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To the Editor: It is possible that the results of the WHI investigation¹ may be explained in part by the action of estrogen on biological factors that increase breast cancer risk in postmenopausal women.² Oral estrogens, through their metabolic action, oppose insulin resistance. Furthermore, through their hepatocellular actions, they cause an increase in sex hormone–binding globulin level, and a decrease in insulin-like growth factor I (IGF-I) activity, due to both a reduction in IGF-I level and an increase in IGF-binding protein-1 level.² IGF-I is a potent mitogen for breast tissue and breast cancer cells.

By contrast, MPA and other progestins oppose the estrogen-induced reduction in IGF-I level.^2-3 This could contribute to the increase in breast cancer risk observed with the use of estrogens plus progestin as previously reported by Chlebowski et al.⁴

Carlo Campagnoli, MD
ginendocrinol@oirmsantanna.piemonte.it

Chiara Abbà, MD; Simona Ambroggio, MD; Clementina Peris, MD
Unit of Endocrinological Gynecology
Sant'Anna Gynecological Hospital
Torino, Italy

1. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712. FREE FULL TEXT 2. Campagnoli C, Biglia N, Cantamessa C, et al. HRT and breast cancer risk: a clue for interpreting the available data. Maturitas. 1999;33:185-190. PUBMED 3. Heald A, Selby PL, White A, Gibson JM. Progestins abrogate estrogen-induced changes in the insulin-like growth factor axis. Am J Obstet Gynecol. 2000;183:593-600. FULL TEXT | WEB OF SCIENCE | PUBMED 4. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen-plus-progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative randomized trial. JAMA. 2003;289:3243-3253. FREE FULL TEXT

Letters Section Editor: Robert M. Golub, MD, Senior Editor.

JAMA. 2004;292:684.

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