Dr Lisa Pickles. GP Brig Royd, Ripponden. November 2016. HRT. Dr Lisa Pickles. GP Brig Royd, Ripponden. November 2016.

Plan for this afternoon. ‘I’d like to go on HRT.’ The initial and FU consultations. Key messages. Other snippets. References/things to look up.

The initial HRT consultation. How to structure this. Where to start? What areas need to be covered and in what order?

Consultation: history Work out: Indication vasomotor symptoms esp. flushes ( it is the best treatment for this). Consider for low mood, urogenital atrophy and altered sexual function. Patient expectations. (NICE NG23– suggest try HRT for low mood. SSRIs for depression as per other NICE guidance)

Consultation: contraindications Pregnancy and BF. Abnormal vaginal bleeding. VTE. Active or recent angina/MI. Ca breast – suspected, current or past. Ca endometrium or other oestrogen dependent cancer. Active liver disease with abnormal LFTs.

Consultation: side effects What would you mention?

Consultation: side effects I mention: Sore breasts. Leg cramps. Headache. Bloating, mood/PMS sx (progesterone SE) (NOT weight gain, but CARE – most women put weight on because of the menopause itself. Not due to HRT). Ask patient to read the PIL that you will supply for more information.

Consultation:risks Mention: Ca breast (E only has less risk than combined). VTE . Stroke. Endometrial ca , only if unopposed with uterus. Ovarian cancer – small increased risk.

Consultation: risks (background) Womens Health Initiative study (USA) and Million Women study (UK) highlighted an increased risk of CHD and breast cancer . 2002/3. Led to halving of use of HRT. However, average age was >60years in WHI. Fairly high E doses. Further analysis suggested a limited ability of WHI and MWS to show a causal association between HRT and Ca breast. Nice November 2015. Guidelines to provide a consensus to facilitate appropriate prescribing of HRT.

Risks-breast cancer (background) Note: Recent epidemiological review of observational/cohort studies in August 2016. British Journal of Cancer. Some of the data we use when discussing risk with women may underestimate* the risk of breast cancer by a quarter to a half in some cases. The absolute risk of breast cancer remains small, but perhaps not as small as we thought! *Due to – on recruitment not taking HRT, however, some patients may start it later on . - if age of menopause not ascertained, then those with early menopause will ‘water down’ the risk.

Risks-breast cancer (background) NB: the figures quoted by NICE for observational studies took into account the fact that previously reported studies may have underestimated risk, by having large confidence intervals. Therefore, no change is needed. RCT evidence is higher graded quality evidence than observational studies. And, the return of breast cancer risk to baseline a few years after stopping HRT suggests that HRT doesn’t CAUSE malignant transformation, but that certain types of HRT may promote the growth of cancer cells already present.

Risks-breast cancer (summary) No increased risk E only. For E+P: 5 extra cases per 1000 women taking comb HRT for 7.5 years. Background risk 22 per 1000, increases to 27 per 1000 (RCT data) Risk reduces on stopping HRT, gone after 5 years. Baseline risk of ca breast varies from woman to woman And, there is no increased mortality risk

Risks-breast cancer (information) I show patients: http://www.menopausematters.co.uk/pdf/Understanding%20Risk%20of %20Breast%20Cancer.pdf (RCT evidence) More detailed info: http://www.gpnotebook.co.uk/simplepage.cfm?ID=x2015112513505186 5742 (complicated and confusing to look at! RCT and observational evidence)

Risks-VTE HRT tablets increase risk 2-4x. Transdermal doesn’t. So, transdermal indicated if increased risk VTE eg. BMI>30, age >60. Small background risk therefore low actual numbers. It's estimated that for every 1,000 women taking HRT tablets for 7.5 years, less than two will develop a blood clot due to HRT. Most of the increased risk happens in the 1st year of use.

Risks-Heart disease E only – lower risk or unchanged heart disease risk, if taken < 60yrs old. E+P – unchanged heart disease risk, if taken < 60 years old. ‘Window of opportunity’ started in early postmenopausal years, may be beneficial. However, in already diseased arteries, may be harmful. Danish osteoporosis trial– if HRT started within 10 years of LMP, CHD halved. Therefore, assess and manage Risk Factors for CHD and stroke. OK to prescribe if RFs are managed. Note: OK to use in Type 2 DM. Manage CV RFs . No adverse effect on glycaemic control.

