Tony ParsonsWarwick Medical School
August 2008
2
STRAW reproductive aging system
Lengthdecreases-2 days
3
“Menopause that occurs in women < 40 years old.”
Utian. Climacteric 1999.
(About 1% of population or less)
CA MS
4
“Cessation of menstruation that follows bilateral oophorectomy (surgical menopause), Iatrogenic ablation of ovarian function by chemotherapy or pelvic radiation therapy.”
(No perimenopause transition for these women)
Utian. Climacteric 1999.
CA MS
5
Early loss of fertility More severe symptoms Greater risk of osteoporosis and
CVD Sequelae of underlying disease
and its treatment Little research regarding
benefits/risks of treatment
6
1.2 million follicles at birth, only about 1,000 by menopause
Most follicular loss due to atresia, not ovulation
Atresia accelerates at around age 35 to 38 years
Age-related uterine changes also contribute to decreased fertility
0
2000
4000
6000
8000
10000
12000
14000
Thousands
Q1 03 Q2 03 Q3 03 Q4 03 Q1 04 Q2 04 Q3 04 Q4 04
Main drop after Million Women Study, not WHI
Now stable Increasing use of low dose, but in
switchers rather than starters Approx 25 % of discontinuers thought to
have restarted Fewer new prescriptions
Early menopause
Local oestrogens
Alternatives to oestrogen
Systemic HT
Premature natural menopause (<40) Iatrogenic
Bilateral oophorectomy Chemotherapy / radiotherapy
No change in practice Estrogen replacement the norm unless
contraindicated
15% premenopausal women 10 – 40% postmenopausal 10 – 25% women taking systemic
HRT 2/3 by age 75
0
10
20
30
40
50
60
Per
cen
t
Superficial Dyspareunia
Atrophy
Atrophy increased significantly with increase in menopausal age (P < .001).Adapted from Versi E, et al. Int Urogynecol J. 2001;12:107-10. © 2001, Springer-Verlag.
Perimenopause(n = 133)
0–1 Year(n = 52)
2–3 Years(n = 39)
4 Years(n = 67)
Reduced lubrication Dryness Discomfort during intercourse Decreased frequency of
intercourse Vaginal and vulval irritation Discharge Bleeding Relationship problems
20 – 25% with symptoms sought help
Despite 78% feeling active sex life important, only 17% discussed symptoms with health
professional, 59% hide symptoms from partner
Bladder symptoms – only 21% discussed with health
professional
25% of those with genito-urinary atrophy symptoms who seek help, receive treatment
71% with vaginal symptoms - no treatment
89% with bladder symptoms - no treatment
Ask about symptoms and offer treatment
Topical oestrogen may be needed even with systemic HRT
No real contraindications A long-term treatment for a
long-term problem
Systematic review 70 randomised trials Most studies poor quality or too small “Data insufficient to support the
effectiveness of any complementary or alternative therapy”
Nedrow,A et al. Arch Intern Med 2006;166:1453-1465
43 prospective randomised studies Effective (= one or two fewer flushes per
day) SSRIs / Venlafaxine Clonidine Gabapentin Methyldopa Bellergal
Ineffective Soy Red clover
Nelson, HD et al. JAMA 2006;295:2057-71
National Center for Health Statistics. 1999:164-7.
Coronary Artery Disease
Stroke
Lung Cancer
Breast Cancer
Colon Cancer
Endometrial Cancer
Age (years)
Mo
rtal
ity
Rat
e p
er 1
00,0
00
6500
4500
2500
1600
1200
800
400
075–7970–7465–6960–6455–5950–5445–49 80–84 85+
1993 Women’s Health Initiative Studies Designed
1996 PEPI 1998 HERS 2002 WHI (EPT) 2003 MWS 2004 WHI (ET)
Stroke
Threshold levelEarly STOP = clear harm
Threshold levelEarly STOP = clear benefit
Coronary artery diseaseBreast cancer
Risk Benefit
Plan to study until 2005
Additional benefits:• Osteoporosis treatment• Colon cancer• Overall mortality
Additional risks:• VTE
Writing Group for WHI. JAMA 2002.
26% increase Breast cancer
VTE Fracture reductionColon cancer
Early STOP=clear harmThreshold level
29% increase Coronary artery
disease41% increase Stroke
Risk Benefit
Writing Group for WHI. JAMA 2002.
