Short periods of hormone replacement therapy (HRT) are often used to treat vasomotor symptoms around the time of the menopause, but long-term adherence to therapy is low. However, there is accumulating evidence to support the initiation or re-initiation of HRT as a later intervention for a variety of progressive conditions associated with menopause and aging. If the risk-benefit ratio is in favor of HRT, various strategies can be used to improve acceptance and minimize side effects, with the goal of improving the quality, if not the quantity, of life.
If a risk-benefit analysis favors hormone replacement therapy, it may be appropriate and acceptable to initiate systemic or local HRT in some older women to improve the quality of their lives.
Intuitively, prevention is preferable to the treatment of established disease. However, universal therapy for prevention of disease may not be practical, affordable, or acceptable. Many of the health consequences of menopause and aging can be modified by hormone replacement therapy (HRT), using either estrogen alone or estrogen plus a progestin. In recent years, standard teaching suggested that HRT should be continued throughout the menopausal years to confer maximal relief of vasomotor symptoms, optimal effects on bone, lipids, and the urogenital tract, and the possibility of protection from cardiovascular disease, cerebrovascular disease, colon cancer, and neurodegenerative disorders such as Alzheimer’s disease.
Few therapies in modern medicine have the potential to offer such a wide array of health benefits with relatively low cost. Yet, acceptance and continuation rates for HRT continue to be low. Concerns about a possible increase in breast cancer risk appear to be the largest hurdle to initiating HRT, while withdrawal or breakthrough bleeding is the main reason for discontinuing therapy.
As an alternative to long-term use of HRT as a preventive strategy, there is increasing support for periods of HRT use tailored to the woman’s current health concerns. This model focuses on treatment rather than prevention, and therefore has inherent limitations. However, it may be more appealing to those who dislike taking medications unless absolutely necessary, those who prefer to avoid medicalizing this stage of life, and those who fear that breast cancer risk increases with increasing duration of HRT.
In such a model, HRT might be used for 1 to 5 years in the perimenopausal interval to control vasomotor symptoms and irregular bleeding. A second discussion about the use of HRT (and other therapies), particularly for bone protection and relief of urogenital symptoms, may then be initiated in later life, depending on individual symptoms, health status, and risk factors.
Evidence is now accumulating to support the use of HRT as a later intervention for a variety of progressive conditions associated with menopause and aging.
Vasomotor symptoms (Table 1) are usually most troublesome in the perimenopause and early menopausal years, but generally improve spontaneously over a period of 2 to 5 years. Some women have residual bothersome symptoms that persist for years or decades.
Level I evidence from randomized placebo-controlled trials indicates rapid and effective relief of vasomotor symptoms with either oral or transdermal estrogen. If estrogen is not appropriate or not tolerated, relief may be obtained with progestins alone, although higher doses may be required (10 mg to 20 mg of medroxyprogesterone acetate daily). There are also several nonhormonal options for controlling vasomotor symptoms in women for whom HRT is not appropriate, including clonidine, ergot-containing preparations, exercise, acupuncture, dietary phytoestrogens, and black cohosh.
In contrast to vasomotor symptoms that appear early and tend to dissipate with time, urogenital symptoms tend to develop progressively in the years or decades following menopause (Table 2). Urogenital complaints may affect 30% to 50% of menopausal women and may be a source of considerable daily discomfort. Vaginal dryness during sexual arousal is often the first symptom and may precede physical findings.
There is level I evidence to support the use of estrogen for vaginal atrophic symptoms and as prophylaxis for recurrent urinary tract infections.[1,3] Interestingly, systemic HRT may not provide complete relief of vaginal symptoms, necessitating augmentation or replacement with local vaginal estrogen therapy. Low doses of vaginal estrogen can be used to treat urogenital symptoms, even in women with contraindications or intolerance to systemic estrogen therapy. Vaginal estrogen is absorbed systemically, although circulating levels are about 25% of those seen with equivalent oral doses. No appreciable changes in basal serum estradiol levels were seen following vaginal doses of 0.3 mg conjugated estrogens (0.5 gm or 1/8 applicator of Premarin cream) or more than 48 hours after insertion of an estradiol-containing vaginal ring (Estring).[1,4]
In order to accrue significant skeletal benefits from HRT, therapy must be administered for at least 5 to 10 years. However, long-term adherence to HRT is relatively low, and bone loss resumes after discontinuation of HRT. Catch-up bone loss is believed to occur, so that 10 or more years after stopping estrogen, bone mass appears similar in treated women and untreated controls.[5,6]
Clearly, a short period of HRT use for 2 to 5 years around the time of menopause will not provide effective long-term bone protection. In contrast, if current use affords bone protection and the majority of fractures occur in older women, perhaps a case can be made for selectively instituting HRT (or other antiresorptive therapy, as needed) in older women who are at highest risk of fracture.
