nature reviews endocrinology [Link]

1038/s41574-026-01247-8

Review article Check for updates

Neurokinin receptor antagonists for

vasomotor symptoms: from KNDy
neurons to clinical translation
Encarnación Torres , Ellen G. Wall
1,2 1,2
& Víctor M. Navarro 1,2,3

Abstract Sections

Vasomotor symptoms (VMS), including hot flushes and night sweats, Introduction

affect approximately 70% of people experiencing menopause and KNDy neurons during
have a notable effect on quality of life. Until the past few years, the reproductive years

underlying neuroendocrine mechanisms remained poorly understood, KNDy neurons during

menopause: the onset of VMS
limiting therapeutic options beyond menopausal hormone therapy.
The discovery that neurons expressing kisspeptin, neurokinin B and Evidence of the
thermoregulatory role of NKB
dynorphin (KNDy neurons) in the hypothalamic arcuate nucleus and NK3R across species
trigger VMS through modulation of neurons expressing neurokinin 3 Role of substance P and
receptor (NK3R) in the median preoptic area has revolutionized our NK1R in thermoregulation
understanding of VMS pathophysiology. During oestrogen withdrawal, Preclinical models to
hyperactivated KNDy neurons release excessive levels of neurokinin B, study hot flushes

inappropriately triggering heat dissipation responses that are Classic treatments for
menopausal hot flushes
characteristic of hot flushes. This mechanistic insight has enabled
the development of NK3R antagonists as the first non-hormonal Development of neurokinin
receptor antagonists
therapeutic specifically targeting VMS neurobiology. These new
treatments offer promise for populations in which hormone therapy is Clinical considerations
of neurokinin receptor
contraindicated. This Review synthesizes the current understanding antagonists
of VMS neurobiological pathways, examines translational approaches Conclusions
from preclinical animal models to clinical studies, and discusses the
evolution of treatments and mechanism-based interventions that might
fundamentally transform the management of menopausal symptoms.

Harvard Medical School, Boston, MA, USA. 2Department of Medicine, Division of Endocrinology, Mass General
1

Brigham, Boston, MA, USA. 3Harvard Graduate Program in Neuroscience, Boston, MA, USA. e-mail: vnavarro@
[Link]

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Review article

Key points and night sweats. Here, the common assumption has been that the
hypothalamic set point remains unchanged, but oestrogen withdrawal
narrows the thermoneutral zone. Consequently, normal fluctuations
• Neurons expressing kisspeptin, neurokinin B and dynorphin (KNDy in core temperature surpass the lowered threshold for heat loss activa-
neurons) in the hypothalamic arcuate nucleus trigger vasomotor tion, triggering abrupt heat dissipation responses10–13 (Fig. 1). Although
symptoms (VMS) through neurokinin B (NKB) signalling to neurokinin 3 changes in the thermoneutral zone contribute to VMS, in the following
receptor (NK3R)-expressing thermoregulatory neurons in the median sections, this Review delves into novel neuroendocrine pathways that
preoptic area. participate in their onset.
VMS manifest as sudden, brief episodes of intense skin flushing
• Oestrogen withdrawal during menopause causes hyperactivation (especially noticeable on the face, neck and chest) accompanied by
of KNDy neurons, leading to excessive NKB release and inappropriate sweating, which leads to a transient decline in core body tempera-
activation of heat dissipation responses. ture and might trigger autonomic symptoms such as palpitations
and anxiety10,12,13. Each episode typically lasts 1–5 min and is marked
• NK3R antagonists are the first non-hormonal therapeutics specifically by a rapid increase in skin temperature that can exceed core body
targeting the neurobiological mechanism of hot flushes rather than temperature by over 4 °C11,14. Research from SWAN (Study of Women’s
providing symptomatic relief. Health Across the Nation) suggests that 60–80% of women experience
VMS during the menopausal transition, with rates varying by race and
• Fezolinetant (a selective NK3R antagonist) and elinzanetant (a dual ethnicity15. SWAN data reveal pronounced racial and ethnic dispari-
NK1R–NK3R antagonist) achieved FDA approval in 2023 and 2025, ties: African American women report the highest VMS rates (adjusted
respectively, for the treatment of moderate-to-severe VMS. OR 1.63) and longest duration (median ~10 years), whereas women
of Chinese or Japanese heritage report the lowest rates15,16. Hispanic
• Dual NK1R–NK3R antagonism with elinzanetant might provide women show intermediate rates with considerable variation across
additional sleep benefits independent of a reduction in the incidence subgroups17. These disparities persist after adjustment for BMI, edu-
and severity of VMS through modulation of serotonergic pathways. cation attainment level and pre-existing anxiety, which suggests that
additional biological or social factors contribute to racial and ethnic
• Neurokinin receptor antagonists offer critical therapeutic options for differences in VMS. VMS persist for a median of 4–7 years, although
women with hormone therapy contraindications, including those who approximately 20% of people report symptoms for more than a decade
have had breast cancer and are receiving endocrine therapy. after menopause13,16. The intensity and frequency of VMS can severely
affect the quality of life of the individuals who experience them13,16.
Importantly, VMS are not exclusive to natural menopause. VMS
Introduction prevalence approaches 60% in pre-menopausal people who have had
Human core temperature is highly regulated to stay consistently around breast cancer and received therapies such as gonadotropin-releasing
37 °C and varies by no more than approximately 0.3 °C under normal hormone (GnRH) analogues, selective oestrogen receptor modulators
physiological conditions1–3. This tight thermal homeostasis is achieved or aromatase inhibitors18. Androgen deprivation therapy in patients
through a narrow thermoneutral zone, which is controlled by special- with prostate cancer causes similar symptoms in up to 80% of those
ized temperature-sensitive neurons in the hypothalamic preoptic area who undergo treatment19,20. These observations show that VMS rep-
(POA)2,3. This hypothalamic ‘thermostat’ integrates thermal informa- resent a common pathway driven by sex hormone deficiency, inde-
tion from skin and internal thermoreceptors and orchestrates appro- pendent of sex, age or underlying cause. In men receiving androgen
priate autonomic and behavioural responses to maintain the body’s deprivation therapy, oestrogen deficiency rather than testosterone
temperature set point. deficiency per se seems to be the primary driver of VMS, as oestradiol
Despite this robust regulatory system, several physiological and is aromatized from testosterone. Supporting this theory, transder-
pathological states can elevate body temperature beyond its normal mal oestradiol effectively reduces hot flushes in men on androgen
range, each through distinct mechanisms. Fever is the most commonly ­deprivation therapy21,22.
recognized hyperthermic state, characterized by an upward shift in
the temperature set point4–6. During fever, pyrogens (such as IL-1β, KNDy neurons during reproductive years
IL-6 and TNF; produced by the host immune system in response to KNDy neurons are critically involved in the pulsatile release of lutein-
bacterial or viral infection) in the circulatory system trigger the syn- izing hormone (LH) during reproductive years through an autosynaptic
thesis of prostaglandin E2 (PGE2), which acts on the prostaglandin EP3 feedback loop that involves the stimulatory action of neurokinin B
receptor (EP3R) on median preoptic (MnPO) area neurons, resulting (NKB) acting on its receptor, neurokinin 3 receptor (NK3R; present
in the hypothalamic temperature target increasing by 1–2 °C4–6. The in the majority of KNDy neurons) and the inhibitory action of dynor-
body initially responds by activating cold defence mechanisms, such phin A acting on the κ-opioid receptor23,24. This autosynaptic model
as vasoconstriction and shivering, until the new febrile set point is posits that NKB, via NK3R, enhances the neuronal excitability of KNDy
reached7. By contrast, exercise-induced hyperthermia and environ- neurons. KNDy neurons are interconnected through a dense plexus
mental heat stress do not alter the hypothalamic set point8,9. Instead, of fibres, and NKB release also reaches adjacent KNDy neurons in the
metabolic heat generated during physical exertion or external heat arcuate, thereby promoting the coordinated (synchronized) pulsatile
exposure exceeds the body’s heat dissipation capacity, causing the release of kisspeptin, which directly stimulates GnRH neurons and
hypothalamus to maximally engage heat loss pathways to restore subsequently leads to defined LH pulses23,24 (Fig. 2a). This dynamic
thermal balance8,9. A third hyperthermic response is vasomotor symp- model is highly dependent on the circulating level of sex steroids.
toms (VMS), which encompass hot flushes (also termed hot flashes) When these levels decrease, KNDy neurons become activated and

