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First Consensus Meeting on Menopause in the East Asian Region

Hormone replacement therapy in special cases

Oei Pau Ling and S.S. Ratnam
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore

The use of hormone replacement therapy (HRT) in postmenopausal women has become a recognized and accepted practice worldwide. Since its introduction in the 1920s its benefits have been confirmed in a number of studies. HRT has been shown to prevent the loss of bone density and the attendant risk of osteoporotic fracture. It also decreases the risk of cardiovascular disease and relieves autonomic symptoms such as hot flushes.

In the healthy postmenopausal woman with no other associated health problems, there is no longer a question of the benefits of HRT. However, in certain special circumstances where there are possible contraindications, the benefits of HRT may be outweighed by the risks.

Carcinoma of the breast

There is little that is more frightening and worrying for a woman than the possibility of having cancer. Breast cancer is perhaps even more terrifying as there is also a fear of losing the breast and with it her femininity and sexuality.

One of the most difficult clinical decisions with regard to HRT concerns the symptomatic postmenopausal woman with a history of breast cancer, in whom it is feared that oestrogen therapy will stimulate a recurrence of the cancer. In the past, it was common practice to deny all breast cancer patients HRT. This was due to the overriding concern that oestrogens could promote the growth and dissemination of occult malignant cells, thereby worsening the prognosis and outcome. However, progress in the treatment of breast cancer has seen an improvement in the disease-free interval and survival of the patient. Particularly now in an ageing society, an increasing number of breast cancer patients are spending a significant part of their lives in the postmenopausal years. Many of these breast cancer survivors will also suffer the debilitating symptoms and long-term consequences of osteoporosis and cardiovascular disease. This translates to an enormous burden on a country’s health care system. As such, HRT has now become a more urgent issue in the management of breast cancer patients.

In order to assess the risk of HRT in the breast cancer patient, DiSaia [1] evaluated situations in which patients were exposed to high levels of ovarian hormones at a time when they were harbouring cancer cells. These situations comprised pregnancy coinciding with breast cancer, pregnancy subsequent to breast cancer, breast cancer in both past and current users of oral contraceptive pills, and breast cancer in postmenopausal women receiving HRT. Indirect evidence from these natural experiments indicated that the use of oestrogens does not influence breast cancer outcome.

It has been shown that patients with breast cancer during pregnancy have the same prognosis as those who are not pregnant [2]. Pregnancy after treatment for breast cancer also does not worsen the prognosis. Prophylactic oophorectomy in premenopausal patients to remove the supply of natural oestrogens does not improve patient survival. There are conflicting data as to the link between the use of oral contraceptive pills or the use of postmenopausal oestrogens and breast cancer.

The above experiments clearly do not provide a firm basis on which to recommend HRT to patients with a history of breast cancer. More objective data are needed. Unfortunately, data on the effects of HRT in women who have had breast cancer are either inconclusive or unavailable. The available studies are not randomized, contain small numbers of patients, and the follow-up periods are relatively short. None, however, have shown an increase in the risk of recurrence in breast cancer patients given postmenopausal HRT [3].

In a small group of 25 breast cancer patients who subsequently received HRT, the findings were encouraging, with no obvious adverse effect. The overall survival of the group was 96% [4].

In the largest case-control study to date, breast cancer recurred in 6 out of 90 (7%) patients on HRT, but no deaths were recorded. This compared favourably with the control group in which there was recurrence in 30 out of 180 (17%) non-users (RR 0.40, 95% CI 0.17–0.93) [5].

The results from these small studies are reassuring. However, it is imperative that one does not throw caution to the wind, since there have also been reports of tumour recurrence on HRT, followed by tumour regression once oestrogen therapy was stopped [6].

In the face of this incomplete and inconclusive evidence, there can be no definite answer. What is urgently needed is a prospective, randomized trial to assess the effect of HRT on women who have been treated for breast cancer. Until this question has been answered, each and every patient with a history of breast cancer must be dealt with on a case-by-case basis.

