The Kiss1 gene encodes a family of neuropeptides called kisspeptins, which activate the receptor G protein-coupled receptor-54 and play a role in the neuroendocrine regulation of GnRH secretion. We examined whether estradiol (E2) regulates KiSS-1 in the forebrain of the female mouse by comparing KiSS-1 mRNA expression among groups of ovary-intact (diestrus), ovariectomized (OVX), and OVX plus E2-treated mice. In the arcuate nucleus (Arc), KiSS-1 expression increased after ovariectomy and decreased with E2 treatment. Conversely, in the anteroventral periventricular nucleus (AVPV), KiSS-1 expression was reduced after ovariectomy and increased with E2 treatment. To determine whether the effects of E2 on KiSS-1 are mediated through estrogen receptor (ER)alpha or ERbeta, we evaluated the effects of E2 in OVX mice that lacked functional ERalpha or ERbeta. In OVX mice that lacked functional ERalpha, KiSS-1 mRNA did not respond to E2 in either the Arc or AVPV, suggesting that ERalpha is essential for mediating the inhibitory and stimulatory effects of E2. In contrast, KiSS-1 mRNA in OVX mice that lacked functional ERbeta responded to E2 exactly as wild-type animals. Double-label in situ hybridization revealed that virtually all KiSS-1-expressing neurons in the Arc and AVPV coexpress ERalpha, suggesting that the effects of E2 are mediated directly through KiSS-1 neurons. We conclude that KiSS-1 neurons in the Arc, which are inhibited by E2, may play a role in the negative feedback regulation of GnRH secretion, whereas KiSS-1 neurons in the AVPV, which are stimulated by E2, may participate in the positive feedback regulation of GnRH secretion.

/pdf/regulation-of-kiss1-gene-expression-in-the-brain-of-the-2n23w1irri.pdf

Regulation of Kiss1 gene expression in the brain of the female mouse.

Recently, a subset of neurons was identified in the arcuate nucleus of the hypothalamus that colocalize three neuropeptides, kisspeptin, neurokinin B, and dynorphin, each of which has been shown to play a critical role in the central control of reproduction. Growing evidence suggests that these neurons, abbreviated as the KNDy subpopulation, are strongly conserved across a range of species from rodents to humans and play a key role in the physiological regulation of GnRH neurons. KNDy cells are a major target for steroid hormones, form a reciprocally interconnected network, and have direct projections to GnRH cell bodies and terminals, features that position them well to convey steroid feedback control to GnRH neurons and potentially serve as a component of the GnRH pulse generator. In addition, recent work suggests that alterations in KNDy cell peptides may underlie neuroendocrine defects seen in clinical reproductive disorders such as polycystic ovarian syndrome. Taken together, this evidence suggests a key role for the KNDy subpopulation as a focal point in the control of reproductive function in health and disease.

https://sites.oxy.edu/clint/physio/article/KisspeptinNeurokininBDynorphincellsofArcuateNucleusACentralNodeintheControlofGRHSecretion.pdf

Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion.

Introduction THE pituitary gonadotropins, LH and FSH, play a central role in the mammalian reproductive process. Synthesized in the gonadotropes of the pituitary, the gonadotropins bind to receptors in the gonads leading to effects on steroidogenesis and gametogenesis (Fig. 1). Because these hormones are responsible for sexual maturation and normal reproductive function, the regulation of their synthesis and secretion is essential for the preservation of a species. In recent years, a great deal has been learned about the regulation of synthesis of the gonadotropins using the tools of molecular biology. Before we can fully appreciate these new insights, however, it is important to understand the complex structure of the gonadotropins and to summarize what is known about the regulation of their secretion. In this review, we will discuss the structure of the gonadotropin subunits, the structure of the genes that encode them, and the regulation of their secretion and synthesis.

Molecular biology of the pituitary gonadotropins.

An increase in pulsatile release of LHRH is essential for the onset of puberty. However, the mechanism controlling the pubertal increase in LHRH release is still unclear. In primates the LHRH neurosecretory system is already active during the neonatal period but subsequently enters a dormant state in the juvenile/prepubertal period. Neither gonadal steroid hormones nor the absence of facilitatory neuronal inputs to LHRH neurons is responsible for the low levels of LHRH release before the onset of puberty in primates. Recent studies suggest that during the prepubertal period an inhibitory neuronal system suppresses LHRH release and that during the subsequent maturation of the hypothalamus this prepubertal inhibition is removed, allowing the adult pattern of pulsatile LHRH release. In fact, y-aminobutyric acid (GABA) appears to be an inhibitory neurotransmitter responsible for restricting LHRH release before the onset of puberty in female rhesus monkeys. In addition, it appears that the reduction in tonic GABA inhibition allows an increase in the release of glutamate as well as other neurotransmitters, which contributes to the increase in pubertal LHRH release. In this review, developmental changes in several neurotransmitter systems controlling pulsatile LHRH release are extensively reviewed.

Neurobiological mechanisms of the onset of puberty in primates.