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39 1 Normal physiology 2 Fever 3 Exercise or heat stress 4 Hot flushes

Elevated core temperature

Elevated thermoneutral zone

38
Elevated set point (38–39°C) Heat production
Temperature (°C)

exceeds dissipation Narrowed

thermoneutral
zone
Thermoneutral
Thermoneutral zone
zone
37
Set point (37°C)

Mechanism Mechanism Mechanism

• ±0.3°C variation • Pyrogens → PGE2 → EP3R • Metabolic and/or external heat • Sex steroid withdrawal
• Tight homeostasis • Set point elevation • Maximal heat dissipation • Narrowed threshold range
36 • Increased KNDy activity

Core body temperature Hypothalamic temperature set point (37°C)

Fig. 1 | Distinct mechanisms underlying different hyperthermic states. cold defence mechanisms until the febrile temperature is reached. During
Comparison of thermoregulatory responses across four conditions. Red dashed exercise and/or heat stress (3), the hypothalamic set point remains unchanged;
lines indicate the hypothalamic temperature set point; yellow lines and waves however, metabolic heat production during physical exertion or external
represent core body temperature; blue shaded regions denote the thermoneutral heat exposure exceeds the body’s heat dissipation capacity, causing core
zone (the range of ambient temperatures requiring no active thermoregulation). temperature to rise above the thermoneutral zone and triggering maximal heat
Under conditions of normal physiology (1), core temperature is maintained at loss responses. In conditions of vasomotor symptoms (hot flushes) (4), oestrogen
37 ± 0.3 °C through tight homeostatic control within the thermoneutral zone. withdrawal during menopause narrows the thermoneutral zone without altering
During fever (2), inflammatory mediators (pyrogens) trigger prostaglandin E2 the set point. This narrowing is mediated by increased KNDy neuron activity;
(PGE2) synthesis, which acts on prostaglandin EP3 receptors (EP3R) in consequently, normal minor fluctuations in core temperature can exceed
median preoptic neurons to elevate the temperature set point by 1–2 °C. The the constricted threshold for heat loss activation, triggering inappropriate
thermoneutral zone shifts upward to match the new set point, initially activating cutaneous vasodilation and sweating characteristic of hot flushes.

release NKB and dynorphin, which increases the pulsatile release of commonly used for research35–37 (Fig. 3). Although the neuropeptide
kisspeptin, and thereby GnRH–LH pulses that activate the reproduc- co-expression of KNDy neurons in non-human primates remains less
tive axis23–26. During adulthood, the pulsatile release of GnRH is tightly clear than in humans and rodents, initial studies have suggested that
controlled to facilitate the appropriate pattern of gonadotropin (LH expression of NKB and substance P is similar to that in humans38–41.
and follicle-stimulating hormone (FSH)) release, which promotes game- These species-specific profiles might be critical to accurately translate
togenesis and sex steroid production by the gonads of both sexes. The research findings from animal models to human physiology. However,
increase in circulating levels of sex steroids leads to the closing of the despite these potential co-expression differences, preclinical models
negative feedback loop in the hypothalamic–pituitary–gonadal axis are highly translational to human physiology as the overt role of KNDy
by directly acting on sex steroid receptors on KNDy neurons27. neurons at the apex of the hypothalamic–pituitary–gonadal axis is
A common feature of KNDy neurons in all studied species is their highly conserved amongst mammalian species. In all cases, KNDy neu-
high sensitivity to circulating sex steroids. They express oestrogen rons become activated before puberty onset; through this activation,
receptor-α, androgen receptor and progesterone receptor, which the neurons drive sexual maturation by facilitating the re-activation of
makes them a direct target of the negative feedback of sex steroids GnRH neurons in both sexes and the initiation of GnRH pulses23,24, as
during reproductive years25,26,28,29. This is a crucial feature, as GnRH well as maintaining fertility during reproductive years.
neurons are devoid of these receptors and, thus, they behave largely
as surrogates of KNDy neuron activity. The model described in the KNDy neurons during menopause: the onset
previous paragraph has been widely accepted as the ‘GnRH pulse gen- of VMS
erator’23; however, over the past few years, additions to the model, such To elucidate the neuroendocrine mechanisms that trigger a hot
as the role of glutamate (also released from KNDy neurons), are emerg- flush, we need to understand how KNDy neurons behave during the
ing, which indicates that the GnRH pulse generator is a more complex ­menopausal transition.
mechanism than was initially described by the KNDy model30,31. The first insight into KNDy neurons and their role in menopause
Notable species differences exist regarding the neuropeptide originated from seminal studies by Rance’s group in the 1990s, who
composition of KNDy neurons. Rodents and sheep consistently express demonstrated that neurons that express NKB in the infundibular
kisspeptin, NKB and dynorphin32–34. By contrast, human KNDy neurons nucleus of postmenopausal women (equivalent to the arcuate nucleus
express substance P and seem to lack dynorphin, which highlights the in other species) and ovariectomized monkeys are hypertrophied.
important differences between humans and the animal models that are This finding was prior to the finding that these NKB neurons of the

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a Reproductive age b Menopause

Thermoregulatory
neuron
Vasomotor
symptoms
(hot flushes)

KNDy neurons KNDy neurons

GnRH neuron GnRH neuron

Hypothalamus Hypothalamus

GnRH GnRH

Median Median
eminance eminance

Anterior Anterior
pituitary pituitary
Posterior Posterior
pituitary pituitary

LH and FSH Ovary Oestradiol LH and FSH Ovary ↓ Oestradiol

Dynorphin κ-opioid receptor Kisspeptin KISS1R Neurokinin B NK3R Substance P NK1R

Oestradiol production LH secretion after withdrawal of sex steroids

Volume of maximum

100
oestradiol (%)

80
60 80
40
LH levels (mIU/ml)

20
0
10 20 30 40 50 60 70 80 40
Age (years)
Progesterone production
Volume of maximum
progesterone (%)

100
80 20
60
40
20
0 0
10 20 30 40 50 60 70 80 Reproductive years Menopause Postmenopause
Age (years)
Age

Warm-sensitive neurons or neurokinin receptor neurons

c KNDy neuron projections
GnRH neurons NK3R neurons NK1R neurons
α β γ α β γ α β γ

