Overview

During her reproductive years, a woman's ovaries produce the hormones estrogen and progesterone Hormone Replacement Therapy (HRT) | Menopause | Imaginis - The Women's Health & Wellness Resource Network

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Hormone Replacement Therapy (HRT)

Overview

During her reproductive years, a woman's ovaries produce the hormones estrogen and progesterone in the ovaries. Estrogen works to regulate a woman's monthly menstrual cycle and secondary sexual characteristics (such as breast development and function), and also rises at different times in the menstrual cycle to prepare the body for fertilization and reproduction. Progesterone also rises in a cyclical fashion to prepare the uterus for possible pregnancy and to prepare the breasts for lactation (milk production). As a woman reaches menopause, typically around 50 years old, her body produces less and less estrogen and progesterone. It is estimated that 40 million women will reach menopause in the next 20 years.

Decreased levels of estrogen during menopause may cause hot flashes, vaginal dryness, sleep disturbances, or other bothersome side effects. The dryness of tissue surrounding the vagina and urethra may cause pain during sexual intercourse or urination, and HRT helps to relieve these and other menopausal symptoms. Hormone replacement therapy (HRT) is synthetic estrogen and progesterone (progestin) designed to "replace" a woman's depleting hormone levels.

Past research has shown that HRT may also help prevent osteoporosis, heart disease, short-term memory loss, depression and other diseases in post-menopausal women. However, recent research has found that HRT may not provide these benefits and may pose other risks, including an increased risk of ovarian cancer (with long-term use) and cancer of the uterine lining (in women do not take progestin with estrogen). See sections below for more information. While HRT is highly effective at relieving menopausal symptoms and may provide protection against conditions such as osteoporosis, there is also some evidence that supports a link between HRT and an increased risk for breast cancer. In July 2002, the National Institutes of Health halted a large study on HRT, called the Women's Health Initiative because the combined estrogen/progestin regimen of the therapy was found to cause 8 cases of invasive breast cancer for every 10,000 women on HRT (a 26 percent increase in breast cancer risk compared to women who do not take HRT) (1). Though these numbers can be alarming, some experts believe that limited, short-term use of HRT can be safe among some women who are not at high risk of breast cancer or other diseases. Therefore, patients and physicians should make the decision about HRT together, based on the individual medical situation. See the HRT and breast cancer section below for more information.

Menopause

Menopause is the time in a woman’s life when she stops menstruating, signaling the end of her reproductive life. Natural menopause typically occurs in women when they are in their late forties or early fifties. However, some women will go through menopause at an earlier or later age. Menopause is considered premature if it occurs before age 35. Premature menopause may occur for several reasons, including certain types of cancer treatment, mumps and certain autoimmune disorders such as lupus or rheumatoid arthritis. Also, women who smoke tend to go through menopause at an earlier-than-average age.

Before menstruation stops at menopause, a woman will go through premenopause and perimenopause. During premenopause, menstrual periods begin to become irregular. During perimenopause, a woman’s menstrual periods will become highly irregular and she may experience symptoms of menopause, such as hot flashes, vaginal dryness, or sleep disturbances. Perimenopausal occurs a few years before a woman reaches menopause. Once a woman reaches menopause, menstruation will stop forever unless she takes HRT.

Symptoms and Effects of Menopause

The symptoms of menopause vary significantly from woman to woman. Some women only experience mild menopausal symptoms while others have severe discomfort. The most common symptom of menopause is hot flashes. Hot flashes may be accompanied by sweating, flushing, or heart palpitations. It is estimated that more than 60% of menopausal women experience hot flashes.

During menopause, changes also occur in the vagina and urinary tract. Vaginal tissue becomes thinner, drier, and less elastic, which may cause discomfort or pain during sexual intercourse. Urinary tract tissue also becomes less elastic, which may cause a release of urine during laughter, coughing, sneezing, or exercise. Many menopausal women also find that urinary tract infections occur more frequently during this time. Other symptoms of menopause may include mood changes, insomnia (or other sleep disturbances), depression, or anxiety. HRT can relieve many of these symptoms.

