0021-972X/99/$03.00/0 The Journal of Clinical Endocrinology & Metabolism Copyright © 1999 by The Endocrine Society

Vol. 84, No. 6 Printed in U.S.A.

EXTENSIVE PERSONAL EXPERIENCE The Individualized Approach to Menopause Management BRIAN W. WALSH Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts 02115

Most clinicians who care for women after the menopause are quite familiar with the benefits and risks of hormone replacement therapy (HRT) (1). They know that estrogen treatment relieves hot flashes, which can improve sleep, and that it reverses urogenital atrophy, to relieve dyspareunia. Clinicians are aware that estrogen treatment prevents postmenopausal bone loss, thereby reducing the risk of osteoporotic fractures. They know that estrogens have favorable effects on blood lipids and other cardiovascular risk factors (2), which can substantially lower the risk of cardiovascular disease, the leading cause of death for postmenopausal women. Fortunately, prescribing HRT to many women is relatively straightforward and highly effective. Many women will do quite well with the first standard hormone regimen they are given. For example, some women who have severe hot flashes get significant relief from HRT and are not troubled by side-effects. Not every case is this easy, however. Many women experience problems with HRT, resulting in a high discontinuation rate. Thus, large numbers of women will require an individualized approach to hormone treatment, posing a formidable challenge to the clinician. I have identified five common but challenging scenarios. Each case is entitled by the exact words I frequently hear in my practice. These words are followed by the strategies I use in management—some solutions are based on the results of well-designed clinical trials, others derive from personal experience. Case 1: “I can’t stand this bleeding any more!” Solving bleeding problems

H.R. is a 54-yr-old woman who experienced her last menses at age 49. She recalls having some hot flashes and sleep disturbance then, but is not troubled by those symptoms at present. Because she is a 1-pack-per-day smoker for the past 35 years, her internist recommended measurement of her bone density. This showed that the density of her hip and spine was 1.9 standard deviations below peak (i.e. a T-score of 21.9). She presents to your office requesting HRT, to prevent osteoporosis. Her neighbor had recently had good Received February 5, 1999. Accepted March 23, 1999. Address correspondence and requests for reprints to: Brian W. Walsh, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. E-mail: [email protected]

results with “those new combined hormones that don’t cause bleeding” and she would like to try them. You establish that she has no contraindications to hormone use. Her physical examination is notable only for mild obesity (height 59 399, weight 168). Her mammogram is normal. You urge her to stop smoking. You prescribe 0.625 mg conjugated equine estrogens with 2.5 mg medroxyprogesterone acetate daily. One month later she calls to say the hormones “aren’t working. . . they cause bleeding,” which is light but nearly continuous. You verify that she hasn’t missed any pills. You reassure her that this bleeding is common and hopefully short-lived. After three months of treatment she again calls to report the bleeding is less often, but still bothersome. You increase her progestin dose to 5 mg daily. She returns to the office after 6 months of treatment, still complaining of the bleeding. A transvaginal ultrasound shows her endometrial stripe to be thin, at 3.2 mm. You discuss lowering the estrogen dose to 0.3 mg daily. Three months later, she reports that she bleeds for only a few days per month, but even this amount of bleeding is unacceptable. You discuss cyclic hormonal treatment, but she really wants to have no bleeding at all. You discuss other drugs that can prevent osteoporosis, such as raloxifene and alendronate. She decides to stop the HRT and will contact you after she thinks over her options. 1. Set realistic expectations from the start. The vast majority of patients who have a uterus will bleed when they begin taking continuous combined hormone replacement. In fact, more than 60% of patients will experience some amount of bleeding even after 6 months of treatment (3). I tell patients that the hope and intent is that they will eventually stop bleeding, but that unfortunately they will probably experience bleeding for several weeks or even longer before amenorrhea occurs. If this initial bleeding would be unacceptable to them, I would not prescribe continuous combined hormone replacement. 2. Avoid situations where continuous combined HRT is likely to fail. Amenorrhea is the consequence of endometrial atrophy. The lower the estrogen exposure of the endometrium (relative to the progestin exposure), the more likely atrophy will occur. Thus, women who have elevated endogenous estrogen levels are more likely to have breakthrough bleeding.