KNDy neuron

↑ Kisspeptin ↑ Neurokinin B ↑ Substance P

Median eminence Preoptic area

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Fig. 2 | KNDy neuron function during reproductive years versus menopause. across the reproductive lifespan in women. b, Following oestrogen withdrawal
a, Reproductive years: KNDy neurons in the infundibular nucleus (equivalent in menopause, loss of inhibitory feedback leads to hyperactivation and
to the arcuate nucleus in rodents). KNDy neurons co-express kisspeptin, hypertrophy of KNDy neurons. This results in increased release of NKB (and
neurokinin B (NKB), dynorphin and, in humans, substance P. NKB acts through potentially substance P) not only within the KNDy network but also to NK3R-
neurokinin 3 receptor (NK3R) in an autosynaptic manner to synchronize KNDy expressing neurons in the median preoptic (MnPO) area, triggering vasomotor
neuron activity, promoting pulsatile kisspeptin release onto GnRH neurons in symptoms (hot flushes). The dashed line from the ovary indicates diminished
the median eminence. This drives pulsatile GnRH secretion and subsequent gonadal steroid production. The graph shows the characteristic high-amplitude,
release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from high-frequency LH secretion pattern after oestradiol withdrawal. c, A detailed
the anterior pituitary, which stimulates ovarian oestradiol and progesterone view of KNDy neuron projections. KNDy neurons project to gonadotropin-
production. In the circulation, sex steroids provide negative feedback directly to releasing hormone (GnRH) neurons (via kisspeptin acting on KISS1R) for
KNDy neurons via oestrogen receptor-α, androgen receptor and progesterone reproductive control and to thermoregulatory neurons in the MnPO area
receptor, maintaining homeostatic control of the reproductive axis. The graphs (via NKB acting on NK3R, and potentially substance P acting on NK1R) for
show the characteristic pattern of oestradiol and progesterone production temperature regulation.

arcuate nucleus co-express kisspeptin and dynorphin42–44, which hap- flushes may be associated with only a single LH pulse (of longer dura-
pened in the late 2000s in studies in sheep and rodents, and led to their tion), as was observed in several individuals included in that study52.
­designation as KNDy neurons32–34. In other words, there has not been enough time to clear all LH in cir-
During menopause, reduced oestradiol levels lead to increased culation from the previous pulse before the next temperature event
neuronal activity in KNDy neurons, due to loss of oestrogenic inhibitory is triggered. An additional determining factor is that the thresholds
feedback27,45–47. This heightened KNDy neuron activity is associated required for kisspeptin to activate kisspeptin receptor in GnRH neurons
with enhanced synthesis and release of NKB, which first amplifies (which is extremely low) and for NKB to activate NK3R and induce a VMS
NK3R signalling within the highly interconnected KNDy population mechanism in the MnPO area might be considerably different, leading
of neurons45–47. Then, KNDy neurons increase the output of NKB to to the lack of complete synchronization between GnRH and MnPONK3R
a group of NK3R-expressing (NK3R+) neurons located in the hypo- neuron activation; that is, between hot flushes and LH pulses.
thalamic MnPO (MnPONK3R) that contribute to the regulation of body The nature of MnPONK3R neurons, as the receiver of KNDy input,
temperature45–47 (Fig. 2b,c). Activation of MnPONK3R neurons by a NK3R is still a matter of active investigation. If the populations of NK3R+
agonist (senktide) or directly by NKB from KNDy neurons triggers heat and EP3R+ neurons that have been involved in thermoregulation (hot
dissipation responses (that is, an increase in peripheral (skin) tempera- flushes and fever, respectively) are both located in the MnPO area, it
ture and a decrease in core temperature), which replicates the heat loss begs the question of whether there is overlap between these popu-
events characteristic of menopausal hot flushes45–47. lations, or whether they could be the same neurons (Fig. 4a). Both
Because LH pulses and hot flushes share a common source, we populations share a glutamatergic phenotype, with almost all MnPOEP3R
could anticipate a temporal correlation between them. In fact, this neurons and MnPONK3R neurons expressing VGluT2 (refs. 56,57).
correlation has been a subject of considerable scientific debate since Single-cell transcriptomic analyses in mice have revealed that Tacr3
much earlier than the identification of KNDy neurons. Studies in the (NK3R) and Ptger3 (EP3R) are indeed co-expressed within specific
late 1970s established what became a commonly accepted paradigm. In thermoregulatory neuronal clusters in the POA, which suggests that
1979, Casper and colleagues and Tataryn and colleagues reported that these populations might represent overlapping components of an
hot flushes showed a high correlation with LH pulses in their cohorts of integrated thermoregulatory network rather than entirely separate
menopausal women48,49, which suggested a causal relationship. How- circuits58,59. This potential overlap has important functional implica-
ever, subsequent research published in the early 1980s challenged this tions; because EP3R+ neurons respond to inflammatory mediators in
apparent synchronization. This research demonstrated that women the same way that NK3R+ neurons respond to NKB from KNDy neu-
with isolated gonadotropin deficiency or pituitary insufficiency expe- rons, alterations in one of these pathways might result in changes
rienced hot flushes despite absent LH pulses50,51, which indicated that in the other. This interaction might be clinically relevant, especially
it is not LH pulses that trigger hot flushes, but that they share a com- as NK3R antagonists (discussed in subsequent sections) are used to
mon upstream regulator. Today, we recognize this common upstream treat hot flushes, which could potentially interfere with normal fever
regulator as KNDy neurons. Nonetheless, an analysis published in 2019 responses. Nonetheless, the published trials investigating the use of
that used LH readings and two independent mathematical modelling NK3R antagonists to treat hot flushes have not found notable issues
approaches showed that LH pulses and hot flushes are not consist- with fever suppression; however, whether this potential outcome has
ently synchronized in the majority of menopausal women, with only been specifically monitored is unclear.
one of 11 participants showing a high probability of matched intervals
between LH pulses and hot flush episodes52. However, this seeming Evidence of the thermoregulatory role of NKB and
dissociation between LH pulses and hot flushes in mathematical mod- NK3R across species
elling might only reflect fundamental differences in the temporal Across species, exogenous NKB or the NK3R agonist senktide produce
kinetics of endocrine versus thermoregulatory responses rather than rapid, route-dependent and context-dependent thermoregulatory
independent mechanisms. effects (Supplementary Table 1). In men, treatment with intravenous
It is worth noting that in the absence of sex steroids, the hyperacti- NKB at 0.04–5.12 nmol/kg/h for 90 min did not produce hot flushes,
vation of KNDy neurons can lead to clusters of increased synchronized cardiovascular changes or gonadotropin effects, whereas treat-
activity, also referred to as multi-peak synchronization events27,53–55, ment with 10.24 nmol/kg/h provoked hot sensations in a subset of
that might translate into several temperature events. That is, several hot individuals, which was accompanied by a mild rise in heart rate and