CHD
Breast cancer
Stroke
VTE
DVT
PE
Colorectal cancer
Hip fractures
Total fractures
OverallHazardRatio
Attributable Risk
per 10,000Women/YearHealth Event
1.29
1.26
1.41
2.11
2.07
2.13
0.63
0.66
0.76
7
8
8
18
13
8
6
5
44
Benefitper 10,000
Women/Year
Overall Relative and Attributable Risk Overall Relative and Attributable Risk for Women 50 to 80 Years of Agefor Women 50 to 80 Years of Age
Nominal95%
1.02–1.63
1.00–1.59
1.07–1.85
1.58–2.82
1.47–2.87
1.39–3.25
0.43–0.92
0.45–0.98
0.69–0.85
Adjusted95%
0.85–1.97
0.83–1.92
0.86–2.31
1.26–3.55
1.14–3.74
0.99–4.56
0.32–1.24
0.33–1.33
0.63–0.92
Confidence Interval
DVT = deep vein thrombosis; PE = pulmonary embolism.Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
Even with WHI figures HRT for women with moderate menopausal symptoms will be cost effective
D e c line d sc r e e n inga nd q ue st io nna ir e
A tte nd e d sc r e e n ingD e c line d q ue st io nna ir e
P r o sp e c t iv e fo llo w -upB r e a st c a nc e r inc id e nc eB r e a st c a nc e r m o r ta lity
A tte nd e d sc r e e n ingC o m p le te d q ue st io nna ir e
(N = 1 0 8 4 1 1 0 )~ 2 5 % w o m e n 5 0 -6 4 y r s in U K
W o m e n inv ite d to a t te nd N H S B S P a nd c o m p le teM illio n W o m e n S tud y q ue st io nna ir e
- L ife s ty le fa c to r s (e .g . H T use )- B r e a st c a nc e r r isk fa c to r s
Data on 828,923 postmenopausal womenData on 828,923 postmenopausal women• Mean age 55.9 yearsMean age 55.9 years• Mean time from baseline to cancer diagnosis Mean time from baseline to cancer diagnosis 1.2 yrs1.2 yrs
Selection bias Breast cancer incidence greater than in
general population HRT use more common Time to diagnosis implausibly short Apparent loss of HRT effect within 1 year of
stopping Misclassification of time, type and
duration of HRT Multiple errors – poorly written, poorly
reviewed
0
10
20
30
40
50
60
70
80
50 55 60 65
Age (years)
Cu
mu
lati
ve in
cid
ence
per
100
0 w
om
en
10yrs use oestrogen-progestagenHRT: excess 19 per 1000
10 yrs use oestrogen only HRT:excess 5 per 1000
Never users of HRT
10yrs use oestrogen only HRT: excess10 per 1000
Never users of HRT
Breast
Endometrial
Adapted from Lancet 2003;362:419-27
Endometrial Cancer
Breast Cancer
Revisiting the animal work
Early versus late use of HRT – is there really a window of opportunity ?
E versus E + P
1Clarkson TB, et al. J Clin Endocrinol Metab. 1998;83:721-6; 2Adams MR, et al. Arterioscler Thromb Vasc Biol. 1997;17:217-21; 3Clarkson TB, et al. J Clin Endocrinol Metab. 2001;86:41-47; 4Williams JK, et al. Arterioscler Thromb Vas Biol. 1995;15:827-36.
Premenopausal Years Postmenopausal YearsOvariectomy
Plaque Area (% of placebo)
Time
Healthy diet CEE + atherogenic diet1. 70%1,2
Atherogenic diet CEE + atherogenic diet2. 50%3
Healthy dietAtherogenic
dietHealthy diet
+ CEE3. 0%4
~ 6 Year Human Equivalent
0
2
4
6
8
10
0 10 20 30 40
Weeks
Mic
e W
ith
Le
sio
ns
(n
)
Iliac –EstradiolIliac +Estradiol
New Lesions Established Lesions
Rosenfeld ME, et al. Atherosclerosis. 2002;164:251-9.