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EXTENSIVE PERSONAL EXPERIENCE

Such women would include those who are overweight, such as this patient, and those who are recently postmenopausal. Women with a history of menorrhagia, particularly due to submucous fibroids, are also more likely to have troublesome bleeding with continuous treatment. Thin women without submucous fibroids who are several years beyond the menopause are the best candidates for continuous HRT. 3. Try increasing the progestin dose. Progestins oppose the proliferative effects of estrogen on the endometrium. Thus, the incidence of bleeding is lower with a higher progestin dose: although 60% of women will bleed after 6 months of 2.5 mg medroxyprogesterone daily, only 47% will bleed when given 5 mg daily. However, some patients may not tolerate the higher progestin dose, due to side effects such as bloating, fluid retention, breast tenderness, and mood swings. 4. Rule out structural abnormalities of the uterus: the role of biopsy, ultrasound, hysteroscopy. First, try to improve the bleeding by adjusting the dose of hormones. If this fails, look for the etiology of this bleeding. Transvaginal ultrasonography can identify a thickened endometrium (i.e. 5 mm or greater), which would warrant biopsy. If the biopsy is inconclusive, a hysteroscopy can identify endometrial polyps and submucous fibroids, which could be removed. If the endometrial stripe is less than 5 mm, significant endometrial pathology is unlikely, and no further evaluation is needed (4, 5). Bleeding that occurs years after achieving amenorrhea is particularly worrisome and warrants biopsy: several cases of endometrial cancer have been reported with that presentation. (6) 5. Try lowering the estrogen dose. Until recently, 0.625 mg conjugated estrogen daily was considered to be the “minimum effective dose” of estrogen. A recent study found that a lower dose, 0.3 mg daily, may be effective in preventing osteoporosis (7). For patients who find the bleeding intolerable despite an increase in the progestin dose, consider lowering their estrogen dose. Some patients may experience a return of hot flashes when the estrogen dose is lowered, but this is usually well tolerated. 6. Switch to a cyclic regimen. Some patients will ultimately decide that predictable bleeding, particularly if it is light and brief, is preferable to erratic bleeding. 7. Reassess the need for HRT, and perhaps switch to a nonestrogen treatment. Some patients bleed despite all the above maneuvers. Reassess the reasons why the patient chose to take HRT and consider nonestrogen alternatives. For example, if the patient has low bone density, a selective estrogen receptor modulator (SERM), e.g. raloxifene, or a bisphosphonate, e.g. alendronate, may be offered to the patient.

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history of osteoporosis: her mother enjoyed good health until she experienced a hip fracture at age 69. For unclear reasons, her mother died 2 months thereafter. M.R. also recalls her mother losing considerable height, perhaps as much as 3 inches, which was evident several years before her hip fracture. M.R.’s bone density measurement showed her hip and spine to be 1.6 standard deviations below peak (i.e. a T-score of 21.6). She is very concerned about this result. She would be open to estrogen treatment but is very worried that this could increase her risk of breast cancer: her paternal aunt died of this condition. She has no contraindications to estrogen use. Her physical examination and mammogram are normal. You reassure her that the magnitude of the benefits of estrogen are believed to exceed the magnitude of any increase in breast cancer risk. She leaves your office with a prescription for 0.625 mg of conjugated equine estrogens with 2.5 mg medroxyprogesterone acetate daily. She returns for an annual examination 1 yr later. She just had her bone density measured again and received a T-score of 21.9. She is dismayed that it is lower than the one done 1 year earlier. She acknowledges that she never filled her prescription for HRT. You discuss other drugs that can prevent osteoporosis, such as raloxifene and alendronate. She decides to begin treatment with raloxifene, hoping that it will prevent osteoporosis and possibly breast cancer. 1. Acknowledge that fear of breast cancer is a major barrier to HRT use and is a common reason for discontinuation. Most of our patients are unaware that cardiovascular disease is the leading cause of death of postmenopausal women in industrialized countries. Only 4% of deaths in women are due to breast cancer, far less than the 45% of deaths caused by cardiovascular disease (8). This reality is in stark contrast to our patient’s perceptions. In a Gallup survey done in 1995, 40% of women identified breast cancer as the leading cause of death in women; only 19% correctly identified heart disease. Clearly, breast cancer is a major fear of our patients and significantly influences their decision-making process. 2. Understand that the risk of breast cancer is probably increased to a small degree with long-term (i.e. more than 5–10 yr) postmenopausal estrogen use (9 –11). There is no significant evidence indicating that durations of HRT for less than 5 yr will increase the risk of breast cancer. For those patients who will take estrogens for short durations for symptom relief, reassurance can be given. For durations of greater than 5–10 yr, most but not all (12) studies have found an increase in breast cancer risk, probably on the order of 2% excess risk per year of estrogen treatment (13).

