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.
Highlights
Neurons synthesizing gonadotropin-releasing hormone-I (GnRH) represent the final common pathway of the hypothalamus in the neuroendocrine regulation of reproduction
PERIKARYON SIZE OF KISSPEPTIN-IR AND PREPRONKB-IR NEURONS Kisspeptin-IR cell bodies (P = 0.01) as well as preproNKB-IR cell bodies (P = 0.002) were hypertrophied and their profile area was significantly larger in the infundibular nucleus (Inf) of aged women (284.2 ± 27.3 μm2 for kisspeptin-IR and 298.1 ± 19.7 μm2 for preproNKB-IR neurons) in comparison with men (154.8 ± 19.2 μm2 for kisspeptin-IR and 190.4 ± 20.4 μm2 for preproNKB-IR neurons; Figures 1C,D,G,H and 2)
SEX DIFFERENCE IN PERIKARYON SIZE OF KISSPEPTIN AND PREPRONKB NEURONS The studies of a putative sex difference in the perikaryon size of kisspeptin-IR and preproNKB-IR neurons relied on previous work indicating that the profile area of neurons in the Inf is significantly greater in postmenopausal women than in aged men (Rance www.frontiersin.org et al, 1993)
Summary
Neurons synthesizing gonadotropin-releasing hormone-I (GnRH) represent the final common pathway of the hypothalamus in the neuroendocrine regulation of reproduction. The pulsatile pattern of GnRH secretion into the hypophysial portal circulation is shaped by a sex steroid-sensitive neuronal circuitry that acts upstream from GnRH cells (Christian and Moenter, 2010). In both males (Tilbrook and Clarke, 2001) and females (Moenter et al, 2009), gonadal steroid hormones exert homeostatic negative feedback on GnRH release via this upstream circuitry. In females, elevated estradiol in the late follicular phase of the reproductive cycle causes a switch from negative to positive feedback to induce a surge of GnRH from the hypothalamus.
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