The International Menopause Society The IMS Updated Recommendations on postmenopausal hormone...

The International Menopause SocietyThe International Menopause Society

The IMS Updated Recommendationson postmenopausal hormone therapy

February 27, 2007

Climacteric 2007;10:181–94

Introducing Introducing

The International Menopause SocietyThe International Menopause Society

The society for the study of all aspectsof the climacteric in men and women

• Established in 1978

• Registered as a non-profit organization in Geneva, Switzerland

• Central Office in Lancaster, UK

Executive Director: Jean Wright, UK

Introducing Introducing The International Menopause SocietyThe International Menopause Society

Officers and Board, 2005–2008

OfficersPresident: Amos Pines, Israel

General Secretary: David Sturdee, UKTreasurer: Martin Birkhäuser, Switzerland

Santiago Palacios, SpainJames Pickar, USARegine Sitruk-Ware, USASven Skouby, Denmark

Mark Brincat, MaltaTobie De Villiers, South AfricaMarco Gambacciani, ItalyKobchitt Limpaphayom, ThailandFrederick Naftolin, USA

Board members

Introducing Introducing The International Menopause SocietyThe International Menopause Society

The Society’s Journal,The Society’s Journal,

ClimactericClimacteric

• Editors-in-Chief: David W. Sturdee, UKand Alastair H. MacLennan, Australia

• Published in six issues per year plus Supplements

• Indexed in Index Medicus, Medline, Current Contents

• Impact factor: 2.299

• 11th of 52 journals in Obstetrics & Gynecology section

IntroductionIntroduction

• The following Recommendations express the views of the IMS on the principles of hormone therapy (HT) in the peri- and postmenopause periods

• Throughout the Recommendations, the term HT will be used to cover all therapies including estrogens, progestogens, combined therapies and tibolone

• The 2004 IMS Statement is still valid and serves as a basis for the current updated Recommendations



• The IMS is aware of possible geographical variations related to different priorities of medical care, different prevalence of diseases, and country-specific attitudes of the public, the medical community and the health authorities toward menopause management, which may all impact on hormone therapy



• The following recommendations, therefore, give a global and simple overview that serves as a common platform on issues related to the various aspects of hormone treatment

• These Recommendations were reviewed and discussed by representatives of more than 60 national and regional menopause societies from all continents

• These Recommendations can be easily adapted and modified according to local needs


• Hormone therapy should be part of an overall strategy including lifestyle recommendations regarding diet, exercise, smoking and alcohol for maintaining the health of postmenopausal women

Part I. Governing principlesPart I. Governing principles

IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY


• HT must be individualized and tailored according to symptoms and the need for prevention, as well as personal and family history, results of relevant investigations, the woman’s preferences and expectations

• The risks and benefits of HT differ for women around the time of menopause compared to those for older women

• HT includes a wide range of hormonal products and routes of administration, with potentially different risks and benefits

• The term ‘class effect’, when associated with HT, is confusing and inappropriate




• Women experiencing spontaneous or iatrogenic menopause before the age of 45 and particularly before 40 are at higher risk for cardiovascular disease and osteoporosis

• They will benefit from hormone replacement, which should be given at least until the normal age of menopause




• Counseling should convey the benefits and risks of HT in simple terms, e.g. absolute numbers rather than as percentage changes from baseline expressed as a relative risk

• This allows a woman and her physician to make a well-informed decision about HT




• HT should not be recommended without a clear indication for its use




• Women taking HT should have at least an annual consultation to include a physical examination, update of medical history, relevant laboratory and imaging investigations and a discussion on lifestyle

• There are no reasons to place mandatory limitations on the length of treatment

• Whether or not to continue therapy should be decided at the discretion of the well-informed hormone user and her health professional, dependent upon the specific goals and an objective estimation of benefits and risks




• Dosage should be titrated to the lowest effective dose

• Lower doses of HT than have been used routinely can maintain quality of life in a large proportion of users

• Long-term data on lower doses regarding fracture risk and cardiovascular implications are still lacking




• Progestogen should be added to systemic estrogen for all women with a uterus to prevent endometrial hyperplasia and cancer

• Natural progesterone and some progestogens have specific beneficial effects that could justify their use besides the expected actions on the endometrium