Case 2: “I don’t want to get severe osteoporosis like my mom did, but I’m scared that estrogen will give me breast cancer.” Responding to the fear of breast cancer

3. Most women who develop breast cancer do not have a family history. Many women assume that, if they don’t have a family history of breast cancer, they are not at risk. This is not the case, as over 80% of women diagnosed with breast cancer do not have a family history (14).

M.R. is a 56-yr- old woman whose last menses occurred at age 53. She comes to your office to discuss her recent bone density measurement. This was done because of a family

4. Consider alternatives to estrogen treatment that could satisfy the patient’s needs. Raloxifene increases bone density without stimulating the endometrium (15). Hence, vaginal bleeding

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does not occur, and a progestin is not needed. In addition, interval analysis of approximately 8,000 women who have received raloxifene in placebo-controlled clinical trials has found that raloxifene may lower the risk of breast cancer by more than 50% (16). Raloxifene may also be cardioprotective—it has been found to favorably alter cardiovascular risk factors by lowering serum levels of low density lipoprotein cholesterol, fibrinogen, and lipoprotein(a), without increasing triglyceride levels (17). Case 3: “The estrogen makes me feel so much better. . . but I HATE my progestin!” Alternatives to the standard progestin

W.E. is a 49-yr-old woman whose last menses were 7 months ago. She describes herself as “not a pill-taker” and had planned to “breeze though the menopause” using relaxation techniques and exercise. Her hot flashes began 3 yr ago and, much to her surprise, were more severe than she expected. In fact, they have not gotten any better over these past 3 yr. At this point she is desperate for a good night’s sleep. She requests estrogen treatment. She has no contraindications to estrogen use. Her physical examination and mammogram are normal. You prescribe 0.625 mg of conjugated equine estrogens daily, with 5 mg medroxyprogesterone acetate on days 1 to 14, each month. One month later, she reports that she feels “like a new person”. The hot flashes are far less frequent and severe. The quality of her sleep is dramatically improved. Four months later she reports that she feels wonderful when she takes just the estrogen, but has mood swings, depression, and breast tenderness when she adds on the progestin. Her monthly withdrawal bleeding is light and is appropriately timed on days 11 to 14. She admits that she “couldn’t bring herself to take the progestin” last month. You suggest she take the medroxyprogesterone every other month. She calls your office 2 months later to report that her withdrawal bleeding was quite heavy after taking her medroxyprogesterone—and that her mood swings were intolerable. You discuss megestrol acetate 40 mg, micronized progesterone 100 mg, and norethindrone acetate 0.70 mg as alternative progestins. She ultimately tries all three and finds them to be “basically the same as medroxyprogesterone”. You offer vaginal progesterone, but she declines as it sounds “messy”. She decides to stop the estrogen. Unfortunately, her hot flashes recur with a vengeance. She resumes taking her estrogen. You discuss the increased risk of endometrial cancer with unopposed estrogen use. She is somewhat uneasy with this, but sees no other alternative to unopposed treatment. You discuss lowering her estrogen dose to 0.3 mg daily and performing annual endometrial biopsies. She is comfortable with this plan. Shortly after lowering her estrogen dose, she experiences some hot flashes that she can easily tolerate. Her annual endometrial biopsies remain benign for the following 4 yr, after which she discontinues her estrogen. She has no menopause symptoms thereafter. 1. Try lowering the dose or the frequency of the progestin. In the past, the usual dose for medroxyprogesterone acetate was 10