0
2
4
6
8
10
0 10 20 30 40
Weeks
Mic
e W
ith
Le
sio
ns
(n
)
Carotid –EstradiolCarotid +Estradiol
Meta-analysis of 30 trials 27,000 participants
Odds ratio for mortality differed with age at enrolment Under 60 - 0.61 Over 60 - 1.03
[Nurse’s Health Study HRT within 2 years of LMP - 0.63]
Salpeter et al J Gen Int Med 2004;19:791-804
The dotted vertical line indicates the overall CHD odds ratio (1.24). P-values for interaction were not significant.Manson JE, et al. N Engl J Med. 2003;349:523-34.
0.5 1.0 1.5 2.0 2.5
Hazard Ratio for CHD
1.27
1.05
1.44
0.89
1.22
1.71
Age (years)
50–59
60–69
70–79
Years Since Menopause
<10
10–19
20
Zandi PP, et al. JAMA. 2002;288:2123-9.
0.00
0.02
0.04
0.06
0.08
0.10
0.12
65 70 75 80 85 90 95 100
Dis
cret
e A
nn
ual
Haz
ard
Age (years)
WomenHT NonusersHT Use <3 YearsHT Use 3-10 YearsHT Use >10 Years
Men
Past users of HRT ( > 10 years) 83 % reduction in risk of AD
Current users who started after 60 (using for 3 – 10 years) 112 % increase in risk
Zandi et al JAMA 2002
1500 women who had one or both ovaries removed before 50
1500 controls 27 years mean follow-up Only 20% who had bilateral
oophorectomy received oestrogen until 50
Incidence of dementia with HT equal to controls
Incidence without HT doubledRocca et al , Neurology 2007
0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7
Cu
mu
lati
ve P
rop
ort
ion
Time (years)
Unweighted HR = 1.24(95% CI, 1.01–1.54)
Chlebowski RT, et al. JAMA. 2003;289:3243-53.
E+P
Placebo
0.00
0.01
0.02
0.03
0.04
0.05
0 1 2 3 4 5 6 7 8
Time (years)
Cu
mu
lati
ve H
azar
d
CEE
Placebo
Women’s Health Initiative Steering Committee. JAMA. 2004;291:1701-12.
Kaplan-Meier Estimate
HR = 0.77
95% nCI = 0.59–1.01
95% aCI = 0.57–1.06
Prospective case-control Women with possible DVT recruited prior
to confirmation or exclusion of diagnosis Idiopathic DVT, no risk factors
Unopposed oestrogen OR 1.22 [0.57 – 2.61]
Combined EPT OR 2.70 [1.44 – 5.07]
Hospital based case-control study
Current users oral EPT OR 3.5 [1.8 – 6.8]
Current users transdermal
OR 0.9 [0.5 – 1.6]
Scarabin et al. Lancet,2003;362:428-32
Low doses may confer protection while higher doses may increase risk
Risks may be lower with transdermal
Thrombogenic effects C-reactive Protein
Birge ss Menopause 2006;13(5):719-20
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
1 2 3 4 5 6+
Pe
rce
nt
VT
E E
ve
nts
CEE/MPA
Placebo
HazardHazardYearYear RatioRatio
11 3.603.60
22 2.262.26
33 1.671.67
4 4 1.841.84
55 2.492.49
6+6+ 0.900.90
P < .05, significant fordecreasing risk over time.
Year
HR = 2.11
95% nCI = 1.58–2.82
95% aCI = 1.26–3.55
Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33.
Ch
ang
e in
Pla
sma
CR
P (
%)
-20
0
20
40
60
80
100
Oral CEE TransdermalEstradiol
Oral CEE TransdermalEstradiol
6 Months 12 MonthsCRP = C-reactive protein.Decensi A, et al. Circulation. 2002;106:1224-8.
Use of HT at the menopause will have different effects from HT started 10 to 15 years later
No data to suggest change of indications for HT at the menopause
Increasing evidence that progestogen adds to risks esp. breast cancer, DVT
Duration of use will usually be influenced by increase in breast cancer risk – is there any with unopposed oestrogen ?
Early menopause or
Symptoms affecting quality of life Prevention of osteoporosis/ fracture
Prevention of heart disease likely but not a primary indication
Protection against other conditions currently unproven (but increasing evidence for dementia, various cancers and osteoarthritis)
Thrombosis Breast cancer
Only breast cancer risk is cumulative Consider
Age at menarche Age at first child Breast feeding Smoking Alcohol Premenopausal BMI Family history
E or E + P ?
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