Compliance with Hormone Replacement Therapy: Are Women Receiving the Full Impact of Hormone Replacement Therapy Preventive Health Benefits? Veronica A. Ravnikar, MD Assistant Professor of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School Massachusetts General Hospital Boston, Massachusetts
he benefit of long-term use of estrogen therapy in postmenopausal women has been well established. Osteoporosis prevention and cardiovascular disease prevention are well-defined end points for estrogen replacement therapy (ERT).1"2 The Food and Drug Administration has currently approved the use of ERT for prophylaxis against osteoporosis. However, the indication for cardiovascular disease prevention has not yet been obtained. The latter may be most important because more women die of heart disease. However, we need more studies to define clearly the duration of use of ERT and the sequencing of ERT for a cardiovascular risk indication. Nevertheless, long-term use of ERT for osteoporosis prevention has been documented to decrease the incidence of hip fractures. ERT would be needed for at least 5-6 years to achieve optimum benefit. 1-3 This does not mean that the hormones would need to be stopped at that point; a decision would then need to be made whether or not there are any contraindications for further ERT, and whether or not it would be appropriate either to lower the dose or to continue therapy indefinitely. The absolute duration of use, therefore, has not been clearly defined. It is also generally recommended that patients be started on ERT within the first 3 years of menopause. This would give them the optimum benefit for osteoporosis prophylaxis because this is when maximum bone loss occurs. Therefore, patients need to decide on such therapy (for osteoporosis prophylaxis) in close proximity to the perimenopausal period. After this decision is made, they need to continue such treatment for at least 6 years, if not for the rest of their lives. Therefore, if this discussion is limited solely to deciding on treatment for osteoporosis prophylaxis (an approved indication), how do
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we standardize such care? What guidelines should be given to physicians about starting therapy? This article will review some studies that have looked at physician prescribing practices and patient acceptance of hormone therapy. It will analyze what promotes hormone therapy in clinical practice and also what might motivate patients to stay on such therapy. Finally, it will look at studies showing the actual incidence of nuisance side effects. Patients who complain of hot flashes and vaginal changes clearly define themselves as women who may need hormone therapy. The fact that physicians may wish to give hormone therapy for osteoporosis prophylaxis would mean that they would have to suggest this therapy even to women who are asymptomatic at the time of menopause. A discussion of hormone therapy has to be clearly recorded on the chart. 4 The first visit with a perimenopausal or postmenopausal patient should take at least an hour, reviewing the issues of preventive health care such as smoking cessation, sustained weekly exercise, proper diet, and proper nutritional intake of vitamins, especially calcium. Subsequently, the usual screening needs to be done: yearly mammography, yearly breast exams, pelvic exams, Pap smears, and endometrial biopsies for abnormal bleeding. It has been well established that endometrial biopsies do not need to be done in the asymptomatic woman prior to the institution of ERT. s However, if the physician decides to give hormone therapy for longterm use, what testing can be used as a screen for osteoporosis? One method is the controversial bone density test, usually done on the lumbar spine because this trabecular bone is more reactive to estrogen deficiency in the early years. 6 Spinal bone densities are done with minimal x-radiation through either Hologic or Lunar DPX systems. These give a numerical value for bone density; if the measurement falls below a certain fracture threshold or is greater than two standard deviations from the norm for women in that age group, then the patient is considered osteopenic. This subgroup of patients would benefit from ERT because they already have documented low bone mass studies and a higher prevalence of fractures of the spine and hip. 2"3"7 The controversy about bone density measurements exists because the normal bone density does not ensure that a patient will not get a fracture in the future. Because most insurance companies do not pay for this test, there is a debate regarding the usefulness of testing and cost-effectiveness. Cummings et als have done a cost-benefit analysis of using bone densitometry in the postmenopausal woman. They have shown clearly that it is not cost effective for mass screening, but they believed that it would improve compliance with long-term therapy. Therefore, if a patient needs a more objective indication for treatment, a low bone density may motivate her to start ERT and stay on it for at least 6 years. Therefore, ERT for the indication of osteoporosis should be suggested to all women, including those who are asymptomatic. A bone density test may be obtained in those women who are having difficulty deciding on such therapy. Hormone therapy should not be withheld in patients who have normal bone densities because these patients may also benefit from the prophylaxis against osteoporosis. Holzman et al9 analyzed the knowledge and ERT-prescribing practices of physicians. Their study showed that physician prescribing practices were based on whether or not the patients had a high symptom index (mainly hot flashes and vaginal atrophy) and whether or not the overall quick assessment by the physician was that the patient's cancer risk was "low." If the patient was asymptomatic and/or if the cancer assessment was high, then that patient did not receive a prescription for hormones. It was clear that the physicians 76