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a b

Hot flushes
and increased
sweating

• Natural menopause Ovariectomized mouse

• Surgical menopause
• Sex steroid-deprivation therapy

KNDy NK3R+ KNDy NK3R+

neuron neuron neuron neuron

Increased secretion Increased

of neurokinin B and Neuronal secretion of
substance P circuitry neurokinin B

NK3R NK3R
Neurokinin B

NK3R NK3R

Substance P
NK1R NK3R

KNDyInfundibular nucleus NK1RMnPO or NK3RMnPO KNDyARC NK3RMnPO

Fig. 3 | Comparative neuroanatomy of the KNDy thermoregulatory circuit in populations involved in thermoregulation. This dual neurokinin signalling might
humans and rodents. Key species differences in neurokinin signalling that are explain why dual NK1R–NK3R antagonists (such as elinzanetant) show efficacy in
relevant to vasomotor symptoms. a, In women experiencing menopause, surgical treating human vasomotor symptoms. b, In ovariectomized mice, KNDy neurons
menopause or sex steroid deprivation therapy, KNDy neurons in the infundibular in the arcuate nucleus similarly project to the MnPO area. However, rodent
nucleus project to thermoregulatory neurons in the median preoptic (MnPO) KNDy neurons predominantly express NKB without substantial substance P co-
area. Human KNDy neurons co-express both neurokinin B (NKB) and substance P, expression. This species difference in neuropeptide co-expression has important
enabling them to signal through both neurokinin 3 receptor (NK3R) and NK1R implications for translating preclinical findings to human physiology and might
on target neurons. The MnPO area contains neurons expressing both NK1R and partially explain differences in therapeutic responses between selective NK3R
NK3R (NK1RMnPO or NK3RMnPO), which might represent overlapping or identical antagonists and dual NK1R–NK3R antagonists.

dose-dependent gonadotropin responses. Extending intravenous Japanese Black cattle, a 4 h intravenous infusion of senktide in female
administration of NKB to 4–8 h at 2.56–5.12 nmol/kg/h also failed cows reduced vaginal temperature in both winter and summer, with a
to change the LH pulse pattern60. In women, intravenous NKB infu- greater mean change than induced by vehicle or GnRH, which indicated
sion (5.12 nmol/kg/h; during the follicular phase) for 30 min elicited that the hypothermic effect is not secondary to gonadotropin-releasing
participant-reported hot flushes within 1–12 min without concur- activity65. Taken together, cross-species evidence supports a unified
rent changes in LH, FSH or oestradiol61. In female rats, the delivery of model in which NK3R activation engages MnPO area heat defence
senktide into the MnPO area (18 or 90 pmol) caused dose-dependent mechanisms to drive thermoregulation.
hypothermia at both 21.5 °C and 29 °C ambient temperature, with tail-
skin vasodilation observed at 29 °C. Subcutaneous administration of Role of substance P and NK1R in thermoregulation
senktide (0.5 mg/kg) in female rats induced a rapid fall in core tem- NKB belongs to the tachykinin family of peptides that includes sub-
perature that was abolished when NK3R-expressing neurons in the stance P and neurokinin A (NKA). An important feature of tachykinins is
MnPO area were ablated45,62. that they can bind to their multiple receptors; however, these receptors
In mice, subcutaneous administration of senktide (0.125– do have different binding affinities for the different tachykinins. Sub-
0.750 mg/kg) decreased core temperature with a transient tail-skin stance P binds neurokinin receptor 1 (NK1R) with the highest affinity,
temperature rise during thermocline testing in both sexes. In ovariec- whereas NKA preferentially binds NK2R and NKB binds NK3R; however,
tomized female mice, 0.5 mg/kg of senktide produced a rapid decline at increasing concentrations of the ligands, binding to all receptors
in core temperature with an acute rise in skin temperature, whereas is possible66. In the context of thermoregulation, in addition to the
ovariectomized female mice receiving oestradiol replacement showed described role of the NKB–NK3R system, substance P–NK1R might
a delayed and blunted drop in core temperature without the acute also participate in both central and peripheral mechanisms. KNDy neu-
surge in skin temperature63,64. In a large animal model, the seasonal rons express NK1R, at least in rodents67, which indicates that the KNDy

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elements might be directly modulated by substance P, thus regulating area, which suggests that substance P might be involved in VMS as a
their activity. Of note, NK2R seems to be absent in KNDy neurons, at result of oestrogen withdrawal43,77.
least in rodents68. The thermoregulatory role of substance P–NK1R might also
Substance P (Tac1) and NK1R (Tacr1) are also present in the POA, include peripheral actions. Studies of fever have implicated NK1R in
according to evidence across multiple species. In rats, dense substance febrile responses primarily via peripheral COX2, which leads to the
P-immunoreactive fibres are present throughout the MnPO area, plac- production of PGE2, highlighting a wide thermoregulatory relevance78.
ing the ligand squarely in this thermoregulatory area69–71, and NK1R Moreover, substance P acts as a potent vasodilator in human and rodent
has been localized on neurons within the POA, which demonstrates skin in a process that involves a nerve-to-blood-vessel reflex (Fig. 4b).
receptor availability for those substance P fibres in preoptic circuits72,73. In healthy men, intra-arterial infusion of substance P induces marked
Functionally, in vitro studies in preoptic hypothalamic slices from rats forearm vasodilation that can be dose-dependently antagonized by
have shown that substance P can modulate the activity of the major- the selective NK1R antagonist L-754,030 (ref. 79). In the skin, prior
ity of thermosensitive neurons that have been recorded74. In vivo, NK1R desensitization alters the nerve-to-blood-vessel increase in skin
although only a subset of preoptic thermosensitive neurons seem blood flow, indicating that substance P–NK1R signalling contributes to
to respond to substance P75, the findings still indicate a modulatory cutaneous vasodilation80. In rats, brief occlusion of blood to one of the
role in thermoregulation for the substance P–NK1R system at this paws induces a consequent increase in skin blood flow that is mainly
site. Because KNDy neurons in humans co-express substance P76, it is driven by local sensory nerves. Direct administration of substance P
possible that, in addition to NKB–NK3R, the substance P–NK1R system reproduces this vasodilation effect, which suggests that substance P
also participates in the onset of VMS at the MnPO area level (Figs. 3 and is a critical nerve-derived factor that induces vasodilation81. None-
4a). In this line, tissue samples from postmenopausal women show theless, substance P is not the only factor released from these fibres
hypertrophy of substance P-containing neurons in the infundibular that is involved in vasodilation, as calcitonin gene-related peptide is

a Central neurokinin receptor pathways b Peripheral neurokinin receptor pathways

MnPO
area
Vasoconstriction Vasodilation

Heat
Arcuate dissipation Sweat
nucleus

MnPO area Arcuate nucleus

Neurokinin B
NK3R

NK1R ? Substance P
NK1R

NK3R+ neuron KNDy neuron

Substance P

Fig. 4 | Central and peripheral neurokinin receptor pathways potentially b, Peripheral neurokinin receptor pathways. In addition to having central
contributing to vasomotor symptoms. a, Central neurokinin receptor mechanisms, substance P might contribute to the cutaneous manifestations
pathways. The hypothalamic circuitry underlying hot flushes is illustrated. KNDy of hot flushes through peripheral vasodilator actions. Substance P released
neurons in the arcuate nucleus release neurokinin B (NKB) and substance P, from sensory nerve terminals in the skin acts on endothelial NK1R to promote
which act on neurokinin 3 receptor positive (NK3R+), and potentially NK1R+ vasodilation (right: dilated vessels with increased heat dissipation indicated
neurons, in the median preoptic (MnPO) area. The MnPO area serves as a critical by red arrows) compared with the vasoconstricted state (left). This peripheral
thermoregulatory hub and also contains prostaglandin EP3 receptor positive mechanism might amplify the cutaneous flushing and sweating characteristic
(EP3R+) neurons that bind prostaglandin E2 (PGE2) and mediate fever responses. of vasomotor symptoms. Of note, except for the established KNDy to
The potential overlap between NK3R+ and EP3R+ neuronal populations MnPONK3R pathway that mediates NKB-induced thermoregulatory responses,
suggests that these neurons might represent components of an integrated other components of this model (including peripheral substance P–NK1R
thermoregulatory network. NK3R antagonists have been suggested to act at contributions and potential interactions with EP3R+ neurons) remain to be
both levels: reducing NKB-mediated autosynaptic activation within the KNDy experimentally validated in the context of vasomotor symptoms.
population and blocking NKB action on MnPO thermoregulatory neurons.

