dr julie ayres specialty doctor in gynaecology ltht bms council

Dr Julie Ayres Specialty Doctor in Gynaecology LTHT BMS Council

Management of the menopause with hormones The menopause Definition Symptoms HRT Where are we now with it? Risks and benefits Who for? Which type?

The Menopause -Definition The last menstrual period i.e. only diagnosed in retrospect 12 months later

When should we expect symptoms?

Menopausal symptoms Vasomotor

Menopausal Symptoms Genitourinary

Menopausal Symptoms Weight gain

Menopausal Symptoms - confusion

Menopausal symptoms poor concentration

Menopausal Symptoms feeling more emotional

Osteoporosis Fractures Wrist Hip Spine Height loss Dowagers Hump Back Pain

Predictions about the menopause It will happen It will be unpredictable

Menopausal women need help and advice

Hormone Replacement Therapy - WHY? Problem? Oestrogen deficiency Answer? Oestrogen replacement

HRT Ups and Downs HRT History Used x 60 years+ Past Issues Endometrial cancer Add progestogen (combined HRT) Reduced risk of CHD Reduced risk of osteoporosis It was looking good! Breast cancer WHO data RR 1.35

HRT More Ups and Downs Increased risk of Heart disease/Stroke WHI (2002) Many women stopped HRT altogether Many doctors advised against starting/continuing HRT Higher risk of breast cancer MWS (2003) Many more women just stopped HRT CSM reviewed WHI / MWS and issued guidance Dec 2003 Knee-jerk reaction HRT TO BE USED AT THE LOWEST DOSE FOR THE SHORTEST POSSIBLE TIME Final nail in the coffin for prescribers

HRT - Benefits Well-established CONTROL OF MENOPAUSAL SYMPTOMS Maintenance of bone density Reduction in risk of OP fractures CSM advise not for first line use

HRT - Benefits Other benefits? Reduced risk colon cancer Observational studies Alzheimers disease? Jury is out Coronary Heart disease - benefit or risk?

HRT Risks DVT Stroke Breast Cancer Coronary Heart disease Risk or benefit?

HRT Possible CV benefits? Nurses Health Study Observational study of 120 000 US nurses 50% reduction in incidence and mortality from coronary heart disease No effect on risk of stroke NEJM M. Stampfer et al. 1991; 325 (11):756-762 Other observational studies suggested similar benefits

HERS Study Secondary prevention study in 2763 women with CHD RCT using CEE/MPA vs. placebo 50% inc in ischaemic events in 1 st yr in HRT group No overall benefit at 5 and 7 years JAMA 1998; 280: 605-13

HRT Headlines

WOMENS HEALTH INITIATIVE RCT Designed to last for 8.5 years look at major health benefits and risks associated with the most commonly used HRT in the US i.e. CEE +/- MPA against placebo JAMA 2002; 288: 321-33

WHI Aims Primary outcome measure = CHD (non-fatal MI + CHD death) Primary adverse outcome = invasive breast cancer Global index summary included; Hip fracture and colorectal cancers Stroke,PE,endometrial cancer and deaths due to other causes

WHI Cont Combined arm (CEE + MPA) 16,608 postmenopausal women aged 50 to 79 years terminated early (5.2 years) Numbers of CA Breast exceeding stopping boundary Oestrogen only arm continued

WHI Results Estimated hazard ratios; CHD 1.29 Ca Breast 1.26 Stroke 1.41 PE 2.13 Colorectal Ca 0.63 Endometrial Ca 0.83 Hip fracture 0.66 i.e. Relative risks

WHI Results Absolute risks - I.e. XS cases per 10,000 women years CHD7 extra cases stroke8 PE8 invasive breast cancer8 i.e. 38 vs. 30 THESE REPRESENT VERY SMALL RISKS TO THE INDIVIDUAL

WHI Results Absolute risk reductions (per 10,000 women years) colorectal cancers6 hip fractures5

WHI - WHAT THE PAPERS DIDNT SAY The oestrogen-only arm continued, XS CVD risk appeared to be assoc with combined HRT Only CEE and MPA were studied Study Population Average age of women was 63 Ave time since menopause = 12 years CV risk profile BP 36.1% High BMI 28.5% Diabetes 4.4% High chol.12.7% Previous history of CHD not excluded (except during the previous 6 months) 7% had history of CHD All women asymptomatic

