Max Brinsmead PhD FRANZCOG

December 2017
 Menopause is technically a woman’s last
menstrual period
 That is the end of potential reproductive life when
follicular activity in the ovaries cease and oestrogen
levels fall
 Often preceded by several years of erratic
cycling. This is called the climacteric...
 A rather confusing term
 For practical purposes a woman is said to be
post menopausal when she has not had a
menstrual period for 12 months (and other
causes of secondary amenorrhoea have been excluded)
 Essentially a diagnosis in retrospect
 Is best made on clinical grounds
▪ Mean age 51 years
▪ At age <45 years called primary ovarian insufficiency
▪ Amenorrhoea
▪ Hot flushes
▪ Other causes of amenorrhoea excluded

 In fact, women drift in and out of a state of

ovarian failure, often over a period of 5 – 10
years...
▪ And this is why measures of FSH and E2 are unreliable
 The effects of oestrogen deficiency
▪ Hot flushes and sweats
▪ Muscle and joint aches
▪ Genital tract atrophy
▪ Accelerated bone mineral loss
▪ Changed fat distribution, increasing insulin resistance
▪ Skin, hair and dentition effects
▪ Impaired endothelial function
▪ ?Cognitive and mood changes
▪ ?Reduced libido
 The pros and cons of hormone replacement
therapy (HRT)
 Premature menopause
 Postmenopausal bleeding
 The effect of Tamoxifen on the Endometrium
 Sensation of heat with sweating and palpitations
▪ Can be documented by measuring skin temperature
 Last 2 – 30 minutes
▪ Frequency quite variable
 May effect just the face and head or the whole body
 Night sweats and insomnia the worst aspect
 Occur in 85% of women
▪ But only 15% so severe as to demand treatment
▪ Tend to decrease with time
▪ But can persist for years in a few women
 Known triggers include:
▪ Heat
▪ Emotion
▪ Alcohol, Caffeine, Smoking
▪ Spicy foods
 Correlate in time with GnRH release but exact
mechanism unknown
 Education
▪ Cultural expectations seem important
 Non pharmacological
▪ Avoid known triggers
▪ Exercise no benefit on RCT
▪ Meditation/Relaxation of benefit in 1:2 RCT’s
▪ Cognitive behavioural therapy best for anxiety, low mood and libido
▪ Acupuncture, homeopathy, Vitamin E, Magnetic devices not
effective
 Pharmacological
▪ ERT & HRT highly effective on RCT
▪ Tibilone
▪ SSRI and SNRI (Selective Serotonin Re-uptake Inhibitors)
▪ Clonidine or Gabapentin
▪ Soy products and Phytoestrogens inconclusive
▪ Black cohosh effective in 66% women but safety for long term use
uncertain, preparations vary & drug interactions can occur
 Non pharmacological
▪ Counselling
▪ Cognitive behavioural therapy best for anxiety,
low mood and libido
▪ Use lubricants or vaginal oestrogen for vaginal
dryness
 Pharmacological
▪ SSRI and SNRI (Selective Serotonin or Selective
Norepinephrine Re-uptake Inhibitors) are only of
use when there is concomitant depression
▪ Testosterone therapy of use in 40 – 60%. Needs
monitoring
 Background
▪ From 1960 – 1990 a number of observational studies
suggested that postmenopausal hormone use (HRT) reduced
the risk of cardiovascular disease
▪ Taken together with the burden of illness from osteoporosis
in older women, HRT was widely prescribed prophylactically
to prevent these two diseases
▪ Vigorously supported by drug firms and many women who
saw this as an “elixir of youth”
▪ In 2002 the results of a large prospective RCT in the US
examined the risks and benefits of HRT in postmenopausal
women
▪ It is called the Women’s Health Initiative (WHI) and it caused
waves around the world
 Recruited 64,500 women for study over 15 years with the aim to
evaluate risks and benefits of a low fat diet, HRT and calcium
supplements
 One part of that study was STOPPED after 5.2 years because of
an increased risk of breast cancer
 There was also an increased risk of cardiovascular disease in this
group
 Thus negating the principal argument for prophylactic HRT
 This RCT involved 16608 women aged 50-79 years with an intact
uterus at baseline in 40 US centres over 1993-98
 Combined HRT (Equine oestrogen 0.625 mg plus Provera 2.5 mg)
was compared to placebo
 Outcomes studied included thromboembolism, stroke, heart
attack, breast, uterine and colon cancer and hip fracture
 Results were published as risk ratios (95% confidence limits) and
as absolute risk per 10,000 women
 Breast Cancer
 RR = 1.26 (CI 1.00 – 1.59)
 8 more cases per 10,000 women years
 Cardiovascular Disease
 RR = 1.29 (CI 1.02 – 1.63)
 7 more cases per 10,000 women years
 Stroke
 RR = 1.41 (CI 1.07 – 1.85)
 7 more events per 10,000 women years
 Pulmonary Embolus
 RR = 2.13 (CI 1.39 – 3.25)
 8 more cases per 10,000 women years
 Colorectal Cancer
 RR = 0.63 (CI 0.43 – 0.92)
 6 fewer cases per 10,000 women years
 Hip Fractures
 RR = 0.66 (CI 0.45 – 0.98)
 4 fewer cases per 10,000 women years
 Endometrial Cancer
 RR = 0.83 (CI 0.47 – 1.47)