mg for cyclic treatment and 5 mg for continuous treatment. Many patients were begun on these doses and are still taking them today. Doses that are half of those have been found to protect the endometrium equally well and are more typically used today. If a patient experiences problems with these higher doses, they may be readily lowered. If patients have problems with the lower doses, they may try taking their progestin every other, or even every third month. However, they may not be as well protected against endometrial cancer and would need to be followed carefully by annual ultrasound or by biopsy. Withdrawal bleeding is commonly reported to be heavier with this schedule, which may limit its tolerability (18). 2. Switch to another progestin altogether, such as megestrol acetate 40 mg daily (19), micronized progesterone 100 mg daily, norethindrone acetate 0.7 mg daily, or 4% vaginal progesterone gel every other day (20). Many women will have far fewer side-effects with a different progestin. Because the reaction to a given progestin appears to be idiosyncratic, it cannot be predicted who will respond well to an alternative progestin. A trialand-error approach is therefore needed. The vaginal progesterone gel can be particularly useful, as it appears to diffuse directly to the uterus, thereby having relatively lower systemic effects. 3. Use unopposed estrogen, especially at a lower dose and monitor carefully. The absolute increase in the incidence of endometrial cancer with unopposed estrogen use is low, approximately 2– 4 women per thousand per year (21). Careful monitoring in properly selected and well-informed patients who have failed all other alternative maneuvers may be appropriate. It is probably worthwhile to lower the estrogen dose to the lowest level, as that may minimize risk. 4. Reassess the need for HRT, and perhaps switch to a nonestrogen treatment. If protection against osteoporosis is needed, a bisphosphonate or a SERM may be offered as an alternative. If cardioprotection is desired, diet, exercise, and possibly a statin (for hypercholesterolemia) may be useful. If relief of urogenital atrophy is the goal, intravaginal estrogen cream or an estradiol-impregnated silicone vaginal ring may be used. Case 4: “Ever since the menopause, I just don’t feel the same. . . even when I take estrogen.” An approach to atypical symptoms

T.P. is a 47-yr-old woman who seeks a second opinion regarding hormone management. She underwent a total abdominal hysterectomy with bilateral salpingoophorectomy 2 yr ago, for chronic pelvic pain. The operative report from this surgery is not available, and she does not know the findings at surgery. She does know that since her operation, she “does not feel like herself”. She cries easily, and her sleep is poor. She frequently feels warm at night but has no clear-cut hot flashes. She has gained 15 pounds since her operation. She has seen three other gynecologists, who have prescribed several different estrogens without any improvement in her sense of well-being. You discuss the possibility of depression with her, which she totally rejects. She states that she felt “perfectly fine before that hysterectomy.”

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EXTENSIVE PERSONAL EXPERIENCE