The theoretical risk of tumour promotion by the use of hormones must be analysed. It has been suggested that HRT is safe in a patient with a tumour that has negative oestrogen receptor status. However, the significance of a negative receptor value may depend on the technique that is used in assaying the receptor content [7].

The evaluated risk has to be balanced against the quality of life of the patient. The severity of the menopausal symptoms would influence the decision, as would the assessment of the risk factors for osteoporosis or cardiovascular disease. There can be no guarantee that breast cancer will never recur, whether in a user or a non-user. It is a definite possibility that there will be some recurrences during the period of hormone use. This possibility as well as the risks and benefits must be understood by the patient before commencing HRT.

It has been suggested that HRT can be offered within certain guidelines [8]. It should be safe to give oestrogens to women who have been treated for breast cancer premenopausally and who have been subsequently stimulated by their own endogenous oestrogens with resumption of their periods, without adverse effect. Oestrogens should also be given when non-hormonal methods have failed and where it would significantly improve the patient’s quality of life. Other categories include patients with a good prognosis, but who are at increased risk of, or who have, osteoporosis and/or cardiovascular disease. Lastly, there is the patient who has had a complete explanation of the risks and benefits and who strongly insists on HRT.

The available alternatives to HRT should be considered. These include progestogens, Bellergal or vitamin E for hot flushes, and bisphosphonates, calcium, anabolic steroids, tamoxifen and calcitonin for osteoporosis.

Carcinoma of the endometrium

During the mid-1970s epidemiological studies showed that the use of oestrogens was associated with an increase in the risk of endometrial cancer. This issue has now been resolved. If a woman with an intact uterus receives a preparation containing a combination of an oestrogen and at least 10 days, but preferably 12 days, of a progestogen, there is no increase in the risk of endometrial cancer [9, 10].

The problem arises with the woman with endometrial cancer. Can such a woman safely take HRT? Creasman [11] observes that there is no substantial evidence to show that oestrogen significantly increases the risk of recurrence of endometrial cancer after treatment; and that the addition of a progestogen to the oestrogen may actually decrease the risk of recurrence. The hormone combination is recommended in view of the potential protective action of the progestational agent.

A committee opinion of the American College of Obstetricians and Gynecologists (1990) [12] states that oestrogens can be used for the patient with a history of endometrial cancer for the same indications as for any other woman without such a history. However, the clinical decision to put the patient on oestrogens must be based on the prognostic indicators and the risk that the patient is willing to assume. The benefits and risks are explained to the patient who then has to make the decision whether or not to go on HRT.

Steroid receptors are one of the prognostic indicators. The tumour that is oestrogen- and progesterone- receptor-negative, which is low grade or a stage-I adenocarcinoma, has a low risk of recurrence and such patients can take oestrogens without fear of provoking a recurrence [13, 14].

There is always the unknown magnitude of the risk of dormant endometrial cancer cells being activated by the HRT. Since in the majority of patients, the endometrial cancer recurs within the first 2 years, most gynaecologists prefer to wait for 2 years before commencement of therapy. In the interim, the patient can be offered alternatives. High doses of medroxyprogesterone acetate can alleviate hot flushes and also prevent bone loss.

Carcinoma of the ovary

Surgery with total hysterectomy, bilateral salpingo-oophorectomy and tumour debulking is the treatment of choice in cancer of the ovary. Unfortunately, the surgical menopause that ensues results in unpleasant symptoms, and in the long term increases the risk of osteoporosis and cardiovascular disease. Also, almost 25% of women who are afflicted with the disease are below the age of 50 [15]. Hence, the role of HRT in ovarian cancer patients after surgery is an important issue.

It has been shown that there are oestrogen and progestogen receptors on the surface of 30–60% of ovarian cells [16, 17]. The significance of these receptors in the development of ovarian cancer is, however, unknown. What is known is that the ovarian cancers with a higher oestrogen receptor content respond better to chemotherapy and are associated with a better prognosis [17]. It is also known that the use of tamoxifen, megestrol and medroxyprogesterone acetate does not change the clinical outcome of ovarian cancers. There is also no known association between HRT and the development of ovarian cancer [10].

