Prescribing and the menopause: Regimens for hormone replacement therapy

Introduction
The indications for hormone replacement therapy (HRT) at the menopause are the relief of distressing symptoms and protection against osteoporosis and cardiovascular disease in women at increased risk, especially those who have had a premature spontaneous or surgical menopause. The potential benefits also make it appropriate to discuss the option of HRT with most menopausal women. However, HRT is only part of the total care of the menopausal woman. Counselling regarding the benefits of exercise, appropriate diet and lifestyle modification is also important in promoting postmenopausal health.

Hormone replacement therapy
The aim of HRT is to provide levels of oestrogen equivalent to the premenopausal midfollicular range. This relieves symptoms, prevents bone loss and has a beneficial effect on lipid profile and the vasculature. Oestrogen is used in conjunction with a progestogen to prevent the development of endometrial hyperplasia.

Oestrogen therapy
Oestrogen therapy may be given orally, transdermally, transvaginally or by subcutaneous implant.

Oral oestrogen
This is the most widely used form of oestrogen. The average doses of 'natural' oestrogens for symptom relief and bone density maintenance are listed in Table 1. 'Natural' oestrogens are preferred as they are metabolised more rapidly and have fewer potential adverse effects on liver metabolism than the more potent synthetic oestrogens (ethinyloestradiol, mestranol). Therapy should be given daily - intermittent therapy does not reduce the risk of endometrial stimulation and may result in the recurrence of symptoms. There is little evidence to suggest one preparation offers greater benefit than another. However, there can be individual variation in the response to different preparations, and if one is ineffective or causes problems, an alternative oral therapy or a different route of administration can be considered. Older women some years past the menopause may be particularly sensitive to oestrogen and require a smaller dose to control symptoms. Therefore, commencing therapy with a small dose of the relatively weaker piperazine oestrone sulphate and increasing the dose over some months is suggested.

Transdermal oestrogen
Transdermal patches are available in 3 sizes designed to deliver 25, 50 or 100 micrograms of oestradiol daily for 3-4 days. They need to be applied twice weekly and can be worn while bathing. The average dose is 50 micrograms twice a week.

Short-term studies of patches have demonstrated effective symptom relief and maintenance of bone density. Longer-term studies on their bone and cardiovascular effects are in progress.

There are advantages to transdermal delivery as it rapidly provides physiological blood levels with less fluctuation than oral therapy and avoids first pass liver metabolism. The different patch sizes allow the dose to be adjusted according to the response. This can be monitored with blood levels, but the clinical response remains the best assessment of appropriate therapy. Although there is no evidence that HRT increases the risk of thromboembolic disease, transdermal oestradiol is preferred in patients with a history of thrombosis to avoid the potential adverse effects of higher oestrogen concentrations on liver clotting factors. Patch therapy with more constant hormone levels may better suit women with migraine triggered by hormone fluctuations.¹ At present, as patches are much more expensive than oral therapy, they should be reserved for use in women who have unrelieved symptoms (provided they are actually due to lack of oestrogen) or who have gastrointestinal adverse effects with oral therapy.

Although in the U.S.A. 40% of women prefer patch therapy, the reported incidence of skin rashes (5-20%), especially in warmer climates, may mean that it does not become as popular in Australia. Warmer climates may also alter the adhesiveness of the patch.

Oral progestogen therapy is still indicated in women with a uterus who use transdermal therapy. Combined oestrogen and progestogen patches are currently being assessed overseas.²

Table 1

Oral oestrogens

Subcutaneous implants
These are an effective way of providing long-term oestrogen therapy and avoiding first pass liver effects. The average dose is a 50 mg oestradiol pellet inserted every 6 months. Women after hysterectomy (who therefore require only oestrogen) may find this more convenient than taking tablets. Serum levels may occasionally become supraphysiological. Tachyphylaxis has been reported in a small number of women after prolonged implant therapy. A woman with a uterus still requires a monthly progestogen course. As the effect of an implant may last up to two years, the progestogen should be continued on a monthly basis, after the last implant insertion, until withdrawal bleeding ceases.

