Hormone Replacement Therapy

During the climacteric and the menopause, the declining levels of oestrogen and progesterone bring about many changes in the female. 80% of menopausal women experience symptoms, such as hot flushes and night sweats. 45% find these symptoms distressing.¹ Most symptoms are usually short-lived over a period of 2-5 years, but they may persist longer in a small proportion of women.
There are also other long-term health problems associated with the menopause. Osteoporosis, cardiovascular disease, stroke and urogenital atrophy all increase after the menopause. They may not necessarily be caused by the fall in oestrogen levels.
The menopause is diagnosed primarily on signs and symptoms:

• The principle change is to the menstrual cycle. Most women have fewer/or less frequent periods.
• For some women there may be a shortening of the cycle to 2-3 weeks, followed by cessation.
• In addition many notice a change in sleep patterns, mood, libido, skin and nails.
• There may also be urinary or vaginal symptoms, such as dyspareunia, recurrent infections or incontinence.

Serum follicle stimulating hormone (FSH) levels are of limited value in diagnosing the menopause as they fluctuate widely in the peri menopause. However serial levels should be taken if premature menopause is suspected, i.e at 40 years old or younger. A level of ≥30 IU/L are within post-menopausal range. It should be repeated 4-8 weeks later to confirm.
Thyroid function tests may be of value in distinguishing menopause from thyroid disease, especially if there has been little benefit after therapeutic trial of hormone replacement therapy (HRT).

Based on current knowledge, the International Menopause society (IMS) believes that "the balance between the benefits and risks of HRT is clearly in favour of use in the early postmenopausal years for symptomatic, healthy women."

• Hot flushes and night sweats
  • Lifestyle changes e.g. exercise, lighter clothing, cooler bedroom, stress reduction and trigger avoidance (caffeine, spicy food, smoking, alcohol) may help.
  • However HRT is the most effective method of symptom control.^2,3 Tibolone and progesterone only therapy also reduce flushing to a lesser extent.
  • Non-hormonal alternatives include selective serotonin re-uptake inhibitors e.g paroxetine and venlafaxine. ^4,5
  • Initial research has shown that gabapentin can reduce hot flushes by 45%.⁶
  • There are also many complementary therapies (black cohosh, red clover and oestrogenic herbs- ginseng), but safety and efficacy data are lacking⁵
• Sleep and mood changes
  These may be helped by measures such as regular exercise and relaxation classes. HRT will often improve sleep patterns by removing night sweats. HRT is most likely to be helpful if there are other symptoms present.
• Urogenital symptoms:
  • Atrophy is relieved by HRT.⁷
  • Low dose topical vaginal oestrogen is the preferred method as it is as effective as systemic preparations but systemic absorption is low. Optimal response to treatment may take up to 1 year.
  • The non-hormonal alternative is a vaginal lubricant, these are less effective. HRTs role in assisting urinary symptoms is currently less clear.
  • Of all problems urge incontinence responds best to HRT, as vaginal oestrogen therapy.
• Decreased libido and sexual function:
  • This will not be directly affected by HRT.
  • Loss of libido after surgical menopause has been assisted by testosterone therapy.
  • There are potential adverse effects and advice on dosing should be sought from a specialist.
  • Tibolone may be helpful in relieving vaginal dryness and also increasing libido.⁸

Hormone replacement may be given using oestrogen alone or in combination with progesterone. It is recommended that oestrogen should always be used with progestogen in women who have a uterus, as unopposed oestrogen may give rise to endometrial hyperplasia and increase the risk of uterine cancer.⁹ Both hormones may be given in several ways:

• Continuous or cyclical oral therapy
• Patches
• Creams or gels
• Nasal sprays
• Local devices such as the progesterone releasing Mirena® coil
• The oestrogen releasing vaginal ring
• Subcutaneous implants.

