Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature

Abstract

Estrogen withdrawal in menopausal women leads to hot flushes, a syndrome characterized by the episodic activation of heat dissipation effectors. Despite the extraordinary number of individuals affected, the etiology of flushes remains an enigma. Because menopause is accompanied by marked alterations in hypothalamic kisspeptin/neurokinin B/dynorphin (KNDy) neurons, we hypothesized that these neurons could contribute to the generation of flushes. To determine if KNDy neurons participate in the regulation of body temperature, we evaluated the thermoregulatory effects of ablating KNDy neurons by injecting a selective toxin for neurokinin-3 expressing neurons [NK 3 -saporin (SAP)] into the rat arcuate nucleus. Remarkably, KNDy neuron ablation consistently reduced tail-skin temperature (T SKIN ), indicating that KNDy neurons facilitate cutaneous vasodilatation, an important heat dissipation effector. Moreover, KNDy ablation blocked the reduction of T SKIN by 17β-estradiol (E 2 ), which occurred in the environmental chamber during the light phase, but did not affect the E 2 suppression of T SKIN during the dark phase. At the high ambient temperature of 33°C, the average core temperature (T CORE ) of ovariectomized (OVX) control rats was significantly elevated, and this value was reduced by E 2 replacement. In contrast, the average T CORE of OVX, KNDy-ablated rats was lower than OVX control rats at 33°C, and not altered by E 2 replacement. These data provide unique evidence that KNDy neurons promote cutaneous vasodilatation and participate in the E 2 modulation of body temperature. Because cutaneous vasodilatation is a cardinal sign of a hot flush, these results support the hypothesis that KNDy neurons could play a role in the generation of flushes.reproduction | gonadotropin-releasing hormone | thermoregulation E strogen withdrawal leads to hot flushes in the majority of menopausal women (1). Hot flushes are also experienced by men and women treated with tamoxifen for breast cancer, men undergoing androgen-ablation therapy for prostate cancer, young oophorectomized women, and hypogonadal men (2, 3). A hot flush is characterized by episodic activation of heat dissipation effectors, including cutaneous vasodilatation, sweating, and behavioral thermoregulation. After a flush is initiated, the activation of heat dissipation mechanisms is so effective that core temperature frequently drops (4). Despite the vast numbers of individuals affected, the etiology of flushes remains an enigma.Hot flushes are closely timed with luteinizing hormone (LH) pulses, providing a clue that the generation of flushes is linked to the hypothalamic neural circuitry controlling pulsatile gonadotropin-releasing hormone (GnRH) secretion (5, 6). Current evidence suggests that pulsatile GnRH secretion is modulated by a subpopulation of neurons in the arcuate (infundibular) nucleus that express estrogen receptor α (ERα), neurokinin 3 receptor (NK 3 R), kisspeptin, neurokinin B (NKB), and dynorphin (7-11). In the hypothalamus of postmenopausal women, ...

Endocrine Therapy for Leptomeningeal Metastases from ER ‐Positive Breast Cancer: Case Report and a Review of the Literature

“…Evidence does not support this concern, and indeed clearly indicates that hormonal therapies or their downstream therapeutic effect penetrate effectively through the normal or abnormal blood-brain barrier. Hot flashes are mediated centrally by a mechanism in the brain, and while the specifics have not been fully worked out, evidence indicates neurons in the hypothalamus or brain stem are responsible for mediating this phenomenon (23,24). Most, if not all, hormonal therapies for breast cancer cause hot flashes; therefore the molecule, or the downstream therapeutic effect of these molecules, must penetrate the CNS to produce hot flashes.…”

Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial

“…18 Subsequent work in rats highlighted the importance of the hypothalamic pre-optic nucleus (MnPO) in the propagation of the NKB-mediated signal that results in hot flushes. The MnPO is a neural area that receives input from, and projects to, the autonomic thermoregulatory pathway and expresses NK3R, [14][15][16][17] and hence results in activation of heat dissipation effectors that characterise hot flushes. Furthermore, in a randomised, double-blind, placebocontrolled crossover study in healthy premenopausal women, peripheral infusion of NKB intravenously induced hot flushes that were typical in location, duration, and observed physiological change to those described by postmenopausal women.…”

“…11,12 It has been known for many years that the hypothalamic-pituitary-gonadal axis regulates circulating sex steroid concentrations throughout life but it is only more recently that the role of the hypothalamic neurons containing colocalised kisspeptin, neurokinin B (NKB), and dynorphin receptors (so called KNDy neurons) has become clear. 13 Furthermore, over the past 20 years, Rance and colleagues have contributed to a growing body of evidence in rodents, [14][15][16][17] primates, 18 and post-mortem studies in human beings 19 that the KNDy neurons, and in particular NKB and its receptor (NK3R), are implicated in the aetiology of the menopausal hot flush (summarised in a comprehensive review by Rance and colleagues 10 ). Two recent publications further implicate NKB and NK3R in menopausal flushing: in a randomised, double-blind, placebo-controlled, crossover study, peripheral infusion of NKB intravenously to healthy premenopausal women induced hot flushes that were typical in location and duration to those described by postmenopausal women, 20 and Crandall and colleagues 21 found that genetic variation in TACR3, which is the gene that encodes NK3R, might account for the variability in experience of hot flushes reported among menopausal women.…”

MANAGEMENT OF ENDOCRINE DISEASE: Flushing: current concepts

“…Post-menopausal women have been shown to demonstrate hypertrophy of these neurons in the hypothalamic arcuate nucleus, changes that have also been demonstrated in young monkeys after ovariectomy and reversed by oestrogen replacement (15). Animal models have studied the connections between KNDy neurons and the pathways that control heat-defence effectors involving the preoptic structures (16) and have also evaluated the thermoregulatory effects of ablating KNDy neurons, indicating that KNDy neurons facilitate cutaneous vasodilatation, an important heat dissipation effector (17). Based on these previous investigations, Prage et al very recently reported a randomised doubleblind placebo-controlled trial, using an oral neurokinin 3 receptor antagonist (MLE4901).…”