Patient Management Issues in Menopause

Patient Management Issues in Menopause
A CME Slide Library From the Council on Hormone Education At the end of this presentation, participants will be able to: Describe women’s beliefs and attitudes about postmenopausal hormone therapy (HT) and how these are affected by multiple sources of information. List factors to consider in determining which patients may be appropriate for HT or other therapies, and discuss how clinicians can integrate the findings from the Women’s Health Initiative into patient care. Identify considerations that are essential for assessing risk/benefit profiles. Examine the role of lower hormone doses and various formulations in the management of patients using postmenopausal HT. Counsel patients with menopausal concerns and direct them to the appropriate resources. Utilize case presentations to develop patient management strategies.

Patient Management Issues in Menopause
Section 1: Appropriate Use of HT Section 2: Barriers to Appropriate Use of HT Section 3: Importance of Individualizing HT 3a. Characteristics of Estrogens 3b. Characteristics of Progestins 3c. Use of Low-Dose HT 3d. Non-Oral HT Formulations Section 4: Non-HT Alternatives for Menopausal Symptoms Section 5: Patient Counseling Strategies HT = hormone therapy (estrogen [E] alone or combined with a progestin [E+P]).

Section 1: Appropriate Use of HT
2004 Patient Management Patient Management Issues in Menopause Section 1: Appropriate Use of HT The Women’s Health Initiative (WHI) has created considerable confusion and controversy regarding the use of postmenopausal hormone therapy (HT; estrogen [E] alone or combined with a progestin [E+P]) among physicians and especially among patients. This slide library is designed to discuss the appropriate use of postmenopausal HT, to review common concerns and patient barriers to HT, to describe techniques for individualizing postmenopausal HT, to identify alternative therapies for postmenopausal women, and to discuss methods of addressing patient concerns.

Reasons Women Gave for Initiating or Continuing HT
2004 Patient Management Reasons Women Gave for Initiating or Continuing HT Menopause-related Symptoms Osteoporosis, Bone Loss, Fracture Prevention Doctor Prescribed It, Told Me to Take It Cardiovascular Disease Prevention Other Depression, Anxiety, Emotional Distress 10 20 30 40 50 60 Although the use of postmenopausal HT has changed since the WHI, the most common reason women initiate or continue HT has been and continues to be to relieve menopausal symptoms.1 In this telephone survey of 1082 US women (aged 50 to 80 years) conducted in 1995, the reason most frequently cited by current users of HT (n = 460) for initiating treatment was menopausal symptoms.1 More recently, in 2003, a study was undertaken to describe the experiences of postmenopausal women who try to stop HT and to identify characteristics associated with inability to stop.2 Grady et al conducted telephone interviews with 670 of 1000 randomly selected female members of the Kaiser Foundation Health Plan, aged 50 to 69 years, who regularly used HT for at least 1 year before July 1, Of these 670 women, 377 had attempted to stop using HT between July 2002 and the time of the interview (March 2003). Of these 377 women who attempted to stop using HT after July 2002, 280 (74%) had not resumed HT at the time of the interview; 97 women (26%) had resumed their use of HT at the time of the interview. The major predictor of resuming HT was the development of troublesome withdrawal symptoms (OR, 8.8; 95% CI, 4.9–16.0). Women with a hysterectomy who had used HT for 10 years and who started HT mainly for reasons other than health promotion were more likely (P < .001) to resume HT use (44%) compared with those with one or two (25%) or none (9%) of these three characteristics. Most of the women (72%) reported they had stopped HT abruptly; 28% reported they had tapered off HT. No differences were observed in the incidence of troublesome withdrawal symptoms or the proportion of women who resumed HT between these two groups. These results suggest that approximately one-quarter of women who try to discontinue HT may develop troublesome withdrawal symptoms that may require the resumption of treatment. Percentage Newton KM, et al. J Womens Health. 1997;6: 1Newton KM, et al. J Womens Health. 1997;6: 2Grady D, et al. Obstet Gynecol. 2003;102:

FDA-Approved Indications for HT
2004 Patient Management FDA-Approved Indications for HT Treatment of moderate-to-severe vasomotor symptoms associated with menopause Treatment of vulvar and vaginal atrophy Prevention of postmenopausal osteoporosis Postmenopausal HT is indicated for Treatment of moderate-to-severe vasomotor symptoms associated with menopause Treatment of vulvar and vaginal atrophy* Prevention of postmenopausal osteoporosis† The treatment of menopausal symptoms remains the primary indication for HT, and is the most common reason why women initiate therapy. Since the WHI was not designed to evaluate the indicated uses of HT, the overall risk/benefit profile of HT cannot be assessed from the results of the WHI alone. *The Food and Drug Administration (FDA) suggests that topical vaginal products should be considered when prescribing HT solely for the treatment of symptoms of vulvar and vaginal atrophy. †The FDA also encourages the consideration of non-estrogen medications when HT is prescribed solely for the prevention of postmenopausal osteoporosis. FDA Guidance for Industry. Available at: Accessed 1/04. FDA Guidance for Industry. Available at: Accessed 1/04.

Women’s Health Initiative (WHI) Updated Results Summary: Breast Cancer
2004 Patient Management Women’s Health Initiative (WHI) Updated Results Summary: Breast Cancer For invasive breast cancer, HR = 1.24 (95% CI, 1.01–1.54; P = .003) after 5 years of E+P For total breast cancer, HR = 1.24 (95% CI, 1.02–1.50; P < .001) after 5 years of E+P Exclusion of women with prior HT use (26.1%), HR was nonsignificant at 1.09 (95% CI, 0.86–1.39) Analysis of breast cancer data showed slightly larger tumors (1.7 cm with E+P use vs 1.5 cm with placebo) and ~10% more regional node positivity The WHI, a large, randomized, placebo-controlled study of risks and benefits of E alone and E+P as preventive therapies for postmenopausal women, enrolled 27,000 women between 1993 and 1998 and was scheduled to conclude in A total of 16,608 women were randomized to the E+P portion of the trial and received mg/d CEE with 2.5 mg/d MPA or placebo. In July 2002, the Data and Safety Monitoring Board (DSMB) of the WHI discontinued the HT arm of the study after an average follow-up period of 5.6 years because the design-specified, weighted, log-rank test statistic for invasive breast cancer (z = –3.19) crossed the designated boundary (z = –2.32), and because the global index (a summary measure of the overall balance of risk and benefits of HT) indicated that the risks of HT may exceed its benefits (z = –1.62). In intent-to-treat analyses, E+P increased total (245 vs 185 cases; HR, 1.24; weighted P < .001) and invasive (199 vs 150 cases; HR, 1.24; weighted P = .003) breast cancers compared with placebo. Data suggest that women reporting prior HT use may have had a greater risk for breast cancers associated with E+P use than never-users (for never-use, HR = 1.09; <5 years of prior use, HR = 1.70; 5 years of prior use, HR = 2.27). The invasive breast cancers diagnosed in the E+P group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P = .04) and were at a more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P = .04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was greater in the combined therapy group (716 [9.4%] of 7656) compared with the placebo group (398 [5.4%] of 7310; P < .001). Chlebowski RT, et al. JAMA. 2003;289: Chlebowski RT, et al. JAMA. 2003;289:

WHI Updated Results Summary: CHD, Fracture, Dementia
2004 Patient Management WHI Updated Results Summary: CHD, Fracture, Dementia CHD data failed to show significance with adjudicated overall 5-year results (HR, 1.24; 95% CI, 1.00–1.54)1 In addition to hip fracture reduction, vertebral fracture was significantly reduced in a non-osteoporotic population (HR, 0.60; 95% CI, 0.38–0.95)2 Dementia increased in women who initiated E+P at age 65 years (HR, 2.05; 95% CI, 1.21–3.48; P = .01)3 Additional 23 cases/10,000 women/year No increase in mild cognitive impairment Manson et al1 reported final CHD outcomes from the WHI. E+P was associated with a nonsignificant HR for CHD of 1.24 (95% nCI, 1.00–1.54; 95% CI after adjustment for sequential monitoring, 0.97–1.60). The elevation in risk was most apparent at 1 year (HR, 1.81; 95% CI 1.09–3.01). Cauley et al2 evaluated whether fracture risk reduction with E+P differed according to risk factors for fractures. 733 women (8.6%) in the E+P group and 896 women (11.1%) in the placebo group experienced a fracture (HR, 0.76; 95% CI, 0.69–0.83; did not differ in women stratified by age, BMI, smoking status, history of falls, personal and family history of fracture, total calcium intake, past use of HT, BMD, or summary fracture risk score). Total hip BMD increased 3.7% after 3 years of treatment with E+P compared with 0.14% in the placebo group (P < .001). Thus, E+P increased BMD and reduced the risk of fracture in healthy postmenopausal women. Shumaker and other investigators for the Women's Health Initiative Memory Study (WHIMS)3 evaluated the effect of E+P on incidence of dementia and mild cognitive impairment (a secondary outcome operationally defined as poor performance on modified Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] tests in 1 area of cognitive function, a report of some functional impairment but not in activity of living, no evidence of psychiatric disorder or other medical condition causing the cognitive decline, absence of dementia) compared with placebo. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years were enrolled in the WHIMS (n = 2229, E+P group; n = 2303, placebo group). Overall, 61 women were diagnosed with probable dementia, 40 (66%) in the E+P group, 21 (34%) in the placebo group. The HR for probable dementia was 2.05 (95% CI, 1.21–3.48; 45 vs 22 per 10,000 person-years; P = .01), resulting in an additional 23 cases of dementia per 10,000 women per year. Alzheimer’s disease was the most common classification of dementia in both study groups. Treatment effects on mild cognitive impairment did not differ between groups (HR, 1.07; 95% CI, 0.74–1.55). CHD = coronary heart disease. 1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Cauley JA, et al. JAMA. 2003;290: ; 3Shumaker SA, et al. JAMA. 2003;289: 1Manson JE, et al. N Engl J Med. 2003;349: 2Cauley JA, et al. JAMA. 2003;290: 3Shumaker SA, et al. JAMA. 2003;289:

WHI Updated Results Summary: Gynecologic Cancers, QOL
2004 Patient Management WHI Updated Results Summary: Gynecologic Cancers, QOL Cancer (after 5 years of E+P)1 Endometrial: HR = 0.81 (95% CI, 0.48–1.36, NS) Ovarian: HR = 1.58 (95% CI, 0.77–3.24, NS) No significant improvement in health-related QOL found in largely asymptomatic women (average age, 63 years)2 Small subset of symptomatic women showed improvement in hot flushes, small benefit in sleep Anderson et al1 evaluated the risk of gynecologic cancers and related diagnostic procedures among women assigned to E+P and placebo in the WHI. In 5.6 years of follow-up, there were 32 cases of invasive ovarian cancer (HR, 1.58; 95% CI, 0.77–3.24), 58 cases of endometrial cancer (HR, 0.81; 95% CI, 0.48–1.36), 1 case of non-endometrial uterine cancer, 13 cases of cervical cancer, and 7 cases of other gynecologic cancers. No appreciable differences were found in the distributions of tumor histology, stage, or grade for either cancer site. The incidence of other gynecologic cancers was low and did not differ by randomization assignment. Hays et al2 explored the effect of HT on health-related quality of life (QOL). Randomization to E+P resulted in no significant effects on general health, vitality, mental health, depressive symptoms, or sexual satisfaction. The use of E+P was associated with a statistically significant but small and not clinically meaningful benefit in terms of sleep disturbance, physical functioning, and bodily pain after one year (the mean benefit in terms of sleep disturbance was 0.4 point on a 20-point scale, in terms of physical functioning 0.8 point on a 100-point scale, and in terms of pain 1.9 points on a 100-point scale). At 3 years, there were no significant benefits in terms of any QOL outcomes. Among women 50 to 54 years of age with moderate-to-severe vasomotor symptoms at base line, E+P improved vasomotor symptoms and resulted in a small benefit in terms of sleep disturbance, but no benefit in terms of the other QOL outcomes. QOL = quality of life; NS = not significant. 1Anderson GL, et al. JAMA. 2003;290: ; 2Hays J, et al. N Engl J Med. 2003;348: 1Anderson GL, et al. JAMA. 2003;290: 2Hays J, et al. N Engl J Med. 2003;348:

WHI Updated Results Summary: Stroke
2004 Patient Management WHI Updated Results Summary: Stroke After 5 years, the risk of stroke was 1.8% for E+P, 1.3% for placebo (HR, 1.31; 95% CI, 1.02–1.68) Attributable risk of 0.5% is <0.1% per year Attributable risk of E+P for stroke increases with age age 50–59 years is 0.04% per year age 70–79 years is 0.13% per year Wassertheil-Smoller et al1 assessed the effect of E+P on stroke. One hundred fifty-one patients (1.8%) in the E+P and 107 (1.3%) in the placebo groups had strokes. Overall, 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat HR for E+P vs placebo was 1.31 (95% CI, 1.02–1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08–2.08). For ischemic stroke, HR = 1.44 (95% CI, 1.09–1.90) For hemorrhagic stroke, HR = 0.82 (95% CI, 0.43–1.56) E+P increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to E+P appeared to be present in all subgroups of women examined. Framingham risk scores reflect the probability of stroke with in 10 years for women age 55–84 years, based on use of antihypertensive medications, as well as systolic blood pressure, age, diabetes mellitus, cigarette smoking, prior cardiovascular disease, atrial fibrillation, and left ventricular hypertrophy by electrocardiogram.2 Two thirds of the women enrolled in the WHI were in the Framingham medium-to-high risk for stroke category; 50% were smokers and 35% were hypertensive.1 Wassertheil-Smoller S, et al. JAMA. 2003;289: 1Wassertheil-Smoller S, et al, JAMA. 2003;289: 2D’Agostino RB, et al. Stroke. 1994;25:40-3.

WHI Study Considerations
2004 Patient Management WHI Study Considerations There were relatively high rates of discontinuation in the conjugated equine estrogens (CEE)/ medroxyprogesterone acetate (MPA) group (42%) and crossover to active treatment in the placebo group (10.7%) WHI did not evaluate symptom relief, and therefore symptom relief was not included in the global index Results do not necessarily relate to lower dosages of these drugs or other formulations or routes of administration The results of the WHI are important and will have a significant effect on the way HT is prescribed in the future. However, the study does have limitations. For example, both the rate of discontinuation in the E+P group and the rate of crossover to E+P from the placebo group were higher than expected. The lack of adherence and increased number of women who “dropped in” to the E+P group from the placebo group may have changed the observed treatment effects. The fact the trial was stopped early decreases the precision of estimates of long-term treatment effects—a longer treatment may have shown a greater reduction in the risk of fractures and colon cancer or a greater increase in the risk of other diseases. In addition, the WHI did not evaluate the role of HT in relieving menopausal symptoms, the most common reason women initiate therapy. Therefore, the benefit of HT in relieving menopausal symptoms was not included in the global index. Finally, the results may not relate to lower dosages, other formulations, or other routes of administration of HT. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

WHI: Results With CEE/MPA
2004 Patient Management WHI: Results With CEE/MPA CHD1 Breast Cancer2 Dementia3*† Stroke4 VTE5 Endometrial Cancer6 Ovarian Cancer6 Colorectal Cancer7 Hip Fracture8 Total Fracture8* Death5 95% nCI 95% aCI 0.5 1.0 2.0 5.0 HR This figure illustrates the HRs with 95% CIs for several outcomes evaluated in the CEE/MPA arm of the WHI.1-7 Where available, both nominal and adjusted CIs (nCI and aCI, respectively) are presented for comparison purposes. Event HR (nCI; aCI) CHD (1.00–1.54; 0.97–1.60) Breast cancer (1.01–1.54; 0.97–1.59) Dementia (1.21–3.48; NA) Stroke (1.02–1.68; 0.93–1.84) VTE (1.58–2.82; 1.26–3.55) Endometrial cancer (0.48–1.36; 0.40–1.64) Ovarian cancer (0.77–3.24; 0.59–4.23) Colorectal cancer (0.38–0.81; 0.33–0.94) Hip fracture (0.47–0.96; 0.41–1.10) Total fracture (0.69–0.83; NA) Death (0.82–1.18; 0.70–1.37) *aCIs not available; †Only in women 65 years of age at baseline. 1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Chlebowski RT, et al. JAMA. 2003;289: ; 3Shumaker SA, et al. JAMA. 2003;289: ; 4Wassertheil-Smoller S, et al. JAMA. 2003;289: ; 5Writing Group for the WHI Investigators. JAMA. 2002;288:321-33; 6Anderson GL, et al. JAMA. 2003; 290: ; 7Chlebowski RT, et al. N Engl J Med. 2004;350: ; 8Cauley JA, et al. JAMA. 2003;290: 1Manson JE, et al. N Engl J Med. 2003;349: 2Chlebowski RT, et al. JAMA. 2003;289: 3Shumaker SA, et al. JAMA. 2003;289: 4Wassertheil-Smoller S, et al. JAMA. 2003;289: 5Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: 6Anderson GL, et al. JAMA. 2003; 290: 7Chlebowski RT, et al. N Engl J Med. 2004;350: 8Cauley JA, et al. JAMA. 2003;290:

WHI Results: Overall Relative and Attributable Risk
2004 Patient Management WHI Results: Overall Relative and Attributable Risk Event Overall HR 95% nCI 95% aCI Attributable Risk per 10,000 Women/Year Benefit per 10,000 Women/Year CHD1 1.24 1.00–1.54 0.97–1.60 6 Breast cancer2 1.01–1.54 0.97–1.59 8 Dementia3* 2.05 1.21–3.48 — 23 Stroke4 1.31 1.02–1.68 0.93–1.84 7 VTE5 2.11 1.58–2.82 1.26–3.55 18 PE5 2.13 1.39–3.25 0.99–4.56 Colorectal cancer6 0.56 0.38–0.81 0.33–0.94 Hip fractures7 0.67 0.47–0.96 0.41–1.10 5 Total fractures7 0.76 0.69–0.83 47 VTE = venous thromboembolism; PE = pulmonary embolism. *Only in women 65 years of age at baseline. 1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Chlebowski RT, et al. JAMA. 2003;289: ; 3Shumaker SA, et al. JAMA. 2003;289: ; 4Wassertheil-Smoller S, et al. JAMA. 2003;289: ; 5Writing Group for the WHI Investigators. JAMA. 2002;288:321-33; 6Chlebowski RT, et al. N Engl J Med. 2004;350: ; 7Cauley JA, et al. JAMA. 2003;290: This slide provides the values for the HRs, CIs, and attributable risks from the WHI. Overall HRs for the major outcomes for CEE/MPA compared with placebo are shown in the black box. For each HR, the CIs that reached statistical significance (ie, those that did not include 1.0) are highlighted in yellow. Summary of findings: Only the increased risk for VTE and PE were statistically significant for both the nCI and aCI. (Note: Publication of the centrally adjudicated results for total fracture and probable dementia did not include an aCI. The nCI for total fracture and probable dementia were statistically significant.) Neither the nCI nor the aCI for CHD were statistically significant. The increased risk for breast cancer and stroke were statistically significant for the nCI, but not the aCI The decreased risk for colorectal cancer was statistically significant for both the nCI and aCI; the decreased risk for hip fracture was statistically significant for the nCI, but not the aCI With the exception of total fractures, the absolute excess risk or benefit attributable to CEE/MPA was low. The WHI findings predict that over 1 year, 10,000 women taking CEE/MPA compared with placebo might be expected to experience 6 more CHD events, 8 more invasive breast cancers, 7 more strokes, 18 more VTEs, 8 more PEs, 6 fewer colorectal cancers, 5 fewer hip fractures, and 47 fewer total fractures. In a subgroup of women age 65 years and older at baseline, 23 more cases of probable dementia would be predicted by these findings. These risk estimates apply only to the population of women represented by the subjects who participated in the WHI, that is, older women initiating HT for the first time who have significant risk factors for chronic disease, such as overweight/obesity and history of smoking. Manson JE, et al. N Engl J Med. 2003;349: Chlebowski RT, et al. JAMA. 2003;289: Shumaker SA, et al. JAMA. 2003;289: Wassertheil-Smoller S, et al. JAMA. 2003;289: Writing Group for the WHI Investigators. JAMA. 2002;288:321-33 Chlebowski RT, et al. N Engl J Med. 2004;350: Cauley JA, et al. JAMA. 2003;290:

2004 Patient Management WHI Summary Results from WHI indicate that CEE mg/d plus MPA 2.5 mg/d should not be initiated or continued for the primary prevention of CHD Risks for CVD and breast cancer must be weighed against the benefit for fracture and colon cancer In summary, results from the WHI on the use of HT indicate that CEE mg/d plus MPA 2.5 mg/d should not be initiated or continued for the primary prevention of CHD. When E+P use is considered, its risks for CVD and breast cancer must be weighed against its benefit in reducing the risk of fracture and colon cancer. CVD = cardiovascular disease. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

Interpretation of the WHI Data
2004 Patient Management Interpretation of the WHI Data Majority of women initiate HT to alleviate menopausal symptoms1 75% of HT users initiate therapy within 5 years of menopause In a 1999 national survey (n = 9400; age 40 years), 24% used HT, 3% E+P for 5 years, 10% used ET for 5 years2 Results should not be extrapolated to symptomatic early menopausal or prematurely menopausal women using HT for symptom relief3 Average age at screening, 63 years Only 4% of WHI participants had moderate to severe vasomotor symptoms Several considerations should be taken into account in interpreting the WHI findings. The average age of WHI participants at initial screening was ~63 years old.1 The average age that nonhysterectomized women initiate HT is 51 years.2 Only 4% of WHI participants had moderate to severe vasomotor symptoms. When the study was stopped in 2002, two-thirds of the participants were 68 years or older. 42% of the women in the CEE/MPA group and 38% of the women in the placebo group discontinued study medication at some time during the trial. The high rate of discontinuation in the CEE/MPA group and the crossover of women from placebo to CEE/MPA (10.7%) may have influenced the study results. Pre-WHI results: In a 1999 national survey (n = 9,400; age 40 years), 24% of women were hormone users; however, only 3% of women used E+P for 5 or more years, and only 10% used E alone for 5 or more years.3 The NAMS Position Statement4 recommends that data from studies such as HERS and WHI should be extrapolated only with caution to women <50 years of age who initiate HT, and should not be extrapolated to women experiencing premature menopause (<40 years of age) and initiating HT at that time. 1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; 2Brett KM, Ruben CA. Am J Obstet Gynecol. 2003;102: North American Menopause Society. Menopause. 2003;10: 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Taylor Nelson Sofres (TNS) Intersearch Corporation. May 17, 2000. 3Brett KM, Ruben CA. Am J Obstet Gynecol. 2003;102: 4North American Menopause Society. Menopause. 2003;10:

2004 Patient Management Post-WHI Survey 1000 high-compliance Kaiser Permanente patients were mailed a letter explaining the WHI study findings and recommendations about continuing HT 670 women agreed to complete an interview 94.5% considered stopping HT 56% of women attempted to discontinue HT 44% chose to continue therapy; of those women 25.7% for relief of vasomotor symptoms 19.2% for osteoporosis 47.2% for other reasons (ie, mood swings, vaginal dryness, urinary incontinence, and depression) Ettinger et al examined the degree that women who were using postmenopausal HT prior to the publication of the WHI results had been informed of the findings. They also analyzed how knowledge of these findings was associated with women’s decisions to continue or discontinue HT. A telephone survey of 670 female members of a large health maintenance organization, aged 50 to 69 years, who had regularly used HT from July 1, 2001, through June 30, 2002 was performed. Selection was limited to women who demonstrated high compliance, which was defined as filling three prescriptions for 100 pills of estrogen from July 1, 2001, through June 30, Of this population, 39% used E alone, 61% used E+P. Most were long-term users (median duration of use, 9 years). Most women (93%) reported hearing about the new findings; however, only 57% considered the quality of this information to be good, regardless of its source: mass media (21%), the health plan (32%), or a health care practitioner (34%). Ettinger B, et al. Obstet Gynecol. 2003;102: Ettinger B, et al. Obstet Gynecol. 2003;102:

Statement on HT From ACOG
2004 Patient Management Statement on HT From ACOG Women who have been taking HT for a number of years should not panic, but discuss their individual situation with their physician With respect to women’s short-term use of HT for relief of menopausal symptoms, it may be reasonable for women to continue use for this purpose because the benefits are likely to outweigh the risks For short-term use of HT for relief of menopausal symptoms, ACOG continues to recommend that this be a personal, individualized decision, made after consultations between a woman and her physician—taking into account a woman’s individual benefits and risks from such use In response to the WHI report, the American College of Obstetricians and Gynecologists (ACOG) issued a statement on the implications of the findings for clinicians and their patients. Points emphasized in the ACOG statement The preliminary data reported from WHI represent an increased breast cancer risk of less than 1% per year for an individual woman. The WHI did not focus on short-term risks and benefits of HT. It may be reasonable for women to continue short-term use of combined HT for relief of vasomotor symptoms, as the benefits from short-term therapy are likely to outweigh the risks. ACOG continues to recommend that the decision to use HT should be a personal and individualized one. A woman’s individual benefits and risks should be addressed in consultation with a physician. American College of Obstetricians and Gynecologists (ACOG). Statement on the Estrogen Plus Progestin Trial of the Women’s Health Initiative. July 9, Available at: press_releases/nr cfm. Accessed 8/19/02. American College of Obstetricians and Gynecologists. Available at: Accessed August 19, 2002.

2003 NAMS Position Statement on HT
2004 Patient Management 2003 NAMS Position Statement on HT Primary indication for systemic HT is the treatment of moderate-to-severe menopausal symptoms Local estrogen recommended for moderate-to-severe vulvar and vaginal atrophy Primary indication for progestogen Endometrial protection HT should not be used for 1° or 2° prevention of CHD or stroke WHI results cannot be extrapolated to Symptomatic perimenopausal women Premature menopause HT should be used at the lowest effective dose for the shortest duration needed The termination of the E+P trial of the WHI study in July 2002 led the NAMS Advisory Panel to prepare a report on postmenopausal HT. Almost a year later, a second report was prepared by this group, presenting clinical recommendations for use of HT in peri- and postmenopausal women. Some of the NAMS recommendations include the following. Treatment of moderate and severe menopausal symptoms (ie, vasomotor symptoms, sleep disruption from vasomotor symptoms) remains the primary indication for systemic estrogen-only therapy and combined E+P. Every systemic HT product is government approved for this indication. The primary menopause-related indication for progestogen use is endometrial protection from unopposed E. For all women with an intact uterus who are using estrogen, clinicians are advised to prescribe adequate progestogen, in either a continuous-combined E+P or continuous-sequential E+P regimen. Women without a uterus should not be prescribed a progestogen. Some women with an intact uterus who choose E+P may experience undesirable side effects from the progestogen component; however, there is insufficient evidence regarding long-term endometrial safety to recommend use of long-cycle progestogen (ie, progestogen every 3-6 months for days), a progestin-containing intrauterine device, or low-dose estrogen without progestogen as an alternative to standard E+P regimens. If utilizing any of these approaches, closer surveillance of the endometrium is recommended, pending more definitive research. North American Menopause Society (NAMS). Menopause. 2003;10: North American Menopause Society. Menopause. 2003;10:

Indications for Extended Use of HT
2004 Patient Management Indications for Extended Use of HT After informed discussion and under ongoing supervision For the woman for whom, in her opinion, benefits of symptom relief outweigh risks, notably after failing an attempt to withdraw from HT For women with moderate-to-severe menopausal symptoms who are at high risk for osteoporotic fracture For prevention of osteoporosis in a high-risk woman when alternate therapies are not appropriate for that woman More of the NAMS recommendations include the following: Extended use of E alone or E+P is acceptable under the following circumstances, provided the woman is well aware of the risks and there is strict supervision. For the woman for whom, in her opinion, benefits of symptom relief outweigh risks, notably after failing an attempt to withdraw from HT. Attempts should be made over time to reduce and cease HT. For women with moderate to severe menopause symptoms who are at high risk for osteoporotic fracture. Attempts should be made over time to lower the dose or cease HT and introduce alternate bone-sparing therapy. For prevention of osteoporosis in a high-risk woman when alternate therapies are not appropriate for that woman. North American Menopause Society. Menopause. 2003;10: North American Menopause Society. Menopause. 2003;10:

Summary of NIH Recommendations
2004 Patient Management Summary of NIH Recommendations While short-term use was not studied in the WHI, women taking HT for relief of menopausal symptoms may reap more benefits than risks Women should keep up with their regular schedule of mammograms and breast self-examinations HT should not be continued or started to prevent heart disease; women should consult their doctor about other methods of CVD prevention For osteoporosis prevention, women should consult their doctor and weigh the benefits against their personal risks; alternate treatments are available to prevent osteoporosis and fractures With the publication of the WHI results, the National Institutes of Health (NIH) also released a new set of recommendations for the use of HT. First, the NIH recommended that HT should not be continued or initiated to prevent heart disease. Instead, women should consult their doctor about other methods of CVD prevention, including lifestyle changes and medications that lower cholesterol and/or blood pressure. Although this study confirmed that HT provides significant protection from hip, vertebral, and overall fracture, women should consult their doctor and weigh the benefits of HT against their personal risk for heart attack, stroke, venous thromboembolism, and breast cancer. National Institutes of Health (NIH). National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. Available at: Accessed 8/19/02. National Institutes of Health. Available at: Accessed August 19, 2002.

Section 2: Barriers to Appropriate Use of HT
2004 Patient Management Patient Management Issues in Menopause Section 2: Barriers to Appropriate Use of HT

Barriers to Appropriate Use of HT
2004 Patient Management Barriers to Appropriate Use of HT Concerns about the long-term safety of HT HT-related vaginal bleeding Inadequate counseling on the risks and benefits Many women who are appropriate candidates for postmenopausal HT do not initiate therapy because of their concerns about the long-term safety of HT.1 Among women who choose to initiate therapy, many discontinue HT because of vaginal bleeding.2 To ensure that the treatment goals of women considering or initiating postmenopausal HT are met, health care providers should address these concerns when counseling their patients. Despite prolific media coverage of the WHI, for example, physicians should help their patients make informed decisions. The Health Employer Data Information System menopause counseling measure, instituted in 2000, is aimed at improving women’s knowledge about HT through better counseling.3 Ettinger et al4 reported that most women (93%) reported hearing about the WHI findings; however, only 57% considered the quality of this information to be good, regardless of its source: mass media (21%), the health plan (32%), or a health care practitioner (34%). 1Newton KM, et al. J Womens Health. 1997;6: 2Goldman GA, et al. Clin Exp Obstet Gynecol. 1998;25:18-9. 3National Committee for Quality Assurance. Washington: National Committee for Quality Assurance; 2000:133–59. 4Ettinger B, et al. Obstet Gynecol. 2003;102:

Women’s Perceptions of Their Greatest Health Problems
2004 Patient Management Women’s Perceptions of Their Greatest Health Problems Cardiovascular Disease 7% Don’t Know/ No Answer Breast Cancer 16% 34% 16% Other Problems 27% The risk of chronic diseases, such as CVD and osteoporosis, increases dramatically with age. However, many American women do not understand their true risk of these diseases. In fact, the problems that women perceive to be their greatest health risks are generally different than their actual causes of death. In a telephone survey of 1,000 US women, approximately 34% of respondents identified breast cancer as the greatest health problem confronting women, while 61% identified all cancers. Less than 8% reported heart disease or stroke as a major concern. Cancer Adapted from Mosca L, et al. Arch Fam Med. 2000;9: Mosca L, et al. Arch Fam Med. 2000;9:

Causes of Death Among Women*
2004 Patient Management Causes of Death Among Women* Other Cancers Heart Disease 15% Breast Cancer 34% 4% Diabetes 3% Chronic Lower Respiratory Disease 6% 10% 28% Other Cerebrovascular Disease In contrast with the previous slide of perceived health concerns, this slide shows actual rates for cause of death among women aged 65 years or older. What is apparent is that a generalized fear of cancer, and breast cancer specifically, skews postmenopausal women’s understanding of their health risks. Such misinformation often plays an important role in women’s decision-making about HT. *Percentage of total deaths in 1999 among women aged 65 years and older. Anderson RN. Natl Vital Stat Rep. 2001;49:1-13. Anderson RN. Natl Vital Stat Rep. 2001;49:1-13.

Absolute Risk of Breast Cancer in the General Population
2004 Patient Management Absolute Risk of Breast Cancer in the General Population Each 50-year-old woman has approximately a 2.8% chance of developing breast cancer by age 60 years This translates to an absolute risk of 2.8 per 100 women All Women Aged 50 Years in the General Population— Risk for Breast Cancer by Age 60 Years In 100 women, 2.8 are at risk To address patients’ confusion regarding breast cancer risk, it may be helpful to discuss a woman’s absolute risk of breast cancer, with or without HT, in addition to discussing relative and attributable risk. RR is the ratio of the risk of disease among those exposed to a risk factor to the risk among those who were not exposed and is independent of the overall incidence of disease in the population. Absolute risk is the overall incidence of a disease in a given population. Attributable risk refers to the excess risk of disease in patients exposed to a potential risk factor, above and beyond the risk expected in patients not exposed to the potential risk factor. Absolute risk of breast cancer is shown in this slide. According to the American Cancer Society, a 50-year-old woman has a 2.8% chance of developing breast cancer before she turns 60 years of age. Therefore, among 100 women, 2.8 are at risk for breast cancer. American Cancer Society. Breast Cancer Facts and Figures 2001–2002. Available at: downloads/STT/BrCaFF2001.pdf. American Cancer Society. Available at:

Absolute Risk of Breast Cancer After 5 Years of HT
2004 Patient Management Absolute Risk of Breast Cancer After 5 Years of HT WHI results indicate a hazard risk for breast cancer of (P < .001) after 5 years of HT use (a 24% increase in risk) This translates into an absolute risk of 3.5 per 100 users Risk of Breast Cancer by Age 60 Years After 5 Years of HT Use (Assuming a 24% Increase in Risk) 3.5 of 100 women who are HT users are at risk (<1 additional woman over baseline risk) In the WHI, Chlebowski et al1 reported that 5.6 years of HT use was associated with an HR for breast cancer of Therefore, women receiving HT experienced an 24% increase in the risk of breast cancer compared with women using placebo. As noted in the previous slide, the absolute risk of breast cancer by age 60 years among 50-year-old women is 2.8 cases per 100 women; a 24% increase in this risk translates into an absolute risk of 3.5 cases per 100 women who use HT for approximately 5 years.1,2 A discussion of the attributable risk associated with HT also may help patients put breast cancer risk with HT into perspective. The attributable risk of breast cancer in HT users, or the excess risk of breast cancer in HT users versus nonusers, is the difference between the incidence rates of HT users compared with nonusers. Therefore, the attributable risk of breast cancer in women who are 50 years of age and use HT for 5 years is 0.7 per 100 women. American Cancer Society. Breast Cancer Facts and Figures 2001–2002. Available at: downloads/STT/BrCaFF2001.pdf; Chlebowski RT, et al. JAMA. 2003;289: 1Chlebowski RT, et al. JAMA. 2003;289: 2American Cancer Society. Available at:

2004 Patient Management WHI: Risk of Invasive Breast Cancer in Women With and Without Prior HT Use Hazard Ratio (95% CI) 0.1 0.5 1.0 4.0 2.0 6.0 Prior HT Use None <5 Years 5 Years Overall % of Population 74.0 14.8 11.2 100 Similar to the results reported in the July 2002 report from the WHI investigators,1 the increased risk of invasive breast cancer was limited to those women with prior use of postmenopausal HT.2 Women with no prior HT use comprised a large proportion of the study population (74%). The HR for breast cancer associated with CEE/MPA use in these women was only marginally greater than 1.0 and was not statistically significant. (The table below provides the data shown graphically in the slide.) Nonsignificant. Chlebowski RT, et al. JAMA. 2003;289: Prior HT Use % of Study Population HR (95% CI) No prior use 74% 1.09 (0.86–1.39) <5 years of prior use 14.8% 1.70 (0.99–2.91) 5 years of prior use 11.2% 2.27 (1.00–5.15) 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Chlebowski RT, et al. JAMA. 2003;289:

Addressing Patients’ Breast Health Concerns
2004 Patient Management Addressing Patients’ Breast Health Concerns The WHI reported a small, increased risk of invasive breast cancer with an average of 5.6 years of E+P use Most observational studies do not show an increased risk of breast cancer with HT use; some suggest a small increased risk with long-term HT use Risk estimates from prospective, randomized trials and observational studies are similar In the WHI, breast cancers in women assigned to E+P were somewhat larger and more likely to involve regional lymph nodes; other studies show that HT users have less aggressive, smaller tumors In summary, the WHI indicated that use of E+P is associated with a small but statistically significant increased risk of invasive breast cancer. Numerous other studies show a similarly small increased risk or no increased risk with use of E+P. Longer durations of use appear to be associated with increasing risk. The E-only arm of the WHI was recently stopped approximately one year prior to its planned completion date. Preliminary analyses indicate no increased risk of breast cancer with a mean of 7 years of use. In the WHI, breast cancers diagnosed in women assigned to receive E+P were somewhat larger and more likely to involve regional lymph nodes. Most other studies show that HT users are more likely to be diagnosed with smaller, lower stage, less aggressive tumors. Additional research is needed to understand these discrepant findings. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: Bush TL, et al. Obstet Gynecol. 2001;98: Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997;350: Chlebowski RT, et al. JAMA. 2003;289: Hulley S, et al. JAMA. 2002;288:58-66. Holli K, et al. J Clin Oncol. 1998;16: Bilimoria MM, et al. Ann Surg Oncol. 1999;6:200-7. Cheek J, et al. Arch Surg. 2002;137: Pappo I, et al. Ann Surg Oncol. 2003;11:52-8.

