Menopause Update

Menopause Update
March 2015
Dr Jane Woyka
GP Associate Specialist
Menopause Unit
Northwick Park and St Mark’s
Hospital
Harrow
Disclaimer
• From time to time I will receive an
honorarium for my time from big pharma,
but I struggle to recall which company or
product and sadly have never had to
declare more than £500 earned in that
fashion in one tax year
Overview
• Menopause is the final permanent
cessation of menstruation after 12
consecutive months of amenorrhoea.
Average age for this is 52
• Premature menopause (<40years of age)
affects approximately 1% of all women
• Perimenopause is the transition from
normal ovulatory menstrual cycles to the
cessation of ovulation and menstruation. It
is the time from first symptoms of
hormonal fluctuation.
Why Menopause?
• Menopause is an unnatural phenomenon
brought about by extended longevity
• Evolution has yet to catch up
High fertility – High mortality
The Menopause
Growth in the UK
Rise in female life expectancy in the last 150 years
Fraser D. Horizons. July 1989.
Why menopause?
Minke whale – only other mammal to
have a menopause
EVOLUTION
• NICE
• Guidance from NICE in 2015 will lead to
– Evidence based management guidelines for women with
menopause and POI
– Quality standards will act as benchmarks for treatment
especially in primary and secondary care
– Hopefully funding will follow!
Pathophysiology of menopause
• Declining number of oocytes
(9,000,000 20/40 foetus, 900,000 at birth, 90,000 at 20,
30,000 at 37 1,000 at 41 , a few 100 at menopause )
• Follicles less responsive to FSH & produce less
oestrogen
• Ovulation less frequent = irregular periods
• FSH & LH increase gradually 4-5 years before last
period
• NB. wide daily variations
Menopause=Ovarian failure
• The two main functions (oestrogen production and
ovulation) of the ovary fail when a critical number of
oocytes( 30,000? )is reached
• Complex endocrine changes which commence a decade
prior to the cessation of menstruation are responsible
for the symptoms
• Oestradiol levels are usually in the normal range despite
this being a time of maximum symptoms
Sleep disturbance
• Is often first sign of the menopause even before night
sweats occur
• Causes fatigue, loss of energy
• Causes irritability/grouchiness,
• Causes difficulties with short-term memory and
concentration
• Sleep deprivation contributes to headaches and muscle
tension
The Hot Flush
• Experienced by 88% of perimenopausal women
• Correlation with pulsatile LH release, but not causative
• Disturbance in thermoregulatory mechanism;
thermoneutral zone narrows at menopause
• Affects the face, head, neck and chest
• May start any time, stop any time, can continue for
several years,
• Underestimated duration more like 10 years (Univ. of
Pennsylvania 2011 )
• Vary hugely between individuals and at different stages
of their menopause, night and day variations
• Can have significant impact on quality of life and sleep
patterns
Hot off the press Hot flushes
2015
• New multiethnic Study of Women’s Health Across the
Nation in USA reveals in 1149 of women who reported
vasomotor symptoms average duration of 7.4 years
• Last longer if they begin premenopausally ,average
duration 11.8 years
• Worse in black women
Is this the reason for the popular misconception that HRT
only delays the advent of hot flushes because
the truth is that symptoms last for many more than 3 years?
Atrophic vaginitis
• Vaginal secretions reduced, both steady state and
sexually
• Vulval soreness, awareness
• Reduced vaginal capacity and smaller introitus
• Reduced vaginal responsivity, orgasm more difficult
• Discomfort and dyspareunia contribute to a reduced
libido
• Reduction of sexual activity
Urogenital atrophy:
Atrophic urethritis and trigonitis
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bladder pain
recurrent urinary tract infections
urinary frequency
urinary urgency
stress incontinence
enhanced awareness of prolapse and vulval itching.
