DHEA, Estradiol, Testosterone, and the Relevance of Their Ratio …The Androgen Receptor …and the Secular Trend  
 
(Contains a new idea: Copyright January 31, 2012, James Michael Howard, Fayetteville, Arkansas, U.S.A.)
 
It is my hypothesis that evolution selected DHEA because it optimizes replication and transcription of DNA.  Therefore DHEA levels affect all tissues.  DHEA naturally begins to decline around the ages of twenty to twenty-five, reaching very low levels in old age.  Since we are mammals, first, and evolved into primates, then humans, I think the basis of our growth and development is dependent upon DHEA.  (If you wish to read more about this, read some of the information about evolution above.  …in "Basics" section, above, if you are this in the "Current Topic" box on the introduction page of my blog.)  Therefore, I think the sex hormones, first estrogen and then testosterone during evolution, evolved to affect the availability of DHEA because of their respective receptors through which I suggest DHEA enters cells.  (Since testosterone drives our sexuality, male and female, I tend to focus on the relationship of testosterone with DHEA.  However, as "female" hormones affect DHEA, with important consequences, I have considered this important relationship in my work elsewhere in my blog or my main page.)
 
It is known that testosterone is involved in the production of androgen receptors.  In fact, it has been found that: "Using a range of testosterone concentrations, we found that low concentrations of testosterone (1 to 10 nmol/L) up-regulate AR expression, while 100 nmol/L down-regulates AR expression." (Blood 2000; 95 (7): 2289-96)  Of importance to my explanation of human evolution, it has also been found that ""T significantly increased the numbers of androgen receptor-immunoreactive cells in every brain region examined." (Biology of Reproduction 2003; 69 (3): 876-84)  DHEA exerts effects at cell surfaces and enters the cell via androgen receptors.  I believe human evolution exhibited significant increases in brain size as a result of exposure to maternal testosterone because of increased testosterone in the Homo erectus females.  (…or whatever "species" of hominid is now considered to have shown this increase in brain size)  Increased maternal testosterone would increase female sexuality as well as increase androgen receptors in their fetuses.  Therefore, the brains of "her" offspring would be able to absorb more DHEA and increase its growth and development.  This female would have sex more often producing more intelligent babies.  …exactly a couple of main differences between the chimpanzee female who produces less testosterone than female humans.
 
Testosterone is involved in the availability of DHEA for growth and development of cells / tissues as well as maintenance of these cells and tissues.  As noted above, large amounts of testosterone can reduce androgen receptors.  It is also known that testosterone reduces sulfatase activity.  DHEA is produced from DHEA sulfate (DHEAS).  Therefore large amounts of testosterone increases DHEAS at the expense of DHEA; often high testosterone is found with high DHEAS.  I think it follows that, if DHEA is involved in cellular activity, then reducing DHEA should reduce cellular (DNA) activity.  Hence, testosterone increases androgen receptors, which increases DHEA entrance to cells to increase, among many things, the production of androgen receptors.  If high testosterone reduces DHEA, then high testosterone reduces both DHEA and androgen receptors.  If you are very healthy, you have the right ratio of testosterone and DHEA.
 
I think the increase in female testosterone increases babies, bright babies.  I think this event started / caused human evolution.  Access to nubile females is important.  Available, fertile females would be selected by evolution.  Therefore, testosterone would increase with time within the population.  If, as pointed out above, female testosterone increases to excess, the availability of DHEA is reduced.  When this situation becomes exaggerated, it exacerbates the negative effects of low DHEA on cells, and tissues, and populations.  I suggest we are experiencing this ongoing effect of human evolution at this time.  Therefore, human evolution will exhibit periodic fluctuations in the testosterone to DHEA ratio.  I think this is the Secular Trend and we are experiencing the negative consequences at this time, such as increasing obesity, type 2 diabetes, cancers, mental disorders, infections, etc. ( Cortisol * )

The ratio of testosterone to estradiol, according to this mechanism, will determine differential gene activity between male and females.  That is, more testosterone will produce increased gene activation which could cause differential growth and development of all tissues between males and females and species.  Since I think increasing testosterone in female hominids is the “cause” of human evolution, one should be aware that human female testosterone is higher than chimpanzee female testosterone while estradiol is approximately the same.

( * It is my hypothesis that cortisol evolved to counteract the effects of DHEA and is the basis of the "fight or flight" mechanism. ("A Theory of the Control of the Ontogeny and Phylogeny of Homo sapiens by the Interaction of Dehydroepiandrosterone and the Amygdala," Copyright 1985, James Michael Howard, Fayetteville, Arkansas, U.S.A. (Registered Copyright TXu220580).) The "cortisol to DHEA ratio" appears numerous times in the medical literature; it is becoming an important mechanism. Therefore, phenomena which increase cortisol may adversely affect the effects of DHEA and increase the probability of morbidity and mortality if the exposure to cortisol is excessive and prolonged.)