kiss1-protein--human and Hot-Flashes

Breast cancer is the most frequently diagnosed cancer in women and the first cause of cancer death in France. Among the different subtypes of breast cancer, the predominant form is characterized by positive hormone receptors (more than 70% of breast cancers). Hormone therapy thus plays a key role in the strategy of management of these cancers both in adjuvant and metastatic situations. The two types of adjuvant hormone therapy used are selective estrogen receptor modulators and aromatase inhibitors. Fulvestrant, an anti-estrogen, is used alone or in combination with other molecules in metastatic situations. Hot flashes are one of the symptoms most frequently reported by patients under hormone therapy. Hormone replacement therapy, which is currently the most effective treatment for hot flashes, is contraindicated in patients with a personal history of breast cancer. Various therapeutic classes of drugs have been tested in this indication but without real efficacy in the various studies carried out to date, and moreover associated with non-negligible side effects. The recent discovery of the implication of the kisspeptin system located at the hypothalamic level in the mechanism of genesis of hot flashes opens the way to possible new symptomatic treatments for hot flashes. Neurokinin 3 receptor antagonists have shown encouraging preliminary results in postmenopausal cancer-free patients and could be considered in patients in hormonal therapy for breast cancer. Broader additional studies are needed to confirm these initial results.

Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Contraindications, Drug; Estrogen Replacement Therapy; Female; Fulvestrant; Hot Flashes; Humans; Kisspeptins; Ovary; Receptors, Neurokinin-3; Selective Estrogen Receptor Modulators; Tamoxifen

Hot flushes remain a debilitating aspect of menopause, disrupting daytime activities and sleep, and may last for years. Estrogen replacement is an effective treatment, but takes time to become maximally effective and is contraindicated in a significant proportion of women, most notably after breast cancer. Effective, non-hormonal therapies are therefore required. Recent years have seen substantial increases in understanding of the role of novel neuropeptides and tachykinins in hypothalamic function, particularly in the regulation of the reproductive axis through control of gonadotropin releasing hormone secretion, but with links to the control of vasomotor function. Neurokinin B, often co-expressed with kisspeptin in hypothalamic neurons, appears to be a key factor in the control of both systems. Several neurokinin B antagonists have been developed; data are emerging as to their effectiveness in the treatment of menopausal hot flushes. While data remain limited, these agents appear to have a remarkably fast onset of action, with the first 1 or 2 days of administration, and with a dramatic effect on both daytime flushes and night sleep disturbance. If safety and long-term function can be confirmed, these novel agents will be an important advance in therapy.

Topics: Female; Gonadotropin-Releasing Hormone; Gonadotropins; Hot Flashes; Humans; Kisspeptins; Menopause; Neurokinin B; Randomized Controlled Trials as Topic; Receptors, Neurokinin-3; Treatment Outcome

Women during perimenopausal period experience a range of symptoms, which interfere with physical, sexual, and social life. About 65-75% of symptoms connected with postmenopausal period are vasomotor symptoms (VMS), such as hot flushes and night sweats. Hot flushes are subjective sensation of heat associated with cutaneous vasodilatation and drop in core temperature. It is suspected that VMS are strongly correlated with pulsatile oversecretion of gonadotropin-releasing hormone (GnRH) and subsequently luteinizing hormone (LH). Evidence has accumulated in parallel showing that lack of negative feedback of steroid hormones synthesized in ovary causes overactivation of hypertrophied kisspeptin/neurokinin B/dynorphin (KNDy) neurons, located in infundibular nucleus. Oversecretion of both kisspeptin (KISS1) and neurokinin B (NKB), as well as downregulation of dynorphin, plays dominant role in creation of GnRH pulses. This in turn causes VMS. Administration of senktide, highly potent and selective NK3R agonist, resulted in increase of serum LH concentration, induction of VMS, increase in heart rate, and skin temperature in postmenopausal women. These finding suggest that modulation of KNDy neurons may become new therapeutic approach in the treatment of VMS.. 摘要 围绝经期的妇女会出现一系列症状, 这些症状会干扰身体, 性生活和社交。绝经期间约65-75％的症状是血管舒缩症状（VMS）, 如潮热和盗汗。潮热是与皮肤血管舒张和核心温度下降相关的主观热感。VMS被怀疑与促性腺激素释放激素（GnRH）脉冲式释放过多和随后的黄体生成素（LH）分泌密切相关。同时研究显示, 卵巢中合成的类固醇激素缺乏负反馈导致位于漏斗核中的肥大Kisspeptin /神经激肽B /强啡肽（KNDy）神经元过度活化。 Kisspeptin（KISS1）和神经激肽B（NKB）的过度分泌以及强啡肽的下调在GnRH脉冲的产生中起主导作用, 反之导致VMS的发生。给予NK3受体特异性激动剂, 高效选择性NK3R激动剂导致绝经后妇女血清LH浓度增加, 诱导VMS发生, 心率增加和皮肤温度升高。这些发现表明, 对KNDy神经元的调节可能成为治疗VMS的新方法。.

