Obstetrics, Gynaecology & Urology Hormone replacement therapy • Menopause Matters •

Principles of hormone replacement therapy

once cardiovascular disease is established, some types of HRT may confer a small increased risk –– HRT should not currently be prescribed for presumed cardiovascular benefit –– HRT should only be prescribed to women who have, or are at risk of cardiovascular disease if there are good indications, and after full discussion

Indications and contraindications for HRT • Indications: –– relief of menopausal symptoms (short-term) –– prevention/treatment of osteoporosis (long-term) –– premature ovarian failure

Treatment options • Contraindications: –– pregnancy –– undiagnosed abnormal vaginal bleeding –– active thromboembolic disorder or acute-phase myocardial infarction –– suspected or active breast or endometrial cancer –– active liver disease with abnormal liver function tests –– porphyria cutanea tarda • Other possible benefits include the reduction in risk of colonic cancer, macular degeneration and cataract formation, with improved dentition and skin healing – these are still controversial and not seen as indications

• Hormones involved: –– estrogen – should be given continuously –– progestogen – given in addition to estrogen in non-hysterectomised patients to reduce the risk of endometrial hyperplasia. Duration and frequency of the progestogen determines the presence and pattern of bleeding • The wide range of types and routes of estrogen and progestogen allows flexibility and enables treatment to be individualised • There is a large variation in the individual’s response to different types and routes of estrogen for symptom control

Risks of HRT

• Oral – usually first choice, cost-effective and acceptable

• Small increased risk of: –– breast cancer with long-term treatment with combined HRT (>5 years). Risk is much less with estrogen-only HRT –– venous thromboembolism—most significant in patients with other risk factors, and less with transdermal HRT compared to oral HRT

• Non-oral therapies: –– are thought to produce more physiological hormone levels than oral therapy, avoiding bolus first-pass effect on the liver –– have different metabolic effects (e.g. on lipid metabolism), significance of these effects is controversial –– are more expensive

• Association between HRT and cardiovascular disease: –– it is possible that when used within 10 years of menopause, HRT may be cardioprotective, but if used

• Indications for non-oral route: –– patient preference –– poor symptom control with oral treatment –– side effects e.g. nausea with oral treatment

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Obstetrics, Gynaecology & Urology Testosterone

–– history of, or risk of venous thromboembolism (when HRT should only be considered after full discussion and appropriate investigation) –– variable hypertension (blood pressure should be controlled before starting HRT) –– hypertriglyceridaemia –– current hepatic enzyme inducing agent, e.g. anticonvulsant therapy –– bowel disorder which may affect absorption of oral therapy –– history of migraine (when steadier hormone levels may be beneficial) –– lactose sensitivity –– history of gallstones

• Women who have had a hysterectomy and ovaries removed may benefit from testosterone replacement therapy along with estrogen, for improved libido. Testosterone implant 6 monthly or twice weekly patch in conjunction with systemic estrogen

Perimenopausal patients • Sequential combined therapies are used in women with an intact uterus who are not yet postmenopausal, i.e. have some continuing ovarian function. Products contain daily estrogen and cyclical progestogen, causing a bleed each month in 85% of patients

Hysterectomised patients Oral

• Side effects are often experienced during the progestogen phase of treatment and can be reduced by using a product containing a different type or route of progestogen

• Low dose – recommended as starting dose • Higher dose – when symptoms are not controlled by the above

• Available as oral or patches

Non-oral

• Low dose – recommended as starting dose

• Patches: –– can be matrix or reservoir –– matrix tend to cause less skin irritation and adhere better –– patches can be changed once or twice weekly

• Long cycle treatment – useful in perimenopausal patients who are having infrequent periods, but may not be sufficiently post menopausal to offer continuous combined therapy to, and will confer a bleed every 3 months

• Gels – are useful if transdermal treatment is the preferred option but skin irritation occurs with patches • Implants: –– usually used as a last resort in patients post-hysterectomy when symptoms are not controlled by other means • All estrogen only preparations can be used in non-hysterectomised patients, as long as an appropriate progestogen is given in addition

http://www.eGuidelines.co.uk/

• Tailor-made sequential combined therapy is useful in patients who develop PMS type symptoms on a fixed HRT, particularly if the regime contains a progestogen of testosterone derivation • The following progestogens can be given with estrogen only regimes: –– micronised progesterone – 200 mg daily at bedtime for 12 days per 28 days (days 15–26 inclusive) –– medroxyprogesterone acetate – 10 mg daily for 14 days per 28 days

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Obstetrics, Gynaecology & Urology Why and when to offer continuous combined therapy

–– intra-uterine progestogen-only system – licensed for use for 4 years as the progestogen part of HRT • Careful explanation is required as to the timing of administration of the separate progestogen, in order to synchronise it with the existing cycle

Post menopausal patients • Continuous combined therapies offer ‘period free’ therapy for patients who are ≥54 years, or more than 1 year post menopausal at any age

