Therapeutic options

OESTROGEN Dosage

There is general agreement now that patients should be started on the minimum effective dose of oestradiol, increasing the dose only if needed to alleviate symptoms. Although there is no direct evidence that higher doses of exogenous oestrogen are associated with increased risk of breast cancer or heart disease there is a link with venous thromboembolic risk. Importantly, lower doses of oestrogen are less likely to produce breast tenderness and bleeding problems which will reduce continuance of therapy.

The minimum dosages of currently available systemic oestrogen are as follows:

• 0.3-0.625 mg oral conjugated equine oestrogens

• 1 mg of oral micronized oestradiol or oestradiol valerate

• 25-50 mcg transdermal oestradiol

• 25-50 mg of implanted oestradiol

• 150 mcg transnasal oestradiol

• 50 mcg oestradiol silicone ring

Data suggest that the benefits of a 2 mg dose of oestradiol for symptoms and bone protection can be maintained by a 1 mg dose and similarly the benefits of a 50 mg oestradiol implant are maintained by a 25 mg implant [13]. Studies are currently ongoing to facilitate the licensing of a 0.5 mg oestradiol containing preparation which appears to adequately relieve symptoms. Exceptions to this 'low dose rule' are women who suffer premature ovarian failure who need higher doses of oestrogen to reproduce the physiological hormone levels which would have been present if the ovaries had not failed early. The optimum route of administration or dosage in this group of young women has yet to be determined.

Route of administration

If we adhere to the principle that we should try to reproduce the most physiological state possible with a 2:1 oestradiol: oestrone ratio then we should avoid the oral route altogether. Oral oestradiol preparations are partially metabolized to oestrone by hepatic first pass metabolism and therefore do not fully restore this ratio. There are twice weekly or once weekly changed transdermal systems containing either oestradiol alone or both oestradiol and progestogen. The combined patches are available in either sequential or continuous regimens. The hormone is adsorbed onto the adhesive matrix which avoids the skin reactions caused by the old alcohol reservoir patches.

Oestradiol can also be used transnasally in a 'pulsed' fashion which is thought to maintain the benefits while minimizing the side effects of chronically elevated oestrogen, for example, breast tenderness. It is also available as a low-volume daily transdermal gel or even as a sili-cone vaginal ring delivering oestradiol systemically for 3 months. The nasal, gel and ring preparations are oestrogen alone and should be combined with progestogen in women with a uterus (see 'Progestogens').

Local (vaginal) oestrogen [14]

Recently developed vaginal HRT regimens have managed to avoid the problem of endometrial stimulation. Creams using oestriol do not produce endometrial hyperplasia and the 17^ oestradiol vaginal tablet and silicone vaginal ring also provide effective relief of local symptoms without any significant endometrial effects. These preparations can be used without progestogenic opposition but are only licensed for 3 months use in the UK and 1 year in Europe. Options for local vaginal oestrogen are as follows:

• 0.01% Oestriol cream and pessaries

• 25 mcg/24 h Oestradiol vaginal tablets

• 7.5 mcg/24 h Oestradiol releasing silicone ring

• Premarin cream - this preparation can potentially cause endometrial hyperplasia and should not be used without progestogenic opposition for more than 3 months.

PROGESTOGEN/PROGESTERONE Regimens

Oestrogen was originally used unopposed in non-hysterectomized women. It was noted that this led to endometrial hyperplasia in up to 30% of cases. Progestogen has therefore been added to oestrogen therapy for the last 30 years to avoid hyperplasia and carcinoma. It is generally accepted that women commencing HRT should start on a sequential regimen, that is, continuous oestrogen with progestogen for 12 to 14 days per month. The typical dosages of the more commonly used progestogens are shown in Table 47.1.

