Parkinson’s disease, DHEA, and Testosterone
New Support of my Hypothesis; November 19, 2014: Acta Neurol Scand 2014: “Prolactin and sex hormones levels in males with Parkinson's disease,” Nitkowska, et al., This report found reduced testosterone and increased prolactin in Parkinson's disease. The increased prolactin indicates that the feedback mechanism of prolactin-stimulated DHEA is not functioning. That is, increased prolactin indicates that DHEA is not being produced, therefore, not reducing prolactin levels. Hence, testosterone and DHEA are low in Parkinson's disease.
Copyright 2006, James Michael Howard, Fayetteville, Arkansas, U.S.A.
(This is my response to an article, Current Biology 2006; 16: 415-420, the abstract of which is below. My response to this article combined some ideas about Parkinson’s disease which I had been considering for some time.) Supporting Material Added Subsequent to this treatise below. (My explanation of how DHEA and testosterone work together to activate genes: “DHEA, Estradiol, Testosterone, and the Relevance of Their Ratio …The Androgen Receptor …and the Secular Trend,” at: http://anthropogeny.com/Androgen%20Receptor%20and%20Secular%20Trend.htm )
It is my hypothesis that DHEA optimizes replication and transcription of DNA. I think DHEA was selected by evolution in the formation of mammals (Hormones in Mammalian Evolution, Rivista di Biologia / Biology Forum 94: 177-184). Also, I have suggested that selection for testosterone within mammals resulted in primates (ibid 95: 319-326) with further selection for testosterone resulting in humans (ibid 94: 345-362). I think testosterone redirects DHEA use for “testosterone target tissues.” Hence, the rise in testosterone changed the physical form of mammals. This may be seen in higher DHEA in chimpanzee males and females and lower testosterone compared to human males and females. For example, the human brain is a “testosterone target tissue” and its use of extra DHEA reduces the size of faces and teeth during hominid evolution.
Dewing, et al., (Current Biology 2006; 16: 415-420) suggest that down regulation of SRY reduces tyrosine hydroxylase. Testosterone replacement has been found to significantly improve motor function in a patient with Parkinson’s (J Clin Neurosci 2006; 13: 133-6). Some of the symptoms of Parkinson’s may be produced by low testosterone. Tyrosine hydroxylase may be regulated by “androgen receptors” (Neurosci Lett 2006; 396: 57-61). DHEA acts via androgen receptors and exerts “intrinsic androgenic activity that is potentially independent of metabolic conversion to other androgens” (J Neurobiol 2003; 57: 163-71). Additionally, DHEA directly stimulates tyrosine hydroxylase (Endocrinology 2005; 146: 3309-18). I suggest testosterone is involved in directing DHEA use towards SRY activation. This could increase dopamine production as well as primate and male development.
It may be that Parkinson’s results from a combination of low testosterone and low DHEA. That is, low testosterone may exacerbate the effects of low DHEA; low testosterone is not directing DHEA sufficiently to SRY activation and low DHEA worsens this condition. Treatment with testosterone only positively affects some Parkinson’s symptoms. Adrenal medullary transplantation for Parkinson’s produces a “long-term reduction of dehydroepiandrosterone sulfate” (J Clin Endocrinol Metab 1990; 71: 773-6). DHEA sulfate is the precursor of DHEA, the active molecule. In this case, a reduction in DHEAS may indicate that DHEA is being converted from DHEAS, thus reducing DHEAS. This may be why this procedure may produce positive effects for Parkinson’s victims. That is, available DHEA is increased.
The findings of Dewing, et al., may represent findings that support treatment of Parkinson’s with testosterone and dehydroepiandrosterone.
Current Biology 2006 Feb 21;16(4):415-420.
Direct Regulation of Adult Brain Function by the Male-Specific Factor SRY.
Dewing P, Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, Vilain E.
of Human Genetics, Pediatrics, and Urology, University of California,
Los Angeles, Los Angles, California 90095.
The central dogma of mammalian brain sexual differentiation has contended that sex steroids of gonadal origin organize the neural circuits of the developing brain . Recent evidence has begun to challenge this idea and has suggested that, independent of the masculinizing effects of gonadal secretions, XY and XX brain cells have different patterns of gene expression that influence their differentiation and function . We have previously shown that specific differences in gene expression exist between male and female developing brains and that these differences precede the influences of gonadal hormones . Here we demonstrate that the Y chromosome-linked, male-determining gene Sry is specifically expressed in the substantia nigra of the adult male rodent in tyrosine hydroxylase-expressing neurons. Furthermore, using antisense oligodeoxynucleotides, we show that Sry downregulation in the substantia nigra causes a statistically significant decrease in tyrosine hydroxylase expression with no overall effect on neuronal numbers and that this decrease leads to motor deficits in male rats. Our studies suggest that Sry directly affects the biochemical properties of the dopaminergic neurons of the nigrostriatal system and the specific motor behaviors they control. These results demonstrate a direct male-specific effect on the brain by a gene encoded only in the male genome, without any mediation by gonadal hormones.
Supporting Material Added after the foregoing treatise:
Parkinsonism Relat Disord. 2006 Feb 16; [Epub ahead of print]
sensitivity of dopaminergic neurons to rotenone-induced toxicity with
Phinney AL, Andringa G, Bol JG, Wolters EC, Muiswinkel FL, Dam AM, Drukarch B.
Department of Medical Pharmacology, Institute for Clinical and Experimental Neurosciences, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Rotenone has been reported to induce various degrees of Parkinsonism in rats. We tested whether advancing age alters the sensitivity of dopaminergic neurons to rotenone. A low, systemic dose of rotenone had no effect on young rats, but led to a 20-30% reduction of tyrosine hydroxylase-positive neurons in the substantia nigra of older rats. The effect was specific to nigral dopaminergic neurons and may be associated with the increase of glial cell activation in older rats. These data suggest that age enhances the sensitivity of dopaminergic neurons to rotenone and should be considered when assessing models of Parkinson's disease.
This may be explained by reduction in DHEA in older animals. Loss of DHEA results in reduced tyrosine hydroxylase activity.