 All Mortality RR = 0.98 (CI 0.82 – 1.18)

 That is unchanged

 The study did not evaluate any aspect of patient

satisfaction or quality of life
 Another arm of the study that involved 10, 739
women after hysterectomy who received
oestrogen-only HRT. Published in 2004

 Confirmed an increased risk of stroke but not cardiovascular

disease or thromboembolism
 A reduced risk of hip fracture but no effect on colon cancer
 A trend towards reduced risk of breast cancer!
 This study found no effect from ERT on a number of measures
of quality of life
 Including cognitive functioning and dementia
 Mortality, cardiovascular disease and cancer was re
evaluated 18 years later in the 27,000 plus
postmenopausal women randomised to EE plus
MPA or placebo

 Women who took HRT for 5 – 7 years did not have increased
risk of all cause mortality
 Or cardiovascular mortality
 Or all cancer mortality
 Follow up was >98%
 Many criticisms of the study made
 Some are statistical
 Some focus on “horse oestrogens” and the progestin used
 All point to the fact that ORAL oestrogens have profound effects on
the liver
 Most point out that many of the participants were long past
menopausal and “too old” to benefit
 Efforts to produce a selective oestrogen analogue
without breast effects resulted in...
 “Evista” = Raloxifene
 “Livial” = Tibilone
 HRT use in Australia and the US fell by 40%
 And the incidence of postmenopausal breast cancer fell by 7%
 But nobody seriously argues that all women should take
HRT forever
 Because the carcinogenic potential for HRT on the breast
does not appear for at least 5 years...
 Combined HRT for the relief of menopausal symptoms is
appropriate for a woman with a uterus in the minimum doses
and for the minimum period required
 Continuing HRT beyond this is a matter for individuals & their
doctors and proceeds on the basis of “informed consensus”
 Patients at risk of thromboembolism should be treated with
special care
 Patients with a history of breast cancer are best treated with
non-hormonal alternatives
 There are better alternatives for the prevention and treatment
of osteoporosis (Biphosphonates & Vitamin D)
 Patients without a uterus can use oestrogen-only ERT with
greater impunity
 NEJM April 2016
 643 healthy women studied as those that were <6
years and those >10 years postmenopausal
 Randomised to receive HRT (1 mg oral 17ß-oestradiol
plus vaginal progesterone) or Placebo
 After 5 years the younger treated group had
significantly less carotid-artery intima media thickness
cf controls (p=0.008) but no difference in CT-assessed
coronary atherosclerosis
 These benefits were not observed in the older age
group (but neither were they worse off as a
consequence of this HRT)
 The most effective treatment for flushes and
vulvovaginal atrophy
 Prevents accelerated bone loss
 Reduces risk of cardiovascular disease
 if commenced before the age of 60
 or within 10 years of menopause
 Reduces risk of colon cancer
 Reduced risk of Alzheimer’s
 if started around the time of menopause
HRT is now called MRT = Menopause Hormone
Therapy
 Causes 1 extra case of breast cancer per 1000
women each year used.
 Due solely to the Progestin used.
 Effect ceases with cessation
 Increased risk of endometrial cancer with
unopposed oestrogen use
 Persists for years after cessation
 VTE risk is increased
 but rare for women <60 years and
 other factors including BMI are important.
 The risk can be reduced by transdermal use
 Do not use continuous combined preparations until age >55 years
 Use sequential preparations and warn about withdrawal bleeding
 These preparations are NOT contraceptive
 And irregular bleeding is often due to spontaneous ovarian activity
 Warn the patient about side effects including...
 Mastalgia
 PV bleeding – acceptable for 3/12 but thereafter investigation required
 Dysphoria
 Thrush
 Non oral routes are preferred but expensive
 Transdermal route recommended for those at risk of VTE incl. BMI >30
 Consider vaginal use of tablets that are not enteric coated
 Remember the use of Mirena as a good method of progestin administration
 Review at least annually
 Is oestrogenic, progestogenic and androgenic
 Reduces hot flushes, bone loss, and vulvovaginal
atrophy
 May improve libido
 Does no increase risk of breast cancer or VTE and will
protect the endometrium
But may increase risk of stroke in women >60 years of age
 Unwanted effects include headache, acne, hirsutism and
sometimes PV bleeding
 Should not be used with any other HRT
 I prefer to wean patients off HRT very slowly over
weeks
 Rebound hot flushes can be quite severe
 This may cause a degree of “HRT drug dependence”

