2014 :updated information on hormone replacement therapy

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GDS_70000_Title_v1 1 HRT : An Update of Evidence Hesham Al-Inany, M.D, PhD

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Page 1: 2014 :Updated information on Hormone Replacement Therapy

GDS_70000_Title_v1 1

HRT : An Update of Evidence

Hesham Al-Inany, M.D, PhD

Page 2: 2014 :Updated information on Hormone Replacement Therapy

Outline

• Menopausal transition• HRT modalities• Risks & Benefits• Emerging concept

Page 3: 2014 :Updated information on Hormone Replacement Therapy

What is Menopausal transition?

• Menopause : permanent cessation of menstruation resulting from loss of ovarian follicular activity (WHO, 2002)

• Menopausal transition: from the first features of approaching menopause until up to 1 year after final menstrual period

• Associated with significant hormonal variability over time• Overall, decline in estrogen levels over the menopausal transition

Burger HG et al. Hormonal changes in the menopause transition. J Clin Endocrinol Metab 2002;84:4025–30. Copyright 2002, The Endocrine Society.

Years around menopause

Estr

adio

l (pm

ol/L

)

FSH

(iu/

L)

0 1 2 3 4 5-1-2-3-4020406080

100120

050

100150

200250300

Page 4: 2014 :Updated information on Hormone Replacement Therapy

AMH & Menopausal transition (2014)• prediction of age of menopause using AntiMullerian Hormone

• Both AMH and mother's ANM have added value in forecasting TTM for the daughter based on her age (Dólleman M et al, 2014)

Page 5: 2014 :Updated information on Hormone Replacement Therapy

Signs and Symptoms During the Menopausal Transition

Adapted from Bungay G et al. Br Med J 1980;281:181–3; Van Keep PA et al. Maturitas 1990;12:163–70.

Vasomotor SymptomsSleep DisordersMood Changes Urogenital Atrophy

Dyspareunia

OsteoporosisAtherosclerosisCoronary Heart DiseaseCerebrovascular Disease

40 yrs 50 yrs

Menopause

60 yrs

Menstrual Disorders

Page 6: 2014 :Updated information on Hormone Replacement Therapy

Prevalence of Vasomotor Symptoms by Years to/from the Final Menstrual Period (2008)

• Meta-analysis of six studies to estimate the natural progression of vasomotor symptoms during the menopause transition : 4- 8 yrs

Figure reproduced with kind permission from Springer Science+Business Media: J Gen Intern Med, Revisiting the duration of vasomotor symptoms of menopause: a meta-analysis. 23, 2008, 1507–13, Politi MC, Schleinitz MD, Col NF, Figure 2.

Menopause

0

10

20

30

40

50

60

70

80

90

100

Per

cent

age

with

vas

omot

or

sym

ptom

svv

Years to/from final menstrual periodY-8 Y-7 Y-6 Y-5 Y-4 Y-3 Y-2 Y-1 Y0 Y1 Y2 Y3 Y4 Y5 Y6 Y7 Y8 Y9 Y10 Y11 Y12 Y13 Y14 Y15 Y16

McKinlay (1974)Gutherie (2003)

Thompson (1973)Oldenhave (1993)

Berg (1988)Nedstrand (1996)

Page 7: 2014 :Updated information on Hormone Replacement Therapy

• Penn Ovarian Aging Study 2007

• Data on 404 women who were followed for a span of 9 years

– 50% White – 50% African American

Prevalence and Severity of Symptoms by Menopausal Stage

Freeman EW, Sammel MD, Lin H, Gracia CR, Pien GW, Nelson DB, Sheng L. Symptoms associated with menopausal transition and reproductive hormones in midlife women. Obstet Gynecol 2007;110:230–40.

