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Progestogen levels, progesterone receptor gene polymorphisms, and mammographic density changes: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study

Lee, Eunjung PhD1; Ingles, Sue A. DPH1; Van Den Berg, David PhD1; Wang, Wei PhD2; LaVallee, Chris MS1; Huang, Mei-Hua PhD3; Crandall, Carolyn J. MD, MS3; Stanczyk, Frank Z. PhD4; Greendale, Gail A. MD3; Ursin, Giske MD, PhD1,5,6

Menopause: The Journal of The North American Menopause Society: March 2012 - Volume 19 - Issue 3 - p 302–310
doi: 10.1097/gme.0b013e3182310f9f
Original Articles

Objective Estrogen plus progestin therapy (EPT) in postmenopausal women increases breast cancer risk and mammographic density to a higher extent than does estrogen therapy alone. Data from the randomized placebo-controlled Postmenopausal Estrogen/Progestinv Interventions trial showed that EPT-induced increases in serum estrone and estrone sulfate levels were positively correlated with increases in mammographic density. Here, after adjusting for serum estrone and estrone sulfate levels, we investigated the roles of posttreatment serum progestogen increase and of progesterone receptor gene (PGR) genetic variations on changes in mammographic density.

Methods We measured the percent mammographic density and serum progestogen levels in 280 Postmenopausal Estrogen/Progestin Interventions trial participants randomized to EPT treatment. Analyses of genetic variations in PGR were limited to 260 white women for whom we successfully obtained PGR genotypes. We used linear regression analyses to determine how an increase in progestogen levels and PGR genetic variation influenced mammographic density change after EPT.

Results The increase in posttreatment serum progestogen level was positively associated with greater increases in mammographic density after adjustment for covariates (P trend = 0.044). Compared with women in the lowest quartile of serum progestogen level, women in the highest quartile experienced a 3.5% greater increase in mammographic density (P = 0.046). We did not find a strong indication that genetic variation in PGR was associated with mammographic density increase or modified the association with serum progestogen; however, confidence in these null findings is constrained by our small sample size.

Conclusions Our results suggest that higher serum progestogen levels resulting from EPT treatment lead to greater increases in mammographic density.

Supplemental digital content is available in the text.Data from the randomized placebo-controlled Postmenopausal Estrogen/Progestin Interventions trial showed that higher serum progestogen levels resulting from estrogen plus progestin therapy lead to greater increases in mammographic density.

From the 1Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA; 2Cancer Prevention Institute of California, Fremont, CA; 3Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA; 4Department of Obstetrics/Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA; 5Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; and 6Cancer Registry of Norway, Oslo, Norway.

Received March 30, 2011; revised and accepted July 28, 2011.

Funding/support: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Mammographic Density Study was funded by National Institutes of Health, Department of Health and Human Services National Cancer Institute grant R01CA77708. This work was also supported by National Institutes of Health NIH/NIEHS T32 ES013678 (to C.L.).

Financial disclosure/conflicts of interest: None reported.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.menopause.org).

Address correspondence to: Giske Ursin, MD, PhD, Cancer Registry of Norway, Cancer Registry of Norway, PB 5313, Majorstuen, 0304 Oslo, Norway. E-mail: Giske.ursin@kreftregisteret.no

©2012The North American Menopause Society