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closeAn Optimal DHEA to Testosterone Ratio Stimulates Genes, Optimally
Posted by jamesmhoward on 17 Oct 2013 at 12:04 GMT
I suggest the findings of Zou, et al., may be explained by reductions in dehydroepiandrosterone (DHEA), any reference to which I could not find in their article. Zou, et al., reported that “These deficits [caused by reductions in ERK5] were not caused by a reduction in the level of testosterone, by physical immobility, by heightened fear or anxiety, or by depression.” It is my hypothesis that testosterone evolved to work with DHEA.
It has been reported that “Knockdown of ERK5 by retroviral infection of shRNA attenuates prolactin-stimulated neurogenesis in SVZ-derived adult neural stem/progenitor cells (aNPCs).” (J Biol Chem. 2013 Jan 25;288(4):2623-31) The significance of this finding is that prolactin is a known, specific stimulator of DHEA. Therefore, it may follow that reductions in ERK5 may actually exert its negative effects because of reduced DHEA.
It is my hypothesis that mammals evolved because of selection for DHEA. (“Hormones in Mammalian Evolution,” Rivista di Biologia / Biology Forum 2001; 94: 177-184 ) This is based on my hypothesis that evolution selected DHEA because it optimizes replication and transcription of DNA. DHEA affects genes. Therefore DHEA levels affect all tissues and the life span. A case may be made that optimal amounts of DHEA are necessary for conception. Since a mother produces DHEA for herself and her fetus, she must have an optimal level of DHEA for conception and maintenance of a fetus until near birth when fetal production of DHEA combines with the mother’s DHEA to signal and initiate birth. Selection pressure within Mammalia for testosterone produced primates and, with exaggeration, humans. I think testosterone increases cellular absorption of DHEA by increasing androgen receptors through which DHEA enters cells. The selection is basically selection for additional cellular DHEA because of testosterone. (If one desires more detail of this: “DHEA, Estradiol, Testosterone, and the Relevance of Their Ratio …The Androgen Receptor …and the Secular Trend,” at: http://anthropogeny.com/A... )
Therefore, I submit that the findings of Zou, et al., may be due to reductions in the DHEA to testosterone ratio.
RE: An Optimal DHEA to Testosterone Ratio Stimulates Genes, Optimally
ZhenguiXia replied to jamesmhoward on 30 Oct 2013 at 23:48 GMT
Dear Dr. Howard,
Thank you for your interests in our work. After a careful consideration, we think that, although your overall hypothesis regarding DHEA in mammal evolution is interesting, it is very unlikely that the alteration of pheromone behavior in our conditional ERK5 KO mice is due to reduced level of DHEA.
ERK5 is conditionally deleted in nestin-expressing neural stem cells in the transgenic mouse model described in this study. The ERK5 KO mice is NOT a systemic KO.
DHEA is mostly produced by the adrenal glands and the gonads. Although brain may produce a small amount of DHEA, ERK5 is NOT expressed in the adult brain in general; ERK5 expression is limited to adult neurogenic regions in the adult brain. Secondly, in our JBC paper, we demonstrate that ERK5 is downstream from prolactin’s pro-neurogenic effects on adult neurogenesis. There is no evidence in the literature that ERK5 stimulates prolactin production or secretion in adult neural stem/progenitor cells, or ERK5 positively mediates prolactin stimulation of DHEA production. Finally, even if ERK5 somehow mediates prolactin stimulated DHEA production/release in adult neural stem/progenitor cells, this group of cells is very small in number in the brain, and brain is not the primary site of DHEA synthesis. Therefore, we think it is unlikely that conditional ERK5 deletion in neural stem cells has a significant effect on the overall level of DHEA.
Best,
Zhengui Xia