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Patient Management Issues in Menopause A CME Slide Library From the Council on Hormone Education.

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Presentation on theme: "Patient Management Issues in Menopause A CME Slide Library From the Council on Hormone Education."— Presentation transcript:

1 Patient Management Issues in Menopause A CME Slide Library From the Council on Hormone Education

2 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]).

3 Section 1: Appropriate Use of HT Patient Management Issues in Menopause

4 Percentage Menopause-related Symptoms Osteoporosis, Bone Loss, Fracture Prevention Doctor Prescribed It, Told Me to Take It Cardiovascular Disease Prevention Other Depression, Anxiety, Emotional Distress Newton KM, et al. J Womens Health. 1997;6: Reasons Women Gave for Initiating or Continuing HT

5 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 FDA Guidance for Industry. Available at: Accessed 1/04.

6 Womens 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 Chlebowski RT, et al. JAMA. 2003;289:

7 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 CHD = coronary heart disease. 1 Manson JE, et al. N Engl J Med. 2003;349:523-34; 2 Cauley JA, et al. JAMA. 2003;290: ; 3 Shumaker SA, et al. JAMA. 2003;289:

8 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 QOL = quality of life; NS = not significant. 1 Anderson GL, et al. JAMA. 2003;290: ; 2 Hays J, et al. N Engl J Med. 2003;348: WHI Updated Results Summary: Gynecologic Cancers, QOL

9 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 S, et al. JAMA. 2003;289:

10 Study Considerations WHI 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

11 *aCIs not available; Only in women 65 years of age at baseline. 1 Manson JE, et al. N Engl J Med. 2003;349:523-34; 2 Chlebowski RT, et al. JAMA. 2003;289: ; 3 Shumaker SA, et al. JAMA. 2003;289: ; 4 Wassertheil-Smoller S, et al. JAMA. 2003;289: ; 5 Writing Group for the WHI Investigators. JAMA. 2002;288:321-33; 6 Anderson GL, et al. JAMA. 2003; 290: ; 7 Chlebowski RT, et al. N Engl J Med. 2004;350: ; 8 Cauley JA, et al. JAMA. 2003;290: WHI: Results With CEE/MPA CHD 1 Breast Cancer 2 Dementia 3 * Stroke 4 VTE 5 Endometrial Cancer 6 Ovarian Cancer 6 Colorectal Cancer 7 Hip Fracture 8 Total Fracture 8 * Death 5 HR % nCI 95% aCI

12 Event Overall HR95% nCI95% aCI Attributable Risk per 10,000 Women/Year Benefit per 10,000 Women/Year CHD – –1.606 Breast cancer – –1.598 Dementia 3 * – Stroke – –1.847 VTE – – PE – –4.568 Colorectal cancer – –0.946 Hip fractures – –1.105 Total fractures – WHI Results: Overall Relative and Attributable Risk VTE = venous thromboembolism; PE = pulmonary embolism. *Only in women 65 years of age at baseline. 1 Manson JE, et al. N Engl J Med. 2003;349:523-34; 2 Chlebowski RT, et al. JAMA. 2003;289: ; 3 Shumaker SA, et al. JAMA. 2003;289: ; 4 Wassertheil-Smoller S, et al. JAMA. 2003;289: ; 5 Writing Group for the WHI Investigators. JAMA. 2002;288:321-33; 6 Chlebowski RT, et al. N Engl J Med. 2004;350: ; 7 Cauley JA, et al. JAMA. 2003;290:

13 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 CVD = cardiovascular disease. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

14 Interpretation of the WHI Data Majority of women initiate HT to alleviate menopausal symptoms 1 –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 years 2 Results should not be extrapolated to symptomatic early menopausal or prematurely menopausal women using HT for symptom relief 3 –Average age at screening, 63 years –Only 4% of WHI participants had moderate to severe vasomotor symptoms 1 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; 2 Brett KM, Ruben CA. Am J Obstet Gynecol. 2003;102: North American Menopause Society. Menopause. 2003;10:

