By Holly Kramer, MD, MPH

The number of women receiving dialysis treatment for kidney failure in the United States (U.S.) continues to increase. By the end of 2004, there were over 210,000 women receiving dialysis in the U.S.(1) and the majority of these women were older than 50 years of age and likely menopausal when they initiated dialysis. Menopause, defined clinically as the absence of menstruation for 12 months, is due to factors associated with aging, toxins or the surgical removal of both ovaries(3). The median age of menopause in the general population is 51 to 52 years(2), but menopause onset may occur earlier in women with kidney failure.(3) Menopause is frequently accompanied by vasomotor symptoms called “hot flashes.” Hot flashes are short periods (less than four minutes usually) of intense warmth over the upper body with sweating, which may then end with a chill sensation. Hot flashes are usually brief with less than 15 percent of women reporting hot flashes occurring for more than five years. In fact, 30 to 50 percent of women suffer with hot flashes for less than one year.(4) Vaginal symptoms such as dryness, itching and pain during sexual intercourse may occur in one out of every three women during the menopause transition, and 1 out of every 2 women after several years of being menopausal.(4) Other symptoms which may be attributed to menopause include insomnia, mood disorders, bladder dysfunction and weight changes.(4)

Few studies have examined menopausal symptoms or estrogen use in women receiving dialysis. The Hemodialysis and Estrogen Levels in Postmenopausal Patients (HELP) Study was a multi-center study investigating the association between dialysis-related and demographic factors and serum estrogen levels in postmenopausal women receiving hemodialysis.(3) Two-hundred thirty-eight post menopausal hemodialysis women participated in the study. The average age of the women at the time menopause started was 48, three years younger than the average age of when menopause starts for women in the general population. Sixty-five percent of the women attributed their menopause to natural causes, while 30 percent said it began when their ovaries were removed. Only 2 percent reported menopause was due to kidney failure and the remaining other rare causes included
chemotherapy and radiation.(3)

Currently, we do not know how many women receiving dialysis for management of kidney failure utilize estrogen replacement therapy and the risks and benefits of estrogen use in this population remain largely unknown. Women with kidney disease are usually excluded from most clinical trials. It appears few women receiving dialysis use estrogen replacement therapy. The HELP Study reported current use of estrogen replacement therapy in only 6 percent of 238 postmenopausal women receiving dialysis and only 17 percent reported past use of estrogen. The majority of women stated they would not take estrogen replacement therapy if a doctor recommended it.(3)

The HELP Study was completed about the time the Women’s Health Initiative (WHI) results were first reported. The WHI Study made many women and clinicians question the use of estrogen replacement therapy in menopausal women. The WHI was a very large randomized trial sponsored by The National Institutes of Health. The trial was designed to determine whether estrogen replacement in menopausal women prevented or delayed the development of cardiovascular disease in menopausal women. Other disease endpoints were also examined including breast cancer, cognitive dysfunction and osteoporosis. More than 68,000 women participated and were randomized (like a flip of the coin) to either placebo (sugar pill), or estrogen plus progestin if they had a uterus or estrogen alone if they did not have a uterus.(5)

In 2002, the study was stopped early, three years prior to the scheduled completion time of 2005. The study was terminated because the overall risk/benefit ratio had passed predefined points which indicated excessive risk.(5) More women assigned to the estrogen plus progestin group developed invasive breast cancer compared to women taking placebo. In addition, there were more heart attacks, strokes and blood clots among the women taking estrogen plus progestin compared to women taking placebo.

Although the numbers of events such as heart attacks, stroke and cancer differed between the treatment and placebo group, the actual difference in number of events was small. This was not communicated very well with the public. In fact, substantial declines in estrogen prescriptions and promotion of estrogens were noted in the first nine months after the WHI results were reported.(6) Many women who needed estrogen for menopausal symptoms did not receive treatment.

Kidney disease is considered a cardiovascular disease risk equivalent because cardiovascular disease risk is so much higher among individuals with kidney disease compared to individuals without kidney disease. Thus, examining the effects of estrogen replacement therapy in women with known cardiovascular disease may be more applicable to women receiving dialysis. The Heart and Estrogen/progestin Replacement Study (HERS) was a large randomized trial which included menopausal women with cardiovascular disease, and over 40 percent of these women had chronic kidney disease.(10) Women with kidney failure were excluded. The 2,763 HERS participants were randomized to estrogen (+/- progestin) or placebo for the secondary prevention of cardiovascular events (heart attack, stroke or death due to heart disease) and followed for an average of four years. New cases of breast cancer were also monitored. No significant difference in cardiovascular outcomes or mortality was noted between the treatment and placebo group. However, the investigators found estrogen replacement therapy was not beneficial for the prevention of cardiac events in women with cardiovascular disease. Moreover, more blood clots and gallbladder disease were found in the women who took estrogen compared to placebo.(10) These results were fairly consistent regardless of presence of kidney disease at baseline.(11)

The HERS and WHI studies were heralded as landmark studies which helped answer many previously unknown clinical questions regarding menopausal treatment. However, these studies have been criticized for enrolling women who had been postmenopausal for up to 10 or 20 years when menopausal treatment may no longer be beneficial for heart disease prevention.

In women with kidney disease, the association between estrogen and blood clots may be stronger due to higher blood levels of estrogen for a given oral dose of estrogen. A small short term study of women receiving dialysis showed the taking of oral estrogen led to higher levels of blood levels of estrogen compared to women without kidney disease matched for body mass index. It is possible the decreased excretion of estrogens by the kidney may lead to higher levels.(14) No long-term studies have examined the risks and benefits of estrogen replacement therapy in women receiving dialysis or in women with kidney disease not receiving dialysis. Due to the risk of clotting the dialysis access, women who desire estrogen replacement for treatment of menopausal symptoms should consider transdermal estrogen to avoid the potential side effects of blood clotting.

Current recommendations for menopausal treatment state women with severe menopausal symptoms such as hot flashes may utilize estrogen replacement therapy but this should be done with the lowest effective dose available and for the shortest amount of time.(4) For example, a woman with severe hot flashes could try low dose estrogen replacement therapy for 12 months and then stop. If the symptoms return, she could restart the estrogen and try taking it only three days of the week instead of everyday.(4) For women receiving dialysis, starting doses of estrogen should be half the dose which would be used in a woman with normal kidney function. Other treatment options for menopausal symptoms include gabapentin (anti-convulsant), clonidine (an anti-hypertensive medication) and certain anti-depressants such as fluoxetine and sertraline.(4) However, these drugs are not as effective for treating severe menopausal symptoms as estrogen itself. Vaginal atrophy, which may lead to painful sexual intercourse, is best treated with vaginal estrogen. Lubricants are also helpful to assist with vaginal dryness.
Every woman is unique and no two menopausal transitions are equal. In the majority of women, menopausal symptoms are usually transient and lessen within a year. Women with severe menopausal symptoms should seek help and discuss concerns with their doctor.

Holly Kramer, MD, MPH, is an Association Professor of Medicine in the Department of Preventive Medicine and Medicine, Division of Nephrology and Hypertension at Loyola University Medical Center.

References can be found on the AAKP Web site at http://www.aakp.org/aakp-library/Menopause.

This article originally appeared in the September 2009 issue of aakpRENALIFE.

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