HT : Helter Skelter
A Decade After WHI
DR R. Boroditsky
Professor and Medical Director
Mature Mature Womens Centre
University of Manitoba
1
Objectives
Learning
After completion
of this Objectives
session, participants will be able to:
• Appreciate the clinical significance of the new safety data
• Understand the management of menopausal symptoms,
focusing on routes of administration of estrogens and
progestogen selection
Workshop: Clinical Quiz + Q and A
2
Gimli Manitoba July 2002
“The Future Ain’t
What It Used to Be”
Yogi Berra
Putting Things In Perspective
66% of the women who took part in the WHI Study were
over 60 years of age – well over the recommended
treatment age (depending on when menopause begins).1*
Similar risks occur with other medications that are
commonly prescribed to and accepted by menopausal
women. For example
Aspirin® treatment has been shown in several
studies to increase the absolute risk of
hemorrhagic stroke by 12 events per 10,000
people.2
References: 1. Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy: The Women’s Health Initiative Randomized Controlled Trial. JAMA.
2004;291(14):1701-1710. 2, He J, et al. Aspirin and Risk of Hemorrhagic Stroke. A Meta-analysis of Randomized Controlled Trials. JAMA. December 1998;280(22):1930-1935.
HT and SSRI Reciprocal
Trend since 2002
McIntyre RS, Konarski JZ, Grigoriadis S, Fan NC, Mancini DA, Fulton KA,
Stewart DE, Kennedy SE. Hormone replacement therapy and
antidepressant prescription patterns: a reciprocal relationship.
CMAJ 2005; 172 (1):57-59
Increased Fracture
Rates since 2002
Islam S, Liu Q, Chines A, Helzner E. Trend in incidence of osteoporosis-related
fractures among 40- to 69-year-old women: analysis of a large insurance
claims database, 2000-2005. Menopause 2009; 16(1): 77-83
Increased Arthralgia


Affects 30-50% of menopausal women
Pain and stiffness more than twice as
common in women after stopping HT
(OR 2.16; 95% CI, 1.95-2.40)
Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing
use of estrogen plus progestin. JAMA 2005; 294:183–93.
Patient Concerns
It is largely
fear of breast cancer
that fuels the debate
about hormone replacement
therapy” Scientific American
Sept 1996
Why Women Choose or
Continue HT
• Perceived Benefit
• Social Support
“In The Closet User”
Fisher WA, Sand M, Lewis W, Boroditsky RS. Canadian
menopause study-I: Understanding women’s intentions to
utilize hormone replacement therapy. Maturitas 37(2000) 1-14.
Physician Concerns
• Time restraint
• Unaware of latest safety
data
• Confusing and conflicting
data
Who do I believe?
• Perceived /Actual risks
• Perceived /Actual benefits
Latest Safety Data
16
Premature Menopause
• Medically a distinct group
• ↑ risk of negative effects on
cardiovascular system, bone,
cognition, mood & sexuality
Santen RJ, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010;95(7 Suppl 1):S1-S66.
Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17(2):242-55.
Risks of Premature Menopause
• Risk of overall mortality and
CVD increase with earlier age of
onset of premature
menopause1
• Guidelines recommend HT to
restore natural estrogen levels
until at least the average age of
natural menopause (~51
years)2,3
1. Shuster LT, et al. Premature menopause or early menopause: long-term
health consequences. Maturitas 2010;65(2):161-6.
2. Menopause and osteoporosis update 2009. J Obstet Gynaecol Can 2009;31(1 Suppl
1):s1-s48. Canadian Consensus on Menopause, 2006 update. J Obstet Gynaecol Can
2006;28 Spec ed;s1-s112.
3. Estrogen and progestogen use in postmenopausal women: 2010 position
statement of The North American Menopause Society. Menopause
2010;17(2):242-55.
NEW SAFETY DATA
Cardio-Vascular Disease
19
Atherosclerosis Timeline
Foam
cells
Fatty
streak
Intermediate
lesion Atheroma Rupture
Fibrous
plaque
Endothelial dysfunction
Growth mainly by lipid
accumulation
Thrombosis,
hematoma
Estrogen prevents Estrogen worsens
Image from Pepine 1998. Am J Cardiol 82 (suppl 10a) 23-27.
