Menopause

1. Max Brinsmead PhD FRANZCOG October 2013 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) • Postmenopausal bleeding • Premature menopause

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 • No increased risk of breast cancer (after 7 and 15 years) • (Another observational study in Europe showed ↑risk of breast Ca after 5 years) • 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 • From the International Menopause Society (2011) • Any HRT should be part of an overall health strategy that includes: • Diet, Exercise, Smoking cessation and alcohol moderation • Individualised according to symptoms, personal & family history, risk factors, investigations and patient preferences • Counsel with absolute numbers rather than risk ratios and back up with written information • Use the least effective dose but no absolute limit on duration • Use progestogens when uterus is present but consider use of modern progestins or natural progesterone • Local (vaginal) oestrogen only and intrauterine progestogogen (Mirena) are good options • Review not less than annually

14. Current Consensus Statements on HRT Use ( IMS 2011 - 2) • Patients without a uterus can use oestrogen-only ERT with greater impunity • Androgens only for women with clinical signs or symptoms of androgen deficiency • Patients at risk of thromboembolism should be treated with special care. Use transdermal preparations or Tibilone • Patients with a history of breast cancer are best treated with non-hormonal alternatives • There are better alternatives for the treatment of osteoporosis (Biphosphonates & Vitamin D) but HRT may be considered for prophylaxis in at-risk women <60 years of age • Likewise there is evidence that HRT may protect from cardiovascular disease if started at age <60 years

15. 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

16. 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

17. 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

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 • Androgens desirable after oophorectomy or adrenal failure • Management of patients who have oestrogen-dependent tumours or residual pelvic endometriosis poses real problems • Donor eggs are an option for infertility