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understood the benefits and risks of hormone replacement but did not use this knowledge base in clinical practice. It is every primary care physician's responsibility to discuss potential use of ERT with his or her patients. Each patient's benefit-risk equation should be individualized, and a maintenance program needs to be discussed. However, from the patient's point of view, it has been well demonstrated that women do not use long-term hormone therapy even when it is appropriately prescribed. In an unpublished report by Sonja MacKinley, a majority of the women studied were given hormone prescriptions. Very few finished those prescriptions beyond the first year postmenopausally. The main reason for the confusion at that point was that they did not really understand why they were taking the hormones in the first place. 4 The Menopause Clinic in Nottingham, England (where ERT is given free of charge) offered such therapy for 100 women who had definite osteoporosis (sustained distal radial fracture). Only 36% complied, with 54% compliance in ages 50-55.10 Most of the compliance issues revolved around nuisance side effects such as menses, bloating, and weight gain. An excellent study was done by a group at the University of Iowa College of Medicine. ~~They surveyed the knowledge and attitudes of postmenopausal women, some on ERT and some not on ERT, as well as a group of premenopausal women. The researchers assessed the women's knowledge of osteoporosis, risk factors, symptoms, and dietary lifestyle changes that could reduce the risk of osteoporosis. The patients who took ERT had the same incidence of hot flashes, depression, and insomnia as compared with the postmenopausal women who did not. The patients who never took ERT had a higher average number of relatives with uterine cancer, although patients currently taking ERT had a higher average number of friends with uterine cancer. Curiously, both postmenopausal groups had similar family histories and both had friends with hip fractures, so this did not influence the group that was not on ERT to start estrogen therapy. Both postmenopausal groups equally expressed concern as to the risks of osteoporosis. Most women in all three groups knew that a decrease in dietary calcium was a risk factor for osteoporosis and that being overweight was not a risk factor. However, only 27% of the postmenopausal women not taking ERT knew that the lack of estrogen was a significant factor in osteoporosis compared with 89% of those currently taking ERT and 88% of the premenopausal women. Only 28% of those taking ERT knew that smoking contributes to osteoporosis. All three groups believed that having a test to determine their risk of developing osteoporosis would be a positive factor in a decision to take the therapy. This confirms the statement about the judicious use of bone densitometry to screen for patients who are already osteopenic. The most unfavorable factor cited by women already taking ERT and by the premenopausal women was that ERT would cause them to have periods. The physician's recommendation to take ERT seemed to be of paramount importance. Seventy-five percent in both categories agreed that if the physician clearly stated that ERT was important, they would probably use it. Physicians, therefore, can greatly enhance compliance if they educate patients in the office, develop a risk-benefit ratio on an individual basis, do the proper screening, and follow up procedures. 4 Women who received care from gynecologists were much more likely to be on an ERT regimen than those cared for by other specialists. The majority of women who stopped the hormones did so on their physician's advice and were those being seen by internists. By the same token, it is assumed that gynecologists would not be able to handle all the patients needing such care in the postmenopausal period. A study done in England looked at the patterns of referral to a menopause
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clinic and showed that the demand for hormone replacement therapy was so great that the majority of patients referred to Dulwich Hospital had to either wait for appointments or go elsewhere. 12 The researchers came to the following conclusions: 1) More menopause clinics and hospitals dealing with postmenopausal care are necessary. 2) General practitioners should be encouraged to prescribe ERT without referring to hospital-based clinics as long as these physicians are clear on how to use such therapy safely and how to follow up patients safely. 3) Menopause clinics should be established within the community on the same basis as family planning clinics and well-women clinics. This is an interesting suggestion, because there are now many breast cancer screening centers being created throughout the United States. It would be useful if such breast cancer centers could be associated with gynecologists who could provide menopausal counseling and care. Another issue is the nuisance side effects that create difficulty in patient compliance with hormone therapy. Ferguson's group n noted that the major reason why patients do not continue hormone therapy is because of the resulting menstrual periods. On a scale of 1.0-5.0 (with 5.0 being very negative), patients rated having periods at a factor of 3.4-3.8. Patients who take a sequential regimen do not necessarily have periods, especially after longtime use of hormone therapy. Padwick et aP 3 have suggested that if patients have withdrawal bleeding after the tenth of the month (taking estrogen every day of the month and the progesterone only for the first 12 days of the month), this is normal. They showed by an analysis of endometrial biopsies that any bleeding after the tenth day of the month was associated with full secretory transformation of the endometrium. This has led to the recommendation that patients who are on sequential therapy (ie, taking the progestin only part of the month) keep menstrual calendars. If they have bleeding at appropriate intervals, that is a normal bleeding pattern. The only other way to diagnosis progesterone adequacy at the endometrial level is to do an endometrial biopsy and see secretory transformation when the patient in the progestin phase. However, frequent endometrial biopsies, although necessary at times, will decrease patient compliance with therapy. Newer techniques, such as using vaginal probe ultrasound to determine endometrial thickness, may help avoid excess biopsies. 14Finally, judicious use of progestins to achieve an appropriate endometrial response is also important. In a study of the potencies of progestins on estrogen-primed endometrium, 5 and 10 mg of medroxyprogesterone acetate (MPA) were equal and comparable to 0.35 mg of norethindrone, 10 mg of dydrogesterone, or 200 mg of progesterone daily.iS MPA is used most frequently in the United States. A dose of 2.5 mg given daily or 5 mg given sequentially for 12 days is appropriate. Bleeding patterns (and/or endometrial biopsies when appropriate) can be used to assess potency in the individual patient. If insufficient, a change to a different progestin may be in order (see above equivalent doses). The principle behind continuous-combined therapy (estrogen and progestin therapy given every day of the month) is that the progestin dose can be decreased significantly. The patient usually has no bleeding because of the development of endometrial atrophy. It is also assumed that lowering the progestin dose to a minimum will have a greater cardiovascular benefit. However, one of the difficulties with this form of therapy is that there are a number of patients who have continuous breakthrough bleeding, especially for the first 3-6 months.16 There are also documented cases of such patients having breakthrough bleeding after 2 or 3 years of therapy. It is difficult to assume that continuous therapy is better than sequential therapy. If there is any question about abnormal bleeding, a baseline biopsy may be helpful. My experience is that when patients understand when they should expect bleeding and when they should call the office for 78