Psychological effects
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Irritability
Mood swings, depression, anxiety
Forgetfulness
Low self-esteem
Panic attacks
Lack of concentration
Generally not feeling yourself
Difficulty coping
Aggression
General Symptoms
Loss of collagen and elasticity
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Aches & pains
Hair loss
Thinning of the skin
Everything goes south
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Itchiness
Formication (feeling of something crawling over you)
Tearfulness
Palpitations
Loss of energy
Weight increase, reduced metabolic rate
Diagnostic Case studies
• Thank you for seeing this 51 year old lady who is having
difficulty sleeping and wakes once or twice a night
feeling very hot. She can’t be menopausal, as her
periods continue to be entirely regular. I think she is
depressed and have commenced antidepressants which
don’t seem to be helping. She wonders if she could be
menopausal and has requested a referral to your clinic.
Diagnostic Case studies
• Thank you for seeing this 51 year old lady who is having
difficulty sleeping and wakes once or twice a night
feeling very hot. She can’t be menopausal, as her
periods continue to be entirely regular. I think she is
depressed and have commenced antidepressants which
don’t seem to be helping. She wonders if she could be
menopausal and has requested a referral to your clinic.
• Right age
• Right symptoms…vasomotor, mood, sleep
• Regular periods do not discount a menopause diagnosis
Diagnostic Case studies
• Thank you for seeing this 41 year old lady whose periods
have become rather irregular and is tired, gaining weight
and is somewhat depressed. She has lots of bony
aches and pains, she thinks her hair is getting thin and I
am sure she is menopausal.
Diagnostic Case studies
• Thank you for seeing this 41 year old lady whose periods
have become rather irregular and is tired, gaining weight
and is somewhat depressed. She has lots of bony
aches and pains, she thinks her hair is getting thin and I
am sure she is menopausal.
• Wrong age (1percent)
• Irregular periods can have other causes
• Weight gain, depression, fatigue, hair changes, can have
other causes
• check her TSH as well as her FSH
Diagnostic Case studies
• Thank you for seeing this lady of 58 who has over the
several years had many varied symptoms of not being
able to relax, of having panic attacks, feeling stressed all
the time and not being able to sleep, headaches and
anxiety.
• She has seen specialists of various disciplines.
Oestradiol is less than 73, and clearly she has a
hormone imbalance.
• As you see from her symptom chart she has every single
symptom of the menopause
Diagnostic case studies
• Thank you for seeing this lady of 58 who has over the
several years had many varied symptoms of not being
able to relax, of having panic attacks, feeling stressed
and not being able to sleep, headaches and anxiety.
• She has seen specialists of various disciplines.
Oestradiol is less than 73, and clearly she has a
hormone imbalance.
• As you see from her symptom chart she has every single
symptom of the menopause
• wrong age,
• long standing symptoms, nil vasomotor,exclusively
psychological,
• Normal hormone profile for age
• Rare to have every single symptom
Diagnostic Case studies
• Please see this lady of 55 whose periods have started
again after 2 years and who would like to go on HRT.
She has a sister who died of a blood clot taking the oral
contraceptive.
Diagnostic Case studies
• Please see this lady of 55 whose periods have started
again after 2 years and who would like to go on HRT.
She has a sister who died of a blood clot taking the oral
contraceptive.
Beware!
• Postmenopausal bleed
• Family history thromboembolic disease
Diagnosis:
Is this menopause?
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Age,
Menstrual history
Symptoms
Diagnostic tests eg FSH,Oestrodiol level,
thyroid function tests, ultasound
Symptom Score Chart
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Daytime Sweats & Flushes
Night-time Sweats & Flushes
Unable to sleep
Headaches
Tiredness
Loss of energy
General aches & pains
General Itchiness
Formication (feeling of something crawling over you)
Tearfulness
Depression
Feeling of unworthiness
IrritabilityAnger
Bitterness
Panic Attacks+ /Palpitations
Aggression
Symptom Score Chart (2)
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Daytime FrequencyUrgency
Urge Incontinence (leakage if you do not get there in time)
Stress incontinence (leakage if cough, sneeze or laugh)
Night-time Frequency
Bed WettingVaginal dryness/soreness
Vaginal ItchingSoreness I
pain with Intercourse
Bleeding with intercourse
Loss of libido (sex drive)Difficulty achieving orgasm
Loss of Memory
Loss of concentration
Inability tocope
Feelings of personality disintigration
Causes
Surgical, Early, Disease related,
Natural
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family history,
medication,
autoimmune profile, diabetes screen
What is this patient’s personal risk
profile?
