Transcript figo - General Practice New Zealand

Women at menopause
Dr. Helen Roberts MB, MPH, FAChSHM
Research Manager Family Planning
Senior Lecturer Women’s Health
Department Obstetrics and Gynaecology
University of Auckland
New Zealand
• HRT remains an appropriate treatment only for women
with moderate to severe vasomotor symptoms of
menopause.
• It has no role in the primary or secondary prevention of
cardiovascular or cerebrovascular disease
Indications for HT use
 Indications for HT are hot flushes, night
sweats and genito- urinary symptoms
 Longitudinal study evidence does not
suggest that mood changes or cognitive
disturbance related to the menopausal
transition
http://consensus.nih.gov/
Which women should not use HT?
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Previous breast cancer
Previous deep vein thrombosis (DVT)
Previous pulmonary embolus
Previous heart attack
Previous stroke
High risk of cardiovascular disease
How many women have these
symptoms and how long do they last?
Flushes
30% of women while still having
periods-don’t do hormone levels to
decide who to treat
Majority of women they are self
limiting and stop within a few years
 80% women they last 5 years-10%
even longer
How many women have these
symptoms and how long do they last?
Genito–urinary symptoms
 50% of women
 Symptoms are vaginal dryness,
dyspareunia, recurrent urinary tract
infections
 Symptoms are long term
Decision about
stopping
hormone therapy
 Mrs Grant is a 54 year old woman was referred by her general
practitioner to discuss her ongoing use of oral hormone therapy
 She started this when she was 46 years old because of night
sweats. At this time she was still menstruating and has continued to
have regular periods while taking hormone therapy
 Her general practitioner has advised her that she can now probably
stop using hormones as her flushes are likely to have gone, but she
is keen to continue treatment. She asked to be referred for a second
opinion.
Roberts H. BMJ 2010; 341:c2421
Types and doses of hormones
 What regimen of HT is this woman
using?
……….sequential
 If she had wanted a subsidised Rx
what would you give her?
 “guidelines are for lowest dose
possible for symptom relief” –so what
would you Rx?
How can we give these hormones?
Estrogen
 Oral- only one fully subsided
 Patch/gel
 Spray
 Implant
 Vaginal cream
Progestogen
 Oral
 IUS-Mirena
What HT do we usually start with?
Oral—only delivery Rx fully subsidised
E only if hysterectomy
E+P if uterus
E is given continuously every day
P 10-14 days/month if menopause<1
yr ago-sequential
 P continuous if menopause>1yr ago
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Types and doses of hormones
Estrogen -different from E in contraception
 CEE (conjugated equine estrogens)-mares
 17 β estradiol.
 Estradiol valerate…..fully funded
Progestogen- often same as P in contraception
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Medroxyprogesterone acetate…fully funded
Levonorgestrel
Norethisterone
Utrogestan-what is this?
Continuous
oestrogen
Sequential
Continuous
progestogen for progestogen if
14 days if < 1 yr
> 1 yr
postmenopausal postmenopausal
0.3 mg CEE
(premarin)
5 mg MPA
(provera)
2.5 mg MPA
0.5- 1 mg 17 β
estradiol (estrofem)
0.7 mg NET
=2 Noriday
Kliovance
0.5-1 mg estradiol
valerate(progynova)
0.06mg LNG
=2 Microlut
0.03 mg LNG
=1 Microlut
Furness S, Roberts H, Lethaby A, Farquhar C
Cochrane Database of Syst Rev 2009 CD000402
What low dose products are available?
 Kliovance-1 mg E2 + 0.5mg NETA (NZ)
 Angelique- 1mg E2 + 2mg drospirinone
 Novofem- 1mg E2 + 12days 1mg NETA
 Eviana-
0.5mg E2 + 0.1 mg NETA
How well do hormones help symptoms?