15 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 B, et al. Obstet Gynecol. 2003;102:

16 American College of Obstetricians and Gynecologists (ACOG). Statement on the Estrogen Plus Progestin Trial of the Womens Health Initiative. July 9, Available at: press_releases/nr cfm. Accessed 8/19/02. 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 womens 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 womans individual benefits and risks from such use

17 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 North American Menopause Society (NAMS). Menopause. 2003;10:

18 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 North American Menopause Society. Menopause. 2003;10:

19 National Institutes of Health (NIH). National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. Available at: Accessed 8/19/02. 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

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

21 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

22 Womens Perceptions of Their Greatest Health Problems Adapted from Mosca L, et al. Arch Fam Med. 2000;9: Breast Cancer Cancer Other Problems Cardiovascular Disease Dont Know/ No Answer 34% 27% 16% 7% 16%

23 Causes of Death Among Women * *Percentage of total deaths in 1999 among women aged 65 years and older. Anderson RN. Natl Vital Stat Rep. 2001;49:1-13. Heart Disease Other Cancers Other Diabetes Chronic Lower Respiratory Disease Cerebrovascular Disease Breast Cancer 34% 10% 6% 3% 15% 28% 4%

24 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 American Cancer Society. Breast Cancer Facts and Figures 2001–2002. Available at: downloads/STT/BrCaFF2001.pdf. In 100 women, 2.8 are at risk

25 Absolute Risk of Breast Cancer After 5 Years of HT WHI results indicate a hazard risk for breast cancer of 1.24 (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) American Cancer Society. Breast Cancer Facts and Figures 2001–2002. Available at: downloads/STT/BrCaFF2001.pdf; Chlebowski RT, et al. JAMA. 2003;289:

26 Nonsignificant. Chlebowski RT, et al. JAMA. 2003;289: WHI: Risk of Invasive Breast Cancer in Women With and Without Prior HT Use Prior HT Use None <5 Years 5 Years Overall % of Population Hazard Ratio (95% CI)

27 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

28 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

29 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 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:

30 Cumulative Amenorrhea Rates: CEE/MPA for EE Population (n = 1555) 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: / / / /1.5 Placebo Women's HOPE Study

31 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 Espeland MA, et al. J Clin Endocrinol Metab. 1997;82: ; Matthews KA, et al. Int J Obes Relat Metab Disord. 2001;25:863-73; Sites CK, et al. Metabolism. 2001;50:

32 Placebo CEE mg CEE/MPA (con) mg/2.5 mg CEE/MPA (cyc) mg/10 mg CEE/MP (cyc) mg/200 µg *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: Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial Weight Change (kg) * Body Weight Changes After 3 Years of Treatment

33 Placebo n = 218 Treatment Groups Mean Change From Baseline (kg) 0.625/2.5 n = /1.5 n = mg n = mg n = mg n = 235 CEECEE/MPA Utian WH, Pickar JH. Obstet Gynecol. 2002;99(suppl):57S. Mean Change in Weight After 13 Cycles Women's HOPE Study 0.45/2.5 n = /1.5 n = 213

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

35 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

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

37 Steroids Native Synthetic Chemically synthesized from a natural material such as soy, Mexican yam 17 -estradiol (E 2 ) 17 -estradiol (E 2 ) Estrone Estrone Estrone sulfate Estrone sulfate Synthetic conjugated estrogens Synthetic conjugated estrogens Esterified estrogens Esterified estrogens Estriol Estriol Natural Found in Nature Synthetic Laboratory Synthesized Natural Source No chemical modifications CEE CEE Ethinyl estradiol (EE) Ethinyl estradiol (EE) Diethylstilbestrol Diethylstilbestrol Classifications of Estrogens: Natural Versus Synthetic