Addressing Patients’ Breast Health Concerns continued
2004 Patient Management Addressing Patients’ Breast Health Concerns continued Positive family history of breast cancer is not a contraindication for HT In observational studies, breast cancer survival rates are better in HT users Million Women Study reported greater risk of fatal breast cancer among HT users, however breast cancer survival rates were equivalent among HT users and nonusers In breast cancer survivors, HT use has not been shown to worsen mortality or recurrence Research on breast cancer risk and HT use also indicates that a positive family history of breast cancer is not a contraindication for HT. Numerous studies show that total mortality rates are lower among women who use HT. A notable exception to this is the Million Women Study; however, if breast cancer mortality rate is calculated in the same manner as it is calculated in most other studies (ie, breast cancer deaths/breast cancer cases), the mortality rate among current HT users in the Million Women Study was lower than the rate observed in never-users. The relatively short follow-up time for the WHI prevented determination of mortality due to breast cancer; however, all-cause mortality was slightly lower (and not statistically different) for HT users (HR for total mortality 0.98; nCI, 0.82–1.18 and aCI, 0.70–1.37). Several hypotheses for why breast cancer patients who are taking HT may have a reduced risk of dying from breast cancer are Detection/surveillance bias Selection bias Tumors diagnosed in HT users are generally smaller, lower grade, and less aggressive than those in nonusers Lastly, among women treated for breast cancer, HT use has not been shown to worsen recurrence or mortality rates. Sellers TA, et al. Ann Intern Med. 1997;127: Dupont WD, et al. Cancer. 1999;85: Million Women Study Collaborators. Lancet. 2003;362:419–27. Hunt K, et al. BJOG. 1990;97: Henderson BE, et al. Arch Intern Med. 1991;151:75-8. Willis DB, et al. Cancer Causes Control. 1996;7: Grodstein F, et al. N Engl J Med. 1997;336: Sellers TA, et al. Ann Intern Med. 1997;127: Rodriguez C, et al. Am J Epidemiol. 2001;153: DiSaia PJ, et al. Am J Clin Oncol. 2000;23:541-5. Decker DA, et al. Menopause. 2003;10: O'Meara ES, et al. J Natl Cancer Inst. 2001;93:

HT-Related Breakthrough Bleeding
2004 Patient Management HT-Related Breakthrough Bleeding All available continuous-combined E+P regimens are associated with breakthrough bleeding Less breakthrough bleeding with lower doses Definitions and indices used to report bleeding patterns vary Most postmenopausal women will experience amenorrhea within 1 year of initiating therapy Women who are postmenopausal >3 years may experience less bleeding than recently menopausal women Managing patient expectations about breakthrough bleeding is critical Continuous-combined regimens of E+P eliminate the cyclic bleeding that occurs with sequential regimens. But continuous regimens are associated with breakthrough bleeding, which can be perceived by women as bothersome. Almost all such regimens are associated with breakthrough bleeding; many, although not all, women will experience this phenomenon within the initial months of therapy.1-4 Most women will achieve amenorrhea from continuous-combined regimens within 1 year of starting E+P. Unless a women is clearly aware of this statistic, however, the unpredictability and inconvenience of breakthrough bleeding may result in early discontinuation. Women who are more than 3 years postmenopausal may experience less bleeding, but this does not suggest that delaying therapy until this time is warranted. Rather, it emphasizes the critical importance of counseling in the early menopausal stage. Early postmenopausal women who cannot tolerate irregular breakthrough bleeding may benefit from cyclic E+P, a regimen that provides predictable withdrawal bleeding. If a newly menopausal woman desires amenorrhea, she can be switched to continuous E+P after 1 year. Archer DF, Pickar JH. Climacteric. 2002;5:45-69; Archer DF, et al. Fertil Steril. 2001;75:1080-7; Archer DF, Pickar JH. Obstet Gynecol. 2000;96: ; Lerner S. Menopause. 1995;2: 1Archer DF, Pickar JH. Climacteric. 2002;5:45-59. 2Archer DF, et al. Fertil Steril. 2001;75: 3Archer DF, Pickar JH. Obstet Gynecol. 2000;96: 4Lerner S. Menopause. 1995;2:

Cumulative Amenorrhea Rates: CEE/MPA for EE Population (n = 1555)
2004 Patient Management Women's HOPE Study Cumulative Amenorrhea Rates: CEE/MPA for EE Population (n = 1555) 72.8 51.8 46.2 0.45/2.5 0.625/2.5 0.45/1.5 0.3/1.5 Placebo 41.8 27.9 In the Women’s HOPE study, the rates of cumulative amenorrhea and cumulative no bleeding were analyzed in efficacy-evaluable and intent-to-treat populations. Results from the CEE/MPA groups and the placebo group in the efficacy-evaluable population are shown on this slide. The efficacy-evaluable population included patients who recorded taking study medication and completed 13 cycles, completed all thirteen 28-day diary cards without missing any bleeding data, and did not miss ≥3 consecutive days or ≥5 discontinuous days of taking or recording study medication during any treatment cycle. Episodes of vaginal bleeding or spotting were recorded in the patients’ daily diary cards. The following definitions were used to characterize bleeding episodes in the study. Bleeding: vaginal bleeding requiring sanitary protection Spotting: vaginal bleeding not requiring sanitary protection No bleeding: absence of vaginal bleeding with or without spotting Amenorrhea: absence of vaginal bleeding or spotting Bleeding data were analyzed in a cumulative fashion and by individual cycles. In the cumulative analysis, cumulative amenorrhea was defined as the percentage of patients experiencing consecutive cycles of amenorrhea through cycle 13. Throughout the course of the study, the rates for cumulative amenorrhea were greater in the lower-dose CEE/MPA groups than in the CEE 0.625/MPA 2.5 group. The difference between these groups was most apparent during the earlier cycles. Women in all of the CEE/MPA groups exhibited significantly lower rates of cumulative amenorrhea than those taking placebo (P < .05) for each cycle range analyzed. EE = Efficacy-evaluable population included women who recorded taking study medication and completed all 13 cycles without missing data on bleeding. Archer DF, et al. Fertil Steril. 2001;75: Archer DA, et al. Fertil Steril. 2001;75:

Patient Concerns Regarding Weight and HT
2004 Patient Management Patient Concerns Regarding Weight and HT Changes Commonly Observed at Menopause Weight gain Increased central adiposity HT Is Associated With Lower body weight and BMI compared with nonusers Less visceral adipose tissue Similar weight increase to that observed with placebo Many patients cite weight gain as a reason for discontinuing HT.1 Weight gain and increased central adiposity are common during the decade following the menopause.2 Although reports from cross-sectional comparisons and randomized prospective clinical trials indicate that HT does not have a negative impact on weight, a widespread belief remains that HT may cause weight gain.2 In reality, several studies have demonstrated that HT users are more likely to weigh less, have lower body mass indices, and have less visceral adipose tissue than nonusers.3,4 Espeland MA, et al. J Clin Endocrinol Metab. 1997;82: ; Matthews KA, et al. Int J Obes Relat Metab Disord ;25:863-73; Sites CK, et al. Metabolism. 2001;50: 1Goldman GA, et al. Clin Exp Obstet Gynecol. 1998;25:18-9. 2Espeland MA, et al. J Clin Endocrinol Metab. 1997;82: 3Matthews KA, et al. Int J Obes. 2001;25: 4Sites CK, et al. Metabolism. 2001;50:

Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial
2004 Patient Management Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial Body Weight Changes After 3 Years of Treatment * Weight Change (kg) The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial was a 3-year, placebo-controlled, randomized, clinical trial of 875 women. Although it was designed to assess the cardiovascular effects of one E-only and three E+P regimens, it also gathered data on weight changes. Women treated with CEE, with or without MPA, gained an average of 1.3 kg less weight (P = .006) at the end of 3 years in comparison with placebo-treated women. All of the treatment regimens resulted in significantly less weight gain compared with placebo. CEE 0.625 mg CEE/MPA (con) 0.625 mg/2.5 mg CEE/MPA (cyc) 0.625 mg/10 mg CEE/MP (cyc) 0.625 mg/200 µg Placebo *P = .006 vs all active therapy groups; no differences were observed between E-only and E+P groups. Con = continuous regimen; cyc = cyclic regimen (progestin first 12 days of each cycle). Espeland MA, et al. J Clin Endocrinol Metab. 1997;82: Espeland MA, et al. J Clin Endocrinol Metab. 1997;82:

Mean Change in Weight After 13 Cycles Mean Change From Baseline (kg)
2004 Patient Management Women's HOPE Study Mean Change in Weight After 13 Cycles Mean Change From Baseline (kg) CEE CEE/MPA Placebo n = 218 0.625 mg n = 212 0.45 mg n = 231 0.3 mg n = 235 0.625/2.5 n = 241 0.45/2.5 n = 232 0.45/1.5 n = 228 While many patients express concern that HT use causes weight gain,1,2 the results of randomized clinical trials, such as the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial,3 and a recent meta-analysis4 indicate that changes in weight with HT are generally no different from those observed with placebo. The Women’s HOPE study confirmed these findings, reporting no significant effects on body weight compared to placebo with the use of any CEE or CEE/MPA regimen.5 In fact, there was significantly more weight gain with placebo compared to low dose CEE 0.45/MPA 1.5 after 1 year of therapy. 0.3/1.5 n = 213 Treatment Groups Utian WH, Pickar JH. Obstet Gynecol. 2002;99(suppl):57S. 1Nachtigall LE. Obstet Gynecol. 1990;75:77S-83S. 2Goldman GA, et al. Clin Exp Obstet Gynecol. 1998;25: Espeland MA, et al. J Clin Endocrinol Metab. 1997;82: Norman RJ, et al. Cochrane Lib. 2002;1: Utian WH, et al. Obstet Gynecol. 2002;99 (suppl):57S.

Section 3: Importance of Individualizing HT
2004 Patient Management Patient Management Issues in Menopause Section 3: Importance of Individualizing HT

Individualizing Patient Management With HT
Type of estrogen/progestin Dose of estrogen/progestin Type of regimen (cyclic vs continuous) Metabolic profiles of hormone combinations Flexibility of treatment Experience with therapy Patient satisfaction with therapy There are a variety of factors to consider when administering HT. For example, the type of estrogen and progestin, the type of HT regimen, and the dose of HT may all affect patient adherence. Metabolic factors may also be important in choosing an HT regimen. Since each estrogen/progestin combination has a unique lipid profile, health care practitioners may also want to consider the metabolic profiles of available HT formulations when initiating HT in a particular patient. Health care practitioners may also prefer to administer therapies available in a variety of different doses and regimens, making it easier to tailor therapy to an individual patient. Their experience with a particular therapy and their patients’ satisfaction with that therapy should also be considered.

Section 3a: Characteristics of Estrogens
2004 Patient Management Patient Management Issues in Menopause Section 3a: Characteristics of Estrogens

Classifications of Estrogens: Natural Versus Synthetic
2004 Patient Management Classifications of Estrogens: Natural Versus Synthetic Steroids Natural Found in Nature Synthetic Laboratory Synthesized Ethinyl estradiol (EE) Diethylstilbestrol Natural Source No chemical modifications CEE Native  Synthetic Chemically synthesized from a natural material such as soy, Mexican yam 17b-estradiol (E2) Estrone Estrone sulfate Synthetic conjugated estrogens Esterified estrogens Estriol There are many estrogens available today. These compounds can generally be classified as natural, native/synthetic, or synthetic. Natural estrogens, such as CEE, can be formulated as a drug with minimal processing and no chemical modification. Native/synthetic estrogens, such as 17-estradiol, exist in nature but must be synthesized from compounds present in plants. Synthesizing 17-estradiol and other steroid hormones from the Mexican yam or the soy bean requires several chemical steps. Although the steroid hormones synthesized from these plants are chemically the same as those produced by the human body, there is no scientific evidence to date that indicates that consumption (either ingestion or as topical creams) of the Mexican yam, sweet yam, or soy bean leads to the formation of 17-estradiol, estrone, or other steroids in the human body. The human body lacks the necessary enzymes to convert plant sterols into active steroid hormones. Finally, synthetic steroids are produced by chemists and are not found in nature. Many patients believe that native/synthetic estrogens are safer and are equally or more effective than standard estrogens; however, estrogen receptors (ERs) cannot distinguish between chemically identical estrogens from different sources. Moreover, few studies have compared the safety and efficacy of natural, native/synthetic, and synthetic estrogens.

Section 3b: Characteristics of Progestins
2004 Patient Management Patient Management Issues in Menopause Section 3b: Characteristics of Progestins

Classification of Progestins
2004 Patient Management Classification of Progestins Steroids Natural Found in Nature Synthetic Laboratory Synthesized Native  Synthetic Progesterone Structurally Related to Progesterone Structurally Related to Testosterone Pregnane Derivatives MPA Megestrol acetate Cyproterone acetate Chlormadinone acetate Medrogestone Dydrogesterone 19-Norpregnane Derivatives Nomegestrol acetate Demegestone Trimegestone Promegestone Nesterone Ethinylated Norethindrone Norethynodrel Lynestrenol Norethindrone acetate (NETA) Tibolone Ethynodiol acetate Levonorgestrel Desogestrel Norgestimate Gestodene Nonethinylated Dienogest Drospirenone Progestins can be divided into two types: natural and synthetic. However, the only natural progestin is progesterone, which can be found in humans and certain animals, but not in plants. Synthetic progestins are defined as progestins that are synthesized chemically. Synthesized progestins can be categorized into two groups: those that are structurally related to progesterone, and those that are structurally related to testosterone. This classification scheme does not imply the source of the steroid precursor. Progestins that are structurally related to progesterone can be subdivided into those with (pregnane derivatives) and without (19-norpregnane derivatives) a methyl group at carbon 10. Pregnane derivatives include MPA and megestrol acetate, while 19-norpregnane derivatives include trimegestone and demegestone. Both pregnane derivatives and 19-norpregnane derivatives can also be classified as to whether they are acetylated or nonacetylated. All pregnane-derived progestins are acetylated except dydrogesterone, and all 19-norpregnane derivatives are nonacetylated besides nomegestrol acetate. Progestins structurally related to testosterone are either ethinylated (those that contain an ethinyl group at carbon 17) or nonethinylated. Ethinylated progestins include norethindrone acetate and levonorgestrel. Dienogest and drospirenone are the only nonethinylated progestins. Ethinylated progestins can be further divided into those that have an estrane structure, such as norethindrone and tibolone, and those with a 13-ethylgonane structure, such as norgestimate. Stanczyk FZ. Rev Endocr Metab Disord. 2002;3: Stanczyck FZ. Rev Endocr Metab Disord. 2002;3:

Metabolic Effects of Oral E+P Regimens
2004 Patient Management Metabolic Effects of Oral E+P Regimens Percent Change From Baseline After 12 Months of Therapy* Regimen† Total Cholesterol LDL-C HDL-C Triglycerides CEE/MPA 0.625/2.5 –2.2 –9.3 11.2 32.8 CEE/MPA 0.45/1.5 –2.6 –6.7 9.7 24.8 EE/NETA 0.05/1 –7.0 –7.5 12.1 E2/NETA 1/0.5 –10.5 –10.8 –12.4 2.2 E2/Norgestimate 1/0.09 –1.9 1.2 9.4 Because progestins in oral contraceptives (OCs) and HT are used for different purposes (ie, to suppress ovulation versus to protect the endometrium during hormone use), the preferable characteristics of a progestin used in an OC may be different than those for progestins used in HT.1,2 Progestins with low androgenicity are preferred because progestins that exhibit androgenic activity may have significant adverse metabolic effects. Although progestins with minimal androgenic effects are preferable, hormone replacement with an androgen may have a role in treating a select, adequately estrogenized population of postmenopausal women experiencing sexual dysfunction. The metabolic effects of an E+P formulation depend on the type and dose of the estrogen and progestin, and the formulation’s route of administration. A summary of the metabolic effects of various oral E+P formulations is shown on this slide. (NOTE: These data are not from head-to-head clinical trials.) All forms of E+P reduce total cholesterol.1-4 With the exception of estradiol/norgestimate therapy, all forms of E+P also reduce low-density lipoprotein cholesterol (LDL-C).1-4 Unopposed oral estrogen therapy is associated with increased high-density lipoprotein cholesterol (HDL-C).1 Norethindrone acetate (NETA), an androgenic progestin, attenuates these benefits and leads to significant reductions in HDL-C levels.2,3 Combined therapy with MPA or norgestimate does not have these effects.1,4 All forms of oral E+P also increase triglycerides to varying degrees.1-4 *Data shown are from 4 different controlled clinical trials; †All doses are in mg/d. Lobo RA, et al. Fertil Steril. 2001;76:13-24; Activella™ (estradiol/norethindrone acetate tablets). Physician Package Insert; femhrt® (norethindrone acetate/ethinyl estradiol tablets). Product Information; Ortho-Prefest™ (estradiol/ norgestimate) tablets. U.S. draft labeling physician package insert. 1Lobo RA, et al. Fertil Steril. 2001;76:13-24. 2Activella™ (estradiol/norethindrone acetate tablets). Princeton, NJ: Kalamazoo, MI: Pharmacia & Upjohn 3femhrt® (norethindrone acetate/ethinyl estradiol tablets). Cincinnati, OH: Parke-Davis 4Ortho-Prefest™ (estradiol/norgestimate) tablets. Raritan, NJ: Ortho-McNeil Pharmaceutical. 1999:1-14.