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co-released with substance P to induce a longer-lasting increase in skin model useful for assessing questions about the menopause transition
blood flow (compared with the increase induced by substance P alone). state (such as those pertaining to fluctuating hormones), but they
The interaction between substance P and calcitonin gene-related also complicate hot flush mechanistic studies in which a clean on or
peptide might determine the overall magnitude of the peripheral off of sex steroids is advantageous. First, ovaries that are intact but
vasodilation82. Collectively, these findings support a mechanism by follicle-depleted maintain androgenic capacity (for example, andros-
which substance P released from nerve terminals activates endothelial tenedione), which might confound thermoregulatory readouts and
NK1R to amplify transient vasodilation (Fig. 4b), providing a plausible central adaptations tied to oestrogen withdrawal97,98. Second, the time
peripheral amplifier of the cutaneous flush in VMS. Evidence for a to failure is dose dependent and protocol dependent (for example, long
peripheral role of NK3R in vasodilation is currently missing. dosing hastens failure), increasing between-cohort heterogeneity96.
These thermoregulatory mechanisms triggered by NK1R activa- Third, repeated high-dose dosing and potential off-target effects add
tion might be particularly relevant as new antagonists target NK1R and variables absent in ovariectomized models99,100. Therefore, ovariec-
NK3R simultaneously. tomy yields an immediate, reproducible withdrawal of gonadal ster-
oids without residual ovarian hormone production, which enables
Preclinical models to study hot flushes the clean dissection of the KNDy–MnPO neurocircuitry in rodents.
The ovariectomized model Four-vinylcyclohexene dioxide remains valuable when the scientific
Hot flushes arise when circulating sex steroids are withdrawn, regard- question explicitly requires perimenopausal dynamics or ovary-intact
less of age and sex. They occur after bilateral oophorectomy in women systemic physiology.
and are typically more frequent and severe in this context than with
natural menopause, which indicates that abrupt oestrogen deprivation Assessment of hot flushes in rodent models
is a potent trigger83,84. Hot flushes are also common in men receiving As mentioned above, the study of hot flushes in rodents is often decou-
androgen deprivation therapy for prostate cancer, where castration pled from ageing to better isolate thermoregulatory changes. The
or GnRH analogues abruptly suppress production of sex steroids85,86. definition of a rodent hot flush (minute-scale temperature changes)
Similarly, children and adolescents treated with GnRH analogues (for remains to be standardized. However, the methodology to record fast
precocious puberty or gender dysphoria) frequently report hot flushes, temperature changes that resemble hot flushes frequently uses a com-
showing that older age is not a requisite for hot flush occurrence87,88. bination of telemetry responders attached to the skin of the tail and
Together, these clinical observations support sex steroid withdrawal, inserted into the abdominal cavity to simultaneously monitor tail-skin
not chronological age, as the principal driver of hot flush pathophysiol- temperature and core temperature, respectively, or infrared thermal
ogy. Thus, removing the age effect allows for the reliable use of animal cameras101,102 (Box 1).
models of a shorter lifespan than humans, such as rodents, for the An important, and potentially confounding, factor is that most
study of VMS. work in rodents on menopausal thermoregulation has focused on
Rodents do not experience a process that is similar to human circadian (hours-scale) changes of temperature after oestrogen with-
menopause; they undergo reproductive senescence with progressively drawal, typically using the ovariectomized model. In gonad-intact
declining ovarian function that usually leads to absent oestrous cyclic- rodents, tail-skin vasodilation falls during the active (dark) phase.
ity between 14 and 18 months of age89. Nevertheless, the hypothalamic Ovariectomy blunts this dark-phase drop in tail-skin temperature,
circuits that coordinate reproduction and thermoregulation are highly and oestradiol restores it, proving it is a robust, hours-scale change
conserved across species, and ovariectomy in rodents provides a robust that tracks baseline thermoregulatory control, not discrete hot flush
model of loss of gonadal steroids for these mechanistic studies90,91. events. Body temperature shows strong circadian rhythms in both
The optimal interval after ovariectomy for modelling menopause-like humans and rodents (with the caveat that rodents are nocturnal, and
hypothalamic changes remains debated. Multiple lines of evidence thus the rest and sleep phase occurs during daylight)103. By contrast, in
indicate that intervals longer than 2 weeks can uncover neuroendo- women, a hot flush is a minutes-long heat-loss event; that is, they have
crine remodelling not evident at 1–2 weeks after ovariectomy. Some a shorter timescale than circadian changes11.
evidence comes from classic works that showed that hypothalamic To get closer to the biology underlying hot flushes in humans
GnRH content in mice is unchanged 2 weeks after ovariectomy yet is and generate brief (minutes-long) surges in tail-skin temperature
decreased after 1–2 months92. Studies in rodents from the past 5 years and drops in core temperature, several approaches have been used in
emphasize that different lengths of time from ovariectomy surgery are rodents. The first of these is the forced treadmill exercise in ovariec-
required to reveal the different outcomes (behavioural, neurochemi- tomized mice, which induces a rapid tail-skin temperature surge that
cal and thermoregulatory outcomes)93,94. Work in our laboratory has is blocked by oestradiol and selective serotonin (also referred to as
shown that changes at 4 months after ovariectomy in rodents replicate 5-hydroxytryptamine or 5-HT) reuptake inhibitors (SSRIs)104,105. Sec-
human-like hypothalamic transcriptomic changes during menopause ond, yohimbine (an α2-blocker) can increase levels of noradrenaline
better than changes at 1–2 weeks (E. Torres, unpublished work). in ovariectomized rats106. Third, naloxone (a μ-opioid receptor and
κ-opioid receptor antagonist) can be used in morphine-dependent
Progressive ovarian failure with 4-vinylcyclohexene dioxide rats, which might act through the blockade of the inhibitory action
Four-vinylcyclohexene dioxide selectively ablates primordial and pri- of the dynorphin receptor (κ-opioid receptor) in KNDy neurons107–109.
mary follicles while leaving the ovary in the animal, yielding a gradual Fourth, anxiogenic CO2 challenge can be used110. Finally, direct KNDy
follicle depletion that has been used to model the perimenopausal neuron manipulations through the activation of NK3R (see the sec-
transition in mice and rats. Dosing typically spans ~15–20 days and the tion ‘Evidence of the thermoregulatory role of NKB and NK3R across
latency to ovarian failure varies with dose, strain and exposure length. species’ for the effect of NKB and senktide treatments) or by optoge-
However, residual ovarian interstitial tissue can produce androgens netic and/or chemogenetic activation of KNDy neurons can induce
for months95–97. These features make the 4-vinylcyclohexene dioxide temperature surges46. However, whether rodent models of sex steroid