Hypothetical Pathogenic
Sequence
No HT
Adventitia
MMP-9
Media
Internal
Elastic
Lamina
Fibrous
Cap
Plaque
Fatty Streak/Plaque
Fibrous
Cap
Fibrous
Cap
Plaque
Plaque
Necrotic Core
Necrotic Core
HT Early & Continued
HT
Mural Thrombus
HT Late
HT
Age 35-45 years Age 45-55 years Age 55-65 years Age >65 years
Nurses’ Health Study:
Major Coronary Heart Disease and Stroke
Conjugated
estrogen
Person years
Multi-variate RR
Never
313,661
1.0
0.3 mg
19,964
0.58
0.37-0.67
0.625 mg
116,150
0.54
0.44-0.67
1.25 mg
39,026
0.70
0.51-0.97
95% CI
Grodstein et al. Ann Intern Med 2000; 133: 933-41.
22
Impact of Age on CV Risk from HT(E+P)
Data from Multiple RCTs
Younger Women < 60
TOTAL (95% Cl)
0.001
0.68 (0.48, 0.96)
0.01
Favours HT
0.1
1
10
100
Favours control
Older Women > 60
TOTAL (95% Cl)
0.01
1.03 (0.91, 1.16)
0.1
Favours HT
1
10
100
Favours control
Salpeter SR, et al. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J
Gen Intern Med 2006;21(4):363–6.
WHI Re-Analysis: HT(E+P) Use in Women 50-59
Does Not Increase CVD Risk
“There were no significant increases in risk due to hormone therapy for any
outcome at ages 50 to 59 years. There was a reduction in total mortality in
the age group 50 to 59 years.”
Rossouw J, et al JAMA 2007;297(13):1465-1477
24
WHI Re-analysis: Effect of Estrogen Alone on
Major Outcomes for Women <60 Years Old
Event
% difference in RR to
Placebo (95% CI)
# of events/10,000
women/yr of CEE alone
therapy
Coronary heart disease
-37 (0.36-1.09)
-11
Stroke
-11 (-.47-1.69)
-2
Venous thromboembolism
+37 (0.70-2.68)
+4
Breast Cancer
-18 (0.65-1.04)
-8
Fractures
-30 (0.59-0.83)
-56
New-onset diabetes
-12 (0.77-1.01)
-14
Total mortality
-29 (0.46-1.11)
-11
Hodis H, Mack WJ. Postmenopausal hormone therapy in clinical perspective. Menopause 2007;14(5):944-57.
WHI Re-analysis: Effect of Estrogen Alone on
Major Outcomes for Women <60 Years vs 70-79 Years
Differences in Outcomes in Women Who Received CEE*
50-59 Years
70-79 Years
Acute MI
-12
+16
Death
Adverse events
(Global index of
chronic diseases)
-13
-18
+19
+48
*Expressed as absolute rates per 10,000 women annualized over the
average follow-up period of 10.7 years
LaCroix AZ, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a
randomized controlled trial. JAMA.2011;305(13):1305-14.
WHI Messaging in 2011
Among postmenopausal women with prior hysterectomy
followed for 10.7 years, CEE use for a median of 5.9 years was
not associated with an increased or decreased risk of CHD,
DVT, stroke, hip fracture, colorectal cancer or mortality
A decreased risk of breast cancer
persisted !!
Maybe The Progestogen Is The
Problem?
LaCroix et al JAMA 2011; 305(13):1305-1314
Why Transdermal? Why Now?
• Needs assessment revealed gaps in practitioner
knowledge
• Extensive information on oral hormone therapy;
only delivery system looked at in WHI
• Since then – information has continued to evolve
over past 10 years
• New science on transdermal delivery system
• There is a difference
Transdermal Estrogens:
Impact on Cardiovascular Risk Factors
• Estrogen and Thromboembolism Risk (ESTHER) study1
– Lower risk of VTE compared with oral E2
•
•
•
•
Markers of inflammation unaffected2
Triglycerides decreased3
Less effect on SHBG and TBG2
Less favourable for HDL and LDL changes4 - CEE alone and
CEE + MPA have a favourable effect on HDL-C
• Decreased CV risk in patients with metabolic syndrome5-7
SHBG = sex hormone-binding globulin; TBG = thyroxine-binding globulin.
1.
2.
3.
4.
5.
6.
7.
Canonico M, et al. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER
study. Circulation 2007;115(7):840-5.
Shifren JL, et al. A comparison of the short-term effects of oral conjugated equine estrogens versus transdermal estradiol on C-reactive protein, other serum markers of
inflammation, and other hepatic proteins in naturally menopausal women. J Clin Endocrinol Metab 2008;93(5):1702-10.