73%

Sub

ject

s (%

)

Aches

Sub

ject

s (%

)

Decreased libido

Sub

ject

s (%

)

Depression80

60

40

20

0Sub

ject

s (%

)

Vaginal dryness

Sub

ject

s (%

)

Hot flushes

Sub

ject

s (%

)

Poor sleep

Prem

enop

ausa

lLa

te p

rem

enop

ausa

lEa

rly tr

ansi

tion

Late

tran

sitio

nPo

stm

enop

ausa

l

Prem

enop

ausa

lLa

te p

rem

enop

ausa

lEa

rly tr

ansi

tion

Late

tran

sitio

nPo

stm

enop

ausa

l

Menopausal stage Menopausal stageMild

Moderate or severe

80

60

40

20

0

80

60

40

20

0

80

60

40

20

0

80

60

40

20

0

80

60

40

20

0

Page 8: 2014 :Updated information on Hormone Replacement Therapy

Figure modified with permission from Obermeyer CM, Menopause Across Cultures: A Review of the Evidence, Menopause, 7, 3:184-92.

Comparative Frequencies of Hot Flushes in Different Parts of the World• A review of cross-cultural evidence on vasomotor symptoms from

available studies

Page 9: 2014 :Updated information on Hormone Replacement Therapy

HRT Remains the Most Effective Therapy for Vasomotor Symptoms 2006

• No significant efficacy of botanicals in reducing vasomotor symptoms

Newton KM et al. Ann Intern Med 2006;145:869–79. Reprinted from Annals of Internal Medicine, 145, Newton et al, Treatment of Vasomotor Symptoms of Menopause with Black Cohosh, Multibotanicals, Soy, Hormone Therapy, or Placebo, 869-879, Copyright (2006), with permission from American College of Physicians.

Baseline 3 months 6 months 12 months0

1

2

3

4

5

6

7

8

Vaso

mot

or s

ympt

oms

per d

ay

Black Cohosh

Multibotanical

Multibotanical + soy

HRT: CEE +/- MPA

Placebo

Page 10: 2014 :Updated information on Hormone Replacement Therapy

Outline

• Menopausal transition• HRT modalities• Risks & Benefits• Emerging concept

Page 11: 2014 :Updated information on Hormone Replacement Therapy

UterusSequential therapy without tablet break

Regular bleeding at end of cycle

How is HRT Given?

Continuous Sequential HRTEstrogen

ProgestogenDay 14

De Villiers TJ et al. Climacteric 2013;16:316–337..

Continuous EstrogenEstrogen

No tablet break No bleeding as no uterus

Uterus

Continuous Combined HRTEstrogenProgestogen

Day 14 Combined therapy without tablet break No bleeding at end of cycle

Page 12: 2014 :Updated information on Hormone Replacement Therapy

Estrogens Used in HRT 2007

Equivalent dose for bone endpoints*

Estrogen Ultra Low Low Standard High

Conjugated equine estrogens (mg) 0.151 0.3 0.625 1.25Micronized 17β-estradiol (mg) 0.52 1 2 4Estradiol valerate (mg) 1 2Transdermal 17β-estradiol (μg) 143 25 50 100

*Estrogenic effects may vary for other endpoints

Table reproduced from Maturitas, 40, Gambacciani M, Genazzani AR. Hormone replacement therapy: the benefits in tailoring the regimen and dose. 195–201, Copyright (2001), with permission from Elsevier. 1. Lindsay R et al. Obstet Gynecol 1984;63:759–63; 2. Panay N et al. Climacteric 2007;10:120–31;

The Estrogen Dose Counts

Page 13: 2014 :Updated information on Hormone Replacement Therapy

Estradiol: Benefits on Vasomotor Symptoms

• Dose–response effect for reducing moderate-to-severe hot flushes (n=333)

Figure reproduced with permission from Notelovitz M, Lenihan JP, Mcdermott M, Kerber IJ, Nanavati N, Arce JC. Initial 17β-Estradiol Dose for Treating Vasomotor Symptoms. Obstet Gynecol 2000;95:726–31.

*p<0.05, ***p<0.001 vs. placebo

*

*

Mea

n nu

mbe

r of m

oder

ate-

to-

seve

re h

ot fl

ushe

s pe

r wee

k

Weeks

0

10

20

30

40

50

60

70

80

0 1 2 3 4 5 6 7 8 9 10 11 12

Placebo0.25 mg Estradiol0.5 mg Estradiol1 mg Estradiol2 mg Estradiol

***

***

****

**

Page 14: 2014 :Updated information on Hormone Replacement Therapy

Role of Progestogens in HRT

• Estrogen provides the benefits of HRT on menopausal symptoms• For women who have not had a hysterectomy, the addition of a progestogen to HRT is necessary

to protect the endometrium from the stimulatory effects of unopposed estrogen

Writing Group for the PEPI Trial. JAMA 1996;275:370–5.

