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Menopause

Description

An in-depth report on the treatment of menopause-related symptoms.

Alternative Names

Estrogen; Hormone replacement therapy

Medications

Hormone Replacement Therapy (HRT)

Doctors used to believe that HRT could help reduce the risk of heart disease and other health risks in addition to treating menopausal symptoms. The results of an important study, called the Women's Health Initiative (WHI), led doctors to revise their recommendations regarding HRT.

The WHI, started in 1991, enrolled 161,809 women between the ages of 50-79 in 40 different medical centers. Part of the study was intended to examine the health benefits and risks of hormone replacement therapy, including the risks of breast cancer, heart attacks, strokes, and blood clots.

In 2002, one component of the WHI, which studied the use of estrogen and progestin in women who had a uterus, was stopped early because the health risks exceeded the health benefits. The main reason for stopping the estrogen-progestin study was a 26% increase in breast cancer. This combination therapy study also showed an increased risk for heart attack, stroke, blood clots, and dementia. There was a reduced risk for colorectal cancer and bone fractures but these benefits did not outweigh the considerable risks.

In 2004, a second component of the WHI, which studied estrogen-only therapy in women who no longer have a uterus, was stopped early. This was primarily because of an increase in the risk for strokes and blood clots. The study also found the estrogen-only therapy had no effect on heart attack or colorectal cancer risk. An update in 2006 suggested that estrogen-only therapy does not increase breast cancer risk over the short term (average 7 years) but may increase risk when taken for a longer time (15 years or more).

While the WHI study suggests that HRT should not be prescribed for prevention of chronic diseases, many doctors still accept its use for short-term treatment of moderate to severe hot flushes and other menopausal symptoms, and in women undergoing premature menopause for medical or other reasons. Current guidelines recommend using the lowest possible dose for the shortest duration of time.

Hormones Used in HRT. Hormone replacement therapy uses either estrogen alone (known as ET or unopposed estrogen ) or in combination with forms of progesterone (known as combined hormone therapy or EPT). Progesterone is referred to by one of several names:

• Progesterone is the name for the natural hormone
• Progestin is the term for any hormone, natural or synthetic, that causes progesterone effects
• Progestogen is any hormone that has effects similar to progesterone

Both ET and EPT are available in many forms, including oral tablets, skin patches, and vaginal and skin applications. A new form approved by the FDA in 2004 is a topical estrogen gel which is applied to the arm.

Menopausal Symptoms and HRT. HRT is mainly recommended for relieving menopausal symptoms, including vaginal atrophy and dryness, hot flashes, sleep problems, and mild depression. HRT does not prevent certain other problems associated with menopausal changes such as thinning hair.

Oral hormonal medications and skin patches are equally effective in reducing hot flashes, mild depression, and sleep problems. Progestins may sometimes be prescribed alone for hot flashes and other acute menopausal symptoms, though they can cause side effects, such as mood swings, bloating, and breast tenderness. Estrogen creams, rings, or vaginal tablets restore vaginal elasticity and lubrication and improve sexual pleasure.

Osteoporosis and HRT. HRT may be useful for some women at high risk for osteoporosis, although other drugs, such as bisphosphonates, should be considered first. It increases bone density and also appears to improve balance and protects against falling. Studies also report reductions in fractures (especially hip fractures) among women taking HRT, but the benefits may not outweigh the risks of HRT. It appears that the beneficial effects wear off soon after therapy is stopped. Estrogen must be taken life long for maximum protection against osteoporosis, which then increases the risk for adverse health effects.

Adverse Effects of HRT.

• Heart Disease. In spite of estrogen's benefits on cholesterol levels and other factors that affect the heart, evidence suggests that HRT does not prevent heart disease. In fact, it may actually be harmful for women with existing heart disease, at least in the first few years, and may also worsen the outlook after a heart attack. However, a 2004 review of 30 studies found that HRT does not significantly impact mortality from cardiovascular disease.
• Stroke. Studies have reported a slightly increased risk of stroke in women taking HRT within the first two years of treatment and in HRT users with a history of major stroke or small strokes (transient ischemic attacks). A 2005 review found that HRT increased the risk of stroke, particularly ischemic (a type of stroke caused by an interruption in blood flow to part of the brain) stroke. In addition, HRT appears to worsen the outlook for women who have had a stroke.
• Mental Decline. Observational studies had suggested that hormone replacement therapy (HRT) helped prevent mental decline and even Alzheimer's disease after menopause. Other studies have found no differences in mental performance and no protection from Alzheimer's disease in women taking HRT compared to non-users. A 2004 review of the Women’s Health Initiative Memory Study found that combined HRT did not reduce the risk of cognitive impairment, and actually increased the risk of dementia among women ages 65 and over.
• Thromboembolism. HRT is associated with a higher risk for thromboembolism, in which blood clots form in deep veins. This places women at risk for pulmonary embolism, in which the blood clot travels to the lungs.

