Lowering oral contraceptive norethindrone dose increases estrogen and progesterone receptor levels with no reduction in proliferation of breast epithelium: a randomized trial

• Published in: Contraception (Stoneham) 2012-09, Vol.86 (3), p.238-243
• Main Authors: Hovanessian-Larsen, Linda, Taylor, DeShawn, Hawes, Debra, Spicer, Darcy V, Press, Michael F, Wu, Anna H, Pike, Malcolm C, Pearce, C. Leigh
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Biopsy, Large-Core Needle; Breast epithelial cells; Cell Proliferation - drug effects; Combined oral contraceptives; Contraceptives, Oral, Combined - pharmacology; Dose-Response Relationship, Drug; Estrogen receptor; Estrogen Receptor alpha - drug effects; Estrogen Receptor alpha - metabolism; Ethinyl Estradiol - pharmacology; Female; Genital system. Reproduction; Gynecology. Andrology. Obstetrics; Humans; Image-Guided Biopsy; Immunohistochemistry; Mammary Glands, Human - drug effects; Mammary Glands, Human - metabolism; Mammary Glands, Human - pathology; Medical sciences; Norethindrone - pharmacology; Obstetrics and Gynecology; Pharmacology. Drug treatments; Progesterone receptor; Progestin dose; Proliferation markers; Receptors, Progesterone - drug effects; Receptors, Progesterone - metabolism; Ubiquitin-Protein Ligases - drug effects; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0010-7824; 1879-0518
• DOI: 10.1016/j.contraception.2011.12.015

Abstract Background This study was conducted to compare breast epithelial-cell proliferation and estrogen and progesterone receptor levels in women taking one of two oral contraceptives (OCs) containing the same dose of estrogen but different doses of the progestin norethindrone (NET). Study Design Thirty-three women were randomly assigned 1:1 to one of two OCs with 35-mcg ethinylestradiol (EE2) but different doses of NET — 1 or 0.4 mg. At the end of the active pill phase of the third OC cycle, a breast biopsy was performed and the percentages of epithelial cells of the terminal duct lobular units were measured for Ki67 (MIB1), progesterone receptors A and B (PRA and PRB, respectively), and estrogen receptor α (ERα). Results The biopsies from 27 women had sufficient epithelium for analysis. The percentages of cells positive for PRA, PRB and ERα were approximately double with the lower progestin dose (PRA: p=.041; PRB: p=.030; ERα: p=.056). The Ki67 percentage was not reduced with the lower progestin dose (12.5% for 0.4-mg NET vs. 7.8% for 1.0-mg NET). Conclusions The increase in PRA-, PRB- and ERα-positive cells with the 60% lower progestin dose OC appears likely to account for its failure to decrease breast-cell proliferation. This breast-cell proliferation result is contrary to that predicted from the results of lowering the medroxyprogesterone acetate dose in menopausal hormone therapy.