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abnormal bleeding, their ability to stay on the hormone therapy is greatly enhanced. Another issue of concern to patients is whether or not they will have mood swings and problems with cyclical depression that they may have had premenopausally. Anecdotal reports indicate that patients taking progesterone, especially cyclically, may have more breast tenderness and more premenstrual syndrome (PMS) symptoms. This impression was not validated in studies done by Kirkham et al, 17 who did a 1-month course, double-blind crossover study with intermittent progestin use. Kirkham and associates did not find any increase in PMS symptoms or any increase in depression scores. A criticism of the study is that it is a 1-month study, and continuous use might increase symptoms. However, if patients are having severe PMS symptoms despite an adjustment of the progestin dose to the lowest level possible, then continuous-combined therapy may alleviate these symptoms. Again, such a change has to be weighed against the possibility of having more bleeding. Patients also worry about weight gain. Because weight gain in the over40 age group (probably because of a decrease in basal metabolic rate and physical activity) is an important and difficult issue with which to deal, it is a major concern with patients. When studied by Nachtigall, ~sindividuals who were on hormone therapy had no increase in weight. Further studies have shown that ERT actually prevents the age-related increase in body fat seen after the menopause. 19 The final issue is that of breast tenderness, and whether taking hormones can obscure lesions and make the breast more dense. We studied this at the Brigham and Women's Hospital and found that only a small percentage of women actually have any defined changes in breast tissue while they are taking hormone therapy. 2° In a majority of patients, the parenchyma does not change significantly and, therefore, it presumably does not decrease the sensitivity of mammography. In conclusion, compliance issues are of major importance if we are to make any impact with ERT. The difficulty lies mainly in the fact that we do not have any specific tests to determine which patient would do better with hormone therapy and which would not. However, I believe that education, careful evaluation, and careful discussion with the patient is of primary importance in enhancing compliance. The judicious use of bone densitometry to select patients who are already osteopenic may help compliance in a small subset. Finally, patients should be made aware that other issues of their health care (exercise, smoking, diet, and alcohol intake) also need to be addressed to improve longevity and their quality of life.
REFERENCES 1. Douglas PK, Felson DT, Anderson JJ, Wilson PFW, Moskowitz MA. Hip fracture and the use of estrogens in postmenopausal women. N Engl J Med 1987;317:116974. 2. Christiansen C. Hormonal prevention and treatment of osteoporosis---state of the art 1990. Surg Biochem Mol Biol 1990;37:447-9. 3. Stevenson JC. Pathogenesis, prevention, and treatment of osteoporosis. Obstet Gynecol 1990;75:36S-41S. 4. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol 1987;156:1332. 5. Archer DF, McIntyre-Seltman KF, Wilborn WW Jr, Dowling EA, Cone F, Creasy GW, et al. Endometrial morphology in asymptomatic women. Am J Obstet Gynecol 1991;165:317-22. Will Vol.2, No. 2 Summer1992
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6. Ravnikar VA. Problem solving in menopausal osteoporosis. In: Weissman B, Eisenberg R, eds. Radiol Rep 1988;1(1):60-5. 7. Mazess RB. Bone density in diagnosis of osteoporosis: Thresholds and breakpoints. Calcif Tissue Int 1987;41:117-8. 8. Cummings SR, Browner WS, Ettinger B. Should prescription of postmenopausal hormone therapy be based on the results of bone densitometry? Ann Intern Med 1990;113:565-7. 9. Holzman GB, Ravitch MM, Metheny W, Rothert ML, Holmes M, Hoppe RB. Physician's judgements about estrogen replacement therapy for menopausal women. Obstet Gynecol 1984;63:303-11. 10. Wallace WA, Price VH, Elliot CA, MacPherson MBA, Scott BW. Hormone replacement therapy acceptability to Nottingham postmenopausal women with a risk factor for osteoporosis. J R Soc Med 1990;83:699-701. 11. Ferguson KJ, Hoegh C, Johnson S. Estrogen replacement therapy--a survey of women's knowledge and attitudes. Arch Intern Med 1989;149:133-6. 12. Garnett T, Mitchell A, Studd J. Patterns of referral to a menopause clinic. J R Soc Med 1991;84:128-30. 13. Padwick ML, Pryse-Davies J, Whitehead MI. A simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens. N Engl J Med 1986;315:930-4. 14. Lin MC, Gosink BB, Wolf SI, Feldesman MR, Stuenkel CA, Braly PS, et al. Endometrial thickness after menopause: Effect of hormone replacement. Radiology 1991;180:427-32. 15. King RJ, Whitehead MI. Assessment of the potency of orally administered progestins in women. Fertil Steril 1986;46:1062-6. 16. Magos AL, Brincat M, Studd JWW, et al. Amenorrhea and endometrial atrophy with continuous oral estrogen and progesterone therapy in postmenopausal women. Obstet Gynecol 1985;65:496. 17. Kirkham C, Hahn PM, VanVugt A, Carmichael JA, Reid RL. A randomized double blind placebo controlled, crossover trial to assess the side effects of medroxyprogesterone acetate in hormone replacement therapy. Obstet Gynecol 1991;78:93-7. 18. Nachtigall LE. Enhancing patient compliance with hormone replacement therapy at menopause. Obstet Gynecol 1990;75:77S-80S. 19. Hassager C, Christiansen C. Estrogen/gestagen therapy changes soft tissue body composition in postmenopausal women. Metabolism 1989;38:662-5. 20. Stomper PC, Van Voorhes BJ, Ravnikar VA, Meyer JA. Benign mammographic changes associated with postmenopausal hormone therapy--a longitudinal study. Radiology 1990;174:487-90.
