Hypertrophy and Increased Kisspeptin Gene Expression in the Hypothalamic Infundibular Nucleus of Postmenopausal Women and Ovariectomized Monkeys

Rometo, Adonna Marie; Krajewski, Sally J.; Voytko, Mary Lou; Rance, Naomi E.

doi:10.1210/jc.2007-0553

Cited by 335 publications

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“…We hypothesized that estrogen withdrawal in humans leads to menopausal flushes by increasing the activity of KNDy neurons. This hypothesis is supported by the increased NKB and kisspeptin gene expression in postmenopausal women (12,13), the close timing of LH pulses and flushes (5), the putative role of KNDy neurons in stimulating pulsatile LH secretion (7)(8)(9)(10), the expression of ERα in KNDy neurons (12), and the demonstration that estrogen suppresses hot flushes (3) as well as NKB and kisspeptin gene expression in young ovariectomized monkeys (13,16). In the present study, ablation of KNDy neurons consistently decreased tail skin vasodilatation in OVX rats, mimicking the thermoregulatory effects of E 2 treatment.…”

Section: Discussionmentioning

confidence: 87%

“…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)(8)(9)(10)(11). In the hypothalamus of postmenopausal women, these kisspeptin/NKB/ dynorphin (KNDy) neurons undergo an unusual somatic hypertrophy and express increased kisspeptin and NKB gene transcripts (12)(13)(14)(15). Studies of cynomolgus monkeys indicate that the changes in KNDy neurons in postmenopausal women are secondary to withdrawal of ovarian estrogens and not due to aging per se (13,(15)(16)(17).…”

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confidence: 99%

“…In the hypothalamus of postmenopausal women, these kisspeptin/NKB/ dynorphin (KNDy) neurons undergo an unusual somatic hypertrophy and express increased kisspeptin and NKB gene transcripts (12)(13)(14)(15). Studies of cynomolgus monkeys indicate that the changes in KNDy neurons in postmenopausal women are secondary to withdrawal of ovarian estrogens and not due to aging per se (13,(15)(16)(17). Mutations in the genes encoding kisspeptin, NKB, or their receptors result in hypogonadotropic hypogonadism, a syndrome characterized by lack of pubertal development, impaired gonadotropin secretion, absence of secondary sex characteristics, and infertility (18)(19)(20)(21).…”

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

Mittelman-Smith

Williams

Krajewski-Hall

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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 (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, ...

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Section: Discussionmentioning

confidence: 87%

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confidence: 99%

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confidence: 99%

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

Mittelman-Smith

Williams

Krajewski-Hall

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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161

110

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“…Likewise, Kiss1 mRNA levels were found to be inhibited by androgen, estrogen and progesterone in sheep and/or monkeys [24,31]. Indirect proof for the presence of a similar mechanism in humans comes form expression analyses in postmenopausal women that showed increased KISS1 mRNA expression at the infundibular region of the hypothalamus [25]. Intriguingly, sex steroid regulation of Kiss1 mRNA expression at the AVPV region, at least in rodents, seems to be diametrically opposite, with androgens and estrogens carrying stimulatory actions [29,30].…”

Section: Major Regulators Of Kiss1 Expression: Central and Peripheralmentioning

confidence: 99%

“…Interestingly, in the sheep, kisspeptin neurons mediating positive and negative feedback effects of sex steroids seem to be intermingled within the ARC; neurons responding positively to estrogen being mostly located at its caudal portion [23]. In primates, including humans, only inhibitory responses to sex steroids have been documented in ARC/infundibular neurons, as major mechanism for their negative feedback on gonadotropin secretion [24][25][26] (see Section 4). It remains to be defined whether and how kisspeptin neurons contribute to the generation of the pre-ovulatory surges in primates.…”

Section: Control Of Gnrh Neurons By Kisspeptin Pathwaysmentioning

confidence: 99%

Kisspeptin signaling in the brain: Recent developments and future challenges

Tena‐Sempere

2010

Molecular and Cellular Endocrinology

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Kisspeptins, a family of peptides encoded by the KISS1 gene which binds GPR54 (or KISS1 receptor), have recently emerged as essential neuropeptide regulators of key aspects of reproductive maturation and function, including puberty onset, neuroendocrine control of ovulation and metabolic regulation of fertility. Yet, while the neuroanatomy of kisspeptin system has begun to be deciphered, and the involvement of kisspeptins in the above phenomena has been experimentally documented in recent years, precise information on the signaling events underlying these functions has remained scarce. Similarly, the nature and mechanisms of action of most of the regulatory signals of KISS1 expression in the brain are largely unknown. In this review, we will comprehensively summarize some of the recent developments in these areas of kisspeptin physiology, with the ultimate aim to delineate unresolved questions and future pathways for the progression of this active field of Neuroendocrinology.

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Kisspeptin expression in guinea pig hypothalamus: Effects of 17β‐estradiol

Bosch

Xue

Rønnekleiv

2012

J of Comparative Neurology

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Kisspeptin is essential for reproductive functions in humans. As a model for the human we have used the female guinea pig, which has a long ovulatory cycle similar to that of primates. Initially, we cloned a guinea pig kisspeptin cDNA sequence and subsequently explored the distribution and 17β-estradiol (E2) regulation of kisspeptin mRNA (Kiss1) and protein (kisspeptin) by using in situ hybridization, real-time PCR and immunocytochemistry. In ovariectomized females, Kiss1 neurons were scattered throughout the preoptic periventricular areas (PV), but the vast majority of Kiss1 neurons were localized in the arcuate nucleus (Arc). An E2 treatment that first inhibits (negative feedback) and then augments (positive feedback) serum luteinizing hormone (LH) increased Kiss1 mRNA density and number of cells expressing Kiss1 in the PV at both time points. Within the Arc, Kiss1 mRNA density was reduced at both time points. Quantitative real-time PCR confirmed the in situ hybridization results during positive feedback. E2 reduced the number of immunoreactive kisspeptin cells in the PV at both time points, perhaps an indication of increased release. Within the Arc, the kisspeptin immunoreactivity was decreased during negative feedback but increased during positive feedback. Therefore, it appears that in guinea pig both the PV and the Arc kisspeptin neurons act cooperatively to excite gonadotropin-releasing hormone (GnRH) neurons during positive feedback. We conclude that E2 regulation of negative and positive feedback may reflect a complex interaction of the kisspeptin circuitry, and both the PV and the Arc respond to hormone signals to encode excitation of GnRH neurons during the ovulatory cycle.

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Hypertrophy and Increased Kisspeptin Gene Expression in the Hypothalamic Infundibular Nucleus of Postmenopausal Women and Ovariectomized Monkeys

Abstract: The cynomolgus monkey experiments provide strong evidence that the increase in KiSS-1 neuronal size and gene expression in postmenopausal women is secondary to ovarian failure. These studies suggest that kisspeptin neurons regulate estrogen negative feedback in the human.

Cited by 335 publications

References 39 publications

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

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

Kisspeptin signaling in the brain: Recent developments and future challenges

Kisspeptin expression in guinea pig hypothalamus: Effects of 17β‐estradiol

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