In addition, HRT is important in improving quality of life, especially in younger patients. In view of the reassuring data, HRT can be used in women with a history of ovarian cancer.

Other carcinomas

Other than breast and endometrial cancers, there is no known association between HRT and an increase in mortality for any cancer site. There is no evidence of adverse or protective effects on the risk of ovarian, cervical, vulvar, vaginal, rectal, pancreatic, renal, lung, brain, malignant melanomas or other skin tumours, thyroid and other endocrine cancers [10]. The available evidence suggests that there is no association between the use of HRT and the subsequent development of any cancers other than those of the breast and the endometrium. Therefore, a history of any of these cancers should not be a contraindication to the use of HRT.

HRT appears to have a protective effect against cancer of the liver, biliary tract and colon. The risk estimates for these cancers were found to be reduced by about 40%, especially in women on the oestradiol-progestogen combination [10].

The Nurses’ Health Study [18] reported a marginally significantly reduced risk of colorectal cancer in past users of postmenopausal oestrogens. A case-control study in Italy [19] showed that the use of HRT could decrease the risk of colorectal cancer. In another case-control study, Jacobs et al. [20] also noted a decreased risk of colonic cancer in women on HRT, particularly after 5 years of use.

From the results of these studies, any protective effect of HRT against colonic cancer should be important in the debate about its potential risks and benefits. Perhaps HRT should also be considered prophylactically and encouraged in women with a history of colorectal cancer.

Benign breast disorders

Benign breast disease encompasses a variety of conditions which range from clinically evident lesions to benign physiological symptoms related to cyclic, developmental or involutional changes [21]. Women with a history of benign breast disorder often worry that taking HRT can precipitate the onset of breast cancer. The relationship between HRT and benign breast disorder, and whether benign breast disease is related to breast cancer, is still uncertain.

A meta-analysis of 37 studies suggested that HRT was associated with a very small (RR 1.06) increase in breast cancer [22]. The Nurses’ Health Study [18] also found that a history of benign breast disease was a risk factor for breast cancer among current users of postmenopausal HRT. However, HRT in patients with benign breast disorder has also been found to be associated with a reduction in the subsequent development of breast cancer [23]. Similarly, the CASH study did not find any increase in the risk of breast cancer with postmenopausal HRT in the presence of benign breast disease [24].

The available data are therefore inconclusive and inconsistent. Before putting a patient with a benign breast condition on HRT, the risks and benefits should first be thoroughly discussed with her.

Uterine myomas

Uterine myomas are a common occurrence, affecting one in every five women. Most are not even aware of the fact that they have a myoma, especially if it is small or asymptomatic. However, for a woman with a significant problem with uterine myomas, the onset of the menopause promises atrophy of the uterine myomas, and relief and cessation of the problem. For these women, the concern would be whether initiating HRT would cause the persistence and enlargement of the oestrogen-dependent myomas.

Uterine myomas are generally not stimulated by postmenopausal HRT [25]. However, it is important to maintain vigilance and continue regular pelvic examinations. If there is an increase in the size of the uterine myoma, HRT should be discontinued.

In a randomized study of postmenopausal women with small and asymptomatic fibroids, the fibroids were evaluated sonographically before and at the end of 1 year of HRT. The women who were on oral hormones showed no increase in the size of the fibroids. However, in the transdermal group, there was a significant increase in fibroid size [26].

Psychosis/psychiatric illness

Various psychotic and psychiatric disorders can occur in the postmenopausal woman. However, they are no more common than at other times of life. The menopause does not have a negative effect on mental health, many of the psychiatric problems being due to the vicissitudes of life [25].

It can be difficult to define the nature of the problem because of the subjectivity of the complaints and the effect of the postmenopausal symptoms. For example, emotional lability during this period may simply be due to poor sleep. Also, the treatment of hot flushes can have a domino effect of relieving other symptoms.

Despite the various symptoms of depression, mood changes and irritability which can occur in association with the menopause, there is no specific psychological syndrome or specific psychiatric disorder. There is a lack of evidence to link depression with the menopause. Although oestrogen treatment may improve mood, most studies show a large placebo response [27].

