Transcript Managing the Menopause - Back to Medical School

Dr Julie Ayres
Specialty Doctor in Gynaecology
LTHT
BMS Council
Management of the menopause with
hormones
 The menopause
 Definition
 Symptoms
 HRT
 Where are we now with it?
 Risks and benefits
 Who for?
 Which type?
The Menopause
-Definition
The last menstrual
period
i.e. only diagnosed in
retrospect 12 months
later
When should we expect symptoms?
Menopausal symptoms
Vasomotor
Menopausal Symptoms
Genitourinary
Menopausal Symptoms – Weight gain
Menopausal Symptoms - confusion
Menopausal symptoms – poor
concentration
Menopausal Symptoms – feeling more
emotional
Osteoporosis
 Fractures
 Wrist
 Hip
 Spine
 Height loss
 Dowager’s Hump
 Back Pain
Predictions about the menopause
It will happen
It will be unpredictable
Menopausal women need help and advice
Hormone Replacement Therapy - WHY?
 Problem?
 Oestrogen deficiency
 Answer?
 Oestrogen replacement
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
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
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
HRT - Benefits
 Other benefits?
 Reduced risk colon cancer

Observational studies
 Alzheimer’s disease?

Jury is out
 Coronary Heart disease

- benefit or risk?
HRT – Risks
 DVT
 Stroke
 Breast Cancer
 Coronary Heart disease
 Risk or benefit?
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
HERS Study
 Secondary prevention study in 2763 women with CHD
 RCT using CEE/MPA vs. placebo
 50% inc in ischaemic events in 1st yr in HRT group
 No overall benefit at 5 and 7 years
 JAMA 1998; 280: 605-13
HRT Headlines
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
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
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
WHI Results
 Estimated hazard ratios;
 CHD
 Ca Breast
 Stroke
 PE
 Colorectal Ca
 Endometrial Ca
 Hip fracture

i.e. Relative risks
1.29
1.26
1.41
2.13
0.63
0.83
0.66
WHI Results
 Absolute risks - I.e. XS cases per 10,000 women years
 CHD
7 extra cases
 stroke
8
 PE
8
 invasive breast cancer 8 i.e. 38 vs. 30
 THESE REPRESENT VERY SMALL RISKS TO THE
INDIVIDUAL
WHI Results
 Absolute risk reductions (per 10,000 women years)
 colorectal cancers
6
 hip fractures
5
WHI - WHAT THE PAPERS DIDN’T
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
Summary of Unreported Data
 Entry criteria do not reflect standard practice in the
clinical selection of women for HRT
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
WHI – What else have we learnt?
 Confirms reduced risk of OP fractures
 Confirms reduced risk of colorectal cancer
 (combined HRT)
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
WHI - Overall Conclusion
 Don’t give HRT to
women who don’t
need it!
 We still didn’t know
about the effect of
HRT on the CVS in
younger women.
HRT and Breast Cancer – The Bad News
 Daily Mail – Aug
2003
 “HRT doubles
the risk of
breast cancer!”
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
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)
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
Million Women Study - Results
 RR in users of E only (Ca Br)
 RR in users of E+P
= 1.30
= 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
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 1.97
 BMI >25 - RR 1.46
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……...
Estimated Extra Cases of Breast Cancer per 1000
Women by 60y
 5 years E from 50y
 10 years E
 5 years E+P
 10 years E+P
-
- 1.5 extra cases
5 extra cases
- 6 extra cases
- 19 extra cases
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)
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
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
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)
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
Update on HRT and CVD
– The Good News!
 Women’s Health
initiative (WHI)
 Re-analysis
 Complete U-turn
published

