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Dehydroepiandrosterone Induces a Neuroendocrine Phenotype in Nerve Growth Factor-Stimulated Chromaffin Pheochromocytoma PC12 Cells


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Endocrinology, doi:10.1210/en.2007-0645


Dehydroepiandrosterone Induces a Neuroendocrine Phenotype in Nerve Growth Factor-Stimulated Chromaffin Pheochromocytoma PC12 Cells


Christian G. Ziegler, Flavie Sicard, Peter Lattke, Stefan R. Bornstein, Monika Ehrhart-Bornstein and Alexander W. Krug


Medical Clinic III (C.G.Z., F.S., S.R.B., M.E.-B., A.W.K.), Carl Gustav Carus University Hospital, University of Dresden, and Institute of Clinical Chemistry and Laboratory Medicine (P.L.), Carl Gustav Carus University Hospital, 01307 Dresden, Germany


Address all correspondence and requests for reprints to: Dr. Med. Alexander W. Krug, University Hospital Carl Gustav Carus, Medical Clinic III, University of Dresden, Fetscherstra?e 74, 01307 Dresden, Germany. E-mail: alexander.krug@uniklinikum-dresden.de.


The adrenal androgen dehydroepiandrosterone (DHEA) is produced in the inner zone of the adrenal cortex, which is in direct contact to adrenal medullary cells. Due to their close anatomical proximity and tightly intermingled cell borders, a direct interaction of adrenal cortex and medulla has been postulated. In humans congenital adrenal hyperplasia due to 21-hydroxylase deficiency results in androgen excess accompanied by severe adrenomedullary dysplasia and chromaffin cell dysfunction.


Therefore, to define the mechanisms of DHEA action on chromaffin cell function, we investigated its effect on cell survival and differentiation processes on a molecular level in the chromaffin cell line PC12. DHEA lessened the positive effect of NGF on cell survival and neuronal differentiation. Nerve growth factor (NGF)-mediated induction of a neuronal phenotype was inhibited by DHEA as indicated by reduced neurite outgrowth and decreased expression of neuronal marker proteins such as synaptosome-associated protein of 25 kDa and vesicle-associated membrane protein-2. We examined whether DHEA may stimulate the cells toward a neuroendocrine phenotype. DHEA significantly elevated catecholamine release from unstimulated PC12 cells in the presence but not absence of NGF. Accordingly, DHEA enhanced the expression of the neuroendocrine marker protein chromogranin A.


Next, we explored the possible molecular mechanisms of DHEA and NGF interaction. We demonstrate that NGF-induced ERK1/2 phosphorylation was reduced by DHEA. In summary, our data show that DHEA influences cell survival and differentiation processes in PC12 cells, possibly by interacting with the ERK1/2 MAPK pathway. DHEA drives NGF-stimulated cells toward a neuroendocrine phenotype, suggesting that the interaction of intraadrenal steroids and growth factors is required for the maintenance of an intact adrenal medulla.

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Ouch Mary, this one makes my brain hurt, lot of that going on lately.


Hope I am getting the gist of this.


I think this actually might be pretty significant. A couple of years ago when I first started looking for possible connections to family anomalies one of the first roadblocks I encountered was that there was very little established verification of an interconnect between the adrenal cortex and adrenal medula. Simultaneous problems in both areas in one person were just rarely seen or perhaps identified.


At that point I was only able to come up with a couple of weird cases, usually related to anatomical malformations associated with CAH, so far our family is negative for that. Yet the symptoms that were coming up were seemly more consistent with something awry in the medulla. We do have the elevated DHEAS that shows up on bloodwork. It might account for the possible involvement of the medulla as a side effect to over production in the cortex. Can't quite make it out but looks like maybe more than one this has to be off.


It might help account for some of the swings in blood pressure(? maybe) that some of the cyclers come up against.


This is one of those that will have to swim around a bit before it sinks in.



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