Morphological Evidence for Enhanced Kisspeptin and Neurokinin B Signaling in the Infundibular Nucleus of the Aging Man
Molnár CS, Vida B, Sipos MT, Ciofi P, Borsay BA, Rácz K, Herczeg L, Bloom SR, Ghatei MA, Dhillo WS, Liposits Z, Hrabovszky E. Endocrinology. 2012 Sep 25. [Epub ahead of print]


Laboratory of Endocrine Neurobiology (C.S.M., B.V., M.T.S., Z.L., E.H.), Institute of Experimental Medicine, Hungarian Academy of Sciences, and Department of Neuroscience (Z.L.), Faculty of Information Technology, Pázmány Péter Catholic University, 1083 Budapest, Hungary; Institut National de la Santé et de la Recherche Médicale Unité 862 (P.C.), Neurocentre Magendie, 33077 Bordeaux, France; Department of Forensic Medicine (B.A.B., K.R., L.H.), Faculty of Medicine of the University of Debrecen, 4012 Debrecen, Hungary; and Department of Investigative Medicine (S.R.B., M.A.G., W.S.D.), Hammersmith Hospital, Imperial College London, London W12 0HS, United Kingdom.


Peptidergic neurons synthesizing kisspeptin (KP) and neurokinin B (NKB) in the hypothalamic infundibular nucleus have been implicated in negative sex steroid feedback to GnRH neurons. In laboratory rodents, testosterone decreases KP and NKB expression in this region. In the present study, we addressed the hypothesis that the weakening of this inhibitory testosterone feedback in elderly men coincides with enhanced KP and NKB signaling in the infundibular nucleus. This central hypothesis was tested in a series of immunohistochemical studies on hypothalamic sections of male human individuals that were divided into arbitrary "young" (21-49 yr, n = 11) and "aged" (50-67 yr, n = 9) groups. Quantitative immunohistochemical experiments established that the regional densities of NKB-immunoreactive (IR) perikarya and fibers, and the incidence of afferent contacts they formed onto GnRH neurons, exceeded several times those of the KP-IR elements. Robust aging-dependent enhancements were identified in the regional densities of KP-IR perikarya and fibers and the incidence of afferent contacts they established onto GnRH neurons. The abundance of NKB-IR perikarya, fibers, and axonal appositions to GnRH neurons also increased with age, albeit to lower extents. In dual-immunofluorescent studies, the incidence of KP-IR NKB perikarya increased from 36% in young to 68% in aged men. Collectively, these immunohistochemical data suggest an aging-related robust enhancement in central KP signaling and a moderate enhancement in central NKB signaling. These changes are compatible with a reduced testosterone negative feedback to KP and NKB neurons. The heavier KP and NKB inputs to GnRH neurons in aged, compared with young, men may play a role in the enhanced central stimulation of the reproductive axis. It requires clarification to what extent the enhanced KP and NKB signaling upstream from GnRH neurons is an adaptive response to hypogonadism or, alternatively, a consequence of a decline in the androgen sensitivity of KP and NKB neurons.