Bleeding problems

If bleeding is heavy or erratic the dose of progestogen can be doubled or duration increased to 21 days. Persistent bleeding problems beyond 6 months warrant investigation with ultrasound scan and endometrial biopsy. After 1 year of therapy women can switch to a continuous combined regimen which aims to give a bleed free HRT regimen which will also minimize the risk of endometrial hyperplasia. Alternatively, women can be switched to the

Table 47.1 Minimum doses of progestogen given orally in HRT as endometrial protection

Sequential

Continuous

combined

combined

Progestogen type

daily dosage

daily dosage

C19 - testosterone derived progestogens

Norethisterone

5mg

0.5 mg

Levonorgestrel

75 mcg

n/a

Levonorgestrel (IUS)

n/a

20 mcg (10 mcg

in development)

Norgestrel

150 mcg

50 mcg

C21- progesterone derived progestogens

Dydrogesterone

10 mg

5 mg

Cyproterone

2mg

1 mg

Medroxyprogesterone

5mg

2.5 mg

acetate

Micronized

200 mg

100 mg

Progesterone

Cyclogest pessaries

400 mg

200 mg

Crinone gel (4 or 8 %)

Alternate

Twice weekly

day/12 days

of cycle

IUS, Intrauterine system.

IUS, Intrauterine system.

tissue selective agent tibolone. With both these regimens there may be some erratic bleeding to begin with but 90% of those that persist with this regimens will eventually be completely bleed free. If starting HRT de novo a bleed free regimen can be used from the outset if the last menstrual period was over a year ago.

Progestogenic side effects

It is vital that we maximize compliance if patients are to receive the full benefits from hormone replacement therapy (HRT). One of the main factors for reduced compliance is that of progestogen intolerance. Progestogens have a variety of effects apart from the one for which their use was intended, that of secretory transformation of the endometrium. Symptoms of fluid retention are produced by the sodium retaining effect of the renin-aldosterone system which is triggered by stimulation of the miner-alocorticoid receptor. Androgenic side effects such as acne and hirsuitism are a problem of the testosterone derived progestogens due to stimulation of the androgen receptors. Mood swings and PMS-like side effects result from stimulation of the central nervous system progesterone receptors [15].

Minimizing progestogen intolerance

The dose can be halved and duration of progestogen can be reduced to 7-10 days. However, this may result in bleeding problems and hyperplasia in a few cases (5-10%) so there should be a low threshold for performing ultrasound scans and endometrial sampling in these women. Natural progesterone has less side effects due to progesterone receptor specificity but is only available in a vaginal form in the UK (200-400 mg pessaries or 4-8% progesterone gel) though micronized oral progesterone is available in France. The levonorgestrel intrauterine system, recently granted a 4 year license in the UK for progestogenic opposition, also minimizes systemic progestogenic side effects by releasing the progestogen directly into the endometrium with low systemic levels. However, in severely progestogen intolerant women, even the low systemic levels of the 20 mcg levonorgestrel intrauterine system can still produce side effects. A smaller, lower dose, 10 mcg system is in phase III clinical trial stage of development and should be ideal for the severely progestogen intolerant woman [16]. A new progestogen, drospirenone, a spironolactone analogue, has recently been incorporated with low dose oestrogen in a continuous combined formulation. It is not only progesterone receptor specific but also has anti-androgenic and anti-mineralocorticoid properties, the former making it useful for hirsuitism and the latter for fluid retention. Also, it may have anti-hypertensive benefits.

Progestogenic risks

The Women's Health Inititiative (WHI) [17] and Million Women Study (MWS) [18] studies showed clearly that there is an excess risk of breast cancer using oestrogen and progestogen HRT compared to oestrogen alone. It has therefore been mooted that even non-hysterectomized women should be treated with oestrogen-only containing preparations. According to the MWS data, after 10 years of oestrogen and progestogen HRT there would be an extra 19 per 1000 cases of breast cancer and no cases of endometrial cancer; after 10 years of oestrogen alone in non-hystectomized women, there would be an extra 5 cases per 1000 of breast cancer and 10 cases per 1000 of endometrial cancer (total 15:1000). From this simplistic point of view, it would seem reasonable that all women (even with a uterus) should receive oestrogen alone. However, this does not take into account the excess cases of endometrial hyperplasia and bleeding problems. This would generate excessive investigations such as endome-trial sampling, hysteroscopies and even hysterectomies which would not be without their own morbidity and mortality.

Current advice remains that progestogenic opposition should still be used. However, it is imperative that we continue to seek improved ways of administering the progestogens which are important in protecting the endometrium to avoid progestogenic side effects and minimize effects on breast tissue, for example, vaginal and intrauterine progestogens and natural progesterone. However, there is a lack of data as to the risk of breast cancer in women using oestrogen with a levonorgestrel intrauterine system.