PEPI Trial: multicenter RCT : Results of Endometrial Biopsy

Conclusion: Adding a progestogen is needed to safeguard the endometrium

Placebo CEE alone CEE+MPA sequential

CEE+MPA continuous

N 119 119 118 120

Normal 98% 38% 95% 99%

Simple hyperplasia 1% 28% 3% 1%

Complex hyperplasia 1% 23% 2% 0%

Atypia 0% 12% 0% 0%

Adenocarcinoma 1% 0% 0% 0%

Page 15: 2014 :Updated information on Hormone Replacement Therapy

Progestogens: Receptor Binding Activity

Progestogen Progestogenic Estrogenic Androgenic Anti-androgenic Glucocorticoid Anti-mineralo-

corticoid

Progesterone + – – ± + +Dydrogesterone + – – ± – ±Drospirenone + – – + – +MPA + – ± – + –Norethisterone + + + – – –

Table reproduced from Maturitas, 46 (S1), Schindler AE, Campagnoli C, Druckman R, Huber J, Pasqualini JR, Schweppe KW, Thijssen JHH. Classification and pharmacology of progestins. 7–16. Copyright (2003),

The Progestogen Counts

• All progestogens have a protective effect on the endometrium

• However, not all progestogens have the same receptor binding effect

+ Effective; ± Weakly effective; – Not effective

Page 16: 2014 :Updated information on Hormone Replacement Therapy

2013 IMS Recommendations on Menopausal Hormone Therapy – General Principles for Use

• HRT remains the most effective therapy for vasomotor symptoms

• Use lowest effective dose of estrogen

• More favorable if treatment is started earlier in menopause

De Villiers TJ et al. Climacteric 2013;16:316–337..

Page 17: 2014 :Updated information on Hormone Replacement Therapy

Outline

• Menopausal transition• HRT modalities• Risks & Benefits• Emerging concept

Page 18: 2014 :Updated information on Hormone Replacement Therapy

Bone

Mineral

Density

HRT Risks and Benefits

MetabolicEffects

Benefits

Relief of Menopause Symptoms

CV

Risk

EndometrialCancer

Risks

Breast Cancer

Page 19: 2014 :Updated information on Hormone Replacement Therapy

Odds ratio (fixed)95% CI

1.00 [0.68, 1.46]1.02 [0.06, 16.44]0.92 [0.41, 2.07]0.98 [0.78, 1.22]0.50 [0.04, 5.54]0.32 [0.01, 8.24]0.97 [0.06, 15.82]2.64 [0.10, 66.41]0.33 [0.01, 8.21]0.97 [0.54, 1.72]1.79 [0.42, 7.67]1.26 [0.96, 1.64]

0.97 [0.78, 1.21] Total 1.03 [0.91, 1.16]

HRT Reduced the Risk of CHD events inYounger Postmenopausal Women (2006)

In a meta-analysis of data from 23 studies (n=39,049)• HRT reduced CHD events by 32% in younger* women

• In older women**, there was no reduction in CHD with HRT (OR 1.03; CI 0.91 to 1.16)

*<10 years post-menopause or <60 years; **≥10 years post-menopause or ≥60 yearsCHD, coronary heart disease; OR, odds ratio

Odds ratio (fixed)95% CI

3.03 [0.12, 75.28]

0.16 [0.01, 4.12]

3.03 [0.12, 75.06]

1.00 [0.06, 16.10]

0.33 [0.01, 3.19]

1.25 [0.06, 26.10]

0.33 [0.01, 8.12]

0.31 [0.01, 8.29]

0.05 [0.00, 1.16]

0.12 [0.00, 2.93]

0.87 [0.53, 1.41]

0.56 [0.30, 1.03]

Total 0.68 [0.48, 0.96]0.001

Favors HT Favors control Favors HT0.01 0.1 1 10 100

Favors control

Older women**

1000.01 0.1 1 10

Younger women*

Figure reproduced with kind permission from Springer Science+Business Media: J Gen Intern Med, Coronary Heart Disease Events Associated with Hormone Therapy in Younger and Older Women, 21, 2006, 363-66, Salpeter SR, Walsh JME, Greyber E, Salpeter EE, Figures 1 & 2.