Summary of Unreported Data Entry criteria do not reflect standard practice in the clinical selection of women for HRT

WHI - What have we learnt? Breast Cancer? Confirms increased risk Ca Br with longer term use of combined HRT (CEE and MPA) Use > 10 years i.e. > 5 years use during study - only in women who had used HRT for 5 years previously

WHI What else have we learnt? Confirms reduced risk of OP fractures Confirms reduced risk of colorectal cancer (combined HRT)

WHI - What else have we learnt? Cardiovascular disease? Suggests possible increased risk of CVD assoc with CEE and MPA IN THIS POPULATION These data should not be applied to other types, doses and routes of HRT ? effect of different hormones (WHISP trial-1mg E2/0.5mg NET) ?Primary prevention (as in observational studies) only applies to women without pre-existing atherosclerosis 50-59 years (WHI) appeared at reduced risk

WHI - Overall Conclusion Dont give HRT to women who dont need it! We still didnt know about the effect of HRT on the CVS in younger women.

HRT and Breast Cancer The Bad News Daily Mail Aug 2003 HRT doubles the risk of breast cancer!

MILLION WOMEN STUDY Accepted that; - HRT increases risk of breast cancer Designed to; - Assess effects of specific types of HRT on incident and fatal breast cancer

Million Women Study Recruitment 1 084 110 women aged 50-64 years attending NHSBSP = quarter of British women between 50-64 Observational study Questionnaire completed before screening Average follow-up: 2.6 years (incidence) 4.1 years (mortality)

Million Women Study - Results RR Ca Br ever users = 1.43 cf never users In current users only RR 1.66 RR 1.01 in past users slightly increased in 1st year after HRT use no different to never users thereafter

Million Women Study - Results RR in users of E only (Ca Br) = 1.30 RR in users of E+P = 2.00 RR in users of tibolone = 1.45 Risk increased for increasing duration of use RR death from Ca Br Current users = 1.22 Past users = 1.05 Not statistically significant

Million Women Study - Results No significant variation between different oestrogen types, doses or routes (oral / transdermal / implants) No significant difference between different progestogen types (MPA / norethisterone / norgestrel) or sequential / continuous Only factor modifying risk was low BMI BMI 25 - RR 1.46

Million Women Study - Results In developed countries the risk of breast cancer in never users = est @ 20/1000 between 50 and 60 Collaborative group figures Using the RR estimates from this study the different patterns of use of HRT would be expected to result in...

Estimated Extra Cases of Breast Cancer per 1000 Women by 60y 5 years E from 50y- 1.5 extra cases 10 years E- 5 extra cases 5 years E+P- 6 extra cases 10 years E+P- 19 extra cases

Million Women Study - Potential Biases Observational study ?Differences between women attending NHSBSP or not (75% attend) ?Effect of women not participating (71% participated) ?Results overestimated because of increased durations of treatment (from baseline to diagnosis)

Million Women Study in Context Study confirms increased risk of breast cancer associated with HRT Study suggests 20 000 extra breast cancers in UK due to HRT in past 10 years 15 000 due to E+P 5 000 due to E Postmenopausal obesity - 50 000 Alcohol intake 45-64y - 16 000

What does the evidence suggest about HRT and breast cancer? Putting all the evidence together (45 studies) Risk estimates vary++ with a number of studies showing no increase in risk 20% - RR < 0.9 33% - RR >1.1 47% - RR 0.9 1.1 MWS is a clear outlier, with much higher risk estimates than all other studies Bush et al Obstet Gynecol 2002;98:498-508

HRT and Breast Cancer The Good News WHI Oestrogen only arm 11000 women on CEE Terminated at 7 years No benefit on CHD risk Slightly increased risk of stroke (12/10000) Reduced risk hip fracture No effect on colon cancer NO INCREASE IN BREAST CANCER RR 0.77 (not statistically significant)

WHI revisited Average age = 63 Ave 12 years since menopause 70% women over 60 To achieve sufficient power in the study Assumption made re protective effects being same at all ages Study not powered to do subgroup analysis by age

Update on HRT and CVD The Good News! Womens Health initiative (WHI) Re-analysis Complete U-turn published JAMA. 2007;297:1465- 1477.