• Medical history,
• family history,
• BMI, BP, lipid profile, blood glucose, liver
function
• Abnormal bleeding ?cause
• Vaginal examination, transvaginal ultrasound,
endometrial biopsy, hysteroscopy
• FRAX (osteoporosis risk score)
What would be the benefits of
treatment?
• Immediate symptom control
Vasomotor, urogenital, other menopause-related
complaints, such as joint and muscle pains, mood
swings, sleep disturbances and sexual dysfunction
including reduced libido may improve during HRT
• Early menopause
• Osteoporosis
• Long term health
Symptom control
• HRT remains the most effective therapy for vasomotor
and oestrogen-deficient urogenital symptoms
• Other menopause-related complaints, such as joint and
muscle pains, mood swings, sleep disturbances and
sexual dysfunction (including reduced libido) may
improve during HRT
Vasomotor symptoms
Source: Adapted from Freedman, RR. Seminars in Reproductive Medicine
2005; 23 (2): 117-125
Postmenopausal changes
in the vaginal epithelium
PREMENOPAUSAL
POSTMENOPAUSAL
Erectile tissue
Folds or rugae
Muscular coat
Inner lining
contains large
amount glycogen
Loss of folds
Loss of inner
lining and
glandular function
Samsioe G. A profile of the Menopause, 1995:49 (Figure 6.4)
Vaginal atrophy: Vaginal and
cellular changes
superficial
intermediate
parabasal
Thick, healthy, well-estrogenized
lining of the vagina
Thin, dry lining of vagina
due to menopause
(after estrogen loss)
Symptoms of vaginal atrophy
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Reduced lubrication
Dryness
Discomfort during intercourse
Decreased frequency of intercourse
Vaginal and vulval irritation
Discharge
Bleeding
Relationship problems
Lower urinary tract atrophy
• Estrogen receptors in bladder trigone,
detrusor muscle, urethral sphincter
• Deficiency leads to dysuria, frequency,
urgency, urge incontinence, nocturia
Pelvic floor atrophy
• Estrogen deficiency leads to changes in
collagen in pelvic floor
• Bulging of vaginal walls
• Descent of cervix
• Dragging sensation
• Shortened urethra
• Recurrent UTIs and stress incontinence
Reporting and Treatment
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Symptoms
Discussed
OTC
Prescribed
Vaginal
Bladder
Cumming G, Currie H et al. Menopause International 2007;13:79-83
Long term health
• Osteoporosis
• Premature ovarian
insufficiency
• Cardiovascular disease ?
• Memory and cognition?
Effects on Estrogen on bone
• Inhibits bone resorption, Interleukin 6
• Osteoclast apoptosis regulated by
estrogen
• Estrogen deficiency—osteoclasts live
longer—increased bone resorption
• Enhances intestinal calcium absorption
• Protects bone from resorptive effects of
PTH
National Osteoporosis Society Position statement
2011
Informed decision
Protective hip and spine fracture(grade A evidence fracture
risk reduction with HRT in hip and spine }
Recommend HRT after early menopause
Benefits exceed risk in postmenopausal women under age
60
HRT can be used as treatment for osteoporosis in women
under age 60 with no risk factors—CVD, VTE, breast
cancer
1. T. J. de Villiers and J. C. Stevenson The WHI: the effect of hormone replacement
therapy on fracture prevention Climacteric June 2012; 15(3): 263
International Menopause Society view
• HRT is effective in preventing the bone loss associated
with the menopause and decreases the incidence of all
osteoporosis-related fractures, including vertebral and
hip, even in patients at low risk
• HRT is an appropriate first-line therapy in
postmenopausal women presenting with an increased
risk for fracture, particularly under the age of 60 years
and for the prevention of bone loss in women with
premature menopause
Premature ovarian insufficiency
• Special considerations
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Symptom control
Bone health
Cardiovascular health
Dementia
Fertility
Reduced life expectancy
Are there any possible
contraindications to taking
HRT?
