British Mtdical BulUun (1992) Vol. 48, No. 2, pp. 426-^457 © The Britiih Council 1992

Management of the menopause M S Marsh 12 1 M I Whitehead

1 The Menopause Clinic, Academic Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, London, UK 2 The Wyrm Institute for Metabolic Research, London, UK

The management of the peri- or postmenopausal patient, whether symptomatic or asymptomatic, involves a careful assessment of the problems and expectations of each patient and the matching of appropriate treatment to their needs. The effects of the menopause and its treatment on the patient's immediate and long-term health must be taken into account. This may involve consideration of aspects of medical topics as diverse as gynaecological endocrinology, bone metabolism, oncology and cardiology. Although the benefits of oestrogen therapy are well established the response to therapy must be carefully monitored. Vigilance in the monitoring and seeking out of adverse effects both in individuals and populations must continue to ensure that any problems with this form of therapy are detected at the earliest possible stage.

Discussion with a patient about hormone replacement therapy (HRT) may arise from one of three situations: the patient may request treatment for troublesome symptoms; she may seek information about treatment because of particular concerns about the long term sequelae of ovarian failure; or she may request advice about the long term benefits and risks of HRT during a medical consultation for other matters. The proposed increase in numbers of 'Health Promotion' clinics that is outlined in die Government White Paper may lead to more and more women receiving HRT as a result of such 'opportunistic screening'. Certain approaches to management apply equally to all three categories of patient. However^ differences exist. For example, the symptomatic patient will be most concerned diat treatment will

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successfully relieve her symptoms. The patient seeking information about treatment because of long term health concerns (often precipitated by a family history of osteoporosis) will want to know whether these are or are not justified, and what screening techniques are available to confirm or refute her anxieties. The apparently fit and healthy asymptomatic woman without concerns wants to know whether HRT will or will not be of benefit to her. Whether patients are seen in the General Practitioner's surgery, a hospital outpatient setting or in a specialist menopause clinic the principles of management remain the same. As few patients will require specialist investigations, the place where they are seen is largely unimportant. The quality of the care and the interest of the physicians and other involved staff is paramount. The majority of this chapter outlines the management protocol that has been developed at King's College Hospital Menopause Clinic. We suspect that it is similar to that used in many menopause clinics that have evolved independently across the United Kingdom. PRE-TREATMENT ASSESSMENT In symptomatic women, the history alone usually establishes the diagnosis of oestrogen deficiency in the majority of patients; there is no substitute for an adequate history. The onset of hot flushes and night sweats, with or without symptoms of lower genital tract atrophy, which are associated with oligomenorrhoea or amenorrhoea in a woman over 40 years is virtually diagnostic of climacteric. Problems with diagnosis often arise, however, in two sets of circumstances. The first is in those women who incorrectly ascribe to 'the change' all manner of ills and complaints which, on direct enquiry, will often be found to have pre-dated the onset of the climacteric by many years. Thus, in all women accurate notes about the duration and intensity of the presenting symptoms must be taken not only to provide a baseline so that the effects of treatment can be assessed in the future but also to distinguish menopausal symptoms from those arising coincidently. In the second set of circumstances the patient may deliberately not volunteer symptoms (usually because of embarrassment) or the doctor and patient may misattribute uncommon oestrogen deficiency symptoms to other causes. Therefore direct enquiry is always vital to discover whether symptoms are present that the patient is reluctant to volunteer, for example those secondary to genital tract atrophy. Symptoms that are commonly misattributed

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include: sleep disturbances, mood disturbance, impairment of memory and concentration, and muscle and joint pains. A checklist of symptoms associated with oestrogen deficiency is given in Table 1. Detailed information about previous treatment, past psychological disturbance and possible contraindications to oestrogen treatment should be sought. Physical examination of the women at first presentation provides an opportunity for screening for coincidental thyroid disease and hypertension and other cardiovascular and respiratory diseases in addition to breast, abdominal and pelvic examination and the taking of a cervical smear, if appropriate. Indications for and types of special investigations Further investigation in most patients is not required. With regard to mammography, we adhere to the recommendations of the Forrest report. Mammography is recommended when the patient is over 50 years of age and has not had one for 3 years. We also offer mammography to younger high risk patients, such as those with a relevant family history, or those with a past history of relevant breast disease such as lobular or ductal hyperplasia or epitheliosis with atypia, whether or not HRT is prescribed. Ultrasound screening for ovarian cancer in those with a strong family history should be considered if the facility is available and, again, this advice is not influenced by the decision to use or withhold HRT. Table 1 Symptoms attributable to oestrogen deficiency Neuroendocrine

Hot flushes Night sweats Insomnia Mood changes Anxiety Irritability Loss of memory and concentration

Lower urogenital tract

Genital tract atrophy Dysparcunia Loss of libido Urethra! syndrome

Other

Joint aches Paraesthesia Dry skin Dry or brittle hair Brittle nails

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Women with a strong family history of ovarian cancer are at an increased risk for the disease.' Hormone profiles are seldom needed in patients with typical symptoms. They are of no value in predicting either the duration or the severity of symptoms and are seldom helpful for diagnosis as in most women this should be clear from the history alone. In women who are thought to be in the early stages of the climacteric the normal fluctuations of plasma FSH and oestradiol make interpretation of the results difficult. Hormone profiles may be helpful in the management of the patient with amenorrhoea but not typical oestrogen deficiency symptoms or in those women under 40 years of age who develop amenorrhoea and oestrogen deficiency symptoms. At least 2 and perhaps 3 sets of FSH and LH values are required to refute or support the diagnosis of premature menopause. Opinions differ on the criteria for offering lipid profiles. We offer a fasting lipid profile to the patient with a relevant family history (e.g. arterial disease in a first or second degree relative under the age of sixty years) or a past history of lipid abnormality or arterial disease. If abnormal, this provides a baseline to assess the effects of oestrogen and other (e.g. diet) treatments. Seldom will an abnormal result prevent use of HRT; indeed, hypercholesterolaemia and an elevation in the potentially atherogenic low density lipoprotein subfraction (LDL) will improve with treatment. However, hypertriglyceridaemia may worsen with oral oestrogen therapy and this route of administration is best avoided in patients with this condition; transdermal oestrogen causes triglyceride levels to fall or remain unchanged2 and is therefore the preferred method of oestrogen administration. Fibrinolytic/coagulation investigations include fibrinogen, assessment of platelet function and protein C, protein S and antithrombin III levels and may be indicated in women with a past history of deep vein thrombosis or pulmonary embolism. In such patients we believe it important to establish: whether the thrombosis was associated with an obvious precipitating factor, such as surgery or prolonged immobilisation; whether oestrogen was implicated (as with thrombosis in early pregnancy or in association with use of the combined oestrogen/progestogen contraceptive pill); how long the patient continued to menstruate after the thrombotic event; and whether the episodes were recurrent. We suspect that women who have had recurrent thrombotic episodes associated with early pregnancy or use of the combined pill are at

