The Menopause and HRT

Aims Gain an understanding of what is meant by “menopause”, and how it is diagnosed Gain an understanding of the treatment options Think about the risks and benefits of HRT

Objectives The menopause HRT Alternatives to HRT What is it? What are the symptoms? How should it be investigated? HRT Indications Choice Risks Side effects Alternatives to HRT

The Menopause

The menopause – what is it? From the British Menopause Society: Permanent cessation of menstruation Only diagnosed after 12 months spontaneous amenorrhoea – a retrospective diagnosis Climacteric/perimenopause – period of change leading up to the menopause

The menopause – why does it happen? Women are born with around 1.5m oocytes 1/3 are lost by the time of menarche. Most women menstruate about 400 times, and 20-30 follicles start to develop each time. Eventually the supply of responsive oocytes in the ovaries runs out

The menopause – hormonal changes Ovarian follicular activity begins to fail as responsive oocytes run out Leads to reduction in oestrogen and progesterone levels Low level of oestrogen causes disruption of cycle and menopausal symptoms -ve feedback loop causes rise in levels of luteinising hormone and follicle stimulating hormone

2) Politi MC, Grimm C, Bentz EK et al; J Gen Intern Med. 2008 Sep Epidemiology – UK Final menstrual period usually occurs between the ages of 40 and 58, with an average age of 511 Final menstrual period below the age of 40 is considered to be premature menopause1 Evidence suggests that in the average woman symptoms start to increase from 2 years before the last menstrual period, reach a peak at 1 year following it, and have resolved by 8 years2 1) Nelson H; Lancet, 2008 Mar 2) Politi MC, Grimm C, Bentz EK et al; J Gen Intern Med. 2008 Sep

How common are symptoms? 80% of women experience menopausal symptoms1 45% of these find the symptoms distressing1 Most women manage the symptoms themselves – 10% seek medical advice for their symptoms2 1) RCPE, 2003 2) Roberts; BMJ, 2007

Symptoms Menstrual irregularity Hot flushes/sweats Urinary/vaginal symptoms Sleep disturbance Mood changes Loss of libido Others

Menstrual irregularity Cycle may lengthen to months, or shorten to weeks1 Increase in blood loss is common1 Majority of women experience irregularities, but 10% have a sudden cessation of menstruation2 1) Nelson H; Lancet, 2008 Mar 2) “Menopause”; Clinical Knowledge Summaries

2) “Menopause” Clinical Knowledge Summaries Hot flushes/sweats Common 70-80% of peri-menopausal women1 Tend to affect head, neck, face and chest. Usually last for a few minutes but can happen multiple times during the day and night. Most common in the first year after the last menstrual period2 1) RCPE 2003 2) “Menopause” Clinical Knowledge Summaries

Urinary/vaginal symptoms Dyspareunia Vaginal discomfort/dryness Recurrent UTI Urinary incontinence Occur in 30% in early post-menopausal period, rising to 47% later in life1 1) Grady; NEJM, 2006

Sleep disturbance and mood change Sleep disturbance – commonly reported symptom, probably related to mood changes – anxiety, depression, memory loss, poor concentration1 Development of psychological symptoms has been linked to high BMI, and low amounts of physical activity2 1)Young T et al;. Sleep, 2003, Sep 2) Di Donato P et al;. Maturitis, 2005, Nov

Loss of libido/other changes Loss of libido may be related to hormonal changes, but also psychological factors, vaginal dryness, partner Others (probably due to low oestrogen): Brittle nails Thinning of skin Hair loss Generalised aches and pains

Investigations Generally not required, but blood tests include: TFT FBC ?FSH LH, oestrogen and progesterone levels not normally helpful

1) “Menopause” Clinical Knowledge Summaries FSH1 Only needed if doubt about diagnosis – eg. in premature menopause Can be very variable during peri-menopause – single measures are unreliable, and levels should be checked when women are not using any oestrogen containing medications (including COCP) FSH > 30 is generally taken as post-menopausal range. 1) “Menopause” Clinical Knowledge Summaries

1) British Menopause Society Associated problems1 Increased risk of cardiovascular disease + stroke Increased risk of osteoporosis Redistribution of body fat ?Alzheimer’s Disease – more common in women so may be hormonal link, but no evidence HRT reduces risk 1) British Menopause Society