JAMA. 2007;297:14651477.
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!
WHI Re-analysis
 CHD – Relative risks;
 <10 years since meno
 10 – 19 years
 >20 years
- HR = 0.76
- HR = 1.10
- HR = 1.28
 CHD – Absolute risks
 Per 10 000 person years
 <10 years
 10 – 20 years
 >20 years
= -6
=4
= 17
WHI Re-analysis
 Stroke
 RR – 1.32
 Risk unaffected by No. of years since menopause
 No increased risk in women 50 – 59 years
WHI Re-analysis
 Mortality
 50 – 59 years – HR = 0.70
 60 – 69 years – HR = 1.05
 70 – 79 years – HR = 1.14
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.’
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 Women’s Health 2006;15:35-44
HRT and age
 What does it mean??
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.
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
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
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)
HRT Summary – known risks
 Endometrial cancer (unopposed E)
 DVT/PE – 2-3 background risk
 CVD – Increased with CEE/MPA in older women
 1st 10 years after menopause = Cardiovascular ‘window of
opportunity’
 Stroke – Increased with CEE+/- MPA when started in
older women
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)
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!
When to prescribe HRT?
What are the indications?
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
Hot Flushes
HRT - When?
 Indications for HRT
 Control of menopausal symptoms
 Premature menopause
 Prevention and treatment of osteoporosis
HRT – When not to?
 Who would you NEVER want to prescribe HRT for?
 Who would you prescribe for but be more cautious
about?
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
CAUTIONS
 Fibroids
 Hypertension
 Migraines
 Endometriosis
 Family history of breast cancer
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
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.
Which HRT?
What do we need to know to
decide which HRT?
WHICH HRT?
 Symptoms?
 Vaginal / Bladder?

Local Treatment
 Systemic?

Systemic treatment
 +/- local treatment
Which HRT ?- Vaginal
 Creams
 Pessaries
 Tablets
 Ring (Estring)
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
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
SYSTEMIC SYMPTOMS - WHICH
HRT?
 Uterus - Yes / No?
 No -
Oestrogen only
 Yes - Combined HRT
(Oestrogen and
progestogen)
Oestrogen only HRT
 Oral? or
 Non-oral?
Oral Oestrogens
 3 different types
 Conjugated equine estrogens
 Estradiol
 Estradiol valerate
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
Non-oral oestrogen - Which?
 Patch
 Gel
 (Vaginal ring Menoring)
 (Intranasal spray)
 Implant

NB Tachyphylaxis
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
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
 Avoid first pass metabolism - ideal for;
 Liver disease
 Diabetics
 Hypertriglyceridaemia
 Gallstones
 h/o VTE
 Hypertensives
 Epileptics
 ? Coronary heart disease
Non-oral oestrogens
 Also ideal first line for
 Malabsorption
 Migraine
 Otherwise oral vs non-oral?
 Patient choice
HRT + Intact uterus
 Current practice - add progestogen to reduce risk of
endometrial hyperplasia and carcinoma.
 Pre- or postmenopausal?
 <12 months amenorrhoea

Cyclical progestogen
 >12 months amenorrhoea (or >54 on cyclical)

Continuous combined / Tibolone
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
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 </= 5 years
 Low doses available - less BTB
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
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)
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
PROGESTOGENS - Which?
 Ist line choice - doesn’t 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
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
Intrinsa
 ‘New Viagra for women’?
 Testosterone patches
 300microg Testosterone
 Indication – HSDD



Hypoactive sexual desire disorder
HBSO
Concomitant estrogen
 Not Premarin!
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.
Intrinsa
 Use
 Thin, clear, oval matrix-type
transdermal patch
 Twice-a-week application to
abdomen
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?
For how long??
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
HRT -Summary
 Extremely effective for
control of menopausal
symptoms
 Right dose = lowest dose
that controls a woman’s
symptoms
 Short term benefits
outweigh the risks for most
women
 Premature menopause
 HRT to at least 50 years
Helping women help themselves
 Each woman needs information to
decide for herself
 www.menopausematters.co.uk
 www.yorkshiremenopause.co.uk
 www.thebms.org.uk