• Hormone dependent cancer,
• Venous thromboembolism (thrombophilia
screen)
• Cardiovascular risk?
Risks of HRT
VTE
• Oral oestrogens increase the risk of VTE x
2-3
– WHI – Nos xs VTE > Nos Ca Breast
– PE is cause of 1/3 deaths attributable to HRT
• VTE risk;
– increases with age
• Still low in women <60 years
– Increases with BMI
HRT and VTE recurrence
• 1023 consecutive postmenopausal women
aged 45 to 70, previous confirmed VTE,
between Jan 2000 to Dec 2008
• Followed up average 79 months
• Oral estrogens—HR 6.4
• Transdermal estrogens—HR 1.0
Olie V et al, Menopause 2011;18(5):488-493
HRT and risk of VTE; systematic
review and meta-analysis
Pooled O R
Pooled 95% CI
2.5
1.9-3.4
Transdermal
1.2
0.9-1.7
Randomised controlled
trials
2.1
1.4-3.1
Observational studies
Oral oestrogen
Oral oestrogen
Canonico M, Plu-Bureau G, Lowe G, Scarabin P-Y. BMJ 2008; 336: 1227-31
Does progestogen alter the risk of
VTE?
– Canonico (BMJ) – meta-analysis
• Oral E + P – similar to E alone
– ESTHER
• French case controlled study;
• Results;
– VTE in current users of oral E - HR 4.6
– VTE in current users of transdermal E – HR 1.1
– There was no significant difference in VTE risk between women
using oral oestrogen alone or combined with any progestogen
– VTE in women using transdermal oestrogen;
» with either progesterone or pregnane derivatives (including
dydrogesterone, cyproterone acetate, and medroxyprogesterone
acetate)
- HR 0.9
» with 19-norpregnane derivatives (nomegestrol acetate or
promegestone)
– HR 3.2
ENDOMETRIAL CANCER
• Unopposed oestrogen increases risks of endometrial
hyperplasia & endometrial cancer. Both are duration and dose
dependant.
• Cyclical progestogen (at least 12 days per month) greatly (not
completely) reduces the risk
• Mirena is approved for endometrial protection.
• Continuous combined HRT reduces the risk of endometrial CA
Ovarian Cancer 2015
• Recent meta analysis of 21, 488 women all from USA or
Australia suggests taking HRT even for a short time is
associated with increased risk of developing the two
most common types of ovarian cancer
• Causation unproved
• After stopping HRT the incidence decreases
• Observational data, risk of bias from factors such as
smoking, obesity
• Absolute risk very small. For 5 years use at age 50,
incidence is 0.2 extra cases per 1,000 women per year,
extra deaths 0.1 per 1,000 women per year
Risks of HRT
Breast Cancer risk with oestrogen
alone
WHI
No excess risk with E alone after 7
years RR 0.77
Nurses heart study
Increased risk with E alone only
after 20years use RR 1.42
Risks of HRT
Breast Cancer risk with combined
HRT
WHI
Confirms increased risk Ca Br with
longer term use of combined
HRT (CEE and MPA)
- RR 1.26
( only in women who had
used HRT x 5 years before WHI)
Breast cancer risk WHI
BREAST CANCER RISK
Risk for post-menopausal women (mean age 63) developing
breast cancer over a five year period
(15 out of 1000)
1000 people
Risk to general
population
Additional risk for
cc HRT users:
4 cases / 1000
“Significant reduction
in breast cancer risk in CEE
alone study”
La Croix AZ et al JAMA 2011,
Manson JAMA 2013
HRT and Breast Cancer cont.
• Risk returns to same as never users within
5 years
• Mortality from breast cancer is not
increased
• Drinking 2 to 3 units of alcohol per day
may be more harmful to the breasts than
HRT!
