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
Climacteric 2007;10:181–94
IntroductionIntroduction
• 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
Climacteric 2007;10:181–94
IntroductionIntroduction
• 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
Climacteric 2007;10:181–94
• 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
Climacteric 2007;10:181–94
• 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
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• HT should not be recommended without a clear indication for its use
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part I. Governing principlesPart I. Governing principles
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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)
Part Part III. Potential serious adverse effects of HT:III. Potential serious adverse effects of HT:Breast cancerBreast cancer
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part Part III. Potential serious adverse effects of HT:III. Potential serious adverse effects of HT:Breast cancerBreast cancer
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part Part III. Potential serious adverse effects of HT:III. Potential serious adverse effects of HT:Breast cancerBreast cancer
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Part Part III. Potential serious adverse effects of HT:III. Potential serious adverse effects of HT:Breast cancerBreast cancer
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
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• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
Climacteric 2007;10:181–94
• 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
Climacteric 2007;10:181–94
Part V: ConclusionsPart V: Conclusions
IMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPYIMS UPDATED RECOMMENDATIONS ON POSTMENOPAUSAL HORMONE THERAPY
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