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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