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Effects on Bone, Plasma Estradiol Concentrations, Endometrium, and Lipid Levels

Harry K. Genant, MD; Johna Lucas, MD; Stuart Weiss, MD; Mark Akin, MD; Ronald Emkey, MD; Heidi McNaney-Flint, MD; Robert Downs, MD; Joseph Mortola, MD; Nelson Watts, MD; Hwa Ming Yang, PhD; Niranyan Banav, PhD; John J. Brennan, PhD; Joseph C. Nolan, PhD

Arch Intern Med. 1997;157(22):2609-2615.

Abstract
Background
Prospective studies have shown that doses equivalent to conjugated equine estrogens of 0.625 mg/d or higher are needed to produce a significant increase in bone mineral density of the lumbar spine.

Objectives
To determine the effects of unopposed esterified estrogens on bone mineral density, lipid levels, and endometrial tissue structure, and to relate these effects to changes in plasma estradiol levels.

Methods
Four hundred six postmenopausal women were given calcium, 1000 mg/d, and randomly assigned to receive continuous esterified estrogens (0.3, 0.625, or 1.25 mg/d) or placebo for 24 months. Bone mineral density measurements and endometrial and laboratory assessments were conducted every 6 months; plasma estradiol concentrations were measured after 12, 18, and 24 months.

Results
All doses of esterified estrogens produced significant increases in bone mineral density of the lumbar spine compared with baseline and with placebo at 6,12, 18, and 24 months. Mean plasma estradiol levels increased with esterified estrogens dose, and individual subject bone mineral density changes appeared related to plasma estradiol concentrations. Clinically relevant rates of endometrial hyperplasia were noted only in the groups receiving 0.625 and 1.25 mg of esterified estrogens daily. Lipid changes were dose related and apparent in all groups.

Conclusions
Esterified estrogens at doses from 0.3 to 1.25 mg/d, administered unopposed by progestin, produce a continuum of positive changes on bone and lipids. Plasma estradiol concentrations increased with esterified estrogens dose and were related to positive bone mineral densities. The 0.3-mg dose resulted in positive bone and lipid changes without inducing endometrial hyperplasia.

Arch Intern Med. 1997;157:2609-26155

Author Affiliations
From the University of California School of Medicine (Dr Genant); the Cleveland Clinic, Fort Lauderdale, Fla (Dr Lucas); the San Diego Endocrine and Medical Clinic, San Diego, Calif (Dr Weiss); Pharmaco, Austin, Tex (Dr Akin); the Bone Research Center, Reading, Pa (Dr Emkey); Physicians to Women, Stuart, Fla (Dr McNaney-Flint); the Medical College of Virginia, Richmond (Dr Downs); Beth Israel Hospital, Boston, Mass (Dr Mortola); Emory University, Atlanta, Ga (Dr Watts); and Solvay Pharmaceuticals, Inc, Marietta, Ga (Drs Yang, Banav, Brennan, and Nolan). Members of the clinical investigatorsfor the Estratab/Osteoporosis Study Group are listed in a box on page 2611.

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