LE Magazine May 2003
Testosterone
Testosterone supplementation
therapy for older men: potential benefits and
risks.
Serum testosterone levels decline gradually and
progressively with aging in men. Many manifestations
associated with aging in men, including muscle atrophy and
weakness, osteoporosis, reduced sexual functioning and
increased fat mass, are similar to changes associated with
testosterone deficiency in young men. These similarities
suggest that testosterone supplementation may prevent or
reverse the effects of aging. A MEDLINE search was performed
to identify studies of testosterone supplementation therapy in
older men. A structured, qualitative review was performed of
placebo-controlled trials that included men aged 60 and older
and evaluated one or more physical, cognitive, affective,
functional or quality-of-life outcomes. Studies focusing on
patients with severe systemic diseases and hormone
deficiencies related to specific diseases were excluded. In
healthy older men with low-normal to mildly decreased
testosterone levels, testosterone supplementation increased
lean body mass and decreased fat mass. Upper and lower body
strength, functional performance, sexual functioning and mood
were improved or unchanged with testosterone replacement.
Variable effects on cognitive function were reported, with
improvements in some cognitive domains (e.g., spatial, working
and verbal memory). Testosterone supplementation improved
exercise-induced coronary ischemia in men with coronary heart
disease, whereas angina pectoris was improved or unchanged. In
a few studies, men with low testosterone levels were more
likely to experience improvements in lumbar bone mineral
density, self-perceived functional status, libido, erectile
function and exercise-induced coronary ischemia with
testosterone replacement than men with less marked
testosterone deficiency. No major unfavorable effects on
lipids were reported, but hematocrit and prostate specific
antigen levels often increased. Based on these results,
testosterone supplementation cannot be recommended at this
time for older men with normal or low-normal testosterone
levels and no clinical manifestations of hypogonadism.
However, testosterone replacement may be warranted in older
men with markedly decreased testosterone levels, regardless of
symptoms, and in men with mildly decreased testosterone levels
and symptoms or signs suggesting hypogonadism. The long-term
safety and efficacy of testosterone supplementation remain
uncertain. Establishment of evidence-based indications will
depend on further demonstrations of favorable clinical
outcomes and symptomatic, functional and quality-of-life
benefits in carefully performed, long-term, randomized,
placebo-controlled clinical trials.
J Am Geriatr Soc 2003
Jan;51(1):101-115
Testosterone, cytochrome P450 and
cardiac hypertrophy.
Cytochrome P450 mono-oxygenases (CYP) play an essential
role in steroid metabolism, and there is speculation that sex
hormones might influence cardiac mass and physiology. As CYP
mono-oxygenases activity is frequently altered during disease,
we tested our hypothesis that CYP mono-oxygenase expression
and testosterone metabolism are altered in cardiac
hypertrophy. We investigate major CYP mono-oxygenase isoforms
and other steroid-metabolizing enzymes and the androgen
receptor in normal, hypertrophic, and assist device-supported
human hearts and in spontaneously hypertensive rats (SHR). We
show increased and idiosyncratic metabolism of testosterone in
hypertrophic heart and link these changes to altered CYP
mono-oxygenase expression. We show significant induction of
5-alpha steroid reductase and P450 aromatase gene expression
and enhanced production of dihydrotestosterone, which can be
inhibited by the 5-alpha reductase inhibitor finasteride. We
show increased gene expression of the androgen receptor and
increased levels of lipid peroxidation in diseased hearts, the
latter being markedly inhibited by CYP mono-oxygenase
inactivation. We show alpha-MHC to be significantly repressed
in cardiac hypertrophy and restored to normal on testosterone
supplementation. We conclude that heart-specific steroid
metabolism is of critical importance in cardiac
hypertrophy.
FASEB J 2002 Oct;16(12):1537-49
The effect of testosterone on regional
blood flow in prepubertal anaesthetized pigs.
This work was undertaken to study the effects of
testosterone on the coronary, mesenteric, renal and iliac
circulations and to determine the mechanisms of action
involved. In prepubertal pigs of both sexes anaesthetized with
sodium pentobarbitone, changes in left circumflex or anterior
descending coronary, superior mesenteric, left renal and left
external iliac blood flow caused by intra-arterial infusion of
testosterone were assessed using electromagnetic flowmeters.