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greater risk of further thrombosis with use of HRT. It is stressed that the potency of the synthetic oestrogens, such as ethinyl oestradiol, which are used in the combined pill is much, much greater than the potencies of the natural oestrogens as used in HRT. 3 In women who have had one venous thrombosis following an obvious precipitating factor at a relatively young age (e.g. a deep venous thrombosis following immobilisation at age 25 years) and who continue to menstruate regularly until the late 40's, it makes no sense to us to withold HRT—especially via a non-oral route. The average daily plasma oestradiol values achieved during the reproductive era are higher than those achieved with transdermal administration of oestradiol in HRT. From an endocrine viewpoint, it is illogical to allow a woman to be exposed to her own normal ovarian function and then to withhold non-oral HRT. Liver function tests are required in patients with active or recent liver disease. The usual indications for endometrial biopsy apply. Thus, biopsy is indicated when the premenopausal/perimenopausal bleeding pattern has been irregular (e.g. intermenstrual or postcoital bleeding) or heavy, or if there is postmenopausal bleeding. Although approximately 2% of postmenopausal women who have not experienced abnormal bleeding will have endometrial hyperplasia, routine pre-treatment biopsy on all women is not deemed necessary if a combined sequential regimen of oestrogen and progestogen is to be prescribed. Pre-treatment endometrial abnormalities usually cause an abnormal bleeding pattern during the first few months of therapy and are thereby unmasked. An endometrial biopsy within the first three months of treatment is, however, deemed advisable if continuous combined treatment (in which the oestrogen and progestogen are both prescribed continuously, everyday) is to be used, as the bleeding pattern during the first 6 months with this form of HRT may not predict the endometrial status (see Ellerington, Whitcroft & Whitehead, this issue). The out-patient endometrial sampling technique preferred in this unit is Vabra suction curettage which, although uncomfortable for some patients, provides a specimen of tissue which our histologists consider adequate for reliable interpretation in most patients. The histology of specimens so obtained correlates well with those from D&C but both methods may miss endometrial polyps. Other histological sampling methods, such as the Pipelle, appear to produce comparable specimens to the Vabra in premenopausal women but the Pipelle has not been formally assessed in

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postmenopausal women taking HRT. The literature concerning cytological sampling methods suggests that the technique is only of value if the samples are examined by a cytologist with extensive experience in evaluating this type of specimen. Because of financial constraints bone density measurements are not currently routinely performed before treatment in our Clinic, nor are measurements advised routinely during HRT although, for reasons to be discussed, this policy is under review. A bone scan is, we believe, of immense value in asymptomatic women who are concerned about the risk of later osteoporotic fracture either because of a family history or because that patient possesses other risk factors for fracture and would take HRT if the bone density was shown to be significantly reduced. Table 2 lists the risk factors that are known to be associated with an increased risk of osteoporotic fracture. We consider premature loss of ovarian function, either natural or surgical, to be the most important. The limitations of these risk factors need to be explained. They have been derived from studies of populations and can be unreliable in the individual. For example, some groups have observed that only 40% of women with low bone density have been identified from such factors. At present, the otherwise asymptomatic woman with risk factors for osteoporosis has one of two choices: to take HRT (or another anti-resorptive, agent such as calcitonin) empirically or to try to obtain a bone density measurement. Because NHS resources are so limited this may mean going to the private sector. Hopefully this situation will improve as more NHS resources become available. The advisability of, performing serial measurements during HRT will be discussed below.

Table 2 Risk factors for osteoporosis Female sex All races except Afro-Caribbean Low body weight for height Early menopause Family history Sedentary lifestyle Alcohol abuse Cigarette smoking High caffeine intake? Other causes of bone loss (steroids, hyperthyroidism)

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The value of the clinic nurse The results of investigations must sometimes be awaited because an abnormal result might preclude the use of HRT (e.g. fibrinolytic/coagulation studies). However, in most patients once the initial assessment has been completed a full discussion of the possible causes of the patients symptoms can occur. Patient expectations of treatment should be sought and discussed, especially if they are unrealistic. For example, the woman with oestrogen deficiency flushes and sweats who also complains of chronic depression due to adverse social factors must be advised that the latter will not respond to HRT whereas the former will be improved. The possible methods of administering HRT should be explained and their benefits and risks should be outlined. Such discussion takes time and 30-45 minutes are often required. Many primary care physicians will consider this unrealistic. However, suitably trained nursing staff are an important part of the clinic team and can establish a rapport with the patient before and after the medical consultation. The nursing staff are able to reinforce medical advice. In patients taking regimens likely to reestablish vaginal bleeding the importance of recording when such bleeding occurs should be made clear and a bleeding chart can be given to the patient if she feels this will help her in recording the pattern of bleeding and the time of tablet taking. It is vital that at subsequent visits medical staff can establish the bleeding pattern and thereby the endometrial response to the added progestogen in sequential oestrogen/progestogen therapy. For some patients it is helpful if the medical or nursing staff mark bleeding charts to make the time of tablet taking clearer. An example of a bleeding chart is shown in Figure 1.

METHODS OF TREATMENT Explanation may be the only treatment required for some women with mild symptoms, who find that the reassurance that they are not psychiatrically disturbed and that their symptoms are part of a well-recognised syndrome sufficient. Not all women want to take HRT. They may reasonably adopt a conservative approach and wait to see whether their symptoms spontaneously resolve. We believe it is important to explain the long-term consequences of hormone deficiency to such patients, especially if there is a relevant family history of osteoporosis.

1 CHART INSTmiCTtOMS

§ 2

UlS lor menstruation

YEAfl MONTH

1 2

3

4

5

7

8

9

T for tablet Uken

t for spotting

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 28 27 28 2» 30 31

Menstruation Tablets Remarks Menstruation Tab Ms Remarks Menstruation Tablets Remarks Menstruation Tattoo Remarks Menstruation Tablets Remarks Menstruation Tablets Remarks

Fig. 1 Example of bleeding chart. Patients mark the days of tablet taking and bleeding.

o

2

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Patients who seek therapy mainly for the relief of symptoms should be informed of the long term effects of each of the treatments available and the method chosen should reflect both the short and the long term wishes of the patient. The method of treatment of the asymptomatic patient will be decided following an assessment by the patient of the information concerning long term risks and benefits provided by the medical staff. Non-hormonal treatments The treatment of hot flushes and other obviously climacteric symptoms using sedatives and hypnotics cannot be recommended but appears to be a widespread practice in the United Kingdom.4'5 There are no placebo controlled studies showing that such treatments effectively relieve hot flushes, night sweats or vaginal dryness but they may have a role in the management of co-existing psychiatric disease. In those patients with climacteric symptoms who also complain of psychological difficulties (e.g. anxiety, irritability, loss of self confidence and depressed mood) we believe it is wise to withhold psychoactive drugs until an adequate trial of HRT has been completed. By this we mean a 3 month course of HRT with monitoring of the response. Endogenous depression and other long term psychiatric illness which pre-dated the onset of the climacteric are, in our experience, unlikely to respond to oestrogen therapy. Clonidine (Dixarit®: Boehringer Ingleheim) is the most extensively investigated non-hormonal treatment used for hot flushes. Although the placebo response may be significant in climacteric women6'7 clonidine has been shown to be better than placebo in four studies6"9 and of equal effect in a fifth.10 Two studies have demonstrated that clonidine is inferior to oestrogen in relief of vasomotor symptoms.9'11 Vaginal dryness may be improved by lubricant jellies although many patients complain that these only have a short effective life during intercourse. The use of non-hormonal treatments for osteoporosis is discussed elsewhere in this issue (Compston, this issue). The use of progestogens alone Progestogens are effective in the treatment of hot flushes and an efficacy better than placebo has been noted using oral norethis-

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terone, 10 mg/day12 and 5 mg/day,13 intramuscular or oral medroxyprogesterone acetate14'15 and oral megestrol acetate.16 There is no consistent evidence of an effect of progestogens on other symptoms of the menopause, nor of significant metabolism to oestrogenic substances. Some data suggest that certain progestogens (e.g. norethisterone 5-10 mg/day) may preserve bone density and they may be a suitable treatment for the patient who needs relief from flushes, who is concerned about bone preservation and in whom oestrogens are contraindicated.