• Low-dose vaginal estrogens administered for the relief of urogenital atrophy do not require progestogen co-medication

• Direct delivery of progestogen to the endometrial cavity from the vagina or by an intrauterine system is logical and may minimize systemic effects




• Androgen replacement should be reserved for women with clinical signs and symptoms of androgen insufficiency

• In women with bilateral oophorectomy or adrenal failure, androgen replacement has significant beneficial effects, in particular on health-related quality of life and sexual function




• HT remains the most effective therapy for vasomotor and estrogen-deficient urogenital symptoms

• Other menopause-related complaints, such as joint and muscle pains, mood swings, sleep disturbances and sexual dysfunction (including reduced libido) may improve during HT

Part II. Benefits of hormone therapy:Part II. Benefits of hormone therapy:GeneralGeneral



• Quality of life and sexuality are key factors to be considered in the management of the aging individual

• The administration of individualized HT (including androgenic preparations when appropriate) improves both sexuality and overall quality of life

Part II. Benefits of hormone therapy:Part II. Benefits of hormone therapy:GeneralGeneral



• HT is effective in preventing the bone loss associated with the menopause and decreases the incidence of all osteoporosis-related fractures, including vertebral and hip, even in patients at low risk

• Although the magnitude of decline in bone turnover correlates with estrogen dosage, even lower than standard-dose preparations maintain a positive influence on bone indices in most women

Part II. Benefits of hormone therapy:Part II. Benefits of hormone therapy:Postmenopausal osteoporosisPostmenopausal osteoporosis



• HT is an appropriate first-line therapy in postmenopausal women presenting with an increased risk for fracture, particularly under the age of 60 years and for the prevention of bone loss in women with premature menopause

• The protective effect of HT on bone mineral density declines after cessation of therapy at an unpredictable rate, although some degree of fracture protection may remain after cessation of HT

Part II. Benefits of hormone therapy: Part II. Benefits of hormone therapy: Postmenopausal osteoporosisPostmenopausal osteoporosis



• The initiation of standard-dose HT is not recommended for the sole purpose of the prevention of fractures after the age of 60 years

• The continuation of HT after the age of 60 for the sole purpose of the prevention of fractures should take into account the possible long-term effects of the specific dose and method of administration of HT, compared to other proven therapies

Part II. Benefits of hormone therapy: Part II. Benefits of hormone therapy: Postmenopausal osteoporosisPostmenopausal osteoporosis



• Cardiovascular disease is the principal cause of morbidity and mortality in postmenopausal women

• Major primary prevention measures (besides smoking cessation, and diet control) are weight loss, blood pressure reduction, and diabetes and lipid control

• There is evidence that HT may be cardioprotective if started around the time of menopause and continued long-term (often referred to as the ‘window of opportunity’ concept)

Part II. Benefits of hormone therapy:Part II. Benefits of hormone therapy:Cardiovascular diseaseCardiovascular disease



• HT markedly reduces the risk of diabetes and, through improved insulin resistance, it has positive effects on other related risk factors for cardiovascular disease such as the lipid profile and metabolic syndrome

• In women less than 60 years old, recently menopausal, without prevalent cardiovascular disease, the initiation of HT does not cause early harm, and may reduce cardiovascular morbidity and mortality

• Continuation of HT beyond the age of 60 should be decided as a part of the overall risk-benefit analysis

Part II. Benefits of hormone therapy:Part II. Benefits of hormone therapy:Cardiovascular diseaseCardiovascular disease



• HT may reduce the risk of colon cancer

• HT initiated around the time of menopause or by younger postmenopausal women is associated with a reduced risk of Alzheimer’s disease

• HT has benefits for connective tissue, skin, joints and intervertebral disks

Part II. Benefits of hormone therapy:Part II. Benefits of hormone therapy: OtherOther



• Studies on the risks of postmenopausal hormone use have mainly focused on breast and endometrial cancer, venous thromboembolism (pulmonary embolism or deep vein thrombosis), stroke and coronary events

Part Part III. Potential serious adverse effects of HTIII. Potential serious adverse effects of HT



• The incidence of breast cancer varies in different countries. Therefore, currently available data cannot necessarily be generalized