Risks-stroke E and E+P small increased risk of ischaemic stroke. Transdermal probably not.

Risks-Heart disease and stroke Information based on NICE: http://www.gpnotebook.co.uk/simplepage.cfm?ID=-1684406264 (CHD) http://www.gpnotebook.co.uk/simplepage.cfm?ID=1845887032 (stroke)

Risks-ovarian cancer Some conflicting studies. Not looked at by NICE Possibly 1 extra case / 1000 women on HRT for 5 years.

Benefits- osteoporosis Bone density HRT shown to reduce the risk of fracture ( as well as preserving bone density). Some suggestion benefit may last longer, the longer HRT is taken. Benefit falls on stopping HRT. Some studies suggest HRT use around the menopause may provide a long term protective effect many years after stopping (though protection declines). Some suggestion benefit may last longer, the longer HRT is taken.

Summary-risks/benefits HRT increases the risk of No impact on risk of Benefits VTE: only oral HRT, not transdermal. Ischaemic stroke: with oral HRT. Weak evidence that transdermal preparations have less impact on stroke risk. Breast cancer: risk is related to treatment duration and reduces after stopping. Ovarian cancer: NICE did not look at this but probably small increased risk. Coronary heart disease if started in women <60y and the woman is still <65y old. Type 2 diabetes. Fragility fractures: reduces risk. Vasomotor symptoms: reduces frequency. Low mood: improves. Muscle mass and strength: increases (limited evidence). Musculoskeletal symptoms: improved (based on clinical experience). Sexual desire: increased.

Consultation: Examine BP. Weight/BMI. PV – only if indicated by eg abnormal bleeding. Encourage ‘breast aware’ /mammograms and up to date smears.

Consultation:prescribe CSM statement 2003 and NICE ‘minimum effective dose should be used for the shortest time’ BMS recommendations 2013 ‘the optimum dose and duration should be decided according to the severity of a woman’s symptoms and her response to therapy’ ‘arbitrary limits should not be placed on the duration of usage of HRT’

Consultation:prescribe NICE. Tailor the dose to symptoms. Younger women may require higher doses of E eg. 2-4mg orally or 100mcg patch. Older women may be controlled on 1-2mg orally or 25-50mcg patch.

Consultation:prescribe Consider: Start low and build up as necessary. Oral v patches (or gel) . Oral cheaper. Offer choice. Consider transdermal >60y, if RFs for VTE or stroke, if migraine. Systemic or local (cream, pessary or ring). Choice of oestrogen. conjugated E (premarin) v oestradiol. (tibolone, see end.)

Consultation:prescribe Strength of oestrogen. Tablets: -1mg oestradiol< or = 0.625mcg conjgd E* < -2mg oestradiol < or = 1.25mcg conjgd E* (tibolone 2.5mg probably the ‘weakest’ in effect). Patches: -0.25mg oestradiol patch ~/= 1mg oral oestradiol - 0.5mg oestradiol patch ~/= 2mg oral oestradiol. (also, patches 0.75mg and 1mg strengths) * Conjugated oestrogens are rarely used nowadays.

Consultation:prescribe Unopposed (E only). If patient has had hysterectomy. Combined (E + P). Has uterus. -Cyclical v continuous. can use latter if amenorrhoeic for > 1 year, is age 54 or if has been on cyclical HRT for 1 year.

Consultation:prescribe Tibolone. Is a Selective Estrogen Receptor Modulator (SERM). Has oestrogenic, progestogenic and androgenic properties, so consider as continuous, combined preparation. Is a fairly ‘weak’ oestrogen. Less ca breast risk than combined (slightly more than E only), BUT increased ca endometrium risk and stroke risk. Not to use in > 60 years old due to CVA risk.