 Placebo response for flushes up to 50%
 HT – 75% improvement (2-3 less per day)
- takes a few weeks to help
Cochrane Review MacLennan 2002
 Progestogens alone-Depo Provera or oral MPA 10-20mg
daily-almost similar response to estrogen
 Other treatments
SSRI/SNRI -1.13 flushes less/day than placebo
Clonidine -1.63 less
Gabapentin-2.05 less
Genito –urinary symptoms
 Not self limiting-may need long term treatment
 Vaginal estrogen better than oral
 A level evidence for vaginal atrophy
 B level evidence for recurrent UTIs
 May help urgency in women with overactive
bladder
 May make stress incontinence worse
Vaginal estrogens
Ovestin cream/pessary-estriol 0.5 mg
Funded- so cost $15 for 3/12
Vagifem-estradiol 25 mcg vaginal tabs
Not funded- cost $75 for 30 tabs but Mercy
pharmacy $47.80 + courier (09-6235703)
 Each night PV for first 2 weeks the twice weekly
 Takes 4-6 weeks to work
 Estring: vaginal ring:90 days-Pfizer under Section
29. Cost $75 + pharmacy charge (0800736363)
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Long term Rx with vaginal E
 Systemic absorption smallest with estriol
 Vagifem:E2 levels in normal postmenopausal range
NAMS position statement
 Progestogen not generally indicated
 Insufficient data to recommend annual
endometrial surveillance in asymptomatic women
 Continue Rx for women as long as symptoms
remain
NAMS Menopause 2007;3:357-69
Notelovitz Obstet Gynecol 2002;99:556-62
 Her GP had talked to Mrs Grant about
the results from WHI
 What would have been discussed?
Women’s Health Initiative Study
Randomised placebo controlled study
Postmenopausal women 50-79 yrs
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HRT v placebo
With uterus
0.625 mg Premarin
+2.5mg Provera
16,608 women
Stopped at 5.2
years
ERT v placebo
 No uterus
 0.625mg Premarin
 10,739 women
 Stopped at 7 years
How are results of the WHI presented?
 Presented as Hazard Ratio (HR)
 If HR is 1.0- then no change in risk
 If HR is more than 1.0 eg 1.4 then that is
an increased risk
 HR of 1.4 means 40% increase in risk
 If HR is 2-then double the risk
 If HR is less than 1.0 eg 0.6 then that is a
decreased risk
 HR of 0.6 is 40% decrease in risk
Hazard ratio (HR) results for WHI *
Outcome
HR for E+P
HR for E only
Stroke
1.41(1.07-1.85)
1.39(1.10-1.77)
Breast cancer
1.24(1.01-1.54)
0.77(0.59-1.01)
DVT
1.95(1.43-2.67)
1.47(1.06-2.06)
Coronary heart
1.24(1.00-1.54)
0.95 (0..70-1.16)
Dementia(>65)
2.05(1.21-3.48)
1.49(0.83-2.66)
Gall bladder
1.59(1.20-1.97)
1.67(1.35-2.06)
Hip fracture
0.66(0.45-0.98)
0.61(0.41-0.91)
Total fracture
0.76(0.69-0.85)
0.70(0.63-0.79)
Colorectal ca
0.63(0.43-0.92)
1.08(0.75-1.55)
* No increase in mortality with these publications
Hazard ratio (HR) results for WHI
Outcome
HR for E+P
HR for E only
Stroke
41% increase
39% increase
Breast cancer
24% increase
0.77(0.59-1.01)
DVT
95% increase
47% increase
Coronary heart
1.24(1.00-1.54)
0.77(0.59-1.01)
Dementia(>65)
Double the risk
1.49(0.83-2.66)
Gall bladder
59% increase
67% increase
Hip fracture
34% decrease
39% decrease
Total fracture
24% decrease
30% decrease
Colorectal ca
37% decrease
1.08(0.75-1.55)
WHI-Absolute risks 10,000 women/yr
aged 50-79
E+P v placebo
Breast cancer
E only v placebo
+8
Heart disease
PE
+8
+7
Stroke
+8
+12
Hip fracture
-5
-6
Colorectal ca
-6
JAMA 2004;291:1701-1712
JAMA 2002;288:321-333
New HT pamphlet for women
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Google “Family Planning”
Resources
View our free resources
Scroll down to women
Hormone therapy
http://www.familyplanning.org.nz/Lin
kClick.aspx?fileticket=jowmpHhWWO
o%3d&tabid=922&mid=815
E+P and breast cancer
• Increased incidence of breast cancer
HR=1.25(1.07-1.46)
• Diagnosed at more advanced stage
• Increased abnormal mammograms
 Higher risk if previously on HT before study
 Higher risk if started HT within 5 years of
menopause
Chlebowski. JAMA 2003;289:3243-53
E+P -Breast cancer:
the issue of the time frame
!