At least three large epidemiologic studies involving approximately 15000 women support this approach. The Rancho Bernardo Study, the Study of Osteoporotic Fractures, and the Swedish Hip Fracture Study each reported preservation of bone mass or fracture protection among women who were current estrogen users of at least 10 years’ duration, even if the estrogen use had not started until after the age of 60. In each study, the benefits of estrogen were reduced or absent in short-term users or past users. Current estrogen users in one of the studies also demonstrated improved muscle strength, neuromuscular function, and a lower risk of falling.
A recent study by Genant and colleagues demonstrated dose-related improvements in bone density beginning at a dose of 0.3 mg of esterified estrogen. It is not yet clear whether these low doses will provide reliable fracture protection or whether the results can be extrapolated to older women with established osteoporosis. Nevertheless, these findings provide reassurance that the dose-related estrogenic side effects (i.e., breast tenderness, nausea, vaginal discharge), which may be particularly troublesome for older women, can be minimized without sacrificing the full therapeutic effect.
Postmenopausal estrogen therapy is associated with endothelial vasodilation and beneficial changes in the lipid profile. Numerous case-control and cohort studies have demonstrated a 40% to 50% reduction in the risk of coronary heart disease (CHD) among postmenopausal HRT users. The protection dissipates following cessation of therapy, suggesting that it is mediated by a direct vascular action.
In contrast to the extensive epidemiologic data, the recently published Heart and Estrogen/Progestin Replacement Study (HERS) did not indicate any overall benefit from continuous combined therapy with conjugated estrogens and medroxyprogesterone acetate (Prempro, a US product) among women with established CHD. The authors also reported a trend toward greater mortality among HRT users, particularly in the first year. Unfortunately, a combination product was used, so it is not clear whether the unexpected results were due to the estrogen component, the progestin component, or the combination. Furthermore, there was a high rate of discontinuation of HRT in the first year, and the authors were unable to determine whether it was the initiation or discontinuation of HRT that was associated with the non-significant increase in CHD events in the first year.
Nevertheless, these findings suggest that continuous combined HRT (i.e., Prempro) should not be initiated in older women with established CHD for the purpose of secondary prevention. These recommendations cannot be extrapolated to primary prevention or applied to other HRT preparations or combinations. At present, the data do not support changing an existing HRT regimen in an older woman, with or without CHD. Until the data indicate otherwise, it does not seem logical to withhold HRT in older women without established CHD, particularly if the balance of the risk-benefit ratio is in favor of HRT. Results from large randomized trials such as the Women’s Health Initiative may help clarify this issue.
A recent wave of media attention has prompted inquiry from many postmenopausal women about the use of HRT for the prevention or treatment of disorders such as Alzheimer’s disease. Estrogen appears to have a neuroprotective role, likely mediated by its antioxidant properties and its ability to enhance cerebral blood flow, improve cerebral glucose metabolism, and reduce ß-amyloid deposition. It follows that loss of these protective effects after the menopause may contribute to the neurocognitive deterioration that occurs with normal aging.
Several epidemiologic studies have suggested that estrogen deficiency may contribute to the development of Alzheimer’s disease and that estrogen replacement may play a role in the prevention and treatment of Alzheimer’s disease.[1,12] Some studies have also suggested that the protective effect was related to the cumulative dose and duration of estrogen use. Despite encouraging results in smaller pilot studies, a recent 1-year randomized placebo-controlled trial failed to demonstrate an improvement in disease progression or cognitive outcome with either of two estrogen doses in women with mild to moderate Alzheimer’s disease. These findings suggest that the antioxidant effects of estrogen may be sufficient to slow the initiation phase but not the propogation phase of neurodegeneration.
Although the evidence linking HRT and Alzheimer’s disease is intriguing, it is still of limited quality and requires confirmation in large placebo-controlled trials such as the one currently being conducted by the National Institute of Health as part of the Women’s Health Initiative. Until these results are available (likely after 2005), it would not appear prudent for physicians to promote the use of HRT in older women solely for neurocognitive protection. However, it would not be logical to withhold HRT from a motivated women who wishes to try HRT for neurocognitive protection, provided that the balance of the risk-benefit ratio is in favor of HRT.
