Comparative effects of oral conjugated equine estrogens and micronized 17beta-estradiol on breast proliferation: a retrospective analysis.
OBJECTIVE
To evaluate the effects of oral conjugated equine estrogens (CEE) and micronized 17beta-estradiol (E2) on breast proliferation in a postmenopausal primate model.


METHODS
Data from nine studies were analyzed retrospectively. The primary outcome measure was breast epithelial proliferation determined by immunolabeling for the Ki67 antigen. Other measures included progesterone receptor expression and endometrial thickness (as surrogate markers of systemic estrogen exposure) and urinary estrogen metabolite profile. All CEE doses were given at the human equivalent of 0.625 mg/day (n = 281), whereas E2 was given at the human equivalent of 1.0 mg/day or less (n = 131).


RESULTS
Oral CEE resulted in a modest overall increase in breast epithelial proliferation of 75% that reached significance at P < 0.05 compared with placebo in one of four parallel-arm studies. In contrast, oral E2 resulted in a more substantial increase in breast epithelial proliferation of 259% (all studies) to 330% (parallel-arm studies only) that reached significance at P < 0.05 in all five E2 studies evaluated. Breast epithelial expression of progesterone receptor, a widely used marker of estrogen receptor activity, and endometrial thickness showed similar increases after treatment with CEE and E2 (P < 0.05 in all available studies). Relative amounts of urinary methoxyestrogens and the 2-hydroxyestrogen-to-16alpha-hydroxyestrone ratio were higher after CEE compared with E2 treatment (P < 0.05 for all).


CONCLUSIONS
This retrospective analysis of oral estrogen effects in postmenopausal macaques suggests that standard doses of CEE may result in less estrogen-induced epithelial proliferation in the breast compared with E2.
Wood
Charles E
CE
Departments of 1Pathology/Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040, USA. chwood@wfubmc.edu
Clarkson
Thomas B
TB
Chen
Haiying
H
Veenstra
Timothy D
TD
Xu
Xia
X
Scott
Latanya
L
Cline
J Mark
JM
D000818:Animals; D001940:Breast / Q000187:drug effects* / Q000473:pathology*; D001943:Breast Neoplasms / Q000139:chemically induced; D049109:Cell Proliferation / Q000187:drug effects; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D004717:Endometrium / Q000187:drug effects; D015914:Estrogen Replacement Therapy / Q000379:methods*; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D017698:Postmenopause / Q000187:drug effects; D011960:Receptors, Estrogen / Q000187:drug effects; D011980:Receptors, Progesterone / Q000187:drug effects; D012189:Retrospective Studies; D012307:Risk Factors
D003271:Contraceptive Agents, Female; D004966:Estrogens, Conjugated (USP); D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D017258:Medroxyprogesterone Acetate