Figure 1
Darkfield photomicrogaphs of adjacent hypothalamic sections from intact, cycling control (INTACT) (a,c) or ovariectomized (OVX) (b,d) cynomolgus monkeys hybridized with either neurokinin B (NKB) (a,b) or pro-opiomelanocortin (POMC) (c,d) probes. The outlines of the base of the brain, pituitary stalk (PS) and third ventricle (3V) have been superimposed on these photomicrographs. Note the marked increase in the number of labelled NKB neurones in the OVX monkeys. Scale bar = 0.5 mm in all photomicrographs.
Source publication
Degeneration of the ovary in middle-aged women results in castrate levels of ovarian steroids and increased gonadotropin secretion from the anterior pituitary gland. Ageing in women is also accompanied by significant changes in energy homeostasis. We have observed alterations in hypothalamic morphology and gene expression in older women, including...
Contexts in source publication
Context 1
... mRNA-expressing neurones were located predominantly in the infundibular nucleus (at the level examined) in a distribution similar to that described in the human, rat and monkey hypothalamus (5, 28±30). Ovariectomy induced a marked increase in NKB gene expression (Fig. 1). The number of neurones expressing NKB mRNA in the infundibular nucleus doubled from 33.8 AE 3.0 neurones/section (unilaterally) in the INTACT group (n 8) to 67.9 AE 6.5 neurones/section in the OVX group (n 9, P < 0.001) (Fig. 2). In addition, there was an almost four-fold increase in the number of autoradiographic grains/cell ...
Context 2
... was no effect of ovariectomy on the gene expression of POMC neurones in the young cynomolgus monkey. Figure 1(C,D) shows the distribution of neurones expressing POMC mRNA in the infundibular nucleus at a level corresponding to plate 840 of the monkey hypothalamic atlas (22). This distribution was similar to previous reports of POMC neurones in both human and monkey hypothalamus (8,30,32). ...
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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...
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Citations
... Since these KNDy neurons are projected to the MnPO (median preoptic) nucleus of the hypothalamus where they bind to NK3 (Neurokinin 3) Receptors, which results in heat dissipation causing vasomotor symptoms. [33][34][35] Estrogen receptors are widely distributed in the central nervous system and are thought to play an important role in cognitive functions like memory and executive function. The two isoforms of Estrogen receptors namely Estrogen Receptor Alpha and Beta have been found important for the same. ...
Menopause is an inevitable phase of life in women which comes with various physical and mental health issues. Middle age, specifically the fourth decade of life is the common age for the onset of menopause in which fluctuation in sex steroid hormones leads to physical as well as mental symptoms. Vasomotor symptoms such as hot flashes and night sweating gradually progress in the menopausal transition and last around 5-6 years after the onset. These are the earliest symptoms that have been reported by around 85% of women. More than 50% of women suffer from sleep disturbance whereas around 40% of women reported depressive symptoms while entering the menopausal phase. Anxiety disorders are quite prevalent and most of the time comorbid with depression. Common presentation is usually in the form of generalized anxiety and Panic attack symptoms. Mood swings, irritability, and anxiety symptoms are heightened in the menopausal transition. Cognitive impairment during the peri-menopausal and post-menopausal phases such as disturbance in concentration and memory is very common at this age. Women with mild menopausal symptoms are advised for lifestyle modification whereas those with moderate to severe symptoms need pharmacological therapy along with lifestyle changes. ARTICLE INFO
... E2 deficiency increases LH pulsatility and hot flashes, and this close temporal relationship between temperature and reproduction is mediated by KNDy neuronal activity (19). Indeed, while ovariectomy (E2-deficient state) increased ARC KNDy gene expression and neuronal hypertrophy, E2 supplementation reversed it (24,329,330), suggesting that E2 withdrawal leads to increased KNDy expression in rodents. Furthermore, tract tracing studies revealed that KNDy neurons project to the MnPO (the thermoregulatory center) and GnRH axons in the median eminence of the hypothalamus (331). ...
