Childhood obesity and its impact on the development of adolescent PCOS

Abstract

Obesity exacerbates the reproductive and metabolic manifestations of polycystic ovary syndrome (PCOS). The symptoms of PCOS often begin in adolescence, and the rising prevalence of peripubertal obesity has prompted concern that the prevalence and severity of adolescent PCOS is increasing in parallel. Recent data have disclosed a high prevalence of hyperandrogenemia among peripubertal adolescents with obesity, suggesting that such girls are indeed at risk for developing PCOS. Obesity may impact the risk of PCOS via insulin resistance and compensatory hyperinsulinemia, which augments ovarian/adrenal androgen production and suppresses sex hormone-binding globulin (SHBG), thereby increasing androgen bioavailability. Altered luteinizing hormone (LH) secretion plays an important role in the pathophysiology of PCOS, and although obesity is generally associated with relative reductions of LH, higher LH appears to be the best predictor of increased free testosterone among peripubertal girls with obesity. Other potential mechanisms of obesity-associated hyperandrogenemia include enhanced androgen production in an expanded fat mass and potential effects of abnormal adipokine/cytokine levels. Adolescents with PCOS are at risk for comorbidities such as metabolic syndrome and impaired glucose tolerance, and concomitant obesity compounds these risks. For all of these reasons, weight loss represents an important therapeutic target in obese adolescents with PCOS.

Figure 1

(A–E) Basic diagrammatic representations of some of the ways that obesity could be related to PCOS. Importantly, relationships are not mutually exclusive. As described in the text, robust data support the relationship depicted in (A), although data also support the relationships shown in (B)–(D). Note that each arrow could represent a chain of relationships (e.g., for [A], obesity contributes to insulin resistance, which leads to hyperinsulinemia, which enhances ovarian androgen production). In addition, each arrow could encompass a vast number of different relationships (e.g., obesity could influence development of PCOS via its effects on sex steroid production, sex steroid bioavailability, follicular development, peripheral steroid metabolism, etc.). As an example of the relationship depicted in (D), both obesity and PCOS appear to have effects on insulin resistance that are at least partly independent of each other. PCOS, polycystic ovary syndrome.

Figure 2

Total testosterone, SHBG, and free testosterone concentrations in obese (BMI-for-age percentile ≥ 95; solid squares) and normal weight girls (BMI-for-age percentile < 85; open squares) grouped by Tanner stage. Data shown as mean ± SEM. *p < 0.05; **p ≤ 0.01; ***p ≤ 0.001; ****p ≤ 0.0001 before Bonferroni correction. SEM, standard error of the mean; SHBG, sex hormone–binding globulin. (Reprinted with permission from McCartney et al. [35])

Figure 3

Free testosterone concentration in obese peripubertal girls partitioned into pubertal stages as follows: early pubertal, Tanner breast stage 2 or Tanner stage 1 with estradiol ≥ 20 pg/mL; mid-pubertal, Tanner breast stage 3; and late pubertal, Tanner breast stages 4 or 5. Shaded boxes represent the normal range of free testosterone for each pubertal group. (Reprinted with permission from Knudsen et al. [37])

Figure 4

Schematic of potential mechanisms by which obesity contributes to the development of adolescent PCOS. Please refer to the text for details. ACTH, adrenocorticotropic hormone; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; IL-6, interleukin 6; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; SHBG, sex hormone binding globulin; TNF-α, tumor necrosis factor α.