• Why? –– no physiological reason for menstrual bleeds if can be avoided –– most women prefer a no-period option –– cheaper for patient – one prescription charge instead of the two for sequential combined therapy –– thought to be less risk of endometrial hyperplasia in the long term with continuous combined compared to sequential therapy • When? –– patient known to be post-menopausal at whatever age, ideally by having at least one year of amenorrhoea –– if sequential therapy started whilst patient is still having periods, wait till age 54 years. At 54 years 80% of women will have cessation of ovarian function –– change from sequential to continuous combined by advising patient to finish current sequential pack and start new therapy at the end of the expected bleed

• The criteria should be fulfilled in order to offer such treatment to patients who no longer have a continuing ovarian cycle, so that steady levels of both estrogen and progestogen can be achieved • Start with low dose preparations and increase as necessary for symptom control • Continuous combined therapies are available as oral or patches • Patients should be advised to expect some bleeding in the first few months of treatment, but should have settled by six months

Follow up

Gonadomimetic (tibolone)

• When commenced on HRT, or when HRT changed, see after 3 months to: –– assess effect of therapy –– enquire about side effects and bleeding pattern –– check blood pressure and weight

Initial follow up

• Because of its androgenic component, tibolone can be particularly helpful for postmenopausal patients with reduced libido • Current evidence suggests that tibolone does not increase mammographic breast density, as it may occur with other types of HRT • Long-term use of tibolone is thought to be associated with a similar increased risk of breast cancer to that of estrogen alone, which is less than that of estrogen plus progestogen

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Annual review • When settled on therapy see annually to: –– check effectiveness of therapy and presence of side effects –– update on best type of therapy for patients –– discuss pros and cons of continuing HRT, in particular, discussing increased risk of breast cancer with long-term HRT –– check blood pressure

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Obstetrics, Gynaecology & Urology –– encourage breast awareness –– cervical smear 3 yearly –– carry out pelvic examination (only if clinically indicated)

–– unrealistic expectations – counsel

When to refer

Management of side effects

• Persistent side effects following logical therapy changes as per side effect management

• In all patients allow 3 months on treatment before making any changes as frequently side effects subside

• Inadequate control despite logical changes in HRT as per poor symptom control

• Estrogenic symptoms include breast tenderness/enlargement, leg cramps, bloating, nausea and headache. Consider the following: –– try evening primrose oil –– reduce estrogen dose, particularly in older patients –– take medication with food –– change route of administration –– change type of oral estrogen • Progestogenic symptoms include PMS type symptoms, breast tenderness, lower abdominal pain, backache, depressed mood, acne/greasy skin. Consider the following: –– change progestogen –– change route of administration –– offer tailor-made combination (remember recommended dose and duration for endometrial protection) –– if post menopausal, consider changing to continuous combined or tibolone to avoid symptoms related to progestogen fluctuation

• Bleeding problems: –– during sequential therapy – change in pattern of bleeding including increased duration, frequency and/ or heaviness, and irregular bleeding –– during continuous combined therapy or tibolone – if still bleeding after 6 months of therapy or if bleeding occurs after a spell of amenorrhoea –– SERMS – any bleeding whilst on therapy should be treated as a post menopausal bleed • Complex medical history • History of hormone dependent cancer • Patient request

Management of poor symptom control • Poor symptom control: –– check compliance –– allow 3 to 6 months on therapy to ensure full effect –– inadequate estrogen dosage – increase dose or change from oral to non-oral route –– poor absorption due to bowel disorder – change to non-oral route –– drug interactions e.g. barbiturates, phenytoin, carbamazepine – increase oral dose or change to non-oral route –– poor patch adhesion – change delivery system –– incorrect diagnosis – review indications

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Obstetrics, Gynaecology & Urology Management flowchart for patients with menopause Symptoms but HRT inappropriate, consider: n Clonidine n SSRIs n Progestogens n Gabapentin

Menopausal assessment: n Lifestyle n Past/family history

n Bone densitometry

n Risk/benefit analysis

n Life style factors n Bisphosphonates

n Complementary therapies

n SERMS n Strontium ranelate

Urogenital symptoms only, consider:

Decision to commence HRT

n Calcium/Vitamin D n Parathyroid hormone

n Local estrogen Without uterus

Risk factors for osteoporosis but HRT inappropriate, consider:

n Symptoms

Systemic HRT required

With uterus

Estrogen only Post-menopausal Oral estrogen If non-oral indicated

Oral continuous combined HRT or Gonadomimetic (tibolone)

Non-oral estrogens:

Perimenopausal Fairly regular cycle Oral sequential HRT

If non-oral indicated

If non-oral indicated

Non-oral continuous combined HRT

Non-oral sequential HRT

Infrequent cycle but not postmenopausal

n Patch n Gel n Implant

Long cycle HRT

Starting with low dose Review: n Symptom control n Side-effect management n When to refer full guidelines available from... http://www.menopausematters.co.uk Menopause Matters. Hormone replacement therapy.

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May 2005, updated January 2011.

http://www.eGuidelines.co.uk/