Oestrogen therapy Routes of administration

Exogenous oestrogens can be prescribed orally or parenterally. Currently available parenteral methods of delivery include transdermal patches, vaginal creams or pessaries and subcutaneous implantation. The ability of any of these methods to relieve symptoms and to preserve bone is dependent on the plasma levels achieved and is not specifically related to the route of administration. It is possible to compare the relative potencies of the different oestrogens which are available and the different methods of delivery using a variety of endpoints including effects on the endometrium, liver protein induction, affinity for the oestrogen receptor and the ability to conserve bone density. These aspects are dealt with in more detail in other chapters. In clinical practice the maintenance dose for symptomatic relief is dependent upon the nature of the symptom. This is low with symptoms of lower genital tract atrophy; indeed, many manufacturers recommend use of vaginal creams/pessaries/ tablets only twice a week after a loading dose has been administered (see below). Such low doses, on our current understanding, do not conserve bone mass. To relieve flushes, sweats and psychological symptoms effectively oestrogens have to be given every day and certain doses will also preserve bone density (see Compston, this issue). Suitable doses of oestradiol are: 2 mg/day orally (Progynova®: Schering); 50 ugm/day transdermally (Estraderm®: Ciba Geigy); 50 mg every six months by implant (Organon) and conjugated equine oestrogens (Premarin®: Wyeth-Ayerst) 0.625 mg day. The pharmacokinetics, pharmacodynamics and metabolic consequences of these and other methods of treatment are dis-

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cussed elsewhere (see Ellerington, Whitcroft & Whitehead, this issue) and will not be discussed further here. The oral route of administration is the commonest method of giving oestrogens to postmenopausal women in the United Kingdom and a variety of preparations are available both alone (Table 3) and in combination with progestogen in a calendar pack (Table 4). Oestradiol transdermal therapeutic systems (TTS)—more usually called patches (Estraderm®, Ciba-Geigy, Horsham)—contain 17-P oestradiol dissolved in alcohol within a thin, clear, circular multilayered patch with an outer impermeable membrane. After 3-4 days most of the alcohol in the patch has been absorbed and thereafter oestradiol absorption becomes irregular so the patch must be changed twice a week. This method of parenteral administration of oestrogen seems to be well tolerated.17 The most troublesome problem is of skin reactions which lead to discontinuation of this method in approximately 5% of patients. Some women develop minor skin irritation which in most cases can be overcome by changing the site of the patch on a daily basis. The patches generally stay in place during baths or showers but some women find that the patches regularly come adrift in water; these patients are advised to remove the patch prior to bathing, to replace it onto its plastic backing to avoid alcohol evaporation and to reapply it later on a fresh area of well dried skin after bathing. Table 3 Oral 'natural' oestrogens suitable for Hormone Replacement Therapy currently available in the UK Product

Generic composition

Dose mg/day

Harmogen® (Abbott) Hormonin® (Shire)

piperazine oestrone sulphate oestriol

1.5 mg 0.27 mg

oestrone

1.4 mg

oestradiol

0.6 mg

Prcmarin® (Wyeth-Ayerst)

conjugated equine oestrogens

0.625 mg or 1.25 mg or 2.5 mg

Progynova® (Schering)

oestradiol valerate

1 mg or 2mg

Climaval® (Sandoz)

ocstradiol valerate

1 mg or 2mg

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Table 4 Combination calendar packs of Hormone Replacement Therapy Product

Generic composition

Cycloprogynova® 1 mg

oestradiol valerate 1 mg/day (21 days) levonorgestrel 0.25 mg/day (10 days)

2mg

oestradiol valerate 2 mg/day (21 days) levonorgcstrel 0.5 mg/day (10 days)

Estrapak*

oestradiol 50 ug/day (28 days-8 patches) norethisterone acetate 1 mg/day (12 days)

Prempak-C*

0.625 mg conjugated equine oestrogens 0.625 mg/day (28 days) norgestrel 0.15 mg/day (12 days) 1.25 mg

conjugated equine oestrogens 1.25 mg/day (28 days) norgestrel 0.15 mg/day (12 days)

Trisequens®

oestradiol 2 mg/day + oestriol 1 mg/day (22 days) norethisterone acetate 1 mg/day (10 days) oestradiol 1 mg/day + oestriol 0.5 mg/day (6 days)

Trisequens Forte®

oestradiol 4 mg/day + oestriol 2 mg/day (22 days) norethisterone acetate 1 mg/day (10 days) oestradiol 1 mg/day + oestriol 0.5 mg/day (6 days)

A transdermal method of delivery for progestogen (which is likely to become available in the near future) seems to be well tolerated18 and is discussed elsewhere (see Ellerington, Whitcroft & Whitehead, this issue). Particular advantages and disadvantages of oral and transdermal oestrogen administration are shown in Table 5. Both are easy to administer and can be stopped quickly should side-effects occur. Neither can guarantee compliance. Vaginal oestrogen creams are used for the treatment of vaginal dryness and atrophic vaginitis and traditionally it was thought that the effect was mainly local. However, the use of the manufacturers' recommended dose of conjugated oestrogen cream (1.25 mg/day), everyday, will produce plasma levels of oestradiol and oestrone that are similar to the same dose given orally.19 Much lower doses (0.1 mg/day) do not cause a detectable rise in plasma oestrogen levels but will produce beneficial changes in the vaginal epithelium.20 There are reports that vaginal administration

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Table 5 Advantages and disadvantages of oral versus transdermal oestrogens Transdermal

Oral

Disadvantages Skin reaction

Gastric side effects

Poor adhesion

First pass effect (higher dose required) Unphysiological

Advantages Constant rate of delivery

No external evidence of treatment

Twice weekly administration Physiological?

of small doses of oestradiol suppresses FSH and LH levels; this suggests systemic absorption but the degree is not known. Oestriol, as used in Ovestin® cream (Organon) is not protein bound and has a short half life in plasma because it is rapidly excreted by the kidneys. Thus, it is of low potency. Absorption of oestrogen through an atrophic vaginal epithelium is poor. Therefore three to four weeks of daily local oestrogen therapy is recommended when therapy is commenced to mature the epithelium, after which only a small dose once or twice a week is needed to maintain a beneficial effect.21 There is no evidence that either intermittent vaginal oestradiol or oestriol has a bone conserving effect. Crystalline implants containing 17-f3 oestradiol in a cholesterol base are available in 25, 50 and 100 mg sizes. They are inserted into the subcutaneous fat of the abdominal wall or buttock under local anaesthetic, a procedure that causes little, if any, discomfort and that takes approximately 5 minutes. The standard dose for HRT is a 50 mg implant repeated every six months. This appears to preserve bone mass (see Compston, this issue), produce favourable changes in the lipid and lipoprotein fractions (see Meade, this issue) and relieve menopausal symptoms. Unlike all other methods of delivering oestrogens, implant therapy guarantees compliance. The plasma levels of oestradiol achieved with standard doses of implant treatment are generally higher than those with transdermal and oral administration. This is of unknown significance. With implants the rate of absorption appears exponential, being greatest initially. As the oestradiol levels begin to fall some patients experience a recurrence of symptoms even though their oestradiol levels are within the therapeutic range. This can lead to patients requesting further implantation at ever decreasing intervals.