HRT and Breast Cancer
- IMS View
• The reanalysis of the WHI data is reassuring that
women at low risk for breast cancer do not increase the
incidence of breast cancer while using conujugated
oestogen only therapy.
• Decision to use HRT should be based on individual risks
and benefits which are different for each woman
BRCA patients
• Increasing numbers young women with BRCA
1and 2 mutations coming to clinic for HRT
following prophylactic risk reducing surgery
(BSO) or who may be prescribed tamoxifen
• These are YOUNG women, ie POI with all the
attendant problems…osteoporosis risk,
oestrogen and testosterone surgically, suddenly
deprived
• NICE says stop HRT at 50
Lifetime risk of cancer in BRCA1 and
BRCA2 carriers
Female breast
Ovary
Male breast
Pancreas
Colon
Prostate
BRCA1,%
60-90
40 – 60
0.1-1
0
5 – 10
8
BRCA2,%
45-85
10 – 30
5-10
7
5 – 10
25
Are there any possible
contraindications to taking
HRT?
• Hormone dependent cancer,
• Venous thromboembolism
• Increased risk of stroke and heart
attack…..HRT is dangerous!
UK deaths
• 120,000 women die due to CVD per year
• 12,000 women die due to breast cancer
per year
Effect of estrogen lack
• Change in BMI, fat
distribution
• Inc LDL cholesterol
• Decreased HDL
• Increase TGs
• Blood pressure
• Glucose/insulin
metabolism
• Endothelial dysfunction
• 4 fold increased risk CVD
• Prem menopause—53%
inc risk CHD
What about HRT?
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•
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Should be good!
Favourable effects on:
W/H ratio
Lipids—total cholesterol, LDL, lipoprotein(a)
Clearance of small dense LDL, postprandial lipid
clearance, LDL oxidation at vessel wall
• Vascular function—NO, calcium channels, ACE activity,
smooth muscle proliferation
• Atheroma formation, vascular remodelling (dose
dependant)
• Conflicting findings—observational studies and
randomised trials
Premenopause
~5%
~15%
15-25 yrs
25-35 yrs
Benefits of Endogenous E2
Perimenopause
35-45 yrs
45-55 yrs
Primary Benefits of HT
Mikkola TS, et al. Ann Med. 2004;36:402-13.
Postmenopause
55-65 yrs
65 yrs
No Benefits of HT
“ HRT is dangerous”
dinosaurs clinging to outdated views
• Old studies reviewed
• Lots of Danish studies, DOPS, KEEPS,
• They haven’t just grabbed the top of the
crime series subtitled charts
WHI TRIALS
• WHI RCTs, PUBLISHED 2002, DESIGNED 25YRS AGO!
(1): CEE 0.625mg/MPA v placebo
(2): CEE 0.625mg v placebo (TAH)
• Increased risk of coronary events in study (1)
RR 1.29 (29%) = 7 extra cases / 10K women / year
Why did this happen?
• High doses of Estrogen for age group, av 63 yrs / poor progestogen
(MPA) / unhealthy subjects
– thrombogenesis in diseased arteries
JAMA 2002; 288: 321-333 ; Stevenson Maturitas 2007
73
WHI Studies: Coronary Heart Disease
HRT and CHD: Absolute risk by age
19
18
14
Absolute
excess risk
of CHD per
10 000
personyears
10
6
2
-2
-6
-1
-2
-10
p-value for trend
= 0.16
n=27,347
Taken from: Rossouw et al.JAMA. 2007;297:1465-1477
50-59 years
60-69 years
Age at randomisation
70-79 years
Final analysis-JAMA
• Women aged 50-59
• Minimal risks
• Likely significant benefits:
• Lower risk CVD, lower risk death, no
increased risk stroke, breast cancer—only
increased if HRT taken before
• MWS and WHI review 2012
Danish Osteoporosis Study
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•
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1006 women
HRT vs placebo rct
Followed up for 16 years
HRT use associated with significant lower
incidence CVD, death and osteoporotic
fracture with no increased breast cancer,
stroke or VTE
Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomized
trial. Schierbeck L L, Rejnmark L, Tofteng C L, et al. BMJ 2012;345:e6409
the Danish Osteoporosis Prevention Study (DOPS)
Primary endpoint and mortality and major risks for HRT in the total population
during randomisation phase (up to year 2002).