Part Part III. Potential serious adverse effects of HT:III. Potential serious adverse effects of HT:Breast cancerBreast cancer



• The degree of association between breast cancer and postmenopausal HT remains controversial. Women should be reassured that the possible risk of breast cancer associated with HT is small (less than 0.1% per annum)




• For combined HT, observational data from the Million Women Study suggested that breast cancer risk was increased as early as the first year, raising serious reservations on possible methodologic flaws

• On the contrary, randomized controlled data from the Women‘s Health Initiative (WHI) Study indicate that no increased risk is observed in women initiating HT, for up to 7 years. It should be noted that the majority of subjects in the WHI Study were overweight or obese




• Data from the WHI and Nurses’ Health Study suggest that long-term estrogen-only administration for 7 and 15 years, respectively, does not increase the risk of breast cancer in American women. Recent European observational studies suggest that risk may increase after 5 years

• There are insufficient data to evaluate the possible differences in the incidence of breast cancer using different types and routes of estrogen, natural progesterone and progestogens, and androgen administration




• Baseline mammographic density correlates with breast cancer risk. This does not necessarily apply to the increase in mammographic density induced by HT

• The combined estrogen–progestogen therapy-related increase in mammographic density may impede the diagnostic interpretation of mammograms




• Unopposed estrogen administration induces a dose-related stimulation of the endometrium

• Women with a uterus should have progestogen supplementation

• Continuous combined estrogen–progestogen regimens are associated with a lower incidence of endometrial hyperplasia and cancer than occurs in the normal population

• Direct intrauterine delivery systems may have advantages• Regimens containing low-/ultra-low-dose estrogen and

progestogen cause less endometrial stimulation and less bleeding

Part Part III. Potential serious adverse effects of HT:III. Potential serious adverse effects of HT: EEndometrial cancerndometrial cancer



• The HT-related risk for serious venous thromboembolic events increases with age (although minimal until age 60) and is also positively associated with obesity and thrombophilia

• By avoiding first-pass hepatic metabolism, transdermal estrogen may avert the risk associated with oral HT

• The impact on the risk of a thromboembolic event may also be affected by progestogen, depending on the type

Part Part III. Potential serious adverse effects of HT:III. Potential serious adverse effects of HT: Thromboembolism and cardiovascular eventsThromboembolism and cardiovascular events



• Late starters of standard-dose HT may have a transient slightly increased risk for coronary events

• The risk of stroke is correlated with age. HT may increase the risk of stroke after the age of 60

• Safety data from studies of low-dose and ultra-low-dose regimens of estrogen and progestogen are encouraging

Part Part III. Potential serious adverse effects of HT:III. Potential serious adverse effects of HT: Thromboembolism and cardiovascular eventsThromboembolism and cardiovascular events



• The efficacy and safety of complementary alternative medicines have not been demonstrated and further studies are required

• Selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors and gabapentin are effective in reducing vasomotor symptoms in short-term studies. Their long-term safety needs further evaluation

Part IV:Part IV: Alternative treatments Alternative treatments



• There are no medical or scientific reasons to recommend unregistered ‘bioidentical hormones’

• The measurement of hormone levels in the saliva is not clinically useful

• These ‘customized’ hormonal preparations have not been tested in studies, and their purity and risks are unknown

Part IV:Part IV: Alternative treatments Alternative treatments



• There is urgent need for further research, especially into the relative merits of lower doses, regimens and routes of administration

Part V: ConclusionsPart V: Conclusions



• The safety of HT largely depends on age

• Women younger than 60 years should not be concerned about the safety profile of HT

• New data and re-analyses of older studies by women’s age show that, for most women, the potential benefits of HT given for a clear indication are many and the risks are few when initiated within a few years of menopause


Part V: ConclusionsPart V: Conclusions


Adjunctive slidesAdjunctive slides

• The following slides may be useful for presentation in regard to the IMS Recommendations

• Some slides demonstrate data on which the statements are based. This is not, however, a full slide presentation on specific topics.

