Management of Menopausal Symptoms in the Cancer Patient

The article by Castiel highlights the benefits and potential risks of estrogen replacement in cancer patients. For patients with malignancies that are not “estrogen sensitive,” adding hormone replacement therapy (HRT) to the therapeutic regimen can only improve quality of life. This is a very important consideration for many patients undergoing the trials and tribulations of cancer therapy. For patients with breast and endometrial cancer, the issues are somewhat more complex. However, a growing number of physicians are becoming convinced that the patient should decide whether or not to take hormone replacement based on a careful explanation of the issues involved.

Patients should be aware that estrogen affects many tissues in the body, in addition to the classic target tissues of the uterus and breast.[1,2] Estrogen exerts well-established effects on bone that can prevent osteoporosis; cardioprotective benefits through effects on plasma lipid levels and vessel walls; and effects in the brain, protecting against the onset and symptoms of Alzheimer’s disease.[3-6]

It is now known that estrogen functions differently in various tissues. Furthermore, it is hoped that a greater understanding of the mechanisms underlying these various actions of estrogen will ultimately lead to the development of an estrogen that provides all of the benefits without the potential, undesirable effects.

Cardiovascular Disease Protection

According to American Heart Association statistics, more women than men die of cardiovascular disease in the United States every year, and cardiovascular disease continues to be the leading cause of death among women over age 35. A woman’s risk of coronary artery disease increases dramatically after menopause, regardless of the age of onset or cause of menopause.

Numerous factors contribute to a woman’s risk of cardiovascular disease. These include smoking, inactivity, obesity, a poor cholesterol profile, and estrogen deficiency. Retrospective studies have shown that postmenopausal estrogen therapy reduces the risk of cardiovascular disease by approximately 50%.[7,8] The mechanism of this cardioprotective effect is not completely understood, but it is believed to be multifactorial.

Estrogen has a known effect on serum lipoproteins: It increases high-density lipoprotein cholesterol by up to 15% and decreases low-density lipoprotein cholesterol and total cholesterol by nearly 20%. Changes in the lipid profile may account for approximately 30% to 50% of the reduction in cardiovascular events seen with estrogen. The addition of a progestin slightly abrogates the effect of estrogen on the lipid profile, but, according to the Postmenopausal Estrogen-Progesterone Intervention (PEPI) study, this abrogation is minimal.

Most observational studies have found estrogen to be effective in both the primary and secondary prevention of cardiovascular disease. In the Nurses’ Health Study, which involved over 59,000 women, current users of estrogen replacement enjoyed up to a 50% reduction in the relative risk of cardiovascular disease.[1,2,9] It is important to note that most studies performed in America have utilized conjugated equine estrogen (Premarin), whereas European studies have used estradiol valerate.

Retrospective angiographic studies have shown that estrogen exerts a statistically significant, independent protective effect against coronary atherosclerosis. Improved survival has been observed in women who use estrogen or hormone replacement after coronary angioplasty or coronary artery bypass surgery. Four cohort studies have found a great mortality and morbidity benefit related to estrogen use among women with coronary atherosclerosis. These same studies have shown that survival is significantly better among women with serious cardiovascular disease who use HRT.

The Heart and Estrogen-Progestin Replacement Study

A randomized, double-blind, placebo-controlled trial was conducted to assess the ability of hormone replacement to reduce the risk of death and recurrent cardiovascular incidents (events) in women with established cardiovascular disease. The Heart and Estrogen-Progestin Replacement Study (HERS) enrolled more than 2,700 postmenopausal women with documented serious coronary heart disease who ranged in age from 44 to 79 years (mean, 67.7 years). Many of these women had significant comorbidities and were taking a variety of cardiac medications. The patients were randomly assigned to either placebo or a daily dose of combined continuous conjugated equine estrogens plus medroxyprogesterone acetate.

At 1 year, there was a 52% increase in the relative risk of coronary heart disease events in the HRT group, but the actual incidence of such events was low, occurring in 4.3 of 100 women in the HRT group vs 2.8 of 100 women in the placebo group. In both groups, the incidence of coronary heart disease events was less than 5%, which is the rate used in the study to estimate the number of subjects needed to achieve statistical power.

The trial also revealed a statistically different time trend between the two groups with respect to coronary heart disease events: More events occurred in the HRT group than in the placebo group during year 1, but fewer events occurred by years 4 and 5. Specifically, the incidence of recurrent coronary heart disease events with HRT was comparable to that seen with placebo by the 8th month of use and was lower after the 36th month of use.

The authors of the trial concluded that these results should not affect the current recommendations for estrogen or hormone replacement in women without coronary heart disease. However, in women with newly diagnosed coronary heart disease, HRT should not be initiated solely for the purpose of preventing additional coronary heart disease events.

The HERS researchers did not evaluate the cardiovascular effect of treatment with unopposed estrogen, which is commonly prescribed in women who have undergone a hysterectomy. They also did not investigate the usefulness of other estrogen-progestin formulations.

It is important for clinicians to recognize that HERS assessed only one therapeutic regimen; clearly, there is a need for studies of other regimens. In addition, the HERS participants were older and less healthy than the average perimenopausal woman who is considering taking estrogen or hormone replacement. Although women in the trial who took the estrogen-progestin regimen appeared to have an increased risk for primary coronary heart disease events during the first year of therapy, that risk declined over subsequent years.