3
HR
2
1
0
mortality,
heart failure,
MI
mortality
Schierbeck L L et al. BMJ 2012;345:bmj.e6409
DVT
Stroke
breast cancer
other cancer
KEEPS
Kronos Early Estrogen Prevention Study
Design:
•
720 postmenopausal women mean
age 52y studied for 4 years
Interventions:
•
CEE 0.45 mg, transdermal
estradiol 50 mcg / placebo
•
Micronised progesterone 200 mg
daily for 12 days per month
Outcome Measures:
•
U/S carotid artery I/M thickness & CT
coronary calcium scores
Outcomes:
•
No significant changes seen in CIMT
/ CAC scores
Summary of Randomised Trials
Risks of HRT – Effect of Age
• Meta analysis of 30 RCTs in women using HRT from
1966 to Sept 2002
• 26 708 women mean age 54 years
• Significant lower mortality (39%) in women < 60y
• OR 0.61 (0.31 – 0.95)
• No sig change in mortality in women > 60y
Salpeter et al JGIM 2004; 791-804
• Meta-analysis of 23 trials
• 39,049 participants
• Odds ratio for CHD differed with age at
enrolment
– Under 60 - 0.68—32% reduction (significant)
– Over 60 - 1.03
Salpeter et al J Gen Int Med
2004;19:791-804
Summary—HRT and CHD
• Window of opportunity
• Best if started within 6 years of menopause
and/or before age 60
• Increased benefit with longer use
• Use for at least 5 years
• Benefit depends on type (esp progestogen),
dose, age at initiation
• Used appropriately, HRT is effective for primary
prevention of CHD
• No apparent increase adverse effect with HRT
after MI (BMJ April 2012)
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
CVD
- IMS View
• In women less than 60 years old, recently
menopausal, without prevalent
cardiovascular disease, the initiation of
HRT does not cause early harm, and may
reduce cardiovascular morbidity and
mortality
• Continuation of HRT beyond the age of 60
should be decided as a part of the overall
risk-benefit analysis
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
Additional potential benefits
• ? Reduced risk Alzheimer’s disease, but
evidence of damage to neurones if
commenced after 60
• Increasing evidence of reduced risk
cardiovascular disease if started early
• Recent studies indicate increased
longevity in women starting treatment
perimenopausally
HRT Summary
Known risks
• Endometrial cancer (unopposed E)
– Eliminated by progestogen
– Continuous progestogen provides better long-term protection
• DVT/PE – 2-3 background risk
– Greatest risk in 1st 12 months
– much Less with non-oral
• CHD – Increased when CEE/MPA STARTED in older women, or
with pre-existing CHD
• Stroke – Increased when CEE+/- MPA STARTED in older
women (> 60 years)
• Breast cancer
– Probably increased slightly after a minimum of 5 years’ use of
combined HRT over the age of 50
– Risk associated with E alone is very much less and may not be
significant until 20 years
– Mortality is not increased
HRT Conclusions
IMS, Global, BMS
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•
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HRT most effective for symptom control
Beneficial for bone health
May decrease mortality and CVD
Benefits outweigh risks in women <60 or
within 10 years of menopause, risks small
• Decision and treatment should be
individualised
WHICH HRT?
Vaginal symptoms....... local therapy
Systemic........oral, trandermal
VAGINAL OESTROGENS
• Creams, pessaries and tablets;
– Use daily for 2 weeks then twice weekly
– Vagifem now has license for indefinite us, but
note the strength of pessary is now 10 mcg
Estradiol ring (Estring)
– Change every 3 months
– Licensed for 2 years continuous use
SYSTEMIC SYMPTOMS WHICH HRT?
