Hot flushes and prostate cancer: pathogenesis and treatment

Authors


Introduction

Hot flushes are defined as a subjective feeling of warmth, mainly to the upper part of the torso, followed by excessive perspiration. In 1896, Cabot [1] studied the effects of castration on the treatment of prostatic enlargement and he was the first to describe, ‘… uncomfortable flushes of heat, similar to those experienced by women at the time of the menopause’. Half a century later, in 1941, Huggins and Hodges [2] showed the dependence of prostate cancer on androgens. They described hot flushes in nine of 21 castrated patients, starting 2–3 weeks after surgery. The present review examines the pathogenesis and management of hot flushes with special reference to their occurrence in the treatment of prostate cancer.

The pathogenesis of hot flushes

Hot flushes most commonly occur in association with menopause and ovarian failure. Thus initially it was not unreasonable to assume that hot flushes were caused by low levels of sex hormones, i.e. the ‘sex hormone withdrawal theory’. This theory is very attractive and is supported by the occurrence of hot flushes after oophorectomy [3] and after surgical [4–6] or medical [7–9] castration for prostate cancer. The theory is also favoured by the encouraging response to oestrogen replacement therapy [10–12]. Why then do patients with congenital hypogonadism (Kallman and Turner syndromes) and prepubertal girls not normally develop hot flushes? They only develop hot flushes when treated with sex hormones (oestrogen, testosterone) and are then suddenly deprived of them. This suggests that is not the absolute plasma sex hormone level that it is important, but its dynamic reduction (momentum). This is the most widely accepted theory, despite the failure to correlate pre-castration plasma testosterone levels with the incidence of hot flushes after orchidectomy.

In 1936, Albright [13] was the first to question the sex hormone withdrawal theory. He suggested that hot flushes were the result of raised gonadotrophin levels and therefore a pituitary as opposed to a gonadal cause for hot flushes was postulated. Information about this derives mainly from studies in the female. There is a correlation between the flush-score and plasma LH and FSH in premenopausal women [14]. Casper et al.[15] and Tatayan et al.[16] showed a close synchrony between the occurrence of hot flushes and LH pulse (LH pulsatile theory). Although not every LH surge was accompanied by a hot flush, hot flushes only occurred with an LH surge. In contrast to this, there seems to be no correlation between gonadotrophin levels and hot flushes in postmenopausal women [17,18]. Furthermore, hot flushes fail to occur in Klinefelter's syndrome (high gonadotrophin levels) and gonadotrophin treatment. However, they do occur in hypophysectomized patients and during LH-RH therapy for prostate cancer. The attention of researchers was therefore drawn to a hypothalamic causative factor.

Similarities between hot flushes and symptoms of sympathetic drive suggest that catecholamines may be involved. Casper et al.[15] failed to show any correlation between hot flushes and peripheral catecholamine levels. They concluded that central rather than peripheral adrenergic drive may be a possible mechanism for hot flushes. Indeed, there is good evidence that noradrenaline is the hypothalamic neurotransmitter responsible for hot flushes. Beckman [19] showed in animal experiments that the intrahypothalamic administration of noradrenaline affects thermoregulation. The thermoregulatory centre in the hypothalamus is anatomically close to the GnRH (LH-RH) secreting neurones. These neurones are stimulated by noradrenaline to secrete LH-RH. Increased hypothalamic noradrenaline therefore stimulates LH-RH neurones and by proximity resets the thermoregulatory centre (i.e. the ‘watering-can’ effect) to activate heat-losing mechanisms. These include cutaneous vasodilatation and profuse perspiration.

The association between sex steroids and hypothalamic catecholamines is not fully understood; a proposed hypothesis involves 2-hydroxylated oestrogens (catecholestrogens) [20]. They are the most common metabolites of oestrogen and have a similar structure to catecholamines. The concentration of catecholestrogens in the hypothalamus is 10 times higher than oestrogen [21]. Catecholestrogens inhibit catechol-o-methyl transferase and activate tyrosine hydroxylase. The former inactivates catecholamines and the latter promotes catecholamine synthesis. Low levels of hypothalamic catecholestrogens will therefore result in increased noradrenaline levels and hot flushes.

