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

Patient Management Issues in Menopause

A CME Slide Library From the

Council on Hormone Education


Section 1: Appropriate Use of HT

Section 2: Barriers to Appropriate Use of HT

Section 3: Importance of Individualizing HT3a. Characteristics of Estrogens3b. Characteristics of Progestins3c. Use of Low-Dose HT3d. 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


Percentage

Menopause-relatedSymptoms

Osteoporosis, Bone Loss,Fracture Prevention

Doctor Prescribed It,Told Me to Take It

Cardiovascular DiseasePrevention

Other

Depression, Anxiety,Emotional Distress

0 10 20 30 40 50 60

Newton KM, et al. J Womens Health. 1997;6:459-65.

Reasons Women Gave for Initiating or Continuing HT

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: http://www.fda.gov/cder/guidance/5417dft.pdf. Accessed 1/04.

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

Chlebowski RT, et al. JAMA. 2003;289:3243-53.

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.1Manson JE, et al. N Engl J Med. 2003;349:523-34; 2Cauley JA, et al. JAMA. 2003;290:1729-38; 3Shumaker SA, et al. JAMA. 2003;289:2651-62.

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.1Anderson GL, et al. JAMA. 2003;290:1739-48; 2Hays J, et al. N Engl J Med. 2003;348:1839-54.

WHI Updated Results Summary: Gynecologic Cancers, QOL

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;289:2673-84.

Study ConsiderationsWHI

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

*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;289:3243-53; 3Shumaker SA, et al. JAMA. 2003;289:2651-62; 4Wassertheil-Smoller S, et al. JAMA. 2003;289:2673-84; 5Writing Group for the WHI Investigators. JAMA. 2002;288:321-33; 6Anderson GL, et al. JAMA. 2003; 290:1739-48; 7Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004; 8Cauley JA, et al. JAMA. 2003;290:1729-38.

WHI: Results With CEE/MPACHD1

Breast Cancer2

Dementia3*†

Stroke4

VTE5

Endometrial Cancer6

Ovarian Cancer6

Colorectal Cancer7

Hip Fracture8

Total Fracture8*

Death5

HR0.5 1.0 5.02.0

95% nCI

95% aCI

EventOverall

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 1.24 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 8

Colorectal cancer6 0.56 0.38–0.81 0.33–0.94 6

Hip fractures7 0.67 0.47–0.96 0.41–1.10 5

Total fractures7 0.76 0.69–0.83 — 47

WHI Results: Overall Relative and Attributable Risk

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;289:3243-53; 3Shumaker SA, et al. JAMA. 2003;289:2651-62; 4Wassertheil-Smoller S, et al. JAMA. 2003;289:2673-84; 5Writing Group for the WHI Investigators. JAMA. 2002;288:321-33; 6Chlebowski RT, et al. N Engl J Med. 2004;350:991-1004; 7Cauley JA, et al. JAMA. 2003;290:1729-38.

WHI Summary

Results from WHI indicate that CEE 0.625 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;288:321-33.

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 symptoms1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; 2Brett KM, Ruben CA. Am J Obstet Gynecol. 2003;102:1240-9. 3North American Menopause Society. Menopause. 2003;10:497-506.

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;102:1225-32.

American College of Obstetricians and Gynecologists (ACOG). Statement on the Estrogen Plus Progestin Trial of the Women’s Health Initiative. July 9, 2002. Available at: http://www.acog.org/from_home/publications/press_releases/nr07-09-02.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 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

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;10:497-506.

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;10:497-506.

National Institutes of Health (NIH). National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. Available at: http://www.nhlbi.nih.gov/health/women/pht_facts.htm. 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

Section 2:

Barriers to Appropriate

Use of HT


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

Women’s Perceptions of Their Greatest Health Problems

Adapted from Mosca L, et al. Arch Fam Med. 2000;9:506-15.

Breast Cancer

Cancer

Other Problems

Cardiovascular Disease

Don’t Know/ No Answer

34%34%

27%27%

16%16%

7%7%

16%

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 LowerRespiratory

Disease

Cerebrovascular Disease

Breast Cancer 34%

10%10%

6%6%

3%3%

15%15%

28%

4%4%

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: http://www.cancer.org/downloads/STT/BrCaFF2001.pdf.