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Under these circumstances we advise that the time between implants should not be reduced otherwise plasma oestradiol values rise and 'tachyphylaxis' may develop.22 This is a situation in which oestrogen deficiency symptoms and possibly those of oestrogen overdosage are present with oestrogen levels in and often above the therapeutic range. The effects on humans of supraphysiological levels of oestrogen are unknown. We believe that in the patient who has developed tachyphylaxis the vicious circle has to be broken and further implantation should be withheld. This may cause significant symptoms (flushes, sweats, depressed mood etc) and smaller doses of oestrogen administered either transdermally or orally may be given to provide partial symptomatic relief as the oestradiol levels are falling. However, we stress that this is only our suggestion because there are no data on long term management of patients with tachyphylaxis. After the plasma levels have fallen we believe implant treatment should be used again with caution and alternative methods of delivering oestrogen should be considered. If implant therapy is used again in these women then it would seem wise to measure the serum oestradiol levels every 6-9 months. Concern has recently developed about the long lasting effects of oestradiol implants on the endometrium after implant therapy has been withdrawn. The duration of endometrial stimulation after the last implantation can be prolonged, up to 43 months,23 and oestradiol levels may remain above the normal postmenopausal range over this time (see Fig. 2). Therefore, cyclical progestogens should be given not for a denned time but until withdrawal bleeding has not occurred for 3 consecutive months. Side effects of oestrogens The side effects attributable to oestrogens are few. The commonest symptoms are very similar to those of early pregnancy, a time when oestrogen levels are rising, and include breast tenderness, nipple sensitivity and nausea. It is common for women to experience breast tenderness at the start of treatment but this is usually transient and resolves within 6-8 weeks. It is commoner and usually more severe in patients who are starting treatment several years post menopause. Therefore, it seems prudent to start these women on a low dose of oestrogen, for example transdermal oestradiol, 25 ngm/day or conjugated equine oestrogens, 0.625 mg every second day. The

440

a E a. o

E o to

E

HORMONE REPLACEMENT THERAPY 2000" 18001600 ' 1400" 1200" 1000"

-- Pottmenopausal range (< IBB pmol/l)

800"

600400" 200" 0 5

10 15 20 25 30 Months since last implant

35

40

Fig. 2 Plasma oestradiol levels in 3 women at time of last implant and during observation period without oestrogen treatment (Adapted from: Ganger K, et al., 1990.23).

dosage may be increased after 1-2 months to suitable maintenance regimens. In approximately 4% of women taking oral therapy and in 2% of those using transdermal oestrogens epigastric discomfort appears transiently at the start of treatment. In a small proportion of these patients, usually those taking oral therapy, it may continue; a change to parenteral administration usually solves the problem. If either breast tenderness or epigastric discomfort persist for more than 3 months overdosage of oestrogen must be suspected. The dosage should be reduced and the symptoms reassessed after 3 months. Certain women appear to have a predisposition to oestrogenic side effects, for example those with a long history of intermittent breast tenderness during the reproductive era or those who experienced severe nausea in pregnancy. Oestrogen and progestogen therapy The need for progestogen addition

The only well-substantiated reason for adding progestogen to the oestrogen in HRT is to protect the endometrium from the development of hyperplasia and carcinoma. This protective effect should not be extrapolated to the breast. The data on the effects of progestogen addition to the oestrogen on breast cancer axe inconsistent and we do not give combined oestrogen/progestogen

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therapy to women who have undergone hysterectomy. They receive oestrogen alone. In non-hysterectomised women cyclical unopposed oestrogen therapy, in which oestrogens are given without a progestogen for 3 weeks in every 4, is associated with a high incidence of breakthrough bleeding and increases the risk of cystic glandular and atypical hyperplasia,24 and carcinoma.25 Neither the presence, pattern or absence of withdrawal bleeding is a guide to the endometrial status and therefore an annual endometrial biopsy has been advocated. An increased risk of endometrial carcinoma can continue for a long time after such therapy has been stopped. The risk of carcinoma is increased for 12 years after as short an exposure to cyclical therapy as 12 months;26 in patients who took cyclical therapy for 3 years a relative risk of 8.8 has been reported during a 14 year period of follow up 27 {see Vessey et al., this volume). There is no published information concerning the management of patients after cyclical treatment has been stopped; annual endometrial biopsy or 'progestogen challenge' testing are two possible strategies. Progestogens: types, dose, timing and duration of administration

The addition of a progestogen sequentially protects the endometrium against hyperplasia and carcinoma,28 and the duration of progestogen treatment each month is as important as the dose. Several authors have reported an incidence of zero with 12 or more days of progestogen addition29-30 and this could therefore be considered the optimum duration of progestogen addition each month. The progestogens commonly available are either derived from progesterone and are C21 steroids—dydrogesterone (Duphaston®: Duphar), medroxyprogesterone acetate (Provera®: Upjohn)—or are C19 derivatives of nortestosterone (norethisterone, levonorgestrel). Natural progesterone has also been used although its short oral half-life means that satisfactory serum levels can only be achieved with once daily administration when given as a suppository per vaginum or per rectum. The treatment schedules which are commonly used for HRT differ somewhat between the United States and Europe. In the United States the oestrogen is usually administered for 25 days each month. In the United Kingdom the oestrogen, irrespective of the route of administration, is generally given continuously and a progestogen is added for 10-12 days each cycle. The commercial

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'combined packs' use oestrogen for 28 days (Prempak-C®, Estrapak®, Trisequens®) or for 21 days (Cyclo-progynova®) (see Table 4). In treatment regimens which are 'made up' by the physician and in which the oestrogen and progestogen are prescribed separately, the oestrogen is usually prescribed continuously with the progestogen added for the first 12 days of each calendar month. This makes it easy for the patient to remember to take her tablets and for her to remember the day of onset of the withdrawal bleeding. In the perimenopausal women it is advisable to time the addition of progestogen to produce a withdrawal bleed in phase with the existing menstrual cycle. The woman who develops hot flushes at age 45 whilst still menstruating regularly, but with a cycle length other than 28 days, will often develop irregular bleeding if instructed to take the progestogenic phase of her sequential therapy for the first twelve days of each month, or if a 28 day cycle, as in a combination pack (see Table 4), is adhered to. In this situation we advise the patient to time addition of the progestogen so that the last progestogen tablet is taken the day before the first day of the next, anticipated period. Thus, with a 21 day menstrual cycle the progestogen is taken from day 9 through to day 20: with a 45 day cycle the progestogen is added from day 33 to day 44. Failure to co-ordinate endogenous and exogenous oestrogen and progestogen in perimenopausal women increases the risk of breakthrough bleeding requiring endometrial sampling. Unnecessary and unhelpful manipulations of the dose and type of progestogen and oestrogen may occur. Intermittent endogenous production of oestrogens may continue for many years after the appearance of oestrogen deficiency symptoms. There is a wide interpatient variation in the endometrial response to the different progestogens. Routine endometrial biopsy can be avoided, however, because the timing of the onset of the withdrawal bleeding, in relation to the progestogen phase of treatment, appears to predict the endometrial status. Our current understanding is that in biopsies obtained at the end of the phase of progestogen addition, proliferative endometrium (which indicates a lack of progestational effect) is more likely to develop into hyperplasia or carcinoma whilst secretory endometrium is less likely to do so. Studies of the bleeding patterns in women taking oral oestrogen in sequential regimens with 12 days of progestogen have shown that bleeding that starts on day 11 or later is invariably associated with secretory changes.31 With transder-

