Activation of heat-loss mechanisms can occur following relatively small changes in core temperature in symptomatic postmenopausal women<\/p>\n
Menopausal vasomotor symptoms (VMS) comprise hot flushes and night sweats. During a hot flush, characteristic physiological changes include cutaneous vasodilatation and sweating, accompanied by a sensation of heat. Heat loss may subsequently reduce core body temperature, and some episodes are followed by chills.<\/p>\n
Evidence from human physiological studies, human postmortem studies, experimental animal models and pharmacological studies implicates altered hypothalamic thermoregulation following loss of ovarian oestrogen signalling. Particular attention has focused on hypothalamic neurons that express kisspeptin, neurokinin B and dynorphin, collectively termed KNDy neurons.<\/p>\n
Normal thermoregulation
Body temperature is regulated by neural pathways that integrate signals from peripheral and central thermoreceptors. The preoptic region of the hypothalamus has an important role in coordinating autonomic responses to changes in temperature.<\/p>\n
When body temperature reaches the threshold for heat loss:<\/p>\n
cutaneous blood flow increases through vasodilatation;
\nsweating increases evaporative heat loss; and
\nbehavioural cooling responses may occur.<\/p>\n
At lower temperatures, heat-conservation and heat-production mechanisms include vasoconstriction and shivering.<\/p>\n
The range between the threshold for activation of heat-loss responses and the threshold for heat-conservation responses has been termed the thermoneutral zone, or interthreshold zone.<\/p>\n
In an experimental study, postmenopausal women who experienced hot flushes had a reduced thermoregulatory null zone compared with asymptomatic women. The sweating threshold and vasoconstriction threshold were separated by a smaller temperature interval in symptomatic women.<\/p>\n
Physiology during a hot flush
A hot flush involves activation of physiological heat-dissipation mechanisms.<\/p>\n
Documented changes include:<\/p>\n
increased cutaneous blood flow;
\nincreased skin temperature;
\nsweating; and
\nsubsequent heat loss.<\/p>\n
Small increases in core body temperature have been observed before some objectively recorded hot flushes. Freedman and Woodward monitored eight postmenopausal women and recorded 37 hot flushes using skin-conductance measurements. Core temperature increased before 24 of these episodes.<\/p>\n
These findings, together with evidence of a reduced thermoregulatory null zone, indicate that activation of heat-loss mechanisms can occur following relatively small changes in core temperature in symptomatic postmenopausal women.<\/p>\n
A hot flush therefore does not require a large increase in core body temperature. The measurable physiological event principally consists of vasodilatation and sweating followed by heat dissipation.<\/p>\n
Oestrogen withdrawal and hypothalamic changes
VMS commonly emerge during the menopausal transition, when ovarian follicular function declines and circulating concentrations of oestradiol become variable and subsequently low.<\/p>\n
Low circulating oestrogen concentration alone does not determine whether VMS occur. Symptomatic and asymptomatic postmenopausal women can have comparable oestrogen concentrations. Research has therefore examined the effects of loss of ovarian steroid feedback on central thermoregulatory pathways.<\/p>\n
Human postmortem studies have identified changes in neurons within the infundibular nucleus of the hypothalamus, which corresponds to the arcuate nucleus in commonly studied experimental animals.<\/p>\n
Rance and Young demonstrated hypertrophy of neurons expressing neurokinin B in postmenopausal women, together with increased neurokinin B gene expression. Subsequent human studies identified increased expression of kisspeptin and neurokinin B in this neuronal population following menopause.<\/p>\n
Experimental studies in ovariectomised animals have produced similar changes, and oestrogen administration reverses several of these effects. These animal data support an association between loss of ovarian steroid negative feedback and changes in the KNDy neuronal system.<\/p>\n
KNDy neurons
KNDy neurons are named because they co-express:<\/p>\n
Kisspeptin;
\nNeurokinin B (NKB); and
\nDynorphin.<\/p>\n
These neurons express oestrogen receptor-\u03b1 and have established functions in reproductive neuroendocrinology.<\/p>\n
Experimental studies indicate that KNDy neurons participate in the neuronal network underlying pulsatile gonadotrophin-releasing hormone secretion. Within experimental models, neurokinin B provides stimulatory signalling within the KNDy network and dynorphin provides inhibitory signalling, while kisspeptin stimulates GnRH neurons.<\/p>\n
Detailed mapping of the connections between KNDy neurons and thermoregulatory pathways has been performed predominantly in animal models. In rats, arcuate KNDy neurons project to preoptic hypothalamic regions that contain neurokinin-3 receptors (NK3R), including regions involved in heat-defence responses.<\/p>\n
In these models:<\/p>\n
activation of NK3R in the median preoptic region reduces body temperature;
\nKNDy-neuron ablation reduces cutaneous vasodilatation; and
\nKNDy-neuron ablation modifies the effects of oestrogen on thermoregulation.<\/p>\n
These findings are experimental animal evidence and do not constitute direct demonstration of the complete neural pathway in living menopausal women.<\/p>\n
Human evidence for neurokinin B involvement
Several forms of human evidence support involvement of the NKB\u2013NK3R pathway in menopausal VMS.<\/p>\n
Postmortem studies demonstrate increased neurokinin B expression and structural changes in hypothalamic neurons after menopause.<\/p>\n
In a randomised, double-blind crossover study, intravenous administration of neurokinin B to healthy premenopausal women produced episodes with features characteristic of hot flushes, including increased skin temperature and subjective flushing.<\/p>\n
Further evidence has come from clinical studies of neurokinin-receptor antagonists. NK3R blockade reduces the frequency and severity of menopausal VMS, providing pharmacological evidence that signalling through this receptor contributes to VMS.<\/p>\n
The detailed neuronal sequence proposed to connect oestrogen withdrawal, KNDy neuronal activity and activation of thermoregulatory heat-loss pathways is consequently based on converging evidence from human postmortem and physiological studies, animal experiments and human pharmacological studies rather than direct observation of the entire pathway in living humans.<\/p>\n
Current treatment of vasomotor symptoms
Management is based on symptom severity, individual clinical circumstances, contraindications and patient preference. Current NICE and British Menopause Society (BMS) guidance describe hormonal, non-hormonal pharmacological and psychological approaches to VMS.<\/p>\n
Hormone replacement therapy: NICE recommends offering HRT for VMS associated with menopause. For women with a uterus receiving systemic oestrogen, a progestogen is generally required for endometrial protection; oestrogen-only systemic HRT is generally used following total hysterectomy. Treatment choice, route and dose should be individualised according to clinical circumstances and the licensed product information.