Menopausal Symptoms:

  • Irregular menstrual periods
  • Hot flashes
  • Vaginal dryness
  • Mood changes
  • Insomnia (or other sleep disturbances)
  • Depression
  • Anxiety

More information on menopause.

Common Regimens of HRT

Estrogen and progestin are the two hormone supplements most often used in HRT. Taking estrogen without progestin to balance the hormonal cycle may cause over-stimulation of the endometrium tissue, the lining the uterus. This may lead to uncontrolled tissue growth called hyperplasia, which may lead to endometrial cancer. Progestin counteracts this risk. Therefore, women who have not had their uteruses removed are usually prescribed estrogen and progestin together. Progestin may also be prescribed alone, usually to prevent hot flashes or other menopausal problems.

Premarin, the most commonly prescribed estrogen used with HRT, is a conjugated estrogen. Premarin contains a mixture of natural estrogen from the urine of pregnant mares. Some research has shown that conjugated estrogens may prevent heart disease and osteoporosis. Esterified estrogen, derived from plants, may increase bone density. Estradiol is the most potent estrogen and is available in a variety of forms. The most common forms of HRT are pills and skin patches.

Brand Names and Common Daily Dosages of HRT for Post-Menopausal Women:

Estrogen:

  • Premarin, 0.625-1.25 mg
  • Estrace, 1.0-2.0 mg
  • Ogen, 0.625-1.25 mg
  • Estraderm, 0.05-0.1mg patches
  • Climara, 0.05-0.1 mg patches
  • Vivelle, 0.0375-0.1 mg patches

Progesterone:

  • Provera, 2.5-10mg
  • Cycrin, Curretab, Amen 10mg
  • Micronized ("natural") Progesterone 100mg, 200mg
  • Norethindrone 0.5-1.0mg po qd

Combination Estrogen and Progesterone:

  • Prempro (0.625mg Premarin + 2.5 Provera)
  • Premphase (0.625mg Premarin + 5.0mg Provera 14 days of the month)(called Premique in UK; Provelle in Australia)
  • Estratest (esterified estrogen and methyltestosterone)

Source: Hormone Replacement Therapy & Menopause by Ann Brown, MD, Duke University Medical Center. (2)

Heart Disease and HRT

Heart disease is the leading cause of death in post-menopausal women. Since a woman's risk of heart disease increases significantly at menopause, when her body stops producing estrogen, researchers have long been interested in determining whether HRT can help protect women against heart disease.

Past studies have provided hope that HRT can reduce heart disease risk. For example, studies have also shown that HRT may prevent the spasm of arteries that deliver blood and oxygen to the heart and lower the level of proteins that may cause harmful blood clots in those arteries. Studies showed that estrogen therapy may also help heal damaged blood vessels, prevent blood from coagulating (thickening), and may help to keep the walls of blood vessels pliable and open. In a 1997 study reported in the medical journal, Obstetrics and Gynecology, researchers found a lower incidence of coronary artery calcification in women who took HRT. Moreover, according to epidemiologist Deborah Grady, MD, for patients who have already had one heart attack, HRT may reduce the chance of a second heart attack by 84%.(3) Estrogen/progestin combinations may also help decrease heart disease by working to lower LDL ("bad") cholesterol levels and increasing HDL ("good") cholesterol levels.

However, recent studies have contradicted the beneficial effects of HRT on the heart. In fact, these newer studies suggest that HRT may actually increase the risk of heart disease in some women. In July 2002, the National Institutes of Health (NIH) stopped short a major study of HRT, called the Women's Health Initiative, because early findings showed that HRT was harmful to the heart. The NIH found that for every 10,000 women who take a combined estrogen/progestin version of HRT, 7 more will have a heart attack, 8 more will have a stroke, and 18 more will have blood clots, including 8 with blood clots in the lungs. The most recent analysis of the study's results (from 2003) showed that estrogen plus progestin use was associated with a 24% overall increase in the risk of heart disease, with an 81% increased risk in the first year of use The study did find benefits to HRT, including fewer hip fractures (often a sign of osteoporosis) and a decreased risk of colon cancer.