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mal oestradiol withdrawal bleeding starting around day 9 of the phase of progestogen addition is associated with secretory endometrium.32 Bleeding starting earlier during the progestogen phase is associated with proliferative endometrium. Further studies are required to determine whether a similar relationship applies with oestradiol implants. The doses of the commonly used progestogens, when added for 12 days each calendar month to oral and transdermal oestrogens, that are required for secretory transformation are shown in Table 6. Comprehensive dose ranging studies have not been performed when progestogens are added to oestradiol implants but norethisterone acetate 2.5 mg-5 mg/day appears to cause secretory transformation in the majority of patients. Side effects of progestogens

The side effects of the added progestogen are the most troublesome problems in the management of patients using HRT. In our experience they are the commonest reason for poor compliance with treatment. Breast tenderness, bloatedness, nausea, oedema and abdominal cramps are common physical symptoms that may be experienced during the progestogen phase of treatment. Psychological complaints include depression, anxiety and irritability and are often very similar or identical to the symptoms of the pre-menstrual syndrome. Some patients partially overcome these problems by taking the progestogen in divided daily doses or last thing at night; others may benefit from a change from one type of progestogen to another, e.g. from a C-19 to a C-21 derivative or vice versa. It is impossible to predict the response of an individual patient to each progestogen. In general, the C-19 nortestosterone derivatives seem to be associated with more androgenic effects such as greasy skin and hair, whilst the C-21 derivatives tend to cause psychological complaints. Rectal or vaginal progesterone has not been extensively researched when used for addition in HRT. In our experience it Table 6 Daily doses of various progestogens to be taken for twelve days per month in patients receiving oral or transdermal oestrogens Medroxyprogesterone acetate

10 mg/day

Norethisterone acetate

0.7-2.5 mg/day

Norgestrel

150 (ig/day

Dydrogestcrone

10-20 mg/day

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causes drowsiness in some women but this is generally avoided as the suppository is usually inserted once daily in the late evening. Only a minority of patients are intolerant of all forms of progestogen. In such women the management options available are to stop HRT, to give unopposed oestrogen therapy and perform annual endometrial biopsies or, in rare cases, to perform hysterectomy and then give oestrogens alone. Tibolone (Livial®: Organon) can be tried. In our limited experience this preparation can cause chronic 'PMT' in patients who are progestogen sensitive. This may be due to the progestogenic activity of the tibolone molecule. Combination Oestrogen/Progestogen packs

A variety of combination packs incorporating sequential regimens of HRT are available (Table 4). With Trisequens® and Cycloprogynova® the progestogen is incorporated with the oestrogen in a single tablet and thus the progestogen cannot be avoided. With Estrapak® and Prempak-C® the progestogen tablet is separate from the oestrogen. For various reasons some of these combination packs may not be ideal. Cyclo-Progynova® incorporates only 21 days of oestradiol in the 28 day cycle of treatment; symptoms may reappear during the 7 days off oestrogen. Cyclo-Progynova® 1 mg is unlikely to preserve bone in most women: if bone conservation is required then Cyclo-Progynova® 2 mg should be prescribed. With both doses of Cyclo-Progynova® the progestogen phase is of only 10 days duration. It is doubtful whether the addition of oestriol that is incorporated in Trisequens® confers any advantages; the progestogen phase in this regimen is also of 10 days duration. However, the combination packs have played a major role in the treatment of postmenopausal women because, generally speaking, they are well tolerated, easy to prescribe and easy for patients to comprehend. Separate prescribing of oestrogens and progestogens, as discussed above, allows a more flexible approach when tailoring treatment to individual patient requirements and is of particular value in the perimenopausal woman or when the progestogen component needs to be changed because of unacceptable side effects. The use of continuous/combined regimens of oestrogens and progestogens and the use of the drug Livial® are discussed elsewhere in this issue and will not be described further here.

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Androgen therapy

Testosterone implants are available in 100 mg doses and are inserted in the same manner as oestradiol implants. The two forms of hormone implant may be inserted together into the same site. Several studies have demonstrated that libido in postmenopausal women is improved by oestrogen therapy alone.33'34'35 The addition of testosterone may,36'37 or may not,33 confer additional benefits and the literature is contradictory. In our experience, some women who are still fond of their partner and whose interest in the sexual relationship has not been improved by oestrogens derive benefit from testosterone addition. The latter also appears to increase levels of energy, drive and general enthusiasm for life. In theory, testosterone implants may cause androgenic side effects such as hirsutism and deepening of the voice. We usually use 50 mg (a 100 mg implant cut in half) every 6-9 months. Hirsutism occurs very infrequently and is reversible if no further testosterone implants are inserted. We have not encountered voice change. FOLLOW-UP ASSESSMENTS In most cases the patient should be assessed again after 3 months of treatment. Maximum benefits may not occur until then and oestrogenic side-effects such as breast tenderness and nausea should have resolved and a regular, interpretable, pattern of bleeding should have been established. At this and subsequent visits the blood pressure should be taken, the bleeding pattern noted and any difficulties with treatment discussed. It is particularly important to ascertain to what extent the presenting symptoms which were due to oestrogen deficiency have been relieved, and whether side-effects due to the added progestogen have appeared. Inadequate control of symptoms Inadequate control of menopausal symptoms after 3 months of use of standard oestrogen dosages such as conjugated equine oestrogens 0.625 mg/day or transdermal oestradiol 50 |ig requires an increase in dosage: usually this is doubled. Some patients appear to absorb oral oestrogens from the gastrointestinal tract (GIT) poorly. In our experience, this is more likely with GIT disease (such as Crohn's) especially if partial small bowel resection has occurred. Thus, in patients receiving what would be considered a

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more than adequate dose of oral therapy (conjugated equine oestrogens 1.25 mg/day; oestradiol valerate 2-4 mg/day) who have derived minimal symptomatic relief then measurement of the serum oestrogen levels will indicate the degree of absorption. A change to a parenteral form of oestrogen administration such as patches or implants is indicated if serum levels of oestradiol are below the lower limit of the therapeutic range (200 pmol/1) despite the administration of higher than average oral dosages. In some women taking once daily oral oestrogen therapy, oestrogen deficiency symptoms (particularly flushes and sweats) recur approximately 18-20 hours after tablet ingestion. This may be due to a decline in oestrogen levels between tablet taking. It may be solved by taking small doses of oestrogens more frequently, i.e. conjugated equine oestrogens 0.625 mg morning and evening rather than conjugated oestrogens 1.25 mg as a single dose. Some women using transdermal oestrogens complain that the patches adhere poorly. Lack of contact between the skin and the semi-permeable membrane through which the oestrogen passes will compromise delivery not only directly but also because the alcohol, which is needed for oestradiol delivery, may have evaporated before the patch is due to be changed. This appears to occur more frequently with use of the 100 (ig/day patch which is oblong. Using two smaller 50 ng/day patches, which are circular, may improve adherence and absorption. In some patients the smaller, circular patches appear to adhere better. Abnormal bleeding on oestrogen/progestogen HRT The causes for irregular, incorrectly timed or heavy bleeding are shown in Table 7. As illustrated, there are 4 major groups. If the bleeding episode is isolated and obviously associated with missed treatment or intestinal hurry due to antibiotic therapy or gastroenteritis then, in our opinion, no further action need be taken except to advise the patient to make contact immediately should further unscheduled bleeding occur. Investigation may then become necessary. Failure to coordinate exogenous with endogenous hormones in perimenopausal women taking sequential therapy has been discussed. An alteration in the timing of the progestogen phase of treatment will usually stop the unscheduled bleeding. With sequential therapy a pattern of bleeding that is regular but that starts before the 11th day of progestogen addition when