The push-pull perfusion technique was used in combination with a sequential bleeding schedule to estimate simultaneously the release patterns of LHRH and LH in unanesthetized oviuriectomized sheep and to determine the temporal relationship between the release of these two hormones. Ovariectomized (>30 days) ewes received unilateral push-pull cannula (PPC) implants (od, 0.85 mm) into the median eminence. After at least 6 days of recovery, each ewe was fitted with an indwelling jugular catheter. For push-pull perfusion, a stylette was removed from the outer PPC, and an inner cannula assembly (od, 0.40 mm) was inserted. Artificial cerebrospinal fluid was pushed through the inner cannula and pulled up between the cannulae at 20 μl/min. Continuous 10-min perfusate fractions were collected, acidified, and stored at -20 C for LHRH RIA. Blood samples were obtained every 10 min via the jugular catheter, each being drawn 5 min after the start of a perfusate collection interval. Plasma LH levels were determined by R...

Simultaneous measurement of luteinizing hormone-releasing hormone and luteinizing hormone release in unanesthetized, ovariectomized sheep.

Various hypothalamic lesions were placed in long term ovariectomized rats, and their effects on pulsatile discharges of LH were noted in order to determine which neural regions are involved in the control of this mode of LH secretion. Complete hypothalamic deafferentiation did not affect pulsatile patterns of LH secretion unless the anterior portion of the cut also lesioned the anterior portion of the arcuate nuclei, in which case pulsatile LH discharges were completely blocked. Pulsatile LH secretion was not blocked by bilateral electrolytic lesions placed in ventromedial, paraventricular, or suprachiasmatic nuclei or anterior or posterior portions of the arcuate nuclei, although the nuclei were not completely destroyed by the lesions. When bilateral electrolytic lesions of the anterior portions of the arcuate nuclei were combined with anterior hypothalamic deafferentation, however, pulsatile discharges of LH were completely blocked. These results suggest that two pathways can stimulate the pulsatile mode of LH secretion independently of each other. One of these pathways involves the arcuate nuclei and possibly nearby structures, while the other appears to include extrahypothalamic structures and to enter the hypothalamus anteriorly.

Hypothalamic and extrahypothalamic mediation of pulsatile discharges of luteinizing hormone in the ovariectomized rat

Role of VIP in the regulation of LH secretion in the female rat

Hypophysectomy was performed on intact female rats during the proestrous LH surge and on ovariectomized rats, and plasma concentrations of LH were measured every 5 min for approximately the next hour. The disappearance rate of LH from ovariectomized rats corresponded to an initial half-life of 23.1 ± 2.9 min, which is within the range previously reported for this species. The disappearance of LH from intact rats, however, corresponded to an initial half-life of 13.7 ± 0.7 min. In a second experiment, blood was taken from ovariectomized rats and from intact female rats during the LH surge. The sera were injected iv into hypophysectomized female rats (with ovaries intact) bearing chronic venous catheters, and plasma concentrations of LH were measured every 5 min for the next hour. LH from ovariectomized rats disappeared at a rate corresponding to an initial halflife of 22.7 ± 2.2 min, while the half-life for LH from proestrous intact rats was 13.4 ± 1.2 min. These results suggest a change in the circulating...

A comparison of the disappearance rates of luteinizing hormone from intact and ovariectomized rats.

Recent reports on the effects of progesterone on the frequency of pulsatile LH release in several species have compelled a reevaluation of the regulation of pulsatile LH secretion by gonadal steroids

Inhibitory Effects of Estrogen and Progesterone on Several Parameters of Pulsatile LH Release in the Ovariectomized Rat

Vasoactive intestinal peptide (VIP) inhibits pulsatile luteinizing hormone (LH) secretion in the ovariectomized rat. Hypothalamic nuclei known to contain VIPergic neurons were destroyed electrolytically to determine whether either an increased response or a loss of response to exogenous VIP would result. Bilateral electrolytic lesions were made of either the suprachiasmatic (SCN) or paraventricular (PVN) nuclei in separate experiments; all animals received an intracerebroventricular cannula at the same time. Sham-lesioned animals were used as a control. One week later, a catheter was placed in the jugular vein of each rat and, after a recovery period of at least 2 h, blood samples were taken every 5 min for 3 h. After a control period of 1.5 h, either VIP or saline was infused into the third ventricle for an additional 1.5 h. Two doses of VIP were used: 3.5 nmol/h, previously shown to be inhibitory, and 0.4 nmol/h, which is ineffective in ovariectomized rats. LH was measured in the plasma by radioimmunoassay. The high dose of VIP lowered mean LH levels and pulse frequency but had no effect on pulse amplitude in both sham-lesioned and SCN-lesioned rats. The low dose of VIP did not affect pulsatile LH patterns in sham-lesioned rats, but did lower mean LH and pulse frequency in SCN-lesioned rats, indicating a denervation hypersensitivity subsequent to SCN lesions. Destruction of the PVN abolished the inhibitory effect of the high dose of VIP on pulsatile LH release. The low dose of VIP was ineffective in both PVN- and sham-lesioned animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of lesions of the suprachiasmatic and paraventricular nuclei on the inhibition of pulsatile luteinizing hormone release by exogenous vasoactive intestinal peptide in the ovariectomized rat.

Richard F. Weick

Papers

Hypothalamic and extrahypothalamic mediation of pulsatile discharges of luteinizing hormone in the ovariectomized rat

Role of VIP in the regulation of LH secretion in the female rat

A comparison of the disappearance rates of luteinizing hormone from intact and ovariectomized rats.

Inhibitory Effects of Estrogen and Progesterone on Several Parameters of Pulsatile LH Release in the Ovariectomized Rat

Effects of lesions of the suprachiasmatic and paraventricular nuclei on the inhibition of pulsatile luteinizing hormone release by exogenous vasoactive intestinal peptide in the ovariectomized rat.