| Popis: |
Hot flushes are the most commonly reported symptom in postmenopausal women, occurring in approximately 73% of women and causing significant morbidity in 25%, affecting social life and even the ability to work. With improved healthcare and increased life expectancy (death rates decreased by 19% in the last 10 years), women spend a considerable proportion of their lives (30 years on average) in the menopause. At present 36% of the women in the UK are over 50 years of age. If left untreated, hot flushes resolve within one year, or less, in the majority of postmenopausal women. A third will report symptoms that last up to 5 years after natural menopause, and in 20% hot flushes persist for up to 15 years. This equates to as many as 1.5 million women in the UK. Despite this the mechanism of flushing is still poorly understood. A hot flush resembles a heat dissipation response, in that both are characterised by sweating and peripheral vasodilation. It follows that the underlying mechanism may involve some dysfunction in thermoregulation, which in humans is controlled by the medial preoptic area of the hypothalamus (MPOA), and effectors include cutaneous vessels for vasodilation and vasoconstriction. Therefore a dysfunction in thermoregulation may lie within the control centre (MPOA), its messengers (adrenergic neurones controlling vasoconstriction and cholinergic neurones controlling vasodilation) or the effectors (cutaneous vessels). Studies by Freedman et al, using an ultrasensitive temperature probe, suggest that hot flushes are triggered by small elevations in core body temperature (Tc) acting within a narrowed thermoneutral zone, mainly due to a lowering of the sweating threshold, in symptomatic postmenopausal women. However, the trigger remains unknown. Oestrogen is likely involved as these changes occur at times of relative oestrogen withdrawal; however, there is little correlation between hot flushes and circulating oestrogen levels. This suggests that other mechanisms are involved. Noradrenaline is thought to be the primary neurotransmitter responsible for lowering the thermoregulatory set point and triggering hot flushes. Animal studies have shown that intrahypothalamic injection of noradrenaline acts to narrow the thermoregulatory zone and hot flushes can be provoked in symptomatic postmenopausal women with the α2-adrenergic antagonist yohimbine, and ameliorated with clonidine, an α-adrenergic agonist. Furthermore, clonidine has been shown to widen the thermoregulatory zone in humans. Serotonin or 5-hydroxytriptamine (5-HT) is involved in many bodily functions including mood, anxiety, sleep, sexual behaviour and eating, and is thought to play a key role in thermoregulation. Oestrogen withdrawal is associated with decreased blood serotonin levels, which is returned to normal with oestrogen therapy. Furthermore, selective serotonin reuptake inhibitors (SSRI), designed to increase the available serotonin at the serotonergic synapse, have been shown in placebo-controlled trials to be effective in reducing the number and severity of hot flushes. It has also been shown that flushing women have a diminished vasoconstrictor response to cold and that they have increased blood flow to the forearm and hand during a flushing episode. Alterations in skin blood flow during a flushing attack have also been demonstrated in castrate men, and, as with women, improvements in symptoms are seen with hormone replacement. The aim of this thesis was to better understand the mechanism of flushing in postmenopausal women and hypogonadal men by assessing the role of cutaneous vessels. I measured cutaneous microvascular perfusion, using LASER Doppler imaging with iontophoresis, in postmenopausal women who flush and compared it with postmenopausal women with no flushing, and found that perfusion responses to vasoactive agents were increased in women with flushing. Paradoxically, these women with apparently ‘better’ endothelial function had evidence of serum cardiovascular risk factors. In a double-blind longitudinal cross over study, the role of the alpha-adrenergic system in the pathophysiology of flushing was investigated, by treating women with clonidine and placebo. There was an increase in perfusion responses with both clonidine and placebo. Clonidine was not shown to be superior to placebo in reducing the number and severity of flushes. The role of serotonin, both peripherally and centrally was studied by treating postmenopausal women, who experienced severe flushing, with venlafaxine (a serotonin and noradrenaline reuptake inhibitor that acts as a selective serotonin reuptake inhibitor at low doses). Flushing symptoms, as assessed by hot flush diaries and Greene climacteric scale (GCS) scores, were reduced, as were skin blood flow perfusion responses. Central serotonin transporters (SERT) were assessed in vivo using SPECT (single photon computed tomography) imaging and a radioligand, [123I] -beta-carbomethoxy-3-β-(4 iodophenyl)tropane ([123I] beta-CIT), with a high affinity for serotonin transporters. [123I] beta-CIT binding was significantly reduced, and this was associated with a significant reduction in BDI scores; in a group of non-depressed women. Adiposity is associated, both, with an increased risk of postmenopausal flushing and impaired endothelial function, but in this study, there were no differences demonstrated between obese and lean participants at baseline, despite significant differences in serum markers of endothelial dysfunction. Oestrogen receptors are also present on endothelial cells and as the most commonly used, and most effective, treatment for vasomotor symptoms, cutaneous microvascular perfusion was assessed following 8 weeks of HRT, and demonstrated an increase in both endothelium dependent and independent vasodilation. Hot flushes are also common in men on luteinising hormone releasing hormone (LHRH) agonists for prostate cancer therapy. Perfusion responses in these men were assessed prior to commencement of therapy (baseline), and after 8 and then 24 weeks of therapy. No differences were detected at baseline, between those who developed flushing as a result of treatment, and those who did not. At 8 weeks, those with flushing demonstrated increased skin blood flow compared to those without flushing. At 24 weeks, 2 gentlemen with flushing had kept diaries and these demonstrated an improvement in flushing, but no alteration in perfusion responses. ACh- and SNP-stimulated vasodilation was, however, reduced when compared to healthy controls. In this thesis, the data appear to support a role of skin blood flow in the mechanism of hot flushing in both postmenopausal women and hypogonadal men, which may be controlled or altered via neurotransmitters at a local level. The placebo response was significant, but alterations in skin blood flow do not appear to have mediated the adiposity effect. |