In 100 women, 2.8 are at riskIn 100 women, 2.8 are at risk

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 3.5 of 100 women who are HT users are at risk (<1 additional woman over baseline risk)(<1 additional woman over baseline risk)

3.5 of 100 women who are HT users are at risk 3.5 of 100 women who are HT users are at risk (<1 additional woman over baseline risk)(<1 additional woman over baseline risk)

American Cancer Society. Breast Cancer Facts and Figures 2001–2002. Available at: http://www.cancer.org/downloads/STT/BrCaFF2001.pdf; Chlebowski RT, et al. JAMA. 2003;289:3243-53.

Nonsignificant.Chlebowski RT, et al. JAMA. 2003;289:3243-53.

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

74.0

14.8

11.2

100

Hazard Ratio (95% CI)

0.1 0.5 1.0 4.02.0 6.0

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

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

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;96:899-905; Lerner S. Menopause. 1995;2:175-80.

Cumulative Amenorrhea Rates: CEE/MPAfor EE Population (n = 1555)

75.5

86.182.1

88.996.0

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13

Cycle

Pat

ien

ts (

%)

EE = Efficacy-evaluable population included women who recorded taking study medicationand completed all 13 cycles without missing data on bleeding.Archer DF, et al. Fertil Steril. 2001;75:1080-7.

0.45/2.50.625/2.5

0.45/1.50.3/1.5

Placebo

72.8

51.846.2

41.8

27.9

Women's HOPE Study

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;82:1549-56; Matthews KA, et al. Int J Obes Relat Metab Disord. 2001;25:863-73; Sites CK, et al. Metabolism. 2001;50:835-40.

0.0

0.5

1.0

1.5

2.0

2.5

Placebo CEE0.625 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

*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;82:1549-56.

Postmenopausal Estrogen/Progestin Intervention (PEPI) TrialW

eig

ht

Ch

ang

e (

kg) **

Body Weight Changes After 3 Years of Treatment

0

1

2

3

Placebon = 218

Treatment Groups

Mea

n C

han

ge

Fro

m B

asel

ine

(kg

)

0.625/2.5n = 241

0.45/1.5n = 228

0.625 mgn = 212

0.45 mgn = 231

0.3 mgn = 235

CEE CEE/MPA

Utian WH, Pickar JH. Obstet Gynecol. 2002;99(suppl):57S.

Mean Change in Weight After 13 CyclesWomen's HOPE Study

0.45/2.5n = 232

0.3/1.5n = 213

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

Section 3a:

Characteristics of Estrogens


SteroidsSteroids

Native Native Synthetic Synthetic

Chemically synthesized Chemically synthesized from a natural material from a natural material such as soy, Mexican yamsuch as soy, Mexican yam 1717-estradiol (E-estradiol (E22)) EstroneEstrone Estrone sulfateEstrone sulfate Synthetic conjugated Synthetic conjugated estrogensestrogens Esterified estrogensEsterified estrogens EstriolEstriol

NaturalNaturalFound in NatureFound in Nature

SyntheticSyntheticLaboratory SynthesizedLaboratory Synthesized

Natural SourceNatural Source

No chemical No chemical modificationsmodifications CEECEE

Ethinyl estradiol (EE)Ethinyl estradiol (EE) DiethylstilbestrolDiethylstilbestrol

Classifications of Estrogens: Natural Versus Synthetic

Section 3b:

Characteristics of Progestins


Classification of ProgestinsSteroidsSteroids

NaturalNaturalFound in NatureFound in Nature

SyntheticSyntheticLaboratory SynthesizedLaboratory Synthesized

Pregnane DerivativesPregnane Derivatives• MPAMPA• Megestrol acetateMegestrol acetate• Cyproterone Cyproterone

acetateacetate• Chlormadinone Chlormadinone

acetateacetate• MedrogestoneMedrogestone• DydrogesteroneDydrogesterone

Structurally Related Structurally Related to Progesteroneto Progesterone

Structurally Related Structurally Related to Testosteroneto Testosterone

19-Norpregnane 19-Norpregnane DerivativesDerivatives

• Nomegestrol Nomegestrol acetateacetate

• DemegestoneDemegestone• TrimegestoneTrimegestone• PromegestonePromegestone• NesteroneNesterone

