Hyperandrogenism in obese girls: what is the significance?
Polycystic ovary syndrome (PCOS) is marked by (primarily ovarian) hyperandrogenemia and ovarian dysfunction. In many cases, PCOS first manifests during adolescence, and both peripubertal hyperandrogenemia and obesity are considered risk factors for the development of PCOS. Many, but not all, pubertal girls with obesity including those in early puberty exhibit relative hyperandrogenemia. However, the causes of peripubertal obesity-associated hyperandrogenemia, and mechanisms by which hyperandrogenemia could support progression to PCOS, are unknown.
Early data suggest that adrenal androgen responsiveness to ACTH is exaggerated in overweight peripubertal girls; this may partly reflect the effects of hyperinsulinemia. However, LH is the proximate stimulus for ovarian androgen production, and LH appears to be a better predictor of free testosterone than insulin in obese girls. Studies in adults with PCOS and in animal models suggest that excess androgens decrease GnRH pulse generator sensitivity to sex steroid negative feedback, augmenting GnRH pulsatility. These relationships LH stimulating androgen production and androgens increasing GnRH (and LH) secretion may constitute a vicious cycle that links peripubertal hyperandrogenemia and the development of full-blown PCOS.
How obesity and hyperandrogenemia affect the normal pubertal sequence of GnRH secretion is unclear. Early puberty is characterized by sleep-associated increases of LH (and by inference GnRH) pulse frequency, while LH pulse frequency decreases during sleep in late puberty. Early data suggest that these wake-sleep changes may partly reflect differential sensitivity of the GnRH pulse generator to negative feedback suppression depending on sleep status. We have proposed a working model in which relative hyperandrogenemia during puberty as may occur in obesity disrupts these relationships. Indeed, both early and late pubertal girls with obesity especially those with hyperandrogenemia exhibit blunted wake-sleep changes of LH pulsatility. Such alterations may increase LH release and limit FSH production, worsening hyperandrogenemia and promoting progression toward PCOS.
Declaration of interest: The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.