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

39 Classification of Progestins Steroids Natural Found in Nature Synthetic Laboratory Synthesized Pregnane Derivatives MPA MPA Megestrol acetate Megestrol acetate Cyproterone acetate Cyproterone acetate Chlormadinone acetate Chlormadinone acetate Medrogestone Medrogestone Dydrogesterone Dydrogesterone Structurally Related to Progesterone Structurally Related to Testosterone 19-Norpregnane Derivatives Nomegestrol acetate Nomegestrol acetate Demegestone Demegestone Trimegestone Trimegestone Promegestone Promegestone Nesterone NesteroneNonethinylated Dienogest Dienogest Drospirenone Drospirenone Ethinylated Norethindrone Norethindrone Norethynodrel Norethynodrel Lynestrenol Lynestrenol Norethindrone acetate (NETA) Norethindrone acetate (NETA) Tibolone Tibolone Ethynodiol acetate Ethynodiol acetate Levonorgestrel Levonorgestrel Desogestrel Desogestrel Norgestimate Norgestimate Gestodene Gestodene Stanczyk FZ. Rev Endocr Metab Disord. 2002;3: Native Synthetic Progesterone Progesterone

40 Percent Change From Baseline After 12 Months of Therapy * Metabolic Effects of Oral E+P Regimens *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. Regimen Total CholesterolLDL-CHDL-CTriglycerides CEE/MPA 0.625/2.5–2.2– CEE/MPA 0.45/1.5–2.6– EE/NETA 0.05/1–7.0–7.5– E 2 /NETA 1/0.5–10.5–10.8– E 2 /Norgestimate 1/0.09–

41 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 Sturdee DW, et al. Br J Obstet Gynaecol. 2000;107:

42 PEPI Trial *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: n = PlaceboCEECEE/MPA (con) CEE/MPA (cyc) CEE/MP (cyc) mg0.625 mg/2.5 mg mg/10 mg mg/200 µg 3(2.5%) 74(62%) 1(<1%) 6(5%) 6(5%) Endometrial Effects After 3 Years of HT

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

44 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:

45 Low- and Standard-Dose HT Preparations Available in the US Oral (mg)Transdermal (mg) Low-dose estrogenCEE 0.45 CEE 0.30 Esterified estrogens 0.30 E E E Standard-dose estrogenCEE Esterified estrogens Estropipate E E 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* E 2 1.0/NETA 0.5 E 2 1.0/norgestimate 0.09 EE 0.005/NETA 1.0 E /NETA 0.25 *MPA 5.0 mg is used continuously or sequentially with CEE mg; Norgestimate is used intermittently with E mg.

46 Effect of Low Doses of Transdermal Estrogen on Vasomotor Symptoms Mean Hot Flush Frequency (number per week) *P <.05 at weeks P <.05 at week 2; P <.01 at weeks n = 324. TS = transdermal system; E 2 -TS = estradiol 0.02 mg/day provided in one or two 7-day transdermal delivery systems. Speroff L, et al. Obstet Gynecol. 1996;88: Placebo-TS 2 Placebo-TSs E 2 -TS (0.02 mg/day)* 2 E 2 -TSs (0.04 mg/day)

47 Effect of Various Transdermal Estrogen Doses on Spinal BMD *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: * * * * * * * * * * * * * * * E mg/day E mg/day E mg/day E mg/day Placebo

48 The Womens Health, Osteoporosis, Progestin, Estrogen (Womens HOPE) Study

49 Women's HOPE Study 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 Design Utian WH, et al. Fertil Steril. 2001;75:

50 Women's HOPE Study 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: Treatment Groups Placebo 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

51 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: Demographic and Baseline Characteristics Total (n = 2673) Mean ± SD Age (years) Age at menopause (years) Years since menopause Weight (kg) BMI (kg/m 2 ) 53.3 ± ± ± ± ± 2.8 Women's HOPE Study

52 Placebo 0.45/ / / /1.5 Placebo *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. Change in Number of Hot Flushes Over 12 Weeks (n = 241) Women's HOPE Study

53 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. Placebo / /2.5 Placebo 0.45/ /1.5 Changes in Severity of Hot Flushes Over 12 Weeks (n = 241) Women's HOPE Study