Consultation:prescribe Possible indications for tibolone. - ‘hormone’ SE on other HRT. - if libido a problem? - if risk factors or concern re ca breast? Testosterone – may help libido, but no licensed preparations. Would need specialist referral to consider Testosterone gel 10mg per day. Choose preparation. No local formulary. MIMs list (or BNF).

Consultation:prescribe There is no low dose (25mcg) continuous combipatch preparation. Commonly, 25mcg Evorel patch (or Estrogel) is used + oral micronized progesterone (utrogestan) 100mg per day.

Consultation:prescribe Supply. 3 months supply. Then annually if all well. Duration . Discuss annually (NICE) with HCP. Trials of stop/reduce if wished. If symptoms persist, the benefits of HRT usually outweigh the risks (BMS 2013) If premature ovarian insufficiency, usually till 51 (see next slide).

Consultation:prescribe Premature Ovarian Insufficiency The WHI/ca breast findings do not apply to this young group. HRT in POI – simply replaces ovarian hormones that should normally be produced at this age (inform patient of this) - should generally continue till average age of menopause (51) Note: COC (up until age 50) can be used as an alternative for symptoms (but little data on long term osteoporosis and CV disease effect ) eg. Qlaira – contains same oestrogen, oestradiol valerate.

Prescribing Quiz

Consultation: follow up Inform re arrangements. At Brig Royd, see GP for 1st consultation and rx. If all well, can see nurse at 3months and annually. Back to GP every 2 years. Adv to see GP if any problems. Note: NICE suggests annual review to discuss pros and cons of continuation. And, NICE suggests that most women need 2-5 years of treatment for vasomotor symptoms.

Consultation: PIL/information PIL of your own choice eg patient.info Direct to menopausematters.co.uk or www.nhs.uk/conditions/menopause Other: eg.http://www.menopausematters.co.uk/pdf/Understanding%20 Risk%20of%20Breast%20Cancer.pdf ca breast risk. eg. www.daisynetwork.org.uk (patients with POI)

Consultation contd: Summary of 1st consultation. a. Discuss. Indication Expectations CI SE Risks/benefits. Assess cardiovascular risk. b. Examine. BP and weight. c.Prescribe. Combined/unopposed. Tablets/patches. Choose preparation. 3 months supply. Start low and increase dose if necessary. d.Follow up. Arrange. e.Issue leaflet. Due to time limits, ? carry out a. + b. + e., then return for prescription and further explanation at a 2nd appointment.

Follow up consultations. At review: Ask re SE, bleeding. Check re planned duration of use. Consider whether to stop. Or can the strength be reduced? Offer restart if symptoms recur and appropriate. Can cyclical combined be changed to continuous? ( yes if has taken for 1* year). *some authorities suggest longer eg. 3 years. But more complete endometrial protection if on continuous than cyclical - so of benefit if taking continuous. Revisit risk/benefit ratio and provide with up to date information. Check BP and up to date w smear and mammogram. Provide 12 month supply and arrange FU.

Follow up consultations: Dealing with problems. – ‘hormone’ SE: change of preparation. Often P effect (fluid retention/ PMS like)– dydrogesterone better. tolerated than MPA. Reduce E if sore breasts. - if poor symptom control. Increase E, change route, add vaginal E (if vag dryness) ?expectation, check patches stick.

Follow up consultations: Dealing with problems. - bleeding. Heavy or erratic bleeding on cyclical combined – dose of progesterone should be doubled or increased duration to 21 days (consider hysteroscopy/scan if persists> 3m (NICE). After switch to continuous combined – if irregular bleeding persists beyond 3-6m, then change back to cyclical for at least another year.

Key messages. Tailor dose and duration to the patient. Risk/benefit ratio – remember menopause matters PIL (ca breast). HRT <60 years old has favourable risk/benefit profile. Weight is not a SE (but menopause causes weight gain). Check BP. Opposed oestrogen if has uterus (carries greater ca breast risk than unopposed). Prescribe. Offer tablets or patches (preferably patches >60, stroke or VTE risk, migraine).

