Neurokinin B and the Control of the Gonadotropic Axis in the Rat: Developmental Changes, Sexual Dimorphism, and Regulation by Gonadal Steroids

Abstract

Neurokinin B (NKB), encoded by Tac2 in rodents, and its receptor, NK3R, have recently emerged as important regulators of reproduction; NKB has been proposed to stimulate kisspeptin output onto GnRH neurons. Accordingly, NKB has been shown to induce gonadotropin release in several species; yet, null or even inhibitory effects of NKB have been also reported. The basis for these discrepant findings, as well as other key aspects of NKB function, remains unknown. We report here that in the rat, LH responses to the NK3R agonist, senktide, display a salient sexual dimorphism, with persistent stimulation in females, regardless of the stage of postnatal development, and lack of LH responses in males from puberty onward. Such dimorphism was independent of the predominant sex steroid after puberty, because testosterone administration to adult females failed to prevent LH responses to senktide, and LH responsiveness was not restored in adult males treated with estradiol or the nonaromatizable androgen, dihydrotestosterone. Yet, removal of sex steroids by gonadectomy switched senktide effects to inhibitory, both in adult male and female rats. Sexual dimorphism was also evident in the numbers of NKB-positive neurons in the arcuate nucleus (ARC), which were higher in adult female rats. This is likely the result of differences in sex steroid milieu during early periods of brain differentiation, because neonatal exposures to high doses of estrogen decreased ARC NKB neurons at later developmental stages. Likewise, neonatal estrogenization resulted in lower serum LH levels that were normalized by senktide administration. Finally, we document that the ability of estrogen to inhibit hypothalamic Tac2 expression seems region specific, because estrogen administration decreased Tac2 levels in the ARC but increased them in the lateral hypothalamus. Altogether, our data provide a deeper insight into relevant aspects of NKB function as major regulator of the gonadotropic axis in the rat, including maturational changes, sexual dimorphism, and differential regulation by sex steroids.

ENDOCRINOLOGY AND ADOLESCENCE: Deciphering puberty: novel partners, novel mechanisms

“…Considering the relevant role of NKB signaling in the central control of the reproductive axis, the involvement of NKB in the onset of puberty has begun to be evaluated recently; yet, the number of studies on this particular area remains scarce (39,41,42). Notwithstanding, our data on immature rats demonstrate that, like adult, cyclic females, prepubertal female rats are able to respond to the NKB agonist, senktide, with robust LH responses (41).…”

“…The basis for these discrepant observations remains partially unknown, but they may stem from differences in the age, sex, species, and prevailing gonadotropin levels. Indeed, evidence for inhibitory effects of senktide on LH secretion comes mostly from animal models with pre-elevated LH concentrations, namely gonadectomy (GNX) without adequate sex steroid replacement (37,38,39). In this context, proof of desensitization of NKB-induced LH responses has been presented in the monkey (28).…”

“…In the same vein, a modulatory role of NKB signaling on puberty has been very recently proposed in the female sheep (42), in which increased NKB fiber immunoreactivity, but not cell numbers, was detected in post-pubertal vs prepubertal ewes. One interesting issue that warrants investigation is the potential sexual dimorphism in the roles of NKB in the control of puberty, at least in some species, as our recent data suggest that LH responses to senktide are lower in magnitude in male vs female rats before puberty, and, in contrast to females, they become null in male rats during the pubertal transition to adulthood (39). A synoptic compilation of the clinical and experimental data supporting a role of NKB pathways in the central control of puberty is presented in Table 2.…”

Differential modulation of gonadotropin responses to kisspeptin by aminoacidergic, peptidergic, and nitric oxide neurotransmission

“…Surprisingly, in our experiments, senktide did not modify basal LH or FSH levels in young adult male rats, an observation that is in contrast to the potent stimulatory effects of this agonist on gonadotropin secretion in adult male mice (12,32). However, the possibility of an experimental artifact can be discarded since parallel studies, using strictly similar peptide preparations and experimental conditions, revealed potent stimulatory effects of senktide on LH secretion in female rats at various developmental stages (30), as well as in male rats, during the infantile and prepubertal period (48). Moreover, despite the inability to modify basal gonadotropin levels, preactivation of NKB signaling significantly attenuated LH and FSH responses to Kp-10.…”

“…Collectively, these and related findings have led to the hypothesis that NKB (auto)regulates Kp output from ARC Kiss1 neurons onto GnRH neurons (33,34,53). However, stimulatory, inhibitory, or null effects of the agonist of NKB, senktide, on LH secretion have been reported, depending on the sex steroid milieu and the functional state of the gonadotropic axis (5,22,30,32,42,43,48,51), a phenomenon whose basis remains unknown. Moreover, the ability of NKB to modulate GnRH/gonadotropin responses to Kp remains unexplored.…”