Endometrial Response to Sequential Versus Continuous E+P
2004 Patient Management Endometrial Response to Sequential Versus Continuous E+P Open-label, prospective study, 1312 women taking sequential E+P (with 10 days of progestin) and 921 not using any HT were given continuous E+P for 9 months At baseline, sequential E+P was associated with complex hyperplasia (5.3%) and atypical hyperplasia (0.7%) Continuous-combined E+P Was not associated with an increased risk of hyperplasia Converted the endometrium to normal in those with complex hyperplasia arising during sequential E+P Sequential therapy was associated with a higher risk of endometrial hyperplasia than continuous therapy In an open-label prospective study conducted in the UK, Sturdee and colleagues enrolled 1312 women (mean age, 53 years) who were using, at baseline, sequential E+P with at least 10 days of progestin per cycle. The most commonly used regimen included 12 days of progestin per cycle. The study also enrolled 921 women (mean age, 54 years) who were not using any HT at baseline. Both groups of women were given continuous 2 mg 17-estradiol and 1 mg norethisterone acetate for 9 months. At baseline, complex endometrial hyperplasia was observed in 59 women (5.3%) initially receiving sequential E+P. Atypical hyperplasia was seen in 8 women (0.7%) receiving sequential E+P. After 9 months, no cases of hyperplasia were observed in the 1196 biopsies of women who completed the study, including in 38 of the 59 women with complex hyperplasia at baseline who completed the study. Therefore, continuous E+P converted the endometrium to normal in women with hyperplasia who had been using sequential E+P. In the women who did not complete the study (n = 21), the hyperplasia reverted to normal in 12 women and persisted in 4. Of these 4, one never took continuous E+P, and the other 3 received it for 3 months or less. Of the remaining 5 women, 1 was not treated with continuous E+P and had no final biopsy, 1 was lost to follow-up, and 3 refused a final biopsy. Sturdee DW, et al. Br J Obstet Gynaecol. 2000;107: Sturdee DW, et al. Br J Obstet Gynaecol. 2000;107:

Endometrial Effects After 3 Years of HT
2004 Patient Management PEPI Trial Endometrial Effects After 3 Years of HT 74 (62%) 6 (5%) 6 (5%) 3 (2.5%) 1 (<1%) Placebo CEE CEE/MPA (con) CEE/MPA (cyc) CEE/MP (cyc) 0.625 mg mg/2.5 mg mg/10 mg mg/200 µg n = As part of the PEPI trial, 875 postmenopausal women were randomly assigned in nearly equal numbers to the following groups: placebo; CEE (0.625 mg/d for all groups); CEE plus continuous MPA 2.5 mg/d; CEE plus MPA 10 mg/d for 12 d/mo; or CEE plus MP 200 mg/d for 12 d/mo. In the 596 women with a uterus (intent-to-treat analysis), thirteen cases of endometrial hyperplasia were distributed among the three CEE + progestin groups, with no differences observed between the three treatments. There was no significant difference in the occurrence of abnormal biopsy specimens between the women who received placebo and those who received any of the CEE + progestin regimens. Histologic findings from the 527 women who underwent endometrial biopsies suggest that continuous or cyclic progestin regimens “provide long-term endometrial protection of postmenopausal women with a uterus.” *Positive biopsies include simple hyperplasia, complex hyperplasia, atypia, or adenocarcinoma. con = continuous regimen; cyc = cyclic regimen (CEE daily, progestin first 12 days of each cycle). The Writing Group for the PEPI Trial. JAMA. 1996;275:370-5. The Writing Group for the PEPI Trial. JAMA. 1996;275:370-5.

Patient Management Issues in Menopause Section 3c: Use of Low-Dose HT

Trend Toward Lower Doses
2004 Patient Management Trend Toward Lower Doses Accumulating evidence suggests that lower E+P doses may provide similar benefits with reduced side effects Current guidelines from the FDA, ACOG, NAMS, and SOGC recommend the use of the lowest effective doses of E+P Grimes DA, Lobo RA. Obstet Gynecol. 2002;100: American College of Obstetricians and Gynecologists. ACOG News Release. Available at: from_home/publications/press_releases/nr cfm. Accessed 12/18/02. North American Menopause Society. Amended Report from the NAMS Advisory Panel on Postmenopausal Hormone Therapy. Available at: Accessed 12/18/02. Society of Obstetricians and Gynaecologists of Canada (SOGC). Can Fam Physician. 2004;49: Lower doses of estrogen and progestin in postmenopausal HT are attracting increased clinical interest. Evidence is accumulating that lower estrogen and progestin doses may provide benefits similar to those of the more commonly prescribed doses with reduced side effects. The FDA and the clinical guidelines developed by numerous organizations, including NAMS, ACOG, and the Society of Obstetricians and Gynaecologists of Canada, recommend prescribing estrogen at the lowest effective dose. Grimes DA, Lobo RA. Obstet Gynecol. 2002;100: North American Menopause Society. Available at: Accessed December 18, 2002. American College of Obstetricians and Gynecologists. Available at: press_releases/nr cfm. Accessed December 18, 2002. Society of Obstetricians and Gynaecologists of Canada. Can Fam Physician. 2004;49:

Low- and Standard-Dose HT Preparations Available in the US
2004 Patient Management Low- and Standard-Dose HT Preparations Available in the US Oral (mg) Transdermal (mg) Low-dose estrogen CEE 0.45 CEE 0.30 Esterified estrogens 0.30 E2 0.50 E E Standard-dose estrogen CEE Esterified estrogens Estropipate E2 1.0 E2 0.05 Low-dose estrogen + low-dose progestin CEE 0.45/MPA 1.5 CEE 0.30/MPA 1.5 Standard-dose estrogen + standard-dose or low-dose progestin CEE 0.625/MPA 2.5 CEE 0.625/MPA 5.0* E2 1.0/NETA 0.5 E2 1.0/norgestimate 0.09† EE 0.005/NETA 1.0 E2 0.05/NETA 0.25 E2 0.05/NETA 0.25 A number of E-only and E+P formulations are currently available in the US, including several low-dose estrogen preparations and two low-dose estrogen with low-dose progestin combinations. Preparations considered “lower-dose” estrogen formulations include doses of CEE or esterified estrogens less than mg/d, doses of E2 less than 1.0 mg/d, or doses of transdermal E2 less than 0.05 mg/d. Recent clinical trials have evaluated the efficacy and safety of these lower-dose regimens. The results of several of these studies will be presented in this section of the slide library. *MPA 5.0 mg is used continuously or sequentially with CEE mg; †Norgestimate is used intermittently with E2 1.0 mg.

Effect of Low Doses of Transdermal Estrogen on Vasomotor Symptoms
2004 Patient Management Effect of Low Doses of Transdermal Estrogen on Vasomotor Symptoms Placebo-TS 2 Placebo-TSs E2-TS (0.02 mg/day)* 2 E2-TSs (0.04 mg/day)† Mean Hot Flush Frequency (number per week) *P < .05 at weeks 2-11. †P < .05 at week 2; P < .01 at weeks 3-12. n = 324. TS = transdermal system; E2-TS = estradiol 0.02 mg/day provided in one or two 7-day transdermal delivery systems. Speroff L, et al. Obstet Gynecol. 1996;88: This slide shows the results of 2 independent, 12-week, randomized, double-blind, placebo-controlled studies on the effects of two lower doses of transdermal E2 (0.02 mg/d and 0.04 mg/d).1 These studies included 324 hysterectomized women (mean age, 49 years) with moderate-to-severe vasomotor symptoms (56 to 140 hot flushes per week). Mean hot flush frequency decreased by 84% after 12 weeks of treatment. The decrease in hot flush frequency was significant as early as weeks 2 and 3 compared with placebo. This reduction in vasomotor symptoms is similar to that achieved with transdermal E2 at doses of 0.05 mg/d.2 1Speroff L, et al. Obstet Gynecol. 1996;88: 2Climara® (estradiol transdermal system). Prescribing information. Wayne, NJ: Berlex Laboratories; 2001.

Effect of Various Transdermal Estrogen Doses on Spinal BMD
2004 Patient Management Effect of Various Transdermal Estrogen Doses on Spinal BMD E2 0.1 mg/day E mg/day E mg/day E mg/day Placebo * * * * * * * * * * * * * * * In this placebo-controlled, parallel-group study, 261 surgically or naturally menopausal women were randomized to transdermal E2 at one of 4 doses (0.1 mg/d, 0.05 mg/d, mg/d, and mg/d) or placebo. The evaluable group (n = 259) had a mean age of 52 years and had been menopausal for a mean of 32 months. After 2 years of treatment, there were significant differences between all active treatments and placebo at the lumbar spine. The mean changes from baseline were 6.2% for E2 0.1 mg/d, 2.7% for 0.05 mg/d, 1.0% for mg/d, and 1.3% for mg/d. All E2 doses were also associated with significantly greater changes in bone mineral density (BMD) at the femoral neck compared with placebo. *P < .05 vs placebo. 261 women (mean age, 52 years; mean time since menopause, 32 months) were randomized. Nonhysterectomized women (n = 100) received MPA 2.5 mg/day. McKeever C, et al. Clin Ther. 2000;22: McKeever C, et al. Clin Ther. 2000;22:

2004 Patient Management The Women’s Health, Osteoporosis, Progestin, Estrogen (Women’s HOPE) Study The Women’s Health, Osteoporosis, Progestin, and Estrogen (Women’s HOPE) study is the largest trial to date that investigated lower-dose postmenopausal hormone therapy (HT). This study compared the effects of the standard CEE dose (0.625 mg/d) with those of a three-quarter dose (0.45 mg/d) and a half-dose of CEE (0.3 mg/d), with and without medroxyprogesterone acetate (MPA). Two of the combined regimens used a lower-than-standard dose of MPA (1.5 mg/d). Utian WH, et al. Fertil Steril. 2001;75:

Women's HOPE Study Design
2004 Patient Management Women's HOPE Study Design Methodology: prospective, randomized, double-blind, placebo-controlled, multicenter trial Purpose: Investigate efficacy and safety of lower doses of CEE and CEE/MPA Patients: 2673 healthy, postmenopausal women (40–65 years of age) with an intact uterus Outcomes: vasomotor symptoms, vaginal atrophy, bleeding profile, endometrial hyperplasia, metabolic profile, and bone mineral density The Women’s HOPE study was a prospective, randomized, double-blind, placebo-controlled, multicenter trial designed to investigate the efficacy and safety of lower doses of CEE and CEE/MPA. To be included in the study, women had to be generally healthy, be between 40 and 65 years of age, have an intact uterus, and be within 20% of their ideal body weight. They also were required to have experienced their last menses at least 1 year before enrollment. Outcomes included the impact of various doses of CEE and CEE/MPA on endometrial safety, vasomotor symptoms, vaginal atrophy, metabolic profiles, bleeding profiles, and BMD. Utian WH, et al. Fertil Steril. 2001;75: Utian WH, et al. Fertil Steril. 2001;75:

Women's HOPE Study 8 Treatment Groups CEE 0.625 mg
2004 Patient Management Women's HOPE Study 8 Treatment Groups CEE mg CEE mg + MPA 2.5 mg Placebo CEE 0.45 mg + MPA 2.5 mg CEE 0.45 mg CEE 0.45 mg + MPA 1.5 mg CEE 0.3 mg CEE 0.3 mg +MPA 1.5 mg After the prestudy screening, women were randomized to 1 of 8 treatment groups: CEE mg, CEE 0.45 mg, CEE 0.3 mg, CEE mg/MPA 2.5 mg, CEE 0.45 mg/MPA 2.5 mg, CEE 0.45 mg/MPA 1.5 mg, CEE 0.3 mg/MPA 1.5 mg, or placebo. Patients were instructed to take 2 tablets (CEE or matching placebo or CEE/MPA or matching placebo) orally once daily in a double-blind, double-dummy fashion. Patients also were instructed to take a daily calcium carbonate supplement (600 mg/d). A double-blind, double-dummy design was used to administer study medication. All groups received a calcium carbonate supplement (600 mg elemental calcium/day). Utian WH, et al. Fertil Steril. 2001;75: Utian WH, et al. Fertil Steril. 2001;75:

Demographic and Baseline Characteristics
2004 Patient Management Women's HOPE Study Demographic and Baseline Characteristics Total (n = 2673) Mean ± SD Age (years) Age at menopause (years) Years since menopause Weight (kg) BMI (kg/m2) 53.3 ± 4.9 48.5 ± 4.3 4.7 ± 4.2 65.5 ± 8.7 24.4 ± 2.8 The characteristics of the women who were evaluated for safety and efficacy in the Women’s HOPE Study are shown in this slide. There were no significant differences between treatment groups in any of the baseline characteristics. On average, participants were 53 years old, had experienced menopause at age 49 years, weighed 65.5 kg, and had a body mass index of 24 kg/m2. Most participants were Caucasian (88%); however, 6% were African American, 4% were Hispanic, and 2% were Asian. Less than 1% were Native American, Arabic, or “other.” No significant differences between 8 treatment groups were observed. Women were 88% Caucasian, 6% African American, 4% Hispanic, 2% Asian, and <1% Native American, Arabic, or “other.” Utian WH, et al. Fertil Steril. 2001;75: Utian WH, et al. Fertil Steril. 2001;75:

Change in Number of Hot Flushes Over 12 Weeks (n = 241)
2004 Patient Management Women's HOPE Study Change in Number of Hot Flushes Over 12 Weeks (n = 241) 0.625 0.45 0.3 Placebo 0.45/2.5 0.625/2.5 0.45/1.5 0.3/1.5 Placebo In the Women’s HOPE study, hot flushes were analyzed in women who reported at least 7 moderate-to-severe hot flushes on each of the last 7 days of baseline screening or at least 50 total hot flushes during the last 7 days of baseline screening. Participants recorded the number and severity of hot flushes on daily diary cards throughout the screening and study periods. This graph depicts mean number of hot flushes over a 12-week period for women given unopposed CEE (0.625, 0.45, or 0.3 mg/d), CEE with MPA (0.625/2.5, 0.45/2.5, 0.45/1.5, or 0.3/1.5 mg/d), or placebo. Data for unopposed CEE groups are shown on the left, and CEE/MPA data are shown on the right. Within one week of initiating therapy, all treatment groups (including placebo) experienced a significant reduction in number of hot flushes compared with baseline, except for the CEE 0.3/MPA 1.5 group, which decreased from baseline (P < .001) by the end of the second week. By the third week, all CEE and CEE/MPA treatment groups exhibited a significant (P < .001) reduction in mean daily number of hot flushes compared with the placebo group. These differences were maintained throughout the 1-year trial. Thus, all of the doses of CEE alone or CEE/MPA examined in this study provided significant symptom relief within the first few weeks of use. The reduction in number of hot flushes was comparable in all CEE/MPA groups. The results also suggest that the addition of MPA to lower doses of CEE may enhance the relief of vasomotor symptoms seen with CEE alone. *Adjusted for baseline. Mean hot flushes at baseline = 12.3 (range 11.3–13.8). Analyses included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/week or at least 50 flushes per week at baseline. Utian WH, et al. Fertil Steril. 2001;75: Used with permission. Utian WH, et al. Fertil Steril. 2001;75:

Changes in Severity of Hot Flushes Over 12 Weeks (n = 241)
2004 Patient Management Women's HOPE Study Changes in Severity of Hot Flushes Over 12 Weeks (n = 241) 0.45/1.5 0.625/2.5 Placebo 0.45/2.5 0.3/1.5 Placebo 0.625 0.45 0.3 Patients also reported the severity of their vasomotor symptoms by rating each hot flush as mild (1 point), moderate (2 points), or severe (3 points) and recording the hot flush score on their daily diary cards. Mild hot flushes were defined as a fleeting warm sensation without sweating that did not disrupt activity. Moderate hot flushes were defined as warm sensations with sweating that did not disrupt activity, and severe hot flushes were defined as hot sensations with sweating that did disrupt activity. Daily hot flush severity scores were calculated using the following equation: [(# of mild flushes  1) + (# of moderate hot flushes  2) + (# of severe hot flushes  3)] ÷ total of # hot flushes on that day. Treatment with all active study regimens resulted in significant decreases from baseline (P < .001) by the second week of treatment. Significant differences from baseline were observed in the placebo group by week 3 (P < .05). By the third week of treatment, all CEE and CEE/MPA groups reported significantly lower mean daily severity of hot flushes compared with placebo (P < .05). The benefits of CEE and CEE/MPA in reducing hot flush severity were maintained throughout the course of the study. Hot flush severity: 1 = mild, 2 = moderate, 3 = severe. Mean hot flush severity at baseline = 2.3 (range 2.2–2.4). EE = Efficacy-evaluable population included women who recorded taking study medication and had at least 7 moderate-to-severe flushes/week or at least 50 flushes per week at baseline. Utian WH, et al. Fertil Steril. 2001;75: Used with permission. Utian WH, et al. Fertil Steril. 2001;75:

Superficial Cells (%), Median Change from Baseline
2004 Patient Management Women's HOPE Study Improvement in Vaginal Maturation Index Compared With Baseline and Placebo* † Superficial Cells (%), Median Change from Baseline † † Median Change = 0 CEE CEE/MPA Placebo 0.625 mg 0.45 mg 0.3 mg 0.625/ 2.5 mg 0.45/ 2.5 mg 0.45/ 1.5 mg 0.3/ 1.5 mg Lower doses of CEE alone and CEE/MPA were also effective in improving vaginal cytology in postmenopausal women. In the Women’s HOPE Study, vaginal atrophy was assessed by vaginal maturation index (VMI), or the proportion of vaginal superficial cells relative to the number of parabasal and intermediate cells in a lateral vaginal wall smear.* The percentage of superficial cells was increased significantly from baseline at cycles 6 and 13 in all CEE and CEE/MPA groups (P < .001), but not in placebo. Changes from baseline were significantly greater in all active treatment groups compared with placebo (P < .05). Significant differences were also observed between CEE and CEE 0.625/MPA 2.5 (P < .05), CEE 0.45 group (P < .05), and CEE 0.3 (P < .001). No differences in median changes in VMI were detected between the CEE 0.45 and the CEE 0.45/MPA 2.5 or CEE 0.45/MPA 1.5 groups, or between the CEE 0.3 and CEE 0.3/MPA 1.5 groups. The values for the median change from baseline in VMI were similar in the CEE 0.625/MPA 2.5 and CEE 0.45/MPA 1.5 groups. *Reported using the revised Bethesda System (National Cancer Institute Workshop. Acta Cytol. 1992;36: ). Treatment Groups *P < .05 vs baseline and placebo for all active treatment groups at all time points; †P < .05 vs CEE 0.625 Utian WH, et al. Fertil Steril. 2001;75: Utian WH, et al. Fertil Steril. 2001;75:

Cumulative Amenorrhea Rates: CEE/MPA for EE Population (n = 1555)
2004 Patient Management Women's HOPE Study Cumulative Amenorrhea Rates: CEE/MPA for EE Population (n = 1555) 72.8 51.8 46.2 0.45/2.5 0.625/2.5 0.45/1.5 0.3/1.5 Placebo 41.8 27.9 In the Women’s HOPE study, the rates of cumulative amenorrhea and cumulative no bleeding were analyzed in efficacy-evaluable and intent-to-treat populations. As noted previously in this slide library (see also slide #35), the efficacy-evaluable population included patients who recorded taking study medication and completed 13 cycles, completed all thirteen 28-day diary cards without missing any bleeding data, and did not miss ≥3 consecutive days or ≥5 discontinuous days of taking or recording study medication during any treatment cycle. The following definitions were used to record episodes of vaginal bleeding or spotting in the patients’ daily diary cards: Bleeding: vaginal bleeding requiring sanitary protection Spotting: vaginal bleeding not requiring sanitary protection No bleeding: absence of vaginal bleeding with or without spotting Amenorrhea: absence of vaginal bleeding or spotting As shown in this slide, the rates for cumulative amenorrhea were greater in the lower-dose CEE/MPA groups than in the CEE 0.625/MPA 2.5 group. The difference between these groups was most apparent during the earlier cycles. Women in all of the CEE/MPA groups exhibited significantly lower rates of cumulative amenorrhea than those taking placebo (P < .05) for each cycle range analyzed. EE = Efficacy-evaluable population included women who recorded taking study medication and completed all 13 cycles without missing data on bleeding. Archer DF, et al. Fertil Steril. 2001;75: Archer DA, et al. Fertil Steril. 2001;75:

Cumulative No Bleeding Rates: CEE/MPA for EE Population (n = 1555)
2004 Patient Management Women's HOPE Study Cumulative No Bleeding Rates: CEE/MPA for EE Population (n = 1555) 98.8 94.5 93.8 91.8 86.3 89.6 69.8 66.7 64.9 53.9 0.45/2.5 0.625/2.5 0.45/1.5 0.3/1.5 Placebo This slide shows cumulative no-bleeding rates for patients in the CEE/MPA or placebo groups in the efficacy-evaluable population. Cumulative no bleeding was defined as the percentage of patients who experienced consecutive cycles of no bleeding (absence of vaginal bleeding with or without spotting). Rates of cumulative no bleeding were qualitatively similar to those for cumulative amenorrhea, but the percentage of patients with cumulative no bleeding was higher than the percentage of patients with cumulative amenorrhea. In general, cumulative no-bleeding rates in the CEE/MPA groups increased with decreasing doses of CEE. The rates were significantly higher in the lower-dose CEE/MPA groups than in the CEE 0.625/MPA 2.5 group for cycles 1-13 (P < .05). EE = Efficacy-evaluable population included women who recorded taking study medication and completed all 13 cycles without missing data on bleeding. Archer DF, et al. Fertil Steril. 2001;75: Archer DA, et al. Fertil Steril. 2001;75:

Mean Percent Change From Baseline
2004 Patient Management Women's HOPE Study LDL Cholesterol * Cycle 6 Cycle 13 Mean Percent Change From Baseline † *† *† *† *† *† *† *† *† *† *† *† *† *† Treatment Groups 0.625 mg 0.625/ 2.5 mg 0.45 mg 0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg 0.3/ 1.5 mg Placebo CEE CEE/MPA The Women’s HOPE study also evaluated the effects of lower doses of CEE and CEE/MPA on the lipid profile. This slide shows the mean changes from baseline in low-density lipoprotein (LDL) cholesterol associated with each treatment at cycle 6 and cycle 13. LDL cholesterol was significantly reduced (P < .02) compared with baseline and with placebo (P < .05) in all of the active treatment groups, with the exception of the CEE 0.3/MPA 1.5 group (vs baseline) at cycle 13. The addition of MPA to CEE did not affect the changes seen with CEE alone. *P < .05 vs baseline. †P < .05 vs placebo. Lobo RA, et al. Fertil Steril. 2001;76:13-24. Lobo RA, et al. Fertil Steril. 2001;76:13-24.

Mean Change From Baseline (%)
2004 Patient Management Women's HOPE Study HDL Cholesterol *† Cycle 6 Cycle 13 *† *† *† *† *† *† *† *†‡ Mean Change From Baseline (%) *†‡ *†‡ *‡ *‡ *‡ Treatment Groups 0.625 mg 0.625/ 2.5 mg 0.45 mg 0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg 0.3/ 1.5 mg Placebo CEE CEE/MPA The changes from baseline in high-density lipoprotein (HDL) cholesterol at cycle 6 and cycle 13 are shown above for each treatment group. HDL cholesterol increased (P < .001) from baseline at both time points for all of the active treatment groups. The increases in HDL cholesterol at cycle 13 were greater (P < .04) for all active treatment groups compared with placebo, with the exception of the CEE 0.3/MPA 1.5 group. With the exception of CEE 0.625/MPA 2.5 at cycle 13 and CEE 0.45/MPA 1.5 at cycle 6, the increases in HDL observed in the CEE/MPA groups were significantly lower (P < .05) than those in the corresponding CEE-only group. *P < .05 vs baseline. †P < .05 vs placebo. ‡P < .05 vs comparable CEE alone. Lobo RA, et al. Fertil Steril. 2001;76:13-24. Lobo RA, et al. Fertil Steril. 2001;76:13-24.

Mean Change From Baseline (%)
2004 Patient Management Women's HOPE Study Triglycerides *† *† Cycle 6 Cycle 13 *† *† *† *† *† *† * * * *‡ *‡ Mean Change From Baseline (%) * * Treatment Groups 0.625 mg 0.625/ 2.5 mg 0.45 mg 0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg 0.3/ 1.5 mg Placebo CEE CEE/MPA This slide shows the changes from baseline in triglycerides observed in each treatment group at cycle 6 and cycle 13. Triglycerides were increased compared to baseline for women in all treatment groups (except the placebo group at cycle 13 [P = .061]). Women taking CEE only (except for CEE 0.3 at cycle 13), CEE 0.625/MPA 2.5, and CEE 0.45/MPA2.5 at cycle 13 experienced greater increases in triglycerides compared with placebo,. The addition of MPA to CEE moderated the increase in triglycerides in the groups receiving lower CEE doses. *P < .05 vs baseline. †P < .05 vs placebo. ‡P < .05 vs comparable CEE alone. Lobo RA, et al. Fertil Steril. 2001;76:13-24. Lobo RA, et al. Fertil Steril. 2001;76:13-24.

Women's HOPE Study Changes in Spine BMD CEE CEE/MPA
2004 Patient Management Women's HOPE Study Changes in Spine BMD CEE CEE/MPA There is evidence that doses of HT lower than those most commonly prescribed may be effective in preventing bone loss in older women1; however, prior to the Women’s HOPE study, the effects of lower doses of HT in early postmenopausal women had not been well documented. The 2-year bone substudy of the Women’s HOPE study (n = 822) evaluated the skeletal effects of lower doses of CEE and CEE/MPA in postmenopausal women who were within 4 years of their last menstrual period.2 These graphs include data from the intent-to-treat population, which consisted of all women randomized to treatment who recorded taking at least 1 dose of the study drug and had at least 1 BMD measurement after baseline. After 2 years, women assigned to all of the active treatment groups had significant gains from baseline (P < .001) in spine BMD. These changes were statistically different from those in the placebo group (P < .001). In addition, adding 2.5 mg MPA to mg or 0.45 mg CEE significantly increased spine BMD relative to to the equivalent dose of CEE alone (P < .05). These data demonstrate that lower doses of CEE and CEE/MPA effectively prevent bone loss in the spine in early postmenopausal women. Intent-to-treat population only. Lindsay R, et al. JAMA. 2002;287: 1Recker RR, et al. Ann Intern Med. 1999;130: 2Lindsay R, et al. JAMA. 2002;287:

Changes in Total Hip BMD
2004 Patient Management Women's HOPE Study Changes in Total Hip BMD CEE CEE/MPA CEE and CEE/MPA also effectively prevent bone loss in the hip in early postmenopausal women. After 2 years, women assigned to all of the active treatment groups had significant gains from baseline in hip BMD (P < .05). These changes were statistically different from those in the placebo group (P < .001). There were no significant differences in hip BMD between CEE/MPA and the comparable dose of CEE alone at 24 months, nor were there differences among any of the groups taking CEE alone. Intent-to-treat population only. Lindsay R, et al. JAMA. 2002;287: Lindsay R, et al. JAMA. 2002;287:

Endometrial Hyperplasia Rates After 1 and 2 Years of Low-Dose E+P
2004 Patient Management Women's HOPE Study Endometrial Hyperplasia Rates After 1 and 2 Years of Low-Dose E+P Year 1 Year 2 Hyperplasia Rate (%) 0.00 0.00 0.00 0.00 0.00 0.00 Treatment Groups 0.625 mg 0.625/ 2.5 mg 0.45 mg 0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg 0.3/ 1.5 mg Placebo CEE CEE/MPA As part of the Women’s HOPE Study, the endometrial safety of 2 years of treatment with lower doses of continuous combined conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) was evaluated in 822 healthy postmenopausal women with intact uteri (mean age, 52 years) who were enrolled in this randomized, double-blind, placebo-controlled, multicenter study. Patients were randomly assigned to one of eight treatments: CEE 0.625, CEE 0.625/MPA 2.5, CEE 0.45, CEE 0.45/MPA 2.5, CEE 0.45/MPA 1.5, CEE 0.3, CEE 0.3/MPA 1.5 (all doses mg/day), or placebo for 2 years. Endometrial biopsies were evaluated at baseline and years 0.5, 1, 1.5, and 2 using a centralized protocol. As shown in the bar chart, no cases of endometrial hyperplasia were seen in the four CEE/MPA groups. For the CEE-alone groups, a dose-related increase in incidence from 3.17% (CEE 0.3 mg) to 27.27% (CEE mg) was seen at 2 years. The number of cases increased from year 1 to year 2, even in the low-dose CEE 0.3 group. Thus, 2 years of treatment with lower doses of CEE/MPA provided endometrial protection comparable to that seen with commonly prescribed doses. These results are especially relevant with recent guidance from the FDA to use the lowest effective dose of HT for the shortest duration needed to achieve treatment goals. Pickar JH, et al. Fertil Steril. 2003;80: Pickar JH, et al. Fertil Steril. 2003;80:

Endometrial Hyperplasia Rates With Lower Doses of NETA
2004 Patient Management Endometrial Hyperplasia Rates With Lower Doses of NETA Hyperplasia Rate After 12 Months (%) E2 1 mg E2 1 mg/NETA 0.1 mg E2 1 mg/NETA 0.25 mg E2 1 mg/NETA 0.5 mg The endometrial safety of lower doses of NETA has also been evaluated. In this double-blind, randomized, multicenter trial among 1,176 postmenopausal women evaluating the effects of continuous-combined therapy of 17-estradiol and 3 doses of NETA, each dose of NETA effectively prevented endometrial hyperplasia after 12 months. There were no significant differences among any of the combined treatment arms. When administered with a 1 mg dose of 17-estradiol, only 0.1 mg of NETA is needed to protect the endometrium. n = 1176. P < .001 for all continuous-combined groups vs unopposed E2. Kurman RJ, et al. Obstet Gynecol. 2000;96:373-9. Kurman RJ, et al. Obstet Gynecol. 2000;96:373-9.

Low-Dose HT: Conclusions
2004 Patient Management Low-Dose HT: Conclusions Research findings demonstrate that lower doses of estrogen and progestin Relieve vasomotor symptoms and prevent vaginal atrophy Are associated with a reduced incidence of endometrial bleeding, especially in the early months of therapy Provide effective endometrial protection Prevent early postmenopausal bone loss Lower-dose regimens provide clinicians and patients with expanded options for individualizing HT E alone at lower dosages for longer durations may be associated with increased rates of endometrial hyperplasia Recent studies, including the Women’s HOPE study, indicate that lower-than-standard doses of estrogen and progestin provide benefits that are comparable to those associated with the most commonly prescribed regimens. Lower doses of estrogen and progestin relieve vasomotor symptoms and vaginal atrophy, protect the endometrium, and prevent early postmenopausal bone loss. In addition, lower doses are associated with more favorable bleeding profiles compared to the most commonly prescribed doses. Greater awareness among clinicians and their patients about the potential for fewer side effects, less bleeding, and comparable efficacy with the use of lower doses of estrogen and progestin will benefit many postmenopausal women. Unopposed estrogen at lower dosages for longer durations may be associated with increased rates of endometrial hyperplasia.

Section 3d: Non-Oral HT Formulations
2004 Patient Management Patient Management Issues in Menopause Section 3d: Non-Oral HT Formulations

Non-Oral Estrogen and Progestin Formulations
2004 Patient Management Non-Oral Estrogen and Progestin Formulations Estrogen Estradiol ring Nasal estradiol Estradiol gel Vaginal estrogen Progestin Levonorgestrel IUD/IUS Vaginal progesterone gel Trimegestone Lotion Several non-oral formulations of estrogen and progestin are available for the relief of vasomotor and/or urogenital symptoms, and protection of the endometrium. Estrogen Estradiol ring1-4 Nasal estradiol5,6 Estradiol gel7 Vaginal estrogen Progestin8 Levonorgestrel IUD/IUS Vaginal progesterone gel Trimegestone Lotion Combination Estradiol/progesterone vaginal ring9 1Al-Azzawi F, et al. Climacteric. 2003;6: 2Buckler H, et al. BJOG. 2003;110:753-9. 3Speroff L. Obstet Gynecol. 2003;102: 4Farish E, et al. Climacteric. 2003;6: 5Ozsoy M, et al. Int J Gynaecol Obstet. 2002;79:143-6. 6Wattanakumtornkul S, et al. Menopause. 2003;10:88-98 7Archer DF, for the EstroGel Study Group. Menopause. 2003;10: 8Dickerson VM. Int J Fertil Womens Med. 2003;48: 9Hamada AL, et al. Gynecol Endocrinol. 2003;17:

Section 4: Non-HT Alternatives for Menopausal Symptoms
2004 Patient Management Patient Management Issues in Menopause Section 4: Non-HT Alternatives for Menopausal Symptoms

Non-HT Alternatives for Menopausal Health Issues
2004 Patient Management Non-HT Alternatives for Menopausal Health Issues Lifestyle modifications Menopausal complaints Non-prescription therapies Prescription therapies Osteoporosis therapies Lipid-lowering drugs Neurocognitive therapies Although HT is the most effective treatment for relieving vasomotor symptoms and the symptoms of vaginal atrophy, other therapeutic options have been suggested for symptom relief. In addition, a number of proven therapies are available for the management of common health issues in postmenopausal women. Medications such as bisphosphonates, selective estrogen receptor modulators (SERMs), and calcitonin are available for women at risk for osteoporosis or osteoporotic fracture. In addition, lipid-lowering drugs should be used in dyslipidemic patients. More and more women are turning to alternative therapies to control symptoms of menopause and other ailments; however, there is little evidence regarding the safety and efficacy of many such products.

Scope of Alternative Medicine Use in the US
2004 Patient Management Scope of Alternative Medicine Use in the US 19901 19972 20013 Adults surveyed 1539 2055 3764 Utilization prevalence (%) 33.8 42.1 49.7 Number of visits (millions) 427 629 — Covered by insurance (%) 36 42 The use of alternative therapies has increased dramatically in recent years. A 1990 survey revealed that of 1539 adults surveyed in the US, 33.8% used alternative treatments.1 A follow-up survey demonstrated that this figure had increased to 42.1% by 1997. A more recent survey conducted in 2001 by Michigan’s Behavioral Risk Factor Surveillance System found that almost half of Michigan’s residents had used at least one form of complementary or alternative medicine in the previous 12 months.2 In addition, there was a 47% increase in visits to practitioners of alternative therapies from 1990 to 1997, thereby exceeding total visits to all US primary care practitioners. 1Eisenberg DM, et al. JAMA. 1998;280: ; 2Rafferty AP, et al. Am J Public Health. 2002;92: Newton KM, et al. Obstet Gynecol. 2002;100:18-25. 1Eisenberg DM, et al. JAMA. 1998;280: 2Rafferty AP, et al. Am J Public Health. 2002;92:

2004 Patient Management Proportion of Women Using Alternative Therapies for Any Reason and for Menopausal Symptoms Herbal Remedies Chiropractic Massage Therapy Dietary Soy Products Acupuncture Homeopathic Physician Visit Herbalist Visit Relaxation or Stress Management Ever Used Using Now Used for Menopausal Symptoms A telephone survey of 886 women aged 45 to 65 years conducted in Washington State demonstrated that the use of alternative therapies for menopausal symptoms is common. Overall, 76% of women had used at least one form of alternative therapy, and 22% had used at least one form of alternative therapy specifically for menopausal symptoms. Relaxation and stress management, herbal remedies, and dietary soy products were the most commonly used alternative therapies for menopausal symptoms. n = 886 (ages 45 to 65 years). Reprinted from Newton KM, et al. Use of alternative therapies for menopause symptoms: results of a population-based survey. Obstet Gynecol. 2002;100:18-25, ©2002, with permission from the American College of Obstetricians and Gynecologists. Newton KM, et al. Obstet Gynecol. 2002;100:18-25.