Vaginal oestrogen
This is appropriate therapy for a woman with isolated atrophic urogenital symptoms. It is available in creams (dienoestrol, conjugated equine oestrogen, oestriol) and tablets (oestradiol) and is used daily for two weeks and then 2-3 times a week. Symptoms may take some weeks to respond. Oestrogen is well absorbed vaginally and can potentially have systemic effects. It has once been reported to produce gynaecomastia in a male sexual partner. Although endometrial proliferation may not occur at recommended doses, it may be prudent in long-term users to use an intermittent (e.g. annual) progestogen challenge test. (Give 10 mg medroxyprogesterone acetate for 12 days to see if there is a withdrawal bleed indicating endometrial proliferation and therefore the need for cyclical progestogen.)

Unopposed oestrogen
Unopposed oestrogen therapy is recommended only for women after hysterectomy. In women with a uterus, it is associated with a 4-8x increased risk of endometrial carcinoma. This risk is negated by the use of monthly progestogen for 12 days. However, some women are totally unable to tolerate progestogen. If, after a full discussion of the risks, unopposed oestrogen is used, a yearly endometrial assessment (hysteroscopy and biopsy) should be performed. Endometrial resection cannot be used as an alternative to progestogen therapy. Although resection will greatly reduce the likelihood of withdrawal bleeding, microscopic patches of endometrium may be left which will respond to oestrogen therapy.

Progestogen therapy
Progestogens must be given in an adequate dose for at least 12 days a month to counteract the proliferative effect of oestrogen on the endometrium. A progestogen should also be used if there has been residual endometriosis after a pelvic clearance. Progestogens can produce adverse dose-dependent changes in lipoprotein levels as well as the adverse effects of mood change, abdominal bloating and weight gain.

Cyclical therapy
Medroxyprogesterone acetate 10 mg for 12-14 days per month (from the 1 st to the 12th day of the calendar month) is the standard recommended regimen. At this dose the drug has little effect on lipid profile or carbohydrate metabolism. Other useful and valid second line drugs are norethisterone, dydrogesterone and cyproterone acetate (see Table 2). Withdrawal bleeding occurs in the majority of women 2-3 days after cessation of progestogen.

Compliance with cyclical therapy may be enhanced by the use of the recently released combined pack of micronised oestradiol and norethisterone acetate tablets.

Continuous combined therapy
Daily oestrogen and progestogen is becoming increasingly popular as continuous progestogen in appropriate doses (see Table 2) will almost completely inhibit endometrial proliferation producing atrophy and amenorrhoea. Amenorrhoea makes this type of treatment attractive to most women, particularly those many years past the menopause. There is a significant incidence of irregular bleeding in the first 3-6 months of this regimen (especially in perimenopausal women), although 90% are amenorrhoeic by 12 months. Endometrial protection has been demonstrated by this regimen for up to about 8 years in some studies as has maintenance of bone density. Endometrial biopsy is suggested in women who bleed after having previously been amenorrhoeic on this regimen. As the long-term safety of this regimen is unknown, it cannot presently be recommended as standard therapy. It is an alternative if withdrawal bleeding cannot be tolerated or if there are adverse progestogenic effects. Similarly, the endometrial protection of progestogens given every 3 months rather than monthly is still being assessed.

The theoretical possibility of continuous progestogen altering blood lipids and negating the presumptive beneficial effect of oestrogen has not been demonstrated to be a problem presumably because a lower dose may be used.³,⁴

Table 2

Progestogens

Intrauterine administration
A new progestogen-containing lUD has been developed in Scandinavia. When available, it will provide an alternative option of a progestogen delivery system having only the desired local effect on the endometrium without systemic adverse effects while providing the additional effects of contraception and reduced menstrual loss.5

Testosterone therapy
Testosterone implants in a dose of 50 mg 6 monthly have been used as an adjunct to oestrogen therapy when there is a persistent problem with lack of libido. They have had beneficial results in limited clinical trials and may be particularly effective in younger women after a surgical menopause. With the above dose, serum levels remain within or just above the normal female range and do not cause hirsutism, voice changes or adverse lipid effects. This therapy is not universally accepted and psychosexual counselling may be more appropriate.

Problem management
Problems with HRT can be avoided by adequate pre-therapy counselling, but may be seen in up to 15% of patients. When HRT is prescribed, women should be warned of the 'physiological' effects of oestrogen including initial breast tenderness, increased vaginal discharge and probable heavy first withdrawal bleed, and be told that it may take up to 6 months to stabilise therapy.