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withdrawal experience spontaneous VMS, just as in women experienc-

ing menopause, remains unknown. Despite scattered mentions of Box 1 | Methodological approaches for
irregular tail-skin temperature surges, the field lacks a standardized, measuring thermoregulatory responses
consensus definition for spontaneous, minutes-scale flush events in preclinical models and clinical studies
at rest that can be differentiated from circadian oscillations. Most
laboratories therefore rely on the protocols described here of pro-
Rodent methods
voked events or circadian end points to study vasomotor changes. This
• Skin thermal imaging using forward-looking infrared cameras
knowledge gap in rodent models has limited the translational potential
enables non-invasive, real-time visualization of surface
of preclinical models.
temperature changes in freely moving animals, which is
particularly useful for detecting rapid tail-skin vasodilation
Non-human primate models
characteristic of heat-dissipation responses in mice and rats.
Non-human primates also exhibit events similar to hot flushes after
• Implantable telemetry probes enable simultaneous monitoring
ovariectomy, which are quantifiable by infrared thermography in freely
of core body temperature (intra-abdominal probe) and
moving animals. Studies in rhesus macaques have documented dis-
peripheral skin temperature (tail probe), providing continuous
crete facial, ear and nasal temperature rises after ovariectomy that are
data acquisition during spontaneous behaviour or in response to
reversible with oestrogen111,112. These findings support the translational
pharmacological or physiological challenges.
validity of these models; however, their use as a tool to study VMS has
been limited.
Human methods
• Multiple complementary approaches are used to assess
Classic treatments for menopausal hot flushes vasomotor symptoms in clinical studies.
Traditional treatments for hot flushes encompass several distinct thera-
• Skin surface probes attached to the chest, forehead or finger
peutic categories with varying degrees of efficacy and associated risks
provide continuous quantitative temperature recordings with
that highlight considerable unmet medical needs in this population. In
high temporal resolution.
this section, we summarize the main approaches that have been used
• Thermal imaging captures heat patterns across large body
and their potential interaction with the KNDy model. This list is not
regions, which is particularly useful for visualizing the
exhaustive and should not be used as guidance for treatment.
characteristic facial, neck and chest flushing during hot flushes.
• Self-report diaries and electronic assessment enable patients
Menopausal hormone therapy
to record the frequency, severity, duration and subjective
Hormone therapy represents the most effective category of treatments,
experience of vasomotor symptom episodes, and remain the
with efficacy rates (reduction in VMS incidence and severity) ranging
gold standard for clinical trial end points.
from 55% to >90%. Combined hormone therapy (oestrogen plus pro-
• Cardiovascular monitoring, including blood pressure
gestin) demonstrates the highest efficacy113,114, followed by oral and
measurement, helps characterize the autonomic
transdermal oestrogen monotherapy preparations115–119. In the context
accompaniments of hot flushes, including the transient heart
of the KNDy model, binding of exogenous oestrogen (with or without
rate increases and blood pressure fluctuations that might occur
progestin) to oestrogen receptors in KNDy neurons can be predicted,
during hot flushes.
thus mimicking the action of endogenous sex steroids in inhibiting
• The combination of objective physiological measures
KNDy neurons (that is, reducing the hyperactivation and hypertro-
with subjective symptom reports provides comprehensive
phy) and thus preventing the release of NKB onto MnPONK3R neurons.
assessment of vasomotor symptoms.
However, this high efficacy of hormone therapy comes with potential
risks that require individualized assessment, including increased risks
of breast cancer, thromboembolism, stroke and cardiovascular events.
of serotonin or fluoxetine (Prozac) directly into the rat hypothalamus
Antidepressants raises core temperature via serotonin 2 receptor (5-HT2) signalling133.
Antidepressants are the primary non-hormonal pharmaceutical option, Furthermore, peripheral administration of fluoxetine prevents the
with SSRIs achieving moderate efficacy of 45–65% reductions in symp- increase in tail-skin temperature in ovariectomized models134,135 and
tom incidence and severity120–122. Paroxetine, which for a long time was increases core temperature, which suggests the blockade of hot flush
the only FDA-approved non-hormonal treatment for hot flushes, was mechanisms. In humans, antidepressants are given systemically and
reported to achieve 60–65% efficacy123, although escitalopram and chronically, producing adaptive effects that might modify heat defence
citalopram also achieved moderate symptom reduction (incidence and outputs.
severity)124,125. Serotonin–noradrenaline reuptake inhibitors (SNRIs), Direct serotonergic modulation of KNDy neurons in the preven-
such as venlafaxine, have also been used to achieve a similar range of tion of hot flushes is also plausible but requires further investiga-
moderate reductions in hot flushes126,127. However, these medications tion. A study published in 2024 found serotonin 2 receptor C (5-HT2C)
carry risks of sexual dysfunction128,129, weight gain130 and substantial expression in KNDy neurons of female rats, with functional effects on
drug–drug interactions, which are particularly problematic in patients reproductive function136, but analogous data linking serotonin directly
with breast cancer who are taking tamoxifen131,132. to the KNDy control of VMS in humans are not yet available.
The mechanism (or mechanisms) by which SSRIs and SNRIs affect
VMS lack complete experimental evidence. SSRIs and SNRIs might Gabapentinoids
modulate thermoregulatory responses through effects on seroton- Analgesics such as gabapentin and pregabalin offer moderate efficacy
ergic signalling in the POA. In rodents, acute and local administration (45–51%), particularly for night-time symptoms, but are associated