A condition which is known to have an association with HRT is Alzheimer’s disease. The Leisure World study indicates that Alzheimer’s disease and related dementia occur less frequently in users of HRT. The effect of this lower risk is greater with increasing dose and duration of use. In patients with Alzheimer’s disease, the administration of oestrogens was shown to improve cognitive performance [28]. Besides reducing the risk of Alzheimer’s disease in the postmenopausal woman, HRT also delays the age of onset [29].

Premature menopause

Premature menopause is a relatively common condition which is thought to affect 1% of women under the age of 40 years [30]. The consequence of premature ovarian failure is similar to that of the natural menopause. However, with a younger age of onset of the menopause, this would translate into a greater risk of cardiovascular disease, cerebrovascular disease and osteoporosis. Hence, once the diagnosis of premature menopause is made, HRT should be offered prophylactically to such women.

Commencement of hormone replacement therapy in the older woman

There are benefits of initiating HRT in the older women, some years after the menopause. Even in women over the age of 65, hormones would still have a positive influence on the bones. Hormones can decrease bone loss and reduce the risk of osteoporotic fracture. The Framingham study [31] demonstrated that the use of oestrogens in women aged 65–74 protects against hip fracture.

The issue of whether starting HRT in the elderly woman has any cardioprotective effect has not been addressed. However, some positive benefit can be expected [25].

HRT also reduces the risk and delays the age of onset of Alzheimer’s disease in the postmenopausal woman [29]. This is therefore another good reason for considering HRT in elderly women.

Caution should, however, be employed when starting HRT. Although rare, there are case reports of haematometra following initiation of HRT. This is thought to be due to cervical stenosis occurring after a period of hypo-oestrogenism [32].

Endometriosis

In the patient with severe, incapacitating endometriosis, total pelvic clearance with abdominal hysterectomy and bilateral salpingo-oophorectomy may be the ultimate solution to bring relief in this chronic condition. Such patients are often still relatively young and the question that arises is whether HRT would activate any dormant residual endometriotic tissue. It has been shown that a minority of women after radical surgery develop a recurrence of endometriosis related to the commencement of HRT [33, 34]. There are also case reports of endometriosis arising de novo following HRT [35]. Hence, this differential diagnosis should be considered in such patients if they present with pelvic pain and/or a mass.

HRT, however, should be discussed with patients after radical surgery for endometriosis as recurrences are rare and the benefits of oestrogen replacement would in most cases outweigh the small risk of recurrence. There are various suggestions to minimize the risk of recurrence. These include the addition of progestogen, the combination of oestrogen and testosterone, keeping the therapy to a minimum [36], and delaying initiation of HRT [37].

Urogenital tract conditions

Urogenital tract conditions have been reported to affect more than 50% of postmenopausal women [38]. Complaints range from vaginal discomfort, vaginal discharge and infection, vaginal dryness, irritation and pressure, dyspareunia, dysuria and recurrent lower urinary tract infections to urinary incontinence. Ageing may be responsible for a number of these symptoms; others are possibly related to the menopause.

The lower urethra has a high concentration of oestrogen receptors and therefore shows marked atrophic changes in the postmenopausal woman. This results in the urethral syndrome which benefits from HRT [39].

Urinary incontinence is another common and persistent problem in the postmenopausal woman. Onset of the menopause has been linked to the onset of urinary incontinence in many instances. However, oestrogens alone will not cure stress incontinence. Postmenopausal HRT in hypo-oestrogenic incontinent women does not affect the number of incontinent episodes or quality of life [40].

Low oestrogen levels can lead to atrophy of the mucosa which results in urge, frequency and dysuria. Oestrogen can cure or alleviate the symptoms due to local urogenital atrophy. It can also induce positive changes in the vaginal bacterial flora of postmenopausal women and therefore reduce the risk of developing urinary tract infections [38, 41, 42].