Persistent menopausal symptoms - may respond to an increase in oestrogen dose, a different oestrogen preparation or a different route of delivery.

Persistent breast tenderness - may respond to a reduction in oestrogen dose, a different oestrogen preparation, a constant dose of a progestogen (i.e. continuous combined therapy) or possibly the addition of oil of evening primrose (up to 1 g 3 times daily).⁶

Heavy withdrawal bleeds - indicate excessive endometrial stimulation and require a reduction in oestrogen dose, an increase in progestogen dose or a change in type of progestogen preparation.

Bleeding during progestogen therapy - indicates inadequate endometrial protection and requires an increase in progestogen dose, a change of progestogen preparation or alteration to a twice daily dose.

No bleeding - not a problem as this means the endometrium is atrophic.

Irregular bleeding - must always be investigated to exclude endometrial pathology - hysteroscopy and biopsy are the most valid current assessments.

Intolerance of bleeding - consider continuous combined therapy, reduced frequency of cyclical progestogen or unopposed therapy in association with regular endometrial biopsy or, finally, endometrial resection.

Premenstrual symptoms during progestogen therapy occur in about 15 % of women. They may improve with a reduction in progestogen dose (not length of therapy), a change of progestogen preparation, the use of the lower and constant dose of progestogen in a continuous combined regimen or a reduced frequency of cyclical progestogen plus monitoring with yearly endometrial biopsy.

Contraception
HRT as described is not contraceptive. If there is no contraindication, a low dose oral contraceptive pill will provide hormone replacement, contraception and cycle control. It can be continued safely in non-smokers until about the age of 50. At this age, if menopausal symptoms persist off medication and FSH is elevated, HRT with natural oestrogens is indicated. If oral contraception is unacceptable, barrier methods of contraception are appropriate.

Duration of therapy
If therapy is instituted for control of symptoms, a period of 5 years and perhaps up to 10 years may be needed to prevent recurrence of symptoms after cessation of therapy. This should be withdrawn slowly to prevent a rebound of symptoms. The duration of therapy for the possible prevention of osteoporosis and cardiovascular disease needs to be long term (at least 10-20 years). It would seem logical to continue treatment long term if it is beneficial and devoid of adverse effects and the woman chooses to do so.

Contraindications
The list of relative and absolute contraindications to hormone therapy has contracted significantly as theoretical objections (based mainly on extrapolations of oral contraceptive experience) have been discounted. However, there are some remaining areas of doubt.

Oestrogen dependent cancer - e.g. endometrium and breast. In women with these tumours, individual assessment must be made in terms of expected survival and quality of life. In early stage disease, it may be that the prognosis is optimistic enough to be confident that HRT will not affect the outcome. Alternatively, a woman with advanced disease and severe menopausal symptoms may opt for quality rather than quantity of life after considering the options with her doctors.⁷

Thromboembolic disease - Recent spontaneous thromboembolism is a problem to be approached with great caution. However, there is convincing evidence that HRT does not cause thromboembolism and a past history of a DVT, etc. with predisposing factors (e.g. pregnancy) is not a contraindication, although non-oral oestrogen is recommended.

Other situations which require great care and cross specialty consultation are active liver disease and SLE.

There are some pre-existing conditions which may be aggravated by HRT, e.g. gall stones, fibroids and endometriosis, but, provided there is careful monitoring, these conditions are not contraindications to HRT. HRT is not contraindicated in women with a past history of myocardial infarction or with controlled hypertension. In fact, epidemiological data demonstrate a significant reduction in risk of cardiovascular disease in HRT users⁸, suggesting that HRT should be recommended as potentially beneficial to women with these problems.

When it is felt that the use of oestrogen is inadvisable, relief from hot flushes may be gained by the use of progestogens alone (10-30 mg medroxyprogesterone acetate). There is inconsistent evidence of the value of clonidine (75 micrograms twice daily), oil of evening primrose (1 g 3 times daily) or vitamin E (500-1000 IU daily).

Conclusion
The appropriate management of the menopausal woman comprises assessment of individual symptoms and risk factors, provision of information and tailoring of therapeutic regimens - thus enabling her to make an informed choice about her health care options.