Topics: Dynorphins; Feedback, Physiological; Female; Hot Flashes; Humans; Hypothalamus; Kisspeptins; Neurokinin B; Neurons; Postmenopause; Vasomotor System

Despite affecting millions of individuals, the etiology of hot flushes remains unknown. Here we review the physiology of hot flushes, CNS pathways regulating heat-dissipation effectors, and effects of estrogen on thermoregulation in animal models. Based on the marked changes in hypothalamic kisspeptin, neurokinin B and dynorphin (KNDy) neurons in postmenopausal women, we hypothesize that KNDy neurons play a role in the mechanism of flushes. In the rat, KNDy neurons project to preoptic thermoregulatory areas that express the neurokinin 3 receptor (NK3R), the primary receptor for NKB. Furthermore, activation of NK₃R in the median preoptic nucleus, part of the heat-defense pathway, reduces body temperature. Finally, ablation of KNDy neurons reduces cutaneous vasodilatation and partially blocks the effects of estrogen on thermoregulation. These data suggest that arcuate KNDy neurons relay estrogen signals to preoptic structures regulating heat-dissipation effectors, supporting the hypothesis that KNDy neurons participate in the generation of flushes.

Topics: Animals; Body Temperature Regulation; Dynorphins; Estradiol; Estrous Cycle; Female; Hot Flashes; Humans; Hypothalamus; Kisspeptins; Luteinizing Hormone; Models, Biological; Neurokinin B; Neurons; Ovariectomy; Postmenopause; Preoptic Area; Rats; Receptors, Neurokinin-3; Signal Transduction; Skin; Tail; Vasodilation

The etiology of postmenopausal hot flashes is poorly understood, making it difficult to develop and target ideal therapies. A network of hypothalamic estrogen-sensitive neurons producing kisspeptin, neurokinin B and dynorphin-called KNDy neurons-are located adjacent to the thermoregulatory center. KNDy neurons regulate pulsatile secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Dynorphin may inhibit this system by binding κ opioid receptors within the vicinity of KNDy neurons. We hypothesize that hot flashes are reduced by KNDy neuron manipulation.. A double-blind, cross-over, placebo-controlled pilot study evaluated the effects of a κ agonist. Hot flash frequency was the primary outcome. Twelve healthy postmenopausal women with moderate to severe hot flashes (aged 48-60 y) were randomized. Eight women with sufficient baseline hot flashes for statistical analysis completed all three interventions: placebo, standard-dose pentazocine/naloxone (50/0.5 mg), or low-dose pentazocine/naloxone (25/0.25 mg). In an inpatient research setting, each participant received the three interventions, in randomized order, on three separate days. On each day, an intravenous catheter was inserted for LH blood sampling, and skin conductance and Holter monitors were placed. Subjective hot flash frequency and severity were recorded.. The mean (SEM) hot flash frequency 2 to 7 hours after therapy initiation was lower than that for placebo (standard-dose κ agonist, 4.75 [0.67] hot flashes per 5 h; low-dose κ agonist, 4.50 [0.57] hot flashes per 5 h; placebo, 5.94 [0.78] hot flashes per 5 h; P = 0.025). Hot flash intensity did not vary between interventions. LH pulsatility mirrored objective hot flashes in some--but not all--women.. This pilot study suggests that κ agonists may affect menopausal vasomotor symptoms.

Topics: Analgesics, Opioid; Cross-Over Studies; Double-Blind Method; Dynorphins; Female; Gonadotropin-Releasing Hormone; Hot Flashes; Humans; Kisspeptins; Luteinizing Hormone; Middle Aged; Neurokinin B; Neurons; Pentazocine; Placebos; Postmenopause; Receptors, Opioid, kappa

Recent evidence suggests that vasomotor symptoms (VMS) or hot flashes in the postmenopausal reproductive state and polycystic ovary syndrome (PCOS) in the premenopausal reproductive state emanate from the hyperactivity of Kiss1 neurons in the hypothalamic infundibular/arcuate nucleus (KNDy neurons).. We demonstrate in 2 murine models simulating menopause and PCOS that a peripherally restricted kappa receptor agonist (PRKA) inhibits hyperactive KNDy neurons (accessible from outside the blood-brain barrier) and impedes their downstream effects.. Case/control.. Academic medical center.. Mice.. Administration of peripherally restricted kappa receptor agonists and frequent blood sampling to determine hormone release and body temperature.. LH pulse parameters and body temperature.. First, chronic administration of a PRKA to bilaterally ovariectomized mice with experimentally induced hyperactivity of KNDy neurons reduces the animals' elevated body temperature, mean plasma LH level, and mean peak LH per pulse. Second, chronic administration of a PRKA to a murine model of PCOS, having elevated plasma testosterone levels and irregular ovarian cycles, suppresses circulating levels of LH and testosterone and restores normal ovarian cyclicity.. The inhibition of kisspeptin neuronal activity by activation of kappa receptors shows promise as a novel therapeutic approach to treat both VMS and PCOS in humans.