TESTOSTERONE Preparations/regimens

Unfortunately, only 100 mg/6 months implanted testosterone pellets are licensed for use in women; 25 mg pellets exist but must be ordered on a named patient basis. The realization that there is currently an unfilled market for female androgen replacement has led to the development of the 300 mcg per day testosterone transdermal system to treat 'hypoactive sexual desire disorder'. While the license for this product is awaited it is necessary to continue improvising if one wishes to use preparations other than implants.

One option is to use testosterone gel which comes in 50 mg, 5 ml sachets at a dose of 0.5-1.0 ml/day. If the free androgen index is kept within the physiological range there are rarely any side effects such as hirsuitism. Levels should be checked at baseline and repeated at 4-6 weeks. Research so far has suggested at worst a neutral effect on the cardiovascular system, for example, arterial compliance and lipid effects. Alternatives to this include scaled down dosages of testosterone injections and oral preparations though many avoid the latter route because of hepatic concerns.

THE HRT CONTROVERSY

Over the last few years, health professionals and their patients have been inundated with information regarding the potential benefits and risks of hormone replacement therapy. Information is available from a variety of sources; some are more reliable than others. The popular press subeditors, responsible for the headlines, often sensationalize the risks of HRT. This has left the average health professional in a very difficult position as to what to advise their patients and has left patients bemused as to where they should turn to obtain reliable advice.

Breast

Recent prospective randomized data from the WHI combined HRT study have confirmed the previous observational data from the Imperial Cancer Research Fund [19] (now 'Cancer Research UK') regarding the risks of breast cancer with HRT. The WHI study was stopped prematurely by the data safety monitoring board after running a mean of 5.2 rather than 8.5 years. This was because it was deemed that the risk versus benefit statistic was exceeded due to an excess of breast cancer and coronary heart disease cases in the treatment arm (continuous combined conjugated equine oestrogens 0.625 mg and medroxyprogesterone acetate 2.5 mg). The data from the WHI study suggested an excess risk of breast cancer with combined hormone therapy of 4 cases per 1000 women after 5 years. A further analysis of the data this year detected a hazards ratio for breast cancer of 1.24 (p > 0.001) for an average of 5.6 year's exposure to HRT [20].

The MWS, a large questionnaire survey by Cancer Research UK of women attending the NHS breast screening programme, reported an increased risk of breast cancer diagnosis with all HRT regimens (Relative Risk [RR] 1.66 95% CI 1.58-1.75); there was a statistically higher risk with oestrogen/progestogen HRT (RR 2.00 [1.91-2.09]) than that seen with oestrogen alone (RR 1.30 [1.22-1.38]) or tibolone (RR 1.45 [1.25-1.67]). This was alarmingly reported by the press as a doubling of risk of breast cancer with HRT, failing to mention the absolute risk in terms of actual numbers of cases. For oestrogen alone it represented an additional 1.5 per 1000 cases after 5 years of use and for oestrogen/progestogen, an additional 6 per 1000 cases after 5 years of HRT. In women aged 50-64, whose baseline risk is 32:1000 anyway, this translated to 33.5 per 1000 and 38 per 1000 cases, respectively.

The higher risk estimates from the MWS compared to WHI were probably due to the observational nature of the MWS which underestimated duration of usage of HRT as it did not count years of HRT exposure from baseline to breast cancer reporting on the UK cancer registry. Also, bearing in mind the natural biology of breast cancer development, it is unlikely that the cancers diagnosed after 1 year had developed de novo - it is more likely that these cancers were missed by mammography at baseline and that HRT had acted as a promoter rather than an initiator. Although the MWS reported on there being an increase in mortality, this was of borderline significance RR 1.22 (CI 1.00-1.48) (p = 0.05); the absence of tumour details also made it difficult to draw any definitive conclusions on this issue. Numerous authors have expressed their reservations regarding the limitations of both the MWS and WHI data [21,22]. On the positive side, a second WHI study in hysterectomized women using unopposed oestrogen reported that the rate of invasive breast cancer diagnosed was 23% lower in the conjugated oestrogen group compared to the placebo and this comparison narrowly missed statistical significance (p = 0.06). This result was unanticipated and appears to suggest that it is the addition of progestogen to oestrogen which leads to the increased risk of breast cancer, not oestrogen alone [23].

