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Slide 1
Dr Julie Ayres Specialty Doctor in Gynaecology LTHT BMS
Council
Slide 2
Management of the menopause with hormones The menopause
Definition Symptoms HRT Where are we now with it? Risks and
benefits Who for? Which type?
Slide 3
The Menopause -Definition The last menstrual period i.e. only
diagnosed in retrospect 12 months later
Slide 4
When should we expect symptoms?
Slide 5
Slide 6
Slide 7
Slide 8
Menopausal symptoms Vasomotor
Slide 9
Menopausal Symptoms Genitourinary
Slide 10
Menopausal Symptoms Weight gain
Slide 11
Menopausal Symptoms - confusion
Slide 12
Menopausal symptoms poor concentration
Slide 13
Menopausal Symptoms feeling more emotional
Slide 14
Osteoporosis Fractures Wrist Hip Spine Height loss Dowagers
Hump Back Pain
Slide 15
Predictions about the menopause It will happen It will be
unpredictable
HRT Ups and Downs HRT History Used x 60 years+ Past Issues
Endometrial cancer Add progestogen (combined HRT) Reduced risk of
CHD Reduced risk of osteoporosis It was looking good! Breast cancer
WHO data RR 1.35
Slide 19
HRT More Ups and Downs Increased risk of Heart disease/Stroke
WHI (2002) Many women stopped HRT altogether Many doctors advised
against starting/continuing HRT Higher risk of breast cancer MWS
(2003) Many more women just stopped HRT CSM reviewed WHI / MWS and
issued guidance Dec 2003 Knee-jerk reaction HRT TO BE USED AT THE
LOWEST DOSE FOR THE SHORTEST POSSIBLE TIME Final nail in the coffin
for prescribers
Slide 20
HRT - Benefits Well-established CONTROL OF MENOPAUSAL SYMPTOMS
Maintenance of bone density Reduction in risk of OP fractures CSM
advise not for first line use
Slide 21
HRT - Benefits Other benefits? Reduced risk colon cancer
Observational studies Alzheimers disease? Jury is out Coronary
Heart disease - benefit or risk?
Slide 22
HRT Risks DVT Stroke Breast Cancer Coronary Heart disease Risk
or benefit?
Slide 23
HRT Possible CV benefits? Nurses Health Study Observational
study of 120 000 US nurses 50% reduction in incidence and mortality
from coronary heart disease No effect on risk of stroke NEJM M.
Stampfer et al. 1991; 325 (11):756-762 Other observational studies
suggested similar benefits
Slide 24
HERS Study Secondary prevention study in 2763 women with CHD
RCT using CEE/MPA vs. placebo 50% inc in ischaemic events in 1 st
yr in HRT group No overall benefit at 5 and 7 years JAMA 1998; 280:
605-13
Slide 25
HRT Headlines
Slide 26
WOMENS HEALTH INITIATIVE RCT Designed to last for 8.5 years
look at major health benefits and risks associated with the most
commonly used HRT in the US i.e. CEE +/- MPA against placebo JAMA
2002; 288: 321-33
Slide 27
WHI Aims Primary outcome measure = CHD (non-fatal MI + CHD
death) Primary adverse outcome = invasive breast cancer Global
index summary included; Hip fracture and colorectal cancers
Stroke,PE,endometrial cancer and deaths due to other causes
Slide 28
WHI Cont Combined arm (CEE + MPA) 16,608 postmenopausal women
aged 50 to 79 years terminated early (5.2 years) Numbers of CA
Breast exceeding stopping boundary Oestrogen only arm
continued
Slide 29
WHI Results Estimated hazard ratios; CHD 1.29 Ca Breast 1.26
Stroke 1.41 PE 2.13 Colorectal Ca 0.63 Endometrial Ca 0.83 Hip
fracture 0.66 i.e. Relative risks
Slide 30
WHI Results Absolute risks - I.e. XS cases per 10,000 women
years CHD7 extra cases stroke8 PE8 invasive breast cancer8 i.e. 38
vs. 30 THESE REPRESENT VERY SMALL RISKS TO THE INDIVIDUAL
Slide 31
WHI Results Absolute risk reductions (per 10,000 women years)
colorectal cancers6 hip fractures5
Slide 32
WHI - WHAT THE PAPERS DIDNT SAY The oestrogen-only arm
continued, XS CVD risk appeared to be assoc with combined HRT Only
CEE and MPA were studied Study Population Average age of women was