DISCUSSION The low compliance rates associated with hormone replacement therapy stem from several factors. One antidote seems to be clear and consistent communication between physician and patient, according to Dr. Ravnikar. The patient should be informed about the benefits, the possible risks, the expected duration, the need for regular screening, and symptoms of problems (especially breakthrough bleeding), along with their probable cause. The physician should have established clear end points, or goals, for the therapy and share these with the patient. Current figures show that 22% of postmenopausal women undertake hormone replacement therapy, but only 40% of these will continue after their first year. The benefits such therapy offers in terms of preventing osteoporosis and cardiovascular disease may be underestimated in that they are based on poor compliance rates. Bleeding is the greatest single cause of noncompliance, often because it is poorly understood and feared by patients as a sign of cancer. Dr. Ravnikar encourages her patients who are on cyclical therapy to expect a normal bleeding pattern and keep a regular menstrual calendar. She also finds that break80
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through bleeding (in the case of combined therapy) need not become the regimen's breaking point, as long as the patient understands what is going on. The underlying factors are to educate, clarify, and identify danger signs, and to help the woman to understand that she's undergoing the therapy for an important reason. Dr. McQuarrie said the best way to achieve compliance is to begin treatment while the woman is having symptoms (eg, hot flushes). Dr. Ciotti suggested that some women prefer to undergo regular menstrual periods when they go on hormone replacement therapy--it feels more normal to them. It is important to determine the patient's preference, and not to generalize about reasons for noncompliance. Dr. Speroff interjected that patients should not be given the impression that shedding the endometrium is necessary to protect against cancer. Various hormone replacement therapy regimens were discussed. Ms. Lindberg said that she had the impression that unopposed estrogen would no longer be prescribed for a woman with an intact uterus. Dr. Ravnikar replied that, subsequent to the development of the progestin-added regimen, some physicians have gone back to unopposed estrogen use, particularly in women who would stand to benefit from a cardiovascular standpoint and who for one reason or another can't take progestin regularly. Such patients have to be fully informed about the risks of endometrial hyperplasia and endometrial cancer, and they must be carefully monitored with yearly endometrial biopsies, Dr. Ravnikar cautioned. Sometimes women can be adversely affected by the type of progestin they use, Dr. Ravnikar observed. The symptoms are similar to those of premenstrual syndrome: bloating, weight gain, and depression. Dr. Speroff shared the findings of Kirkham et al in which the premenstrual-like symptoms of a group of progestin users were no greater than those of a placebo group. Nonetheless, for women experiencing them, such symptoms are real, he concluded. When asked about the effectiveness of transdermal estrogen administration, Dr. Ravnikar said this method yields excellent long-term therapeutic results even though there may be cyclical changes in estradiol levels within a 3-4-day period. Smokers may benefit from this method because they have been shown to metabolize estrogen differently. However, a decision about whether or not to employ this method depends on the desired end point, because transdermal systems have been found to prevent bone loss but haven't been shown to have the best immediate effect on lipids in short-term studies (6 weeks to 3 months). The discussion turned to hormone therapy in women with a previous history of breast or endometrial cancer. Dr. Ravnikar said most oncologists would permit hormone therapy after a stage I, grade 1 endometrial tumor. Hormone therapy following breast cancer presents a more controversial picture in that there is a debate over whether the presence of estrogen and progesterone receptors play a role apart from their use as a prognostic factor. Trials looking at the recurrence rates of breast cancer in women undergoing hormone replacement therapy are urgently needed. The reverse side of the same issue is that more and more cases of breast cancer are diagnosed and treated premenopausally; that population of women will undergo menopause earlier and face greater risks of osteoporosis and heart disease, Dr. Ravnikar said. Dr. Speroff added his observation that 510 years ago, no one gave estrogen to women after breast cancer, whereas a show of hands at two recent medical meetings confirmed that now about 50% of physicians do. To his mind, this indicates a growing appreciation for the impact of estrogen on osteoporosis and cardiovascular disease. Responding to a more general question, Dr. Ravnikar agreed that women should have a baseline negative mammogram before embarking upon horWHI Vol. 2, No. 2 Summer 1992
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mone therapy, because it helps when charting the benign tissue changes that occur in about 14% of w o m e n undergoing therapy. As pointed out by Dr. Speroff, women in that age bracket ought to be having an annual mammogram for regular preventive screening anyway. Ms. Romans asked how long it will take to see the benefits of hormone replacement therapy in terms of a significant reduction in osteoporosis and cardiovascular disease. Improvements in lipid ratios (high-density versus lowdensity lipoproteins) are seen within 3-6 months, and bone density studies have concluded that the effects begin to be evident after around 6 months and definitely after 12-18 months, Dr. Ravnikar replied. Other studies show the relative risk of fracture decreases sharply after 5 years of therapy. Overall, it will probably be 15-20 years before any wide-scale reduction in the fracture rate is seen, especially because the Food and Drug Administration has yet to settle upon consistent criteria for defining a decrease in the osteoporosis rate (eg, lumbar spine abnormalities, hip fractures, or bone density mapping).