More than 50% of postmenopausal women experience deficient vaginal lubrication and frequent vaginal infection. These problems can lead to a decreased frequency of all forms of sexual activity [43]. Systemic as well as local HRT can alleviate these complaints.

The use of preoperative oestrogen treatment before a vaginal repair operation for genital prolapse shows no difference in users and non-users with respect to the incidence of infection or relapse [44].

Corticosteroid usage

Corticosteroids are used in the treatment of collagen diseases as well as in other conditions such as inflammatory bowel disease [45], asthma, chronic obstructive airways disease and chronic active hepatitis. A cross-sectional study suggests that a significant number of women — over 250,000 in the UK — are taking continuous oral steroids, with most taking no prophylaxis against the risks of osteoporosis [46]. Corticosteroid-induced osteoporosis is a major problem in collagen diseases [47]. As these conditions affect predominantly women, HRT to prevent osteoporosis becomes an important issue.

There is an influence of the female sex hormones on rheumatoid arthritis [48]. However, HRT has not been shown to cause a flare-up in the disease. On the contrary, HRT leads to improvements in some of the disease parameters [49, 50]. It is also an effective prophylaxis as well as treatment in rheumatoid arthritis-associated bone loss [50, 51]. As HRT also leads to symptomatic improvement in rheumatoid arthritis, it has been suggested that in addition to being a prophylactic measure against osteoporosis, it can also be a useful adjunct to conventional antirheumatic therapy [50].

Systemic lupus erythematosus is strongly associated with oestrogens, being a largely female disease which has its onset during the menstruating years and tending to abate at the menopause. Despite its tendency to improve at the time of the menopause, HRT does not cause the disease to flare up and is not contraindicated in women with lupus [48, 52, 53].

It is obvious that there are advantages in instituting HRT in women taking corticosteroids. At the UK Consensus Group Meeting on Osteoporosis, the agreed strategies of therapy in corticosteroid-induced osteoporosis include HRT, as well as monitoring of the bone density [54].

Liver disorders

HRT is contraindicated in acute liver disease. However, once the episode of acute illness has passed, HRT may be initiated. It should preferably be administered by the transdermal route. This bypasses the liver and therefore should not interfere with the hepatic enzymes and proteins synthesized in the liver [15].

In patients with chronic liver or biliary disease, impaired liver function is a metabolic contraindication to the use of oestrogens. However, in cholestatic liver disease and chronic liver disease, there is an increased incidence of osteoporosis. HRT may thus be necessary to reduce the osteoporosis in selected individuals who are carefully monitored.

Transdermal HRT was used in a case report of a woman with chronic active hepatitis and a high rate of bone loss. Her menopausal symptoms were completely resolved and the quantitative bone density measurements improved, with no deterioration in liver function tests or corticosteroid requirement [55].

Postmenopausal women with primary biliary cirrhosis have a high risk of osteoporosis. In view of this, HRT has been advocated in these women to reduce osteoporosis [56].

Diabetes mellitus

Oestrogen and progestogen can affect glucose tolerance and insulin resistance. In healthy postmenopausal women, the use of HRT does not increase the risk of developing non-insulin-dependent diabetes mellitus. This risk is also not affected by the type of oestrogen or the combination with progestogen [57].

In diabetic postmenopausal women, the question is whether the use of hormones would cause a deterioration in the diabetes. When transdermal HRT is employed, there is no change in the glucose or insulin concentration. However, with the oral regimen, there is a deterioration in glucose tolerance [58]. Therefore, in the diabetic woman, the preferred route of administration would be transdermal.

Women with diabetes are at increased risk of developing and dying from coronary heart disease. The potential benefits of HRT in preventing coronary heart disease in diabetic women have been extrapolated from studies in non-diabetic women. The question, however, is whether the same cardioprotective benefits are present in diabetic women. Diabetic women appear to have a blunted response to the high-density lipoprotein (HDL)-raising effects of postmenopausal HRT. In addition, they have an exaggerated hypertriglyceridaemic response which could potentially increase the risk of acute pancreatitis. Diabetic women may therefore have less cardioprotection from postmenopausal HRT than do their non-diabetic counterparts [59].