63 Ave time since menopause = 12 years CV risk profile BP 36.1%
High BMI 28.5% Diabetes 4.4% High chol.12.7% Previous history of
CHD not excluded (except during the previous 6 months) 7% had
history of CHD All women asymptomatic
Slide 33
Summary of Unreported Data Entry criteria do not reflect
standard practice in the clinical selection of women for HRT
Slide 34
WHI - What have we learnt? Breast Cancer? Confirms increased
risk Ca Br with longer term use of combined HRT (CEE and MPA) Use
> 10 years i.e. > 5 years use during study - only in women
who had used HRT for 5 years previously
Slide 35
WHI What else have we learnt? Confirms reduced risk of OP
fractures Confirms reduced risk of colorectal cancer (combined
HRT)
Slide 36
WHI - What else have we learnt? Cardiovascular disease?
Suggests possible increased risk of CVD assoc with CEE and MPA IN
THIS POPULATION These data should not be applied to other types,
doses and routes of HRT ? effect of different hormones (WHISP
trial-1mg E2/0.5mg NET) ?Primary prevention (as in observational
studies) only applies to women without pre-existing atherosclerosis
50-59 years (WHI) appeared at reduced risk
Slide 37
WHI - Overall Conclusion Dont give HRT to women who dont need
it! We still didnt know about the effect of HRT on the CVS in
younger women.
Slide 38
HRT and Breast Cancer The Bad News Daily Mail Aug 2003 HRT
doubles the risk of breast cancer!
Slide 39
MILLION WOMEN STUDY Accepted that; - HRT increases risk of
breast cancer Designed to; - Assess effects of specific types of
HRT on incident and fatal breast cancer
Slide 40
Million Women Study Recruitment 1 084 110 women aged 50-64
years attending NHSBSP = quarter of British women between 50-64
Observational study Questionnaire completed before screening
Average follow-up: 2.6 years (incidence) 4.1 years (mortality)
Slide 41
Million Women Study - Results RR Ca Br ever users = 1.43 cf
never users In current users only RR 1.66 RR 1.01 in past users
slightly increased in 1st year after HRT use no different to never
users thereafter
Slide 42
Million Women Study - Results RR in users of E only (Ca Br) =
1.30 RR in users of E+P = 2.00 RR in users of tibolone = 1.45 Risk
increased for increasing duration of use RR death from Ca Br
Current users = 1.22 Past users = 1.05 Not statistically
significant
Slide 43
Million Women Study - Results No significant variation between
different oestrogen types, doses or routes (oral / transdermal /
implants) No significant difference between different progestogen
types (MPA / norethisterone / norgestrel) or sequential /
continuous Only factor modifying risk was low BMI BMI 25 - RR
1.46
Slide 44
Million Women Study - Results In developed countries the risk
of breast cancer in never users = est @ 20/1000 between 50 and 60
Collaborative group figures Using the RR estimates from this study
the different patterns of use of HRT would be expected to result
in...
Slide 45
Estimated Extra Cases of Breast Cancer per 1000 Women by 60y 5
years E from 50y- 1.5 extra cases 10 years E- 5 extra cases 5 years
E+P- 6 extra cases 10 years E+P- 19 extra cases
Slide 46
Million Women Study - Potential Biases Observational study
?Differences between women attending NHSBSP or not (75% attend)
?Effect of women not participating (71% participated) ?Results
overestimated because of increased durations of treatment (from
baseline to diagnosis)
Slide 47
Million Women Study in Context Study confirms increased risk of
breast cancer associated with HRT Study suggests 20 000 extra
breast cancers in UK due to HRT in past 10 years 15 000 due to E+P
5 000 due to E Postmenopausal obesity - 50 000 Alcohol intake
45-64y - 16 000
Slide 48
What does the evidence suggest about HRT and breast cancer?
