Puberty is a complexly coordinated biological process that transits an individual from childhood to adulthood1. Puberty initiation is marked by secretion of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons and secreted GnRH triggers signaling cascades and gonadal activations 2. This neuro-hormonal process follows the cascade below:
1. Hypothalamus release pulses of GnRH
2. Anterior pituitary cells respond by secreting Leutenizing hormone (LH) and follicle stimulating hormone (FSH) into the circulation
3. Ovaries and testis respond to increasing amounts of LH and FSH by growing and beginning to produce estradiole and testosterone
4. Increased levels of estradiol and testosterone produced by the body initiates female and male puberty
Neurokinin B (a tachykinin peptide) and kisspeptin (a neuropeptide): both present in the same hypothalamic neurons; critical parts of the control system that switches on the release of GnRH at the start of puberty
LH (luteinizing hormone): a larger protein hormone secreted into the general circulation by gonadotrope cells of the anterior pituitary gland; the main target cells of LH are the Leydig cells of testes and the theca cells of the ovaries
FSH (follicle stimulating hormone): another protein hormone secreted into the general circulation by the gonadotrope cells of the anterior pituitary; The main target cells of FSH are the ovarian follicles and the Sertoli cells and spermatogenic tissue of the testes
GnRH (Gonadotropin Releasing Hormone): a peptide hormone released from the hypothalamus that stimulates gonadotrope cells of the anterior pituitary
Gonadotropin: protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates, including the mammalian hormones follitropin (FSH)and lutropin (LH)
For more information, refer to: http://en.wikipedia.org/wiki/Puberty#Components_of_the_endocrine_reproductive_system
To see how GnRH release affect testosterone production, follow the link:
Kisspeptin and kisspeptinocentric view of GnRH release
Inactivation of kisspeptin signaling from kissepeptin receptor KISS1R is associated with hypogonadotropic hypogonadism and absent or delayed puberty in man3,4. As seen in study by Oakley et al., kisspeptin signaling works by signaling in the brain that mediates a negative feedback action of sex steroids on gonadotropin secretion, that generates preovulatory GnRH/LH surge, ultimately triggering the sexual maturation at puberty15.
Such discovery led to more studies on signaling pathways triggering puberty initiation in mammals and the notion of “kisspeptinocentric view”of the neural control of GnRH release!
Neurokinin B has a similar role as Kisspeptin in GnRH release
A study by Topaloglu and co-workers in 2009 reported that mutation of the genes encoding neurokininB (NKB) (TAC3) and its receptor (TAC3R) are also associated with hypogonadotropic hypogonadism as reported earlier for KISS1R mutations5,6 .
In sheep, it was found that Kisspeptin and NKB are co-expressed in the arcuate neuron, and that they are required for a pulsatile release of GnRH in humans and maintenance of adult gonadal function3,4.
In mice experiments, deletion of KISS yielded similar results as seen in human studies; however, deletion of NKB did not lead to infertility as did in human studies. In other rodent studies NKB signaling pathway exhibited no action, or rather had an inhibitory action, on GnRH release5,6. These issues had to be reconciled with human genetics and more studies were in need to discover the NKB signaling pathway5,6.
Discovering the Effect of NKB signaling on GnRH release in Primate
In the present study by Ramaswamy et al., a series of experiments were performed to discover the action of NKB signaling on GnRH release in rhesus monkey14. Rhesus monkey was selected, especially for its attribute in having a similar post-natal pattern of pulsatile GnRH release to that in human14.
Many conditions followed in this study. Only juvenile males were selected because during stage of development, spontaneous GnRH release is more restraint in male that that of female14. Therefore, any stimulatory action of NKB on GnRH release maybe more readily detected14. Also, the subjects were castrated to eliminate any confounding effects of testicular feedback on gonadotropin secretion14.
Discussion of Role of NKB in GnRH Release
Neurokinin B, kisspeptin-10 (Kp-10), a NKB receptor (NK3R) peptide agonist senktide, and GnRH antagonist acylin and GnRH were synthesized or obtained to be injected in a dose-manner, bolus injections to observe LH discharge the rhesus monkeys.
The injection of senktide elicited a robust LH discharge. Injection of NKB also elicited a marked discharge of LH, as well as GnRH14 (Figure 5).
Senktide- induced LH release was abolished when pretreated with GnRH-R antagonist, acyline (Figure 6). GnRH injection elicited LH discharge similar to that released spontaneously by endogenous pulsatile GnRH release supported by GnRH discharge from the hypothalamus of juvenile in response senktide iv bolus being equivalent to that produced spontanesouly in pubertal and postpubertal animals14.
Kp-10 produced a LH discharge with amplitude greater than that observed in senktide response (Figure 7). Therefore, it is concluded that Kp-10 is the most potent releaser of GnRH14.
The LH response to the NK3R agonist was abolished when introduced to pretreated animal with the NK3R antagonist SB222200, but LH discharge induced by Kp-10 was not affected14, revealing that SB222200did not interfere with stimulatory action of Kp-10 (Figure 8). This proposes that NK3R and KISS1R signaling pathways are independent and that NKB pathway does not affect KP-10 induced GnRH release14.
Using double label fluorescence immunohistochemistry, et al. found that NKB is expressed in arcuate kisspeptin neurons in primates (Figure 9).
Ramaswamy et al. provides a description of a GnRH- releasing action of NK3R agonists in a primate14. Although repetitive activation of NK3R failed to sustain pulsatile GnRH release, a single iv bolus of NKB and senktide elicited a robust discharge of GnRH14. It also provides a clue to where NKB signaling to GnRH neurons may take place14. Because this study does not provide an answer to how NKB signaling pathway occurs and whether NKB and kisspeptin signal work in parallel or in a cascade-manner to result in pulsatile GnRH release, further studies in the future may be addressed to investigate actions of these two peptides and how they work together in driving neuro-endocrine axis, governing the initiation of puberty and reproduction14.
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