Risk factors for heart disease include:

  • previous heart attack
  • high blood pressure
  • atherosclerosis (narrowed arteries)
  • diabetes mellitus (a disorder caused by failure of the pancreas to release enough insulin into the body)
  • smoking
  • family history of heart disease
  • high cholesterol
  • obesity
  • excessive consumption of alcohol
  • lack of exercise

HRT and Osteoporosis

Osteoporosis is a degenerative bone disease that affects approximately one third of women over age 50. HRT is commonly prescribed to help prevent osteoporosis in post-menopausal women and appears to be particularly effective against osteoporosis if taken during the first five years after menopause begins. It is estimated that HRT can lead to a 50% to 80% decrease in vertebral fractures and a 25% decrease in non-vertebral fractures with five years of use. However, women may lose protection once they have stopped taking HRT. The Women's Health Initiative study results also showed HRT to be beneficial for bone health. On average, the researchers found that if a group of 10,000 women takes estrogen plus progestin for a year, 5 fewer cases of hip fractures will occur than in 10,000 nonusers.

Risk factors for osteoporosis include:

  • advancing age
  • female gender and post-menopausal
  • family history of osteoporosis
  • thin or small build
  • Caucasian or Asian
  • smoking
  • excessive alcohol
  • too little exercise or physical activity (sedentary lifestyle)
  • low calcium intake (now or as a child)
  • use of certain medications, such as steroids (commonly used to treat asthma and arthritis)
  • high doses of thyroid hormone
  • menopause before age 45

Symptoms and indicators for osteoporosis include:

  • back pain
  • height loss (indicates collapse of a spinal vertebra)
  • curving spine
  • broken bone (especially from a minor fall or non-traumatic event)
  • history of broken bones from minor injuries
  • chest x-ray showing osteopenia and/or vertebral wedging or collapse

HRT may also prevent osteoarthritis, a degenerative joint disease. Osteoarthritis is a major cause of hip and knee replacement surgeries among the elderly. As with osteoporosis, protection against osteoarthritis ends after HRT has been stopped.

However, HRT is not the only option for women considering osteoporosis prevention or treatment. In addition to HRT, patients can help decrease the risk of osteoporosis by taking calcium, magnesium, vitamin D, exercising or taking medications such as raloxifene (brand name Evista), alendronate (brand name Fosamax), calcitonin (brand name, Miacalcin), or risedronate sodium (brand name, Actonel).

HRT and Alzheimer’s Disease/Dementia

Alzheimer's disease is a degenerative brain disease that leads to confusion and memory loss as well as restlessness, problems with perception, speech trouble, trouble moving, and paranoia. Currently, there is no cure for Alzheimer's disease. However, some small studies suggest that estrogen or various combinations of HRT may delay the development of Alzheimer's.

Past studies suggest that women who take HRT have a reduced risk for Alzheimer's disease. In one study, elderly women were followed for five years. Among the women who did not take estrogen, 16% developed Alzheimer's disease compared to only 1.7% who did take estrogen. In another study, women who suffered only moderate memory problems from Alzheimer's disease improved their memory while on HRT.(3)

However, in 2003, results from the Women's Health Initiative Memory Study showed that estrogen plus progestin doubled the risk for developing dementia in post-menopausal women age 65 and older. Dementia is defined as a decline in mental ability in which the patient can no longer function independently on a day-to-day basis. The risk increased for all types of dementia, including Alzheimer's disease.

HRT and Diabetes

Patients with Type II (adult onset) diabetes are resistant to the action of insulin (a hormone released by the pancreas in response to high levels of sugar in the body). Past studies suggest that HRT may improve the body's response to insulin. Rather than making the body's blood sugar level go up, HRT may improve blood sugar metabolism.

Negative Effects of HRT

Side effects of hormone replacement therapy (HRT) vary from individual to individual but may include:

  • bloating
  • nausea
  • breast tenderness (typically during the first three to four months of treatment)
  • vaginal bleeding
  • fluid retention
  • weight gain
  • depression
  • possible increase in migraine headaches

Since estrogen has been linked to an increased risk of endometrial cancer (cancer of the lining of the uterus), there is a concern that HRT may increase the risk of a recurrence of endometrial cancer in women who have a history of the cancer. Physicians typically prescribe progestin with estrogen to counteract the risk of endometrial cancer.