Putting all the evidence together (45 studies) Risk estimates
vary++ with a number of studies showing no increase in risk 20% -
RR < 0.9 33% - RR >1.1 47% - RR 0.9 1.1 MWS is a clear
outlier, with much higher risk estimates than all other studies
Bush et al Obstet Gynecol 2002;98:498-508
Slide 49
HRT and Breast Cancer The Good News WHI Oestrogen only arm
11000 women on CEE Terminated at 7 years No benefit on CHD risk
Slightly increased risk of stroke (12/10000) Reduced risk hip
fracture No effect on colon cancer NO INCREASE IN BREAST CANCER RR
0.77 (not statistically significant)
Slide 50
WHI revisited Average age = 63 Ave 12 years since menopause 70%
women over 60 To achieve sufficient power in the study Assumption
made re protective effects being same at all ages Study not powered
to do subgroup analysis by age
Slide 51
Update on HRT and CVD The Good News! Womens Health initiative
(WHI) Re-analysis Complete U-turn published JAMA. 2007;297:1465-
1477.
Slide 52
WHI Re-analysis Women aged below 60 years and less than 10
years past menopause have a lower risk of coronary disease, a lower
risk of death from any cause, and no increased risk for
stroke!
Slide 53
WHI Re-analysis CHD Relative risks; 20 years- HR = 1.28 CHD
Absolute risks Per 10 000 person years 20 years= 17
Slide 54
WHI Re-analysis Stroke RR 1.32 Risk unaffected by No. of years
since menopause No increased risk in women 50 59 years
Slide 55
WHI Re-analysis Mortality 50 59 years HR = 0.70 60 69 years HR
= 1.05 70 79 years HR = 1.14
Slide 56
BMS Statement re WHI It is quite astonishing that the study
which initially warned us of all the dangers of HRT is now showing
us virtually the opposite. But where is the publicity about this?
And will the regulatory authorities act with the same speed as they
did to warn against HRT to now correct their advice.
Slide 57
Nurses Health Study Revisited HRT started < 10 years since
menopause RR 0.66 E alone RR 0.72 - E + P = sig. reduced risk HRT
started > 10 years since menopause (i.e. similar to pop. In WHI)
RR 0.87 E alone RR 0.90 E + P = no sig. relation J Womens Health
2006;15:35-44
Slide 58
HRT and age What does it mean??
Slide 59
HRT and Cardio-protection There appears to be a Window of
opportunity in the first 10 years after the menopause during which
HRT may reduce the risk of cardiovascular disease.
Slide 60
Other studies Macaque Monkeys + BSO + atherogenic diet
Oestrogen at menopause 70% reduction in dev of atherosclerosis
Oestrogen at 6 yrs post- menopause No difference in atherosclerosis
cf. no Rx Studies on IMT show no benefit on thickened IMT but lack
of progression in thin IMT
Slide 61
International Menopause Society Statement on HRT and CVD
Initiating hormone therapy in older women with established
atherosclerosis is not likely to produce any cardiac or
neuroprotection and therefore should not be recommended for those
indications; but, for the younger age groups, these recent results
of the WHI and Nurses Health Study are in line with the window of
opportunity theory, which is based on the assumption that estrogen
is cardioprotective when the arterial endothelium is still intact.