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Table 7 Causes of irregular or incorrectly timed withdrawal bleeding in women taking sequential hormone replacement therapy Failure of compliance

Missed oestrogen or progestogen tablets Failure to change the patch at the appropriate time

Failure of absorption

Intestinal hurry (patch or oral therapy) - gastroenteritis - antibiotic administration - inflammatory bowel disease - malabsorption syndromes Poor patch adherence

Failure to synchronise exogenous with endogenous hormones Pelvic causes

Fibroids (especially fibroid polps) Endometrial abnormalities - polyps - proliferative endometrium - cystic hyperplasia - adenomatous/atypical hyperplasia - adenocarcinoma other gynaecological pathology - ovarian tumours - cervical or vulval lesions

oral oestrogens are used (9th day with transdermal oestrogens) indicates that an increased dose of progestogen is needed. It is stressed that it may take three months to establish a regular bleeding pattern when therapy is started and due allowance must be made for this. If, after 6-9 months of treatment the bleeding is still occurring early then an endometrial biopsy is probably not required although there are no published data to support this recommendation. More prolonged periods of incorrectly timed withdrawal bleeding require endometrial assessment using the methods outlined above. The increase in the dose of progestogen required to produce a correctly timed withdrawal bleed often need not be large, for example 12 days per calendar month of 0.7 mg/day of norethisterone acetate—2 Micronor® (Ortho-Cilag) or Noriday® (Schering) tablets—often need only be increased to 12 days of 1.05 mg/ day (3 Micronor® or Noriday®). The daily dose of medroxyprogesterone acetate could be increased from 10 mg to 15 mg. Uncommonly, however, much higher doses are required and we have patients taking oral or transdermal oestrogens who require 2.5 mg/ day or 5 mg/day of norethisterone acetate to achieve a satisfactory bleeding pattern. These higher doses of norethisterone acetate may be required routinely with implant therapy because the latter may achieve higher plasma oestradiol values. If the bleeding pat-

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tern fails to respond to an increase in the progestogen dose then an endometnal assessment must be considered. Endometrial or fibroid polyps are often missed at outpatient endometrial sampling and at D&C. Hysteroscopy should be considered in patients who have had a negative endometrial aspiration and/or a D&C and who persistently bleed at an inappropriate time despite hormonal manipulation. Patients should be seen every 3-4 months until a satisfactory bleeding pattern is established or a cause for the inappropriate bleeding has been identified and treated. Side-effects that can be attributed to the progestogen phase of treatment may be relieved by changing to a different progestogen at an appropriate dosage (see above and Table 6). The management of patients who are intolerant of all progestational agents has already been referred to. Surveillance on treatment The timing of subsequent visits depends on whether or not the patient is continuing to experience difficulties with treatment. In the majority of women no significant problems will have occurred and the next visit can be 6 months later and yearly thereafter. In the patient without relevant risk factors the blood pressure should be recorded at each visit; in accord with the Forrest recommendations mammograms should be offered (if available) every 3 years in low risk women between 50 and 65 years of age and cervical smears should be performed every 3 years. Our current understanding is that HRT does not increase the risk of cervical cancer and the frequency of smears is not influenced by the use of HRT. Our usual practice is to perform breast and pelvic examinations every 12-18 months. However, this practice has arisen largely from 'tradition' and is not based upon extensive research aimed at defining the optimal time for such examinations. Nevertheless, we continue this policy because advancing age increases the risk of breast cancer (independent of the use of HRT), and because the incidence of certain gynaecological cancers (endometrial and ovarian) is increased in the age range 45-65 years (again, independent of HRT). Furthermore, in an increasingly litigious environment the prescribing physician may be wise to adopt practices of unknown clinical value for medico-legal defence. The association between use of HRT and breast cancer is beyond the scope of this chapter.

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If the bleeding pattern is satisfactory we do not perform an endometrial biopsy. At present, bone density measurements are not routinely advised at follow up. However, we have always thought these of value in the patient known to have a low bone density who is taking HRT solely for bone conservation, and in those women who have been on bone conserving doses of HRT (for symptomatic relief) and are contemplating stopping HRT because their symptoms have diminished. This policy is under review. In a 3 year prospective, controlled study (performed in collaboration with the Wynn Institute for Metabolic Research, London) of 66 women taking HRT, we have observed significant loss of bone density in the spine in 5% of women and in the proximal femur in 15% of women. All HRT treated women were taking doses of oestrogens previously thought to be effective bone conservers in all women. In the 'non-responders' the failure of response was not due to poor compliance. If these results are confirmed by other groups then a reevaluation of the minimum effective oestrogen doses for bone conservation may be required. However, it is not clear whether increasing the oestrogen dose will reduce the incidence of 'nonresponse'. COMPLIANCE Compliance is an extremely important aspect of the management of any patient using any form of drug therapy. Failure to take HRT correctly (particularly the progestogen) may cause endometrial hyperstimulation and eventually carcinoma. For this reason the potential dangers of unopposed oestrogen therapy in nonhysterectomised women must be explained and must be understood by the patient. Follow-up visits provide an opportunity to ensure that the treatment is being taken correctly; a change from separate prescribing of the oestrogen and progestogen to commercially available packaged sequential regimens may facilitate compliance for the patient who has difficulties using separate prescribing. The importance of careful recording of the bleeding pattern in sequential regimens must be emphasised and the reporting of any untoward side-effects should be encouraged. If the patient can contact medical or nursing staff directly involved in her treatment by telephone whenever problems arise and receive informed advice concerning her difficulties then com-

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pliance is enhanced; unnecessary visits to the clinic and to other health care workers are reduced and the most appropriate method of treatment is found more quickly, safely and efficiently. CONTRA-INDICATIONS TO OESTROGEN TREATMENT Absolute contra-indications to oestrogen therapy are few but abnormal vaginal bleeding of unknown cause, pregnancy, and endometrial and breast cancer would be included by most workers. There are very few published data on the effects of HRT in women who have breast cancer. Because the required studies have not been performed it is not known whether HRT does or does not increase the risk of recurrence. Thus, a cautious approach has to be recommended. The symptoms of oestrogen deficiency may be so severe that quality of life is reduced and if non-hormonal therapies have proved ineffective then HRT may have to be considered. Identical comments apply to endometrial cancer. Otosclerosis is a rare cause of hearing impairment: classically the hearing deteriorates during pregnancy. We have observed the hearing deteriorate rapidly in two women given HRT: however, other workers have not observed hearing loss in women with this condition given HRT. Relative contra-indications are listed in Table 8. For most women these conditions are seldom reasons for withholding oestrogen treatment. In many cases the decision to start treatment is made by the patient once all the known risks are discussed. There are many reports that sequential oestrogen/progestogen therapy reverses cases of cystic hyperplasia to normal proliferative endometrium.38"40 Some cases of adenomatous and atypical hyperplasia respond likewise but others do not. 3941 Therefore, such a treatment regimen may be used in patients with pre-existing hyperplasia but further histological assessment of the endoTable 8 Relative contraindications to oestrogen therapy Previous endometrial hyperplasia Previous myocardial infarction or stroke Previous venous thromboembolic disease Hypertension Active liver disease Gallstones Endometriosis Fibroids