Page 20: 2014 :Updated information on Hormone Replacement Therapy

HRT and the Risk of Ischemic Stroke (WHI)

Risk of Ischemic Stroke• The use of estrogen-only and estrogen-progestogen therapy is associated with an up to

1.5-fold increased relative risk of ischemic stroke. The risk of hemorrhagic stroke is not increased during use of HRT. This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age

US WHI studies combined - additional risk of ischemic stroke1 over 5 years’ use

Age range(years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio (95% CI)

Additional cases per 1,000 HRT users over 5 years (95% CI)

50–59 8 1.3 (1.1–1.6) 3 (1–5)1No differentiation was made between ischemic and hemorrhagic stroke

Page 21: 2014 :Updated information on Hormone Replacement Therapy

Risk of Stroke Associated with Route of Administration (2010)• Case-control study from the UK General Practice Research Database

Renoux C et al. BMJ 2010;340:c2519.

• Low-dose transdermal HRT did not appear to increase stroke risk

(1.15–3.11)

(0.62–1.05)

(1.12–1.40)

(1.16–1.90)

Adj

uste

d R

R v

s. n

ever

-use

of

HR

T (9

5% C

I)

Page 22: 2014 :Updated information on Hormone Replacement Therapy

Risk of Thromboembolism Associated with Different Progestogens (2007)

ESTHER case-control study 271 consecutive VTE cases (mean age: 61.6 years) and 610 controls (mean age: 61.5 years)

Canonico M. Circulation 2007;115:840–5.

Adj

uste

d O

Rs

(95%

CI)

for

VTE

with

ora

l and

tran

sder

mal

es

trog

en v

s. n

on-u

sers

(e.g. Dydrogesterone)

Micronized progesterone and dydroprogesterone appear to have an acceptable thrombotic risk profile

4.2 (1.5–11.6)

0.7 (0.3–1.9) 0.9 (0.4–2.3)

3.9 (1.5–10.0)

(e.g. Nomegestrol acetate)

Page 23: 2014 :Updated information on Hormone Replacement Therapy

Breast Cancer with HRT: Risk Perception vs. Reality

Figure reproduced with permission from http://www.keepstudy.org/why_keeps/keeps_causeDeath.pdf. Accessed 1 November 2012

PERCEPTIONLeading causes of death

perceived by women

REALITYActual causes of death

among US women

Old age (1%)

Heart disease (18%)

Other cancer (13%)

Breast cancer (39%)

Lung cancer (2%)

Ovarian cancer (9%)

Stress (2%)Smoking (1%)

Other/don’t know (16%) Heart

disease(45%)

Other (25%)

Lung cancer (5%)

Ovarian cancer (<2%)

COPD (4%)

Pneumonia (4%)

Other cancer (11%)

Breast cancer (4%)

Page 24: 2014 :Updated information on Hormone Replacement Therapy

Growth

1 cm

0 1 2 3 4 5 6 7 89 10 11 12 13 14 Years

2.5 cm1 mm

Pre-mammographic Mammographic Window

Clinically detected

Breast Tumor

Chronological Development of Breast Cancer 2011

Fritz MA and Speroff L. Clinical Gynecologic Endocrinology and Infertility (8th edn) Wolters Kluwer 2011; pp. 667–8.

Page 25: 2014 :Updated information on Hormone Replacement Therapy

Is HRT Associated with Increased Breast Cancer Risk? Evidence from WHI

1. Rossouw JE et al. JAMA 2002;288:321–33; 2. Langer R et al. Climacteric 2012;15:206–12; 3. Stefanik M et al. JAMA 2006;295:1647–57; 4. Santen R et al. J Clin Endocrinol Metab 2010;95(Suppl 1):s1–66; 5. Gompel A et al. Climacteric 2012;15:241–9.

