Hormone replacement therapy

Menopause Matters


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Principles of hormone replacement therapy

Indications and contraindications for HRT

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

Risks of HRT

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

Treatment options

  • 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
  • Oral – usually first choice, cost-effective and acceptable
  • 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
  • Indications for non-oral route:
    • patient preference
    • poor symptom control with oral treatment
    • side effects e.g. nausea with oral treatment
    • history of, or risk of venous thrombo-embolism (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

Hysterectomised patients

Oral

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

Non-oral

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

Testosterone

  • 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 can be given in conjunction with systemic estrogen but availability is currently limited

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
  • 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
  • Available as oral or patches
  • Low dose – recommended as starting dose
  • 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
  • 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
    • 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
  • 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

Gonadomimetic (tibolone)

  • 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

Why and when to offer continuous combined therapy

  • 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

Follow up

Initial follow up

  • 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

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
    • encourage breast awareness
    • cervical smear 3 yearly
    • carry out pelvic examination (only if clinically indicated)

Management of side effects

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

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
    • unrealistic expectations – counsel

When to refer

  • Persistent side effects following logical therapy changes as per side effect management
  • Inadequate control despite logical changes in HRT as per poor symptom control
  • 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
    • Selective estrogen receptor modulators (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 flowchart for patients with menopause

Management flowchart for patients with menopause

 

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References

full guidelines available from…
http://www.menopausematters.co.uk

Menopause Matters. Hormone replacement therapy. May 2005, updated January 2011.
First included: July 2005, updated December 07, Jun 08.


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