Value of the micropig model of menopause in the assessment of benefits and risks of postmenopausal therapies for cardiovascular and reproductive tissues

Fertil Steril. 2003 Mar;79 Suppl 1:779-88. doi: 10.1016/s0015-0282(02)04826-4.

Abstract

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.

Design: Prospective, randomized, controlled periclinical trial.

Setting: Medical university animal facility.

Animal(s): Fifteen sexually mature Yucatan micropigs and 15 ovariectomized micropigs.

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

Main outcome measure(s): 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.

Result(s): 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.

Conclusion(s): 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Body Weight / drug effects
  • Body Weight / physiology
  • C-Reactive Protein / biosynthesis
  • Cholesterol / blood
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / prevention & control*
  • Disease Models, Animal*
  • Estrogen Receptor Modulators / pharmacology*
  • Estrogens, Conjugated (USP) / pharmacology*
  • Female
  • Hormone Replacement Therapy / methods*
  • Mammary Glands, Animal / pathology
  • Menopause / blood
  • Menopause / physiology
  • Organ Size / drug effects
  • Organ Size / physiology
  • Prospective Studies
  • Pyrrolidines / pharmacology*
  • Swine
  • Swine, Miniature*
  • Tunica Intima / pathology
  • Uterus / pathology

Substances

  • Estrogen Receptor Modulators
  • Estrogens, Conjugated (USP)
  • Pyrrolidines
  • C-Reactive Protein
  • levormeloxifene
  • Cholesterol