WHI evidence

WHI RR for breast cancer: 1.26 (95% CI 1.00–1.59) for current use of HRT

(CEE + MPA)1

Relative risk of 1.26 with combined HRT translates to an excess (attributable) risk of 4 per 1000 women taking HRT for 5 years4

Excess risk of breast cancer from HRT increases with

increase in underlying risk5

Determination of risk should underlie decision to use HRT

• No increased risk was identified for women who had had hysterectomy receiving CEE alone 2012

Page 26: 2014 :Updated information on Hormone Replacement Therapy

HRT and Breast Cancer Risk - WHI

US WHI studies – additional risk of breast cancer after 5 years’ use

Age range(years)

Incidence per 1,000 women in placebo arm over 5 years

Risk ratio (95% CI)

Additional cases per 1,000 HRT users over 5 years (95% CI)

CEE estrogen-only50–79 21 0.8 (0.7–1.0) -4 (-6–0)1

CEE + MPA 50–79 14 1.2 (1.0–1.5) +4 (0–9)

When the analysis was restricted to women who had not used HRT prior to the study there was noincreased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than non-users

1 WHI study in women with no uterus, which did not show an increase in risk of breast cancer

Netherlands Summary of Product Characteristics (SmPC) , estradiol/dydrogesterone 2/10, 1/10, 1/5, 0.5/2.5 issued 13 April 2012.

Page 27: 2014 :Updated information on Hormone Replacement Therapy

HRT and Breast Cancer Risk – Million Women Study

Million Women Study – Estimated additional risk of breast cancer after 5 years’ use

Age range(years)

Additional cases per 1,000 neverusers of HRT over a 5 year period1

Risk ratio (95% CI) #

Additional cases per 1,000 HRT users over 5 years (95% CI)

Estrogen only HRT50–65 9–12 1.2 1–2 (0–3)

Combined estrogen-progestogen50–65 9–12 1.7 6 (5–7)

# Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of useNote: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately1Taken from baseline incidence rates in developed countries

Netherlands Summary of Product Characteristics (SmPC) , estradiol/dydrogesterone 2/10, 1/10, 1/5, 0.5/2.5 issued 13 April 2012.

Page 28: 2014 :Updated information on Hormone Replacement Therapy

Choice of Progestogen and Breast Cancer Risk:E3N French Cohort Study 2008

Fournier A et al. Breast Cancer Res Treat 2008;107:103–11; Fournier A et al. J Clin Oncol. 2008 ;26:1260–1268.

Risk of all breast cancer

Risk elevation may not be uniform for all progestogens

N = 80,377 women, for an average treatment duration of 8.1 years

Overall 77.7% were ductal breast cancers vs. 22.3% lobular breast cancers

Estrogen/other progestogens

(0.83–1.22)

(0.94–1.43)

(1.50–1.91)

1.161.00

Estrogen/progesterone

Baseline risk without HRT

Estrogen/dydrogesterone

1.69

00.20.4

0.8

1.2

1.6

1.0

2.22.01.8

1.4

0.6

Rel

ativ

e ris

k (9

5% C

I)

≥5 years

(0.8–1.5)

(0.8–2.7)

(1.2–3.8)

1.51.1

≥5 years<5 years <5 years

2.1

00.20.4

0.8

1.2

1.6

1.0

2.22.01.8

1.4

0.6

Ductal carcinoma Lobular carcinoma

1.1

(0.8–1.17)

Risk of breast cancer subtypes with E/D

Significantly different from the risk without HRT

Not statistically significantly different from risk without HRT

Page 29: 2014 :Updated information on Hormone Replacement Therapy

Choice of Progestogen and Breast Cancer Risk: Finnish Cohort Study 2009

Lyytinen H et al. Obst Gyn 2009;113:65–73.

