Examples

Oral (pills or tablets)

Generic Name	Brand Name
conjugated estrogens	Cenestin, Enjuvia, Premarin

Enjuvia contains plant-based, rather than animal-based, estrogen. Risks and benefits are thought to be the same for both types of estrogen.

Generic Name	Brand Name
esterified estrogens	Estratab, Menest
estradiol	Estrace
estropipate	Ogen, Ortho-Est

Transdermal (patch placed on the skin that releases estrogen continuously)

Generic Name	Brand Name
estradiol (low-dose)	Climara
estradiol	Alora, Climara, Estraderm, Vivelle-Dot

Vaginal ring (inserted high into the vagina; releases estrogen continuously for 3 months)

Generic Name	Brand Name
estradiol	Femring

Skin cream (applied daily to the legs, thighs, or calves)

Generic Name	Brand Name
estradiol	Estrasorb

Skin gel (applied daily to an arm from wrist to shoulder)

Generic Name	Brand Name
estradiol	Estrogel

How It Works

Estrogen replacement therapy (ERT) increases the estrogen level in your body. Estrogen impacts multiple systems of the body.

When given through an estrogen patch, vaginal ring, or skin cream or gel (transdermal estrogen), estrogen enters the bloodstream directly, without passing through the liver. The estrogen in pills must be processed by the liver before entering the bloodstream, which stresses an impaired liver.

Low-dose vaginal estrogen affects only the urinary and genital area. For more information, see Low-dose vaginal estrogen for dryness and atrophy.

Patch warning. Direct sunlight or high heat can increase, then lower, the amount of hormone released from a patch. This can give you a big dose at the time and leave less hormone for the patch to release later in the week. Avoid direct sunlight on the hormone patch. Also avoid using a tanning bed, heating pad, electric blanket, hot tub, or sauna while you are using a hormone patch.

Why It Is Used

Estrogen replacement therapy (ERT) is used to increase estrogen levels in postmenopausal women who have no uterus. This helps prevent perimenopausal symptoms, osteoporosis, and colon cancer.

Women in their 20s, 30s, and 40s who experience early menopause after having their ovaries removed (oophorectomy) or because of other medical reasons typically take ERT to reduce their risk of early bone loss and osteoporosis. Historically, women have continued using ERT for years beyond menopause. Some women now discontinue ERT around the age of menopause.

Women with a uterus who take estrogen also need the hormone progestin to prevent the estrogen from overgrowing the uterine lining, which can lead to endometrial (uterine) cancer. Estrogen-progestin is called hormone replacement therapy (HRT).

Do not use estrogen treatment if you:

• Are pregnant.
• Have unexplained vaginal bleeding.
• Have active liver disease or chronic impaired liver function. (Transdermal estrogen does not stress the liver.)
• Have a personal history of breast cancer, ovarian cancer, or endometrial cancer.
• Are a smoker.

Talk to your health professional about your risks versus benefits if you have a family history of breast cancer, ovarian cancer, stroke, blood clots, or endometrial cancer.

How Well It Works

Systemic estrogen replacement therapy (ERT) affects your entire body and reverses the effect of low estrogen. Systemic ERT:

• Helps prevent postmenopausal osteoporosis by slowing bone loss and promoting some increase in bone density.¹
• Reduces the frequency and severity of hot flashes.¹
• Improves depression and sleep problems related to hormone changes.²
• Maintains the lining of the vagina, reducing irritation.
• Increases skin collagen levels, which decline as estrogen levels decline. Collagen is responsible for the stretch in skin and muscle.
• Reduces the risk of dental problems, such as tooth loss and gum disease.
• May reduce the risk of colon cancer.³

Low-dose estrogen. Researchers are studying the effects of low-dose estrogen therapy. A small early study has shown that a low estrogen dose-0.25mg per day-may keep the bones as strong as the higher dose.⁴ However, the long-term risks of taking low-dose estrogen are not yet known.

Side Effects

Risks of estrogen replacement therapy

Systemic estrogen replacement therapy (ERT) causes health problems in a small number of women. Using ERT increases your risks of:³

• Stroke. ERT use slightly increases the risk of stroke.⁵
• Blood clots. ERT slightly increases the risk of blood clots in the legs (deep vein thrombosis) and lungs (pulmonary embolism), which can be life-threatening. This risk is greatest in the first year of use.⁶ A recent small study suggests that oral ERT slightly increases blood clot risk, but the ERT patch does not. When taken orally, ERT seems to increase a clotting factor in the blood; this does not happen with ERT that is absorbed through the skin.⁷
• Breast cancer. The Million Women Study has shown that, in women using ERT for 10 years, the number of breast cancers is slightly higher than in women not taking ERT.⁸ Although the Women's Health Initiative (WHI) trial found no increase in breast cancer over 7 years of ERT use, experts continue to take the breast cancer risk seriously.⁹
• Uterine (endometrial) cancer (only if you have a uterus). Taking progestin with estrogen eliminates this risk.⁸
• Gallstones. Women who use estrogen replacement therapy are more likely to have gallstones that cause symptoms than women who do not use ERT. (High estrogen levels are linked to gallbladder disease.)
• Ovarian cancer (which is rare). In women using ERT over 5 years, the number of ovarian cancers is slightly higher than normal. Using ERT causes ovarian cancer in about 0.4 per 1,000 women. (This is the same as 1 in 2,500 women.) This risk only applies to women who have their ovaries and are taking estrogen.