Time frame for increase in
breast cancer
• Effects of HT on mammograms and breast Ca stage
suggested that E+P hinders breast cancer diagnosis, thus
making the assessment of HT safety of short term use
problematic
• Use for a short period may appear safe, when in fact breast
cancers are being stimulated and masked from diagnosis
during therapy.”
Geller and Chlebowski
Sexuality , Reproduction and Menopause 2003;1:5-9
How can I individualise
the CVD risk for Mrs Grant?
 Predict computer programme
 Coloured pictures by Rod Jackson in
MIMS
How can I individualise
the CVD risk for Mrs Grant?
 Trial evidence can be translated to
individual decisions by transforming RR into
absolute risks.
 HT increase risk of stroke by 40%-RR 1.4
 Mrs Grant with 5% baseline risk has
5X1.4=7% risk if uses HT...2% increase
 If she has 25% baseline risk has (25x1.4)
35% risk if uses HT………….10% increase
Col N American Journal Medicine 2005;118:155S-162S
Risk after stopping HT
 If she stopped the HT now when
would her risk of cardiovascular
disease and breast cancer return to
normal?
Stopping combined HT
-follow up WHI
 Most women stopped Rx pills when instructed
2002 and 1 year later only 4% using HT not
related to study
 Breast risk with combined HT-declined “likely due
to the regression of preclinical cancers following
withdrawal of hormones
 Cardiovascular risks –stroke ,VTE had disappeared
at 2.4 years of follow up
 Hip fracture benefit-also disappeared at 2.4 years
NEJM 2009;360:573-87
Increase in Mortality : WHI Post
intervention follow up
 WHI halted 2002 and women asked to stop
study Rx
 After 2.4 years of post intervention follow
up-now increase in mortality
 HR 1.87 (1.22-2.88) deaths from nonsmall-cell- lung cancer (unrelated to
smoking)
 Thought to be due to stimulation of growth
on already established cancers
 No increase with E alone
Lancet 2009;374:1243-51
Increase in Mortality : WHI Post
intervention follow up
 Although breast cancer incidence declined after
women stopped HT
 After total mean follow up of 11 years
 Still increased incidence if assigned combined HT v
placebo
 HR 1.25 (1.07-1.46) and cancers more likely to be
node positive
 Also now increase in breast cancer deaths if
assigned combined HT v placebo
 HR 1.96 (1.00-4.04)
Lancet 2009;374:1243-51
Would Mrs Grant have had a
different risk if on E alone?
 5 years of E only use: HR= 0.80(0.62-1.04)
 Fewer breast cancers with localised disease
but not fewer more advanced cancers
 The decreased effect was concentrated in
women who had not used E prior to study
entry
Stefanick ML et al JAMA 2006;2951647-57
Would Mrs Grant have had a
different risk if on E alone?
• 1/11 women had short interval avoidable
mammogram
• 1/50 women had breast biopsies-false
positive
• Unlike E+P no delay in breast cancer
diagnosis
• Smaller increase in breast density at 2
years
• 3% with E compared to 7% with E+P
Chlebowski RT J Clin Oncol 2010;28:2690-7
Stopping E only-follow up WHI
 10.7 years since baseline
 E use median 5.9 yrs but median adherent
time for 80% women was 3.5 years
 No overall increased or decreased risk of
CHD, deep vein thrombosis, stroke, hip
fracture, colorectal cancer, or total
mortality.
 A decreased risk of breast cancer persisted
JAMA. 2011;305(13):1305-1314
Breast cancer risk after stopping E only
HR
CI
During intervention
0.70
0.61-1.02
Post intervention
0.75
0.51-1.09
Overall
0.77
0.62-0.95
Editorial comment: The lack of an adverse effect of unopposed
estrogen when used for a short period in the WHI does not
counter the larger body of evidence of an elevated risk of
breast cancer with increasing duration of use ......
JAMA 2011;305:1354-5
Other outcomes after stopping E only
Outcome
Age group
HR (CI)
CHD
50-59
0.59 (0.38-0.90)
60-69
1.00 (0.80-1.24)
70-79
1.06 (0.82-1.36)
Stroke
50-59
1.09 (0.65-1.83)
PE
50-59
1.26 (0.62-2.33)
JAMA 2011;305:1354-5
Editorial
 These data are derived from .......subgroup
analyses of randomized clinical trials and
are not sufficient to alter professional
guidelines.
