Value of the micropig model of menopause in the assessment of benefits and risks of postmenopausal therapies for cardiovascular and reproductive tissues.
OBJECTIVE
To extend the comparative database demonstrating the cardioprotective benefits of estrogen therapy to an additional relevant species and to assess the usefulness of this model for studies designed to assess benefits and risks of postmenopausal therapies.


METHODS
Prospective, randomized, controlled periclinical trial.


METHODS
Medical university animal facility.


METHODS
Fifteen sexually mature Yucatan micropigs and 15 ovariectomized micropigs.


METHODS
Oral conjugated equine estrogens (CEE), 0.625 mg/d, or levormeloxifene, 37.5 mg/d, for 182 days.


METHODS
Coronary artery atherosclerosis was measured by digitization, uteri were weighed, and uterine and mammary tissues were evaluated histologically and morphometrically. Mean blood pressure was measured by oscillometry, C-reactive protein by enzyme-linked immunosorbent assay, and serum lipids by enzymatic methods.


RESULTS
Coronary artery atherosclerosis was reduced 51% in animals that received CEE compared with controls. Levels of C-reactive protein increased by 12% with both treatments. Serum lipid levels and mean blood pressure did not differ among groups. Levormeloxifene produced a 5.9-fold increase in the uterine-to-body weight ratio. Histologic and morphometric data indicate that levormeloxifene has uterotrophic and mammotrophic effects.


CONCLUSIONS
The micropig model extends the comparative evidence for cardioprotection provided by estrogen therapy to an additional highly relevant species, thus supporting the rationale for a clinically beneficial role of estrogen for the heart. The marked uterine effects of levormeloxifene detected by this model are probably highly predictive of the adverse events that would be encountered in clinical trials.
Goodrich
James A
JA
Department of Comparative Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA. goodrija@musc.edu
Clarkson
Thomas B
TB
Cline
J Mark
JM
Jenkins
Alicia J
AJ
Del Signore
Mario J
MJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002097:C-Reactive Protein / Q000096:biosynthesis; D002784:Cholesterol / Q000097:blood; D003324:Coronary Artery Disease / Q000097:blood / Q000517:prevention & control*; D004195:Disease Models, Animal; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D020249:Hormone Replacement Therapy / Q000379:methods*; D008321:Mammary Glands, Animal / Q000473:pathology; D008593:Menopause / Q000097:blood / Q000502:physiology; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D011446:Prospective Studies; D011759:Pyrrolidines / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D017539:Tunica Intima / Q000473:pathology; D014599:Uterus / Q000473:pathology
D020847:Estrogen Receptor Modulators; D004966:Estrogens, Conjugated (USP); D011759:Pyrrolidines; D002097:C-Reactive Protein; C108255:levormeloxifene; D002784:Cholesterol