\nMenopause-specific cognitive behavioural therapy: NICE recommends considering menopause-specific CBT in addition to HRT, when HRT is contraindicated, or when a woman prefers not to take HRT. HSE information also identifies CBT as an option for hot flushes and associated sleep problems.
\nFezolinetant: Fezolinetant is a selective NK3-receptor antagonist. Its EU and Irish marketing authorisation is for moderate-to-severe VMS associated with menopause. NICE recommends it as an option for moderate-to-severe VMS when HRT is unsuitable.
\nElinzanetant: Elinzanetant is an NK1- and NK3-receptor antagonist with EU marketing authorisation for moderate-to-severe VMS. It is included in the BMS July 2026 consensus statement on non-hormonal treatment. As of September 2026, a NICE technology appraisal is awaiting development; it is therefore not currently a NICE-recommended treatment for VMS.
\nSSRIs and SNRIs: The BMS reviews evidence for several SSRIs and SNRIs, including paroxetine, citalopram, escitalopram and venlafaxine. NICE advises that SSRIs and SNRIs should not routinely be offered as first-line treatment for VMS alone. The HSE explicitly describes antidepressant treatment of menopausal hot flushes with SSRIs or SNRIs as off-label.
\nGabapentin and pregabalin: The BMS includes both among non-hormonal medicines shown in randomised placebo-controlled trials to reduce hot flushes. They are not identified by NICE as routine first-line treatments for VMS.
\nClonidine: HSE information states that clonidine can reduce menopausal hot flushes and night sweats. The BMS also discusses clonidine as a non-hormonal option. NICE advises that it should not routinely be offered as first-line treatment for VMS alone.<\/p>\n
The inclusion of a medicine in clinical guidance or a professional consensus statement does not, in itself, establish that it has a licensed indication for menopausal VMS. Prescribing decisions should therefore distinguish between guideline recommendations, evidence supporting use and the authorised indications stated in the relevant product information.<\/p>\n
Clinical relevance
The available physiological evidence establishes several points relevant to general practice:<\/p>\n
Hot flushes involve centrally mediated activation of heat-dissipation mechanisms, including cutaneous vasodilatation and sweating.
\nSymptomatic postmenopausal women can have a reduced thermoregulatory null zone.
\nMenopause is associated with structural and gene-expression changes in hypothalamic neurons expressing neurokinin B and kisspeptin.
\nAnimal studies demonstrate connections between KNDy neurons and preoptic thermoregulatory pathways.
\nHuman neurokinin B administration can reproduce physiological features of flushing.
\nClinical efficacy of neurokinin-receptor antagonism provides human pharmacological evidence for involvement of neurokinin signalling in menopausal VMS.<\/p>\n
The full neuronal pathway responsible for menopausal hot flushes has not been directly observed in living humans. Current understanding is derived from the combined findings of human physiological and postmortem research, experimental animal studies and clinical pharmacology.<\/p>\n
References available on request. <\/p>\n","protected":false},"excerpt":{"rendered":"Activation of heat-loss mechanisms can occur following relatively small changes in core temperature in symptomatic postmenopausal women Menopausal…\n","protected":false},"author":2,"featured_media":621720,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[2121,103,178826,61,60,263983,12359,56024],"class_list":["post-621719","post","type-post","status-publish","format-standard","has-post-thumbnail","category-health","tag-womens-health","tag-health","tag-hot-flushes","tag-ie","tag-ireland","tag-menopausal-vasomotor-symptoms-vms","tag-menopause","tag-oestrogen"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/621719","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/comments?post=621719"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/621719\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media\/621720"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media?parent=621719"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/categories?post=621719"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/tags?post=621719"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}