Treatment - HRT

HRT Effective treatment for menopausal symptoms Previously used widely and for prolonged periods However: Women’s health initiative (2002) – increased risk of coronary heart disease, stroke, breast cancer, PE Million women study (2003) – increased risk breast and ovarian cancer

1) “Menopause” Clinical Knowledge Summaries Indications for HRT1 Treatment of menopausal symptoms where the risk benefit ratio is favourable, in fully informed women, in the lowest possible dose needed to control symptoms and for the shortest possible time In women with premature menopause until the age of natural menopause (50) For prevention of osteoporosis in women unable to use other medications 1) “Menopause” Clinical Knowledge Summaries

Choice Oestrogen + progestogen Oestrogen alone Tibolone

Routes of delivery Oral tablets Patches Creams/gels Nasal sprays IUS Oestrogen releasing vaginal ring S/C implants

Which preparation? Questions: Does the women have an intact uterus? Are symptoms primarily vaso-motor or urogenital? Systemic or local treatment? Combined or oestrogen only? Cyclical (oestrogen with progestogen from day 12-14) or continuous?

She has a uterus Symptoms mainly vasomotor: Perimenopausal – Systemic cyclical combined HRT Postmenopausal – Systemic continuous combined HRT Symptoms mainly urogenital: Perimenopausal – local oestrogen OR systemic cyclical combined HRT Post menopausal – local oestrogen OR systemic continuous combined HRT

She has no uterus Symptoms mainly vasomotor – systemic oestrogen only HRT Symptoms mainly urogenital – local oestrogen OR systemic oestrogen only HRT

Tibolone Selective oestrogen receptor modulator Oestrogenic, progestogenic and androgenic properties Can be used if intact uterus and no bleeding for >1yr Evidence for improvement in sexual function and vasomotor symptoms1 Increased risk of stroke and breast cancer, especially in over 60s2 Less risk with DVT and IHD 1) Al-Azzawi et al; Obstet Gynecol 1999 Feb 2) Kenemans P et al; Lancet Oncol 2009 Feb

HRT Snap!

Contraindications to HRT1 Pregnancy and breast-feeding Undiagnosed vaginal bleeding VTE Active/recent angina or MI Suspected, current, or past breast Ca Endometrial Ca Active liver disease with abnormal LFTs 1) “Menopause”; Clinical Knowledge Summaries

What are the risks? Venous thromboembolism Coronary heart disease Stroke Breast cancer Endometrial cancer Ovarian cancer

What are the risks? Venous thrombo-embolism Increased risk of DVT and PE; highest risk in the first year of use. Number of women having VTE/1000 over 5 years (figures from BNF): No HRT Oestrogen only HRT Combined HRT 50-59 5 7 12 60-69 8 10 18

Rossouw JE et al; JAMA 2007, Apr What are the risks? Coronary heart disease Evidence for protection from CHD is lacking Increased risk of heart disease for women starting combined HRT more than 10 years after the menopause (extra 15 cases/1000 women over 5 years)1 Rossouw JE et al; JAMA 2007, Apr

What are the risks? Stroke Small increased risk of stroke for younger women on HRT, rising in older women Number of women having stroke/1000 over 5 years (figures from BNF): No HRT Oestrogen only HRT Combined HRT 50-59 4 5 60-69 9 12

What are the risks? Breast cancer Over 5 years No HRT Oestrogen only HRT Combined HRT 50-59 10 12 16 60-69 15 18 24 Breast cancer Increased risk is proportional to the duration of treatment Risk returns to untreated levels after 5 years Number of women having breast cancer/1000 over 5 and 10 years (figures from BNF): Over 10 years No HRT Oestrogen only HRT Combined HRT 50-59 20 26 44 60-69 30 39 66

Oestrogen only HRT – 5 years Oestrogen only HRT – 10 years What are the risks? Endometrial cancer Substantial increased risk with oestrogen only HRT Use of progestogen eliminates risk, but needs to be weighed against increased risk of breast cancer Number of women having endometrial cancer/1000 over 5 and 10 years (figures from BNF): No HRT – 5 years Oestrogen only HRT – 5 years No HRT – 10 years Oestrogen only HRT – 10 years 50-59 2 6 4 36 60-69 3 9 54

