Common Questions
Drug Mini-Monograph: Estrogens in the prevention of osteoporosis
See disclaimer below*
Estrogens decrease bone resorption and slow or stop bone loss in postmenopausal women. This is done through a combination of decreasing the activity of osteoclasts, peripheral inhibition of parathyroid hormone, increasing calcitriol concentrations (oral therapy only), increasing intestinal calcium absorption, and decreasing renal calcium excretion. Estrogens are NOT FDA-approved for the treatment of osteoporosis. These are now approved for treatment of moderate to severe vasomotor symptoms, and for prevention of postmenopausal osteoporosis after consideration of all other options and when risk of osteoporosis outweighs risks of CEE products. The United States Preventive Task Force (USPTF) and other groups recommend against the routine use of combination HT or of unopposed estrogen for the prevention of chronic disease in postmenopausal women.
Dosing. Estrogen replacement is available as oral, vaginal, and transdermal (patch, gel, and spray) preparations.
Cautions and contraindications. Avoid in patients with a history of thromboembolic disease, coronary artery disease, cerebrovascular disease, breast cancer, undiagnosed vaginal bleeding, and/or impaired liver function.
The HT portion of the WHI studied outcomes in postmenopausal women (average age 62) for ~5 years after initiation of conjugated estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg daily, conjugated estrogen 0.625 mg (for women who had had hysterectomy), or placebo (1,2).
Estrogen plus progestin Results
Coronary Heart Disease (CHD): In WHI, the risk for CHD was 24% higher among the HT-treated women (HR = 1.24; 95% CI, 1.00 - 1.54) (3). This increased risk was seen in women with and without prior CHD diagnosis and was independent of other factors influencing CHD risk (e.g. use of aspirin or statins). The increased risk of CHD was most marked in the first year of use but persisted through year 5.
Stroke: Risk of stroke was 31% in HT-treated women compared with women on placebo (4). Prior stroke and other risk factors (e.g., blood pressure, use of aspirin, smoking, diabetes) did not influence the relative risk.
Breast cancer: Combination HT increased the risk of total and invasive breast cancer by 24% compared to women taking placebo (HR 1.24; 95% CI 1.00 - 1.59). The cancers were diagnosed at a more advanced stage on HT compared to placebo and there were more abnormal mammograms with HT. Subgroup analysis showed risk increased with duration of HT use. For women with no prior HT use, there was no significant increase in breast cancer rates over the 5 years of the study (5).
Venous Thromboembolic Disease (VTD-deep vein thrombosis and pulmonary embolism): Multiple studies have shown the risk of VTD to be two- to three-fold higher in women on estrogen or combination HT, with highest risk occurring in the year after initiation. In the WHI study, the risk of VTD in treated women was double that of control women (HR 2.06; 95% CI 1.57 - 2.7) (6). The risk increased with age, Factor V Leiden, and being overweight.
Estrogen Only Results
Stroke and Pulmonary Embolism: There was a 39% increase in the risk of stroke and a 34% increase in the risk of pulmonary embolus (2).
| Outcome | ||
|---|---|---|
|
WHI CEE + MPA* N = 16,608Duration = 5.2 yrs |
WHI CEE N = 10,739Duration = 6.8 yrs |
|
| Hazard Ratio (95% Confidence Interval) | ||
| CHD events | 1.24 (1.00 - 1.54) | 0.91 (0.75 - 1.12) |
| Stroke | 1.31 (1.02 - 1.68) | 1.39 (1.10 - 1.77) |
| Pulmonary Embolism | 2.13 (1.39 - 3.25) | 1.34 (0.87 - 2.06) |
| Breast Cancer | 1.24 (1.00 - 1.59) | 0.77 (0.59 - 1.01) |
| Death | 0.98 (0.82 - 1.18) | 1.04 (0.88 - 1.22) |
| Global Index** | 1.15 (1.03 - 1.28) | 1.01 (0.91 - 1.12) |
* CEE=conjugated equine estrogen, MPA=medroxyprogesterone acetate
**Global Index: first event for each participant in each of the major categories (including fracture)
Side effects. There is an increased risk of endometrial cancer in postmenopausal women who are treated with unopposed estrogens for a prolonged period of time. Concomitant use of a progestin (cyclically or continuously) negates this risk.
Other possible side effects include:
- Tenderness, enlargement, concern for increased risk of breast cancer with long-term use
- Venous thromboembolism, pulmonary embolism, hyperlipidemia
- Headache, migraine, dizziness, mental depression, chorea, insomnia, emotional lability, anxiety
- Eyes: Steepening of corneal curvature, intolerance to contact lenses
- GI: Nausea, vomiting, abdominal cramps, bloating, cholestatic jaundice, increased incidence of gallbladder disease, pancreatitis
- GYN: Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough
- bleeding, spotting, increase in size of uterine leiomyomata, vaginal candidiasis, change in amount of cervical secretion
- Skin: Chloasma or melasma that may persist when drug is discontinued, erythema multiforme/nodosum, hemorrhagic eruption, loss of scalp hair, hirsutism, redness and irritation at application site with the estradiol transdermal system
- Miscellaneous: Increase or decrease in weight, reduced glucose tolerance, aggravation of porphyria, edema, changes in libido
Drug interactions. Estrogens may decrease the effects of anticoagulants and phenytoin. Estrogens may also potentiate the effects of corticosteroids via inhibition of hepatic P450 enzyme. Rifampin and phenytoin may decrease the levels of estrogens.
*Disclaimer: This brief overview is limited in scope and designed to serve as a learning resource and an initial reference source. The information presented here should not be used in making treatment decisions. The authors, editors, developers, testers, and the University of Washington School of Medicine are not responsible for any errors in diagnosis or treatment that may result from the use of this material.
- The writing group for the PEPI trial. Effects of hormone therapy on bone mineral density. JAMA 1996; 276: 1389-96.
- Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCro. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291: 1701-12.
- Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, et al.; for the Women’s Health Initiative Investigators. Estrogen plus Progestin and the risk of coronary heart disease. NEJM 2003; 349: 523-534.
- Wassertheil-Smoller S, Hendrix S, Limacher M, Heiss G, Kiiperberg C, Baird A, Kotchen T, et al.;for the WHI Investigators. Effect of Estrogen Plus Progestin on Stroke in postmenopausal women. JAMA 2003; 289: 2673-2684.
- Chlebowski RT, Hendrix SL, Kanger RD, Stefanick ML, Gass M, Lane D; for the WHI Investigators. Influence of Estrogen plus Progestin on breast cancer and mammography in Healthy Postmenopausal Women. JAMA 2003; 289: 3243-3253.
- Cushman M, Kuller LH, Prentice R, Rodabough RJ, Psaty BM, Stafford RS, Sidney S, Rosendaal FR; for the Women’s Health Initiative Investigators. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA 2004; 292: 1573-1580.