Opiates also play a role in the pathogenesis of hot flushes. Stubbs et al.[22] produced hot flushes by administering opiates to healthy volunteers. Naloxone, an opiate antagonist, resulted in vasomotor symptoms when injected into opiate-addicted animals [23,24]. Steroid sex hormones increase β-endorphins, the hypothalamic endogenous opiates; β-endorphins inhibit catecholamine synthesis [25]. There are interactions between these inhibiting mechanisms. The administration of exogenous opiates diminishes the activity of oestrogen-2-hydroxylase, which is involved in catecholamine production [26]. The data on these interactions are so far not fully understood.

To summarize the pathogenesis of hot flushes, it is important to understand the negative feedback by plasma sex hormones on hypothalamic noradrenaline secretion (Fig. 1). Peripheral sex hormones activate hypothalamic β-endorphin and catecholestrogen production. These in turn inhibit the synthesis of hypothalamic noradrenaline. A downward momentum in sex hormone plasma levels will result in loss of this negative feedback. As a result, hypothalamic noradrenaline levels are increased. This stimulates LH-RH secreting neurones to secrete gonadotrophin. The increased intrahypothalamic noradrenaline also resets the nearby LH-RH neurones in the thermoregulatory centre, resulting in hot flushes.

Figure 1.

The negative feedback of plasma sex hormone levels on hypothalamic noradrenaline.

Hot flushes and prostate cancer

Since the pioneer work by Huggins and Hodges [2] in 1941, hormonal manipulation for managing prostate cancer has become increasingly popular. The treatment aims to deprive cancer cells of androgens; the leading methods are bilateral orchidectomy and the administration of LH-RH analogues. After bilateral orchidectomy about half of patients have hot flushes and they tend to occur within a few months [5,6]. The plasma level of testosterone reduces to nadir levels within 12–24 h of orchidectomy [27]. Although studies have failed to show a correlation between hot flushes and preoperative testosterone plasma levels [5,28], other studies report a higher incidence of hot flushes after orchidectomy in younger than older patients [29]. With LH-RH analogues, the incidence of hot flushes is higher, at 60–70% [30,31]. The higher incidence after medical castration is not fully understood; in common with orchidectomy, hot flushes occur within several months of starting treatment.

In most cases androgen deprivation is a palliative measure for incurable and inoperable cancer. Surgical castration is irreversible; with medical castration, although reversible, discontinuing treatment does not result in the disappearance of hot flushes. Exposure to hormonal therapy and its side-effects is therefore lengthy, and because it is palliative, side-effects must be addressed and treated effectively. Hot flushes, although not a serious adverse effect, can when severe and frequent be very annoying to the patient and their family, and reduce the quality of life. Thus the occurrence and available treatments should be considered; treatment should be individualized and administered after balancing the benefits and risks.

Treatment of hot flushes

From Fig. 1, showing the current theory of the pathogenesis of hot flushes, treatment would aim to restore the regulatory negative feedback. Sex hormone replacement treatment with oestrogens (DES) was the first to be tried in the mid-20th century. Other forms of replacement therapy include progesterones and androgens. However, in prostate cancer the treatment aims to deprive cancer cells of androgens; androgen replacement therapy would therefore be contraindicated.

Oestrogens and progesterones have been tried, with encouraging results but the main concern with exogenous oestrogen therapy is their thrombo-embolic side-effects. Doses as low as 0.25 mg have been used with up to a 70% complete and a 20% partial response rate [32]. These doses are lower than those associated with salt retention and increased plasma lipids, but most patients still develop painful gynaecomastia [32,33]. Thrombo-embolic events can occur with these low doses. Oestradiol, which is the main oestrogen, has a high first-pass metabolism; it is metabolized into oestrone, which is believed to be the cause of the gynaecomastia [34]. Studies comparing transdermal oestrogen (0.05–0.1 mg/day) and placebo showed a significant reduction in hot flushes in patients treated with the oestrogen patches; 3–4 weeks were needed for a complete effect. The efficacy of low-dose (0.05 mg/day) is lower than high-dose (0.1 mg/day) oestrogen patches. In the low-dose subjects there was a moderate improvement in 25% and no change in another 25%. In the high-dose group there was a 75% moderate to major improvement but 25% did not respond. The side-effect rate was 33% and 8% for the high- and low-dose patches, respectively [35]. This compares favourably with oral oestrogen treatment. In summary, oestrogen replacement therapy shows a dose-related efficacy (80–90%) and side-effect profile.

