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Judy C. Bernbaum,¹ David M. Umbach,² N. Beth Ragan,³ Jeanne L. Ballard,⁴ Janet I. Archer,⁵ Holly Schmidt-Davis,⁶ and Walter J. Rogan³

¹Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA; ²Biostatistics Branch, and ³Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; ⁴Department of Neonatology, Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA; ⁵Survey & Epidemiology Services Division, Social & Scientific Systems, Inc. (formerly Coda, Inc.), Durham, North Carolina, USA; ⁶Westat Inc., Durham, North Carolina, USA

Abstract
Background: Soy formula containing estrogenic isoflavones is widely used in the United States. Infants consuming soy formula exclusively have high isoflavone exposures. We wanted to study whether soy formula prolonged the physiologic estrogenization of newborns, but available quantitative descriptions of the natural history of breast and genital development are inadequate for study design.

Objective: We piloted techniques for assessing infants' responses to the withdrawal from maternal estrogen and gathered data on breast and genital development in infants at different ages.

Methods: We studied 37 boys and 35 girls, from term pregnancies with normal birth weights, who were < 48 hr to 6 months of age, and residents of Philadelphia, Pennsylvania, during 2004–2005. One-third of the children of each sex and age interval were exclusively fed breast milk, soy formula, or cow-milk formula. Our cross-sectional study measured breast adipose tissue, breast buds, and testicular volume ; observed breast and genital development ; and collected vaginal wall cells and information on vaginal discharge. We assessed reliability of the measures.

Results: Breast tissue was maximal at birth and disappeared in older children, consistent with waning maternal estrogen. Genital development did not change by age. Breast-milk secretion and withdrawal bleeding were unusual. Vaginal wall cells showed maximal estrogen effect at birth and then reverted ; girls on soy appeared to show reestrogenization at 6 months.

Conclusions: Examination of infants for plausible effects of estrogens is valid and repeatable. Measurement of breast tissue and characterization of vaginal wall cells could be used to evaluate exposures with estrogen-like effects.

Key words: breast bud, estrogen, human milk, infant formula, testis, vaginal maturation index. Environ Health Perspect 116:416–420 (2008) . doi:10.1289/ehp.10409 available via http://dx.doi.org/ [Online 12 December 2007]

Address correspondence to W.J. Rogan, NIEHS, Post Office Box 12233, Mail Drop A3-05, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-4578. Fax: (919) 541-2511. E-mail: rogan@niehs.nih.gov

We thank T. Gregg, A. DiBenedetto, T. Weimer, and V. Stallings of Children's Hospital of Philadelphia ; B. Stroehla of Coda, Inc. ; and L. Finberg of UCSF.

This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. Children's Hospital of Philadelphia ; Social & Scientific Systems, Inc. (formerly Coda) , Silver Spring, Maryland ; and Westat, Inc., Rockville, Maryland, were supported by contracts N01-ES-85433 and N01-ES-55546.

W.J.R. accepted travel funds from Nestlé in 1998, and from the American Oil Chemists' Society in 2005 to give talks at meetings. Findings were presented in a poster at the 2006 Pediatric Academic Societies' Annual Meeting, San Francisco, CA, USA, and at the 2006 Children's Environmental Health: Endocrine Disruptors/Risk Assessment and Children symposium in Berkeley, CA, USA. All other authors declare they have no competing financial interests.

Received 25 April 2007 ; accepted 11 December 2007.