Your examination is notable for the fact that she has a sad affect and weeps easily. Her mammogram is normal. You establish that she has not yet tried transdermal estradiol. You prescribe a 100 mg dose, twice weekly. She returns for followup in 6 weeks. She feels no differently. She is interested in androgen supplementation. You prescribe 0.625 mg conjugated estrogen with 2.5 mg methyltestosterone daily. Two months later she reports feeling partially improved. She would like to take a higher dose of these hormones. You increase the dose to 1.25 mg conjugated estrogens with 5 mg methyltestosterone. One month later she reports feeling “50% improved”. Two months later she calls the office to report that she has “backslid totally” and feels even worse. She returns to the office for consultation. You explain that your last resort would be a trial of a selective serotonin reuptake inhibitor. She reluctantly agrees to a 4-week trial of fluoxetine, 20 mg daily. One month later, she reports significant improvement and is willing to continue this treatment. 1. Not all women experience menopause in the same way— even unusual symptoms can be caused by estrogen withdrawal. Try to reserve judgement when a patient reports atypical symptoms that they ascribe to the menopause. If a symptom interferes with a patient’s quality of life, it is worth giving a “diagnostic test” of estrogen. If it resolves with 1–2 months of estrogen treatment, then it is presumably related to the menopause. 2. Not all symptoms experienced by women in their 50’s are due to estrogen withdrawal. Many life events can be coincident with the menopause. These events can be traumatic and can impair a woman’s sense of well-being. Before prescribing hormones for an impaired sense of well-being, it is worthwhile to inquire about other issues that may be troubling the patient. 3. Prescribe a “diagnostic test” of unopposed estrogen for 1–2 months. A transdermal estrogen patch can act like an “artificial ovary” by delivering the predominant human estrogen, estradiol, directly into the systemic circulation at a constant rate. Of all the estrogen treatments now available, this one mimics the premenopausal state the most. This treatment avoids the “peaks and valleys” in blood levels that are produced by oral administration. In addition, estrogens taken orally are largely converted to estrone, a weaker estrogen, by the intestinal mucosa. After intestinal absorption, estrogens are presented to the liver in high concentration, where they can have a pharmacological effect on hepatic metabolism. For all these reasons, a transdermal estrogen may be the best preparation for a “diagnostic test”. If a symptom is not improved by a 2-month course of estrogen, it is unlikely to be caused by the menopause. Other etiologies for that symptom should be considered. 4. Consider a “diagnostic test” of a low dose of testosterone for 2 months. Serum testosterone levels are reduced by oophorectomy. Some women may become symptomatic due to this loss of testosterone and may respond to testosterone treatment. Testosterone supplementation also has the benefit of lowering sex-hormone-binding globulin levels, which increases the proportion of free (bioactive) estrogen and testosterone. Measurement of testosterone levels is usually not

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informative, however. Most commercial testosterone assays lack the sensitivity to provide consistent and meaningful measurements of testosterone, and will not significantly detect methyltestosterone, which was prescribed to this patient. Moreover, even if accurate testosterone levels could be measured, it would probably not be clinically helpful, as there is great individual variation in response to a given testosterone level. For these reasons, patients are best followed by clinical response rather than testosterone levels. 5. Make only one change at a time in your medical management so that you know what change to blame or to give credit. It is tempting to throw every treatment at the patient, to relieve her suffering as rapidly as possible. Unfortunately, this usually generates much confusion and actually extends the evaluation. Avoid this temptation. 6. Add a progestin only after you have established that the estrogen is effective in symptom relief. Many women report impaired sense of well-being with progestins. First try to identify if estrogen and/or androgen improves a patient’s sense of well-being before adding in a progestin. Prescribing both estrogen and progestin together will generate confusion if the patient reports no improvement. First see if estrogen alone gives benefit. There is little risk in prescribing unopposed estrogen for less than 1 yr; durations this short do not increase the risk of endometrial cancer. 7. Consider depression and a trial of a selective serotonin-reuptake inhibitor (SSRI). This patient’s presentation was highly suggestive of depression. Many women with chronic pelvic pain are not cured by hysterectomy, as the pain stems from depression, not from intrinsic pelvic pathology. These patients would be best served by treatment with an SSRI. Unfortunately, many patients will refuse this treatment. I explain to them that their symptoms may be due to “low serotonin levels in their brain,” which can be adjusted by giving a drug that raises serotonin levels. Explained in this way, many patients will agree to a trial of an SSRI. There is also evidence that antidepressants may be more effective if estrogen is given concurrently. Case 5: “My doctor insists that I can’t be having hot flashes because I’m still having periods. He did a blood test that showed that I can’t be menopausal.” Responding to the perimenopausal patient