Cognitive Function

Advancing age brings a general decline in cognitive function. This slowing of central processing speed may contribute to the increased number of hip and wrist fractures among the elderly, as these older individuals are less adept at adverting falls than their younger counterparts. The rate of cognitive decline is determined by numerous factors. Documented risk factors, identified by clinical research on Alzheimer’s disease, include age, family history, and genetic mutations.

One current theory suggests that Alzheimer’s disease develops as a result of failed processing of a protein that responds to injured neurons. Instead of facilitating neuronal repair, this altered protein results in the development of a fragment, beta-amyloid, that contributes to neuronal toxicity.

Alzheimer’s disease has become an important women’s health issue. It occurs about two to three times more commonly in women than in men. It has been postulated that this gender disparity is due, in part, to the loss of estrogen in the postmenopausal woman; the average 70-year-old male has three times the circulating estradiol levels than the average 70-year-old female. Women’s greater life expectancy also places them at greater risk for Alzheimer’s disease.

Estrogen has several different effects on brain function. It stimulates the expression of neurotropic factors within the central nervous system. In vitro, estrogen protects neurons from beta-amyloid toxicity by promoting the breakdown of the amyloid precursor protein to fragments less likely to aggregate in the brain as deposits. Estrogen also increases regional cerebral blood flow and stimulates the production of neurotransmitters, such as acetylcholine and serotonin. Lastly, estrogen stimulates axonal regeneration and the production of synapses.

Colorectal Cancer

Colorectal cancer is the second leading cause of cancer death in US women. In 1998, this cancer was responsible for nearly 25,000 deaths in women.

Epidemiologic studies indicate that women who use HRT may have up to a 34% reduction in the rate of colorectal cancer compared to women who have never used hormone replacement. Overall, colon cancer is reduced by 20% and rectal cancer by 15% in women who have ever taken estrogen.

The exact effect of estrogen on the colon is unknown. However, it is thought that estrogen may affect the production of bile acids that aid in digestion and that seem to be important for the prevention of colorectal cancer.

Hormone Replacement in Breast Cancer Survivors

Given these and other benefits of hormone replacement, it is imperative that we inform patients who were formerly prohibited from using HRT that, indeed, there are risks and benefits that must be considered.[10,11] Breast cancer survivors constitute the most important of these groups. Unfortunately, no prospective, randomized studies have been completed to show whether hormone replacement either favorably or adversely affects the survival of breast cancer patients.[12]

In view of the rapidly accumulating data on the benefits of HRT in average women, can we continue to uniformly object to its use in breast cancer survivors? Shouldn’t these patients be informed about the risks and benefits of hormone replacement, based on current knowledge, and then be allowed to make their own decision?

Conclusions

Over the past 2 decades, there has been enormous growth in our knowledge of the mechanisms of action of estrogen, as well as the benefits of postmenopausal estrogen and hormone replacement. Several observational studies have proven that postmenopausal estrogen use can significantly reduce the risk of cardiovascular disease, osteoporosis, and bone fractures. Estrogen appears to decrease the risk of Alzheimer’s disease and definitely provides relief of menopausal symptoms. Since the cost to the American health care system for the management of cardiovascular disease, osteo-

porosis, and Alzheimer’s disease runs into the tens of billions of dollars, can we afford to ignore this option for any postmenopausal woman? Dr. Castiel poses this question in her thoughtful review. My comments merely reinforce her conclusions.

References:

1. Grady D, Rubin SM, Petitti DB, et al: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 117:1016-1037, 1992.

2. Grodstein F, Stampfer MJ, Colditz GA, et al: Postmenopausal hormone therapy and mortality. N Engl J Med 336:1769-1775, 1997.

3. Jacobs DM, Tang MX, Stern Y, et al: Cognitive function in nondemented women who took estrogen after menopause. Neurology 50:368-373, 1998.

4. Paganini-Hill A, Henderson VW: Estrogen replacement therapy and risk of Alzheimer’s disease. Arch Intern Med 156:2213-2217, 1996.

5. Rice MM, Graves AB, McCurry SM, et al: Estrogen replacement therapy and cognitive function in postmenopausal women without dementia. Am J Med 103:26S-35S, 1997.

6. Tang MX, Jacobs D, Stern Y, et al: Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348:429-432, 1996.

7. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 280(7):605, 1998.

8. Sacks FM, Walsh BW: The effects of reproductive hormones on serum lipoproteins: Unresolved issues in biology and clinical practice. Ann NY Acad Sci 592:272-285, 1990.

9. Wenger NK, Speroff L, Packard B: Cardiovascular health and disease in women. N Engl J Med 329:247-256, 1993.

10. DiSaia PJ, Grosen EA, Kurosaki T, et al: Hormone replacement therapy in breast cancer survivors: A cohort study. Am J Obstet Gynecol 174:1494-1498, 1996.

11. Eden JA, Bush T, Nand S, et al: A case control study of combined continuous estrogen-progestin replacement therapy among women with a personal history of breast cancer. Menopause 2:67-72, 1995.

12. Vassilopoulou-Sellin R, Therriault R, Klein MY: Estrogen replacement therapy in women with prior diagnosis and treatment for breast cancer. Gynecol Oncol 65:89, 1997.