NonethinylatedNonethinylated• DienogestDienogest• DrospirenoneDrospirenone

EthinylatedEthinylated• NorethindroneNorethindrone• NorethynodrelNorethynodrel• LynestrenolLynestrenol• Norethindrone Norethindrone

acetate (NETA)acetate (NETA)• TiboloneTibolone• Ethynodiol acetateEthynodiol acetate• LevonorgestrelLevonorgestrel• DesogestrelDesogestrel• NorgestimateNorgestimate• GestodeneGestodene

Stanczyk FZ. Rev Endocr Metab Disord. 2002;3:211-24.

Native Native Synthetic Synthetic• ProgesteroneProgesterone

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 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 –6.7 12.1

E2/NETA 1/0.5 –10.5 –10.8 –12.4 2.2

E2/Norgestimate 1/0.09 –1.9 1.2 9.7 9.4

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;107:1392-400.

0

20

40

60

80

Nu

mb

er o

f P

atie

nts

Wit

h

Po

siti

ve B

iop

sies

*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;275:370-5.

n = 119 119 118 120120

Placebo CEE CEE/MPA (con) CEE/MPA (cyc) CEE/MP (cyc)0.625 mg 0.625 mg/2.5 mg 0.625 mg/10 mg 0.625 mg/200 µg

33(2.5%)(2.5%)

7474(62%)(62%)

11(<1%)(<1%)

66(5%)(5%)

66(5%)(5%)

Endometrial Effects After 3 Years of HT

Section 3c:

Use of Low-Dose HT


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;100:1344-53.American College of Obstetricians and Gynecologists. ACOG News Release. Available at: http://www.acog.org/from_home/publications/press_releases/nr08-30-02.cfm. Accessed 12/18/02.North American Menopause Society. Amended Report from the NAMS Advisory Panel on Postmenopausal Hormone Therapy. Available at: http://www.menopause.org/news.html#advisory. Accessed 12/18/02.Society of Obstetricians and Gynaecologists of Canada (SOGC). Can Fam Physician. 2004;49:188-91.

Low- and Standard-Dose HT Preparations Available in the US

Oral (mg) Transdermal (mg)

Low-dose estrogen CEE 0.45CEE 0.30Esterified estrogens 0.30E2 0.50

E2 0.0375E2 0.0250

Standard-dose estrogen CEE 0.625Esterified estrogens 0.625Estropipate 0.625E2 1.0

E2 0.05

Low-dose estrogen + low-dose progestin

CEE 0.45/MPA 1.5CEE 0.30/MPA 1.5

Standard-dose estrogen + standard-dose or low-dose progestin

CEE 0.625/MPA 2.5CEE 0.625/MPA 5.0*E2 1.0/NETA 0.5E2 1.0/norgestimate 0.09†

EE 0.005/NETA 1.0

E2 0.05/NETA 0.25E2 0.05/NETA 0.25

*MPA 5.0 mg is used continuously or sequentially with CEE 0.625 mg; †Norgestimate is used intermittently with E2 1.0 mg.

0

25

50

75

1 2 3 4 5 6 7 8 9 10 11 12

Week

Effect of Low Doses of Transdermal Estrogen on Vasomotor Symptoms

Me

an

Ho

t F

lush

Fre

qu

en

cy(n

um

be

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er

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*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;88:587-92.

Placebo-TS

2 Placebo-TSs

E2-TS (0.02 mg/day)*

2 E2-TSs (0.04 mg/day)†

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;22:845-57.

*

* **

*

* * *

** *

****

-4-3-2-101234567

0 26 52 78 104

Treatment Duration (week)

Ch

an

ge

in

BM

D

Fro

m B

as

elin

e (

%)

E2 0.1 mg/day

E2 0.05 mg/day

E2 0.0375 mg/day

E2 0.025 mg/day

Placebo

The Women’s Health, Osteoporosis, Progestin, Estrogen

(Women’s HOPE) Study

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;75:1065-79.