Sanada M, et al. Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: effects on hypertriglyceridemia. Menopause
2004;11(3):331-6.
Walsh BW, et al. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991;325(17):1196-1204.
Modena MG, et al. Effects of hormone replacement therapy on C-reactive protein levels in healthy postmenopausal women: comparison between oral and transdermal
administration of estrogen. Am J Med 2002;113(4):331-4.
Lewandowski KC. Effects of hormone replacement therapy type and route of administration on plasma matrix metalloproteinases and their tissue inhibitors in postmenopausal
women. J Clin Endo 2006;91(8):3123-30.
Chu MC. Metabolic syndrome in postmenopausal women: the influence of oral or transdermal estradiol on inflammation and coagulation markers. Am J Ob Gyn 2008;199(5):526.e1-
Oral vs. Transdermal Estrogen: Risk of Stroke
Cases
(n=15 710)
Controls
(n=59 958)
Rate ratio (95% CI)
Adjusted
14 496
55 834
1.00
Transdermal route
103
441
0.95 (0.75 to 1.20)
Low dose (≤50 μg)
76
384
0.81 (0.62 to 1.05)
Estrogen only
81
317
1.02 (0.78 to 1.34)
Estrogen-progestogen
22
124
0.76 (0.47 to 1.22)
Oral route
618
2025
1.28 (1.15 to 1.42)
Low dose (≤0.625 mg of
equine estrogen or ≤ 2 mg
of estradiol)
515
1753
1.25 (1.12 to 1.40)
Estrogen only
262
802
1.35 (1.16 to 1.58)
Estrogen-progestogen
356
1223
Type of HRT
None
Renoux, et al. BMJ. 2010;340:C2519.
1.24
(1.08 to 1.41)
30
NEW SAFETY DATA
Thromboembolic Disease
31
Risk of VTE with Oral vs. Transdermal Estrogen:
The ESTHER Study
OR = 4.0 (1.9-8.3)
Adjusted Odds Ratio (95% CI)
5
3.5
4
(1.8-6.8)
3
2
1
0.9
1.0
(0.5-1.6)
0
Nonusers
Oral estrogen users
Transdermal
estrogen users
Scarabin P-Y, et al. Lancet. 2003;362:428-432
32
Postmenopausal HT and Risk of VTE:
Results of the E3n Trial
Hazard ratios (95% CI)
Treatment
Age-Adjusted
Multivariable
Adjusted*
Never use (n=181)
1 [reference]
1 [reference]
Past use (n=66)
1.0 (0.7–1.3)
1.1 (0.8–1.5)
Current use of oral estrogens (n=81)
1.5 (0.9–2.3)
1.7 (1.1–2.8)
Current use of transdermal estrogens
(n=174)
1.1 (0.7–1.6)
1.1 (0.8–1.8)
*Adjusted for age, body-mass index, parity, educational level and time-period
Canonico et al. Arterioscler Thromb Vasc Biol 2010;30(2):340-5.
33
Postmenopausal HT and Risk of VTE:
Results of the E3n Trial (cont’d)
Hazard ratios of idiopathic VTE in relation to both estrogens by route of administration and concomitant progestogens
Age-adjusted HR
No progestogens use (n=26)
Multivariateadjusted HR*
---
---
Current use of micronized
progesterone (n=47)
0.9 (0.6 -1.4)
0.9 (0.6 -1.5)
Current use of norpregnane
derivatives (n=69)
1.4 (0.8 -2.5)
1.4 (0.7 -2.4)
1.0 (0.7 -1.5)
1.1 (0.7 -1.8)
Current use of
nortestosterone derivatives
(n=22)
0.5
1.0
1.5
2.0
2.5
Multivariate-adjusted hazard
ratio* (95% CI)
*Adjusted for age, body-mass index, parity, educational level and time-period.
Canonico M, et al. Postmenopausal hormone therapy and risk of idiopathic venous
thromboembolism: results from the E3N cohort study. Arterioscler Thromb Vasc Biol
2010;30(2):340-5.
