Max Brinsmead PhD FRANZCOGJune 2015

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▪ Age 40 – 60▪ 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▪ Genital tract atrophy▪ Accelerated bone mineral loss▪ Changed fat distribution▪ Skin, hair and dentition effects▪ ?Acceleration of atherosclerosis▪ ?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▪ 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▪ Gabapentin▪ Soy products and Phytoestrogens inconclusive▪ Black cohosh effective in 66% women but safety

for long term use uncertain

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

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

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 Dysphoria Thrush

Non oral routes are preferred but expensive Consider vaginal use of tablets that are not enteric coated Remember the use of Mirena as a good method of progestin

administration Wean patients off HRT very slowly over weeks

Rebound hot flushes can be quite severe

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

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 high FSH▪ Beware of resistant ovary syndrome...▪ A condition of great unpredictability

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

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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