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;75:1065-79.

8 Treatment Groups

PlaceboCEE 0.625 mg

CEE 0.45 mg

CEE 0.3 mg

CEE 0.625 mg + MPA 2.5 mg



CEE 0.3 mg +MPA 1.5 mg

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;75:1065-79.

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

Women's HOPE Study

0

2

4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11 12

Week

Ad

jus

ted

Me

an

Da

ily N

um

be

r*0

2

4

6

8

10

12

1 2 3 4 5 6 7 8 9 10 11 12

Week

Ad

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ted

Me

an

Da

ily N

um

be

r* 0.6250.450.3

Placebo

0.45/2.50.625/2.5

0.45/1.50.3/1.5

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;75:1065-79. Used with permission.

Change in Number of Hot Flushes Over 12 Weeks (n = 241)

Women's HOPE Study

0.0

0.5

1.0

1.5

2.0

2.5

1 2 3 4 5 6 7 8 9 10 11 12

Week

Me

an

Se

ve

rity

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;75:1065-79. Used with permission.

0.0

0.5

1.0

1.5

2.0

2.5

1 2 3 4 5 6 7 8 9 10 11 12

Week

Me

an

Se

ve

rity

Placebo 0.6250.450.3

0.45/1.5

0.625/2.5Placebo

0.45/2.5

0.3/1.5

Changes in Severity of Hot Flushes Over 12 Weeks (n = 241)

Women's HOPE Study

Women's HOPE StudyImprovement 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 0.625Utian WH, et al. Fertil Steril. 2001;75:1065-79.

Su

per

fici

al C

ells

(%

),

Med

ian

Ch

ang

e fr

om

Bas

elin

e

0

5

10

15

20

25Cycle 6

Cycle 13

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

PlaceboCEE CEE/MPA

†

† †

Median Change = 0

Cumulative Amenorrhea Rates: CEE/MPAfor EE Population (n = 1555)

75.5

86.182.1

88.996.0

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13

Cycle

Pat

ien

ts (

%)


0.45/2.50.625/2.5

0.45/1.50.3/1.5

Placebo

72.8

51.846.2

41.8

27.9

Women's HOPE Study

0

20

40

60

80

100

1 2 3 4 5 6 7 8 9 10 11 12 13

Cycle

Pat

ien

ts (

%)

0.45/2.50.625/2.5

0.45/1.50.3/1.5

Placebo


Cumulative No Bleeding Rates: CEE/MPAfor EE Population (n = 1555)

Women's HOPE Study

98.894.593.891.886.3

53.9

64.9

66.7 69.8

89.6

LDL CholesterolWomen's HOPE Study

Mea

n P

erce

nt

Ch

ang

eF

rom

Bas

elin

e

-15

-10

-5

0

5

*†*† *†

*†

*†

*†

*† *†

†

*†

*†

*†*† *†

Cycle 6

Cycle 13

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

PlaceboCEE CEE/MPA

*P < .05 vs baseline.†P < .05 vs placebo.Lobo RA, et al. Fertil Steril. 2001;76:13-24.

*

Mea

n C

han

ge

Fro

m B

asel

ine

(%)

0

2

4

6

8

10

12

14

16

18

20

*†‡

*‡

*†

*†

*†

*†

*†

*†‡

*†

*†‡*†

*†

*‡ *‡

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

PlaceboCEE CEE/MPA

*P < .05 vs baseline.†P < .05 vs placebo.‡P < .05 vs comparable CEE alone.Lobo RA, et al. Fertil Steril. 2001;76:13-24.

HDL CholesterolWomen's HOPE Study

Cycle 6

Cycle 13

Mea

n C

han

ge

Fro

m B

asel

ine

(%)

0

5

10

15

20

25

30

35

40

45

*†

*†

*†*†

*†

*‡*† *

*

*†

*‡

*†

* *

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

PlaceboCEE CEE/MPA

*

*P < .05 vs baseline.†P < .05 vs placebo.‡P < .05 vs comparable CEE alone.Lobo RA, et al. Fertil Steril. 2001;76:13-24.