J.K. is a 48-yr-old woman who presents to your office complaining of “night sweats” for the past 6 months. She typically will be awakened 3– 4 times each night, feeling a hot sensation that originates in her chest and rises to her face. After a few minutes, she experiences a drenching sweat that requires her to change her nightgown. She is thoroughly exhausted. Her menses generally occur every 25–29 days, but on occasion may be delayed by an additional few days. She is sexually active and uses the diaphragm for contraception. She is a nonsmoker. Her internist found her to be in good health, with a TSH level of 2 mIU/L and an FSH level of 8 mIU/mL. He told her that she cannot be perimenopausal because her menses are still relatively regular, and he proved this by finding a low FSH level.

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You establish that she has no contraindications to oral contraceptive use. Her physical examination and mammogram are normal. You prescribe a low-dose oral contraceptive containing 20 mg ethinyl estradiol. She returns in 3 months for a blood pressure check, which is normal. She is absolutely delighted that her hot flashes are gone. Her sleep is much improved. Her withdrawal bleeding is light and occurs only during the placebo week. She is pleased that she no longer needs to use her diaphragm. You see her annually for the next 4 years. You discuss switching her to continuous HRT, which she accepts. She experiences persistent breakthrough bleeding on this regimen. After 3 months, you switch her to cyclic HRT. She has appropriately-timed and light bleeding on this regimen. 1. The most severe and frequent hot flashes occur 2–3 yr before the final menses. Hot flashes are not caused by low estrogen levels per se, but by the acute withdrawal of estrogen. During the perimenopause, estrogen levels can decline suddenly, severely, and repetitively. Hence, hot flashes are typically worse at this time (22). 2. The diagnosis of the perimenopause can usually be made from the patient’s history; it rarely requires measurement of folliclestimulating hormone. I explain to patients that measuring the FSH level of a perimenopausal woman is like taking a photograph of the speedometer of her car: it reflects reality at that moment but rapidly becomes obsolete information. Although this patient had ovarian functioning at the moment her FSH level was drawn, she almost certainly has times when her ovaries secrete less estrogen. Clearly she is perimenopausal and would benefit from treatment. A classic history like this patient’s is enough to make a diagnosis. 3. Low-dose oral contraceptives offer nonsmokers many benefits. The estrogen component of an oral contraceptive relieves hot flashes; the progestin component provides regular and light withdrawal bleeding as well as contraceptive efficacy. 4. Know the contraindications of oral contraceptives. Perimenopausal women are not candidates for oral contraceptive treatment if they: 1) smoke, 2) are pregnant, 3) have a history of thromboembolic or liver disease, or 4) have breast and endometrial cancer. In addition, abnormal bleeding warrants evaluation before starting treatment. 5. For perimenopausal women who cannot or will not take oral contraceptives, supplemental estrogen can provide relief. Very often, 0.3 mg conjugated estrogen daily will provide relief. A concomitant progestin is usually not required if the patient has regular menses. The presence of regular menses indicates that she is still ovulatory and can oppose a low dose of estrogen with her endogenous progestin. However, when she becomes oligoovulatory, she will need to add a progestin. This can cause irregular bleeding. For that reason, low-dose oral contraceptives are usually the treatment of choice for perimenopausal women who have no contraindication. 6. Switch from oral contraceptives to conventional cyclic HRT when you think the patient has become menopausal. The decision to switch from oral contraceptives to continuous HRT in this patient was not a good one. The incidence of irregular bleed-

ing in newly postmenopausal women given continuous HRT is high. Bleeding would be less of a problem with cyclic treatment. Finding appropriately-timed bleeding on cyclic HRT usually indicates that the patent has become menopausal. Conclusion