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he benefit of long-term use of estrogen therapy in postmenopausal women has been well established. Osteoporosis prevention and cardiovascular disease prevention are well-defined end points for estrogen replacement therapy (ERT).1"2 The Food and Drug Administration has currently approved the use of ERT for prophylaxis against osteoporosis. However, the indication for cardiovascular disease prevention has not yet been obtained. The latter may be most important because more women die of heart disease. However, we need more studies to define clearly the duration of use of ERT and the sequencing of ERT for a cardiovascular risk indication. Nevertheless, long-term use of ERT for osteoporosis prevention has been documented to decrease the incidence of hip fractures. ERT would be needed for at least 5-6 years to achieve optimum benefit. 1-3 This does not mean that the hormones would need to be stopped at that point; a decision would then need to be made whether or not there are any contraindications for further ERT, and whether or not it would be appropriate either to lower the dose or to continue therapy indefinitely. The absolute duration of use, therefore, has not been clearly defined. It is also generally recommended that patients be started on ERT within the first 3 years of menopause. This would give them the optimum benefit for osteoporosis prophylaxis because this is when maximum bone loss occurs. Therefore, patients need to decide on such therapy (for osteoporosis prophylaxis) in close proximity to the perimenopausal period. After this decision is made, they need to continue such treatment for at least 6 years, if not for the rest of their lives. Therefore, if this discussion is limited solely to deciding on treatment for osteoporosis prophylaxis (an approved indication), how do
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we standardize such care? What guidelines should be given to physicians about starting therapy? This article will review some studies that have looked at physician prescribing practices and patient acceptance of hormone therapy. It will analyze what promotes hormone therapy in clinical practice and also what might motivate patients to stay on such therapy. Finally, it will look at studies showing the actual incidence of nuisance side effects. Patients who complain of hot flashes and vaginal changes clearly define themselves as women who may need hormone therapy. The fact that physicians may wish to give hormone therapy for osteoporosis prophylaxis would mean that they would have to suggest this therapy even to women who are asymptomatic at the time of menopause. A discussion of hormone therapy has to be clearly recorded on the chart. 4 The first visit with a perimenopausal or postmenopausal patient should take at least an hour, reviewing the issues of preventive health care such as smoking cessation, sustained weekly exercise, proper diet, and proper nutritional intake of vitamins, especially calcium. Subsequently, the usual screening needs to be done: yearly mammography, yearly breast exams, pelvic exams, Pap smears, and endometrial biopsies for abnormal bleeding. It has been well established that endometrial biopsies do not need to be done in the asymptomatic woman prior to the institution of ERT. s However, if the physician decides to give hormone therapy for longterm use, what testing can be used as a screen for osteoporosis? One method is the controversial bone density test, usually done on the lumbar spine because this trabecular bone is more reactive to estrogen deficiency in the early years. 6 Spinal bone densities are done with minimal x-radiation through either Hologic or Lunar DPX systems. These give a numerical value for bone density; if the measurement falls below a certain fracture threshold or is greater than two standard deviations from the norm for women in that age group, then the patient is considered osteopenic. This subgroup of patients would benefit from ERT because they already have documented low bone mass studies and a higher prevalence of fractures of the spine and hip. 2"3"7 The controversy about bone density measurements exists because the normal bone density does not ensure that a patient will not get a fracture in the future. Because most insurance companies do not pay for this test, there is a debate regarding the usefulness of testing and cost-effectiveness. Cummings et als have done a cost-benefit analysis of using bone densitometry in the postmenopausal woman. They have shown clearly that it is not cost effective for mass screening, but they believed that it would improve compliance with long-term therapy. Therefore, if a patient needs a more objective indication for treatment, a low bone density may motivate her to start ERT and stay on it for at least 6 years. Therefore, ERT for the indication of osteoporosis should be suggested to all women, including those who are asymptomatic. A bone density test may be obtained in those women who are having difficulty deciding on such therapy. Hormone therapy should not be withheld in patients who have normal bone densities because these patients may also benefit from the prophylaxis against osteoporosis. Holzman et al9 analyzed the knowledge and ERT-prescribing practices of physicians. Their study showed that physician prescribing practices were based on whether or not the patients had a high symptom index (mainly hot flashes and vaginal atrophy) and whether or not the overall quick assessment by the physician was that the patient's cancer risk was "low." If the patient was asymptomatic and/or if the cancer assessment was high, then that patient did not receive a prescription for hormones. It was clear that the physicians 76