Topics: Animals; Buprenorphine; Disease Models, Animal; Female; Hot Flashes; Humans; Kisspeptins; Meloxicam; Menopause; Mice; Neurons; Polycystic Ovary Syndrome; Receptors, Opioid, kappa; Vasomotor System

We have proposed that arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin (KNDy neurons) contribute to hot flushes via projections to neurokinin 3 receptor (NK3R)-expressing neurons in the median preoptic nucleus (MnPO). To characterize the thermoregulatory role of MnPO NK3R neurons in female mice, we ablated these neurons using injections of saporin toxin conjugated to a selective NK3R agonist. Loss of MnPO NK3R neurons increased the core temperature (TCORE) during the light phase, with the frequency distributions indicating a regulated shift in the balance point. The increase in TCORE in the ablated mice occurred despite changes in the ambient temperature and regardless of estrogen status. We next determined whether an acute increase in ambient temperature or higher TCORE would induce Fos in preoptic enhanced green fluorescent protein (EGFP)-immunoreactive neurons in Tacr3-EGFP mice. Fos activation was increased in the MnPO but no induction of Fos was found in NK3R (EGFP-immunoreactive) neurons. Thus, MnPO NK3R neurons are not activated by warm thermosensors in the skin or viscera and are not warm-sensitive neurons. Finally, RNAscope was used to determine whether Tacr3 (NK3R) mRNA was coexpressed with vesicular glutamate transporter 2 or vesicular γ-aminobutyric acid (GABA) transporter mRNA, markers of glutamatergic and GABAergic neurotransmission, respectively. In the MnPO, 94% of NK3R neurons were glutamatergic, but in the adjacent medial preoptic area, 97% of NK3R neurons were GABAergic. Thus, NK3R neurons in the MnPO are glutamatergic and play a role in reducing TCORE but are not activated by warm thermal stimuli (internal or external). These findings suggest that KNDy neurons modulate thermosensory pathways for heat defense indirectly via a subpopulation of glutamatergic MnPO neurons that express NK3R.

Topics: Animals; Body Temperature Regulation; Dynorphins; Female; Glutamic Acid; Hot Flashes; Hot Temperature; Kisspeptins; Mice; Neurokinin B; Neurons; Preoptic Area; Proto-Oncogene Proteins c-fos; Receptors, Neurokinin-3

Neurokinin B (NKB) and kisspeptin are obligate for normal gonadotropin secretion, and links between gonadotropin-releasing hormone (GnRH) pulsatility and vasomotor symptoms have been proposed. Using a selective NKB receptor (NK3R) antagonist, the role of NKB in the hypergonadotropic state in menopausal women was explored.. Eleven postmenopausal women were administered the NK3R antagonist MLE4901 at 40 mg twice daily orally for 7 days. Ten-minute blood sampling for 8 h was performed before and on the last day of NK3R antagonist treatment for luteinising hormone (LH) pulsatility analysis with kisspeptin-10 (0.3 µg/kg i.v. bolus) administered at 6 h on both days. Hot flash frequency and severity were self-reported for 7 days before and during NK3R antagonist administration.. LH fell from 29.3 ± 4.1 to 24.4 ± 3.8 IU/L (p < 0.05) after 7 days of NK3R antagonist treatment, with no change in follicle-stimulating hormone (FSH). Basal (non-pulsatile) LH secretion was reduced (549.0 ± 70.8 vs. 366.1 ± 92.1 IU/L/6 h, p = 0.006), and while the LH pulse frequency did not change in the group as a whole (from 0.8 ± 0.1 to 0.7 ± 0.1 pulses/h, ns), it did fall in the 8 women with hot flashes (from 1.0 ± 0.1 to 0.7 ± 0.1 pulses/h, p < 0.05). These women also reported a reduction in hot flash frequency (from 3.4 ± 1.2 to 1.0 ± 0.6 hot flashes/day, p = 0.008) whilst taking the NK3R antagonist. Kisspeptin-10 did not affect LH secretion with or without the NK3R antagonist.. The administration of an NK3R antagonist indicates a role for NKB in the regulation of LH/GnRH in postmenopausal women, whereas the lack of response to kisspeptin may reflect the hypo-oestrogenic state. These data support a link of LH/GnRH pulsatility and vasomotor symptoms with NK3R antagonism as a potential therapeutic approach.

Topics: Administration, Oral; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Gonadotropins; Hot Flashes; Humans; Kisspeptins; Luteinizing Hormone; Middle Aged; Neurokinin B; Periodicity; Postmenopause; Receptors, Neurokinin-3; Treatment Outcome