54 Improvement in Vaginal Maturation Index Compared With Baseline and Placebo* *P <.05 vs baseline and placebo for all active treatment groups at all time points; P <.05 vs CEE Utian WH, et al. Fertil Steril. 2001;75: Superficial Cells (%), Median Change from Baseline Treatment Groups mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg PlaceboCEECEE/MPA Median Change = 0

55 Cumulative Amenorrhea Rates: CEE/MPA for EE Population (n = 1555) 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: / / / /1.5 Placebo Women's HOPE Study

56 0.45/ / / /1.5 Placebo 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: Cumulative No Bleeding Rates: CEE/MPA for EE Population (n = 1555) Women's HOPE Study

57 LDL Cholesterol Women's HOPE Study Mean Percent Change From Baseline * * * * * * * * * * * * * Cycle 6 Cycle 13 Treatment Groups mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg PlaceboCEECEE/MPA *P <.05 vs baseline. P <.05 vs placebo. Lobo RA, et al. Fertil Steril. 2001;76: *

58 Mean Change From Baseline (%) * * * * * * * * * * * * * * Treatment Groups mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg PlaceboCEECEE/MPA *P <.05 vs baseline. P <.05 vs placebo. P <.05 vs comparable CEE alone. Lobo RA, et al. Fertil Steril. 2001;76: HDL Cholesterol Women's HOPE Study Cycle 6 Cycle 13

59 Mean Change From Baseline (%) * * * * * * * * * * * * * * Treatment Groups mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg PlaceboCEECEE/MPA * *P <.05 vs baseline. P <.05 vs placebo. P <.05 vs comparable CEE alone. Lobo RA, et al. Fertil Steril. 2001;76: Triglycerides Women's HOPE Study Cycle 6 Cycle 13

60 CEE CEE/MPA Intent-to-treat population only. Lindsay R, et al. JAMA. 2002;287: Changes in Spine BMD Women's HOPE Study

61 Intent-to-treat population only. Lindsay R, et al. JAMA. 2002;287: Changes in Total Hip BMD Women's HOPE Study CEE CEE/MPA

62 Pickar JH, et al. Fertil Steril. 2003;80: Endometrial Hyperplasia Rates After 1 and 2 Years of Low-Dose E+P Women's HOPE Study Hyperplasia Rate (%) 0.00 Year 1 Year 2 Treatment Groups mg0.625/ 2.5 mg 0.45 mg0.45/ 2.5 mg 0.45/ 1.5 mg 0.3 mg0.3/ 1.5 mg PlaceboCEECEE/MPA

63 Hyperplasia Rate After 12 Months (%) n = P <.001 for all continuous-combined groups vs unopposed E 2. Kurman RJ, et al. Obstet Gynecol. 2000;96: Endometrial Hyperplasia Rates With Lower Doses of NETA E 2 1 mgE 2 1 mg/NETA 0.1 mg E 2 1 mg/NETA 0.25 mg E 2 1 mg/NETA 0.5 mg

64 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

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

66 Non-Oral Estrogen and Progestin Formulations Estrogen –Estradiol ring –Nasal estradiol –Estradiol gel –Vaginal estrogen Progestin –Levonorgestrel IUD/IUS –Vaginal progesterone gel –Trimegestone –Lotion

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

68 Non-HT Alternatives for Menopausal Health Issues Lifestyle modifications Menopausal complaints –Non-prescription therapies –Prescription therapies Osteoporosis therapies Lipid-lowering drugs Neurocognitive therapies

69 1 Eisenberg DM, et al. JAMA. 1998;280: ; 2 Rafferty AP, et al. Am J Public Health. 2002;92: Newton KM, et al. Obstet Gynecol. 2002;100: Scope of Alternative Medicine Use in the US Adults surveyed Utilization prevalence (%) Number of visits (millions) Covered by insurance (%)3642

70 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. Proportion of Women Using Alternative Therapies for Any Reason and for Menopausal Symptoms Ever Used Using Now Used for Menopausal Symptoms Herbal Remedies Chiropractic Massage Therapy Dietary Soy Products Acupuncture Homeopathic Physician Visit Herbalist Visit Relaxation or Stress Management