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understood the benefits and risks of hormone replacement but did not use this knowledge base in clinical practice. It is every primary care physician's responsibility to discuss potential use of ERT with his or her patients. Each patient's benefit-risk equation should be individualized, and a maintenance program needs to be discussed. However, from the patient's point of view, it has been well demonstrated that women do not use long-term hormone therapy even when it is appropriately prescribed. In an unpublished report by Sonja MacKinley, a majority of the women studied were given hormone prescriptions. Very few finished those prescriptions beyond the first year postmenopausally. The main reason for the confusion at that point was that they did not really understand why they were taking the hormones in the first place. 4 The Menopause Clinic in Nottingham, England (where ERT is given free of charge) offered such therapy for 100 women who had definite osteoporosis (sustained distal radial fracture). Only 36% complied, with 54% compliance in ages 50-55.10 Most of the compliance issues revolved around nuisance side effects such as menses, bloating, and weight gain. An excellent study was done by a group at the University of Iowa College of Medicine. ~~They surveyed the knowledge and attitudes of postmenopausal women, some on ERT and some not on ERT, as well as a group of premenopausal women. The researchers assessed the women's knowledge of osteoporosis, risk factors, symptoms, and dietary lifestyle changes that could reduce the risk of osteoporosis. The patients who took ERT had the same incidence of hot flashes, depression, and insomnia as compared with the postmenopausal women who did not. The patients who never took ERT had a higher average number of relatives with uterine cancer, although patients currently taking ERT had a higher average number of friends with uterine cancer. Curiously, both postmenopausal groups had similar family histories and both had friends with hip fractures, so this did not influence the group that was not on ERT to start estrogen therapy. Both postmenopausal groups equally expressed concern as to the risks of osteoporosis. Most women in all three groups knew that a decrease in dietary calcium was a risk factor for osteoporosis and that being overweight was not a risk factor. However, only 27% of the postmenopausal women not taking ERT knew that the lack of estrogen was a significant factor in osteoporosis compared with 89% of those currently taking ERT and 88% of the premenopausal women. Only 28% of those taking ERT knew that smoking contributes to osteoporosis. All three groups believed that having a test to determine their risk of developing osteoporosis would be a positive factor in a decision to take the therapy. This confirms the statement about the judicious use of bone densitometry to screen for patients who are already osteopenic. The most unfavorable factor cited by women already taking ERT and by the premenopausal women was that ERT would cause them to have periods. The physician's recommendation to take ERT seemed to be of paramount importance. Seventy-five percent in both categories agreed that if the physician clearly stated that ERT was important, they would probably use it. Physicians, therefore, can greatly enhance compliance if they educate patients in the office, develop a risk-benefit ratio on an individual basis, do the proper screening, and follow up procedures. 4 Women who received care from gynecologists were much more likely to be on an ERT regimen than those cared for by other specialists. The majority of women who stopped the hormones did so on their physician's advice and were those being seen by internists. By the same token, it is assumed that gynecologists would not be able to handle all the patients needing such care in the postmenopausal period. A study done in England looked at the patterns of referral to a menopause
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clinic and showed that the demand for hormone replacement therapy was so great that the majority of patients referred to Dulwich Hospital had to either wait for appointments or go elsewhere. 12 The researchers came to the following conclusions: 1) More menopause clinics and hospitals dealing with postmenopausal care are necessary. 2) General practitioners should be encouraged to prescribe ERT without referring to hospital-based clinics as long as these physicians are clear on how to use such therapy safely and how to follow up patients safely. 3) Menopause clinics should be established within the community on the same basis as family planning clinics and well-women clinics. This is an interesting suggestion, because there are now many breast cancer screening centers being created throughout the United States. It would be useful if such breast cancer centers could be associated with gynecologists who could provide menopausal counseling and care. Another issue is the nuisance side effects that create difficulty in patient compliance with hormone therapy. Ferguson's group n noted that the major reason why patients do not continue hormone therapy is because of the resulting menstrual periods. On a scale of 1.0-5.0 (with 5.0 being very negative), patients rated having periods at a factor of 3.4-3.8. Patients who take a sequential regimen do not necessarily have periods, especially after longtime use of hormone therapy. Padwick et aP 3 have suggested that if patients have withdrawal bleeding after the tenth of the month (taking estrogen every day of the month and the progesterone only for the first 12 days of the month), this is normal. They showed by an analysis of endometrial biopsies that any bleeding after the tenth day of the month was associated with full secretory transformation of the endometrium. This has led to the recommendation that patients who are on sequential therapy (ie, taking the progestin only part of the month) keep menstrual calendars. If they have bleeding at appropriate intervals, that is a normal bleeding pattern. The only other way to diagnosis progesterone adequacy at the endometrial level is to do an endometrial biopsy and see secretory transformation when the patient in the progestin phase. However, frequent endometrial biopsies, although necessary at times, will decrease patient compliance with therapy. Newer techniques, such as using vaginal probe ultrasound to determine endometrial thickness, may help avoid excess biopsies. 14Finally, judicious use of progestins to achieve an appropriate endometrial response is also important. In a study of the potencies of progestins on estrogen-primed endometrium, 5 and 10 mg of medroxyprogesterone acetate (MPA) were equal and comparable to 0.35 mg of norethindrone, 10 mg of dydrogesterone, or 200 mg of progesterone daily.iS MPA is used most frequently in the United States. A dose of 2.5 mg given daily or 5 mg given sequentially for 12 days is appropriate. Bleeding patterns (and/or endometrial biopsies when appropriate) can be used to assess potency in the individual patient. If insufficient, a change to a different progestin may be in order (see above equivalent doses). The principle behind continuous-combined therapy (estrogen and progestin therapy given every day of the month) is that the progestin dose can be decreased significantly. The patient usually has no bleeding because of the development of endometrial atrophy. It is also assumed that lowering the progestin dose to a minimum will have a greater cardiovascular benefit. However, one of the difficulties with this form of therapy is that there are a number of patients who have continuous breakthrough bleeding, especially for the first 3-6 months.16 There are also documented cases of such patients having breakthrough bleeding after 2 or 3 years of therapy. It is difficult to assume that continuous therapy is better than sequential therapy. If there is any question about abnormal bleeding, a baseline biopsy may be helpful. My experience is that when patients understand when they should expect bleeding and when they should call the office for 78