Oestrogens mediate their cardioprotective effects by various mechanisms other than raising HDL. The risks and benefits of postmenopausal HRT therefore need to be carefully and thoroughly evaluated in the diabetic woman before commencement of therapy.

Cardiovascular disease

Cardiovascular disease is the leading cause of death in women in the developed world. HRT decreases the risk of coronary heart disease and cerebrovascular accidents in the postmenopausal woman, and is therefore often recommended for these benefits. Evidence shows that the protective benefits of HRT also apply to women who have already suffered from a cardiovascular event such as a myocardial infarction or stroke. The Leisure World study showed that for oestrogen users with a history of myocardial infarction, stroke or hypertension, there is a 50% reduction in the risk of death from a subsequent myocardial infarction or stroke [60]. In women with severe coronary disease documented by arteriography, the survival rate at 5 years is 97% compared with 81% in non-users [61].

Cardiovascular disease being the major cause of mortality and morbidity, puts an enormous burden on a country’s health resources. As such, even after a patient has already had a coronary episode, secondary prevention is still of major importance for public health.

Hypertension

Hypertension is a common medical condition among older women. Over 50% of postmenopausal women are affected by hypertension, especially systolic hypertension [62]. The question in starting HRT in postmenopausal women with hypertension is whether the hormones would worsen the condition. However, oestrogens at the doses used for postmenopausal HRT have been found either to have no effect on blood pressure or to cause a small but statistically significant decrease [63, 64].

A prospective study of the sequential changes in blood pressure in known hypertensive women after the commencement of HRT for amelioration of menopausal symptoms, showed no significant difference in the mean systolic or diastolic blood pressure [65].

The case reports of raised blood pressure after commencing HRT are very rare and probably represent an idiosyncratic response. Therefore, in a woman whose blood pressure is controlled with medication and who is carefully monitored, HRT is not contraindicated. As hypertension is also a risk factor for cardiovascular mortality, HRT could indeed be recommended for its cardiovascular benefits.

Thrombotic phenomenon

It is accepted that HRT is contraindicated in woman with acute episodes of vascular thrombosis or embolism. After the acute event, whether or not the woman is on HRT, she is definitely at increased risk of a repeat episode. The magnitude of this risk and the advisability of commencing HRT have been discussed.

Whitehead and Godfree [66] proposed that a woman with a previous episode of deep vein thrombosis or pulmonary embolism should be evaluated for an inherent abnormality in fibrinolysis and coagulation if the event is spontaneous. In those with a recognized risk factor at the time of the previous episode, administration of low doses of oestrogens for HRT is not believed to increase the risk of another episode.

HRT is not generally thought to cause an increase in the risk of venous thromboembolism. However, recent evidence suggests that current use of HRT is associated with an increased risk of venous thromboembolism. This risk is said to be about 1 in 5000 per year and applies to all types of HRT. There is, however, no association of this risk with past users [67]. Similarly, Jick et al. [68] found that the risk of idiopathic venous thromboembolism is about three times higher among current users of HRT than among non-users. The risk of pulmonary embolism is also increased by current but not past use of postmenopausal HRT [69].

Overall, given the low absolute risk for both users and non-users, the small increase in risk in current users and the relatively low morbidity and mortality of venous thromboembolism, the new data do not seem to change the positive balance of benefits vs risks for HRT. However, in the light of these new data, the use of postmenopausal HRT in women with a history of venous thromboembolism and who are therefore already at higher risk, may not be as innocuous as previously thought. It is therefore of paramount importance to discuss the risks and benefits with the patient before commencing postmenopausal HRT.

In the patient with superficial thrombophlebitis, it is generally believed that oestrogens can be safely used, as there is not thought to be an association between this condition and deep vein thrombosis [66]. However, Daly et al. [67] did find that a significantly higher proportion of patients with venous thromboembolism had a history of superficial thrombophlebitis compared with controls. More research is clearly needed to verify the association, if any, between postmenopausal HRT and superficial thrombophlebitis.

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