Lifestyle Choices That Increase Breast Cancer Risk
2004 Patient Management Lifestyle Choices That Increase Breast Cancer Risk Lack of exercise1,2 Recreational exercise 1.25–2.5 hours per week of brisk walking, RR = 0.82 (95% CI, 0.68–0.97)1 4 hours per week, RR = 0.63 (95% CI, 0.42–0.95)2 Alcohol3 RR = 1.3 (95% CI, 1.0–1.5; ever-use of alcohol over the past 20 years) Obesity4,5 RR = 1.99 for never-users of HT who gained >20 kg (95% CI, 1.43–2.76)4 RR = 2.52 for BMI >31.1 kg/m2 (95% CI, 1.62–3.93)5 Cigarette smoking6 HR = 1.32 (95% CI, 1.10–1.57; relative to all never smokers) A number of lifestyle factors, including physical activity, alcohol consumption, obesity, and tobacco use, may influence the risk of breast cancer in postmenopausal women. McTiernan et al1 found that, compared with less active women, women who engaged in regular strenuous physical activity at age 35 years had a 14% decreased risk of breast cancer (RR, 0.86; 95% CI, 0.78–0.95). Similar but attenuated findings were observed for strenuous physical activity at ages 18 years and 50 years. Women who engaged in the equivalent of 1.25 to 2.5 hours per week of brisk walking had an 18% decreased risk of breast cancer (RR, 0.82; 95% CI, 0.68–0.97) compared with inactive women. In a cohort of 25,624 women followed for a median of 13.7 years,2 greater leisure-time activity was associated with a reduced risk of breast cancer, after adjustments for age, body mass index, height, parity, and county of residence (RR, 0.63; 95% CI, 0.42–0.95), among women who exercised regularly, as compared with sedentary women (P for trend = .04). Li and colleagues3 found that ever-use of alcohol over the past 20 years was associated with a 1.3-fold (95% CI, 1.0 –1.5) increased risk of breast cancer, although this increase was primarily limited to women who consumed >30.0 g/day of alcohol (OR, 1.7; 95% CI, 1.1–2.6). These results are consistent with there being an underlying hormonal basis for the known association between alcohol use and breast cancer. Obesity is also associated with breast cancer risk.4,5 Huang and colleagues4 found a strong positive association between weight gain and breast cancer incidence in never-users of hormones. Morimoto and colleagues5 confirmed previously reported findings that generalized obesity is an important risk factor for postmenopausal breast cancer, but only among women who have never used HT. Lifetime weight gain is also a strong predictor of breast cancer. Reynolds et al6 found that, irrespective of whether they included passive smokers in the reference category, the incidence of breast cancer among current smokers was higher than that among never smokers (HR, 1.32; 95% CI, 1.10–1.57 relative to all never smokers; HR, 1.25, 95% CI, 1.02–1.53 relative to only those never smokers who were unexposed to household passive smoking). This study provides evidence that active smoking may play a role in breast cancer. 1McTiernan A, et al. JAMA. 2003;290:1331-6; 2Thune I, et al. N Engl J Med. 1997;336: ; 3Li CI, et al. Cancer Epidemiol Biomark Prev. 2003;12:1061-6; 4Huang Z, et al. JAMA. 1997;278: ; 5Morimoto LM, et al. Cancer Causes Control. 2002;13:741-51; 6Reynolds P, et al. J Natl Cancer Inst. 2004;96:29-37. 1McTiernan A, et al. JAMA. 2003;290: 2Thune I, et al. N Engl J Med. 1997;336: 3Li CI, et al. Cancer Epidemiol Biomark Prev. 2003;12: 4Huang Z, et al. JAMA. 1997;278: 5Morimoto LM, et al. Cancer Causes Control. 2002;13: 6Reynolds P, et al. J Natl Cancer Inst. 2004;96:29-37.

Magnitude of Various Risk Factors for Breast Cancer
2004 Patient Management Magnitude of Various Risk Factors for Breast Cancer Family History (2 Members) BMI >31.1 kg/m2 Obesity Family History (1 Member) Age at Menarche (Delayed) Lack of Exercise HT for 5 Years This bar graph illustrates differences in the magnitude of risk associated with various risk factors for breast cancer. Huang Z, et al. JAMA. 1997;278: ; Thune I, et al. N Engl J Med. 1997;336: ; Longnecker MP, et al. Cancer Epidemiol Biomark Prev. 1995;4:721-5; McTiernan A, et al. JAMA. 2003;290: Huang Z, et al. JAMA. 1997;278: Smith-Warner SA, et al. JAMA. 1998;279: Thune I, et al. N Engl J Med. 1997;336: Longnecker MP, et al. Cancer Epidemiol Biomark Prev. 1995;4:721-5. McTeirnan A, et al. JAMA. 2003;290:

Non-HT Alternatives for Vasomotor Symptoms
2004 Patient Management Non-HT Alternatives for Vasomotor Symptoms Lifestyle changes (limited effectiveness) Cooling body core temperature Exercise Avoiding hot and spicy foods Pace respirations Relaxing activities A number of lifestyle and social factors may influence hot flush frequency: Warm ambient air temperatures increase a woman’s core body temperature and make her more likely to reach the sweating threshold. Less physical activity increases the relative risk of hot flushes; daily exercise is associated with an overall decreased incidence. Anecdotally, spicy foods have been reported to trigger hot flushes, though there is no clinical evidence to support this relationship. Other lifestyle factors that affect vasomotor symptoms: Cigarette smoking (past and current) increases the relative risk of hot flushes, perhaps because of its effect on estrogen metabolism. North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med ;137:805-13; Huntley AL, Ernst E. Menopause. 2003;10: North American Menopause Society. Menopause. 2004;11:11-33. Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137: Huntley AL, Ernst E. Menopause. 2003;10:

Non-Prescription Remedies
2004 Patient Management Non-Prescription Remedies Some alternative therapies may provide relief of mild vasomotor symptoms for some women Phytoestrogens/isoflavones Dietary or supplements (soy-derived) Red clover Black cohosh Vitamin E – not clinically significant Studies show no effect compared with placebo for Dong quai Ginseng Evening primrose oil Some alternative therapies may provide relief of mild vasomotor symptoms for some women. Among nonprescription remedies, clinical trial results are insufficient to either support or refute efficacy for soy foods and isoflavone supplements (from either soy or red clover), black cohosh, or vitamin E; however, no serious side effects have been associated with short-term use of these therapies. Single clinical trials have found no benefit for dong quai, evening primrose oil, ginseng, a Chinese herbal mixture, acupuncture, or magnet therapy.1 Kronenberg and Fugh-Berman2 reported that soy seems to have modest benefit for hot flushes, but studies are not conclusive, and isoflavone preparations seem to be even less effective than soy foods. Black cohosh may be effective for menopausal symptoms, especially hot flushes, but the lack of adequate long-term safety data precludes recommending long-term use. Black cohosh and foods that contain phytoestrogens may provide relief of menopausal symptoms, but clinical trials do not support the use of other herbs or CAM therapies (eg, dong quai, evening primrose oil, a Chinese herb mixture, vitamin E, and acupuncture). Huntley and Ernst3 concluded that there is no convincing evidence for any herbal medical product (eg, black cohosh, red clover) in the treatment of menopausal symptoms, due in part to poor methodology of the trials. North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med ;137:805-13; Huntley AL, Ernst E. Menopause. 2003;10: 1North American Menopause Society. Menopause. 2004;11:11-33. 2Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137: 3Huntley AL, Ernst E. Menopause. 2003;10:

Alternative Non-Prescription Therapies: Concerns
2004 Patient Management Alternative Non-Prescription Therapies: Concerns Aggressive marketing generates inquiries and use Side effects and drug interactions are not well known but clearly occur Lack long-term safety and efficacy data When possible, providers should record use and amounts Long-term, adequately powered, randomized, placebo-controlled, clinical trials with defined entry criteria are needed FDA efficacy trials require a minimum of 7 to 8 per day or 50 to 60 per week moderate to severe hot flushes The increasing interest in alternative therapies is created by aggressive marketing, thus, patients, and not healthcare providers, are often the initiators and decision-makers about these options. Because of this patient-driven aspect, it is critical that practitioners acknowledge their use and help patients make informed decisions when possible. It is not sufficient to tell patients that such alternatives are “not recommended.” Patients need to know that side effects can occur, and that limited research is only beginning to yield data on whether alternative agents are safe and effective. Ang-Lee et al1 reported side effects associated with alternative therapies during the perioperative period: Direct effects: bleeding from garlic, ginkgo, and ginseng; cardiovascular instability from ephedra; and hypoglycemia from ginseng. Pharmacodynamic herb-drug interactions: potentiation of the sedative effect of anesthetics by kava and valerian. Pharmacokinetic herb-drug interactions: increased metabolism of many drugs used in the perioperative period by St John's wort. Since the safety of alternative therapies in patients at risk for DVT, breast or endometrial cancer, stroke, or hypercoagulation, or who have a history of coronary artery disease is unknown, the use of these products in these populations should be carefully monitored. For moderate to severe hot flushes, the FDA stipulates that a woman enrolled in clinical trials to establish efficacy must have 7-8 hot flushes per day or per week; efficacy studies of non-HT remedies have enrolled women with lower rates of hot flushes. Most studies are of short duration, and small, short-term, randomized trials can be confounded by placebo effect.2 1Ang-Lee MK. JAMA. 2001;286: 2North American Menopause Society. Menopause. 2004;11:11-33.

Phytoestrogens Nonsteroidal plant-derived compounds that bind to ERs
2004 Patient Management Phytoestrogens Nonsteroidal plant-derived compounds that bind to ERs Some bind weakly to ER Many bind strongly to ERb Three main classes Isoflavones (genistein and daidzein): soybeans, soy products, lentils, chickpeas, red clover Lignans (enterodiol and enterolactone): wide variety of fruits, vegetables, and cereals; concentrated in flaxseed Coumestans (coumestrol): bean sprouts, fodder crops (alfalfa) Phytoestrogens are nonsteroidal compounds derived from plants that are structurally similar to estradiol.1 They exhibit both estrogenic activity and antiestrogenic activity.2 In the past, they have been considered “weak” estrogens because their binding affinity for the ER was considerably less than that of estradiol. However, some phytoestrogens have a relatively high binding affinity for ER compared with estradiol.3 There are three main classes of phytoestrogens: isoflavones, lignans, and coumestans. Isoflavones, which include genistein and daidzein, are found in soy beans, soy products, lentils, chickpeas, and red clover. Genistein and daidzein are believed to be responsible for the estrogen-like effects of soy. Lignans, which include enterodiol and enterolactone, are found in many fruits, vegetables, and cereals. Coumestans can be isolated in high concentrations from bean sprouts and fodder crops, such as alfalfa. ER = estrogen receptor. Scheiber MD, Rebar RW. Menopause. 1999;6: 1Scheiber MD, Rebar RW. Menopause. 1999;6: 2Setchell KDR. Am J Clin Nutr. 1998;68(suppl):1333S-46S. 3Clarkson TB, et al. In: Lobo RA, ed. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2nd ed. Philadelphia, PA; Lippincott Williams and Wilkins; 1999.

Dietary Phytoestrogens/Isoflavones
2004 Patient Management Dietary Phytoestrogens/Isoflavones 11 studies examining soy or isoflavone supplementation Only 3 of 8 studies lasting longer than 6 weeks showed significant improvement in hot flushes Longest study (24 weeks) to date showed no benefit for hot flushes Published data show only modest effects; most benefits vanish after 6 weeks Symptoms decreased in all treatment groups, including placebo, by 50%–60% Comparisons are difficult because of variations in products, dosages, scoring systems, and menopausal status Red clover (two 3-month, double-blind, small, controlled trials, >3 hot flushes per day) No significant effect compared with placebo Isoflavones, often called phytoestrogens, are plant-derived diphenolic compounds exhibiting both hormonal and nonhormonal properties. Two common sources of isoflavones are soy and red clover. Randomized, controlled clinical trials have shown that, in general, hot flushes are only slightly reduced in women who consume soy-derived isoflavones when compared with controls. Comparing results from studies is difficult because different products and amounts of isoflavones have been evaluated; symptom indices used to measure efficacy also differed. North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137: North American Menopause Society. Menopause. 2004;11:11-33. Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:

Black Cohosh (Cimicifuga racemosa)
2004 Patient Management Black Cohosh (Cimicifuga racemosa) NIH-funded, large, randomized, prospective, 2-year trial ongoing Preliminary data fails to show binding to ER Binding to serotonin receptor noted 4 randomized trials using placebo and/or estrogen treatment arm 3 of the 4 trials found black cohosh to be beneficial (only 1 of these 3 used placebo as a control) Currently, longest trial is 6 months Four randomized trials of black cohosh with placebo or estrogen control groups have been conducted. Tablets (40 mg/d) vs placebo; duration, 2 months1—Outcomes included frequency and intensity of hot flushes; menopause symptom index (6 symptoms); global rating of health scale; FSH and LH levels. FINDINGS: No significant difference between groups in frequency and intensity of hot flushes (decreased in both groups); significantly greater decrease in sweating in treatment group than in placebo group (P = .04); no changes in global rating scale or FSH and LH levels; study duration was short. Liquid (40 drops twice daily) vs conjugated estrogens (0.25 mg/d) vs diazepam (2 mg/d); duration, 3 months2—Outcomes included Kupperman index scores (modified 5 symptoms); HAM-A; SDS; CGI; VMI. FINDINGS: Kupperman index, HAM-A, SDS, and CGI showed “highly significant reductions” with all three therapies; VMI: “trend towards estrogenic stimulation” for Remifemin and estrogen; no statistical calculations reported. Tablets (4 mg twice daily) vs conjugated estrogens (0.625 mg/d) vs placebo; duration, 3 months3—Outcomes included Kupperman index scores (9 symptoms); hot flushes; HAM-A; VMI. FINDINGS: Significant improvement in Kupperman score, HAM-A (P < .001), and VMI (P < .01); no change in estrogen or placebo groups; hot flushes decreased from 4.9 to 0.7/d in Remifemin group, 5.2 to 3.2 in estrogen group, and 5.1 to 3.1 in placebo group (significance not indicated); lack of effect with estrogen calls other findings into question Tablets (4 mg of triterpene glycosides twice daily) vs estriol (1 mg/d) vs conjugated estrogens (1.25 mg/d) vs estrogen/progesterone combination; duration, 6 months4—Outcomes included Kupperman index scores (modified 17 symptoms); LH and FSH levels. FINDINGS: Kupperman scores improved in all groups (P = .01); no differences among treatment groups; no changes in LH and FSH levels. Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137: 1Jacobson JS, et al. J Clin Oncol. 2001;19: 2Warnecke G. Med Welt. 1985;36:871-4. 3Stoll W. Therapeutikon. 1987;1:23-31. 4Lehmann-Willenbrock E, Riedel HH. Zentralbl Gynakol. 1988;110:611-8.