ERT breast cancer risk is lower than the estrogen-progestin (HRT) breast cancer risk. In the British Million Women study of women who took hormone therapy for 10 years till age 60:⁸

• Estrogen-progestin use increased breast cancer by 19 per 1,000 women.
• Estrogen-alone use increased breast cancer by 5 per 1,000 women.

Side effects that can occur with all forms of estrogen but are more common with oral estrogen (and less common with a patch, cream, gel, or vaginal ring) include:

• Headaches.
• Nausea.
• Vaginal discharge.
• Fluid retention.
• Weight gain.
• Breast tenderness.
• Spotting or darkening of the skin, particularly on the face.
• Asthma. Newly diagnosed asthma appears to be more common among women taking ERT or HRT than women who are not. (Estrogen is thought to be a factor that causes or worsens asthma across the life span.)¹⁰
• Rarely, an increased growth of preexisting uterine fibroids or a worsening of endometriosis.

Some of these side effects, such as headaches, nausea, fluid retention, weight gain, and breast tenderness, may go away after a few weeks of use.

The estrogen patch (transdermal estrogen) may cause skin irritation.

An estrogen ring must be replaced every 3 months. If the ring falls out at any time during the 3-month treatment period, you may rinse it with lukewarm water and reinsert it.

See Drug Reference for a full list of side effects. (Drug Reference is not available in all systems.)

What To Think About

In the Million Women Study of British women ages 50 to 64, taking any form of estrogen for 10 years increased breast cancer risk. The Women's Health Initiative study did not show this increased risk for women taking estrogen alone (ERT) for 7 years.⁹ Therefore, taking long-term ERT probably slightly increases breast cancer risk; taking it with progestin (HRT) further increases breast cancer risk.⁸ However, only women who have had a hysterectomy can take estrogen alone without also worrying about endometrial (uterine) cancer risk.⁸

ERT use slightly increases the risk of stroke. For this reason, the Women's Health Initiative ERT trial was stopped sooner than originally planned. In this large trial, women using ERT had no change in heart disease risk, had fewer hip fractures (a sign of estrogen's bone-protecting effect), and (unlike the larger Million Women Study) had no increase in breast cancer risk during the study's nearly 7 years of ERT treatment.⁹

If you are taking ERT after early menopause caused by a surgical hysterectomy, talk with your health professional about long-term ERT risks and benefits.

If you have your uterus but are unable to tolerate the side effects of progestin in hormone replacement therapy (HRT) or you are concerned about increased breast cancer risk, you may consider estrogen-only replacement therapy (ERT) if testing shows no abnormalities of the uterine lining (endometrium). But close observation for precancerous changes of the endometrium is required, including an annual pelvic exam and an annual endometrial biopsy.

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Citations

1. Speroff L, Fritz MA (2005). Menopause and the perimenopausal transition. In Clinical Gynecologic Endocrinology and Infertility, 7th ed., pp. 621–688. Philadelphia: Lippincott Williams and Wilkins.

2. Rapkin AJ, et al. (2002). The clinical nature and formal diagnosis of premenstrual, postpartum, and perimenopausal affective disorders. Current Psychiatry Reports, 4(6): 419–428.

3. Rossouw JE, et al. (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. JAMA, 288(3): 321–333.

4. Prestwood KM, et al. (2003). Ultralow-dose micronized 17 B-estradiol and bone density and bone metabolism in older women. JAMA, 290(8): 1042–1048.

5. American College of Obstetricians and Gynecologists Women's Health Care Physicians (2004). Stroke. Obstetrics and Gynecology, 104(4, Suppl): 97S–105S.

6. American College of Obstetricians and Gynecologists Women's Health Care Physicians (2004). Venous thromboembolic disease. Obstetrics and Gynecology, 104(4, Suppl): 118S–127S.

7. Scarabin PY, et al. (2003). Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet, 362(9382): 428–432.

8. Million Women Study Collaborators (2003). Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 362(9382): 419–427.

9. Women's Health Initiative Steering Committee (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA, 291(14): 1701–1712.

10. Barr RG, et al. (2004). Prospective study of postmenopausal hormone use and newly diagnosed asthma and chronic obstructive pulmonary disease. Archives of Internal Medicine, 164(4): 379–386.