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abnormal bleeding, their ability to stay on the hormone therapy is greatly enhanced. Another issue of concern to patients is whether or not they will have mood swings and problems with cyclical depression that they may have had premenopausally. Anecdotal reports indicate that patients taking progesterone, especially cyclically, may have more breast tenderness and more premenstrual syndrome (PMS) symptoms. This impression was not validated in studies done by Kirkham et al, 17 who did a 1-month course, double-blind crossover study with intermittent progestin use. Kirkham and associates did not find any increase in PMS symptoms or any increase in depression scores. A criticism of the study is that it is a 1-month study, and continuous use might increase symptoms. However, if patients are having severe PMS symptoms despite an adjustment of the progestin dose to the lowest level possible, then continuous-combined therapy may alleviate these symptoms. Again, such a change has to be weighed against the possibility of having more bleeding. Patients also worry about weight gain. Because weight gain in the over40 age group (probably because of a decrease in basal metabolic rate and physical activity) is an important and difficult issue with which to deal, it is a major concern with patients. When studied by Nachtigall, ~sindividuals who were on hormone therapy had no increase in weight. Further studies have shown that ERT actually prevents the age-related increase in body fat seen after the menopause. 19 The final issue is that of breast tenderness, and whether taking hormones can obscure lesions and make the breast more dense. We studied this at the Brigham and Women's Hospital and found that only a small percentage of women actually have any defined changes in breast tissue while they are taking hormone therapy. 2° In a majority of patients, the parenchyma does not change significantly and, therefore, it presumably does not decrease the sensitivity of mammography. In conclusion, compliance issues are of major importance if we are to make any impact with ERT. The difficulty lies mainly in the fact that we do not have any specific tests to determine which patient would do better with hormone therapy and which would not. However, I believe that education, careful evaluation, and careful discussion with the patient is of primary importance in enhancing compliance. The judicious use of bone densitometry to select patients who are already osteopenic may help compliance in a small subset. Finally, patients should be made aware that other issues of their health care (exercise, smoking, diet, and alcohol intake) also need to be addressed to improve longevity and their quality of life.
REFERENCES 1. Douglas PK, Felson DT, Anderson JJ, Wilson PFW, Moskowitz MA. Hip fracture and the use of estrogens in postmenopausal women. N Engl J Med 1987;317:116974. 2. Christiansen C. Hormonal prevention and treatment of osteoporosis---state of the art 1990. Surg Biochem Mol Biol 1990;37:447-9. 3. Stevenson JC. Pathogenesis, prevention, and treatment of osteoporosis. Obstet Gynecol 1990;75:36S-41S. 4. Ravnikar VA. Compliance with hormone therapy. Am J Obstet Gynecol 1987;156:1332. 5. Archer DF, McIntyre-Seltman KF, Wilborn WW Jr, Dowling EA, Cone F, Creasy GW, et al. Endometrial morphology in asymptomatic women. Am J Obstet Gynecol 1991;165:317-22. Will Vol.2, No. 2 Summer1992
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6. Ravnikar VA. Problem solving in menopausal osteoporosis. In: Weissman B, Eisenberg R, eds. Radiol Rep 1988;1(1):60-5. 7. Mazess RB. Bone density in diagnosis of osteoporosis: Thresholds and breakpoints. Calcif Tissue Int 1987;41:117-8. 8. Cummings SR, Browner WS, Ettinger B. Should prescription of postmenopausal hormone therapy be based on the results of bone densitometry? Ann Intern Med 1990;113:565-7. 9. Holzman GB, Ravitch MM, Metheny W, Rothert ML, Holmes M, Hoppe RB. Physician's judgements about estrogen replacement therapy for menopausal women. Obstet Gynecol 1984;63:303-11. 10. Wallace WA, Price VH, Elliot CA, MacPherson MBA, Scott BW. Hormone replacement therapy acceptability to Nottingham postmenopausal women with a risk factor for osteoporosis. J R Soc Med 1990;83:699-701. 11. Ferguson KJ, Hoegh C, Johnson S. Estrogen replacement therapy--a survey of women's knowledge and attitudes. Arch Intern Med 1989;149:133-6. 12. Garnett T, Mitchell A, Studd J. Patterns of referral to a menopause clinic. J R Soc Med 1991;84:128-30. 13. Padwick ML, Pryse-Davies J, Whitehead MI. A simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens. N Engl J Med 1986;315:930-4. 14. Lin MC, Gosink BB, Wolf SI, Feldesman MR, Stuenkel CA, Braly PS, et al. Endometrial thickness after menopause: Effect of hormone replacement. Radiology 1991;180:427-32. 15. King RJ, Whitehead MI. Assessment of the potency of orally administered progestins in women. Fertil Steril 1986;46:1062-6. 16. Magos AL, Brincat M, Studd JWW, et al. Amenorrhea and endometrial atrophy with continuous oral estrogen and progesterone therapy in postmenopausal women. Obstet Gynecol 1985;65:496. 17. Kirkham C, Hahn PM, VanVugt A, Carmichael JA, Reid RL. A randomized double blind placebo controlled, crossover trial to assess the side effects of medroxyprogesterone acetate in hormone replacement therapy. Obstet Gynecol 1991;78:93-7. 18. Nachtigall LE. Enhancing patient compliance with hormone replacement therapy at menopause. Obstet Gynecol 1990;75:77S-80S. 19. Hassager C, Christiansen C. Estrogen/gestagen therapy changes soft tissue body composition in postmenopausal women. Metabolism 1989;38:662-5. 20. Stomper PC, Van Voorhes BJ, Ravnikar VA, Meyer JA. Benign mammographic changes associated with postmenopausal hormone therapy--a longitudinal study. Radiology 1990;174:487-90.