Design of Trials Evaluating Black Cohosh for Menopausal Symptoms
2004 Patient Management Design of Trials Evaluating Black Cohosh for Menopausal Symptoms Study Design Participants Active Treatment (n) Control (n) 2 week, open-label1 n = 60, with climacteric complaints 40 drops of black cohosh twice daily (4 mg of 27-deoxyacetin) (20) 0.6 mg/d CE (20) 2 mg diazepam daily (20) 12 week, double-blind2 n = 80 , with 3 hot flushes daily 4 tablets daily of black cohosh (4 mg of 27-deoxyacetin) (26) Low-dose E, mg/d (29) Placebo (20) 24 week, open-label3 n = 60, hysterec-tomized, with 1 ovary & climacteric symptoms (<40 years of age) 4 tablets of black cohosh (4 mg of 27-deoxyacetin) (15) Estriol 1-mg tablet daily (15) CE 1.25 mg tablet daily (15) E+P sequential therapy, 1 tablet daily (15) 60 day, double-blind4 n = 85 breast cancer patients with menopausal symptoms 1 black cohosh tablet twice daily with food (42) Placebo (43) This slide is a summary of the design of 4 randomized controlled trials studying treatment of menopausal symptoms with black cohosh.1-4 In general, the design of these studies have significant limitations, and the collective evidence about the efficacy of black cohosh is therefore weak. Three of the randomized controlled trials of black cohosh used the same dosage and outcome measures, yet two of them were open studies and did not have a placebo control.1-3 The Kupperman score was not reduced to values <15 in either of these trials.1,3 The placebo-controlled trial showed a reduction in the Kupperman Index to <15 but yielded nonsignificant differences in the intergroup comparisons.2 The most recent study by Jacobson4 showed no effect but used half the dosage of the three previous trials. This study primarily demonstrated that black cohosh does not reduce hot flushes in breast cancer survivors on tamoxifen. Thus, clinical trial evidence evaluating the efficacy of black cohosh suggests a possible weak effect on vasomotor symptoms, but there is not convincing data at present to prove its efficacy above that of placebo. Better-designed, placebo-controlled trials are required. Huntley AL, Ernst E. Menopause. 2003;10: 1Warnecke G. Medwelt. 1985;36:871-4; 2Stoll W. Therapeutikon. 1987:1-15; 3Lehmann-Willenbrock VE, Reiedel HH. Zentrabl Gynakol. 1988;110:611-8; 4Jacobson JS, et al. J Clin Oncol. 2001;19: 1Warnecke G. Medwelt. 1985;36:871-4. 2Stoll W. Therapeutikon. 1987:1-15. 3Lehmann-Willenbrock VE, Reiedel HH. Zentrabl Gynakol. 1988;110:611-8. 4Jacobson JS, et al. J Clin Oncol. 2001;19:

Results of Trials Evaluating Black Cohosh for Menopausal Symptoms
2004 Patient Management Results of Trials Evaluating Black Cohosh for Menopausal Symptoms Reference Results Warnecke (1985)1 Black cohosh produced “greatest improvement” in all measures, but no actual data given Stoll (1987)2 Black cohosh produced greatest improvement in KI (<15) & HAMA (P < .01) compared with placebo Lehmann-Willenbrock (1988)3 Improvement in all groups (black cohosh, estriol, CE, and E+P; P < .01) for most treatments at most times; no difference between groups Jacobson (2001)4 Both black cohosh and placebo groups improved; NS difference between groups This slide summarizes the results of the 4 randomized controlled trials evaluating the efficacy treatment of menopausal symptoms with black cohosh.1-4 As described in the previous two slides, clinical trial evidence evaluating the efficacy of black cohosh suggests a possible weak effect on vasomotor symptoms, but there is not convincing data at present to prove its efficacy above that of placebo. Better-designed, placebo-controlled trials are required. KI = Kupperman Index; HAMA = Hamilton Anxiety Scale; NS = not significant. Huntley AL, Ernst E. Menopause. 2003;10: 1Warnecke G. Medwelt. 1985;36:871-4; 2Stoll W. Therapeutikon. 1987:1-15; 3Lehmann-Willenbrock VE, Reiedel HH. Zentrabl Gynakol. 1988;110:611-8; 4Jacobson JS, et al. J Clin Oncol. 2001;19: 1Warnecke G. Medwelt. 1985;36:871-4. 2Stoll W. Therapeutikon. 1987;September:1-15. 3Lehmann-Willenbrock VE, Reiedel HH. Zentrabl Gynakol. 1988;110:611-8. 4Jacobson JS, et al. J Clin Oncol. 2001;19:

Topical Progesterone Therapies
2004 Patient Management Topical Progesterone Therapies Wild yam cream contains progesterone precursors (humans lack enzyme to metabolize) Differential rates with minimal absorption of progesterone-containing creams 3 studies have shown that serum levels of progesterone are insufficient to prevent estrogenic stimulation of the endometrium1-3 Mixed results in randomized, placebo-controlled, hot-flush trials4,5 Cooper and colleagues1 recruited 20 postmenopausal women (37–70 years of age) who had undergone hysterectomy and bilateral salpingo-oophorectomy. The 33-day study design was as follows: first 10 days, applied either cream A (progesterone) or B (placebo) 4-day no-treatment washout next 10 days (days 15–24), applied other cream all patients then took oral natural progesterone 100 mg in the morning and 200 mg at night for 5 days Analysis of pregnanediol-3-glucuronide (P3G) confirmed that the systemic absorption of progesterone from progesterone is small (median value after 10 days of treatment, 4.2 mmol/L). Wren et al2 studied 27 postmenopausal women (50–65 years of age) who had an intact uterus, amenorrhoea of more than 12 months duration, and concentrations of follicle-stimulating hormone in the postmenopausal range; women were randomly allocated daily either 16 mg (n = 9), 32 mg (n = 8), or 64 mg (n = 10) of micronised progesterone, applied as a cream for 14 days (days 15–28) of each 4-week treatment cycle. Results showed that use of micronised transdermal progesterone for 14 days over 3 cycles, even at concentrations as high as 64 mg/d, did not increase circulating blood progesterone concentrations sufficiently to induce any evidence of a secretory effect in the endometrium. Lewis and colleagues3 studied 24 postmenopausal women who applied creams (placebo, 20 or 40 mg progesterone/g) twice daily for 3 weeks followed by 1 week washout before a further 3-week treatment. There were small increases in plasma progesterone levels and P3G excretion compared with the placebo group; it was concluded that absorption of progesterone from transdermal creams is low. A study by Komesaroff and colleagues5 suggested that short-term treatment with topical wild yam extract in women suffering from menopausal symptoms is free of side-effects, but appears to have little effect on menopausal symptoms, while Leonetti et al6 found a significant improvement in vasomotor symptoms in women treated with progesterone cream (25 of 30 (83%) treatment subjects and 5 of 26 (19%) placebo subjects [P < .001]). 1Cooper A, et al. Lancet. 1998;351:1255-6; 2Wren BG, et al. Lancet. 1999;354:1447-8; 3Lewis JG, et al. Maturitas. 2002;41:1-6; 4Komesaroff PA, et al. Climacteric. 2001;4:144-50; 5Leonetti HB, et al. Obstet Gynecol. 1999;94:225-8. 1Cooper A, et al. Lancet. 1998;351: 2Wren BG, et al. Lancet. 1999;354: 3Lewis JG, et al. Maturitas. 2002;41:1-6. 4Komesaroff PA, et al. Climacteric. 2001;4: 5Leonetti HB, et al. Obstet Gynecol. 1999;94:225-8.

Progestins for the Treatment of Vasomotor Symptoms
2004 Patient Management Progestins for the Treatment of Vasomotor Symptoms Progestin N Dose Efficacy MPA Oral 27 20 mg/d 25.9%–34.5%  in hot flushes MPA Depot 21 100 mg BID 67%–80%  in hot flushes Depo 71 500 mg + 40 mg megestrol 95%  in hot flushes Megestrol 15 500 mg weekly 69%  in hot flushes 42 150 mg 85%  vs21% placebo While the primary menopause-related indication for progestogen use is endometrial protection from unopposed estrogen,1 the use of progestogen alone may be considered as a treatment for hot flushes if the benefit-risk profile is acceptable to the woman. Medroxyprogesterone acetate (MPA) has been shown in several double-blind, placebo-controlled trials to relieve menopause-associated hot flushes in healthy women, as well as in women with breast or endometrial cancer. Both intramuscular and oral forms have demonstrated efficacy. Intramuscular MPA2-4 Contraindications of depot MPA (DMPA) are the same as for estrogen; adverse effects include weight gain, irregular uterine bleeding, amenorrhea, and nervousness. Oral MPA5,6 has shown efficacy similar to DMPA in relieving hot flushes; however, oral MPA is associated with less uterine bleeding and has been associated with no adverse effect on BMD Megestrol acetate has also been studied for treating hot flushes. In a randomized, placebo-controlled, double-blind crossover trial,7 97 postmenopausal women with a history of breast cancer received 4 weeks of relatively low doses of megestrol acetate (20 mg twice daily). To be eligible for the study, the patients must have had bothersome hot flushes (defined as hot flushes that occurred 7times per week and were sufficiently severe that the patient desired therapeutic intervention for at least one month). Hot flushes were reduced by about 85% in the megestrol acetate group compared with 21% in the placebo group, a significant between-group difference (P < .001). A follow-up telephone survey of study participants determined that 18 (31%) of 58 women continued to use megestrol acetate for periods 3 years with continued control of hot flushes and a minimum of side effects.8 No definitive data are available regarding the long-term safety of megestrol acetate for treatment of hot flushes in women with breast cancer. Side effects associated with megestrol acetate include withdrawal uterine bleeding, generally occurring 1 to 2 weeks after discontinuation of therapy, increased appetite (approved indications for treating unwanted weight loss [160- to 800-mg/day range]) and, possibly, exacerbation of preexisting diabetes and an increase in thromboembolic events. North American Menopause Society. Menopause. 2004;11:11-33. 1North American Menopause Society. Menopause. 2003;10: 2Bullock JL, et al. Obstet Gynecol. 1975;46:165-8. 3Morrison JC, et al. Am J Obstet Gynecol. 1980;138: 4Lobo RA, et al. Obstet Gynecol. 1984;63:1-5. 5Schiff I, et al. JAMA. 1980;244: 6Aslaksen K, Frankendal B. Acta Obstet Gynecol Scand. 1982;61:423-8. 7Loprinzi CL, et al. N Engl J Med. 1994;331: 8Quella SK, et al. Cancer. 1998;82:

Nonhormonal Prescription Therapies
2004 Patient Management Nonhormonal Prescription Therapies Antidepressants SSRI/SNRI therapy Venlafaxine Paroxetine Fluoxetine Anti-convulsants Gabapentin Anti-hypertensives Clonidine (patch or pill) and methyldopa Sedatives Bellergal In women with hot flushes for whom hormones are not an option, nonhormonal prescription alternatives that are FDA-approved for other indications have shown some effectiveness in relieving hot flushes.1 In many cases, these drugs have been studied in women with a history of breast cancer. The data from trials evaluating the efficacy of these nonhormonal prescription therapies for menopausal symptoms are reviewed in the following slides. 1North American Menopause Society. Menopause. 2004;11:11-33.

2004 Patient Management Clinical Trials of Median Hot Flush Score Reduction in Breast Cancer Patients Placebo (n = 347) Soy (n = 66) Clonidine (n = 75) Fluoxetine (n = 20) Median Score Vitamin E (n = 57) Venlafaxine (n = 45) Megestrol (n = 74) This slide includes the results of a cross-study comparison of several similarly conducted placebo-controlled clinical trials on the effects of various therapies on hot flushes in breast cancer survivors.1-7 The studies were all conducted by the same group of investigators, minimizing design variability. Placebo was reported to reduce hot flushes by approximately 25%. The effect of soy was similar to placebo. Clonidine and vitamin E reduced hot flushes slightly more than placebo. However, the improvement in hot flush scores with clonidine was observed in the first week, whereas the benefit with vitamin E was not apparent for several weeks. The antidepressant, venlafaxine, was the most effective of the nonhormonal treatments, reducing hot flush scores by approximately 50% to 60%. NOTE: These data are not from head-to-head trials. In addition, it is likely that patients in these studies may have been taking tamoxifen, which is often associated with increased vasomotor symptoms. Week NOTE: These data are not from head-to-head trials. Loprinzi CL, et al. Lancet Oncol. 2001;2: 1Loprinzi CL, et al. Lancet Oncol. 2001;2: 2Goldberg RM, et al. J Clin Oncol. 1994;12:155-8. 3Barton DL, et al. J Clin Oncol. 1998;16: 4Quella SK, et al. J Clin Oncol. 2000;18: 5Quella SK, et al. Cancer. 1998;82: 6Loprinzi CL, et al. Lancet. 2000;356: 7Loprinzi CL, et al. J Clin Oncol. 2002;20:

Nonhormonal Prescription Therapies: Venlafaxine
2004 Patient Management Nonhormonal Prescription Therapies: Venlafaxine Study Design and Duration Population (n) Venlafaxine Dosage Efficacy Results P-Value Prospective pilot; 5 weeks1 Women with history of breast cancer or current treatment, and men with androgen deficiency, (28) 12.5 mg bid for 4 weeks >50% decrease in overall frequency in 54% of patients <.0002 Double-blind, placebo-controlled; 4 weeks, with open-label 8-week period following2 Women with history of or fear of breast cancer, tamoxifen use, or reluctance to take HT (229) Placebo, mg qd, 75 mg qd, 150 mg qd From baseline: 27% 37% 61% 61% .01* .01* NS Open-label, continuation phase; 8 weeks3 Women with history of breast cancer or current treatment (102) 37.5 mg qd, 75 mg qd, mg qd, 150 mg qd From baseline: 26% 60% 60% 60% Not reported Several clinical studies have been performed to evaluate venlafaxine use for the reduction of hot flushes. All studies used daily diary entries to record frequency and severity of hot flushes; however, they did not meet the FDA requirement for frequency of hot flushes at baseline of 7-8 per day or per week (eg, Loprinzi = 14 per week) In 1998, Loprinzi and colleagues examined whether a low dose of the antidepressant venlafaxine could abrogate hot flushes in breast cancer survivors and men who have undergone androgen-deprivation therapy (n = 28; dose = 12.5 mg orally b.i.d; 1-week baseline period, 4 weeks treatment).1 Fifty-eight percent of patients who completed the study had > 50% reduction in hot flush scores (frequency times severity) during treatment Week 4 versus baseline. Median weekly hot flush scores were reduced by 55% from baseline during Week 4 of treatment. Venlafaxine appears to represent an efficacious new method to alleviate hot flushes. In 2000, Loprinzi et al undertook a double-blind, placebo-controlled, randomized trial to assess the efficacy of venlafaxine in women with a history of breast cancer or reluctance to take hormonal treatment because of fear of breast cancer (placebo [n = 56] or venlafaxine 37.5 mg/d [n = 56], 75 mg/d [n = 55], or 150 mg/d [n = 54]; 4-week treatment phase).2 All venlafaxine treatment started at 37.5 mg daily and gradually increased in the 75 mg and 150 mg groups. 191 patients had evaluable data for the whole study period (50 placebo, 49 venlafaxine 37.5 mg, 43 venlafaxine 75 mg, 49 venlafaxine 150 mg). After week 4 of treatment, median hot flush scores were reduced from baseline by 27% (95% CI 11-34), 37% (26-54), 61% (50-68), and 61% (48-75) in the four groups. Frequencies of some side-effects (mouth dryness, decreased appetite, nausea, and constipation) were significantly higher in the venlafaxine 75 mg and 150 mg groups than in the placebo group. Venlafaxine was shown to be an effective non-hormonal treatment for hot flushes, though the efficacy must be balanced against the drug's side-effects. In 2002, Barton et al conducted an open-label continuation phase study following a double-blind, randomized, placebo-controlled clinical trial that tested three doses of venlafaxine for the control of hot flushes in 102 postmenopausal women.3 The reduction in hot flushes previously reported in the randomized study phase was maintained during the open-label study, and toxicity did not appear to increase over time. This study provides evidence that venlafaxine has intermediate term efficacy and good tolerability as treatment for hot flushes. *Decrease of hot flush score. Schober CE, Ansani NT. Ann Pharmacother. 2003;37: 1Loprinzi CL, et al. J Clin Oncol. 1998;16: ; 2Loprinzi CL, et al. Lancet. 2000;356: ; 3Barton D, et al. Oncol Nurs Forum. 2002;29:33-40. Schober CE, Ansani NT. Ann Pharmacother. 2003;37: 1Loprinzi CL, et al. J Clin Oncol. 1998;16: 2Loprinzi CL, et al. Lancet. 2000;356: 3Barton D, et al. Oncol Nurs Forum. 2002;29:33-40.

Nonhormonal Prescription Therapies: Fluoxetine
2004 Patient Management Nonhormonal Prescription Therapies: Fluoxetine Randomized, double-blind, placebo-controlled, 8-week crossover trial (two 4-week periods) to evaluate the efficacy of fluoxetine (20 mg/day) for vasomotor symptoms N = 81 women with a history of breast cancer or perceived high risk of breast cancer Could be on stable does of tamoxifen or raloxifene At least 14 hot flushes per week 20% improvement compared with placebo (P = .02) Loprinzi et al1 conducted a double-blind, randomized, two-period (4 weeks per period), crossover study to evaluate the efficacy of fluoxetine (20 mg/d) for treating hot flushes in women with a history of breast cancer or a concern regarding their risk for breast cancer with HT use. Eligible patients had to have reported that they averaged 14 hot flushes per week; the FDA standard for entry into clinical trials for vasomotor symptom relief is 60 hot flushes per week. Eighty-one women were randomized and began protocol therapy. By the end of the first treatment period, hot flush scores (frequency  average severity) decreased 50% in the fluoxetine arm versus 36% in the placebo arm. Cross-over analysis demonstrated a significant improvement in hot flush score with fluoxetine compared with placebo (P = .02). The results were not adjusted for potential confounding influences, including age and tamoxifen use. Fluoxetine was well tolerated. The authors concluded that fluoxetine administered at a dose of 20 mg/day resulted in a modest improvement in hot flushes. Contraindications to using fluoxetine (which are also the same for paroxetine) include concomitant use of MAOIs or thioridazine, and caution is advised with concomitant administration of warfarin.2 Loprinzi CL, et al. J Clin Oncol. 2002;20: 1Loprinzi CL, et al. J Clin Oncol. 2002;20: 2North American Menopause Society. Menopause. 2004;11:11-33.

Nonhormonal Prescription Therapies: Paroxetine
2004 Patient Management Nonhormonal Prescription Therapies: Paroxetine 165 women, 18 years of age or older Experiencing 2 to 3 hot flushes per day Doses (n) Median Reduction in Hot Flush Composite Score 12.5 mg (51) 62.2% (P = .007) 25 mg (58) 64.6% (P = .03) Placebo (56) 37.8% Stearns and colleagues conducted a randomized, double-blind, placebo-controlled, parallel-group study across 17 US sites, including urban, suburban, and rural clinics to evaluate the efficacy of paroxetine for vasomotor symptom relief. 165 menopausal women aged 18 years experiencing at least 2 to 3 daily hot flushes (the FDA standard for entry into clinical trials for vasomotor symptom relief is 7 per day) were enrolled; participants must have discontinued any HT for at least 6 weeks (women with any signs of active cancer or undergoing chemotherapy or radiation therapy were excluded). Also, psychotropic drugs must have been discontinued, although patients could be taking tamoxifen, raloxifene, or vitamin E. Participants recorded vasomotor symptoms in daily hot flush diaries. After a 1-week placebo run-in phase, study participants were randomized to receive placebo (n = 56), 12.5 mg/d of paroxetine CR (n = 51) or 25.0 mg/d of paroxetine CR (n = 58) for 6 weeks. Mean reductions in hot flush frequency composite score from baseline to week 6 were statistically significantly greater for those receiving paroxetine CR than for those receiving placebo (from 7.1 to 3.8 for women in the 12.5-mg/d group; from 6.4 to 3.2 for women in the 25-mg/d group; and from 6.6 to 4.8 for women in the placebo group). Mean placebo-adjusted reduction in hot flush composite scores were -4.7 (95% CI, -8.1 to -1.3; P =.007) for the 12.5-mg/d paroxetine group and -3.6 (95% CI, -6.8 to -0.4; P =.03) for the 25.0-mg/d paroxetine group. Contraindications to using paroxetine (which are also the same for fluoxetine) include concomitant use of MAOIs or thioridazine, and caution is advised with concomitant administration of warfarin.2 Adverse effects observed in trials for depression include asthenia, sweating, nausea, decreased appetite, somnolence, insomnia, and dizziness. The recommended initial dose for treating depression is 20 mg/d. Stearns V, et al. JAMA. 2003;289: 1Stearns V, et al. JAMA. 2003;289: 2North American Menopause Society. Menopause. 2004;11:11-33.