Other snippets: Lifestyle: Regular physical activity, reduce alcohol, caffeine, spicy foods, good sleep hygiene, relaxation. CBT: for mood disorders. Anti-depressants: if woman is diagnosed with depression. Testosterone : ( as before – refer) if libido issues, not helped by HRT.

Other snippets: Endometrial cancer risk is greatly reduced with cyclical combined HRT and abolished with continuous combined HRT. Mirena (IUS) can be used as progesterone component of HRT, can now be used for 5 years for this use. HRT is not contraceptive. It can be used with the POP. COC can be used till age 50 and may have HRT like effects till then. Remember that tibolone is unsuitable for women> 60 years in view of stroke risk.

Other snippets: Younger women with surgical menopause tend to need higher doses of HRT. Abrupt cessation of ovarian function rather than gradual failing at natural menopause. Start low and work up. Note BMS 2013 advice that HRT can be used 1st line in management and prevention of osteoporosis (change in thinking). See what NICE says.

Other snippets: Million Women Study (looked at almost 1,000,000 women who were attending for mammograms and who also took HRT. Questionnaire study. On varied regimes) and Womens Health Initiative Study (USA. Criticised as average age studied was 63. Much older than most of our patients) were landmark studies responsible for the ‘HRT scare’. Looked at risks. 2002/2003. A new analysis was published in Journal of FSRH early 2012 looking at MWS, WHI and Collaborative Analysis 1997. Concluded that these studies can only suggest that there may or may not be a link between HRT and Ca breast. Further research is suggested. See BMS 2013.

Other snippets: Lift study. Found increased risk of CVA with tibolone compared other HRT especially if > 60y RR 2.2. (combined HRT RR 1.3). MWS found ca breast risk: E only RR 1.3 Tibolone RR 1.5 Combined RR 2.0

Other snippets: HRT can be given if raised BP is found so long as BP is treated and controlled 1st. ‘Natural remedies’ –black cohosh, isoflavones: some data. Some benefits for vasomotor symptoms. ‘Natural’ not necessarily ‘safe’. May interact with medicines. Also, varying doses in preparations.

Other snippets: HRT increases the risk of gallbladder disease (cholecystitis). This may be reduced by using transdermal rather than oral HRT. Caution if high risk gallbladder disease. Migraine is not a CI, but low dose transdermal preparations may be preferable. Cessation of HRT causes recurrent symptoms in 50%.

Other snippets: NICE says: Offer women who wish to stop HRT a choice of gradually reducing or immediately stopping treatment. Explain that: Gradually reducing or immediately stopping HRT makes no difference to their symptoms in the longer term. Gradually reducing HRT may limit recurrence of symptoms in the short term. Symptoms of urogenital atrophy often come back when treatment with vaginal oestrogen is stopped.

Other snippets: Pharmacological alternatives : SSRIs eg. venlafaxine (SNRI) 37.5mg bd, fluoxetine 20mg od, citalopram 20mg od (but avoid fluoxetine in those on tamoxifen – interacts) Gabapentin may be effective. Further work being done. Could try clonidine. A few patients benefit. Trial data suggests marginal. Non hormonal. Replens – vaginal moisturiser. Note: no evidence for beta-blockers

HRT cases Quiz.

References and things to look up. British Menopause Society www.thebms.org.uk Womens Health Initiative Trial. JAMA 2002. Million Women Study. Lancet 2003. http://cks.nice.org.uk/ BNF. MIMs table of HRT preparations. www.menopausematters.co.uk. Useful website for patients. www.menopauseuk.org . Network of support groups. www.formulary.cht.nhs.uk. Google South West Yorkshire area prescribing committee if problems finding this website. http://www.pennine-gp-training.co.uk/Womens_and_Mens_health_sexual_health.html . Abnormal vaginal bleeding guidelines. And www.cks.nice.org.uk/menorrhagia www.fsrh.org.uk .Contraception for women aged over 40 years. BMJ management of menopause. Summary of NICE 14/11/15 p.30 http://www.pcwhf.co.uk/documents/pcwhf_menopause_guidelines_2016.pdf Primary care womens health forum, Menopause and HRT guidance. NICE 2015 summary. National Osteoporosis Society. www.nos.org.uk