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THE SIGNIFICANCE OF TESTOSTERONE IN HEALTH AND DISEASE IN MEN
Michael Zitzmann
Institute of Reproductive Medicine, University of Munster, Domagkstrasse
11, D-48129 Munster, Germany. zitzmann@uni-munster.de
Introduction
In men fertility persists until very old age; simulteously, an age-associated
decrease in testosterone levels exhibiting a marked inter-individual
variation is observed. Subnormal testosterone levels are not
a general, but frequent feature of aging men. This age-related
deterioration of androgen production can be seen as a combined
dysfunctionality of both the central and peripheral parts
of the sex steroid regulation system and is named "late-onset
hypogonadism" (LOH) or, in general and applying to all men
irrespective of their age, testosterone-deficiency syndrome
(TDS). The direction as well as the weighting of pathological
processes within such a dysbalance may vary, and LOH/TDS presents
with low to low-normal testosterone concentrations and LH
levels which may be slightly decreased, normal or elevated.
There is no clear-cut definition of age in relation to LOH/TDS.
Usually described as disease met in "aging" men, the nosology
with its typical hormone constellations can also be found
in men of "younger age". In principal, it is a diagnosis made
after exclusion of other causes for hypogonadism.
A central clinical question is whether the decrease of androgen
levels described as LOH/TDS translates physiologically. Such
clinical evidence could be sought in similarities between
the symptoms of men with LOH/TDS and symptoms of other hypogonadal
men as well as general symptoms of aging men. In this regard,
one has to be aware that aging is most often accompanied by
a decline of many physiological, cognitive and sexual functions
since the incidence and prevalence of chronic diseases affecting
these parameters increases with aging. Such chronic diseases
are mainly atherosclerosis, diabetes mellitus and obesity.
Thus, in view of the multifactorial origin of aging symptoms,
effects of LOH/TDS may not clearly be detectable. However,
evidence from hypogonadism in younger men suggests a range
of androgen-dependent functions, for which an adverse affection
by LOH/TDS can be assumed. Especially the beneficial effects
of testosterone substitution on these morbidities provide
evidence for a significant role of androgens within the symptomatology
of elderly men with LOH/TDS. These will be discussed in the
following:
Osteoporosis
Osteoporosis and fractures represent a major public health
problem, not only in women but also in men. It has been estimated
that at the age of 50 years, men have a risk of approximately
12-15% of suffering an osteoporotic fracture in later life,
most commonly of the vertebra, hip or forearm. At the age
of 60 years, the risk for a non-traumatic fracture rises to
25%. In the United States, about 150.000 hip fractures occur
in men each year. Because of their higher peak bone mass,
men present with hip, vertebral body, or forearm fractures
about 10 years later than women. Hip fractures in men result
in a 30 % mortality rate at one year after fracture versus
a rate of 17 % in women. Hypogonadism, i.e. androgen deficiency,
has been identified as an independent risk factor for such
incidences. Benefits of testosterone substitution in older
men in terms of improvement of bone mass have repeatedly been
demonstrated. It is essential that the naturally occuring
testosterone molecule is used for substitution therapy, since
estradiol as the aromatisation product of testosterone plays
a pivotal and independent role in enhancing bone mass .
Body composition / Metabolic Syndrome / Cardiovascular risk /
Inflammation
Aging is associated with changes in body composition: body
fat mass is found to increase from around 22% of body weight
in young men to around 30% in the elderly, while lean body
mass is 30% lower in elderly men. Accordingly, changes with
a decrease of lean body mass and increase in fat mass are
observed in hypogonadal men compared with age- and BMI-matched
controls. Thus, decreased androgen levels obviously contribute
to changes in body composition of elderly men. In agreement,
body composition exhibits favorable shifts during androgen
replenishment.
Such evidence is related to the catchwords of this paragraph: these
aspects relate to each other within a nosological complex
increasingly observed in affluent countries and are connected
not only to obesity and a sedentary life-style, but also to
LOH/TDS. Type 2 diabetes mellitus is an increasing pathological
entity and represents an established risk factor for the development
of atherosclerotic vascular disease. Insulin resistance is
the hallmark feature of type 2 diabetes and is simultaneously
an important component of the metabolic syndrome, a pre-clinical
condition also including high visceral fat content, arterial
hypertension and an inflammatory status. There is evidence
to suggest that testosterone is an important regulator of
insulin sensitivity in men. Observational studies have shown
that testosterone levels are low in men with diabetes, visceral
obesity, coronary artery disease and the metabolic syndrome.
