Changes in core temperature may also be associated with alterations in neuroendocrine pathways involving steroid hormones, noradrenaline (NA), the endorphins and serotonin (Figure 19.2). Noradrenaline and serotonin, particularly, are thought to play a key role.
Clonidine is an α2-adrenergic agonist licensed for the treatment of hypertension, migraines and postmenopausal vasomotor symptoms.
Monoamines have been shown to play an important role in the control of thermoregulation, and animal studies have shown that noradrenaline (NA) acts to narrow the thermoregulatory zone. Noradrenergic stimulation of the medial preoptic area of the hypothalamus in monkeys and baboons causes peripheral vasodilatation, heat loss and a drop in core temperature, similar to changes which occur in women during hot flashes.
It has also been shown that plasma levels of a noradrenaline metabolite are significantly increased both before and during hot flash episodes in postmenopausal women.
The hypotensive effect of clonidine is thought to be mediated mainly through selective stimulation of presynaptic α-adrenergic receptors in the region of the vasomotor center in the medulla, however it has a dual action. When first administered, clonidine stimulates peripheral α1-adrenoceptors (ARs) resulting in vasoconstriction, but subsequently acts on the central ARs to inhibit sympathetic drive resulting in vasodilatation.
It has also been shown to widen the thermoregulatory zone in humans. Clonidine is used for postoperative shivering because it is thought that, like general anesthetic agents and sedatives, it decreases shivering thresholds by a generalized impairment of central thermoregulatory control. It has also been demonstrated to increase the sweating threshold.
A meta-analysis  has examined 10, poor-to-fair quality, trials in which clonidine (0.1 mg/day) demonstrated a moderate, but statistically significant, reduction in hot flash frequency and severity at 4 and 8 weeks. This suggests that clonidine is an effective alternative to hormonal therapy; however adverse effects, including dry mouth, insomnia and drowsiness, were noted in 8 out of 10 trials.
Serotonin is involved in many bodily functions including mood, anxiety, sleep, sexual behavior and thermoregulation. Estrogen withdrawal is associated with decreased blood serotonin levels, and short-term estrogen therapy has been shown to increase these levels.
Selective serotonin reuptake inhibitors (SSRIs) are a group of drugs typically used as antidepressants, which are thought to function by blocking the reuptake of serotonin to the presynaptic cell. This increases the amount of serotonin in the synaptic cleft available to bind to the postsynaptic cell. Selective serotonin reuptake inhibitors were commonly prescribed for the treatment of depression in women undergoing treatment for breast cancer. Anecdotally, these same women were noted to have an improvement in their vasomotor symptoms, which occurred as a side effect of treatment. Studies were then carried out to determine the efficacy of these as an effective treatment for flashing.
A meta-analysis  assessed two double-blind randomized placebo-controlled trials (fair and good quality) comparing paroxetine to placebo and concluded that paroxetine was more effective than placebo in reducing the frequency and severity of hot flashes. One study included predominantly women with breast cancer using tamoxifen. Doses used varied from 10 mg/day to 25 mg/day, and although efficacy did not vary with dose, those on higher doses experienced more side effects, including nausea, headaches, drowsiness or insomnia.
This same meta-analysis assessed a further two randomized controlled trials comparing venlafaxine and placebo. In one fair-quality trial, an improvement in quality of life (51% with venlafaxine compared with 15% placebo users) was demonstrated despite no reduction in frequency of flashes. In the second, a good-quality trial, venlafaxine at doses of 37.5, 75, 150 mg/day decreased hot flash frequency compared with placebo. Improvement appeared to be greater with the two higher doses, although adverse effects included dry mouth, constipation, decreased appetite, nausea and sleeplessness. Nausea typically improves in 2–3 days, and can be improved by titrating the dose slowly. Venlafaxine was also found to be superior to clonidine, decreasing flashes by 57% compared with 37% in clonidine users.
Two further studies, published following the meta-analysis by Nelson, and included in a Cochrane systematic review examining non-hormonal treatments in women with breast cancer , demonstrated a reduction in the number and severity of flashes with venlafaxine at low dose and at 75 mg/day when compared with placebo.
Desvenlafaxine is a novel serotonin-norepinephrine reuptake inhibitor, highly selective for serotonin and norepinephrine transporters, with weak or no affinity for dopamine receptors and transporters. Desvenlafaxine restored thermoregulatory function more rapidly than estrogen replacement in two rodent models of vasomotor symptoms and in two double-blind randomized placebo-controlled trials [5, 6]; 100 and 150 mg were found to decrease number of hot flashes after 12 weeks compared with placebo.
Use of these drugs in women with breast cancer using tamoxifen is common; therefore consideration must be given to potential interactions. Tamoxifen must be metabolized by the cytochrome P450 enzyme system, predominantly cytochrome P450 isoenzyme 2D6 (CYP2D6), to become active, and CYP2D6 is inhibited to varying degrees by SSRIs. Paroxetine is an exceptionally potent inhibitor, whereas sertraline inhibits to a lesser degree and citalopram and escitalopram are only weak inhibitors. Evidence is conflicting on the success rates of tamoxifen in preventing recurrence of breast cancer when using a concurrent SSRI. For those women who need to begin treatment with an SSRI for depression, citalopram or escitalopram may be the safest choice, however improvements in flashing are better with venlafaxine and desvenlafaxine, and these appear to be safe choices.
The mechanism of action of gabapentin in the amelioration of vasomotor symptoms is unknown, but it is thought to involve a direct effect on the hypothalamic thermoregulatory centre.
Two double-blind randomized placebo-controlled trials, examined in a meta-analysis , both conducted in women with breast cancer, showed a significant reduction in frequency and severity of hot flashes when taking gabapentin 900 mg per day, but not when taking 300 mg per day. Titrated to 2,400 mg per day continued to be superior to placebo but was not significantly different to estrogen 0.625 mg/day. However, dizziness, unsteadiness and fatigue were reported in the gabapentin-treated group and resulted in a higher dropout rate than in the control group.
Phytoestrogens are chemicals that resemble estrogen and are present in most plants, vegetables and fruits. There are three main types of phytoestrogens; soy isoflavones (the most potent), coumestans and lignans. Soyabean and red clover are also rich in phytoestrogens. These compounds are converted into weak estrogenic substances in the gastrointestinal tract.
Isoflavones are the most researched, and Nelson’s meta-analysis included 17 RCTs. From six trials comparing Promensil (red clover isoflavone) with placebo, only one fair-quality trial found a reduction in flash frequency with Promensil, although there was no overall reduction in the meta-analysis, and no improvement in flash severity was demonstrated in any of the included trials.
Soy isoflavones were compared with placebo in the remaining 11 trials. The meta-analysis revealed an improvement in hot flashes after 12–16 weeks (four trials) and after 6 months (two trials), but were not significantly decreased in studies examining 4–6 weeks’ use.
A systematic review  was also carried out by the Cochrane Collaboration. They included five trials in a meta-analysis, which demonstrated no significant decrease in the frequency of hot flashes with phytoestrogens.
Thirty trials were also studied comparing phytoestrogens with control. Some of the trials found that phytoestrogens alleviated the frequency and severity of hot flashes and night sweats when compared with placebo but many of the trials were of low quality or were underpowered. The great variability in the results of these trials may result in part from the difference in efficacy of the various types of phytoestrogens used, the exact treatment protocol and the fraction of equol producers in the cohort. It is claimed that only 30–40% of the US population possess the gut microflora responsible for converting isoflavones to the active estrogenic equol. It should be noted that there was also a strong placebo response in most trials, ranging from 1% to 59%.