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US Public Health Service. Office of Disease Prevention and Health Promotion. Clinician's Handbook of Preventive Services. 2nd edition. Washington (DC): Department of Health and Human Services (US); 1999.

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Clinician's Handbook of Preventive Services

Clinician's Handbook of Preventive Services. 2nd edition.

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47Estrogen and Progestin

In postmenopausal women, use of supplemental estrogen can reduce the risk of osteoporosis. Osteoporosis contributes to approximately 1.2 million fractures in the United States annually; about two thirds of these fractures occur in women. Women who are older, Caucasian, slender, and those who have had a bilateral oophorectomy or early menopause are at increased risk for developing osteoporosis-related fractures. Approximately 15% of Caucasian women older than age 50 years suffer hip fractures, and approximately 1.5% of women in this population die as a result. According to a recent meta-analysis, use of estrogen was associated with a 25% decrease in the relative risk of hip fracture in women over age 50 years. Numerous observational and nonrandomized experimental studies suggest that the benefits of hormone replacement therapy (HRT) on bone mass and fracture risk wane after stopping estrogen. As a result, preventing fractures in older, postmenopausal women may require indefinite HRT. (See chapter 62 for information on osteoporosis.)

The use of estrogen to prevent coronary heart disease is currently being investigated in a multi-center prospective trial. Coronary heart disease causes approximately 30% of deaths of women over 50 years of age. A large case-control study was recently published that showed a reduced risk of mortality from all causes of 37% for women using post-menopausal HRT. According to Grodstein et al, the largest reduction in the risk of mortality was for coronary heart disease (53%); however, this protective effect was only statistically significant for women with one or more risk factors for cardiovascular disease. Other observational studies have shown that estrogen supplementation is associated with a 35% reduction in the relative risk of death from coronary heart disease. Estrogen supplementation also provides several benefits that improve climacteric symptoms, such as decreasing vasomotor symptoms (hot flushes or flashes) and alleviating genitourinary symptoms (dryness, urgency, incontinence, frequency).

Use of estrogen supplementation may, however, lead to significant adverse health outcomes. In women with an intact uterus who use estrogen for 10 to 20 years, the incidence of endometrial cancer increases eight-fold. Concomitant use of progestin decreases the risk of endometrial cancer to a level comparable to that of women not taking estrogen. Whether use of progestin will blunt any potential cardiovascular benefits of estrogen is unclear. Whether estrogen supplementation increases a woman's risk for breast cancer also remains controversial. This potential risk appears not to be associated with short-term estrogen use (fewer than 5 years), but may increase by approximately 25% with more than 10 years of estrogen use. Adding progestin to estrogen supplementation does not appear to protect against the risk of breast cancer. Estrogen increases the risk of venous thromboembolism.

Recommendations of Major Authorities

  • American Academy of Family Physicians --
  • All perimenopausal women should be counseled about the benefits and risks of postmenopausal HRT.
  • American College of Obstetricians and Gynecologists, American College of Physicians (ACP), Canadian Task Force on the Periodic Health Examination, and US Preventive Services Task Force (USPSTF) --
  • All perimenopausal and postmenopausal women should be counseled regarding the probable risks and benefits of HRT, so that they can participate fully with their health care provider in deciding whether to take preventive hormone therapy. According to the USPSTF, there is insufficient evidence to recommend for or against HRT in all postmenopausal women. According to the ACP, all women, regardless of race, should consider preventive hormone therapy. Women who have had a hysterectomy are likely to benefit from estrogen therapy. There is no reason to add progestin to the hormone regimen in such women. Women who have coronary heart disease or who are at increased risk for coronary heart disease are more likely to benefit from HRT. If such women have a uterus, progestin should be added to the estrogen therapy unless careful endometrial monitoring is performed. The risks of HRT may outweigh its benefits in women who are at increased risk for breast cancer.