NEW SAFETY DATA
Breast Cancer
35
Family History and Lifetime
Risk of Breast Cancer
Number of 1º
Relatives
1
2
Over
Age
12%
24%
24%
48%
50
Under
Family History of Breast
Cancer

Family history
risk

Addition of HRT
No

HRT users
Reduced
mortality rate
risk
Hormone Therapy in Women
with a Family History of
Breast Cancer


Consider HRT as appropriate
Begin screening for
breast cancer 5-10
years before age at
which youngest first
degree relative
diagnosed with cancer
Risk Factors For Breast Cancer
50
8 year ERT *
Additional Cancers per 1,000 Women
5 years of CCEPT use
10 years of CCEPT use
40
15 years of CCEPT use
Late Menopause (10
year delay)
30
Body Mass Index (10
kg increase)
20
Alcohol consumption
(2 drinks/day)
10
*
0
Lack of regular
exercise
Weight gain after
menopause (20 kg or
more)
SOGC – 2002
*
WHI JAMA 2004
Lifestyle and age-related risk factors for breast cancer in
women.4
Factor
Effects of baseline breast cancer risk
Alcohol Consumption
60% increase if 2 drinks per day or more3
Lack of Regular Exercise
(<4 hours/week)
60% increase3
Body Mass Index
3.1% increase for every additional kg/m23
Late Menopause
2.8% increase for each year of delay3
References: 3, Hulley SB, et al. The WHI Estrogen-Alone Trial – Do Things Look Any Better? JAMA. 2004;291(14):1769-1771. 4. The Canadian Consensus Conference on
Menopause and Osteoporosis 2000/2001. J SOGC. 2000/2001;1-86.
Conjugated Equine Estrogen
And Breast Cancer
 CEE vs. placebo HR 0.80 (0.62 – 1.04)
 104 cases (CEE) vs. 133 cases (placebo)
 Younger vs. older women?
 risk decreased
 risk of ductal carcinoma and early stage
disease decreased
Stefanick JAMA 2006;295:1647-1657
WHI Messaging in 2011
Among postmenopausal women with prior hysterectomy
followed for 10.7 years, CEE use for a median of 5.9 years was
not associated with an increased or decreased risk of CHD,
DVT, stroke, hip fracture, colorectal cancer or mortality
A decreased risk of breast cancer
persisted !!
Maybe The Progestogen Is The
Problem?
LaCroix et al JAMA 2011; 305(13):1305-1314
Breast Cancer Risk and
Progestogen Selection
Relative risk of invasive breast cancer by type of HT and duration of exposure, compared with HT never-use
Estrogen alone (n=20,347)
1.29 (1.021.65)
Estrogen + progesterone
(n=40,537)
1.00 (0.83 1.22)
Estrogen + dydrogesterone
(n=31,045)
1.16 (0.941.43)
Estrogen + other progestogens
(n=104,243)
1.69 (1.50 1.91)
0.5
1.0
1.5
2.0
2.5
Adjusted relative risk* (95% CI)
N=80,377 postmenopausal women, mean age 52.4 years. At start of HT, 31.9% of participants were aged 40-45 years; 25.7% were
45-50 years, 20.4% were 50-55 years, 13.8% were 55-60 years, and 8.2% were 60-65 years.
*Adjusted for time since menopause, age at menarche, parity and age at first full-term pregnancy, breastfeeding, age at
menopause, type of menopause, personal history of benign breast disease, family history of breast cancer in first-degree
relatives, family history of breast cancer in other relatives, BMI, previous mammography. Further stratified on year of birth.
Fournier A, et al. Unequal risks for breast cancer associated with different hormone replacement
therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107(1):103-11.
Breast Cancer Risk and
Progestogen Selection
“Emerging data, so far from two independent studies only,
report that progesterone in combination with estrogen does
not increase breast cancer risk if given for 5 yr or less.”
French E3n Cohort Study ,Fournier,Br Ca Res. Treat 2008;107:103-111
44
WHY TRANSDERMAL? WHY NOW?
45
Consider Use of Transdermal Estrogen
First line therapy for relief of menopausal symptoms and for
patients with underlying medical conditions
–
–
–
–
–
Higher risk of DVT or PTE
High triglyceride levels
Gall bladder disease
Hypertension
Metabolic syndrome
Need for “steady state” drug release
– Daily mood swings
– Migraine headaches
– Patients who do shift work
Inability to use oral tablets
– Stomach upset due to oral estrogen intake
– Problems with taking a daily pill
46
ERT: Considerations that Impact
Route of Administration
Smoking
– Free E2 levels may be lower in smokers ( liver metabolism; 