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metrium after 3—6 months is advised. Severe forms of atypical hyperplasia are a strong indication for hysterectomy because the risk of the later development of endometrial carcinoma, independent of the use of HRT, may be as high as 30-50%. Currently, the relationships between arterial and venous thrombotic disease and HRT are controversial. We believe that the inclusion of certain precautions in Data Sheets for HRT preparations is difficult to justify and appears to be based upon experience with the combined oestrogen/progestogen contraceptive pill. We have already commented upon the differences in potency between the synthetic oestrogens as used in the 'pill' and those of natural oestrogens as used in HRT. The dilemma facing the prescribing physician has been increased by reports that HRT (mainly conjugated equine oestrogens given cyclically without a progestogen) reduces the risk of coronary heart disease (CHD) in women generally considered to be at high risk of CHD. Such groups include the obese, those with hypertension and those with high cholesterol levels. There are three reports that unopposed HRT is beneficial in women with angiographically proven coronary artery disease. Thus, certain statements made in HRT Data Sheets are at variance with results from epidemiological and clinical studies. There are no published data of which we are aware from which it could be concluded that previous myocardial infarction should be considered a contra-indication to oestrogen therapy. Indeed, as stated above, the evidence suggests that unopposed oestrogens may be beneficial rather than harmful in women with coronary artery disease.42'43 Controversy exists as to whether natural oestrogens have any clinically relevant effect on fibrinolysis and coagulation. The risk of spontaneous venous thrombosis does not appear to be increased in an apparently normal population taking postmenopausal oestrogens. Some authors have failed to demonstrate fibrinolytic/coagulation changes with oral HRT: others have, but the spectrum of the effects and the severity of change are less with natural oestrogens than with the synthetic oestrogens used in the combined 'pill'.44 Although data are much more sparse, non-oral HRT does not appear to influence fibrinolysis/coagulation.45 Thus, in 'at risk' patients (those with previous thrombosis) we think it prudent to avoid the oral route and use the parenteral route.46'47 Although with both methods of delivery oestrogen reaches the liver, the parenteral route avoids any possible exaggerated effects of rela-

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tively large boluses of oestrogen passing directly to the liver as occurs with oral administration. We do not understand why some consider varicose veins to be a contra-indication to the use of natural oestrogens. There is no evidence that physiological doses of natural oestrogens reduce flow in lower limb veins, and we know of no association between deep vein thrombosis and phlebitis in superficial varicose veins in patients on or off HRT. Hypertension with repeated values at or over 160/100 mmHg is considered by some to be a contra-indication to oestrogen therapy. This may require control using suitable antihypertensive therapy, independent of the use of HRT. Oral natural oestrogens cause hypertension in approximately 2% of women and one group has reported that this is associated with excessive weight gain. We do not understand why adequately controlled hypertension should be considered a reason for withholding therapy especially as two groups have reported a reduction in risk of CHD in hypertensives. In women who develop raised blood pressure whilst on oestrogens it might be prudent to withdraw HRT, treat the hypertension and then re-start oestrogens with careful monitoring of the blood pressure. Theoretically, delivery of oestrogens using parenteral methods will have fewer effeas on protein and globulin production (i.e. renin substrate) in the liver as compared to oral treatment. It must be stressed, however, that no study has yet adequately examined the differences in the incidence of hypertension between the two routes of delivery. The route of delivery may be irrelevant if hypertension on HRT is mediated through excessive weight gain. Oestrogens and progestogens affect carbohydrate metabolism and therefore diabetic patients require careful monitoring of their diabetic control during the first months of treatment. It would not be advisable to start oestrogen therapy in diabetics whose control is already unsatisfactory. One report suggests that transdermal oestradiol and norethisterone in a sequential regimen causes less disturbance in glucose metabolism than oral conjugated oestrogens combined sequentially with levonorgestrel (Godsland I, Gangar KF, Walton C et al., unpublished observations). Severe active liver disease in which liver function tests are significantly abnormal is generally considered to be a reason for withholding oestrogen therapy. This advice is based on the assumption that increasing the metabolic load on the liver will cause deterioration in liver function although no studies have

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addressed this problem. If the indications for treatment are strong, the oral route is best avoided for the theoretical reasons explained above. Oral therapy changes the composition of bile in a manner that may lead to an increased risk of gallstones and therefore oral oestrogens should be prescribed with caution to women with preexisting cholelithiasis. One report has suggested that parenteral administration causes fewer adverse changes in the composition of bile and this may be the preferred route of delivery.48 Endometriosis can be reactivated by HRT even when treatment is started many years after the menopause. Thus, any woman who has a history of this condition, however distant, should be warned of this possibility. The need for HRT is usually greatest in women who have undergone a premature and surgically induced menopause for this condition. In theory the likelihood of recurrence will be greater in women who have residual tissue left behind after surgery but this has not been established from appropriate studies. Likewise it is not known whether HRT will cause a return of the disease after apparent removal of all endometrotic tissue. It is often recommended that patients with obvious residual disease should not receive oestrogens for at least 9 months after surgery but this advice is not supported by data. In theory, use of progestogens in these women will reduce the risk of recurrence because they should have an antimitotic, suppressant effect on the endometrium: confirmatory data are awaited. Fibroids are found in up to 60% of middle aged women although in most cases they are small and clinically insignificant. Fibroids usually disappear after the menopause; they are unlikely to do so in the woman receiving HRT and, indeed, may become larger in a minority of women. Fibroids that enlarge and cause symptoms either necessitate withdrawal of HRT or a hysterectomy if the patient wishes to continue HRT. CONTRACEPTION Although fecundity decreases with advancing age and the likelihood of anovulatory menstrual cycles increases over age 40 years a reliable form of contraception should be continued for at least a year after the menopause if this occurs above age 50 years and for 2 years if the menopause occurs before age 50 years. The time of the last spontaneous menstrual period, however, cannot be established in the woman who has commenced HRT when she is

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still menstruating. In these women the time when contraception is no longer needed may be estimated by assuming that the patient behaves like the average woman using the criteria stated above. The estimated age of natural menopause may be adjusted if there is a family history of late menopause. If assumptions are the basis for advice about declining fertility then this must be made clear to the patient; if she considers the risks of pregnancy too great the use of contraception until the age of 55 is a safe approach. In many patients it is necessary to explain that the regular withdrawal bleeding induced by sequential HRT does not reflect spontaneous ovarian activity and a return of fertility, and that contraception is not required after the times recommended above. Although the daily progestogen content of many sequential or continuous combined HRT regimens often exceeds that in the progestogen-only pill, it must be emphasised that no HRT regimen has been evaluated as a contraceptive, and diat HRT must not be used as such. This is particularly relevant in the women using a brand name progestogen-only contraceptive pill to provide the appropriate dose of progestogen in their HRT. The progestogen-only pill, when used alone, exerts its contraceptive effect by a combination of actions. It affects cervical mucus, the endometrium and the ovary. It is impossible to predict which effect is responsible for most of the contraceptive action in any one patient. If an effect on the cervical mucus is the main mechanism in a particular patient then it is not known whether the effect of the oestrogen in HRT will be to antagonise this action and diminish the contraceptive effect.