www.imsociety.org
Slide 62
HRT Summary proven benefits Control of menopausal symptoms Hot
flushes / night sweats Mood swings Vaginal dryness / dyspareunia
Maintenance of BMD and reduced risk of OP fractures inc hip
fractures Reduced risk colorectal cancer (CEE/MPA)
Slide 63
HRT Summary known risks Endometrial cancer (unopposed E) DVT/PE
2-3 background risk CVD Increased with CEE/MPA in older women 1 st
10 years after menopause = Cardiovascular window of opportunity
Stroke Increased with CEE+/- MPA when started in older women
Slide 64
HRT Known Risks Breast Cancer WHI Confirms increased risk Ca Br
with longer term use of combined HRT (CEE and MPA) - RR 1.26 Use
> 10 years >50 years No XS risk with E alone after 7 years
(RR 0.77) Nurses Health Study sig. inc risk assoc with E alone only
after 20 years use (RR 1.42)
Slide 65
HRT and Breast Cancer cont. Risk returns to same as never users
after 5 years Increased risk appears to apply to lean women BMI
< 25 Drinking 2 to 3 units of alcohol per day may be more
harmful than HRT!
Slide 66
When to prescribe HRT? What are the indications?
Slide 67
CSM Recommendations Risk:Benefit favourable for Rx of
menopausal symptoms. Minimum effective dose for shortest duration
Risk:Benefit unfavourable for OP prevention as first line Rx
Risk:Benefit gen unfavourable in healthy women without Sx Premature
menopause HRT to 50 then review
Slide 68
Hot Flushes
Slide 69
HRT - When? Indications for HRT Control of menopausal symptoms
Premature menopause Prevention and treatment of osteoporosis
Slide 70
HRT When not to? Who would you NEVER want to prescribe HRT for?
Who would you prescribe for but be more cautious about?
Slide 71
HRT - When NOT to? There is almost no woman who should be told
that she can NEVER take HRT Assess the risk:benefit profile in each
individual case
Slide 72
CAUTIONS Fibroids Hypertension Migraines Endometriosis Family
history of breast cancer
Slide 73
INDICATIONS FOR SPECIALIST REFERRAL Unexplained vaginal
bleeding Undiagnosed breast lump Personal/family history of VTE
History of breast, endometrial or endometrioid ovarian cancer
Otosclerosis Active liver disease
Slide 74
Which HRT? For the next 2 minutes, work with the person next to
you. Jot down the names of 2 HRT preparations that you might
prescribe, what they contain and who they might be most suitable
for.
Slide 75
Which HRT? What do we need to know to decide which HRT?
Slide 76
WHICH HRT? Symptoms? Vaginal / Bladder? Local Treatment
Systemic? Systemic treatment +/- local treatment
Slide 77
Which HRT ?- Vaginal Creams Pessaries Tablets Ring
(Estring)
Slide 78
VAGINAL OESTROGENS Estriol / Estradiol Use daily for 2 weeks
then twice weekly stop at one year and assess need for further
treatment Vagifem tabs now licensed for indefinite use Estradiol
ring (Estring) Change every 3 months Licensed for 2 years
continuous use
Slide 79
Vaginal Oestrogens Poor systemic absorption Systemic
progestogen not required CSM - Current Problems in
Pharmacovigilance vol. 29, Sept 2003 Use lowest dose and interrupt
treatment at least annually. Ix BTB. N.B. Premarin cream IS
absorbed
Slide 80
SYSTEMIC SYMPTOMS - WHICH HRT? Uterus - Yes / No? No -
Oestrogen only Yes - Combined HRT (Oestrogen and progestogen)
Oral oestrogens Higher doses than non-oral because metabolised
to less potent oestrogen (estrone) in gut and liver - ?significance
Variable absorption - up to 90% may never reach systemic
circulation - may lead to poor symptom control Different oestrogens
may be absorbed differently - try a DIFFERENT one E2 Val = c. 0.75
x E2
Slide 86
Non-oral oestrogen - Which? Patch Gel (Vaginal ring - Menoring)
(Intranasal spray) Implant NB Tachyphylaxis
Slide 87
Non-oral oestrogens - Advantages All are estradiol preparations
Avoid first pass metabolism in liver All are absorbed as estradiol
More physiological - ?significance Advantages Reduce triglycerides
less effect on clotting factors no effect on hepatic renin