sex-hormone-binding globulin)1,2
– Increased dose of oral E may be required
– Transdermal E may be beneficial
Low HDL levels
– Although Transdermal E may be associated with a lower
elevation of HDL, beneficial vascular effects are still evident3
High triglycerides
– Oral E can further elevate TG4
1. Jensen J, et al. N Engl J Med. 1985;313:973-975.
2. Lobo RA, et al. J Reprod Med. 1992;37:77-84.
3. Rosano GM, et al. J Am Coll Cardiol. 2000;36:2154-2159.
ERT = estrogen replacement therapy; E2 = estradiol; E = estrogen
4. The Writing Group for the PEPI trial. JAMA. 1995;273:199-208.
47
ERT: Considerations that Impact
Route of Administration
Decreased Libido and sexual arousal on oral
estrogen and /or smoking
-Increased SHBG
Progestogens : The Same ,But Not The Same
49
Progestogens
• Any substance that possesses progestational activity
• Includes “Natural, Bioidentical” progesterone and
synthetic progestins
• Oral progesterone is broken down in GI tract and
therefore is inactive
• Progestins were developed which are not broken
down in the GI tract and are derived from
progesterone or testosterone (19-nortestosterone)
precursors
• Once micronization was discovered, progesterone
could be given orally
50
Micronized Progesterone Metabolism
• Metabolized primarily by the liver
• Metabolites act at non-sex-steroid receptor sites
• Beneficial effects of metabolites
– Sedation with higher doses of oral progesterone – utilized
therapeutically for sleep
– 11-deoxycorticosterone has aldosterone properties
• May reduce fluid retention
• Adverse effects of metabolites
– May cause nausea and dizziness
– Contraindicated in patients with peanut allergy
51
Impact on Progestogen Selection:
Vascular Effects in Menopausal Women
• Estrogen has direct beneficial effects on
the vasculature
• Estrogen-mediated effects on blood
vessels
– MPA may negate
– MP does not counteract
– Norethindrone Acetate (NETA) (?)
Rosano GM, et al. J Am Coll Cardiol. 2000;36:2154-2159.
52
Bleeding Patterns on Continuous Combined HRT: MPA vs. MP
Study
CEE+MPA
(2.5 mg)1
% of
cycles
% of
patients
Incidence of Bleeding During
First 6 - 12 Months of HT
CEE+MPA (5 Transdermal E2 (50 mg/d) +
mg)1
MP* (100 mg, 25 d/month)
38
27
162
53
59
47
292
203
*MP is associated with a lower incidence of bleeding
1.
3.
Archer DF, et al. Bleeding patterns in postmenopausal women taking continuous combined or sequential regimens of conjugated estrogens with medroxyprogesterone acetate.
Menopause Study Group. Obst Gynecol 1994;83(5 Pt 1):686-92.
2. Gillet JY, et al. Induction of amenorrhea during hormone replacement therapy: optimal micronized progesterone dose. A multicenter study. Maturitas 1994;19(2):103-115.
Foidart JM, et al. Impact of percutaneous oestradiol gels in postmenopausal hormone replacement therapy on clinical symptoms and endometrium. Br J Obstet Gynecol 1997;104:305310.
Comparison of Bleeding Patterns
With Cyclic Progestogens
12 d/mo  12 mo
MP*
(200 mg/d)
MPA*
(10 mg/d)
Intensity
9.6 ± 5.9
11.3 ± 5.7
Duration
4.8 ± 2.5
6.0 ± 2.4
Breakthrough (% of cycles)
6.0
12.3
Amenorrhea (% of cycles)
19.5
3.4
* All patients received transdermal estradiol, 50 µg days 1-25.
Lorrain J, et al. Int J Gynecol Obstet. 1991;13:297-311.
GUIDELINE RECOMMENDATIONS FOR
THE MANAGEMENT OF MENOPAUSAL
SYMPTOMS
SOGC Consensus Update 2009:
Dose and Duration of HT
• Appropriate route and dose, according to symptoms
– Vaginal preferred for vaginal symptoms only
• HT should be prescribed at the appropriate dose and
duration to achieve treatment goals
• Prolonged treatment may be offered with appropriate
assessment and counselling
Menopause and osteoporosis update 2009. J Obstet Gynaecol Can 2009;31(1 Suppl 1):s1-s48.
Canadian Consensus on Menopause, 2006 update. J Obstet Gynaecol Can 2006;28 Spec ed;s1-s112.
Summary
• Primary purpose for prescribing HT remains symptomatic
relief
• Transdermal estrogens are considered part of the
armamentarium of HT
– May offer certain benefits in specific clinical scenarios
• Micronized progesterone may also offer benefits in bleeding
patterns and reduced risk of breast cancer compared to MPA
• Evidence-based recommendations for management of
menopausal symptoms can help guide optimal treatment
decisions
Post Menopausal HT The Future