71 1 McTiernan A, et al. JAMA. 2003;290:1331-6; 2 Thune I, et al. N Engl J Med. 1997;336: ; 3 Li CI, et al. Cancer Epidemiol Biomark Prev. 2003;12:1061-6; 4 Huang Z, et al. JAMA. 1997;278: ; 5 Morimoto LM, et al. Cancer Causes Control. 2002;13:741-51; 6 Reynolds P, et al. J Natl Cancer Inst. 2004;96: Lifestyle Choices That Increase Breast Cancer Risk Lack of exercise 1,2 –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 Alcohol 3 –RR = 1.3 (95% CI, 1.0–1.5; ever-use of alcohol over the past 20 years) Obesity 4,5 –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/m 2 (95% CI, 1.62–3.93) 5 Cigarette smoking 6 –HR = 1.32 (95% CI, 1.10–1.57; relative to all never smokers)

72 Magnitude of Various Risk Factors for Breast Cancer Family History (2 Members) HT for 5 Years ObesityBMI >31.1 kg/m 2 Family History (1 Member) Age at Menarche (Delayed) 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: Lack of Exercise

73 Non-HT Alternatives for Vasomotor Symptoms Lifestyle changes (limited effectiveness) –Cooling body core temperature –Exercise –Avoiding hot and spicy foods –Pace respirations –Relaxing activities North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-13; Huntley AL, Ernst E. Menopause. 2003;10:

74 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 North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-13; Huntley AL, Ernst E. Menopause. 2003;10:

75 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

76 ER = estrogen receptor. Scheiber MD, Rebar RW. Menopause. 1999;6: Phytoestrogens Nonsteroidal plant-derived compounds that bind to ERs –Some bind weakly to ER –Many bind strongly to ER 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)

77 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 North American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:

78 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 Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:

79 Design of Trials Evaluating Black Cohosh for Menopausal Symptoms Huntley AL, Ernst E. Menopause. 2003;10: Warnecke G. Medwelt. 1985;36:871-4; 2 Stoll W. Therapeutikon. 1987:1-15; 3 Lehmann-Willenbrock VE, Reiedel HH. Zentrabl Gynakol. 1988;110:611-8; 4 Jacobson JS, et al. J Clin Oncol. 2001;19: Study DesignParticipantsActive Treatment (n)Control (n) 2 week, open- label 1 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-blind 2 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- label 3 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- blind 4 n = 85 breast cancer patients with menopausal symptoms 1 black cohosh tablet twice daily with food (42) Placebo (43)

80 KI = Kupperman Index; HAMA = Hamilton Anxiety Scale; NS = not significant. Huntley AL, Ernst E. Menopause. 2003;10: Warnecke G. Medwelt. 1985;36:871-4; 2 Stoll W. Therapeutikon. 1987:1-15; 3 Lehmann-Willenbrock VE, Reiedel HH. Zentrabl Gynakol. 1988;110:611-8; 4 Jacobson JS, et al. J Clin Oncol. 2001;19: Results of Trials Evaluating Black Cohosh for Menopausal Symptoms ReferenceResults 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

81 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 endometrium 1-3 Mixed results in randomized, placebo-controlled, hot-flush trials 4,5 1 Cooper A, et al. Lancet. 1998;351:1255-6; 2 Wren BG, et al. Lancet. 1999;354:1447-8; 3 Lewis JG, et al. Maturitas. 2002;41:1-6; 4 Komesaroff PA, et al. Climacteric. 2001;4:144-50; 5 Leonetti HB, et al. Obstet Gynecol. 1999;94:225-8.