Cardiovascular (coronary heart disease and stroke)

Initial cardiovascular data from observational studies suggested up to a 50% reduction in risk of coronary heart disease in HRT users and a neutral effect on stroke. The Heart Estrogen Replacement Study (HERS), however, did not confirm these data in women started on HRT for secondary prevention of coronary heart disease and the WHI did not show any benefit in a primary prevention setting [24]. In fact, WHI suggested that after a mean usage of 5 years there was an excess of heart disease cases in the active treatment arm of the study compared to placebo. The study also found an excess of stroke. The cardiovascular risks in WHI were small, equating to an extra 7-8 cases per 10,000 women per year. These were largely accounted for by an excess of cases in the first couple of years of use, probably due to an initial pro-thrombotic effect of the preparation used. The increase in risk for stroke was clearly age related (age 50-59, 4 cases, 60-69, 9 cases and 70-79 years, 13 cases per 10,000 women per year).

Encouragingly, results from the conjugated oestrogen only arm of the WHI study showed that there was no significant effect on Coronary heart disease (CHD) (primary outcome) compared with placebo (hazard ratio 0.91; 95% CI 0.72-1.15). This latest result again suggests that progestogen may be the problem with HRT. In view of the data from HERS and WHI, guidelines were issued from the American Heart Association and Medicines and Health Care Products Regulatory Agency (MHRA) that HRT should not be used for primary or secondary prevention of CHD.

Future work should now focus on new preparations in younger populations of women. A randomized pilot study from the National Heart and Lung Institute in women using another type of HRT (1 mg oestradiol 0.5 mg norethisterone) after myocardial infarction showed a reduction in risk of re-infarction in the active arm of the study. A larger study, funded by the MRC, is planned as a result of these data [25]. Arecent meta-analysis of randomized controlled trials in women using HRT in over 26,000 women showed that in those who started HRT before the age of 60 years there was a 39% lower mortality compared to those on placebo RR 0.61 (CI 0.39-0.95) [26].

Dementia

Observational and case control data suggested a protective effect for oestrogen for the prevention of Alzheimer's disease. These data have not been supported by the recent randomized controlled data from the WHI memory study (WHIMS) which showed that there was a two fold increase risk of all-cause dementia [11]. However, the WHIMS data were from an older age groupof women (average 67 years)

and it may be that the 'window' for Alzheimer's prevention may be in a much younger age group. There is growing evidence that the chief mechanism of action in all types of dementia is infarction secondary to cerebral micro-emboli. This is much more likely to happen if HRT is started in older age group women due to the predominance of pro-thrombotic events in the first few years. In a younger age group, the beneficial physiological effects of oestrogen on blood flow and lipids could potentially lead to long-term benefits [27].

Endometrial cancer

Some authors suggest that sequential combined HRT appears to slightly increase endometrial cancer risk with long-term use [28]. However, continuous combined HRT appears to confer a small protective effect as witnessed by the trend towards protection in the WHI RR 0.83 (0.47-1.47) and other studies [16,29].

The MWS Investigators recently published the analysis of the endometrial cancer data [30]. Non-HRT users had a risk of 3 cases per 1000 women after 5 years. Encouragingly, sequential combined HRT appeared to have a neutral effect overall on the endometrium. The study confirmed that continuous combined HRT had a protective effect (2/1000 after 5 years) and that women using oestrogen alone had an increased risk (5/1000 after 5 years). Surprisingly, there were also a larger number of endometrial cancers reported in the users of the tissue selective agent tibolone (6/1000 after 5 years). This can possibly be explained by the fact that higher risk women, for example, with a family history of endome-trial cancer or with previous bleeding problems, have preferentially been started on tibolone because it has been viewed as a lower-risk product. The results of a large (>3000 women) two year prospective randomized trial (THEBES) comparing the effect of tibolone to placebo showed no evidence of endometrial hyperplasia or carcinoma with tibolone [31]. The safety monitoring board has encouragingly allowed the study to continue unchanged.

Venous thromboembolism

It is clear from studies including HERS and WHI that there is a two to three fold increase in risk of venous throm-boembolism (VTE) with oral HRT with the greatest risk occurring in the first year of use. However, recent data suggest that transdermal therapy may not increase the risk of VTE [32]. There is biological plausibility for this; avoidance of hepatic first pass metabolism minimizes adverse effects on clotting factors and the fibrinolytic system.

