MON-242 Early Breast Development in Overweight Girls: Does Estrogen Made by Adipose Tissue Play a Role?

Overweight/obese girls (OB) undergo thelarche but not menarche significantly earlier than normal weight girls (NW). It has been proposed that estrogen synthesized by adipose tissue may be contributory, yet OB do not have higher serum estrogen levels than NW matched on breast stage. We hypothesized that in OB, adipose tissue overlying the breast bud may be a ready source of estrogen that is sufficient to initiate thelarche because the primitive breast bud is intimately associated with the mammary fat pad during development (Anbazhagan Am J Anat ’91, Neville J Mammary Gland Biol Neoplasia ’98). Estrogen derived from mammary fat could act locally to induce thelarche but would not be detected in the circulation and therefore would not act systemically to induce uterine maturation/menses. To address this hypothesis, we measured reproductive hormones and imaged the breast, uterus, and ovaries in 80 pubertal, pre-menarchal girls (26 OB, 54 NW) aged 8.2-14.7 yrs. We used total percent body fat (%BF), determined by DXA, as a proxy for mammary fat, taking advantage of the positive correlation between these two measures (Novotny Am J Hum Biol ’11, Schautz Eur J Clin Nutr ’11, Zhu Eur Radiol ’16). We predicted that if estrogen derived from mammary fat contributes to breast maturation, then girls with higher %BF (and thus more mammary fat) would demonstrate immaturity of other estrogen-sensitive tissues (e.g. uterus, endometrial lining, vaginal epithelium) compared with girls of the same breast morphological stage (stages A-E based on Bruni et al. Adolesc Pediatr Gynecol ‘90) with lower %BF. OB were younger than NW (10.1 ± 1.1 vs. 11.3 ± 1.3 yrs, p<0.001) and more likely to be non-Hispanic Black or Hispanic (p=0.03). %BF ranged from 13.1-53.5% (3(rd)-97(th) percentiles). The distribution of Tanner breast and pubic hair stages was similar in NW and OB, and the full spectrum of breast development (A-E) was observed with stages D and E being the most common (59%) overall. Uterine volume, endometrial thickness, sex steroids (E1, E2, T, A’dione), and gonadotropins increased (p<0.001 for all), as expected, with breast morphological stage but %BF was not associated with any index of systemic estrogen action or reproductive hormones in a linear regression model controlled for breast morphological stage. These studies suggest that neither total %BF nor local (mammary) are clinically significant sources of estrogen capable of inducing breast development in OB. Taken together with the comparable gonadotropin levels observed in girls of the same breast morphological stage across a broad range of total %BF, these findings point to earlier activation of the hypothalamic-pituitary-ovarian axis in OB as the most likely cause of earlier thelarche in OB compared with NW. Longitudinal follow-up of this cohort is underway to investigate the effect of %BF on the maturational trajectory of the central components of the female reproductive axis.