WHI Re-analysis Women aged below 60 years and less than 10 years past menopause have a lower risk of coronary disease, a lower risk of death from any cause, and no increased risk for stroke!

WHI Re-analysis CHD Relative risks; 20 years- HR = 1.28 CHD Absolute risks Per 10 000 person years 20 years= 17

WHI Re-analysis Stroke RR 1.32 Risk unaffected by No. of years since menopause No increased risk in women 50 59 years

WHI Re-analysis Mortality 50 59 years HR = 0.70 60 69 years HR = 1.05 70 79 years HR = 1.14

BMS Statement re WHI It is quite astonishing that the study which initially warned us of all the dangers of HRT is now showing us virtually the opposite. But where is the publicity about this? And will the regulatory authorities act with the same speed as they did to warn against HRT to now correct their advice.

Nurses Health Study Revisited HRT started < 10 years since menopause RR 0.66 E alone RR 0.72 - E + P = sig. reduced risk HRT started > 10 years since menopause (i.e. similar to pop. In WHI) RR 0.87 E alone RR 0.90 E + P = no sig. relation J Womens Health 2006;15:35-44

HRT and age What does it mean??

HRT and Cardio-protection There appears to be a Window of opportunity in the first 10 years after the menopause during which HRT may reduce the risk of cardiovascular disease.

Other studies Macaque Monkeys + BSO + atherogenic diet Oestrogen at menopause 70% reduction in dev of atherosclerosis Oestrogen at 6 yrs post- menopause No difference in atherosclerosis cf. no Rx Studies on IMT show no benefit on thickened IMT but lack of progression in thin IMT

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

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 known risks Endometrial cancer (unopposed E) DVT/PE 2-3 background risk CVD Increased with CEE/MPA in older women 1 st 10 years after menopause = Cardiovascular window of opportunity Stroke Increased with CEE+/- MPA when started in older women

HRT Known Risks Breast Cancer WHI Confirms increased risk Ca Br with longer term use of combined HRT (CEE and MPA) - RR 1.26 Use > 10 years >50 years No XS risk with E alone after 7 years (RR 0.77) Nurses Health Study sig. inc risk assoc with E alone only after 20 years use (RR 1.42)

HRT and Breast Cancer cont. Risk returns to same as never users after 5 years Increased risk appears to apply to lean women BMI < 25 Drinking 2 to 3 units of alcohol per day may be more harmful than HRT!

When to prescribe HRT? What are the indications?

CSM Recommendations Risk:Benefit favourable for Rx of menopausal symptoms. Minimum effective dose for shortest duration Risk:Benefit unfavourable for OP prevention as first line Rx Risk:Benefit gen unfavourable in healthy women without Sx Premature menopause HRT to 50 then review

Hot Flushes

HRT - When? Indications for HRT Control of menopausal symptoms Premature menopause Prevention and treatment of osteoporosis

HRT When not to? Who would you NEVER want to prescribe HRT for? Who would you prescribe for but be more cautious about?

HRT - When NOT to? There is almost no woman who should be told that she can NEVER take HRT Assess the risk:benefit profile in each individual case

CAUTIONS Fibroids Hypertension Migraines Endometriosis Family history of breast cancer

INDICATIONS FOR SPECIALIST REFERRAL Unexplained vaginal bleeding Undiagnosed breast lump Personal/family history of VTE History of breast, endometrial or endometrioid ovarian cancer Otosclerosis Active liver disease

Which HRT? For the next 2 minutes, work with the person next to you. Jot down the names of 2 HRT preparations that you might prescribe, what they contain and who they might be most suitable for.

Which HRT? What do we need to know to decide which HRT?

WHICH HRT? Symptoms? Vaginal / Bladder? Local Treatment Systemic? Systemic treatment +/- local treatment

Which HRT ?- Vaginal Creams Pessaries Tablets Ring (Estring)

VAGINAL OESTROGENS Estriol / Estradiol Use daily for 2 weeks then twice weekly stop at one year and assess need for further treatment Vagifem tabs now licensed for indefinite use Estradiol ring (Estring) Change every 3 months Licensed for 2 years continuous use

Vaginal Oestrogens Poor systemic absorption Systemic progestogen not required CSM - Current Problems in Pharmacovigilance vol. 29, Sept 2003 Use lowest dose and interrupt treatment at least annually. Ix BTB. N.B. Premarin cream IS absorbed

SYSTEMIC SYMPTOMS - WHICH HRT? Uterus - Yes / No? No - Oestrogen only Yes - Combined HRT (Oestrogen and progestogen)

Oestrogen only HRT Oral? or Non-oral?