Tibolone is a drug used only after the menopause has been established i.e. amenorrhea for 12 months or more. It combines oestrogenic, progestogenic and weak androgenic activity, and is given continuously as an oral preparation.

The decision as to whether or not to use HRT and if so which preparation, will depend on the presenting symptoms together with the general health of the patient, family history of the patient, and patient preference.¹⁰

• Local delivery e.g. estradiol gel or oestrogen releasing ring, used for short periods of time, are particularly useful in the treatment of urogenital conditions such as atrophic vaginitis or urinary frequency. The use of topical oestrogens should be limited to the smallest possible amount to prevent symptoms, and their use should be reviewed annually with interruptions in treatment to assess the need for continued treatment. The safety of long term or repeated use of topical vaginal oestrogens is not yet known with any certainty, but if treatment is required over a long period of time endometrial hyperplasia may occur and consideration should be given to the use of concomitant progesterone.
• The progesterone releasing Mirena coil may be useful in the treatment of menorrhagia in the peri-menopause.
• Short term systemic therapy with oestrogen alone (if the uterus has been removed) or oestrogen and progesterone may be used to alleviate the vasomotor symptoms of the menopause.
• Systemic HRT may be used for the treatment of premature menopause caused by surgery, radiation, chemotherapy or primary ovarian failure. It should be continued until the time of the natural menopause i.e. approximate age 50 years.

This will depend on the woman's personal preference, and be influenced by other medical factors i.e current medication or medical conditions. If, after 3 months on a preparation, there are significant adverse effects, a switch (based on the advice below - Adverse Effects section) may be made to an alternative preparation.

• Women with a uterus need oestrogen and progestogen.
• Perimenopausal women usually take cyclical preparations which produce a monthly bleed. These are usually tablets or patches.
• Post-menopausal women i.e. at least 12 months after last menstrual period, also have the option of a no-bleed preparation - tibolone.
  • This is usually chosen on the basis of patient preference.
  • In addition to oestrogen/progestogen activity, it also has some weak androgenic activity.
  • It still has an increased risk of breast cancer, although it is lower than combined HRT preparations.
• Women without a uterus need only take oestrogen. This is available as tablets, patches (more expensive but wider range of doses), gel, nasal spray, implants and the 'menoring 50' vaginal ring.

Several recent trials have highlighted some of the risks of treatment with HRT and the evidence from these trials should be taken into account when considering the risk/benefit equation for any one individual woman.

• The Women’s Health Initiative (WHI) study^11,12,13 is an on-going trial on the effects of HRT in women aged 50-79. Although the trial was due to finish in 2005, the part of the trial that involved women taking a combination of oestrogen and progesterone was terminated in 2002, due to an apparent increase in the incidence of breast cancer, coronary heart disease, stroke and pulmonary embolism in women taking the combination treatment. Further analysis of the results has shown however, that there was no statistically significant increase in breast cancer, and that the apparent increase in cardiovascular morbidity was due to a transient fall in the placebo group rather than any increase in the treatment group.¹¹
• The WHI study looked at women who were on average 12 years post menopausal, and other randomised trials such as the HERS¹⁴ and ERAS¹⁵ trials have also excluded younger women and therefore the results cannot be applied to the general population of menopausal women. The trials to date are therefore unable to indicate whether or not treatment with oestrogen and progesterone therapy started at the onset of the menopause is effective for primary prevention of cardiovascular disease or other long-term consequences of sex steroid withdrawal.¹⁶
• HRT may be associated with a small increase in risk (in the order of one extra case per 1000 women per year) for breast cancer, if taken long term.¹⁷ Combined oestrogen-progestogen therapy probably carries a higher risk than that recorded for oestrogen alone. In women younger than 60, HRT (particularly oestrogen-alone) is safe. Discontinuation of HRT brings this risk back to the values for age-matched non-users after 3-5 years.
• Prevalence of stroke and thromboembolism strongly correlates with age; therefore, the impact of the HRT-related increased risk in this respect becomes more important in the late menopause. Low-dose oestrogen or the transdermal route of administration may lead to a more favourable risk profile.¹⁸