• The IMS is now in the process of developing an Educational Slide Kit on the main issues of adult women’s health and menopause

Dose response to estrogen therapyDose response to estrogen therapyNumber of moderate–severe hot flushesNumber of moderate–severe hot flushes

Nu

mb

e r

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 10 11 12

** *

**

*

*

*

Placebo

0.25 mg E2

0.5 mg E2

1 mg E2

2 mg E2

Significantly (p < 0.05)different from placebo

*

Adapted from Notelovitz M, et al. Obstet Gynecol 2000;95:726

*

*

* significantly (p = 0.001)different from placebo

*

**

*

*

*

*

*

Adapted from Panay N, et al. Climacteric 2007;10:120–31

Ultra-low-dose oral therapyUltra-low-dose oral therapyEffect on number of moderate to severe hot Effect on number of moderate to severe hot

flushes by weekflushes by week

0

2

4

6

8

10

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

Me

an

nu

mb

er

0

2

4

6

8

10

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

Me

an

nu

mb

er

* compared to basal levels basal level: mean incidence of hot flushes = 12.3 (11.3–13.8)

0.625

0.45

0.3

Placebo

0.625/2.50.45/2.50.45/1.50.3/1.5

PlaceboCEE/MPACEE

Level I

HOPE StudyHOPE StudyNumber of hot flushes in 13 cyclesNumber of hot flushes in 13 cycles

Adapted from Utian W, et al. Fertil Steril 2001;75:1065–79

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

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 0.625

0.45

0.30.45/1.5

0.625/2.5

Placebo

0.45/2.5

0.3/1.5

Women's HOPE StudyWomen's HOPE StudyChanges in severity of hot flushes over 12 weeksChanges in severity of hot flushes over 12 weeks

( (nn = 241) = 241)

Adapted from Utian W, et al. Fertil Steril 2001;75:1065–79

Unopposed ultra-low-dose Unopposed ultra-low-dose transdermal estradioltransdermal estradiol

• 417 postmenopausal women (60–80 years) mean 67 ± 5 years

• Randomly assigned to placebo or transdermal 14 µg/day for 2 years

• Baseline serum E2 = 4.8 pg/ml

• On treatment E2 = 8.6 pg/ml

Johnson SR, et al. Obstet Gynecol 2005;105:779–87

Unopposed ultra-low-dose Unopposed ultra-low-dose transdermal estradioltransdermal estradiol

• Proliferation 8.5% vs. 1.1% p = 0.6

• Bleeding 12.4% vs. 8.6% p = 0.3

• Atypical hyperplasia × 1

• Adenosarcoma × 1

Johnson SR, et al. Obstet Gynecol 2005;105:779–87

Conclusions:

‘This therapy apparently causes little or no endometrial stimulation’

Endometrial effects:

Age (years) 63 63.6< 60 33.430.860–69 45.345.070–79 21.324.2

Body mass index 28.5 30.1< 25 30.4 2125–29 35.3 34> 30 34.2 45

Hypertensive 35.7 48Rossouw JE, et al. J Am Med Assoc 2002;288:321–33

The Women’s Health Initiative Steering Committee. J Am Med Assoc 2004;291:1701–12

WHI population characteristicsWHI population characteristics

WHI EP arm WHI E arm

Mean % Mean %

* significant

Adapted from JAMA 2003;290:1729 and JAMA 2004;291:1701

Fracture risk in the WHI studyFracture risk in the WHI study

Hazard ratio (95% CI)

Estrogen + progestin Estrogenhormone therapy hormone therapy

Hip 0.67 (0.47–0.96)* 0.61 (0.41–0.91)*

Vertebral 0.65 (0.46–0.92)* 0.62 (0.42–0.93)*

Total 0.76 (0.69–0.83)* 0.70 (0.63–0.79)*

WHI: unopposed estrogenWHI: unopposed estrogen

Compliance more than 80%

Adapted from Cirillo, et al. Arthritis Rheumatism 2006

Estrogen

(n = 5076)

Placebo

(n = 5196)

Hazard ratio

(95% CI)

p

Total joint

replacement

119 169 0.73

(0.58–0.93)

0.01

Hip joint replacement

28 53 0.55

(0.35–0.88)

0.01

Knee joint

replacement

93 121 0.8

(0.61–1.05)

0.11

0.000

0.005

0.010

0.015

0 1 2 3 4 5 6 7

Time (years)