Basics of Estrogen/Progestin Prophylaxis

1. Considerations

Table 47.1 presents the relative risk of selected conditions associated with long-term HRT. In addition, consider the following factors:

  • Coronary heart disease risk factors, such as family history, blood pressure, weight, smoking status, cholesterol
  • Osteoporosis risk factors, such as race, body build, physical activity level, bone mineral density
  • Breast cancer risk factors, such as personal and family history, late parity (after age 30 years), early menarche (before age 12 years), and late menopause (after age 50 years)
  • Patient desire to decrease climacteric symptoms, such as decreased vasomotor and genitourinary tract symptoms
  • Patient tolerance for side effects, such as endometrial bleeding and breast tenderness
  • Patient willingness to participate in follow-up, such as endometrial sampling and mammography

Table 47.1. Relative Risk of Selected Conditions for a 50-Year-Old White Woman Treated with Long-Term Hormone Replacement.


Table 47.1. Relative Risk of Selected Conditions for a 50-Year-Old White Woman Treated with Long-Term Hormone Replacement.

2. Dosage and Administration

To prevent irreversible bone loss, begin estrogen replacement soon after the onset of menopause. An absolute upper age limit for estrogen replacement has not been established. Use of progestin or careful endometrial monitoring is recommended for women with intact uteri.

Several different regimens for hormone replacement have been developed. Oral preparations have been better evaluated for primary prevention than has transdermal or other routes of administration. The most common initial oral dosage in the United States is 0.625 mg of conjugated estrogen taken every day. For women who cannot tolerate this dosage, 0.3 mg of conjugated estrogen daily with 1500 mg of calcium daily may provide protection against bone loss. Cyclic regimens of estrogen have been widely used, but they provide no physiologic advantages and cause patient confusion. Progestin may be given cyclically or continuously. The usual dosage for cyclic administration is 5 mg to 10 mg of progesterone acetate (or equivalent) daily for the first 10 to 14 days of the month. The usual dosage for continuous administration of progesterone acetate is 2.5 mg daily.

3. Contraindications

Contraindications to estrogen replacement include:

  • Unexplained vaginal bleeding
  • Active liver disease
  • Chronic impaired liver function
  • Recent venous thrombosis (with or without emboli)
  • Carcinoma of the breast
  • Endometrial carcinoma, except in certain circumstances

Conditions that may be relative contraindications to estrogen replacement include:

  • Seizure disorders
  • Hypertension
  • Uterine leiomyomas
  • Familial hyperlipidemia
  • Migraine headaches
  • Thrombophlebitis
  • Endometriosis
  • Gallbladder disease

4. Adverse Reactions

The most common side effects of estrogen therapy include endometrial bleeding, breast tenderness, nausea, bloating, and headaches. Other risks include an increased risk of endometrial cancer and the potential risk of breast cancer and thromboembolic events. When a progestin is added to estrogen therapy, the most common side effects are bloating, weight gain, nausea, irritability, breast tenderness, and depression. These symptoms generally can be alleviated by decreasing the dose of progestin. If progestin is used in a continuous regimen, it causes unpredictable endometrial bleeding in 30% to 50% of women. Such bleeding abates after 6 to 8 months of use because of uterine atrophy.

5. Surveillance

The American College of Physicians (1992) has issued the following recommendations for surveillance of endometrial cancer in women taking estrogen:

For Women Taking Unopposed Estrogen

At onset of treatment:

  • Pelvic examination
  • Endometrial evaluation (endometrial biopsy, transvaginal ultrasound, or dilatation and curettage) to rule out hyperplasia or cancer

Evaluation of vaginal bleeding:

  • Any episode of vaginal bleeding should prompt evaluation by endometrial biopsy, transvaginal ultrasound, or dilatation and curettage unless the woman has had a normal evaluation in the previous 6 months

Frequency of screening while on treatment:

  • Probably yearly

For Women Taking Estrogen and Progestin

At onset of treatment:

  • Pelvic examination
  • No endometrial evaluation required

Evaluation of vaginal bleeding:

  • For women on cyclic estrogen-plus-progestin therapy: If bleeding occurs other than at the time of expected withdrawal bleeding (days 10 through 15 if the progestin is given on days 1 through 10), an endometrial biopsy, transvaginal ultrasound, or dilatation and curettage should be performed.
  • For women on continuous estrogen-plus-progestin therapy: If bleeding is heavy (heavier than a normal menstrual period), prolonged (more than 10 days), or frequent (more often than monthly), and if bleeding persists longer than 10 months after beginning therapy, an endometrial biopsy, transvaginal ultrasound, or dilatation and curettage should be performed.

Frequency of screening while on treatment:

  • No routine screening required

6. Breast Cancer Surveillance

Both the American College of Obstetricians and Gynecologists and the American College of Physicians recommend screening for breast cancer at the same frequency and with the same methods as those used for women who are not taking estrogen/progestin replac ement.

Patient Resources

  • Hormone Replacement Therapy: Facts To Help You Decide; Action for a Healthier Life: A Guide for Mid-Life and Older Women. American Association of Retired Persons, Fulfillment Services, 601 E St, NW, Washington, DC 20049; (202)434-2277.
  • Osteoporosis in Women: Keeping Your Bones Healthy and Strong. American Academy of Family Physicians, 8880 Ward Parkway, Kansas City, MO 64114-2797; (800)944-0000. Internet address:
  • Age Page — Osteoporosis: The Bone Thinner; Age Page -- Should You Take Estrogen? National Institute on Aging, Bldg 31, Room 5C27, 31 Center Dr MSC 2922, Bethesda, MD 20892-2922; (301)496-1752. Internet address:
  • Hormone Replacement Therapy; Preventing Osteoporosis. American College of Obstetricians and Gynecologists, 409 12th St SW, Washington, DC 20024; (800)762-2264. Internet address:

Selected References

  1. American Academy of Family Physicians. Summary of Policy Recommendations for Periodic Health Examination . Kansas City, Mo: American Academy of Family Physicians; 1997.
  2. American College of Obstetricians and Gynecologists, Committee on Technical Bulletins. Hormone Replacement Therapy . Washington, DC: American College of Obstetricians and Gynecologists; 1992. ACOG Technical Bulletin 166.
  3. American College of Obstetricians and Gynecologists. Guidelines for Women's Health Care. Washington, DC: American College of Obstetricians and Gynecologists; 1996.
  4. American College of Physicians. Guidelines for counseling postmenopausal women about preventive hormone therapy. Ann Intern Med . 1992; 117:1038–1041. [PubMed: 1443972]
  5. Barrett-Connor E, Bush TL. Estrogen and coronary heart disease in women. JAMA . 1991; ; 265:1861–1867. [PubMed: 2005736]
  6. Canadian Task Force on the Periodic Health Examination. Prevention of osteoporotic fractures in women by estrogen replacement therapy. In: The Canadian Guide to Clinical Preventive Health Care. Ottawa, Canada: Minister of Supply and Services; 1994: chap 52.
  7. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med . 1992; 117:1016–1037. [PubMed: 1443971]
  8. Grodstein F, Stampfer MJ, Colditz GA, et al. Postmenopausal hormone therapy and mortality. N Engl J Med. . 1997; 336(25):1769–1775. [PubMed: 9187066]
  9. Henrich JB. The postmenopausal estrogen/breast cancer controversy. JAMA . 1992; 268:1900–1902. [PubMed: 1404715]
  10. Mann KV, Wiese WH, Stachenko S. Postmenopausal osteoporosis and fractures. In: Goldbloom RB, Lawrence RS. Preventing Disease: Beyond the Rhetoric. New York, NY: SpringerVerlag; 1990: chap 24.
  11. US Preventive Services Task Force. Postmenopausal hormone prophylaxis.In: Guide to Clinical Preventive Services. 2nd ed. Washington, DC: US Department of Health and Human Services; 1996: chap 68.


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