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


METHODS
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.
Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Linda
L
Hovanessian-Larsen
DeShawn
D
Taylor
Debra
D
Hawes
Darcy V
DV
Spicer
Michael F
MF
Press
Anna H
AH
Wu
Malcolm C
MC
Pike
C Leigh
CL
Pearce
D000328:Adult; D062005:Biopsy, Large-Core Needle; D049109:Cell Proliferation / Q000187:drug effects; D003277:Contraceptives, Oral, Combined / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha / Q000187:drug effects* / Q000378:metabolism; D004997:Ethinyl Estradiol / Q000494:pharmacology; D005260:Female; D006801:Humans; D061705:Image-Guided Biopsy; D007150:Immunohistochemistry; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009640:Norethindrone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000187:drug effects* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism
D003277:Contraceptives, Oral, Combined; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D004997:Ethinyl Estradiol; C513496:MIB1 ligase, human; D044767:Ubiquitin-Protein Ligases; D009640:Norethindrone