Kisspeptin (KP) and neurokinin B (NKB) are neuropeptides that govern the reproductive endocrine axis through regulating hypothalamic gonadotropin-releasing hormone (GnRH) neuronal activity and pulsatile GnRH secretion. Their critical role in reproductive health was first identified after inactivating variants in genes encoding for KP or NKB signaling were shown to result in congenital hypogonadotropic hypogonadism (CHH) and a failure of pubertal development. Over the past two decades since their discovery, a wealth of evidence from both basic and translational research has laid the foundation for potential therapeutic applications. Beyond KP’s function in the hypothalamus, it is also expressed in the placenta, liver, pancreas, adipose tissue, bone, and limbic regions, giving rise to several avenues of research for use in the diagnosis and treatment of pregnancy, metabolic, liver, bone, and behavioral disorders.
The role played by NKB in stimulating the hypothalamic thermoregulatory center to mediate menopausal hot flashes has led to the development of medications that antagonize its action as a novel non-steroidal therapeutic agent for this indication. Furthermore, the ability of NKB antagonism to partially suppress (but not abolish) the reproductive endocrine axis has supported its potential use for the treatment of various reproductive disorders including polycystic ovary syndrome (PCOS), uterine fibroids, and endometriosis. This review will provide a comprehensive up-to-date overview of the preclinical and clinical data that have paved the way for the development of diagnostic and therapeutic applications of KP and NKB.
... The model has been supported by mammal experiments and human studies. For example, ovariectomy increased NKB expression in ARC of monkeys, while estrogen treatment reduced it (74,75). Post-menopausal women were found to have higher expression of Kiss1 mRNA (32). ...
The discovery of kisspeptin as a critical central regulatory factor of GnRH release has given people a novel understanding of the neuroendocrine regulation in human reproduction. Kisspeptin activates the signaling pathway by binding to its receptor kisspeptin receptor (KISS1R) to promote GnRH secretion, thereby regulating the hypothalamic-pituitary-gonadal axis (HPG) axis. Recent studies have shown that kisspeptin neurons located in arcuate nucleus (ARC) co-express neurokinin B (NKB) and dynorphin (Dyn). Such neurons are called KNDy neurons. KNDy neurons participate in the positive and negative feedback of estrogen to GnRH secretion. In addition, kisspeptin is a key factor in the initiation of puberty, and also regulates the processes of female follicle development, oocyte maturation, and ovulation through the HPG axis. In male reproduction, kisspeptin also plays an important role, getting involved in the regulation of Leydig cells, spermatogenesis, sperm functions and reproductive behaviors. Mutations in the KISS1 gene or disorders of the kisspeptin/KISS1R system may lead to clinical symptoms such as idiopathic hypogonadotropic hypogonadism (iHH), central precocious puberty (CPP) and female infertility. Understanding the influence of kisspeptin on the reproductive axis and related mechanisms will help the future application of kisspeptin in disease diagnosis and treatment. In this review, we critically appraise the role of kisspeptin in the HPG axis, including its signaling pathways, negative and positive feedback mechanisms, and its control on female and male reproduction.
... Metabolic functions of estradiol in women have been difficult to define, however, partly due to logistical and ethical constraints in designing definitive experiments with rigorous control. OVX-mediated estradiol depletion had small effects on female rhesus macaque body weight in 1 study [83], and no effects on female body weight were observed in 2 studies of cynomolgus macaques [84,85]. While a putative selective estrogen receptor modifier (SERM) can promote weight loss in OVX rhesus monkeys [86], estradiol replacement therapy has no effect on body weight in OVX cynomolgus macaques [85,87]. ...
Context:
Ovarian estradiol supports female sexual behavior and metabolic function. While ovariectomy (OVX) in rodents abolishes sexual behavior and enables obesity, OVX in nonhuman primates decreases, but does not abolish, sexual behavior, and inconsistently alters weight gain.
Objective:
We hypothesize that extra-ovarian estradiol provides key support for both functions, and to test this idea, we employed aromatase inhibition to eliminate extra-ovarian estradiol biosynthesis and diet-induced obesity to enhance weight gain.
Methods:
Thirteen adult female marmosets were OVX and received (1) estradiol-containing capsules and daily oral treatments of vehicle (E2; n = 5); empty capsules and daily oral treatments of either (2) vehicle (VEH, 1 mL/kg, n = 4), or (3) letrozole (LET, 1 mg/kg, n = 4).