Regarding the age-related aspect of these morbidities, this
is of special importance in men with LOH/TDS. Short-term interventional
studies support the assumption that testosterone replacement
therapy in hypogonadal men induces respective clinical improvements,
also concerning inflammatory markers and cardiac status..
Hypogonadism may play a role in the pathogenesis of insulin-resistant
states and androgen replacement therapy could be a potential
treatment for improvements in glycemic control and reduction
of cardiovascular risk, particularly in diabetic men. Nevertheless,
long-term studies are required to determine the potentially
beneficial role of testosterone in this regard.
Anemia
Androgens increase erythropoiesis. This is facilitated by
several pathways involving enhancement of erythropoietin secretion
and independently promoting differentiation of erythroid progenitor
cells. Correspondingly, hypogonadal men often present with
anemia. Testosterone substitution therapy in hypogonadal men
restores red blood cell mass and, hence, oxygen supply. Under
certain circumstances, polycythemia can be induced during
androgen substitution, especially when supraphysiological
concentrations of testosterone are reached or patients are
older. Polycythemia or elevated hematocrit represent a risk
factor for cerebral ischemia while its role in relation to
cardiovascular disease remains unclear. Thus, transdermal
gel preparations are the more favorable treatment option for
LOH/TDS.
Spatial cognition
Aging is associated with deterioration of multiple aspects
of cognitive performance. Studies in humans concerning the
relationship between endogenous androgen levels and cognitive
performance have produced evidence that especially abilities
of spatial cognition are positively affected by testosterone.
Especially older men with LOH/TDS exhibit lower visuospatial
abilities than eugonadal controls. It has been demonstrated
that testosterone substitution improves spatial cognition
in hypogonadal men, which is an estradiol-independent effect.
Cerebral imaging procedures suggest areas involved in processing
of spatial information such as the ventral processing stream
to be actived by testosterone.
Depression
Mood disturbances and dysthymia are frequently observed in
older men and can be related to testosterone concentrations
in cross-sectional approaches, such as the Massachusetts Male
Aging Study. Correspondingly, a depressed mood is frequently
observed in hypogonadal men, a situation which is manageble
by testosterone supplementation. Administration of testosterone
can benefit both psychological aspects of depression (such
as depressed mood, guilt and psychological anxiety) and somatic
aspects of depression (such as sleep, appetite, and libido).
Mood changes in hypogonadal men improve early after institution
of testosterone replacement, and this improvement is usually
maintained at a plateau reached after 2 months. Overall, enhancement
of positive mood aspects is more prominent than the decrease
in negative mood parameters.
Sexual functions
Aging in men is accompanied by a decrease in libido as well
as sexual activity, as process closely related to androgen
concentrations. Sexual functions improve rapidly during testosterone
replacement therapy in hypogonadal men, irrespective of their
age, an effect which is not dose-dependent. The improvements
affect all aspects of sexual life including motivation, performance,
and activity. Arterial integrity is a key component for penile
cavernous vasodilation, a process leading to erection and
directly regulated by androgens. It has been demonstrated
that erectile dysfunction is an early marker of cardiovascular
events. Especially in hypogonadal patients, the therapeutic
approach with phosphodiesterase type 5 (PDE-5)-inhibitors
often proves unsuccessful. There is some evidence that additional
testosterone treatment in men with erectile dysfunction and
low androgen levels is synergistic to PDE-5 inhibitors. Especially
men with LOH/TDS and diabetes mellitus type 2 are likely to
benefit from testosterone substitution in regard to erectile
function .
Conclusions
Summarizing the data concerning the association of LOH/TDS
with clinical signs and symptoms in elderly males, it is manifest
that a clinical significance exists. Nevertheless, in many
instances data quality is weak, and androgen levels are only
one of the many factors determining the symptomatology of
elderly men. Therapeutic approaches with testosterone preparations
are recommended in cases of low testosterone levels in connection
with the above named symptom complexes. Special recommendations
for the treatment of older men are available.
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