• Uterus - Yes / No
No Yes -
Oestrogen only
Combined HRT
Oestrogens
• Synthesised non body identical
• Conjugated equine oestrogens (Premarin)
1.25mg, 0.625mg, 0.3mg
• Oral contraceptive
Body identical , synthesised from wild yam
17 beta-oestradiol, oestradiol valerate
• 2mg, 1mg
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
Non-oral oestrogen Which?
• Patch
– Once / twice weekly,
below waist
• Gel
– Once daily to upper
arms / thighs
• 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 –
•
•
•
•
less effect on clotting factors
reduce triglycerides
no effect on hepatic renin substrate
no effect on CRP
Implants
first choice for young hysterectomised
patients?
•
•
•
•
•
Deliver high dose oestrogen 25-100mcg
Can add Testosterone Implant
Good compliance
One “dose” every six months
Availability sometimes problematic,
though we do have estrapel
Implants
disadvantages
• Regular minor surgical procedure
• Careful and controlled blood monitoring to
avoid tachyphylaxis
• Uncertainty over supply
Implants or oestrogen gels for
patients with intact uterus
Endometrial protection
• Mirena IUS
• Oral daily progestogen
• Vaginal daily progestogen
HRT + Intact uterus
Current practice - add progestogen to reduce risk
of endometrial hyperplasia and carcinoma.
Premenopausal
<12 months amenorrhoea
Cyclical progestogen
Postmenopausal
>12 months amenorrhoea (or >54 on cyclical)
Continuous combined / Tibolone
Progestogens
C 19 norethisterone, levonorgestrol,
Best endometrial protector,but more androgenic therefore more
PMS,etc
C17 dydrogesterone, medroxyprogesterone acetate(MPA)
Less potent at controlling bleeding, may cause bloating.
Drospirenone
Related to spironolactone, Aldosterone antagonist
activity.Increases sodium and water excretionDecreases
potassium excretion?slight weight loss?reduction in BP, slight
antiandrogenic properties .Currently in one low dose CCT
Micronised progesterone (Utrogestan)
Associated with drowsiness. Is the only “bioavailable progestogen”
Cyclogest supps
Patients choice
ASK!
Transdermal progesterone alone does not
exist
Easiest all in one, change twice weekly
• Evorel range...Sequi, Conti, Evorel alone
Oral once daily
• Femoston, Kliofem/vance, Elleste duet
Choosing a progestogen
(for those with intact uterus)
•
•
•
•
Best tolerated ( PMS, acne, bloating)
Cycle control
Continuous or sequential?
Patient choice… to bleed or not
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
Progestogen routes
- Intrauterine
•
Intra-uterine System (Mirena)
– Licensed in UK for endometrial
protection with oestrogen
• 4 years max
– Only way to use continuous P in
pre/peri-menopausal women
– Can be combined with any oestrogen
– Also provides extremely effective
contraception
• No other HRT products are
contraceptive
– Effect on the breast??
• Small, short-term studies indicate
lower risk
What HRT regimens are theoretically the best ?
Estradiol patch or gel
• Evorel , estradot 25-100mcg
• Oestrogel 2-4 apps
• Sandrena gel 0.5-2.0mg/day
Progesterone/Progestogens
• Oral: Utrogestan cc100mg, sc200mg 12/28
• Vaginal: Utrogestan, Cyclogest
• IUS Mirena
Closest combined oral regimen
• Femoston range 1:10, 2:10, Conti 1:5, Conti low dose 0.5:2.5
Is testosterone needed too?
Patients with absent or irradiated ovaries have no
testosterone source except adrenals(small)
Loss of libido and psychosexual issues suggest androgenic
replacement is required
Androgens: Practical prescribing
What androgens do I currently
recommend?
•Testim gel / Testogel / Tostran (0.5 – 1.0ml / day)
– Unlicensed in women but data for efficacy and safety
– Pea sized blob to abdomen daily (1 week/tube or sachet)
• or,1 pump every 2/3 days (Tostran)
– FAI < 6.5 (physiological female upper limit – no beards!)