TriglyceridesWomen's HOPE Study

Cycle 6

Cycle 13

-4

-3

-2

-1

0

1

2

3

4

Baseline 6 mo 12 mo 18 mo 24 mo

CEE 0.625/MPA 2.5 mg/dayCEE 0.45/MPA 2.5 mg/dayCEE 0.45/MPA 1.5 mg/dayCEE 0.3/MPA 1.5 mg/dayPlacebo

-4

-3

-2

-1

0

1

2

3

4


Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

CEE 0.625 mg/dayCEE 0.45 mg/day

CEE 0.3 mg/dayPlacebo

CEE CEE/MPA

Intent-to-treat population only.Lindsay R, et al. JAMA. 2002;287:2668-76.

Changes in Spine BMDWomen's HOPE Study

-4

-3

-2

-1

0

1

2

3

4


Me

an

Ch

an

ge

Fro

m B

as

eli

ne

(%

)

CEE 0.625 mg/dayCEE 0.45 mg/day

CEE 0.3 mg/dayPlacebo

-4

-3

-2

-1

0

1

2

3

4


CEE 0.625/MPA 2.5 mg/dayCEE 0.45/MPA 2.5 mg/dayCEE 0.45/MPA 1.5 mg/dayCEE 0.3/MPA 1.5 mg/dayPlacebo

Intent-to-treat population only.Lindsay R, et al. JAMA. 2002;287:2668-76.

Changes in Total Hip BMDWomen's HOPE Study

CEE CEE/MPA

Pickar JH, et al. Fertil Steril. 2003;80:1234-40.

Endometrial Hyperplasia Rates After 1 and 2 Years of Low-Dose E+P

Women's HOPE Study

0

5

10

15

20

25

30

Hy

per

pla

sia

Ra

te (

%)

0.000.000.000.000.000.00

Year 1

Year 2

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

PlaceboCEE CEE/MPA

0

2

4

6

8

10

12

14

16

Hy

per

pla

sia

Ra

te A

fter

1

2 M

on

ths

(%

)

n = 1176.P < .001 for all continuous-combined groups vs unopposed E2.Kurman RJ, et al. Obstet Gynecol. 2000;96:373-9.

Endometrial Hyperplasia Rates With Lower Doses of NETA

E2 1 mg E2 1 mg/NETA0.1 mg

E2 1 mg/NETA0.25 mg

E2 1 mg/NETA0.5 mg

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

Section 3d:

Non-Oral HT Formulations


Non-Oral Estrogen and Progestin Formulations

Estrogen

– Estradiol ring

– Nasal estradiol

– Estradiol gel

– Vaginal estrogen

Progestin

– Levonorgestrel IUD/IUS

– Vaginal progesterone gel

– Trimegestone

– Lotion

Section 4:

Non-HT Alternatives for

Menopausal Symptoms


Non-HT Alternatives for Menopausal Health Issues

Lifestyle modifications

Menopausal complaints

– Non-prescription therapies

– Prescription therapies

Osteoporosis therapies

Lipid-lowering drugs

Neurocognitive therapies

1Eisenberg DM, et al. JAMA. 1998;280:1569-75; 2Rafferty AP, et al. Am J Public Health. 2002;92:1598-600.Newton KM, et al. Obstet Gynecol. 2002;100:18-25.

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 —

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

0 10 20 30 40 50

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

1McTiernan A, et al. JAMA. 2003;290:1331-6; 2Thune I, et al. N Engl J Med. 1997;336:1269-75; 3Li CI, et al. Cancer Epidemiol Biomark Prev. 2003;12:1061-6; 4Huang Z, et al. JAMA. 1997;278:1407-11; 5Morimoto LM, et al. Cancer Causes Control. 2002;13:741-51; 6Reynolds P, et al. J Natl Cancer Inst. 2004;96:29-37.

