Detection of PCOS in adolescent girls is predicated primarily on hyperandrogenic symptoms such as hirsutism and acne, which arise as a result of increased serum androstenedione and testosterone levels.10 In addition, the most likely source of these androgens is the ovaries, rather than the adrenal glands.17,18 In normal puberty, increased production of adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEA-S) mark the onset of enhanced steroidogenesis, and stimulates the growth of pubic hair. This is followed by increases in ovarian androgens, which facilitate the development of sexual hair growth. In PCOS girls, it has been suggested that the adrenal contribution to the androgen pool may be greater than that of the ovary.19 Increased adrenal androgen may be a significant factor in the pathogenesis of PCOS, as accelerated pubic hair growth in girls before the age of 8 years, termed premature pubarche, increases the risk of functional ovarian hyperandrogenism, insulin resistance, and polycystic ovaries following puberty.20 This is particularly true of premature pubarchal girls with oligomenorrhoea, compared with those with regular cycles.21 Moreover, in these girls the acquisition of hyperandrogenism and hyperinsulinemia is correlated with a progressive reduction in recorded birth weight.20 The link between low birth weight and insulin resistance in children appears to be persistent throughout life, as indicated by studies performed in early and late adulthood.22–24 Low birth weight is commonly associated with fetal adrenal hypoplasia, and correspondingly low serum DHEA-S levels.25,26 However, adrenarche has been found to be most dramatic in children who were small for gestational age at birth, and, in particular, in those that exhibit postnatal catch-up growth. In this regard, it has been demonstrated in pairs of discordant siblings with similar weights in childhood that DHEA-S levels were higher in those of low birth weight compared with those born with normal weight.27 Increased DHEA-S secretion in girls serves as an endocrine marker for adrenarche, which is independent of and precedes gonadarche by several years. Thus, if as proposed, fetal growth modulates adrenarche, then increased DHEA-S may have reflected an exaggerated adrenarche in these children. Alternatively, it is unclear whether the relationship of premature pubarche and risk of PCOS is predicated on increased androgen production by the adrenal glands, a collective increase in circulating androgens (adrenal plus ovarian), or greater androgen bioactivity.
The rather broad range of LH secretion in PCOS suggests that other mechanisms may be instrumental in the excessive production of androgens. In particular, the presence of hyperinsulinemia and insulin resistance may enhance androgen production in adolescent girls at risk for PCOS.28 Previous studies have localised receptors for insulin, as well as insulin-like growth factor I (IGF-I) and IGF-II, to the theca compartment of ovaries from both normal adult women and PCOS patients.29 Accordingly, in vitro studies of normal human theca tissue have demonstrated that these growth factors are capable of enhancing androgen responses to LH, as well as independently stimulating androgen production.30–32 These findings are consistent with the observation that a reduction of hyperinsulinemia has been associated with significant decreases of serum androgens, without corresponding changes in LH, in women with PCOS treated with insulin-lowering drugs, and indirectly suggest a role for insulin in LH-stimulated androgen synthesis. Whether the physiological insulin resistance of puberty increases the risk of hyperandrogenemia in girls predisposed to PCOS is unknown.
Another mechanism that may impact hyperandrogenism is increased androgen bioactivity. Specific to girls with premature pubarche and those at risk for adolescent PCOS, hyperinsulinemia and hyperandrogenemia have been correlated to lowered sex-hormone binding globulin (SHBG), which provides an increased availability of free testosterone.33 In particular, the coexistence of obesity may lead to hyperandrogenism through several pathways. Reduction in SHBG and increased free testosterone levels are directly correlated with obesity.33 In addition, obese adolescents, particularly those with evidence of acanthosis nigricans, are highly likely to have insulin resistance with compensatory hyperinsulinemia, which may further suppress SHBG, leading to increased bioactive androgens. Finally, hyperandrogenemia, itself, may depress SHBG production.34