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Endocrinology Unit (L.I.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Barcelona; Hormonal Laboratory, Hospital Materno-Infantil Vall d’Hebron, Autonomous University of Barcelona (N.P.), 08035 Barcelona; and Endocrinology Unit, Consorci Hospitalari de Terrassa (M.V.M.), 08227 Terrassa, Spain; and Department of Pediatrics, University of Leuven (F.d.Z.), 3000 Leuven, Belgium
Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu 2, 08950 Esplugues, Barcelona, Spain. E-mail: libanez{at}hsjdbcn.org
Precocious pubarche in girls is often preceded by low weight at birth and followed by hirsutism, ovarian hyperandrogenism, and oligomenorrhea in adolescence, the latter usually being accompanied by dyslipidemia and hyperinsulinism, which are, in turn, two major risk factors for cardiovascular disease in later life. We hypothesized that insulin resistance may be a key pathogenetic factor in this sequence.
We tested the hypothesis by assessing the effects of an insulin-sensitizing agent, metformin, given at a daily dose of 1275 mg for 6 months to 10 nonobese adolescent girls (mean age, 16.8 yr; body mass index, 21.9 kg/m2; birth weight, 2.7 kg) with hirsutism, ovarian hyperandrogenism (diagnosis by GnRH agonist test), oligomenorrhea, dyslipidemia, and hyperinsulinemia after precocious pubarche. Before the metformin trial, longitudinal studies in these girls had shown that hyperinsulinism was present at prepubertal diagnosis of precocious pubarche, and that it increased markedly in late puberty or early postmenarche.
Metformin treatment was well tolerated and was accompanied by a marked drop in hirsutism score, insulin response to oral glucose tolerance test, free androgen index, and baseline testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate levels (all P < 0.01). During metformin treatment, the LH and 17-hydroxyprogesterone hyperresponses to GnRH agonist were attenuated (P < 0.01); serum triglyceride, total cholesterol, and low density lipoprotein cholesterol levels decreased; and high density lipoprotein cholesterol rose. All girls reported regular menses within 4 months. Withdrawal of metformin treatment was followed, within 3 months, by a consistent reversal toward pretreatment conditions.
In conclusion, metformin treatment reduced hyperinsulinemia, hirsutism, and hyperandrogenism; attenuated the LH and 17hydroxyprogesterone hyperresponses to GnRH agonist; improved the atherogenic lipid profile; and restored eumenorrhea in nonobese adolescent girls with a history of precocious pubarche. These observations corroborate the idea that insulin resistance may indeed be a prime factor underpinning the sequence from reduced fetal growth, through precocious pubarche, to adolescent endocrinopathies that are reminiscent of so-called polycystic ovary syndrome.
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L. Ibanez, N. Potau, A. Ferrer, F. Rodriguez-Hierro, M. V. Marcos, and F. de Zegher Reduced Ovulation Rate in Adolescent Girls Born Small for Gestational Age J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3391 - 3393. [Abstract] [Full Text] [PDF]
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M. R. Palmert, C. M. Gordon, A. I. Kartashov, R. S. Legro, S. J. Emans, and A. Dunaif Screening for Abnormal Glucose Tolerance in Adolescents with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1017 - 1023. [Abstract] [Full Text] [PDF]
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L. Ibanez, K. Ong, N. Potau, M. V. Marcos, F. de Zegher, and D. Dunger Insulin Gene Variable Number of Tandem Repeat Genotype and the Low Birth Weight, Precocious Pubarche, and Hyperinsulinism Sequence J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5788 - 5793. [Abstract] [Full Text] [PDF]
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L. Ibanez, C. Valls, A. Ferrer, M. V. Marcos, F. Rodriguez-Hierro, and F. de Zegher Sensitization to Insulin Induces Ovulation in Nonobese Adolescents with Anovulatory Hyperandrogenism J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3595 - 3598. [Abstract] [Full Text] [PDF]
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