DISCUSSION The low compliance rates associated with hormone replacement therapy stem from several factors. One antidote seems to be clear and consistent communication between physician and patient, according to Dr. Ravnikar. The patient should be informed about the benefits, the possible risks, the expected duration, the need for regular screening, and symptoms of problems (especially breakthrough bleeding), along with their probable cause. The physician should have established clear end points, or goals, for the therapy and share these with the patient. Current figures show that 22% of postmenopausal women undertake hormone replacement therapy, but only 40% of these will continue after their first year. The benefits such therapy offers in terms of preventing osteoporosis and cardiovascular disease may be underestimated in that they are based on poor compliance rates. Bleeding is the greatest single cause of noncompliance, often because it is poorly understood and feared by patients as a sign of cancer. Dr. Ravnikar encourages her patients who are on cyclical therapy to expect a normal bleeding pattern and keep a regular menstrual calendar. She also finds that break80
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through bleeding (in the case of combined therapy) need not become the regimen's breaking point, as long as the patient understands what is going on. The underlying factors are to educate, clarify, and identify danger signs, and to help the woman to understand that she's undergoing the therapy for an important reason. Dr. McQuarrie said the best way to achieve compliance is to begin treatment while the woman is having symptoms (eg, hot flushes). Dr. Ciotti suggested that some women prefer to undergo regular menstrual periods when they go on hormone replacement therapy--it feels more normal to them. It is important to determine the patient's preference, and not to generalize about reasons for noncompliance. Dr. Speroff interjected that patients should not be given the impression that shedding the endometrium is necessary to protect against cancer. Various hormone replacement therapy regimens were discussed. Ms. Lindberg said that she had the impression that unopposed estrogen would no longer be prescribed for a woman with an intact uterus. Dr. Ravnikar replied that, subsequent to the development of the progestin-added regimen, some physicians have gone back to unopposed estrogen use, particularly in women who would stand to benefit from a cardiovascular standpoint and who for one reason or another can't take progestin regularly. Such patients have to be fully informed about the risks of endometrial hyperplasia and endometrial cancer, and they must be carefully monitored with yearly endometrial biopsies, Dr. Ravnikar cautioned. Sometimes women can be adversely affected by the type of progestin they use, Dr. Ravnikar observed. The symptoms are similar to those of premenstrual syndrome: bloating, weight gain, and depression. Dr. Speroff shared the findings of Kirkham et al in which the premenstrual-like symptoms of a group of progestin users were no greater than those of a placebo group. Nonetheless, for women experiencing them, such symptoms are real, he concluded. When asked about the effectiveness of transdermal estrogen administration, Dr. Ravnikar said this method yields excellent long-term therapeutic results even though there may be cyclical changes in estradiol levels within a 3-4-day period. Smokers may benefit from this method because they have been shown to metabolize estrogen differently. However, a decision about whether or not to employ this method depends on the desired end point, because transdermal systems have been found to prevent bone loss but haven't been shown to have the best immediate effect on lipids in short-term studies (6 weeks to 3 months). The discussion turned to hormone therapy in women with a previous history of breast or endometrial cancer. Dr. Ravnikar said most oncologists would permit hormone therapy after a stage I, grade 1 endometrial tumor. Hormone therapy following breast cancer presents a more controversial picture in that there is a debate over whether the presence of estrogen and progesterone receptors play a role apart from their use as a prognostic factor. Trials looking at the recurrence rates of breast cancer in women undergoing hormone replacement therapy are urgently needed. The reverse side of the same issue is that more and more cases of breast cancer are diagnosed and treated premenopausally; that population of women will undergo menopause earlier and face greater risks of osteoporosis and heart disease, Dr. Ravnikar said. Dr. Speroff added his observation that 510 years ago, no one gave estrogen to women after breast cancer, whereas a show of hands at two recent medical meetings confirmed that now about 50% of physicians do. To his mind, this indicates a growing appreciation for the impact of estrogen on osteoporosis and cardiovascular disease. Responding to a more general question, Dr. Ravnikar agreed that women should have a baseline negative mammogram before embarking upon horWHI Vol. 2, No. 2 Summer 1992
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mone therapy, because it helps when charting the benign tissue changes that occur in about 14% of w o m e n undergoing therapy. As pointed out by Dr. Speroff, women in that age bracket ought to be having an annual mammogram for regular preventive screening anyway. Ms. Romans asked how long it will take to see the benefits of hormone replacement therapy in terms of a significant reduction in osteoporosis and cardiovascular disease. Improvements in lipid ratios (high-density versus lowdensity lipoproteins) are seen within 3-6 months, and bone density studies have concluded that the effects begin to be evident after around 6 months and definitely after 12-18 months, Dr. Ravnikar replied. Other studies show the relative risk of fracture decreases sharply after 5 years of therapy. Overall, it will probably be 15-20 years before any wide-scale reduction in the fracture rate is seen, especially because the Food and Drug Administration has yet to settle upon consistent criteria for defining a decrease in the osteoporosis rate (eg, lumbar spine abnormalities, hip fractures, or bone density mapping).
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