Sexual dimorphism of kisspeptin and neurokinin B immunoreactive neurons in the infundibular nucleus of aged men and women

Abstract

The secretory output of gonadotropin-releasing hormone (GnRH) neurons is critically influenced by peptidergic neurons synthesizing kisspeptins (KP) and neurokinin B (NKB) in the hypothalamic infundibular nucleus (Inf). These cells mediate negative feedback effects of sex steroids on the reproductive axis. While negative feedback is lost in postmenopausal women, it is partly preserved by the sustained testosterone secretion in aged men. We hypothesized that the different reproductive physiology of aged men and women is reflected in morphological differences of KP and NKB neurons. This sexual dimorphism was studied with immunohistochemistry in hypothalamic sections of aged human male (≥50 years) and female (>55 years) subjects. KP and NKB cell bodies of the Inf were larger in females. The number of KP cell bodies, the density of KP fibers, and the incidence of their contacts on GnRH neurons were much higher in aged women compared with men. The number of NKB cell bodies was only slightly higher in women and there was no sexual dimorphism in the regional density of NKB fibers and the incidence of their appositions onto GnRH cells. The incidences of NKB cell bodies, fibers, and appositions onto GnRH neurons exceeded several-fold those of KP-IR elements in men. More NKB than KP inputs to GnRH cells were also present in women. Immunofluorescent studies identified only partial overlap between KP and NKB axons. KP and NKB were colocalized in higher percentages of afferents to GnRH neurons in women compared with men. Most of these sex differences might be explained with the lack of estrogen negative feedback in aged women, whereas testosterone can continue to suppress KP, and to a lesser extent, NKB synthesis in men. Overall, sex differences in reproductive physiology of aged humans were reflected in the dramatic sexual dimorphism of the KP system, with significantly higher incidences of KP-IR neurons, fibers and inputs to GnRH neurons in aged females vs. males.

Kisspeptin across the human lifespan:evidence from animal studies and beyond

“…Interestingly, however, in the same manner that sexual dimorphism exists with regard to response to kisspeptin administration, Hrabovszky and coworkers demonstrated that kisspeptin neuron population is markedly different between ageing males and females with a much greater effect observed in females (Hrabovszky et al 2011). Although much remains to be known about the effect of ageing, the findings are interesting and corroborate existing knowledge regarding the influence of sex steroids on kisspeptin production.…”

Hypophysiotropic Gonadotropin-Releasing Hormone Projections Are Exposed to Dense Plexuses of Kisspeptin, Neurokinin B and Substance P Immunoreactive Fibers in the Human: A Study on Tissues from Postmenopausal Women

“…Human hypothalamic and pituitary tissues from 5 postmenopausal female subjects (53-83 years) were obtained at autopsies [7,26] from the Forensic Medicine Department of the University of Debrecen, with the permission of the Regional Committee of Science and Research Ethics (DEOEC RKEB/IKEB: 3183-2010). The subjects were not known to suffer from neurological or endocrine disorders and the postmortem intervals before dissection were below 36 h.…”

“…Dissection guidelines from the hypothalamic blocks were the optic chiasm rostrally, the mammillary bodies caudally and the anterior commissure dorsally [7,26]. The hypophysis was also taken out from the sella following the removal of the brain.…”

“…Accordingly, GnRH neurons receive KP-IR afferent contacts [7,17,18,19,20] and show depolarization [12,21,22] and cFos expression [11,23] in response to KP. Similarly to KP fibers, NKB-IR axons also establish axo-somatic and axo-dendritic contacts with GnRH neurons in rats [24], mice [25] and humans [9,26,27] and 16% of the GnRH-IR perikarya in the preoptic area of the rat exhibit NK3 immunoreactivity [14]. Somewhat conflictingly, mouse GnRH neurons do not give electrophysiological responses to the NK3 receptor agonist senktide in slice preparations [28], and senktide does not induce GnRH release from the preoptic area which contains the GnRH cell bodies [29].…”

Development of the neurons controlling fertility in humans: new insights from 3D imaging and transparent fetal brains

“…For immunolabeling of mouse tissues (genotyped and tissue prepared as described in the supplementary Materials and Methods), two antibodies previously characterized on mouse sections were used: rabbit anti-GnRH (1:3000), a gift from Prof. G. Tramu (Centre Nationale de la Recherche Scientifique, URA 339, Université Bordeaux I, Talence, France) (Beauvillain and Tramu, 1980); and rabbit anti-GnRH (LR5; 1:1000), a gift from Dr R. Benoit (Montreal General Hospital, Quebec, Canada). Human samples were immunolabeled using a guinea-pig anti-GnRH (EH#1018; 1:10,000), produced by Dr Erik Hrabovszky (Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine of the Hungarian Academy of Sciences, Budapest, Hungary) and previously characterized in post-mortem human hypothalami (Hrabovszky et al, 2011). The mouse antibody directed against the human GnRH-associated peptide 1 (GAP1) was characterized on adult human hypothalami by Skrapits et al (2015).…”