•Intrinsa patches – no longer available, pretty useless
•Livial - weakly androgenic
•Testosterone implants - ?availability
•Pill Plus (COC with DHEA) on the way
Hypoactive Sexual Desire Disorder (HSDD)
DSM IV definition
(Or low libido!)
•‘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.
Very common at the menopause....
Usually multifactorial in origin and can be difficult to
manage.
Consideration should be given to treatment of vaginal
dryness and any psychosexual problems addressed.
Other medical treatments
• Clonidine
– Licensed for HF
– 37% reduction in HF (20% placebo)
• Venlafaxine
– 37.5mg – 75mg daily
• Low dose SSRIs
– NB some SSRIs inhibit cytoP450 eg paroxetine
• Not to be used with Tamoxifen which req P450 for biotransformation to
active metabolite
• (Venlafaxine, citalopram is OK )
• Gabapentin 900mg (divided doses)
– Response varies; overall 30% reduction in Sx
– S/Es can be a prob e.g. Fatigue, somnolence
Complementary therapies
•
•
•
OsteopathyHerbal medicine Chiropracter
Acupuncture
Reflexology
Shiatsu
Homeopathy
Aromatherapy Nutritional
Therapy
•
Yoga
Hypnotherapy Counselling
•
Alexander technique
Meditation
•
Herbal Treatments
• Claims have been made for ;
– Black Cohosh
–
–
–
–
–
• (care - liver!)
Sage (hot flushes)
Ginkgo Biloba (memory)
Agnus Castus (PMS)
St. John’s Wort (antidepressant)
‘Natural’ progesterone creams
• These are classed as food supplements
– Poor quality control
– Standardisation not required
– Potentially unreliable information (contents, dose,
contaminants etc.)
Lifestyles
Exercise
Diet
Good sleep
Fun
Be kind to yourself (and others)
DUA(VEE)VIVE: SERM/Estrogen combination
(Tissue Selective Estrogen Complex TSEC)
BZA/CEE (TSEC) – summary, phase III “SMART” trials
•
•
•
•
Improvement in menopause symptoms
– Pinkerton et al Menopause 2009
Good endometrial suppression and amenorrhoea rates
– Archer et al Fertil Steril 2009
Bone-sparing effects
– Lindsay et al Fertil Steril 2009
No effect on mammographic density / breast tenderness; inhibitory in
animal studies
– Ethun et al Menopause 2012
What is “ bio identical” treatment
• Unregulated products produced by compounding
pharmacists containing various strengths of oestrogen,
progestogene testosterone , DHEA
• Saliva samples are taken to indicate individual deficiency
and a personalised compound is made up at great cost
and without resort to recommended
progestogen/oestrogen dosage regimens
“Compounded Bio-identical Hormones”
US Senate is drafting a bill on BI hormones for 2014
“NAMS members are concerned about pharmacy compounders
who operate as manufacturers without following Good
Manufacturing Practices”
KEY POINTS 1
The decision whether to use HRT should be made by each woman having been
given sufficient information by her health professional to make a fully informed
choice.
The HRT dosage, regimen and duration should be individualised, with annual
evaluation of pros and cons.
Arbitrary limits should not be placed on the duration of usage of HRT; if
symptoms persist, the benefits of HRT usually outweigh the risks.
HRT prescribed before the age of 60 has a favourable benefit/risk profile.
KEY POINTS 2
It is imperative that women with POI are encouraged
to use HRT at least until the average age of the menopause
If HRT is to be used in women over 60 years of age,
lower doses should be started, preferably with a transdermal
route of administration.
It is imperative that in our ageing population research and development of
increasingly sophisticated hormonal preparations should continue to maximise
benefits and minimise side effects and risks.
This will optimise quality of life and facilitate the primary prevention of long-term
conditions which create a personal, social and economic burden.
What to do?
• Try your best......
– Stay up to date
– Document patient’s wishes
– Document a formal risk/benefit analysis
– Stand up to (incorrectly) opinionated
colleagues
– Stay/become a member of the BMS
www.thebms.org.uk
www.imsociety.org
Knowledge Dispels Fear!
Please join the BMS!
www.thebms.org.uk