Many patients are effectively managed by standard hormone regimens. For those women who are not, there are strategies to provide a more individualized approach. In this way, we can provide the best of care to all postmenopausal women—so they can enjoy many healthy years after the menopause. References 1. Walsh BW. 1995 Menopause. In: Ryan KJ, Berkowitz RS, Barbieri RL, editors. Gynecology, Principles and Practice. Chicago: Year Book Medical Publishers. p 437– 460. 2. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar VA, Sacks FM. 1991 Effects of postmenopausal estrogen replacement on the concentrations and the metabolism of plasma lipoproteins. N Engl J Med. 325:1196 –204. 3. Archer DF, Pickar JH, Bottiglioni F. 1994 Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate. Obstet Gynecol. 83:686 – 692. 4. Smith-Bindman R, Kerlikowske K, Feldstein V, et al. 1998 Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA. 280:1510 –1517. 5. Langer RD, Pierce JJ, O’Hanlan KA, et al. 1997 Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. N Engl J Med. 337:1792–1798. 6. Leather AT, Savvas M, Studd JW. 1991 Endometrial histology and bleeding patterns after 8 years of continuous combined estrogen and progestogen therapy in postmenopausal women. Obstet Gynecol. 78:1008 –1010,. 7. Genant HK, Lucas J, Weiss S, et al. 1997 Low-dose esterified estrogen therapy: effects on bone, plasma estradiol concentrations, endometrium, and lipid levels. Arch Intern Med. 157:2609 –2615. 8. Monthly Vital Statistics Report. 1996 45(Suppl):40 – 42. 9. Colditz GA, Hankinson SE, Hunter DJ, et al. 1995 The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med. 332:1589 –1593. 10. Bergkvist L, Adami H, Persson I, et al. 1989 The risk of breast cancer after estrogen and estrogen-progestin-replacement. N Engl J Med. 321:293–297. 11. Brinton LA, Hoover R, Fraumeni JF. 1986 Menopausal oestrogens and breast cancer risk: an expanded case-control study. Br J Cancer. 54:825– 832. 12. Sourander L, Rajala T, Raiha I, et al. 1998 Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy. Lancet. 352:1965–1969. 13. Steinberg KK, Thacker SB, Smith SJ, et al. 1991 A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA. 265:1985–1990. 14. Slettery ML, Kerber RA. 1993 A comprehensive evaluation of family history and breast cancer risk. JAMA. 270:1563–1568. 15. Delmas PD, Bjarnason NH, Mitlak BH, et al. 1997 The effects of raloxifene on bone mineral density, serum cholesterol, and uterine endometrium. N Engl J Med. 337:1641–1647. 16. Jordan VC, Gusman JE, Eckert S, et al. 1998 Incident primary breast cancers are reduced by raloxifene: integrated data from multicenter, double-blind, randomized trails in 12,000 women. Proc Am Soc Clin Oncol. 17:122a (Abstract). 17. Walsh BW, Kuller LH, Wild RA, et al. 1998 Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA. 279:1445–1451. 18. Ettinger B, Selby J, Citron JT, Vangessel A, Ettinger VM, Hendrickson MR. 1994 Cyclic hormone replacement therapy using quarterly progestin. Obstet Gynecol. 83:693–700. 19. Loprinzi CL, Michalak JC, Quella SK, et al. 1994 Megestrol acetate for the prevention of hot flashes. N Engl J Med. 331:347–352. 20. Casanas-Roux F, Nisolle M, Marbaix E, Smets M, Bassil S, Donnez J. 1996 Morphometric, immunohistological and three-dimensional evaluation of the endometrium of menopausal women treated by oestrogen and Crinone, a new slow-release vaginal progesterone. Hum Reprod. 11:357–363. 21. Weiss NS, Szekely DR, English DR, Schweid AI. 1979 Endometrial cancer in relation to patterns of menopausal estrogen use, JAMA. 242:261. 22. Kronenberg F. 1990 Hot flashes: epidemiology and physiology. Ann N Y Acad Sci. 592:52– 86.

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