Nonhormonal Prescription Therapies: Gabapentin
2004 Patient Management Nonhormonal Prescription Therapies: Gabapentin 12-week, double-blind study Dose = 900 mg/d 7 hot flushes per day at baseline 6-week screening Hot flush composite score decreased 54% vs 31% for placebo (P = .01) 50% reported at least 1 adverse event (eg, dizziness, lightheadedness, palpitations, rash, somnolence) vs 27.6% in placebo group; 13.3% withdrew Guttuso and colleagues1 evaluated the efficacy of the anticonvulsant gabapentin in reducing hot flush frequency and severity. A randomized, double-blind, placebo-controlled trial was conducted in 59 postmenopausal women with 7 hot flushes per day (meets FDA criteria for trials evaluating vasomotor symptom relief) to examine the effects of 900 mg/d of gabapentin (could be increased up to 2700 mg/d) on hot flush frequency after 12 weeks of treatment. Patients could be taking stable doses of raloxifene, clonidine, or other antidepressants. Participants recorded vasomotor symptoms in daily diaries. Although higher doses of gabapentin are commonly used for treatment of seizures or neuropathies (up to 3000–3600 mg/day), doses as low as 100 mg/day are typically used as starting doses for hot flushes, particularly in older women.2 After 12 weeks of treatment, the intention-to-treat analysis showed that gabapentin 900 mg/d was associated with a 45% reduction in hot flush frequency and a 54% reduction in hot flush composite score (frequency and severity combined into one score) from baseline, compared with 29% (P = .02) and 31% (P = .01) reductions, respectively, for placebo. Higher, open-label gabapentin dosing (>900 mg/d) was associated with 54% and 67% reductions in hot flush frequency and composite score from baseline, respectively. The most common adverse events in the gabapentin group during the double-blind study were somnolence (6 patients [20.0%]), dizziness (4 patients [13.3%]), and rash with or without peripheral edema (2 patients [6.7%]), none of which occurred in the placebo group.1 Adverse effects previously observed in seizure trials include somnolence, dizziness, ataxia, fatigue, and nystagmus.2 Hypersensitivity to the drug is the only contraindication to gabapentin use.2 Guttuso T, Jr, et al. Obstet Gynecol. 2003;101: 1Guttuso T, Jr, et al. Obstet Gynecol. 2003;101: 2North American Menopause Society. Menopause. 2004;11:11-33.

Nonhormonal Prescription Therapies: Clonidine
2004 Patient Management Nonhormonal Prescription Therapies: Clonidine Randomized, double-blind, placebo-controlled clinical trial1 0.1 mg/d oral 194 breast cancer patients taking tamoxifen Randomized, placebo-controlled Hot flush frequency decreased by 38% after 8 weeks vs 24% with placebo Side effects: dry mouth, drowsiness, constipation, and dizziness2 A randomized, double-blind, placebo-controlled trial evaluated 8 weeks of oral clonidine (0.1 mg/d) for effectiveness of control of hot flushes associated with tamoxifen therapy in 194 postmenopausal women with breast cancer.1 Patients recorded data on hot flushes in daily diaries. Mean decreases in frequency of hot flushes were greater in the clonidine than in the placebo group after 4 weeks (37% vs 20%) and 8 weeks (38% vs 24%). Patients receiving clonidine were significantly more likely to report difficulty sleeping (P = .02). An earlier, double-blind, crossover trial randomized 110 women receiving tamoxifen (median age = 54) to 4 weeks of transdermal clonidine (equivalent to a daily dose of 0.1 mg) or placebo.2 Clonidine significantly reduced frequency of hot flushes (P < .0001); however, the results were of modest clinical significance and accompanied by significant increases in dry mouth, constipation, drowsiness, and itchiness. In an earlier study,3 4 out of 10 women withdrew because of side effects experienced with clonidine. Another early trial of transdermal clonidine (n = 29) reported significant relief of hot flushes with minimal side effects.4 1Pandya KJ, et al. Ann Intern Med. 2000;132: 2Goldberg RM, et al. J Clin Oncol. 1994;12:155-8. 1Pandya KJ, et al. Ann Intern Med. 2000;132: 2Goldberg RM, et al. J Clin Oncol. 1994;12:155-8. 3LauferLR, et al. Obstet Gynecol. 1982;60: 4Nagamani M, et al. Am J Obstet Gynecol. 1987;156:

Clinical Management of Vasomotor Symptoms
2004 Patient Management Clinical Management of Vasomotor Symptoms For mild vasomotor symptoms Encourage lifestyle changes Non-prescription remedies tested only short term dietary isoflavones black cohosh vitamin E Discuss risk-benefits of HT For moderate to severe vasomotor symptoms Systemic HT remains therapeutic standard and only FDA-approved treatment for moderate to severe symptoms Progestins effective; however, large doses required Early studies suggest limited efficacy with some SSRIs and gabapentin; more studies needed, side effects of concern In January 2004, NAMS issued an evidence-based consensus statement on the treatment of vasomotor symptoms associated with menopause. For women seeking relief from mild hot flushes, NAMS recommends first considering lifestyle changes such as exercising regularly, maintaining a healthy body weight, keeping the core body temperature cool, and using paced respiration. If lifestyle changes prove inadequate, dietary isoflavones or supplements containing black cohosh or vitamin E may be tried; however, data on these non-prescription remedies have been inconclusive. For example, although a statistically significant decrease in hot flushes among breast cancer survivors was noted in one trial of vitamin E, the results were not clinically significant. HT remains the therapy most often prescribed for moderate to severe hot flushes and the only one approved by the FDA. HT should be used for the shortest duration consistent with its likely risks and benefits for each individual woman. NAMS recommends considering the use of low-dose HT, which has been shown to provide similar relief of vasomotor symptoms. The use of progestogen alone may be considered as treatment for vasomotor symptoms provided that the benefit/risk ratio is acceptable to the individual woman. The contraceptive, depot-MPA (DMPA), MPA, and megestrol acetate have demonstrated effectiveness in clinical trials and may be useful over the short term provided they are not contraindicated. Progestogens have been linked to an increased risk of breast cancer in some studies. Some prescription antidepressants, such as venlafaxine, paroxetine, and fluoxetine, may decrease hot flushes. Side effects such as nausea and sexual dysfunction should be monitored. Very low doses may be used when initiating therapy to minimize side effects. The anticonvulsant, gabapentin, has also been shown to reduce the frequency of hot flushes compared to placebo. Doses up to 300 mg three times a day may be considered. Adapted from North American Menopause Society. Menopause. 2004;11:11-33. North American Menopause Society. Menopause. 2004;11:11-33.

Current Management of Osteoporosis: A Review
2004 Patient Management Current Management of Osteoporosis: A Review Therapy* Decreases Vertebral Fracture Rates Decreases Hip Fracture Rates Approximate Increases in BMD (%)† Most Common Side Effect HT Yes‡ Yes 5–6 Breakthrough bleeding Alendronate§ 5–8 Gastric ulceration Risedronate§ Upper GI symptoms Raloxifene§ No 1–2 Hot flushes Calcitonin Nasal irritation PTH 9 Leg cramps; dizziness *All therapies include calcium supplementation; †Treatment time is 2 to 3 years; ‡Dose effect; §Long-term safety (>7 years) is unknown. GI = gastrointestinal. American Association of Clinical Endocrinologists. Endocr Pract. 2001;7: Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Endocrine Rev. 2002;23: There are several therapeutic options available for osteoporosis prevention and management.1-9 HT and alendronate decrease vertebral and hip fracture rates and increase spinal BMD by between 5% and 8%.1-3 Risedronate also decreases vertebral and hip fracture rates and increases spinal BMD by 4% to 6%.4 HT at lower doses increases BMD by 2% to 3%.5 Fracture data in early postmenopausal women are only available for HT. The major side effect of HT is breakthrough bleeding, which usually disappears within 1 year. Alendronate is associated with upper gastrointestinal symptoms such as esophageal and gastric erosions and ulceration, which can be severe.6 Risedronate is also associated with gastrointestinal symptoms, but to a lesser degree than alendronate.6 Raloxifene is associated with more modest increases in BMD and a reduced risk of vertebral fracture; however, it does not appear to significantly reduce the risk of hip fracture.7 Since its major side effect is vasomotor symptoms, raloxifene may not be appropriate for early postmenopausal women. Since the bisphosphonates and SERMs have only been available for a relatively short time (<7 years), their long-term safety is unknown.6 They are also considerably more expensive than HT, which may be an important factor for women whose medications are not covered by insurance. Calcitonin also increases BMD by 1% to 2% and is well tolerated.8 However, it is generally considered to be a weaker antiresorptive therapy than HT or bisphosphonates.6 In a large (n = 1637), randomized, placebo-controlled trial,10 20 or 40 g/d of PTH (1-34) was associated with significant decreases in the risk of vertebral and nonvertebral fractures and increases in BMD, with only minor side effects. The FDA has approved the use of PTH 20 g/d for a maximum of 2 years.11 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: Wells G, Tugwell P, Shea, et al. Endocr Rev. 2002;23: Cranney A, et al. Endocr Rev. 2002;23: Cranney A, et al. Endocr Rev. 2002;23: Lindsay R, et al. JAMA. 2002;287: American Association of Clinical Endocrinologists. Endocr Pract. 2001;7: 7Cranney A, et al. Endocr Rev. 2002;23: Cranney A, et al. Endocr Rev. 2002;23: Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Endocr Rev. 2002;23: Neer RM, et al. N Engl J Med. 2001;19: Eli Lilly. Forteo (teriparatide [rDNA origin] injection). Prescribing information. November 2002.

Osteoporosis Prevention and Treatment
2004 Patient Management Osteoporosis Prevention and Treatment Non-pharmacological treatment calcium: 1500 mg/day Vitamin D: 800 IU/day Physical activity: >30 min at least 3 times a week Without fragility fracture With fragility fracture Vasomotor symptoms Vasomotor symptoms Yes No Yes No HT Alendronate, risedronate, and raloxifene HT ± alendronate or risedronate Alendronate, risedronate, and raloxifene 1st choice Alendronate, risedronate, raloxifene, calcitonin Calcitonin, etidronate, HT Calcitonin, raloxifene, etidronate Calcitonin, etidronate, HT 2nd choice This slide presents an algorithm for osteoporosis prevention and treatment in postmenopausal women. All patients should be encouraged to take calcium and vitamins daily and exercise at least 3 times per week.1 If the patient does not have fragility fractures (fractures occurring with minimal trauma), HT should be the first-line therapy if she has vasomotor symptoms, and a bisphosphonate or raloxifene should be the first-line choice if she does not have symptoms. If a patient has fragility fractures and vasomotor symptoms, she should receive HT, with or without a bisphosphonate. If she has fragility fractures and does not have vasomotor symptoms, a bisphosphonate or raloxifene should be prescribed. Of the therapies presented here, only HT and the bisphosphonates have been shown to prevent hip fractures.2 Subsequent to the publication of this algorithm, PTH was indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture (including women with a history of osteoporotic fracture, who have multiple risk factors for fracture, or who have failed or are intolerant of previous osteoporosis therapy). PTH (1-34) 20 g/d has been shown to prevent vertebral and nonvertebral fractures in postmenopausal women with severe osteoporosis.3 The FDA has approved the use of PTH 20 g/d for no longer than 2 years.4 Adapted from Brown JP, Josse RG. Reprinted from CMAJ 12 Nov 2002:167(suppl): Page S22, by permission of the publisher. © 2002 Canadian Medical Association. 1Brown JP, Josse RG, for the Scientific Advisory Council of the Osteoporosis Society of Canada. CMAJ. 2002;167:S1-S34. 2Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Endocr Rev. 2002;23: 3Neer RM, et al. N Engl J Med. 2001;19: 4Eli Lilly. Forteo (teriparatide [rDNA origin] injection). Prescribing information. November 2002.

Section 5: Patient Counseling Strategies
2004 Patient Management Patient Management Issues in Menopause Section 5: Patient Counseling Strategies

Counseling Topics for Patients Considering HT
2004 Patient Management Counseling Topics for Patients Considering HT Review the risks and benefits of HT Discuss the probability of early bleeding while receiving continuous-combined E+P Review other potential side effects Provide information about HT and breast health Emphasize that HT use does not cause weight gain Obtain informed consent Counseling for postmenopausal HT is an ongoing process that requires periodic re-evaluation. There is a mass of information for women to absorb, and each office visit provides an opportunity for repetition as well as the introduction of new information. Women tend to be most interested in the immediate aspects of the process, that is, making the initial decision, coping with side effects, and opting for continuation of therapy. In the initial stages, information about bleeding, weight gain, and breast cancer is probably the most relevant. This needs to be balanced with the risks and benefits of HT overall. The decision to use HT can be presented as a short-term commitment. Patients may find decisions regarding HT less daunting if they realize that the decision to continue therapy will be re-evaluated on a yearly basis.

Counseling Topics for Patients Who Decline or Discontinue HT
2004 Patient Management Counseling Topics for Patients Who Decline or Discontinue HT Asymptomatic obese women may still require progestational therapy Urogenital atrophy will develop Need to increase surveillance for osteoporosis and/or consider alternative osteoporosis regimens Hot flushes and night sweats may return after discontinuation There are several important clinical recommendations that should be mentioned to patients who decline hormone treatment or for HT users who decide to discontinue treatment. Patients who are obese and asymptomatic may still require progestational therapy, and urogenital atrophy and hot flushes may occur after therapy is stopped. Additionally, these patients should be monitored for development of osteoporosis. Alternative therapies to prevent osteoporosis can also be considered.

Informed Consent Is a Process, Not a Form
2004 Patient Management Informed Consent Is a Process, Not a Form Informed Consent Discussions Should Include The diagnosis and the nature of the condition The nature and purpose of the recommended treatment or procedure, including its risks and potential complications All reasonable alternative treatments or procedures, including the option of taking no action, and the risks of each option The relative probability of success for the treatment or procedure Informed consent requires a health care provider to discuss several important points with a patient: Patients should understand the medical diagnosis and the nature of their condition. They should also understand the possible risks and complications associated with a treatment or procedure, and the probability of success if a certain therapy is selected. Reasonable alternatives to a recommended treatment should also be discussed, including the anticipated outcome if the patient decides to take no action. The American College of Obstetricians and Gynecologists. Professional Liability and Risk Management: A Resource for OB-GYNs in Training and in Practice. Washington DC; 2002. The American College of Obstetricians and Gynecologists. Professional Liability and Risk Management: A Resource for OB-GYNs in Training and in Practice. Washington DC; 2002.

What to Remember When Obtaining Informed Consent
2004 Patient Management What to Remember When Obtaining Informed Consent Avoid medical jargon; pay close attention to the patient’s language proficiency Try to make sure there is true understanding by having information repeated back to you Allow enough time for questions and answers Make notations about high-risk issues discussed In obtaining informed consent from a patient, it is often useful (when appropriate) to include significant others or family members in the decision-making process. Linguistic and literacy limitations may affect patient’s ability to understand the elements involved in medical decision-making. Medical jargon should also be avoided. It may be helpful to have the patient repeat information back to you to ensure comprehension of important points. It is important to allow sufficient time for questions and discussion; it may also be helpful to make notations about high-risk issues that are discussed. The American College of Obstetricians and Gynecologists. Professional Liability and Risk Management: A Resource for OB-GYNs in Training and in Practice. Washington DC; 2002. The American College of Obstetricians and Gynecologists. Professional Liability and Risk Management: A Resource for OB-GYNs in Training and in Practice. Washington DC; 2002.

Counseling Women About HT
2004 Patient Management Counseling Women About HT Document reasons for considering HT (eg, use quality-of-life questionnaire) Review annually indications for HT Explain benefits of short-term HT use will often outweigh risks Emphasize that risks attributable to HT in the WHI were low Annual re-evaluation of the use of HT should include a discussion of recent scientific information and an assessment of how the patient is responding to therapy. Information from recent and ongoing studies, such as PEPI, HERS, WISDOM (International Study of Long Duration Oestrogen After Menopause), WHI, and recommendations from ACOG and NAMS and will aid in counseling women who are using HT or who are considering it. The recommendations recently issued by ACOG in response to the WHI indicated that the benefits of short-term HT use are likely to outweigh their risks. This statement should be stressed to those women considering short-term HT to relieve their menopausal symptoms. In addition, the Writing Group for the WHI indicated that the absolute excess risk attributable to HT was low, which also could reassure patients taking or considering HT. American College of Obstetricians and Gynecologists. ACOG News Release. Available at: Accessed 8/19/02. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 1American College of Obstetricians and Gynecologists. Available at: Accessed August 19, 2002. 2Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

Counseling on Duration of HT Use
2004 Patient Management Counseling on Duration of HT Use Individualized Therapy Consider continuing therapy (possibly lower dose) if initial indication was vasomotor symptoms Excess cardiovascular events occurred in the first 2 years in women (average age, 63 years) in the WHI trial Breast cancer risk was not increased with <5 years of HT use in the WHI trial After 5 years, HT was associated with a slight increased risk (<0.1% per year) VTE risk continues for duration of therapy (<0.2% per year) Bone protection is afforded by continuing therapy It is very important when counseling patients on the length of HT use to individualize the therapy for each woman. If the primary indication for initiating hormone use is menopausal symptoms, consider using the lowest effective dose. Excess cardiovascular events occurred in the first 2 years in women (whose average age was 63 years) and VTE risk continues through the duration of use (<0.2% per year) Breast cancer risk was not increased with <5 years of hormone use, and was only slightly increased (<0.1% per year) after 5 years of use. Continuation of hormone use provides protection from fractures. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

Patient Management Issues in Menopause

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