82 Progestins for the Treatment of Vasomotor Symptoms North American Menopause Society. Menopause. 2004;11: ProgestinNDoseEfficacy MPA Oral2720 mg/d 25.9%–34.5% in hot flushes MPA Depot21100 mg BID 67%–80% in hot flushes Depo71500 mg + 40 mg megestrol 95% in hot flushes Megestrol15500 mg weekly 69% in hot flushes Progestin42150 mg 85% vs21% placebo

83 Nonhormonal Prescription Therapies Antidepressants –SSRI/SNRI therapy –Venlafaxine –Paroxetine –Fluoxetine Anti-convulsants –Gabapentin Anti-hypertensives –Clonidine (patch or pill) and methyldopa Sedatives –Bellergal

84 Clinical Trials of Median Hot Flush Score Reduction in Breast Cancer Patients NOTE: These data are not from head-to-head trials. Loprinzi CL, et al. Lancet Oncol. 2001;2: Week Median Score Placebo (n = 347) Soy (n = 66) Clonidine (n = 75) Fluoxetine (n = 20) Vitamin E (n = 57) Venlafaxine (n = 45) Megestrol (n = 74)

85 Nonhormonal Prescription Therapies: Venlafaxine *Decrease of hot flush score. Schober CE, Ansani NT. Ann Pharmacother. 2003;37: Loprinzi CL, et al. J Clin Oncol. 1998;16: ; 2 Loprinzi CL, et al. Lancet. 2000;356: ; 3 Barton D, et al. Oncol Nurs Forum. 2002;29: Study Design and DurationPopulation (n) Venlafaxine DosageEfficacy ResultsP-Value Prospective pilot; 5 weeks 1 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 following 2 Women with history of or fear of breast cancer, tamoxifen use, or reluctance to take HT (229) Placebo, 37.5 mg qd, 75 mg qd, 150 mg qd From baseline: 27% 37% 61% 61%.01*.01* NS Open-label, continuation phase; 8 weeks 3 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

86 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 CL, et al. J Clin Oncol. 2002;20:

87 Nonhormonal Prescription Therapies: Paroxetine 165 women, 18 years of age or older Experiencing 2 to 3 hot flushes per day Stearns V, et al. JAMA. 2003;289: 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%

88 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 T, Jr, et al. Obstet Gynecol. 2003;101:

89 Nonhormonal Prescription Therapies: Clonidine Randomized, double-blind, placebo-controlled clinical trial 1 –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 dizziness 2 1 Pandya KJ, et al. Ann Intern Med. 2000;132: Goldberg RM, et al. J Clin Oncol. 1994;12:155-8.

90 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 Adapted from North American Menopause Society. Menopause. 2004;11:11-33.

91 *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: Current Management of Osteoporosis: A Review Therapy* Decreases Vertebral Fracture Rates Decreases Hip Fracture Rates Approximate Increases in BMD (%) Most Common Side Effect HTYes 5–6Breakthrough bleeding Alendronate § Yes 5–8Gastric ulceration Risedronate § Yes 5–6Upper GI symptoms Raloxifene § YesNo1–2Hot flushes CalcitoninYesNo1–2Nasal irritation PTHYesNo9Leg cramps; dizziness

92 Non-pharmacological treatment calcium: 1500 mg/day Vitamin D: 800 IU/day Physical activity: >30 min at least 3 times a week Without fragility fractureWith fragility fracture Vasomotor symptoms YesNo HT Alendronate, risedronate, raloxifene, calcitonin Calcitonin, etidronate, HT 1st choice 2nd choice Osteoporosis Prevention and Treatment Alendronate, risedronate, and raloxifene 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. Vasomotor symptoms YesNo Calcitonin, etidronate, HT Alendronate, risedronate, and raloxifene Calcitonin, raloxifene, etidronate HT ± alendronate or risedronate

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

94 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

95 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

96 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 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.

97 What to Remember When Obtaining Informed Consent Avoid medical jargon; pay close attention to the patients 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 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.

98 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 American College of Obstetricians and Gynecologists. ACOG News Release. Available at: Accessed 8/19/02. Writing Group for the Womens Health Initiative Investigators. JAMA. 2002;288:

99 Counseling on Duration of HT Use 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 Individualized Therapy


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