Estradiol/ MPA

Estradiol/other progestogens

Stan

dard

inci

denc

e ra

tio (9

5% C

I)

00.20.4

0.8

1.2

1.6

1.0

2.22.01.8

1.4

0.6

2.072.03

1.64

1.13

Estradiol/dydrogesterone

Estradiol/ NETA

(0.49–2.22)

(1.49–1.79)

(1.88–2.18)

(1.76–2.04)

Baseline risk without HRT

Risk elevation may not be uniform for all progestogensRisk elevation may not be uniform for all progestogens

N = 50,210 women >50 years of age, treatment duration 5 years

Page 30: 2014 :Updated information on Hormone Replacement Therapy

Statements from International Societies 2013

International Menopause Society Statement on Breast Cancer1

• Women should be reassured that the possible increased risks of breast cancer associated with HRT are small

• an incidence of <1.0 per 1000 women per year of use• Less than the increased risks associated with common lifestyle factors such as reduced physical activity,

obesity and alcohol consumption

• Micronized progesterone or dydrogesterone used with estradiol may be associated with a better risk profile for breast cancer than synthetic progestogens

1. De Villiers TJ et al. Climacteric 2013;16:316–337.2. Santen R et al. J Clin Endocrinol Metab 2010;95(Suppl1):S1–S66.

USA Endocrine Society Scientific Statement on Breast Cancer2

• Emerging data from 2 independent studies suggest that progesterone (and perhaps dydrogesterone) in combination with estrogen does not increase breast cancer risk if given for 5 years or less

Page 31: 2014 :Updated information on Hormone Replacement Therapy

Outline

• Menopausal transition• HRT modalities• Risks & Benefits• Emerging concept

Page 32: 2014 :Updated information on Hormone Replacement Therapy

Sequential Estradiol/Dydrogesterone:Endometrial Safety and Bleeding• In a comparison of 1/5 or 1/10 vs. 2/10 or 2/20 (n=579)1

– Endometrial safety was recorded across groups• No cases of hyperplasia or malignancy with 1/10 and 2/10• 1 polyp occurred with 1/10

– Cyclic bleeding patterns were seen• Percentage of women with cyclic bleeding was 79% with 1/10 and

91% with 2/10• E 1 mg associated with less cyclic and intermittent bleeding vs. E 2 mg• Higher doses of D associated with higher incidence of bleeds and later day

of onset

• In a comparison of 2/5, 2/10, 2/15 or 2/20 (n=371):2

– Endometrial safety was recorded across groups• No cases of hyperplasia or malignancy with 1/10 and 2/10

– Cyclic bleeding patterns found at all doses (83%, 90%, 87%, 93%, respectively)• Percentage of women with cyclic bleeding was 90% with 2/10

1. Ferenczy A et al. Climacteric 2002;5:26–35; 2. Burch DJ et al. Brit J Obst Gynaecol 1995;102:243–8.

Page 33: 2014 :Updated information on Hormone Replacement Therapy

Continuous Estradiol/Dydrogesterone: Endometrial Safety and Bleeding Patterns 2010• In an open, multicenter study of 1/5 for 1 year (n=290):1

• 1 case of simple hyperplasia without atypia (treatment failure rate of 0.4%)

• Women without bleeding increased from 71% (cycle 1) to ~80% by end of the study• ~50% of bleeding episodes were spotting• 41% women were amenorrheic throughout the study• 7 women withdrew prematurely due to uterine bleeding

• In an open, multicenter study of ultra-low-dose 0.5/2.5 over 1 year (n=446):2

• 1 case of simple hyperplasia (incidence: 0.27%)

• 68% experienced amenorrhea (88% during months 10–12) • 14% had 1 or 2 bleeding/spotting episodes• Spotting alone was the most prevalent bleeding intensity; heavy bleeding was rare

1. Quereux C et al. Maturitas 2006;53:299–305; 2. Bergeron C et al. Maturitas 2010;66:201–5.

Page 34: 2014 :Updated information on Hormone Replacement Therapy

The emerging concepts in HRT• Timing (window of opportunity)

• Early start • Maintenance of estrogenic benefits

• Patient selection • Avoiding generalized prescribing

• Personalization• Tailoring dose to patient• Continuation and tapering the dose with age

Page 35: 2014 :Updated information on Hormone Replacement Therapy

Conclusion

Used by the right woman, at the right dose, HRT can:

• Relieve vasomotor and other menopausal symptoms

• Provide protection against bone loss (second line)

• Provide acceptable bleeding patterns