Oral Oestrogens 3 different types Conjugated equine estrogens Estradiol Estradiol valerate

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 E2 Val = c. 0.75 x E2

Non-oral oestrogen - Which? Patch Gel (Vaginal ring - Menoring) (Intranasal spray) 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 Reduce triglycerides less effect on clotting factors no effect on hepatic renin substrate no effect on CRP

Non-oral Oestrogens - Disadvantages Absorption may vary depending on the route - try a different ROUTE Patches Most matrix patches are equivalent Estradot different patch technology (Absorption is easier to check by serum oestradiol levels)

Non-oral oestrogens Avoid first pass metabolism - ideal for; Liver disease Diabetics Hypertriglyceridaemia Gallstones h/o VTE Hypertensives Epileptics ? Coronary heart disease

Non-oral oestrogens Also ideal first line for Malabsorption Migraine Otherwise oral vs non-oral? Patient choice

HRT + Intact uterus Current practice - add progestogen to reduce risk of endometrial hyperplasia and carcinoma. Pre- or postmenopausal? 12 months amenorrhoea (or >54 on cyclical) Continuous combined / Tibolone

CYCLICAL HRT Monthly progestogen At least 10 days, preferably 12 days 3 Monthly progestogen 2 1/2 months unopposed estrogen + 14 days progestogen Must be oligomenorrhoeic WDB may be heavier ?long-term safety

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

TIBOLONE First no bleed HRT for postmenopausal women Synthetic preparation Estrogenic, progestogenic and androgenic effects Controls symptoms and protects bones Can help libido and low mood Similar risk of breast cancer as E only

PROGESTOGENS - Which? C19 progestogens - structurally related to testosterone norethisterone levo/norgestrel C21 progestogens - structurally related to progesterone i.e. less androgenic dydrogesterone medroxyprogesterone acetate (MPA)

PROGESTOGENS Which? Drospirenone Related to spironolactone Aldosterone antagonist activity Increases sodium and water excretion Decreases potassium excretion ?slight weight loss ?reduction in BP slight antiandrogenic properties Currently in one low dose CCT

PROGESTOGENS - Which? Ist line choice - doesnt really matter May cause side effects - encourage 3 month review e.g. PMS type Take a careful history Change progestogen - preferably to C21 i.e. dydrogesterone / MPA ?Drospirenone Change route

Progestogen routes Oral combined (all) alone (NET, MPA, dydrogesterone) Transdermal combined patches (NET / LNG) Intra-uterine (Mirena) now licensed in UK for use in HRT 4 years max only way to use continuous P in pre-menopausal women

Intrinsa New Viagra for women? Testosterone patches 300microg Testosterone Indication HSDD Hypoactive sexual desire disorder HBSO Concomitant estrogen Not Premarin!

Hypoactive Sexual Desire Disorder (HSDD) DSM IV definition 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.

Intrinsa Use Thin, clear, oval matrix-type transdermal patch Twice-a-week application to abdomen

Mental Checklist of Questions before prescribing HRT Does she want it? Is she adequately informed about risks and benefits? Are the symptoms primarily local or systemic? Does she have a uterus? Is she pre- or postmenopausal? Which E oral/non-oral? Which P?

For how long??

TREATMENT DURATION Symptom relief 3-5 years followed by gradual withdrawal restart HRT if symptoms recur Prevention of osteoporosis 5-10 years minimum (longer after discussion) Premature menopause Treat to average age of menopause (51) Review benefits vs risks NB Risk of breast cancer applies to >51 years

HRT -Summary Extremely effective for control of menopausal symptoms Right dose = lowest dose that controls a womans symptoms Short term benefits outweigh the risks for most women Premature menopause HRT to at least 50 years

Helping women help themselves Each woman needs information to decide for herself www.menopausematters.co.uk www.yorkshiremenopause.co.uk www.thebms.org.uk

dr julie ayres specialty doctor in gynaecology ltht bms council

Documents

hrt headlines slide

pain slide

emotional slide

advice slide

causes slide

unpredictable slide

oestrogen replacement

line use slide