Methods The reduced fertility and decreasing coital frequency of the woman aged over 40 years reduces the user failure rate of all methods of contraception. For this reason, methods that would be reluctantly recommended to the woman under 40 years may be appropriate in the older woman. Good examples are the contraceptive sponge or the use of spermicides alone. These may be reliable in the woman aged over 45 years who finds other methods unacceptable. The non-hormonal methods appropriate for the woman who is receiving HRT are shown in Table 9. Irreversible operative

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Table 9 Methods of contraception for women receiving Hormone Replacement Therapy Reversible

Rhythm or safe period Withdrawal Barrier methods Spermicides IUD

Non-reversible

Sterilisation

methods may be considered less desirable in the older woman as the number of remaining fertile years is relatively low. The perimenopausal woman who is not receiving HRT may use hormonal methods of contraception such as the progesterone-only or the combined contraceptive pill. Current thinking is that the combined pill may be given to women up to the age of 45 years if they are non-smokers, have no other risk factors and in whom other methods of contraception are unsuitable.49 REFERENCES 1 Bourne TH, Whitehead MI, Campbell S, Royston P, Bhan V, Collins WP. Ultrasound Screening for Familial Ovarian Cancer. Gynecol Oncol 1991; 43: 92-97 2 Crook D, Cust MP, Gangar KF et al. Comparison of transdermal and oral oestrogen/progestogen replacement therapy: Effect on serum lipids and lipoproteins. Am J Obstet Gynecol 1992 (In Press) 3 Mashchack CA, Lobo RA, Dezono-Takano et al. Comparison of pharmacodynamic properties of various oestrogen formulations. Am J Obstet Gynecol 1982; 144: 511-518 4 Cardozo L, Gibb D, Studd J, Tuck S, Thom M, Cooper D. The use of hormone implants for climacteric symptoms. Am J Obstet Gynecol 1984; 148: 336-340 5 Cardozo L, Gibb D, Studd J, Tuck S, Thom M, Cooper D. The effect of subcutaneous hormone implants during the climacteric. Maturitas 1984; 5: 177-184 6 Edington R, Chagnon J-P, Steinberg W. Clonidine (Dixarit) for menopausal flushing. Can Mcd Assoc J 1980; 123: 1-4 7 Qayden J, Bell J, Pollard P. Menopausal flushing: Double-blind trial of a nonhormonal medication. Br Med J 1974; 1: 409-412 8 Ylikorkala O. Clonidine in the treatment of menopausal symptoms. Ann Chir Gynaecol Fenn 1975; 64: 242-245 9 Bolli P, Simpson J. Clonidine in menopausal flushing: a double-blind trial. NZ Med J 1975; 82: 196-197 10 Linsay R, Hart D. Failure of response of menopausal vasomotor symptoms to clonidine. Maturitas 1978; 1: 21-25 11 Sonnendecker E, Polakow E. A comparison of oestrogen/progestogen with clonidine in the climacteric syndrome. S Afr Med J 1980; 58: 753-756 12 Appelby B. Norethisterone in the control of menopausal symptoms. Lancet 1962; i: 407-409 13 Paterson M. A randomised double-blind cross-over trial into the effect of

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norethisterone on climacteric symptoms and biochemical profiles. Br J Obstet Gynaecol 1982; 89: 464-472 14 Schiff I, Tulchinsky D, Cramer D, Ryan K. Medoxyprogesterone in treatment of postmenopausal symptoms. J Am Med Assoc 1980; 244: 1443-1445 15 Bullock J, Massey F, Gambrell R Jr. Use of medroxyprogesterone acetate to prevent menopausal symptoms. Obstet Gynecol 1975; 46: 165-168 16 Erlik Y, Meldrum D, Lagasse L, Judd H. Effect of megestrol acetate on flushing and bone metabolism in post-menopausal women. Maturitas 1981; 3: 167-172 17 Padwick M, Endacott J, Whitehead M. Efficasy, acceptability and metabolic effect of transdermal estradiol in the management of postmenopausal women. Am J Obstet Gynecol 1985; 152: 1085-1089 18 Whitehead M, Fraser D, Schenkel L, Crook D, Stevenson J. Transdermal administration of oestrogen/progestogen hormone replacement therapy. Lancet 1990; 335: 310-312 19 Whitehead M, Minardi J, Kitchin Y, Sharpies M. Systemic absorbtion of oestrogen from Premarin vaginal cream. In: Cooke I, ed. The role of oestrogen/ progestogen in the management of the menopause. Manchester: MTP Press, 1978: pp. 63-71 20 Dyer G, Townsend P, Jelowitz J, Young O, Whitehead M. Dose related changes in vaginal cytology after topical conjugated equine oestrogens. Br Med J 1982; 284: 789-790 21 Englund D, Victor A, Johannson E. Pharmacokinerics and pharmaco-dynamic effects of vaginal oestradiol administration from silastic rings in postmenopausal women. Maturitas 1981; 3: 125-129 22 Gangar K, Cust M, Whitehead M. Symptoms of oestrogen deficiency associated with supraphysiological plasma oestradiol concentrations in women with oestradiol implants. Br Med J 1989; 299: 601-602 23 Gangar K, Fraser DI, Whitehead MI, Cust M. Prolonged endometrial stimulation associated with oestradiol implants. Br Med J 1990; 300: 436-438 24 Whitehead MI, King R, McQueen J, Campbell S. Endometrial histology and biochemistry in climacteric women during oestrogen and oestrogen/progestogen therapy. J R Soc Med 1979; 72: 322-327 25 Peterson H, Lee N, Rubin G. Genital neoplasia. In: Mishell Jr D, ed. Menopause, physiology and pharmacology. Chicago: Year Book, 1978: pp. 275-300 26 Shapiro S, Kelly J, Rosenberg L, et al. Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated oestrogens. N Engl J Med 1985; 313: 969-962 27 Paganini-Hill A, Ross R, Henderson B. Endometrial cancer and patterns of use of estrogen replacement therapy: a cohort study. Br J Cancer 1989; 59: 445-447 28 Persson I, Adami H-O, Bergkvist L, et al. Risk of endometrial cancer after treatment with oestrogens alone or in conjunction with progestogens: results of a prospective study. Br Med J 1989; 298: 147-151 29 Whitehead MI, Townsend P, Pryse-Davies J, et al. Effects of various types and dosages of progestogens on the postmenopausal endometrium. J Reprod Med 1982; 27: 539-548 30 Studd J, Thorn M, Paterson M, et al. The prevention and treatment of endometrial pathology in postmenopausal women receiving exogenous oestrogen. In: Pasetto N, Paoletti R, Ambrus J, eds. The menopause and postmenopause. Lancaster: MTP Press, 1980: pp. 127-139 31 Padwick M, Pryse-Davies J, Whitehead MI. A simple method for determining the optimal dose of progestin in postmenopausal women receiving oestrogens. N Engl J Med 1986; 315: 930-934 32 Frascr DI, Parsons A, Whitehead MI, Wordsworth J, Stuart G, Pryse-Davies

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