WOMEN AT MENOPAUSE DR. HELEN ROBERTS MB, MPH, FACHSHM RESEARCH MANAGER FAMILY PLANNING SENIOR LECTURER WOMEN'S HEALTH DEPARTMENT OBSTETRICS AND ...

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?

   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 menopause1yr ago

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
   Medroxyprogesterone acetate…fully funded
   Levonorgestrel
   Norethisterone
   Utrogestan-what is this?

Continuous               Sequential        Continuous
oestrogen                progestogen for progestogen if
                         14 days if < 1 yr > 1 yr
                         postmenopausal postmenopausal

0.3 mg CEE               5 mg MPA             2.5 mg MPA
(premarin)               (provera)

0.5- 1 mg 17 β           0.7 mg NET           Kliovance
estradiol (estrofem)     =2 Noriday

0.5-1 mg estradiol       0.06mg LNG           0.03 mg LNG
valerate(progynova)      =2 Microlut          =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)

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

    HRT v placebo            ERT v placebo
   With uterus            No uterus
   0.625 mg Premarin      0.625mg Premarin
   +2.5mg Provera
   16,608 women           10,739 women
   Stopped at 5.2         Stopped at 7 years
    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       E only v placebo

Breast cancer         +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

   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 non-
  small-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

Do you want to update from the
 comfort of your own home ?
  Dept O+G runs 2 web based courses
   as part of Dip O+G
  Totally distance learning courses
  13-15 weeks
  Can do each courses as one off for
   CME
  Each course is 150 hours and can get
   150 MOPS points over 3 years
  Email j.joubert@auckland.ac.nz

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

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)