Results:
After 7 months, we observed robust sexual receptivity in E2, intermediate frequencies in VEH, and virtually none in LET females (P = .04). By contrast, few rejections of male mounts were observed in E2, intermediate frequencies in VEH, and high frequencies in LET females (P = .04). Receptive head turns were consistently observed in E2, but not in VEH and LET females. LET females, alone, exhibited robust aggressive rejection of males. VEH and LET females demonstrated increased % body weight gain (P = .01). Relative estradiol levels in peripheral serum were E2 >>> VEH > LET, while those in hypothalamus ranked E2 = VEH > LET, confirming inhibition of local hypothalamic estradiol synthesis by letrozole.
Conclusion:
Our findings provide the first evidence for extra-ovarian estradiol contributing to female sexual behavior in a nonhuman primate, and prompt speculation that extra-ovarian estradiol, and in particular neuroestrogens, may similarly regulate sexual motivation in other primates, including humans.
... Thus, CNS changes are the source of hot flushes, and mainly the thermoregulatory centrum in the POA is affected [215]. In addition, hypertrophy of ERα-expressing neurons in the infundibular nucleus is also characteristic, with increased kisspeptin, neurokinin B, and substance P mRNA concentrations [216][217][218][219]. Moreover, at the level of the pituitary, the withdrawal of ovarian estrogen-dependent negative feedback during menopause leads to increased LH synthesis [220] (Figure 7). ...
Estrogen is one of the most important female sex hormones, and is indispensable for reproduction. However, its role is much wider. Among others, due to its neuroprotective effects, estrogen protects the brain against dementia and complications of traumatic injury. Previously, it was used mainly as a therapeutic option for influencing the menstrual cycle and treating menopausal symptoms. Unfortunately, hormone replacement therapy might be associated with detrimental side effects, such as increased risk of stroke and breast cancer, raising concerns about its safety. Thus, tissue-selective and non-classical estrogen analogues have become the focus of interest. Here, we review the current knowledge about estrogen effects in a broader sense, and the possibility of using selective estrogen-receptor modulators (SERMs), selective estrogen-receptor downregulators (SERDs), phytoestrogens, and activators of non-genomic estrogen-like signaling (ANGELS) molecules as treatment.
... In turn, estradiol acts on KNDy neurons through negative feedback. As levels of estrogen decrease at menopause, KNDy neurons undergo hypertrophy (enlargement) and are reversed with estrogen supplementation (17). With respect to thermoregulatory function, KNDy neurons project to the median preoptic nucleus (MnPO) of the hypothalamus. ...
Most studies of menopause and brain aging have focused on the role of the sex steroid hormone, estradiol, as a key mechanisms contributing to cognitive and brain aging in women. An emerging literature demonstrates that beyond endogenous estradiol levels, menopausal symptoms, particularly vasomotor symptoms (VMS), are also key determinants of menopause-related changes in cognition and brain function. Critically, that literature shows the importance of using objective techniques to identify associations of VMS with memory performance, brain structure, and brain function. While self-report measures are important patient-centered outcomes in women's health research, objective measures of VMS typically relate more strongly to indices of cognitive and brain health. Currently, it is premature to make a causal claim about VMS and memory dysfunction, but initial findings raise the possibility that women with VMS might experience an improvement in cognition with VMS treatment. More generally, these findings underscore the utility of investigating female-specific risk factors for cognitive decline.
... The hypertrophy of hypothalamic KNDy neurons in postmenopausal women (with elevated gene expression levels of kisspeptin, NKB, and SP) [17][18][19][20][21][22] are a consequence of estrogen withdrawal; in cynomolgus monkeys these features can be induced by oophorectomy and reversed by estrogen replacement. [32][33][34] KNDy neurons branch extensively within the infundibular nucleus and are linked to the medial preoptic nucleus, which has been identified as the estrogen-sensitive thermoregulation control center. 23,35 It is hypothesized that after menopause KNDy neurons are in a hyperactive state (consistent with the observed hypertrophy) that disrupts thermoregulation and triggers hot flashes. ...
