1. Dr. Helen Roberts MB, MPH, FAChSHM Research Manager Family Planning
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

2. It has no role in the primary or secondary prevention of
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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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?

9. How can we give these hormones?
Estrogen
Oral- only one fully subsided
Patch/gel
Spray
Implant
Vaginal cream
Progestogen
Oral
IUS-Mirena

10. 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 days/month if menopause<1 yr ago-sequential
P continuous if menopause>1yr ago

11. 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?

12. Sequential progestogen for 14 days if < 1 yr postmenopausal
Continuous oestrogen
Sequential progestogen for
14 days if < 1 yr postmenopausal
Continuous progestogen if
> 1 yr postmenopausal
0.3 mg CEE
(premarin)
mg 17 β estradiol (estrofem)
0.5-1 mg estradiol valerate(progynova)
5 mg MPA
(provera)
0.7 mg NET
=2 Noriday
0.06mg LNG
=2 Microlut
2.5 mg MPA
Kliovance
0.03 mg LNG
=1 Microlut
Furness S, Roberts H, Lethaby A, Farquhar C
Cochrane Database of Syst Rev 2009 CD000402

13. What low dose products are available?
Kliovance-1 mg E mg NETA (NZ)
Angelique- 1mg E2 + 2mg drospirinone
Novofem- 1mg E2 + 12days 1mg NETA
Eviana mg E mg NETA

14. 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 flushes less/day than placebo
Clonidine less
Gabapentin-2.05 less

15. 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

16. 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 $ courier ( )
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 ( )

17. 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

18. Her GP had talked to Mrs Grant about the results from WHI
What would have been discussed?

19. Women’s Health Initiative Study Randomised placebo controlled study Postmenopausal women 50-79 yrs
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

20. 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

21. Hazard ratio (HR) results for WHI *
Outcome
HR for E+P
HR for E only
Stroke
1.41( )
1.39( )
Breast cancer
1.24( )
0.77( )
DVT
1.95( )
1.47( )
Coronary heart
1.24( )
0.95 ( )
Dementia(>65)
2.05( )
1.49( )
Gall bladder
1.59( )
1.67( )
Hip fracture
0.66( )
0.61( )
Total fracture
0.76( )
0.70( )
Colorectal ca
0.63( )
1.08( )
* No increase in mortality with these publications

22. 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( )
DVT
95% increase
47% increase
Coronary heart
1.24( )
Dementia(>65)
Double the risk
1.49( )
Gall bladder
59% increase
67% increase
Hip fracture
34% decrease
39% decrease
Total fracture
24% decrease
30% decrease
Colorectal ca
37% decrease
1.08( )

23. WHI-Absolute risks 10,000 women/yr aged 50-79
E+P v placebo
E only v placebo
Breast cancer +8
Heart disease PE +7
Stroke
+12
Hip fracture -5 -6
Colorectal ca
JAMA 2004;291:
JAMA 2002;288:

24. New HT pamphlet for women
Google “Family Planning”
Resources
View our free resources
Scroll down to women
Hormone therapy

25. E+P and breast cancer
Increased incidence of breast cancer HR=1.25( )
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:

26. E+P -Breast cancer: the issue of the time frame!

27. 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

28. How can I individualise the CVD risk for Mrs Grant?
Predict computer programme
Coloured pictures by Rod Jackson in MIMS

31. 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

32. Risk after stopping HT
If she stopped the HT now when would her risk of cardiovascular disease and breast cancer return to normal?

33. 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

34. 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 ( ) 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:

35. 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 ( ) and cancers more likely to be node positive
Also now increase in breast cancer deaths if assigned combined HT v placebo
HR 1.96 ( )
Lancet 2009;374:

36. Would Mrs Grant have had a different risk if on E alone?
5 years of E only use: HR= 0.80( )
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;

37. 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

38. 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):

39. Breast cancer risk after stopping E onlyHR CI
During intervention
0.70
Post intervention
0.75
Overall
0.77
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

40. Other outcomes after stopping E only
Age group
HR (CI)
CHD
50-59
0.59 ( )
60-69
1.00 ( )
70-79
1.06 ( )
Stroke
1.09 ( ) PE
1.26 ( )
JAMA 2011;305:1354-5

41. 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

42. 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 would be 17,251

43. 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”

44. 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:

45. 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

46. ESHRE-European Society of Human Reproduction and Embryology
In the E only WHI study a subgroup analysis among women
aged 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:

47. 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.

48. Fig 1 Bone density in the spine is 2.3 standard deviations
below the mean in young women without osteoporosis

49. Fig 2 Bone density in the proximal femur is 2.5 standard deviations
below the mean in young women without osteoporosis

50. 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.

51. 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.

54. 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??

55. 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 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

56. 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

57. 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

58. 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)

59. 59