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TESTOSTERONE INTERACTIONS IN THE PATHOPHYSIOLOGY AND TREATMENT
OF DEGENERATIVE AND INFLAMMATORY DISEASES
Shippen, E.
Shillington Diagnostic Center, Shillington, Pennsylvania, USA.
Testosterone plays an important role in the pathophysiology of many
disease processes. Although substantial research has
demonstrated many interactions with the immune and
inflammatory systems, there has been a general lack
of application of this knowledge in the treatment
of diseases. Wide differences between individuals
in declining testosterone levels are seen in the longitudinal
follow-up MMAS study of aging males. This study clearly
shows that testosterone declines more steeply in individuals
with concomitant chronic disease. Is the decline in
testosterone the result of the diseases or are the
diseases the result of decline or deficiency of testosterone?
Clearly, however, a lower testosterone level is associated
with the pathophysiologic processes. A case report
of severe ulcerative colitis dramatically improving
with testosterone replacement serves as a launching
point to discussion of the complex mechanisms that
frequently co-exist within different chronic diseases.
How does testosterone interact with vastly different
disease processes? The critical links involve both
immune and inflammatory mechanisms. Inflammatory cytokines
up-regulate aromatase conversion of testosterone to
estradiol which, in turn up-regulates inflammatory
COX-2 metabolites and pro-inflammatory prostaglandins.
Increased estradiol depresses hypothalamic signaling
of FSH and LH thereby reducing testosterone generation
through negative feedback inhibition. A vicious cycle
of lower, anti-inflammatory testosterone and higher
pro-inflammatory estradiol leads to exacerbation and
chronic inflammatory disease processes. Testosterone
replacement has been shown to down-regulate the T-lymphocyte
differentiation pathways in an anti-inflammatory direction.
Key cytokines such as IL-6, a pleotrophic signaling
cytokine, TNFa, a pro-inflammatory peptide and IL-10,
an anti-inflammatory pathway activator, are powerfully
modulated by testosterone. Both the down-regulation
of inflammation and the stimulation of collagen synthesis
needed in repair may reduce the severity and duration
of inflammatory diseases. Many other factors are affected
by testosterone. In cardio-vascular diseases, there
is a close association with disease activity and CRP
and fibrinogen, inflammatory proteins triggered by
IL-6. Additionally, the up-regulation by excess estradiol
of the matrix metalo-proteins, MMPs, which act as
proteolytic enzymes, is important in the degradation
of plaque cap leading to plaque rupture and acute
cardiovascular events. Testosterone treatment reduces
IL-6, CRP and fibrinogen levels with treatment and
reduces MMP activities. The importance of testosterone
in the treatment of diabetes has been dramatically
demonstrated by Jens Moller. One view of the gangrene
changes before and after leaves an indelible impression
of the power of testosterone in healing. Many drugs
are now, also, associated with depressing testosterone
levels. Is there an association with long term treatment
with these drugs, reduced testosterone levels and
increase morbidity from this mechanism? It is important
to integrate knowledge of endocrine changes into the
treatment strategies. Testing for and correction of
testosterone deficiency may add significant adjunctive
benefit to the successful outcomes in these complex
diseases.
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