 However, the long term symptoms are the same

whether slow or sudden withdrawal is used
 HRT for Hot Flushes
 24 trials, 3329 women studied
 Oestrogen only (ERT) or oestrogen plus progestin (HRT) are highly
effective in preventing hot flushes
 Side effects include PV bleeding, mastalgia and dysphoria
 Minimum Doses of Progestin with HRT required to avoid
Endometrial Hyperplasia
 45 studies
 All doses of ERT results in endometrial hyperplasia after 12m
 Counteracted by not less than 1.0 mg Norethisterone or 1.5 mg
Medroxyprogesterone daily
 Alternatives to HRT for Women with Breast Cancer
 16 RCT’s of agent against placebo
 Clonidine, SSRI, SNRI, Gabapentin and relaxation therapy all
mildly effective
 St Johns Wart effective but variable & drug interactions possible
 HRT and ERT for Cognitive Function in Postmenopausal
Women
 24 trials 10,114 women
 Neither ERT nor HRT prevents cognitive impairment with age
 After 1 year of ERT or 3 years of HRT the net effect is
NEGATIVE i.e. Worse cognitive function
 Exercise and Hot Flushes
 No convincing effect
 But one study found that exercise enhanced the ameliorating
effects of soy products
 Vaginal Oestrogen Use
 19 trials 4162 women
 Creams, pessaries and tablets all highly successful in treating
the symptoms of vaginal atrophy
 But vaginal rings that release oestrogen are the best
 14trials examined safety and some showed evidence for
vaginal bleeding, mastalgia, perineal pain and endometrial
hyperplasia
 HRT for Urinary Incontinence in Postmenopausal
Women
 33 trials 19,313 women
 Systematic oestrogen or oestrogen plus progestin makes
urinary incontinence significantly WORSE
 Local (PV) oestrogen has a mildly beneficial effect
 Mostly by reducing urinary frequency
 Definition
▪ Menopause before the age of 40
▪ 45 by some criteria
 Diagnosis
▪ Amenorrhoea with repeatedly high FSH
▪ Beware of resistant ovary syndrome...
 Causes
 Chromosomal
 Chemotherapy or Radiotherapy
 Surgical
 There is a familial component (gene identified)
 May be auto immune
 Smoking
 Hysterectomy even with preservation of the ovaries
 Encourage patient to use HRT
▪ Or ERT when the uterus is absent
 Oral contraceptive preparations are useful
▪ But may be less desirable if BP is elevated
▪ Higher doses of “menopausal HRT” may be
required
 Continue until the age of normal
menopause
 Any increased risk of breast Ca, coronary
heart disease and stroke is outweighed by
protection from osteoporosis to at least
age 40
 Because of the association between bone mass, age of
menopause and osteoporosis there is a general consensus
that premature menopause requires treatment at least until
the mid 50’s
 Also required when symptomatic
 If there is a uterus present then combined HRT in greater
doses than the average is usually required
 E2 by implant and a Mirena is a good option
 Oestrogen only (ERT) required after hysterectomy
 Management of patients who have oestrogen-dependent
tumours or residual pelvic endometriosis poses real problems
 Donor eggs are an option for infertility
 Should be regarded as due to Ca of the endometrium
until proven otherwise
 In fact, only 1:10 is Ca endometrium an the rest are due to
 Polyps
 Atrophic “vaginitis”
 Patient not truly menopausal
 Administered hormones
 Beware of the high risk patient
 Obese, diabetic and often hypertensive
 Infertility (role of PCO disorder controversial)
 Unopposed oestrogen therapy or Tamoxifen
 Late menopause
 Ca of breast or colon etc.
 Make sure that the bleeding is vaginal in origin – not
bowel or bladder
 Examination during bleeding is desirable
 To confirm the symptom & ascertain site
 Take an endocervical smear for cytology
 Ultrasound of the uterus has a role
 Will exclude Ca endometrium with 95 – 98% sensitivity if an
endometrial stripe of ≤ 4mm is seen
 The commonest cause of endometrial widening is polyps
 They are best delineated by saline utrasonography
 Pipelle endometrial biopsy will diagnose up to 99% of Ca
endometrium
 But is often negative or nondiagnostic in cases of polyp
 May require gentle cervical dilatation
 Hysteroscopy & Biopsy is the gold standard
 But may be omitted in selected cases
 Can be done as an outpatient procedure
 Vaginal oestrogen and observation for suspected atrophic vaginitis is
an option
 This drug is widely used after breast cancer surgery
 But within 12m of use 75% of patients will have endometrial
changes on ultrasound
 These consist of microcystic change in the proximal
endometrium and adjacent myometrium
 Postmenopausal patients on Tamoxifen are at small risk of
developing endometrial cancer
 Risk is between 0.2 and 4% per year
 And it will always present with PV bleeding
 Routine ultrasound monitoring of the endometrium is
not recommended
 And ultrasound has a limited role in the investigation of
these patients if they experience bleeding
 Early recourse to hysteroscopy and biopsy is best
 But Pipelle may also have role
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