Cu

mu

lati

ve

ha

zard

fo

r c

olo

rec

tal c

an

ce

r

HR = 0.5695% nCI = 0.38–0.8195% aCI = 0.33–0.94

Placebo

E + P

Adapted from Chlebowski RT, et al. N Engl J Med 2004;350:991–1004

WHI results: effect of HTWHI results: effect of HTon risk of colorectal canceron risk of colorectal cancer

Kaplan–Meier estimateKaplan–Meier estimate

0.89<10

1.221019

1.71> 20

0.56

0.92

1.04

<10

1019

> 20

Effect of HRT/ERT on CHD in Effect of HRT/ERT on CHD in postmenopausal womenpostmenopausal women

CEE + MPA

Years sincemenopause

0 0.5 1.0 1.5 2.0 2.5

Hazard ratio(95% CI)

Hazard ratio(95% CI)

Hazardratios

CEE

Data from WHI

0 0.5 1.0 1.5 2.0 2.5

Timing of initiation

Adapted from Hsia J, et al. Arch Intern Med 2006;166:357–65

Coronary events with ET or Coronary events with ET or placebo by age at baselineplacebo by age at baselineCoronary event

CHD (MI or coronary death)

CABG or PCI

MI, coronary death, CABG,and PCI

MI, coronary death, CABG, PCI, and confirmed angina

Hazard ratio (95% CI)

50–59

60–69

70–79 p = 0.07

p = 0.09

p = 0.09

p = 0.11

0 0.5 1 1.5 2

Years since menopause

Hazard ratio CIAbsolute excess risk

(per 10,000 person-years)

< 10 0.76 0.50–1.16 -6

10–19 1.10 0.84–1.45 4

> 20 1.28 1.03–1.58 17

Adapted from Rossouw JE, et al. JAMA 2007;297:1465–77

HT and risk of cardiovascular HT and risk of cardiovascular disease by years since menopausedisease by years since menopause

p for trend = 0.02

WHI CEE/MPA study: WHI CEE/MPA study: incidence of diabetesincidence of diabetes

0.00

0.01

0.02

0.03

0.04

0.05

0.06

0 1 2 3 4 5 6 7

Inci

den

ce

Time (years)

CEE/MPA (n)Placebo (n)

80147627

78947618

77857403

76757271

74617049

54185049

28422528

1252922

Adapted from Margolis KL, et al. Diabetologia 2004;47:1175–87

Hazard ratio = 0.79

95% CI = 0.67–0.93

Placebo

CEE/MPA

Annual risks and benefits after Annual risks and benefits after 7 years of estrogen-only HT7 years of estrogen-only HT

-15

0

15

5

CVD*

VTE*

7

7

Breast cancer*

Hip fractures

Per

10,

000

wo

man

-yea

rs

Increase

Decrease

Stroke

12

Vertebral fractures

.

.,

All fractures

Adapted from JAMA 2004;291:1701–12MacLennan A, Sturdee D. Climacteric 2004

* = NS

6

6

57

n = 10,739

WHI E-only clinical outcomes WHI E-only clinical outcomes when initiated age 50–59when initiated age 50–59

Annual change in risk (all NS)Annual change in risk (all NS)

-15

0

15

3CVD

VTE1

1Breast cancer 2

Colorectal cancer

Per

10,

000

wo

man

-yea

rs

Increase

Decrease

Stroke0.1

7Global Index

3Total

deaths

Adapted from JAMA 2004;291:1701–12 MacLennan A, Sturdee D. Climacteric 2004

Age-specific incidence of Age-specific incidence of venous thrombosisvenous thrombosis

WHI study; RCT 16,608 womenWHI study; RCT 16,608 women

Cushman M, et al. JAMA 2004;292:1573–80

50–59 60–69 70–79

Placebo E + P Placebo E + P Placebo E + P

Number of cases 13 32 38 76 25 60

Annualized rate/ 0.8 1.9 1.9 3.5 2.7 6.2 1000 person-years

Hazard ratio 1.0 2.27 2.31 4.28 3.37 7.46

95% CI 1.2–4.3 1.2–4.4 2.4–7.7 1.7–6.6 4.3–14.4

Age (years)

Venous thrombosis andVenous thrombosis andbody mass indexbody mass index

WHI study; RCT 16,608 women age 50–79 yearsWHI study; RCT 16,608 women age 50–79 years