Osteoporosis

For many years bone marker and bone density data suggested that HRT had a beneficial effect on the skeleton. The data from the WHI study finally provided strong grade A (randomized placebo controlled) evidence for the gold standard outcome measure, that is, prevention of fractures of the hip and spine (5 less cases per 10,000 women per year).

Colorectal cancer

The WHI study confirmed previous observational studies for the beneficial effect of combined HRT in reducing the incidence of colorectal cancer (6 less cases per 10,000 women per year) although interestingly not with oestrogen alone. As yet, there is still uncertainty as to the mechanism of action of HRT in reducing the risk of colorectal cancer.

CONTRAINDICATIONS TO HRT

Coronary heart disease, stroke and venous thromboem-bolism were considered in the previous section.

Natural oestrogens when given to normotensive or hypertensive women do not cause an elevation in blood pressure, and when given in combination with oral progesterone may actually lower blood pressure; therefore, there is no justification for withholding HRT from hypertensive women.

Fibroids are responsive to oestrogens, and involute after the menopause. HRT may continue to stimulate these benign gynaecological tumours causing some to increase in size. This can cause an increase in menstrual blood loss, but in practice this does not usually represent a problem as treatment can easily be discontinued. However, in patients with a good indication who wish to continue therapy, fibroid resection, embolization, myomectomy or hysterectomy are all options available.

Patients who have suffered with endometriosis and become menopausal, are usually 'cured' of their symptoms. Some may wish to consider HRT and recurrence rates of 4% on HRT can be expected. Recurrence of symptoms is alleviated by stopping HRT.

Treatment of patients with a past history of endometrial cancer is controversial, but there are reports of oestrogen use without any detrimental effects in stage I to III disease [33]. Squamous cervical cancer is not oestrogen sensitive. There are no adverse data in ovarian cancer survivors although there maybe a very small increased risk of ovarian cancer with long-term unopposed oestrogen use in healthy women. There are no data for adenocarcinoma of the cervix, vaginal or vulval cancer.

Breast cancer must be regarded as the principal contraindication to oestrogen treatment, but high-risk women with a strong family history of breast malignancy or those with benign breast disease should not necessarily be denied treatment. It is unclear what the precise risk of breast cancer recurrence is with HRT use. A study in breast cancer survivors using HRT was terminated because of an apparent excess risk. Unfortunately, this led to the premature termination of two other studies running con-comitantly in which no excess risk had been detected [34]. A large tibolone study (LIBERATE) in breast cancer survivors is still in progress and encouragingly has been allowed to continue by the data monitoring board.

DURATION OF THERAPY

According to WHI, the risk of breast cancer appears to increase after 4 years. The MWS has shown a significantly increased risk after only 1 year. However, cancers appearing at 1 year must have been present at baseline with HRT acting as a promoter rather than an initiator. An editorial lead in The Lancet written by an epidemiologist [35] unre-alistically suggested that the duration of therapy should be limited to 3-6 months. Unfortunately, it is recognized that symptoms often return when HRT is ceased, even after many years of use. If the underpinning principle of HRT is that it should be used to improve and maintain a good quality of life, in women in whom this principle is maintained, it is difficult to argue that they should have arbitrary deadlines imposed on them. Thus, duration of therapy requires careful judgement of benefits and risks on an individual basis. If therapy is to be discontinued, the dose should be reduced in a stepwise fashion over a minimum of 6 months to reduce the risk of immediate severe symptom resurgence.

OFFICIAL PRESCRIBING ADVICE

How are health professionals supposed to react to these data and advise their patients? Guidance from the Medicine's and Healthcare Products Regulatory Agency (MHRA) (see 'useful websites') has advised that HRT should not be recommended for primary or secondary prevention of heart disease. It is recommended that HRT be used merely for symptom relief in the short term at the lowest effective dose and alternatives should be considered in the long term for prevention of osteoporosis. Annual reappraisal of HRT use should be carried out with weighing up of the pros and cons on an individual basis. However, the British Menopause Society (see 'useful websites') consensus statement advises that prescribing habits need not be changed by the recent studies because HRT

use in the UK was primarily for symptom relief rather than primary or secondary prevention.

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