Eiran Z. Gorodeski, MD, MPH
Heart and Vascular Institute
Cleveland Clinic
Menopause: The Journal of The North American Menopause Society
2011 ;18:935-6
RCT for younger women
 Will the National Institutes of Health
or industry invest in a second edition
of the Women’s Health Initiative?
 Sample size required to show 30%
treatment effect for age 50-54 would
be 17,251
Different viewpoints on low
CHD risk 50-59 years
 Timing hypothesis or
 Window of opportunity
”If only HT was started early enough
before vasculature is compromised
then it may be cardioprotective”
Surrogate outcome studies
Coronary Artery Calcium Study
–subset WHI (WHI-CACS)
• Women < 60 years at study entry
• Randomised to Estrogen only
• Decreased coronary artery calcium on E v
placebo
• No data re combined HT.
• So suggestion of potential cardioprotective
effect in younger women
NEJM 2007;356:2591-2602
Are surrogate outcomes useful?
 HT and individual biomarkers
 Complex interplay of multiple
pathways relating to factors such as
clotting, atherosclerosis, and
inflammation
 So difficult translate into the overall
effect of HT on CVD
 Clinical endpoints eg MI are needed
Am J Epidemiol 2009;170:24-8
ESHRE-European Society
of Human Reproduction and Embryology
•In the E only WHI study a subgroup analysis among women
aged 50-59 found 14 less CHD events for women taking E
•The number needed to treat to prevent
one CHD in a year would be 1000.
Human Reproduction Update 2006;12:483-497
Back to Mrs. Grant
 On further discussion, she had other reasons for
wishing to continue using hormone replacement.
 She had recently asked her general practitioner to
send her for a bone mineral density scan, and she
brought the result with her.
 The report said that she had osteoporosis
(t score −2.5 at the femoral neck), which she felt
was another good reason to continue with the
treatment.
Fig 1 Bone density in the spine is 2.3 standard deviations
below the mean in young women without osteoporosis
Fig 2 Bone density in the proximal femur is 2.5 standard deviations
below the mean in young women without osteoporosis
BMD scan report
 This patient is a 54 year old woman on
hormone replacement therapy, which is
planned to stop soon.
 Scans of the lumbar spine and left proximal
femur were performed using a lunar dual
energy x ray absorptiometry device.
Anatomy is unremarkable at both sites.
 Bone density in the spine is 2.3 standard
deviations below the mean value in the
young normal population. In the proximal
femur it is 2.5 standard deviations below
the young normal mean.
BMD scan report
 Thus the patient’s bone mineral densities are in
the osteoporotic range.
 Her calculated 10 year risk of a major
osteoporotic fracture is 8%. Her calculated 10 year
risk of hip fracture is 2.4%.
 In the absence of a history of fracture, standard
lifestyle advice (smoking cessation, weight
maintenance, and physical activity, total calcium
intake 1g daily, with maintenance of vitamin D
sufficiency) is probably all that is necessary at this
stage .
 Repeat bone density scanning in three years would
be reasonable.
Final Advice
 So advice for Mrs Grant was that she could
indeed stop her HT and see if her flushes
had now gone
 Is there a better way to stop??
Best way to stop HT?
 RCT of abrupt withdrawal as opposed to
taking usual dose alternate days for 4
weeks
 Women had used hormones for 3-11 years
 Age 50-72 years, mean age 58
 Power calculation 200 women only had 87
 No difference on # or severity of flushes
when followed for a year
 Almost 50% of women (those with most
severe flushes) restarted HT by 1 year after
discontinuation
Menopause 2010;17:72
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WEB 712-contraception
pre and early pregnancy care
Contraception (4 weeks)
Preconceptual counselling
Early normal pregnancy management
First antenatal visit
Early pregnancy screening
Diagnosis of abnormal fetal
development
 Early abnormal pregnancy
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WEB 715-medical
gynaecology 1
 Cervical and breast screening
 Menstrual disorders-bleeding problems
 Menstrual disorders-pelvic
pain,dyspareunia,PMS
 Sexually transmitted infections
 Vaginal discharges
 Vulval problems
 Climacteric and menopause (2 weeks)