Cushman M, et al. JAMA 2004;292:1573–80

< 25 25–30 > 30

Placebo E + P Placebo E + P Placebo E + P

Number of cases 13 24 24 59 38 83

Annualized rate/ 0.9 1.6 1.5 3.5 2.5 5.1 1000 person-years

Hazard ratio 1.0 1.8 1.6 3.8 2.8 5.6

95% CI 0.9–3.5 0.8–3.2 2.1–6.9 1.5–5.4 3.1–10.1

Body mass index

VTE: route of administrationVTE: route of administrationand progestogensand progestogens

ESTHER studyESTHER study

Route/progestogen Odds ratio 95% CI

Oral 4.2 1.5–11.6

Transdermal 0.9 0.4–2.1

Micronized progesterone 0.7 0.3–1.9

Pregnanes 0.9 0.4–2.3

Norpregnanes 3.9 1.5–10.0

Canonico M, et al. Circulation 2007;115:820–2

Relation of years since menopause Relation of years since menopause to progression of atherosclerosisto progression of atherosclerosis

Adventitia

Media

Internalelasticlamina

5 to < 1019%

10 to < 1521%

≥ 1543%

< 517%

Fatty streak/plaque

Fibrouscap

Plaque

Plaque

Fibrouscap

Necrotic core

Plaque

Fibrouscap

MMP-9

Necrotic core

Years postmenopause

% of WHI enrollees

Postmenopausal hormone use and Postmenopausal hormone use and

coronary heart disease, NHS 1976coronary heart disease, NHS 1976––2000 2000 Timing of hormone initiation with respect to ageTiming of hormone initiation with respect to age

RR (95% CI)

Adjusted for age, body mass index, hypercholesterolemia, hypertension, parental coronary heart disease, diabetes, cigarette smoking, dietary data, husband’s education, alcohol intake, physical activity, vitamin E or multivitamin supplementation, aspirin use

Adapted from Grodstein F, et al. J Womens Health 2006;15:35–44

Excluding postmenopausal women with prevalent CHD

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

60 + years

50–59 years

Coronary heart disease events associated Coronary heart disease events associated with hormone therapy in younger and with hormone therapy in younger and

older women: a meta-analysis older women: a meta-analysis

Adapted from Salpeter SR, et al. J Gen Intern Med 2006;21:363–6

* Statistical significance

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6

< 60 years*

> 60 years

23 trials, with 39,049 participants followed for 191,340 patient-years

Odds ratio for total mortality

0.68 (CI, 0.48–0.96)

1.03 (CI, 0.91–1.16)

Summary of published results on incidence Summary of published results on incidence of endometrial cancer in relation to use of of endometrial cancer in relation to use of

hormone therapy (HT)hormone therapy (HT)

Adapted from Grady D, et al. Obstet Gynecol 1995;85:304–13Beral V, et al. J Epidemiol Biostat 1999;4:191–215

Anderson GL, et al. JAMA 2003;290:1739–44

CCEPT, continuous combined estrogen and progestogen;E, estrogen; P, progestogen

Unopposed estrogen < 1 year 1.4 (1.0–1.8)1–4 years 2.8 (2.3–3.5)5–9 years 5.9 (4.7–7.5)10+ years 9.5 (7.4–12.3)

Sequential E + P; ever vs. never 1.3 (1.1–1.4)

CCEPT from WHI 0.8 (0.5–1.4)

Type of HT Relative risk (95% CI)

0

5

10

15

20

25

30

CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate

Women’s HOPE StudyWomen’s HOPE Study

Endometrial hyperplasia rates after 1 and 2 Endometrial hyperplasia rates after 1 and 2 years of low-dose estrogen + progestogenyears of low-dose estrogen + progestogen

Hyp

erp

lasi

a ra

te (

%)

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

0.000.000.000.000.000.00

Year 1

Year 2

Adapted from Pickar JH, et al. Fertil Steril 2003;80:1234–40

0

5

10

15

20

25Cycle 6

Cycle 13

†

Effect of CEE, CEE/MPAEffect of CEE, CEE/MPAon vaginal maturation*on vaginal maturation*