substrate no effect on CRP
Slide 88
Non-oral Oestrogens - Disadvantages Absorption may vary
depending on the route - try a different ROUTE Patches Most matrix
patches are equivalent Estradot different patch technology
(Absorption is easier to check by serum oestradiol levels)
Non-oral oestrogens Also ideal first line for Malabsorption
Migraine Otherwise oral vs non-oral? Patient choice
Slide 91
HRT + Intact uterus Current practice - add progestogen to
reduce risk of endometrial hyperplasia and carcinoma. Pre- or
postmenopausal? 12 months amenorrhoea (or >54 on cyclical)
Continuous combined / Tibolone
Slide 92
CYCLICAL HRT Monthly progestogen At least 10 days, preferably
12 days 3 Monthly progestogen 2 1/2 months unopposed estrogen + 14
days progestogen Must be oligomenorrhoeic WDB may be heavier
?long-term safety
Slide 93
CONTINUOUS-COMBINED HRT Continuous progestogen maintains an
atrophic endometrium Suitable for postmenopausal women No period
HRT Provides better endometrial protection than cyclical Consider
changing from cyclical to CCT
Slide 94
TIBOLONE First no bleed HRT for postmenopausal women Synthetic
preparation Estrogenic, progestogenic and androgenic effects
Controls symptoms and protects bones Can help libido and low mood
Similar risk of breast cancer as E only
Slide 95
PROGESTOGENS - Which? C19 progestogens - structurally related
to testosterone norethisterone levo/norgestrel C21 progestogens -
structurally related to progesterone i.e. less androgenic
dydrogesterone medroxyprogesterone acetate (MPA)
Slide 96
PROGESTOGENS Which? Drospirenone Related to spironolactone
Aldosterone antagonist activity Increases sodium and water
excretion Decreases potassium excretion ?slight weight loss
?reduction in BP slight antiandrogenic properties Currently in one
low dose CCT
Slide 97
PROGESTOGENS - Which? Ist line choice - doesnt really matter
May cause side effects - encourage 3 month review e.g. PMS type
Take a careful history Change progestogen - preferably to C21 i.e.
dydrogesterone / MPA ?Drospirenone Change route
Slide 98
Progestogen routes Oral combined (all) alone (NET, MPA,
dydrogesterone) Transdermal combined patches (NET / LNG)
Intra-uterine (Mirena) now licensed in UK for use in HRT 4 years
max only way to use continuous P in pre-menopausal women
Slide 99
Intrinsa New Viagra for women? Testosterone patches 300microg
Testosterone Indication HSDD Hypoactive sexual desire disorder HBSO
Concomitant estrogen Not Premarin!
Slide 100
Hypoactive Sexual Desire Disorder (HSDD) DSM IV definition
Persistently or recurrently deficient (or absent) sexual fantasies
and desire for sexual activity. The disturbance causes marked
distress or interpersonal difficulty. American Psychiatric
Association. Diagnostic and Statistical Manual of Mental Disorders:
DSM-IV-TR. 4th ed. Arlington, Va; 2000.
Slide 101
Intrinsa Use Thin, clear, oval matrix-type transdermal patch
Twice-a-week application to abdomen
Slide 102
Mental Checklist of Questions before prescribing HRT Does she
want it? Is she adequately informed about risks and benefits? Are
the symptoms primarily local or systemic? Does she have a uterus?
Is she pre- or postmenopausal? Which E oral/non-oral? Which P?
Slide 103
For how long??
Slide 104
TREATMENT DURATION Symptom relief 3-5 years followed by gradual
withdrawal restart HRT if symptoms recur Prevention of osteoporosis
5-10 years minimum (longer after discussion) Premature menopause
Treat to average age of menopause (51) Review benefits vs risks NB
Risk of breast cancer applies to >51 years
Slide 105
HRT -Summary Extremely effective for control of menopausal
symptoms Right dose = lowest dose that controls a womans symptoms
Short term benefits outweigh the risks for most women Premature
menopause HRT to at least 50 years
Slide 106
Helping women help themselves Each woman needs information to
decide for herself www.menopausematters.co.uk
www.yorkshiremenopause.co.uk www.thebms.org.uk