Menopause

1. Max Brinsmead PhD FRANZCOG February 2011 Menopause

2. Definition • 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)

3. Diagnosis • 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

4. Menopausal Problems • 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

5. Hot Flushes (or Flashes) • 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

6. Management of Hot Flushes • 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

7. The HRT Debate • 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

8. The WHI Study • 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

9. The WHI Study Results - 1 • 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

10. The WHI Study Results - 2 • 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

11. WHI Results - 2004 • 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

12. Sequelae to the WHI study • 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

13. Current Consensus Statements on HRT Use • 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

14. Tips for Prescribing HRT • 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

15. Cochrane on the Menopause • 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

16. Cochrane on the Menopause - 2 • 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

17. Cochrane on the Menopause -3 • 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

18. Premature Menopause • 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 • May be auto immune • Smoking • Hysterectomy even with preservation of the ovaries

19. Effect of Age & Menopause on Bone Mineral Densitometry in Women

20. Management of Premature Menopause • 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

21. Postmenopausal Bleeding • 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

22. Management of Postmenopausal Bleeding • 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

23. Tamoxifen and the Endometrium • 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