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with sedation, dizziness, weight gain and cognitive impairment137–139. Historically, NK3R antagonists were first developed to treat
Gabapentin binds the α2δ subunit of voltage-gated calcium channels, schizophrenia. First-generation compounds included osanetant and
reducing presynaptic calcium influx and vesicle release from neurons140. talnetant, but these were discontinued from the development of schizo-
This effect at the level of the MnPO area could reduce the input of NKB phrenia treatment programmes because significant efficacy over
(and potentially substance P) into this area, thus reducing the number placebo could not be demonstrated, despite promising preclinical
of VMS-triggering events; however, this theory remains to be tested results and initial clinical signals66,152–154. Additionally, NK3R antagonists
experimentally. caused dose-dependent suppression of LH and testosterone levels (up
to 70% reductions)155,156, raising safety concerns for chronic psychiatric
Antihypertensive agents use. Today, we know that these effects are probably due to their inhibi-
Women who experience hot flushes present a narrowed neutral ther- tory effect on NK3R action in KNDy neurons during reproductive years
moregulatory zone, as described in the Introduction in this Review, so (see previous sections).
small rises in core temperature can cross this threshold and trigger a hot The development of the KNDy model as the source of VMS in
flush. Central noradrenergic drive lowers this threshold, and agents that several laboratories around the world was a remarkable example of
increase brain levels of noradrenaline (such as yohimbine) can provoke translational research, and it re-awakened the interest in these mol-
hot flushes141. Clonidine, acting as a central α2-adrenergic agonist that ecules, especially in a population of individuals (post-menopausal
reduces noradrenaline release, induces the opposite effect by statisti- women) in whom the potential decrease in circulating levels of sex
cally significantly raising the core-temperature sweating threshold in steroids induced by NK3R antagonism is not a major issue. One of the
women experiencing hot flushes. Randomized trials have also shown first molecules to enter this space was MLE-4901 (pavinetant), which
that clonidine reduces hot flush frequency, albeit modestly141–143. demonstrated efficacy in reducing hot flush frequency in a phase II
crossover trial157. However, the MLE-4901 programme was discon-
Other approaches tinued due to transient increases in transaminase levels that raised
Behavioural therapies such as cognitive behavioural therapy and clini- hepatotoxicity concerns157,158.
cal hypnosis on the basis of level 1 evidence are recommended by the The most recent generation of compounds has demonstrated
North American Menopause Society144. Although cognitive behavioural improved safety profiles while maintaining robust efficacy. Fezolin-
therapy consistently reduces the perceived impact of VMS, clinical etant, a selective NK3R antagonist, achieved FDA approval in 2023,
hypnosis demonstrates more robust effects on hot flush frequency145. becoming the first-in-class neurokinin receptor antagonist approved
Published in 2025, a scoping review found that clinical hypnosis outper- for treating moderate to severe VMS associated with menopause. The
forms cognitive behavioural therapy for both frequency and severity approval was supported by phase II studies159,160 and the BRIGHT SKY
reduction145. Herbal and nutritional approaches show highly variable phase II programme, across SKYLIGHT 1, 2 and 4 studies161–163. Both the
and generally limited results. Soy isoflavones demonstrate the largest SKYLIGHT 1 and SKYLIGHT 2 studies confirmed statistically significant
effect in this category with 9–40% efficacy, although the results are reductions in VMS frequency and severity with sustained effects main-
inconsistent146–148. Most other complementary therapies, including tained through 52 weeks of treatment161–163. These clinical benefits were
red clover, dong quai and ginseng, show no statistically significant further confirmed in the phase IIIb DAYLIGHT study164,165.
benefit compared with placebo149–151. The pipeline for NK3R antagonists continues to evolve. An addi-
This treatment landscape reveals a considerable therapeutic gap. tional NK3R antagonist, SJX-653, has been developed and was demon­
Although menopausal hormone therapy offers excellent symptom strated to reduce LH and testosterone levels in a phase I study in healthy
control, its contraindications or the personal preferences of individuals men166. However, the efficacy of SJX-653 in the treatment of VMS has
make it unsuitable for many people. Non-hormonal pharmaceuticals not yet been reported. Dual NK1R–NK3R antagonists are also being
provide moderate relief, at best, but often with tolerability issues that developed, with elinzanetant being the first compound in this category
limit long-term use. Complementary therapies (alternative medicine that received FDA and UK regulatory approvals (in 2025). Elinzanetant
such as herbal approaches and lifestyle changes), although generally efficacy is supported by the OASIS programme, which encompasses
well-tolerated, lack demonstrated efficacy. For many, treatment is four phase III studies. Results from OASIS 1, 2 and 3 trials demon-
therefore inadequate, or patients must choose between symptom strated a statistically significant reduction in VMS frequency by week 4
relief and safety concerns. This unmet need has driven the develop- (refs. 167,168). Whether the dual antagonistic effect of elinzanetant on
ment of NK3R antagonists over the past few years, which represent NK1R and NK3R will confer an advantage over NK3R-only antagonists
a novel therapeutic approach specifically targeting the underlying remains to be fully evaluated. In the context of hot flushes, a pilot study
neurobiological mechanisms of hot flushes while potentially avoiding published in 2006 treated individuals experiencing severe hot flushes
the risks associated with traditional treatments. with aprepitant, an NK1R antagonist, and did not find reductions in
their severity or frequency beyond placebo169. This study would rule out
Development of neurokinin receptor antagonists an additive effect on the thermoregulatory aspect of NK1R; however,
The clinical development of neurokinin receptor antagonists repre- the preliminary nature of that report warrants further investigation
sents a paradigm shift in the management of menopausal VMS, offering based on the potential roles of NK1R on thermoregulation described
the first non-hormonal therapeutic approach that directly targets the in previous sections of this Review and the data obtained from the
underlying KNDy neuronal circuitry. Building upon the KNDy model, OASIS programme.
these agents specifically antagonize NKB binding to NK3R (and in some The mechanistic advantages of targeting the neurokinin receptors
cases also the binding of substance P to NK1R) within the hypothalamic over existing non-hormonal therapies stem from their direct targeting
thermoregulatory centres that become dysregulated during meno- of the source of VMS (that is, KNDy neurons) and their prevention of
pause. The existing neurokinin receptor antagonists and their actions the stimulatory action of NKB. This approach provides rapid onset of
on VMS are summarized in Supplementary Table 2. action, with notable improvements observed within days rather than

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the weeks typically required for other non-hormonal agents such compounds provide evidence-based, mechanism-targeted relief for
as SSRIs. women experiencing VMS, which are often debilitating. Nonetheless,
Development programmes are expanding to address diverse future studies should address long-term safety beyond 1 year, optimiza-
populations of patients with unmet medical needs. The OASIS 4 study tion of monitoring strategies and exploration of combination therapy
is investigating the efficacy of elinzanetant in women experiencing approaches. In this context, preclinical work has demonstrated the
VMS as a result of endocrine therapy for breast cancer treatment or efficacy of peripherally restricted κ-opioid receptor agonists, which
prevention170, addressing a critical population in which hormonal take advantage of the fact that the blood–brain barrier is porous at the
therapies are contraindicated. level of the basal hypothalamus and allows for the local hypothalamic
Overall, the neurokinin receptor antagonist class represents the action of compounds in the peripheral circulation without reaching
most notable advance in non-hormonal menopause therapy in decades. other parts of the brain. Thus, KNDy neurons can be inhibited by repro-
The timeline of molecules and studies is summarized in Fig. 5. These ducing the effect of dynorphin to achieve a reduction in their activity,

Aprepitant
Pilot study of aprepitant, an NK1R antagonist 2006
Pavinetant
2007 Fezolinetant
Elinzanetant
2008

2009

2010

2011

2012

2013

2014

2015

2016

2017
Phase II study of MLE-4901 (pavinetant),
a NK3R antagonist
2018

Phase IIa study of fezolinetant, a NK3R 2019

antagonist
2020 VESTA, a phase IIb study of fezolinetant
RELENT-1, a phase IIa study of elinzanetant,
2021 a dual NK1R–NK3R antagonist

2022

SKYLIGHT 1, SKYLIGHT 2 and SKYLIGHT 3: 2023

phase III studies of fezolinetant
SWITCH-1, a phase IIb study of elinzanetant 2024 DAYLIGHT, a phase III study of fezolinetant
OASIS 1 and OASIS 2: phase III trials of
OASIS 3 and OASIS 4: phase III studies of 2025 elinzanetant
elinzanetant

Fig. 5 | Historical timeline of neurokinin receptor antagonist development whereas the RELENT-1 phase IIa study introduced elinzanetant as the first
for vasomotor symptoms. Clinical development of neurokinin 1 receptor dual NK1R–NK3R antagonist for VMS219. In 2023, the SKYLIGHT phase III
(NK1R) and NK3R antagonists from early pilot studies to regulatory approvals. programme (SKYLIGHT 1, 2 and 3) led to FDA approval of fezolinetant as
In 2006, aprepitant, an NK1R antagonist already approved for chemotherapy- the first-in-class NK3R antagonist for the treatment of moderate-to-severe
induced nausea, was tested in a pilot study for vasomotor symptoms (VMS) but VMS161,162. The SWITCH-1 phase IIb study provided additional efficacy data for
efficacy beyond placebo was not demonstrated, which initially suggested limited elinzanetant220. In 2024, the DAYLIGHT phase IIIb study provided evidence
therapeutic potential for NK1R-only blockade in hot flushes169. During 2017–2018, supporting the efficacy of fezolinetant164. The OASIS 1 and OASIS 2 phase III trials
MLE-4901 (pavinetant), a selective NK3R antagonist, showed promising efficacy demonstrated the efficacy of elinzanetant for VMS, with additional benefits on
in phase II trials, validating the KNDy hypothesis for VMS treatment; however, sleep disturbance167. In 2025, OASIS 3 (long-term safety) and OASIS 4 (people who
development was discontinued owing to transient hepatic transaminase had had breast cancer) phase III trials completed the elinzanetant development
elevations157,158. In 2019, phase IIa studies with fezolinetant demonstrated proof- programme, leading to UK Medicines and Healthcare products Regulatory
of-concept for selective NK3R antagonism in VMS160. In 2020, the VESTA phase IIb Agency approval ( July 2025) and FDA approval (October 2025)170.
trial further characterized the dose–response relationship of fezolinetant159,218,