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)

0

2

4

6

8

10

12

14

16

Rel

ativ

e R

isk

Magnitude of Various Risk Factors for Breast Cancer

Family History

(2 Members)

HT for 5 Years

ObesityBMI >31.1 kg/m2

Family History

(1 Member)

Age at Menarche (Delayed)

Huang Z, et al. JAMA. 1997;278:1407-11; Thune I, et al. N Engl J Med. 1997;336:1269-75; Longnecker MP, et al. Cancer Epidemiol Biomark Prev. 1995;4:721-5; McTiernan A, et al. JAMA. 2003;290:1331-6.

Lack of Exercise

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;10:465-76.

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;10:465-76.

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

ER = estrogen receptor.Scheiber MD, Rebar RW. Menopause. 1999;6:233-41.

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)

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 placeboNorth American Menopause Society. Menopause. 2004;11:11-33; Kronenberg F, Fugh-Berman A. Ann Intern Med. 2002;137:805-13.

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;137:805-13.

Design of Trials Evaluating Black Cohosh for Menopausal Symptoms

Huntley AL, Ernst E. Menopause. 2003;10:465-76.1Warnecke 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;19:2739-45.

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, 0.625 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)

KI = Kupperman Index; HAMA = Hamilton Anxiety Scale; NS = not significant.Huntley AL, Ernst E. Menopause. 2003;10:465-76.1Warnecke 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;19:2739-45.

Results of Trials Evaluating Black Cohosh for Menopausal Symptoms

Reference ResultsWarnecke (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

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

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.

Progestins for the Treatment of Vasomotor Symptoms

North American Menopause Society. Menopause. 2004;11:11-33.

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

Progestin 42 150 mg 85% vs21% placebo

Nonhormonal Prescription Therapies

Antidepressants– SSRI/SNRI therapy– Venlafaxine– Paroxetine– Fluoxetine

Anti-convulsants– Gabapentin

Anti-hypertensives– Clonidine (patch or pill) and methyldopa

Sedatives– Bellergal

0

20

40

60

80

100

Baseline 1 2 3 4

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;2:199-204.

Week

Med

ian

Sco

re

Placebo (n = 347)Soy (n = 66)Clonidine (n = 75)Fluoxetine (n = 20)Vitamin E (n = 57)

Venlafaxine (n = 45)

Megestrol (n = 74)

Nonhormonal Prescription Therapies: Venlafaxine

*Decrease of hot flush score.Schober CE, Ansani NT. Ann Pharmacother. 2003;37:1703-7.1Loprinzi CL, et al. J Clin Oncol. 1998;16:2377-81; 2Loprinzi CL, et al. Lancet. 2000;356:2059-63; 3Barton D, et al. Oncol Nurs Forum. 2002;29:33-40.

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, 37.5 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,112.5 mg qd,150 mg qd

From baseline: 26%60%60%60%

Not reported

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;20:1578-83.

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;289:2827-34.

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%

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;101:337-45.

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

1Pandya KJ, et al. Ann Intern Med. 2000;132:788-93.2Goldberg RM, et al. J Clin Oncol. 1994;12:155-8.

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.

*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;7:293-312. Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Endocrine Rev. 2002;23:496-578.

Current Management of Osteoporosis: A Review

Therapy*

Decreases Vertebral

Fracture RatesDecreases Hip Fracture Rates

Approximate Increases in

BMD (%)†

Most Common Side Effect

HT Yes‡ Yes 5–6 Breakthrough bleeding

Alendronate§ Yes‡ Yes 5–8 Gastric ulceration

Risedronate§ Yes Yes 5–6 Upper GI symptoms

Raloxifene§ Yes No 1–2 Hot flushes

Calcitonin Yes No 1–2 Nasal irritation

PTH Yes No 9 Leg cramps; dizziness

Non-pharmacological treatment calcium: 1500 mg/dayVitamin D: 800 IU/day

Physical activity: >30 min at least 3 times a week

Without fragility fracture With fragility fracture

Vasomotor symptoms

Yes No

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

Yes No

Calcitonin,etidronate,

HT

Alendronate, risedronate,

and raloxifene

Calcitonin, raloxifene,etidronate

HT ± alendronate or risedronate

Section 5:

Patient Counseling Strategies


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 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

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.

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

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

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: http://www.acog.org/from_home/publications/press_releases/nr07-09-02.cfm. Accessed 8/19/02.Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-33.

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

Documents

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