Objectives:
To evaluate the safety, pharmacokinetics, and preliminary efficacy of NT-814, a dual neurokinin 1,3 antagonist, in postmenopausal women with vasomotor symptoms (hot flashes).
Methods:
We completed a double-blind, randomized, placebo-controlled trial in three US clinical research units in 76 postmenopausal women with moderate/severe hot flashes. Participants were randomized to 14 days of once-daily NT-814 or placebo within each of four sequential dose cohorts; 50, 100, 150, and 300 mg. Participants completed diaries of hot flash frequency and severity and waking due to night sweats before (baseline) and during treatment.
Results:
All prespecified efficacy parameters (24-h hot flash frequency and severity, frequency of waking due to night sweats) decreased in all groups (including placebo). Mean reduction from baseline at week 2 in moderate/severe hot flash frequency was 37% in the placebo group and, respectively, 24% (P = 0.048 vs placebo), 59% (P = 0.155), 84% (P < 0.001) and 66% (P = 0.022) in the 50 mg, 100 mg, 150 mg, and 300 mg NT-814 groups; in waking due to night sweats reduction was 20% (P = 0.059), 55% (P = 0.135), 81% (P < 0.001), and 63% (P = 0.031) in the NT-814 groups and 32% in the placebo group. The improvement with NT-814 ≥150 mg was also evident in the first week of treatment. The most common treatment-related adverse events were mild somnolence and headache, more frequently in the 300 mg group. Safety monitoring identified no concerns.
Conclusions:
Once-daily NT-814 (≥150 mg/d) resulted in a rapid, marked improvement in hot flashes and waking due to night sweats. No safety concerns were identified. Doses up to 300 mg were well tolerated.
... Comprehensive studies of the roles played by ovarian E 2 on energy balance and body composition in nonhuman primates, by contrast, are scarce. OVXmediated E 2 depletion has small effects on female body weight, with no change in body mass index (BMI) in female rhesus macaques [32], and no effect on female body weight in cynomolgus macaques [33,34]. While a putative selective estrogen receptor modifier (SERM) promotes weight loss in OVX rhesus monkeys [35], E 2 replacement therapy has no effect on body weight in OVX cynomolgus macaques [34,36]. ...
... In rhesus macaques one study has documented a 3% increase in body weight at 6 week post-OVX, an effect that was exacerbated by a typical HFD containing~35% of calories from fat [32]. No changes in body weight were reported in cynomolgus macaques maintained on a normal fat diet (~11% calories from fat) after long-term OVX [33,34]. Body weight changes in female cynomolgus macaques have yet to be studied, however, when long-term OVX is combined with HFD. ...
Objective In adult female rodents, ovarian estradiol (E2) regulates body weight, adiposity, energy balance, physical activity,
glucose-insulin homeodynamics, and lipid metabolism, while protecting against diet-induced obesity. The same E2 actions
are presumed to occur in primates, but confirmatory studies have been lacking.
Methods We investigated the consequences of ovariectomy (OVX) and E2 replacement in female marmoset monkeys on
major metabolic and morphometric endpoints. Sexual behavior and uterine diameters were assessed as positive controls for
E2 treatment efficacy. Metabolic parameters were measured 1 mo prior to OVX, and 3 and 6 mo thereafter. During OVX,
animals received empty or E2-containing silastic s.c. implants. To test the interaction between E2 and diet, both treatment
groups were assigned to either a higher fat diet (HFD) or a low-fat diet (LFD).
Results As anticipated, OVX animals exhibited diminished frequency (p = 0.04) of sexually receptive behavior and
increased rejection behavior (p = 0.04) toward their male partners compared with E2-treated OVX females. OVX also
decreased (p = 0.01) uterine diameter. There were no treatment effects on total caloric intake. There were no significant
effects of OVX, E2 treatment, or diet on body weight, body composition, energy expenditure, physical activity, fasting
glucose, or glucose tolerance. Regardless of E2 treatment, serum triglycerides were higher (p = 0.05) in HFD than LFD
females. Postmortem qPCR analysis of hypothalamic tissues revealed higher mRNA expression (p < 0.001) for PGR in E2-
treated monkeys versus OVX controls regardless of diet, but no differences between groups in other selected metabolic
genes. In contrast, regardless of E2 treatment, there was a decreased mRNA expression of PGC1α (PPARGC1A), HTR1A,
and HTR5A in HFD compared with LFD females.