• Osteoporosis risk is lessened Fractures are a major cause of mortality and morbidity in the elderly, however for HRT to be effective, use must be life-long, and protection declines as soon as HRT is stopped. There are alternative, non-hormonal methods to protect bone mass available. These should include general measures including good calcium intake, regular exercise, stopping smoking and reducing alcohol consumption. Treatments include bisphosphonates, calcitonin and raloxifene.
• Decreased risk of colorectal cancer.¹¹This effect is seen only with combined HRT. Little is known of the effect of stopping the HRT.
• Oestrogen may have favourable metabolic and cardioprotective effects in healthy, young postmenopausal women.¹⁸ The results for the age group 50-59 years in the WHI oestrogen-alone arm support this claim. However recent Cochrane meta-analysis disputes this finding.¹⁹ Oestrogen slows the pace of development of atherosclerosis if started in the early postmenopausal period. Progestogens, combined with oestrogen, may decrease the positive oestrogen-related cardiac benefits.

• Pregnancy
• Active thrombophlebitis or thrombo-embolic disorders
• Liver disorders with abnormal function tests
• Dubin-Johnson and Rotor syndromes
• Undiagnosed vaginal bleeding
• Oestrogen dependent tumour.

If in doubt seek specialist advice. The following are NOT contra-indications to HRT:

• Migraine:
  • The risk of stroke according to the evidence is not increased, but HRT can exacerbate migraine.
  • Changes in type and dose of HRT may help, if exacerbated when HRT is started.²⁰
• Hypertension:
• Coronary heart disease (CHD):
  • In general it should not be started in women with active CHD, and it may be necessary to stop in a woman with a new CHD event.
  • However, for some women with severe menopausal symptoms, the benefits may outweigh the risks.
• Diabetes:
  • HRT may increase the risk of CHD.
  • However if it is used, a transdermal route is recommended as it has less impact on triglyceride levels.
• Asthma:
  • This is not worsened by HRT if pre-existing, but there may be increased risk of new diagnoses in HRT users.
• Endometriosis:
  • This may be theoretically reactivated by HRT.
  • The risk appears small, but specialist advice should be sought.
• Fibroids:
  • HRT may enlarge fibroids producing heavy, painful periods.
• Gallbladder and mild liver disease, or history of:
  • If HRT is necessary, a non-oral route should be used, usually trans-dermal.
  • Seek specialist advice.

• Assess menopausal state.
• Check for contra-indications and conditions requiring specialist advice, as above.
• Check current contraception. If peri-menopausal, HRT does not provide contraceptive cover. Do not combine HRT and combined oral contraceptive pill.
• Check risk factors for CHD and osteoporosis.
• Take body mass index and blood pressure readings.
• Examine breasts and/or pelvis if indicated by history.

• When HRT is stopped women should be encouraged not to stop abruptly.
• The dose should be gradually reduced over 2-3 months.
• This can be achieved by lower dosing or breaking the tablet in half/ cutting the patch in half or quarters.
• A lower dose could be introduced on one day for one week, then two days (spaced apart) for one week, then three for one week and so on.
• When the woman has a reduced amount for the whole week, then a dose could be omitted on one day, as per method for reduction, until no HRT is given. This should take 14 weeks.
• If the patient experiences problems at any particular stage, it may be that more than a week is required at that dose.
• Some women may need longer to reduce than others, and there should be flexibility to accommodate this.

• If HRT has just been started then 3 month review is advisable.
• All women should be reviewed annually.
• Breast and/or pelvic examination should be performed if clinically indicated.
• Adverse effects should be monitored and dealt with. See below.
• Blood pressure need not be monitored, but it is a useful opportunity for screening.

Adverse effects account for 35% of HRT withdrawal.