What is hormone replacement therapy (HRT)?
Related cancers: Breast and uterine cancers; possibly ovarian, testicular, and prostate gland cancers
Definition: Hormone replacement therapy (HRT) most often involves the administration of estrogen alone or estrogen in combination with progesterone. Estrogen is a general term for any number of sex hormones, including estradiol, the main estrogen produced by the body, and estriol and estrone, which are products of estradiol metabolism. Progesterone is another sex hormone, which often opposes estrogen in action. Progestin is a general term for progesterone or other substances that have the same effect as progesterone. Alternatively, HRT may involve the administration of androgens, either for transgender men or for men suffering from hypogonadism; however, there is little confirmed evidence to suggest that androgen therapy is carcinogenic in humans.
Exposure routes: Estrogen and progesterone, whether naturally occurring in the body or inhaled, ingested, injected, or absorbed through the skin, travel through the bloodstream. They are then absorbed by estrogen-dependent cells or metabolized by the liver for final excretion in urine and stool.
Where found: Estrogen and progesterone are found in many animal fluids and tissues, including milk and meat, as well as many plants, including palm kernel oil. The estrogen most often used in HRT is extracted from the urine of pregnant mares. Estrogens and progesterones are also used commercially in skin and hair products in low concentrations. The most likely route of excessive exposure is use of prescribed HRT in oral, dermal, or vaginal preparations.
At risk: Women who use HRT are at greatest risk. Workers in facilities where prescription estrogen and progesterone products are made can be also exposed through inhalation or skin contact.
Etiology and symptoms of associated cancers: Prolonged or excessive estrogen exposure causes estrogen-dependent cells to divide more rapidly than normal. Overexposure to estrogen can damage chromosomes or alter gene expression in estrogen receptor cells. Estrogen receptors are proteins within cells that bind to estrogen and stimulate production of certain tissue cells, including breast, ovarian, and uterine lining cells. Overexpression of estrogen receptors causes increased cell division and deoxyribonucleic acid (DNA) replication, which increases the chance for mutations and causes tumor growth. The mechanism by which progesterone is associated with cancer is not known, but many studies have shown that injection of progesterone in animals causes tissue overgrowth and tumor formation in the uterine lining, the breast, and other reproductive tissues.
The cancers that are known to result from HRT include breast cancer (lobular more than ductal) and endometrial, or uterine, cancer. At least one study has shown a causal relationship between HRT and ovarian cancer, but other studies have had conflicting results. The most common symptom of breast cancer is a lump or mass in the breast. Some breast cancers present as calcifications in breast ducts, with no mass. These are usually discovered on mammography. Uterine cancer is slow growing and is often found on imaging studies of the abdomen ordered for vaginal bleeding in a postmenopausal woman or for other symptoms not related to the cancer.
History: Estrogen is a hormone naturally produced by the ovaries, placenta, testes, and adrenal glands. It regulates development of secondary sex characteristics, such as breast development and body hair distribution, and is important in the growth and functioning of all reproductive organs as well as bones. It regulates brain processes associated with reproduction, including mood and interest in sex. One of its most important functions is maintaining the lining of the uterus and preparing the body for pregnancy.
Progesterone is produced by the ovaries in adult women and by the placenta during pregnancy. It is also produced by the adrenal glands and, like estrogen, is found in many body tissues and fluids. Progesterone is essential in the thickening and vascularity of the uterine lining that allow the fertilized ovum to implant and grow during pregnancy. Both hormones are used in oral contraceptives.
Estrogen, alone or with progestin, has been prescribed for menopausal women to relieve unpleasant side effects of menopause and was once thought to prevent heart attacks and retard aging. Progestins are prescribed, among other reasons, to regulate the menstrual cycle and prevent miscarriage.
HRT use flourished in the 1960s and 1970s until researchers started noticing a marked increase in the incidence of endometrial cancer in women treated with estrogen replacement therapy. The results of one of the first studies to make the connection were published in 1975 in the New England Journal of Medicine by D. C. Smith and colleagues, who found a 4.5 times greater risk of endometrial adenocarcinoma in postmenopausal women being treated with estrogen alone. Many other studies followed, and conjugated estrogen, a mixture of naturally occurring estrogens, was listed as a known carcinogen in 1985. Other studies, including a Swedish study by I. Persson and colleagues published in the British Medical Journal in 1989, found that estrogen therapy in combination with progestins did not increase the risk of endometrial cancer, so combination therapy came into common use, with an estimated 40 million prescriptions in the United States in 1992. By 1999, studies were showing an increased risk for breast cancer in patients using estrogen alone or combination (estrogen-progestin) therapy.
The definitive study for the association of breast cancer and HRT was the 1991 Women’s Health Initiative, a US government–sponsored research study consisting of clinical trials and an observational study, which included trials on more than 16,000 postmenopausal women using estrogen alone or combination therapy. The combination therapy part of the study was stopped in 2002, after nearly six years of research, because the findings showed the risks of combined HRT to be greater than the benefits. The study found that the incidence of breast cancer increased and that the risk increased with the duration of HRT. The estrogen-alone part of the study was stopped in 2004 because data indicated an increased risk of stroke in patients taking estrogen supplements. Estrogen-alone therapy did not increase the risk of breast cancer in the study population.
Use of HRT dropped significantly after the Women’s Health Initiative results were published, as did the incidence of breast cancer. Some researchers thought the drop was a direct result of less use of HRT. Other studies concluded that the decrease in the incidence of breast cancer began four years before the Women’s Health Initiative results were announced and that it was more likely to be a result of fewer women getting mammograms. Mammograms were part of the required follow-up for women getting HRT, and it is ironic that many women may have stopped getting mammograms because of decreased medical care that resulted from stopping HRT, which could have delayed detection of breast cancers.
Studies of HRT continue, but the consensus seems to be that women who need HRT for relief of menopausal symptoms should receive therapy in the lowest effective dose for the shortest period of time needed. Estrogen therapy was shown in the Women’s Health Initiative to be effective in treatment of osteoporosis, or thinning of bone tissue, but its use is recommended only for patients who are not candidates for other treatments. HRT is no longer recommended for prevention of coronary artery disease. The benefits of HRT include a decreased risk of colorectal cancer and osteoporosis and relief of troublesome menopausal symptoms. Patients in need of HRT should discuss options with their physicians, who will weigh the benefits and risks of treatment for each patient.
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