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Sensitization to Insulin in Adolescent Girls to Normalize Hirsutism, Hyperandrogenism, Oligomenorrhea, Dyslipidemia, and Hyperinsulinism after Precocious Pubarche

Precocious pubarche in girls is often preceded by low birth weight and followed by ovarian hyperandrogenism, hirsutism, and menstrual disturbances. These symptoms are accompanied by dyslipidemia and hyperinsulinism. The authors proposed that insulin resistance is a key pathogenic factor in this metabolic sequence. This study enrolled 10 girls who were at least 3 years postmenarchal and had a history of precocious pubarche and ovarian hyperandrogenism. Body mass index was within 2 SD from the mean for age. A sequential study design with on-off treatment phases was used. The subjects were treated for 6 months with a once daily dose ofmetformin 1,275 mg followed by discontinuation of therapy for 3 months. Laboratory studies, including a 2-hour oral glucose tolerance test, were conducted at baseline, after 6 months on treatment and after 3 months off treatment. Metformin was associated with a striking decrease in hirsutism, circulating androgen levels, and an improved lipid profile. All girls reported regular menstrual cycles within 4 months. These variables returned to pretreatment levels after the end of therapy. The constellation of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in nonobese young women may be part of a developmental disorder that begins with low birth weight. This study supports longitudinal evidence that insulin resistance is present before puberty and increases over time. These findings raise the possibility that hyperinsulinism and its associated metabolic abnormalities can be prevented in an at-risk target population. Commentary: Premature pubarche may not be an entirely benign condition. Its links to insulin resistance, hyperinsulinism, and several metabolic abnormalities make it a marker for other disease scenarios. From a clinical standpoint, the potential role of insulin resistance makes it a key target for medical management. The underlying pathophysiology has not been fully elucidated, but clinical observations have suggested several treatment modalities. Metformin has been shown to enhance peripheral tissue sensitivity to insulin and inhibit hepatic glucose production. Ibanez et al conducted a randomized clinical trial that demonstrated improvement in several metabolic parameters in their subjects. The authors did not look at the contribution of adrenal androgen production, and the girls were determined to be hyperinsulinemic based on serum insulin values during oral glucose tolerance testing. They did not have basal hyperinsulinism. As noted in an accompanying editorial (Oberfield SE. Metabolic lessons from the study of young adolescents with polycystic ovary syndrome-is insulin, indeed, the culprit? J Clin Endocrinol Metab. 2000;85:3520-3525), this paper is 1 of the few studies that examine the use of metformin in a young population. Despite how the subjects were identified, the results are promising. Identification and treatment of these individuals may prevent more significant problems such as polycystic ovary syndrome and cardiovascular disease. It is hoped that large-scale prospective clinical trials are on the horizon. -AD