• Breast Cancer. Because breast tissue growth is highly sensitive to estrogens, the more a woman is exposed to estrogen over her lifetime, the higher the risk for breast cancer. A number of studies have now reported a higher risk for breast cancer in postmenopausal women taking HRT that contains both estrogen and progestin. A 2005 study suggested that HRT with no or low progestin is safer than standard combination therapy. Several 2006 studies of women who had a hysterectomy indicated that estrogen alone does not increase overall breast cancer risk when the drug is used for 7 years or less. However, women who take the drug for 15 years or more do have an increased risk. Women who are at low risk for breast cancer tend to have fewer breast cancers with estrogen alone, while women at higher risk tend to have more breast cancers. In addition, estrogen therapy may cause abnormal mammogram results. Breast tissue density increases with HRT, which makes mammograms more difficult to read and leads to more breast biopsies. Women who take estrogen HRT should be aware that they need frequent mammogram screenings.
• Endometrial (Uterine) Cancers. Estrogen overstimulates the tissue lining the uterus (the endometrium) and causes uncontrolled cell growth, a condition known as hyperplasia , which is a strong risk factor for cancer. Taking unopposed estrogen replacement therapy (ERT) increases the risk of endometrial cancer at least five-fold. Adding progestin to HRT appears to pose no risk for this cancer.
• Ovarian Cancer. Whether HRT increases the risk for ovarian cancer is unclear, although evidence does seem to suggest a higher risk with the use of unopposed estrogen. Short term used of combined HRT in one study did not increase the incidence of ovarian cancer. Another study reported that women who had used unopposed estrogen or HRT with sequential use (but not continuous use) of progestins were at higher risk. Studies to date, however, have been limited. (Ovarian cancer is very uncommon, with the mortality rate being 43 out of every 100,000 women. Even among long-term HRT users this rate increases only to 64.)
• Gallstones. HRT is associated with a higher risk for gallstones.

Other Drugs Used for Menopausal Symptoms

Despite its risks, hormone replacement therapy appears to be the best treatment for hot flashes. Nonhormonal treatments for hot flashes and other menopausal symptoms include:

Antidepressants. The antidepressants known as selective serotonin-reuptake inhibitors (SSRIs) are sometimes used for managing mood changes and hot flashes. They include fluoxetine (Prozac), sertraline (Zoloft), venlafaxine (Effexor), and paroxetine (Paxil, Asimia). A 2006 review of nonhormonal therapies, found that paroxetine in particular may help hot flashes. However, paroxetine, like other antidepressants, can cause headache, anxiety, and sexual problems.

Gabapentin. Several small studies suggest that gabapentin (Neurontin), a drug used for seizures and nerve pain, may relieve hot flashes. Gabapentin may cause drowsiness, dizziness, fatigue, and swelling of the hands and feet.

Clonidine . Clonidine (Catapres) is a drug used to treat high blood pressure. Studies show it may help manage hot flashes. Side effects include dizziness, drowsiness, dry mouth, and constipation

Testosterone. Some doctors prescribe combinations of estrogen and small amounts of the male hormone testosterone to improve sexual function and increase bone density. Side effects of testosterone include increased body hair, acne, fluid retention, anxiety, and depression. It also adversely affects cholesterol and lipid levels. Long-term benefits or other risks are unknown.

Drugs to Prevent and Treat Osteoporosis

After menopause, a woman is at increased risk osteoporosis. Certain drugs may be prescribed to help prevent bone loss. [For more information on osteoporosis prevention and treatment, see In-Depth Report #18: Osteoporosis.]

Selective Estrogen-Receptor Modulators (SERMs). SERMS are designed to produce the benefits of estrogen, such as bone protection, without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others.

The only SERM prescribed for menopausal conditions is raloxifene (Evista). It is prescribed for prevention and treatment of osteoporosis in post-menopausal women. Raloxifene also decreases LDL ("bad") cholesterol levels, but does not appear to increase HDL ("good") cholesterol.

Bisphosphonates . Bisphosphonates help increase bone mass, and are among the primary drugs against osteoporosis in postmenopausal women and in people taking corticosteroids or hormonal drugs that suppress estrogen. They are proving to reduce the risk of both spinal and hip fractures in women who have had prior bone breaks. The standard bisphosphonates include alendronate (Fosamax) and risedronate (Actonel).