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and therefore in the induction of VMS171. The use of these compounds stress). Second, substance P–NK1R can also induce emesis (vomit-
alone or in combination with neurokinin receptor antagonists remains ing) and NK1R antagonists (such as aprepitant) are commonly used
to be explored in clinical settings. clinically to prevent vomiting in chemotherapy-related nausea187,188.
Third, NK1R+ neurons are critical for nociception and hyperalgesia.
Clinical considerations of neurokinin In rats, ablation of lamina I NK1R+ neurons of the spinal cord abol-
receptor antagonists ishes inflammatory and neuropathic hyperalgesia 189–191. Fourth,
Potential central off-target effects NK1R antagonists increase serotonin levels through enhancement
The efficacy of NK3R antagonists to treat VMS is based on strong evi- of dorsal raphe neuronal activity192–194, with similar effects to SSRIs.
dence from clinical trials across the different molecules described Overall, these effects might account for improvements in mood in
in previous sections. However, the specific site (or sites) of action of individuals experiencing VMS. Early clinical trials demonstrated
NK3R antagonists to exert this role remains to be fully characterized. that NK1R antagonists improve sleep in people with depression and
On the one hand, the majority of KNDy neurons express NK3R, which primary insomnia195. A matching-adjusted indirect comparison of
allows for autosynaptic modulation by NKB to promote the activation the SKYLIGHT 1 and 2 trials and the OASIS 1 and 2 trials found that
of KNDy neurons after sex steroid withdrawal. On the other hand, NKB fezolinetant and elinzanetant achieve similar reductions in VMS fre-
released from KNDy neurons also reaches MnPONK3R neurons, which quency and severity, but elinzanetant demonstrated statistically
become activated and thus promote VMS. Whether the action of NK3R significantly greater improvement in sleep disturbances196. A pooled
antagonists is required at both levels (that is, KNDy and MnPONK3R or analysis suggested that over half of the sleep benefit of elinzanetant
another as-yet unknown NK3R+ neuron population) or if a drug that acts occurs independently of VMS reductions, implying direct effects
at just one of these sites is sufficient to treat VMS, remains unknown. on sleep pathways through NK1R antagonism (according to results
The most advanced NK3R antagonists (fezolinetant and elinzanetant) presented in a conference abstract)197. These findings suggest that for
readily cross the blood–brain barrier172,173, so acting on any or all of patients with prominent sleep challenges accompanying their VMS,
these targets is possible. This crossing of the blood–brain barrier, dual NK1R–NK3R antagonism might offer therapeutic advantages
however, opens the door for central off-target effects. NK3R is widely over selective NK3R blockade.
expressed in the brain, including the cerebral cortex, amygdala, hip- Preclinical studies have also implicated NK1R signalling in the
pocampus, mesencephalon and metencephalon66, and diverse roles MnPO area in sociosexual behaviours. Most of the data point to a pre-
for NKB signalling have been described through the activation of NK3R dominant role in male individuals, in whom NK1R signalling in this
in these areas. First, NKB signalling in the central amygdala is neces- area promotes aggression, mating and ejaculation73,198–200. Evidence
sary and sufficient to strengthen fear memory consolidation174–176. of an enhancing effect on sexual receptivity in female rodents has
These studies suggest a plausible anti-fear action for central NK3R also been reported201,202. Nonetheless, human sexual adverse effects
antagonism, which is relevant to post-traumatic stress disorder and of approved NK1R antagonists are not consistent, although a detailed
anxiety disorders. Although this effect has not been clinically validated characterization at the doses of NK1R and NK3R antagonists used to
in humans, a study (published in 2025) in mice showed that fezolinetant treat VMS is currently missing203.
delivered peripherally impairs fear memory consolidation in male
individuals177, suggesting a potential benefit for NK3R antagonists in Potential peripheral off-target effects
behavioural therapy. Although liver function monitoring has been indicated for the avail-
Second, chronic social isolation in mice induces brain-wide able NK3R antagonists to treat VMS, a direct effect of NKB signalling
upregulation of NKB, and systemic NK3R antagonism prevents at the level of the liver has not been reported and is unlikely. In fact, a
isolation-induced behavioural syndrome (aggression, persistent freely available Human Protein Atlas (Human Protein Atlas, TACR3) that
freezing and startle) that is related to depression and anxiety. Local includes large-scale datasets indicates no meaningful NK3R expression
manipulations show region-specific requirements of NKB signalling in healthy human liver, and only traces in some liver tumours204. Thus,
in the bed nucleus of the stria terminalis, central amygdala and dor- initial hepatotoxicity events are attributed to the chemical composi-
somedial hypothalamus, with each area mediating distinct aspects tion of previous NK3R antagonists (that is, MLE-4901) rather than to
of NKB’s action on stress178,179. These studies position NK3R as a stress the blockade of NK3R.
modulator, and therefore antagonizing it could dampen hyperreactive A peripheral organ with demonstrated expression of NK3R and
fear and/or anxiety states. Although this possibility remains to be tested NK1R is the gastrointestinal tract. Both receptors are expressed in
in humans, in the context of menopause, the targeting of NK3R might enteric neurons and glia that help drive the excitatory cholinergic
also provide important mood benefits in individuals experiencing VMS. transmission required for gut motility205–208. Clinically, this pathway
Finally, stimulation of NK3R in the prefrontal cortex and hippocampus is compatible with the mild motility changes (for example, abdominal
also promotes learning and memory in aged rats. Studies also tie hip- discomfort and diarrhoea) seen in individuals after treatment with
pocampal NK3R to sex-hormone-dependent synaptic plasticity and NK3R antagonists, through a mechanism that seems to be mediated
hippocampal neurogenesis in rat models of Alzheimer disease180–182. by enteric glia208.
In this context, whether NK3R antagonism could affect cognition in As mentioned in previous sections, substance P in the periphery
postmenopausal individuals has not been investigated. might influence vascular tone, acting as a vasodilator79,209. In this con-
NK1R is also widely distributed in the brain and has been involved text, substance P administered intravenously to healthy volunteers led
in several psychosomatic processes. First, just like NK3R, NK1R signal- to increases in heart rate and a small fall in diastolic blood pressure,
ling in the amygdala and prefrontal cortex is involved in fear, anxiety which is consistent with generalized vasodilation. Nonetheless, several
and stress related to post-traumatic stress disorder183–186, which might studies using NK1R antagonists have consistently shown absence of
have implications for the use of NK1R and NK3R antagonists (NK1 changes in blood pressure79,210. NK3R has been documented in repro-
blockade could reduce anxiety and dampen amygdala responses to ductive organs outside the central control of GnRH release, particularly

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Review article

in the placenta and uterus, where it is implicated in pre-eclampsia and neuroscience, transforming fundamental discoveries about hypo-
myometrial leiomyomata211–213. However, no studies have been reported thalamic circuits into mechanism-based therapeutics that address an
to date on the potential effects of NK3R antagonists in these conditions important unmet medical need affecting millions of people worldwide.
and overall cardiovascular effects of the antagonists at the doses used
have been reported to be safe (Supplementary Table 2). Published online: 14 April 2026
Within the immune system, substance P is considered a
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