There are also conflicting studies that show that HRT may increase the risk of blood clots in the veins. Generally, patients who have suffered from phlebitis (the inflammation of a vein, often along with the formation of a blood clot) from either the veins close to the skin (inflammation of varicose veins) or in the deep veins of the leg are not at greater risk of blood clotting. However, if previous blood clotting was associated with estrogen use or a "high-estrogen" state (i.e., pregnancy), it is likely that HRT may cause increased blood clotting.

HRT and Breast Cancer

The link between HRT and breast cancer remains controversial. Some studies have shown the risk of breast cancer to be minimal among women who use HRT while other studies have shown a more significant risk. Although studies have been inconsistent, there appears to be an emerging consensus that HRT may increase the risk for breast cancer.

Recently, women have been overwhelmed with reports that HRT may increase the risk for breast cancer. One particular study of 46,355 women in the Breast Cancer Detection Demonstration Project, a national breast cancer screening program, found nearly a 9% increase in breast cancer risk among women who used combined HRT (estrogen and progestin) each year. However, Dr. Judith Reichman, a professor at the University of California, Los Angeles who spoke at the Congress on Women's Health and Gender-Based Medicine meeting in June 2000, said that the results of the Breast Cancer Detection Demonstration Project are often misinterpreted. Some women may incorrectly assume that a 9% increase in breast cancer risk each year would mean that in 10 years, a woman's risk of breast cancer would be 90%. In reality, the researchers noted a 9% per year incidence of breast cancer among women who took HRT for a long period (typically over five years).

Other studies have shown that HRT can also increase the risk of breast cancer. Most notably, the Women's Health Initiative recently found that postmenopausal women taking estrogen with progestin have an increased risk of breast cancer as well as heart attack, stroke, and blood clots. The results of the Women's Health Initiative are discussed later in this article.

Nevertheless, other studies present a different point of view. In a study published in a March 1999 issue of the medical journal Cancer, 9,494 women with benign (non-cancerous) breast diseases (such as fibroadenoma) who took HRT were found to be at the same risk of developing breast cancer as women with benign breast diseases who did not take HRT. Lead researcher David Page, MD of Vanderbilt University, said that women need to know that the risk of breast cancer for low-dose ERT (HRT with estrogen alone) is minimal, and that there are many benefits to HRT. Dr. Page emphasized that the decision to use HRT or not should be an informed one and not one made out of fear.

The type of estrogen prescribed may have some biologic significance. For instance, ethinyl estradiol is more potent than traditionally used conjugated estrogens and has been associated with a 20% greater breast cancer risk that increases with the length of exposure. In addition, estrogen that is injected into the body (through a vein) rather than taken orally in pill form has been shown to be four times as likely to increase breast cancer risk, according to recent studies.(3)

HRT and Ovarian Cancer

Some research suggests that long-term use of HRT (10 years or more) increases the risk of ovarian cancer. In a study of more than 200,000 women, researchers from the American Cancer Society found that using estrogen replacement therapy (estrogen without progestin) for 10 or more years increases the risk of death from ovarian cancer. While the chances of developing ovarian cancer doubles with prolonged estrogen use, the risk still appears to be small-approximately 2% over a lifetime. However, the study did not include data from women who used combination hormone replacement therapy (estrogen and progestin), which is the most common regimen prescribed today.

While researchers are not certain why estrogen therapy increases the risk of ovarian cancer, they do know that estrogen causes ovarian cells to produce at faster than normal rates. One theory is that the more times a cell divides, the higher the chances that it will result in an abnormal gene copy. If the abnormal copy controls cell growth, this could result in uncontrolled (cancerous) growth.

The Women's Health Initiative Finds Risks with HRT

The Women's Health Initiative was launched in 1991 to study combination HRT (estrogen plus progestin) and estrogen-only HRT. All together, its studies have involved 161,808 healthy post-menopausal women. The following summarizes the study's findings as of 2003.