Women's HOPE StudyWomen's HOPE Study

CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate *p < 0.05 vs. baseline and placebo for all active treatment groups;†p < 0.05 vs. CEE 0.625; ‡p < 0.05 vs. CEE 0.3/MPA 1.5

% S

up

erfi

cial

cel

ls (

me

dia

n)

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

‡

†

‡†

Adapted from Utian WH, et al. Fertil Steril 2001;75:1065–79

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

HT use and risk of colorectal cancerHT use and risk of colorectal cancer

Relative risk (95% CI)

*Statistic refers to colon cancer risk only; †Multivariate risk analysis; ‡Risk assessment adjusted for age only; §Meta-analysis includes two studies of colorectal cancer mortality

Jacobs et al. 1994*†

Newcomb and Storer 1995*†

Folsom et al. 1995*†

Troisi et al. 1997‡

Kampman et al. 1997†

Grodstein et al. 1998†

Paganini-Hill 1999‡

Hully et al. 2002†

Chlebowski et al. 2004†

Meta-analysis: Nanda et al. 1999*†

Meta-analysis: Grodstein et al. 1999‡§

Council on Hormone Education

E+P E+P E

Follow-up 6.8 years 6.2 years 7.1 years

RR of BC (ITT) 1.27 1.26 0.80

95% CI 0.8–1.9 1.0–1.6 0.62–1.04

RR of BC (adherent) 1.49 0.67

95% CI 1.13–1.96 0.47–0.97

Randomized controlled trials: Randomized controlled trials: breast cancer resultsbreast cancer results

Adapted from Hulley, JAMA 1998, Chlebowski, JAMA 2002, JAMA 2003, Stefanick, JAMA 2006

HERS II WHI

Body mass index:Body mass index:the risk with hormone therapy is the risk with hormone therapy is (more) (more) apparent in lean womenapparent in lean women

• BMI > 24.4 kg/m2 – no additional riskSchairer C, et al. JAMA 2000;283:485–91

• BMI > 26 kg/m2 – no additional riskRosenberg L, et al. Arch Intern Med 2006;166:760–5

• Inverse relationship between the risk and BMI with estrogen or combined hormone therapyMillion Women Study. Reeves GK, et al. Lancet Oncol 2006;7:910–18

• 80% of users have a BMI < 25E3N-EPIC. Fournier A, et al. Int J Cancer 2005;114:448–54

Low-dosage micronizedLow-dosage micronized1717ββ-estradiol + calcium prevent bone -estradiol + calcium prevent bone

loss in postmenopausal womenloss in postmenopausal women

Estradiol 2.0 mg

Estradiol 1.0 mg

Estradiol 0.5 mg

Placebo

Adapted from Ettinger B, et al. Am J Obstet Gynecol 1992;166:479–88

-5

-4

-3

-2

-1

0

1

2

3

Mea

n a

nn

ual

% c

ha

ng

eM

ean

an

nu

al %

ch

an

ge

fro

m b

asel

ine

fro

m b

asel

ine *

*

*

Effect of micronized 17β-estradiol + calcium on spinal bone mineral density

**p p < 0.001 vs. placebo< 0.001 vs. placebo

Bone density + Bone quality Bone strength

Osteoporosis and bone strengthOsteoporosis and bone strength

Genetics Architecture

Diet Turnover rate

Exercise Damage accumulation

Hormones Degree of mineralization

Adapted from The NIH Consensus Development Panel on Osteoporosis. JAMA 2001;285:785–95

Different effects of estrogen Different effects of estrogen therapy on connective tissuetherapy on connective tissue

Estrogen therapy

Decreased skin thickness

(reversed)

Cerebral changes(Alzheimer’s decreased)

CVS effects(including carotids)

Genital organs(improved)

Bone loss(stopped and reversed) Cartilage

Cartilage,Cartilage, an estrogen-responsive tissue an estrogen-responsive tissue

Pre-menopause

Post-menopause

0

100

200

300

***

CT

X-I

I (n

g/m

mo

l)

No HRT HRT0

100

200

300

***

CT

X-I

I (n

g/m

mo

l)

Adapted from Mouritzen, et al. Ann Rheum Dis 2003;62:332–6

**p p < 0.001< 0.001

Selective serotonin and/or Selective serotonin and/or noradrenaline reuptake inhibitorsnoradrenaline reuptake inhibitors

