Updated hormone replacement therapy

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

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

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
Estradiol
(pmol/L)
FSH
(iu/L)
0 1 2 3 4 5
-1
-2
-3
-4
0
20
40
60
80
100
120
0
50
100
150
200
250
300

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)

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 Symptoms
Sleep Disorders
Mood Changes Urogenital Atrophy
Dyspareunia
Osteoporosis
Atherosclerosis
Coronary Heart Disease
Cerebrovascular Disease
40 yrs 50 yrs
Menopause
60 yrs
Menstrual Disorders

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
Percentage
with
vasomotor
symptomsvv
Years to/from final menstrual period
Y-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)

• 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%
Subjects
(%)
Aches
Subjects
(%)
Decreased libido
Subjects
(%)
Depression
80
60
40
20
0
Subjects
(%)
Vaginal dryness
Subjects
(%)
Hot flushes
Subjects
(%)
Poor sleep
Menopausal stage Menopausal stage
Mild
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

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

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 months
0
1
2
3
4
5
6
7
8
Vasomotor
symptoms
per
day
Black Cohosh
Multibotanical
Multibotanical + soy
HRT: CEE +/- MPA
Placebo

Uterus
Sequential therapy without tablet break
Regular bleeding at end of cycle
How is HRT Given?
Continuous Sequential HRT
Estrogen
Progestogen
Day 14
De Villiers TJ et al. Climacteric 2013;16:316–337.
.
Continuous Estrogen
Estrogen
No tablet break
No bleeding as no uterus
Uterus
Continuous Combined HRT
Estrogen
Progestogen
Day 14 Combined therapy without tablet break
No bleeding at end of cycle

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 1.25
Micronized 17β-estradiol (mg) 0.52 1 2 4
Estradiol valerate (mg) 1 2
Transdermal 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

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
*
*
Mean
number
of
moderate-to-
severe
hot
flushes
per
week
Weeks
0
10
20
30
40
50
60
70
80
0 1 2 3 4 5 6 7 8 9 10 11 12
Placebo
0.25 mg Estradiol
0.5 mg Estradiol
1 mg Estradiol
2 mg Estradiol
***
***
***
*
*
*

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%

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

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.
.

HRT Risks and Benefits
Benefits
Relief of
Menopause
Symptoms
Risks
Breast
Cancer

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 in
Younger 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 years
CHD, 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 HT
0.01 0.1 1 10 100
Favors control
Older women**
100
0.01 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.

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

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)
Adjusted
RR
vs.
never-use
of
HRT
(95%
CI)

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.
Adjusted
ORs
(95%
CI)
for
VTE
with
oral
and
transdermal
estrogen
vs.
non-users
(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)

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
PERCEPTION
Leading causes of death
perceived by women
REALITY
Actual 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%)

Growth
1 cm
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years
2.5 cm
1 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.

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

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)
CEE estrogen-only
50–79 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 no
increased 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.

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 never
users of HRT over a 5 year
period1
Risk ratio
(95% CI) #
Estrogen only HRT
50–65 9–12 1.2 1–2 (0–3)
Combined estrogen-progestogen
50–65 9–12 1.7 6 (5–7)
# Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of use
Note: Since the background incidence of breast cancer differs by EU country, the number of additional
cases of breast cancer will also change proportionately
1Taken 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.

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)
1.16
1.00
Estrogen/
progesterone
Baseline risk
without HRT
Estrogen/
dydrogesterone
1.69
0
0.2
0.4
0.8
1.2
1.6
1.0
2.2
2.0
1.8
1.4
0.6
Relative
risk
(95%
CI)
≥5 years
(0.8–
1.5)
(0.8–
2.7)
(1.2–
3.8)
1.5
1.1
≥5 years
<5 years <5 years
2.1
0
0.2
0.4
0.8
1.2
1.6
1.0
2.2
2.0
1.8
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

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
Standard
incidence
ratio
(95%
CI)
0
0.2
0.4
0.8
1.2
1.6
1.0
2.2
2.0
1.8
1.4
0.6
2.07
2.03
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
N = 50,210 women >50 years of age, treatment duration 5 years

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

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.

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.

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

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

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