Compared with women taking a placebo (an inactive pill), women who took estrogen plus progestin experienced:

  • Increased risk of heart attack
  • Increased risk of stroke
  • Increased risk of blood clots
  • Increased risk of breast cancer
  • Reduced risk of colorectal cancer
  • Fewer fractures
  • No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older)

The study results also show that for every 10,000 women per year taking estrogen with progestin, there would be:

  • 6 fewer cases of colon cancer
  • 5 fewer cases of hip fracture

Compared with women taking a placebo (an inactive pill), women taking estrogen alone experienced:

  • No difference in risk for heart attack
  • Increased risk of stroke
  • Increased risk of blood clots
  • Uncertain effect for breast cancer
  • No difference in risk for colorectal cancer
  • Reduced risk of fracture

Source: Women's Health Initiative, 2005 (1)

Based on the results of the Women's Health Initiative, the U.S. Food and Drug Administration (FDA) issued a statement in February 2004 encouraging all manufacturers of estrogen and estrogen with progestin drug products indicated for use by postmenopausal women to update the labeling for their products to provide information about possible health risks (5). Furthermore, in May 2005, the U.S. Preventive Services Task Force, supported by the U.S. Agency for Healthcare Research and Quality, issued a new recommendation against the routine use of estrogen to prevent chronic conditions such as heart disease, stroke and osteoporosis in postmenopausal women who have undergone a hysterectomy (6). The Task Force did not examine the effects of estrogen only or combined estrogen and progestin for the treatment of menopausal symptoms, only for the prevention of chronic disease.

Despite these warnings, the National Institutes of Health has stated that the Women's Health Initiative results may not be relevant for women with severe menopausal symptoms. According to the National Institute of Health, "Participants in the Women's Health study were randomly assigned to receive either hormones or placebo, and those women who had menopausal symptoms reported relief from symptoms with hormone use. Women who felt that they needed menopausal hormones to treat severe symptoms may not have been willing to take the chance of not receiving hormones and may, therefore, have been underrepresented in the study." (4)

Imaginis.com Articles on HRT


Conclusion

The following lists summarize the possible benefits and risks of ERT (estrogen without progestin). The benefits and risks may differ when estrogen is combined with progestin. For example, the increased risk of endometrial cancer is not associated with combination hormone therapy.

Possible Benefits of ERT:

  • Relieves menopausal symptoms—hot flashes, vaginal dryness, etc.
  • Prevents and treats osteoporosis
  • May improve mood

Possible Risks of ERT:

  • May increase risk of heart attack and stroke (research is contradictory)
  • May increase risk of blood clots in legs and lungs
  • May increase risk of breast cancer
  • May increase risk of breast cancer when taken for more than 5 years
  • Increases risk of endometrial cancer of the uterine lining (risk counteracted if estrogen is combined with progestin)
  • Increases risk of ovarian cancer
  • May be associated with side effects, such as bloating, nausea, etc.

HRT is a tradeoff between the proven benefits of relieving menopausal symptoms and preventing diseases such as osteoporosis versus the possibility of increasing the risk of breast cancer. If a woman is at high risk of osteoporosis (due to age, family history, small build, etc.) and has a relatively low risk of breast cancer, then HRT may be an easy choice. If a woman is already at high risk of breast cancer due to genetic factors, family history, etc. then the decision to take HRT may be more complicated.

To further add to the confusion, the combined estrogen/progestin arm of the Women's Health Initiative (WHI)-a large clinical trial that was studying HRT, heart disease, osteoporosis, breast cancer, and colon cancer in 63,000 American women between the ages of 50 and 79-was halted in by the National Institutes of Health (NIH) in 2002. Researchers felt that the elevated risk of breast cancer, as well as higher than normal rates of heart attack, stroke, and blood clots, outweighed the benefits that HRT may provide against hip fractures and colon cancer. The arm of the WHI that studied estrogen alone (with progestin) did not find an increase in heath-related problems among women who took estrogen. That arm of the study will continue. At the moment, the best advice experts can give is for women to discuss the benefits and risks of HRT with their physicians and make informed choices.

Additional Resources and References