Women who have not been exposed to appreciable levels of estrogen for many years may be particularly susceptible to estrogen-related side effects such as bloating, breast tenderness, and vaginal discharge. Elderly women may not need or tolerate the doses of estrogen that were traditionally thought to be osteoprotective (Table 3), particularly in light of recent evidence suggesting that some bone protection can be achieved with lower doses.
As there is no urgency to reach full therapeutic doses of HRT, side effects can be minimized by starting with half the anticipated dose, administered daily or on alternate days. Subsequent dose increases can occur gradually over the ensuing weeks until symptoms are alleviated (if applicable), undesirable side effects occur, or the desired dose is reached. In women with a uterus, it may be prudent to delay addition of the progestin for some weeks in order to differentiate side effects attributable to the estrogen and progestin components.
In comparison to women who are recently menopausal, older women tend to have a lower incidence of menstrual or breakthrough bleeding on HRT, although the bleeding may be much more inconvenient and distressing for them. Continuous combined HRT would seem most logical in these circumstances, as there is little rationale for the use of cyclic HRT with its potential for withdrawal bleeding in this age group.
For many mature women and their health care providers, the initial discussion about the risks and benefits of hormone replacement therapy occurs around the time of the menopause and is triggered by the onset of vasomotor symptoms. However, the opportunity for a second discussion about HRT may arise again in the seventh decade or beyond, and is often triggered by an adverse health event in the woman or someone close to her. The latter opportunity should not be overlooked, as it provides a chance to re-evaluate various lifestyle factors, concomitant medication use, musculoskeletal health, cardiac health, and urogenital/sexual health.
If the risk-benefit ratio favors HRT, various strategies can be used to improve acceptance and minimize side effects. These include instituting therapy slowly, considering lower doses, and evaluating systemic versus local therapy. While there are many inevitable health consequences of menopause and aging, the initiation of systemic or local HRT may be both appropriate and acceptable in some older women in order to improve the quality, if not the quantity, of life.
|Table 1. Persistent vasomotor symptoms.|
Hot flushes, night sweats, sleep disturbances, nausea, dizziness, palpitations, anxiety attacks
Fatigue, irritability, and changes in mood, concentration, and memory
Conjugated equine estrogens
0.625 mg tablet
Conjugated estrone sulfate
0.625 mg tablet
Piperazine estrone sulfate
0.625 mg tablet
1 mg tablet
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2. Salamone LM, Pressman AR, Seeley DG, et al. Estrogen replacement therapy. A survey of older women’s attitudes. Arch Intern Med 1996;156:1293-1297. PubMed Abstract
4. Mandel FP, Geola FL, Meldrum DR, et al. Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 1983; 57:133-139. PubMed Abstract
6. Schneider DL, Barrett-Connor EL, Morton DJ. Timing of postmenopausal estrogen for optimal bone mineral density. The Rancho Bernardo Study. JAMA 1997; 277:543-547. PubMed Abstract
7. Cauley JA, Seeley DG, Ensrud K, et al. Estrogen replacement therapy and fractures in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1995;122:9-16. PubMed Abstract
8. Michaelsson K, Baron JA, Farahmand BY, et al. Hormone replacement therapy and risk of hip fracture: Population based case-control study. The Swedish Hip Fracture Study Group. BMJ 1998;316: 1858-1863. PubMed Abstract Full Text
9. Seeley DG, Cauley JA, Grady D, et al. Is postmenopausal estrogen therapy associated with neuromuscular function or falling in elderly women? Study of Osteoporotic Fractures Research Group. Arch Intern Med 1995;155:293-299. PubMed Abstract
10. Genant HK, Lucas J, Weiss S, et al. Low-dose esterified estrogen therapy: Effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Estratab/Osteoporosis Study Group. Arch Intern Med 1997;157:2609-2615. PubMed Abstract
11. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-613. PubMed Abstract
12. Henderson VW. Estrogen, cognition, and a woman’s risk of Alzheimer’s disease. Am J Med 1997;103:11S-18S. PubMed Abstract
13. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease. JAMA 2000;283:1007-1015. PubMed Abstract
Margo R. Fluker, MD, FRCSC
Dr Fluker is the co-chair of the Canadian Consensus Conference on Menopause and Osteoporosis (Society of Obstetricians and Gynaecologists of Canada), the co-director of the Genesis Fertility Centre, and a clinical professor in the Department of Obstetrics and Gynaecology at the University of British Columbia.
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