Progesterones, like oestrogens, stimulate the production of hypothalamic β-endorphins. Their therapeutic efficacy in hot flushes has been reported in several clinical studies. Megestrol acetate (20 mg twice daily) is as effective as oestrogen replacement therapy, with a prompt response rate of 80–90% [32,36]. Starting with 20 mg twice daily, the dose can be reduced to the lowest effective dose, which may be as low as 5 mg twice daily [5]. Cyproterone acetate (CPA) is a steroidal antiandrogen with progestogenic action, and an efficacy in treating hot flushes comparable with that of DES or megestrol acetate [37,38]. The response rate is dose-related; doses as low as 50–100 mg/day may be as effective as 300 mg/day and the dose can be titrated to the response [39]. High doses of 300 mg daily can be hepatotoxic. At this dosage, liver function should be monitored regularly and CPA should be discontinued if there is any evidence of liver dysfunction. At lower doses, its side-effect profile includes fatigue, gynaecomastia and rarely galactorrhea. Treatment for hot flushes should therefore start at 50 mg daily and be titrated up to 300 mg daily in three divided doses if necessary. From the favourable side-effect profile of the progesterones compared with oestrogens, progesterone replacement therapy has been proposed as the first-line treatment for hot flushes.

The direct neurotransmitter affecting the thermoregulatory centre, as noted, is noradrenaline. Activation of heat-losing mechanisms includes sympathetically driven peripheral vasodilatation. Adrenoceptor blockade would therefore prevent hot flushes; indeed, both α- and β-blockade provide symptomatic relief. Several studies, mainly in women [40–43] but also in men [32], have shown a favourable effect of clonidine on hot flushes. Clonidine is an α2-receptor agonist; these receptors have been identified in the hypothalamus and peripherally. They are inhibitory presynaptic receptors whose activation results in a reduced release of noradrenaline. In addition to having a central mode of action, clonidine also stabilizes the peripheral vasculature and reduces the vasodilatation observed with hot flushes. In contrast to clonidine, yohimbine [42] an α2-antagonist, provokes hot flushes. However, α-methyldopa [42] and lofexidine [44] are α2-agonists and they improve hot flushes. Studies examining α2-receptors have shown that they are down-regulated on exposure to radiation-induced body heating; this could explain why high temperatures and hot drinks can provoke hot flushes.

In double-blinded cross-over comparison studies, clonidine was compared with placebo, and significantly reduced hot flushes [40,41]. However, there is a high, dose-related incidence of side-effects; doses of 25–75 µg, twice daily, are better than placebo [40]. Laufer et al.[45] confirmed the beneficial effect of higher doses of up to 400 µg daily, but at the expense of a higher (40%) side-effect incidence. High doses reduce the frequency of hot flushes by 46%. Smith et al.[32] assessed even higher doses of 1 mg daily in 14 patients; they reported no complete response and a partial response rate in only a third. Transdermal administration is as effective as oral but it is frequently complicated by skin reactions [32,46]. Clonidine treatment is inferior to sex hormone replacement treatments and carries a high side-effect rate. It may have a role in patients in whom other treatments are contraindicated.

Of interest is the role of acupuncture in managing hot flushes. A pilot study by Wyon et al.[47] reported a 70% reduction after 10 weeks of regular acupuncture and a sustained reduction of 50% at 3 months. This novel treatment needs further evaluation; there are a few published reports [47,48].

Conclusion

Men receiving androgen deprivation therapy should be questioned about the presence of hot flushes. Their severity should be quantified and treatment individualized. When necessary, the most effective treatment is sex hormone replacement therapy. Oestrogen and progesterone replacement therapies are equally effective. Progestogenic treatments are safe. We propose CPA or megestrol as first-line treatments. CPA should be started at a dose of 50 mg daily and titrated to the response up to 300 mg daily, in three divided doses. The 20 mg daily starting dose of megestrol acetate can be titrated to 5 mg daily. Available second-line treatments include oestrogen therapy or the nonhormonal clonidine. Oestrogen is more effective but has a more serious side-effect profile. The decision should therefore be governed by the risks and benefits. Clonidine treatment should be started at an oral dose of 50 µg twice daily and titrated down to 25 µg or up to 75 µg twice daily, depending on the response. Oestrogen can be given as an oral dose of 0.25 mg daily or as skin patches of 0.05 mg daily; skin patches can be increased to 0.1 mg daily. Novel therapies such as acupuncture deserve consideration, although current information is only derived from small unrandomized studies.

C. Kouriefs, 41 Marryat Road, 1st floor, Wimbledon SW19 5BE, UK.
e-mail: ckouriefs@hotmail.com

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