW, as well as all girls
presenting with premature pubarche. It is not unreasonable to suggest
preventive therapy in some of these children.
William L. Clarke, MD
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Current GGH - Vol. 24 No. 1
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