Insulin Resistance, Premature Adrenarche, and a Risk of the Polycystic Ovary Syndrome (PCOS)

https://doi.org/10.1016/S1043-2760(98)00014-9Get rights and content

Abstract

Timing of puberty and final height are usually normal in girls with a history of premature adrenarche. However, these patients show an increased frequency of ovarian hyperandrogenism, hyperinsulinism and dyslipemia at adolescence. The hyperinsulinemia and lipid disturbances can often be detected in the prepubertal period, recommending long-term follow-up of these patients into adulthood.

Section snippets

Auxological outcome and pubertal milestones of girls with premature adrenarche

In the absence of enzymatic defects of adrenal steroidogenesis, and according to follow-up results in small groups of patients, the pubertal outcome of girls with premature adrenarche has been reported to be normal (Pang 1984). We undertook a study including 127 girls with isolated premature adrenarche from two European populations with similar ethnic characteristics, of whom 69 had entered puberty, 42 had reached menarche and 38 had attained final height (Ibáñez et al. 1992). Advanced bone age

Ovarian function in girls diagnosed with premature adrenarche

Although data on the auxological outcome appeared to be reassuring, an increased incidence of hirsutism and polycystic ovary syndrome (PCOS) in peripubertal and pubertal premature adrenarche girls, although not well documented, have been pointed out by some authors (Yen 1980Ibáñez et al. 1990).

Premature adrenarche and hyperinsulinemia

Hyperinsulinemia, insulin resistance and adrenal hyperandrogenism are common features both in obese and lean women and adolescents with PCOS and FOH (Lucky et al. 1986Jialal et al. 1987Dunaif et al. 1989Nestler et al. 1989O'Meara et al. 1993Rittmaster et al. 1993Apter et al. 1995Ibáñez et al. 1995bMorales et al. 1996). The defects producing insulin resistance in PCOS appear to be genetic, involving the early steps of insulin receptor-mediated signaling, and are associated with increased

Insulin and the peripubertal onset of PCOS/FOH

Puberty has been associated with increasing fasting and glucose- stimulated insulin concentrations and a decrease in insulin sensitivity (Caprio et al. 1989Amiel et al. 1991Potau et al. 1997). The insulin resistance during puberty is restricted to peripheral glucose metabolism, and is associated with concomitant increases in plasma growth hormone, IGF-I and IGFBP-3 levels and a decrease in IGFBP-1 and SHBG concentrations (Holly et al. 1989Amiel et al. 1991Potau et al. 1997). The transient

Dyslipemia and premature adrenarche

Prospective epidemiological studies suggest that hyperinsulinemia may be an independent risk factor for the development of cardiovascular disease, playing a major role in the genesis of dyslipemia in subjects with both normal and impaired glucose tolerance (Laakso et al. 1990Després et al. 1996). The cluster of highly atherogenic metabolic abnormalities of syndrome X [hyperinsulinemia, glucose intolerance, increased very low-density lipoproteins (VLDL) and triglycerides, decreased high-density

Conclusions

Premature adrenarche is not necessarily a benign condition. Long-term follow-up of these patients is highly recommended owing to the increased incidence of ovarian hyperandrogenism, hyperinsulinemia and dyslipemia. Prospective studies of premature adrenarche girls should be undertaken to clarify the pathogenetic link(s) between hyperandrogenism and hyperinsulinism.

References (70)

  • RL Barbieri

    Polycystic ovarian disease

    Annu Rev Med

    (1991)
  • RL Barbieri et al.

    Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism

    J Clin Endocrinol Metab

    (1986)
  • RB Barnes et al.

    Pituitary-ovarian responses to nafarelin testing in the polycystic ovary syndrome

    New Engl J Med

    (1989)
  • MA Birsdall et al.

    Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization

    Ann Intern Med

    (1997)
  • JF Cara et al.

    Insulin-like growth factor I and insulin potentiate luteinizing hormone-induced androgen synthesis by rat ovarian thecal-interstitial cells

    Endocrinology

    (1988)
  • ML De la Puente et al.

    Cross-sectional growth study of the child and adolescent population of Catalonia (Spain)

    Ann Hum Biol

    (1997)
  • JP Després

    The insulin resistance-dyslipidemia syndrome: the most prevalent cause of coronary artery disease?

    Can Med Assoc

    (1993)
  • JP Després et al.

    Hyperinsulinemia as an independent risk factor for ischemic heart disease

    New Engl J Med

    (1996)
  • A Dunaif

    Insulin resistance and ovarian dysfunction

    Endocrinologist

    (1992)
  • A Dunaif

    Hyperandrogenic anovulation (PCOS): a unique disorder of insulin action associated with an increased risk of non- insulin-dependent diabetes

    Am J Med

    (1995)
  • A Dunaif et al.

    Profound peripheral insulin resistance, independent of obesity, in the polycystic ovary syndrome

    Diabetes

    (1989)
  • DA Ehrmann et al.

    Detection of functional ovarian hyperandrogenism in women with androgen excess

    New Engl J Med

    (1992)
  • DA Ehrmann et al.

    Polycystic ovary syndrome as a form of functional ovarian hyperandrogenism due to dysregulation of androgen secretion

    Endocr Rev

    (1995)
  • MW Goldzieher et al.

    The polycystic ovary. I. Clinical and histologic features

    J Clin Endocrinol Metab

    (1962)
  • SM Haffner et al.

    Prospective analysis of the insulin-resistance syndrome (syndrome X)

    Diabetes

    (1992)
  • JMP Holly et al.

    Relationship between the pubertal fall in sex hormone binding globulin and insulin-like growth factor binding protein-1. A synchronized approach to pubertal development?

    Clin Endocrinol

    (1989)
  • R Homburg

    Polycystic ovary syndrome—from gynaecological curiosity to multisystem endocrinopathy

    Hum Reprod

    (1996)
  • L Ibáñez et al.

    Post-pubertal assessment in girls with premature pubarche, clinical, biochemical, and echographic findings [abst]

    Horm Res

    (1990)
  • L Ibáñez et al.

    Natural history of premature pubarche, an auxological study

    J Clin Endocrinol Metab

    (1992)
  • L Ibáñez et al.

    Postpubertal outcome in girls diagnosed of premature pubarche during childhood, increased frequency of functional ovarian hyperandrogenism

    J Clin Endocrinol Metab

    (1993)
  • L Ibáñez et al.

    Source localization of androgen excess in adolescent girls

    J Clin Endocrinol Metab

    (1994)
  • L Ibáñez et al.

    Usefulness of an ACTH test in the diagnosis of non-classical 21-hydroxylase deficiency among children presenting with premature pubarche

    Horm Res

    (1995)
  • L Ibáñez et al.

    Ovarian 17-hydroxyprogesterone hyperresponsiveness to gonadotropin-releasing hormone (GnRH) agonist challenge in women with polycystic ovary syndrome is not mediated by luteinizing hormone hypersecretion, evidence from GnRH agonist and human chorionic gonadotropin stimulation testing

    J Clin Endocrinol Metab

    (1996)
  • L Ibáñez et al.

    Lipid patterns and their relation to insulin levels in girls with a history of premature pubarche [abst]

    Horm Res

    (1996)
  • L Ibáñez et al.

    Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism

    J Clin Endocrinol Metab

    (1996)
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