Role Played by Brainstem Neurons in Regulating Testosterone Secretion via a Direct Neural Pathway between the Hypothalamus and the Testes

Abstract

We previously reported anatomical and functional evidence for a direct, inhibitory neural pathway that regulates testosterone (T) secretion independently of the pituitary. This pathway is activated by the intracerebroventricular (icv) administration of agents that stimulate stress responses, such as IL-1beta, corticotropin-releasing factor (CRF), and norepinephrine (NE), which results in a blunted T response to the administration of human chorionic gonadotropin (hCG). Blunting of the T response is mediated by central beta-adrenergic receptor stimulation. CRF, but not ethanol (EtOH) or IL-1beta, acts directly on the paraventricular nucleus of the hypothalamus to activate the pathway. Here we explored the role played by brain areas hypothesized to be part of this pathway, such as neurons in the dorsal pons [including the locus coeruleus (LC) of the brainstem], where NE is produced. Microinfusion of EtOH or IL-1beta, but not CRF, into these neurons activated the pathway. Electrolytic lesions of this region significantly reversed the inhibitory effect of icv-administered EtOH on hCG-induced T release, while having no effect on the ability of IL-1beta or CRF to do so. However, the icv administration of IL-1beta, EtOH, or CRF, in doses that rapidly inhibit the T response to hCG, all caused a significant depletion of NE from the LC. Collectively, these results indicate that in addition to the paraventricular nucleus, the brainstem area containing the LC is part of a neural pathway that connects the brain to the testes independently of the pituitary. We also speculate that EtOH may stimulate this pathway through NE-dependent activation of the dorsal pons.

Androgen receptor immunoreactivity in rat occipital cortex after callosotomy

“…This is consistent with a previous study showing that right occipital decortication and posterior callosotomy resulted in changes in gonadal T production in vitro without any significant variation on serum T and LH levels (Lepore et al, 2006). All these data are in accordance with other reports describing pure neural links between the nervous system and the gonads (Gerendai et al, 1986;Lee et al, 2002;Selvage et al, 2006). Thus, occipital cortex could be considered a part of the direct neural fine-tuning mechanism involved in the production of male testosterone.…”

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

“…The phosphodiesterases (PDEs) terminate cAMP/ cGMP signalling and have regulatory function in Leydig cells (Catt & Dufau, 1973;Dufau, 1998;Tsai & Beavo, 2011. Although Leydig cell steroidogenesis is mainly activated through LH/hCG receptors, regulation itself is a multi-compartmental process and includes neural (Selvage et al, 2006) and complex endocrine, paracrine and autocrine signalling pathways (reviewed in Saez, 1994;Gnessi et al, 1997;Payne & Hales, 2004) including cGMP (Andric et al, 2010a,b) and adrenergic signalling (Anakwe et al, 1985). In addition, many transcription factors are involved in regulation of the steroidogenic machinery expression (reviewed in Simard et al, 2005;Lavoie & King, 2009;Martinez-Arguelles & Papadopoulos, 2010;Midzak et al, 2011).…”

Sustained in vivo blockade of α1-adrenergic receptors prevented some of stress-triggered effects on steroidogenic machinery in Leydig cells

“…The phosphodiesterases (PDEs) terminate cAMP/cGMP signaling and have regulatory function in Leydig cells (9,17,18,76,77). Although Leydig cell steroidogenesis is mainly activated through LH/hCG receptors, regulation itself is a multicompartmental process comprised of neural (61) and complex endocrine, paracrine, and autocrine signaling pathways (22,51,59) including cGMP (4) and adrenergic signaling (3). All the aforementioned elements of steroidogenic machinery might be involved in the regulation of testicular steroidogenesis, providing an adaptive mechanism by which testicular structures, including Leydig cells, recover from disturbed homeostasis, such as stress, or any other situation disturbing testosterone homeostasis.…”