A Longitudinal Study of Estrogen-Responsive Tissues and Hormone Concentrations in Infants Fed Soy Formula

J Clin Endocrinol Metab. 2018 May 1;103(5):1899-1909. doi: 10.1210/jc.2017-02249.


Purpose: Chemicals with hormonelike activity, such as estrogenic isoflavones, may perturb human development. Infants exclusively fed soy-based formula are highly exposed to isoflavones, but their physiologic responses remain uncharacterized. Estrogen-responsive postnatal development was compared in infants exclusively fed soy formula, cow-milk formula, and breast milk.

Methods: We enrolled 410 infants born in Philadelphia-area hospitals between 2010 and 2014; 283 were exclusively fed soy formula (n = 102), cow-milk formula (n = 111), or breast milk (n = 70) throughout the study (birth to 28 or 36 weeks for boys and girls, respectively). We repeatedly measured maturation index (MI) in vaginal and urethral epithelial cells using standard cytological methods, uterine volume and breast-bud diameter using ultrasound, and serum estradiol and follicle-stimulating hormone levels. We estimated MI, organ-growth, and hormone trajectories by diet using mixed-effects regression splines.

Results: Maternal demographics did not differ between cow-milk-fed and soy-fed infants but did differ between formula-fed and breastfed infants. Vaginal-cell MI trended higher (P = 0.01) and uterine volume decreased more slowly (P = 0.01) in soy-fed girls compared with cow-milk-fed girls; however, their trajectories of breast-bud diameter and hormone concentrations did not differ. We observed no significant differences between boys fed cow-milk vs soy formula; estradiol was not detectable. Breastfed infants differed from soy-formula-fed infants in vaginal-cell MI, uterine volume, and girls' estradiol and boys' breast-bud diameter trajectories.

Conclusions: Relative to girls fed cow-milk formula, those fed soy formula demonstrated tissue- and organ-level developmental trajectories consistent with response to exogenous estrogen exposure. Studies are needed to further evaluate the effects of soy on child development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Breast / drug effects*
  • Breast / growth & development
  • Cattle
  • Child Development / drug effects*
  • Estrogens / pharmacology*
  • Female
  • Humans
  • Infant
  • Infant Formula / chemistry*
  • Infant Nutritional Physiological Phenomena
  • Infant, Newborn
  • Isoflavones / pharmacology
  • Longitudinal Studies
  • Male
  • Milk / chemistry
  • Milk / physiology
  • Milk, Human / chemistry
  • Milk, Human / physiology
  • Phytoestrogens / pharmacology
  • Urethra / drug effects*
  • Urethra / growth & development
  • Uterus / drug effects*
  • Uterus / growth & development


  • Estrogens
  • Isoflavones
  • Phytoestrogens