Calcitonin. Produced by the thyroid gland, natural calcitonin regulates calcium levels by inhibiting the osteoclastic activity, the breakdown of bone. The drug version is derived from salmon and is available as a nasal spray (Miacalcin) and in injected form (Calcimar). Calcitonin is not used to prevent osteoporosis; it is used to treat osteoporosis. Calcitonin may be an alternative for patients who cannot take a bisphosphonate or SERM. It also appears to help relieve bone pain associated with established osteoporosis and fracture.

Low-Dose Parathyroid Injections. Although high persistent levels of parathyroid hormone can cause osteoporosis, daily injections of this hormone stimulate bone production. Unlike most treatments for osteoporosis, including bisphosphonates, the benefits may persist even after the injections have been stopped. Teriparatide (Forteo), a drug made from selected amino acids found in parathyroid hormone, is approved for treatment of osteoporosis in postmenopausal women. Studies suggest it may lower the risk of fracture and increase bone mineral density. In one small study, parathyroid significantly reduced spinal fractures compared to hormone replacement therapy.

Drugs to Prevent and Treat Heart Disease

Statins are the most effective drugs for treatment of unhealthy cholesterol levels and are now strongly recommended as the first choice for lipid-lowering treatment for older women with heart disease. Brands include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). A major analysis of over 200 studies found that statins reduced the risk for heart problems by 60% and stroke by 17%. A 2005 review found that the more that statins lower LDL, the more they reduce CAD and other heart disease risks.

Specific Hormone Replacements Drugs and Brands
HRT Form	Brand Name	Active Ingredient	Side Effects
Oral Estrogens	Premarin	Natural conjugated estrogen, which is a mixture of estrogens derived from the urine of pregnant mares.	Bleeding after withdrawal. It is a primary reason why many women stop treatment, although usually lighter or shorter compared to before menopause. If it is distressing, patient should consider continuous estrogen and progestin therapy. Irregular bleeding. This should be checked with the doctor for possible problems. Nausea and vomiting. If it occurs, usually does so only during the first three months and is minimal. Rarely with low doses. Headaches. Cramps. Risk for blood clots.
	Cenestin	Synthetic conjugated estrogen, which is a mixture of estrogens derived from compounds found in yams and soy.
	Estratab, Menest	Plant-derived estrogens, called esterified estrogens. Usually made from modified soy
	Estrace (oral)	Estradiol, the most potent natural estrogen.
	Ogen, Ortho-Est	Estropipate, a version of estrone, which is a weaker form of estrogen.
	Estrovis	Quinetrol, a synthetic estrogen
	Estinyl	Synthetic form estradiol, the most potent estrogen.
Oral Progestins	Provera, Amen, Curretab, Cycrin	Medroxyprogesterone, a synthetic progestin.	Breast tenderness. Usually subsides in three to four months and can be relieved with over-the-counter pain killers and possibly by decreasing caffeine intake and adding vitamin E. Headache. Fluid build-up. Bloating. Fatigue, unusual tiredness, weakness. Depression, irritability, or other mood changes.
	Norlutin, Aygestin, Norlutate	Norethindrone and norethindrone acetate, synthetic progestins.
		Norgestrel.
Oral Combinations of Estrogen and Progestin	Prempro, Premphase	Conjugated estrogens plus medroxyprogesterone.	May have some of the side effects of both estrogen and progestin. Continuous regimens eliminate menstrual bleeding in more than half of women. Investigators are studying the use of higher progestin doses or a lower estrogen doses and comparing combinations for further reduction of bleeding risk.
	Activelle, Femhrt	Estradiol and norethindrone or norethindrone acetate.
	Ortho-Prefest	Estradiol and norgestimate.
	Angeliq	Estradiol and drospirenone.
Skin Patch Administration of HRT	Estraderm, Alora, Climara, Vivelle, FemPatch, Evorel	Estradiol.	Skin irritation where the patch is applied most common. Hormonal side effects associated with formulation of patch.
	CombiPath	Estradiol plus norethindrone (a progestin).
Vaginal Creams for dryness and irritation	Estrace (cream)	Estradiol (potent estrogen).	Hormonal side effects associated with estrogen or progestins, depending on formulation.
	Ogen (cream)	Estropipate (weaker estrogen.).
	Premarin (cream)	Conjugated natural estrogens.
	Ortho-dienestrol (cream)	Dienestrol (synthetic estrogen).
	Crinone (cream)	A natural progesterone.
Other forms of vaginal administration	Vagifem (vaginal tablet)
	Estring (vagina Ring)	Estradiol.
	Other forms: injections, nasal sprays, and as pellets inserted under the skin twice a year.
Topical Gel	EstroGel	Estradiol.	Hormonal side effects associated with estrogen.

• Review Date: 6/11/2006
• Reviewed By: Harvey Simon, M.D., Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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