What are the risks? Ovarian cancer Over 5 years No HRT Oestrogen only HRT Combined HRT 50-59 2 60-69 3 Ovarian cancer Small increased risk of ovarian cancer, rises with duration of use Number of women having ovarian cancer/1000 over 5 and 10 years (figures from BNF) Over 10 years No HRT Oestrogen only HRT Combined HRT 50-59 4 5 60-69 6 8

1) “Menopause”, Clinical Knowledge Summaries Follow-up1 Initial follow up after 3 months Thereafter, a minimum of annual checks Check effectiveness Side-effects BP + weight Breast examination – if appropriate Pelvic examination – if appropriate Review of risks/benefits 1) “Menopause”, Clinical Knowledge Summaries

Follow-up Effectiveness – if symptom control not good consider: Poor absorption – eg. Bowel problem Drug interaction – eg. Carbemazepine, phenytoin Incorrect diagnosis – eg. Hypothyroidism, diabetes Patient expectations Consider – increasing oestrogen dose, altering brand, changing delivery method

What are the side-effects? Oestrogen: Breast tenderness Leg cramps Bloating Nausea Headaches Bleeding – cyclical preparations produce regular and predictable bleeds, usually towards the end of the progestogen phase Progestogen: Breast tenderness Backache Depression Pelvic pain

Oestrogen related side-effects More likely to occur and be problematic when there has been a longer duration of ovarian failure Often resolve with continued use Consider – Breast tenderness – low fat, high carbohydrate diet Leg cramps – exercise and calf stretches Nausea, bloating – adjust timing of dose, take with food Headaches – try patches (may produce more stable oestrogen levels)

Progestogen related side-effects May be more problematic; may be connected to type, dose and duration of progestogen Consider – Changing progestogen type Reducing dose Altering route to something other than oral “Long-cycle” HRT – (progestogen for 14 days every 3 months – only suitable if periods have stopped). Continuous combined therapy or tibolone (if post-menopausal)

Managing bleeding Heavy/prolonged bleeding – increase dose or duration of progestogen ?IUS Bleeding early in progestogen phase – increase dose, change type of progestogen Painful bleeding – change type of progestogen Irregular bleeding – increase progestogen No bleeding – may occur in 5% due to atropic endometrium; confirm compliance and remember to exclude pregnancy!

Bleeding – when to refer? Perimenopausal woman with intact uterus Change in pattern of withdrawal bleeds Breakthrough bleeding persisting for more than 6 months, or does not reduce on “long-cycle” HRT Persistent or unexplained bleeding after cessation of hormone therapy for 6 weeks

Bleeding – when to refer? Postmenopausal women with an intact uterus Breakthrough bleeding persists for more than 6 months after starting HRT Bleeding occurs after amenorrhoea Persistent or unexplained bleeding after cessation of hormone therapy for 6 weeks

But before changing treatment! Pelvic examination – including visualising cervix Confirm smears up to date TV USS

And don’t forget contraception! HRT does not suppress ovulation – contraception is still needed If an intact uterus: >50 – for one year after LMP <50 – for two years after LMP

HRT Snap!

Treatment - Alternatives

Lifestyle measures1 Regular aerobic exercise Avoid triggers – caffeine, alcohol, smoking, spicy food Wear light clothing Good sleep hygiene Weight loss 1) Alternatives to HRT for management of symptoms of menopause; ROCG (2006)

1) Nelson HD et al; JAMA, 2006 May Medications1 SSRIs/SNRIs – fluoxetine, paroxetine, citalopram and venlafaxine have been shown to reduce symptoms; unlicensed for this use Clonidine – evidence of efficacy in treating hot flushes, but high frequency of side-effects Gabapentin – evidence of efficacy for treating hot flushes; for specialist use 1) Nelson HD et al; JAMA, 2006 May

Complementary therapies Many OTC preparations available Black cohosh Evening primrose oil Dong quai Ginkgo biloba Ginseng St John’s Wort Limited evidence of efficacy and long term safety Some preparations contain oestrogens Some preparations can interact with other medications and may have other adverse side effects

Summary The menopause is a natural and inevitable part of life Menopausal symptoms are very common but most women never seek advice regarding management Although HRT carries risks, it is a good and effective treatment for symptoms Patients should be fully informed and allowed to make the decision themselves about whether to commence HRT

References As detailed on slides + www.gpnotebook.co.uk www.patient.co.uk www.bnf.org NHS CKS RCOG British Menopause Society