Conclusions Our findings, overall, document a greatly diminished role for ovarian E2 in the metabolic physiology of a
female primate, and encourage consideration that primates, including humans, evolved metabolic control systems regulated
by extra-ovarian E2 or are generally less subject to E2 regulation.
... hypertrophy (4,6) and express estrogen receptor-a (7), with increased expression of the kisspeptin and neurokinin B (NKB) genes (4,6). These changes are secondary to estrogen withdrawal, because they have been duplicated by ovariectomy in young monkeys and are reversed with estrogen replacement (6,8,9). KNDy neurons play an important role in stimulating pulsatile GnRH secretion (10)(11)(12)(13) and LH pulses have been closely timed with hot flushes in women (14)(15)(16). ...
We have proposed that KNDy (kisspeptin/neurokinin B/dynorphin) 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 core temperature (TCORE) during the light phase, with frequency distributions indicating a regulated shift in the balance point. The rise in TCORE in ablated mice occurred despite changes in ambient temperature (TAMBIENT) and regardless of estrogen status. We next determined if an acute increase in TAMBIENT or higher TCORE would induce Fos in preoptic EGFP-immunoreactive neurons in Tacr3-EGFP mice. Fos-activation was increased in the MnPO, but there was no induction of Fos 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 if Tacr3 (NK3R) mRNA was co-expressed with VGLUT2 or VGAT mRNA, markers of glutamatergic or GABAergic neurotransmission, respectively. Interestingly, 94% of NK3R neurons in the MnPO were glutamatergic, whereas in the adjacent MPA, 97% of NK3R neurons were GABAergic. Thus, NK3R neurons in the MnPO are glutamatergic and play a role in reducing TCORE, but they are not activated by warm thermal stimuli (internal or external). These studies suggest that KNDy neurons modulate thermosensory pathways for heat-defense indirectly, via a subpopulation of glutamatergic MnPO neurons that express NK3R.
... At the time of puberty onset and adulthood, the den- sity of neurokinin B, co-expression with kisspeptin as mentioned, immunoreactive-cells was the same aspect as the density of kisspeptin. Neurokinin B is a peptide formed from preprotachykinin B in the hypothalamus and is chiefly expressed in the ARC [28,29]. It is co- localized with kisspeptin and plays a similar function to kisspeptin for example, in its modulation of GnRH secre- tion [30]. ...
Early onset puberty and irregular estrous cycles occur more frequently in rats which are fed a high-fat diet. Kisspeptin is an essential factor for the regulation of sexual maturation and is co-expressed with neurokinin B in neurons in the hypothalamic arcuate nucleus. However, the effects of a diet change on kisspeptin neuronal signaling are not well-understood. Therefore, in this study, we examined the immunoreactivity pattern of the kisspeptin/kiss1-receptor (KISS1R) and neurokinin B/neurokinin3-receptor (R). Pups born to high-fat diet rats were exposed to a high-fat diet until the onset of puberty. From puberty, the offspring originally exposed to a high–fat diet were fed a normal diet up to 85 postnatal days (PND 85). We examined kisspeptin/Kiss1-receptor and neurokinin B/neurokinin3-receptor immunoreactivity (IR) in the arcuate nucleus of the pups. The onset of puberty in the high-fat group was significantly earlier than the control group. At the onset of puberty, the densities of kisspeptin and neurokinin B IR cells were significantly higher in the high-fat diet group than in the control group; however, the densities of KISS1 and neurokinin 3-receptor IR cells did not differ between the two groups. At PND 85, the density of kisspeptin and neurokinin B IR cells did not differ between control and high fat group. The density of densities of KISS1 and neurokinin 3-receptor IR cells also did not differ between groups at this stage. These data suggest that a high-fat diet can influence puberty onset and the immunoreactivity of kisspeptin and neurokinin B. These effects can be modified by dietary control.