• Newer SNRI formulations:– Extended release venlafaxine

• 51% reduction in hot flushes/sweats• Less nausea

• Desvenlafaxine succinate – in development– Selective NA & 5HT reuptake inhibitor– Good plasma / brain ratios in animal models

Evans ML, et al. Obstet Gynecol 2005;105:161–6

Deecher DC, et al. J Pharmacol Exp Ther 2006;318:657–65

Lower estrogen levels are associated with Lower estrogen levels are associated with increased prevalence of sexual problemsincreased prevalence of sexual problems

0

10

20

30

40

50

60

Vaginaldryness

Bothered byproblem

Dyspareunia(intensity)

Pain withpenetration

Burning

% R

ep

ort

ing

pro

ble

ms

E2 < 50 pg/ml

E2 > 50 pg/ml

Adapted from Sarrel PM. J Womens Health Gend Based Med 2000;9:S25–32Sarrel PM. Obstet Gynecol 1990;75:S26–30

Adapted from Sarrel PM. J Womens Health Gend Based Med 2000;9:S25–32Sarrel PM. Obstet Gynecol 1990;75:S26–30

n = 93; significance not reported

0.10

1.00

Never 50–63years

Rel

ati

ve

risk

0.50

64–71years

72–99years

MIRAGE study: 426 cases, 545 family controls

Significant interaction between age and HT use on AD risk (p = 0.03). Protective association was seen only in the youngest age tertile (50–63 years; odds ratio = 0.35, 95% CI= 0.19–0.66)

HT may protect younger women from AD or reduce the risk of early-onset forms of AD, or HT used during the early postmenopause may reduce AD risk

Adapted from Henderson VW, et al.; MIRAGE Study Group. J Neurol Neurosurg Psychiatry 2005;76:103–5

Postmenopausal hormone therapyPostmenopausal hormone therapyand Alzheimer's disease risk: and Alzheimer's disease risk:

interaction with ageinteraction with age

HT use

Effect of hormone therapyEffect of hormone therapyIncidence of Alzheimer’s diseaseIncidence of Alzheimer’s disease

The Cache County Memory Study The Cache County Memory Study

65 70 75 80 85 90 95 100

Age (years)

0.12

0.10

0.08

0.06

0.04

0.02

0

Dis

cre

te a

nn

ua

l h

aza

rd

WomenHRT non-usersHRT use < 3 yearsHRT use 3–10 yearsHRT use > 10 yearsMen

Adapted from Zandi PP, et al. JAMA 2002;288:2123–9

Exercise in theExercise in themenopausemenopause

• Any physical activity is better than being sedentary

• Regular exercise reduces total and cardiovascular mortality

• Better metabolic profile, balance, muscle strength, cognition and quality of life are observed in physically active persons. Heart events, stroke, fractures and breast cancer are significantly less frequent

• Benefits far outweigh possible adverse consequences: the more – the better, but too much may cause harm

Exercise in theExercise in themenopause: optimal menopause: optimal exercise prescription exercise prescription

• At least 30 minutes of moderate intensity exercise, at least three times weekly

• Two additional weekly training sessions of resistance exercise may provide further benefit

• Injury to the musculo-articulo-skeletal system should be avoided

AHA 2006 Diet and Lifestyle AHA 2006 Diet and Lifestyle Recommendations 1Recommendations 1

• Balance calorie intake and physical activity to achieve or maintain a healthy body weight

• Consume a diet rich in vegetables and fruits

• Choose whole-grain, high-fiber foods

• Consume fish, especially oily fish, at least twice a week

Circulation 2006;114:82

AHA 2006 Diet and Lifestyle AHA 2006 Diet and Lifestyle Recommendations 2Recommendations 2

• Limit intake of saturated fat to < 7% of energy, trans fat to < 1% and cholesterol to < 300 mg/day by choosing lean meats and vegetable alternatives, selecting fat-free, 1% fat and low-fat products

• Choose and prepare foods with little or no salt

• Increase fiber intake (beans, whole grain, other fruits and vegetables)

• If you consume alcohol, do so in moderation

• Quit smokingCirculation 2006;114:82

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