Changes in heart rate and arterial blood pressure were
prevented by atrial pacing and by connecting the arterial
system to a pressurized reservoir containing Ringer solution.
In 12 pigs, intra-arterial infusion of testosterone for five
minutes to achieve a stable intra-arterial concentration of 1
microg l(-1) increased coronary, mesenteric, renal and iliac
blood flow without affecting the maximum rate of change of
left ventricular systolic pressure (left ventricular
dP/dt(max)) and filling pressures of the heart. In a further
five pigs, a concentration-response curve was obtained by
graded increases in the intra-arterial concentration of the
hormone between 0.125 and 8 microg l(-1). The mechanisms of
these responses were studied in the 12 pigs by repeating the
experiment after haemodynamic variables had returned to the
control values before infusions. In six pigs, blockade of
muscarinic cholinoceptors and adrenoceptors with atropine,
propranolol and phentolamine did not affect the responses
caused by intra-arterial infusion of testosterone performed to
achieve a stable intra-arterial concentration of 1 microg
l(-1). In the same pigs and in the remaining six pigs, the
increases in coronary, mesenteric, renal and iliac blood flow
caused by intra-arterial infusion of testosterone performed to
achieve a stable intra-arterial concentration of 1 microg
l(-1) were prevented by intra-arterial injection of
N(omega)-nitro-L-arginine methyl ester. The present study
shows that intra-arterial infusion of testosterone dilated
coronary, mesenteric, renal and iliac circulations. The
mechanism of this response involved the release of nitric
oxide.
J Physiol 2002 Aug 15;543(Pt
1):365-72
Cyclosporine adversely affects
baroreflexes via inhibition of testosterone modulation of
cardiac vagal control.
Previous studies have shown that the immunosuppressant drug
cyclosporine A attenuates arterial baroreceptor function. This
study investigated whether the modulatory effect of
cyclosporine on baroreceptor function involves inhibition of
the baroreflex-facilitatory effect of testosterone. The role
of cardiac autonomic control in cyclosporine-testosterone
baroreflex interaction was also investigated. Baroreflex
curves relating bradycardic responses to increments in blood
pressure evoked by phenylephrine were constructed in
conscious, sham-operated, castrated rats and in
testosterone-replaced castrated (CAS + T) rats in the absence
and presence of cyclosporine. The slopes of the curves were
taken as an index of the baroreflex sensitivity (BRS).
Short-term (11 to 13 days) cyclosporine treatment or
castration reduced plasma testosterone levels and caused
similar attenuation of the reflex bradycardia, as indicated by
the significantly smaller BRS compared with sham-operated
values (-0.97 +/- 0.07, -0.86 +/- 0.06, and -1.47 +/- 0.10
beats/min/mm Hg, respectively). The notion that androgens
facilitate baroreflexes is further confirmed by the
observation that testosterone replacement of castrated rats
restored plasma testosterone and BRS to sham-operated levels.
Cyclosporine had no effect on BRS in castrated rats but caused
a significant reduction in CAS + T rats. Muscarinic blockade
by atropine caused approximately 60% reduction in the BRS in
sham-operated rats, an effect that was significantly and
similarly diminished by castration, cyclosporine, or their
combination. beta-Adrenergic blockade by propranolol caused no
significant changes in BRS. These findings suggest that
cyclosporine attenuates baroreflex responsiveness via, at
least partly, inhibition of the testosterone-induced
facilitation of cardiomotor vagal control.
J Pharmacol Exp Ther 2002
Apr;301(1):346-54
Sex hormone-binding globulin levels
and cardiovascular risk factors in morbidly obese subjects
before and after weight reduction induced by diet or
malabsorptive surgery.
One of the main goals of weight reduction in morbidly obese
subjects is its benefit on coronary heart disease (CHD) risk.
A cross-sectional study was designed to randomly assign 79
morbidly obese subjects (27 men and 52 women; age: 30 to 45
years) either to a diet protocol (20 kcal per kg fat-free mass
(FFM); 55% carbohydrates, 30% fat and 15% proteins) or to
malabsorptive surgery (biliopancreatic diversion). Fatness
parameters, measured by dual-energy X-ray absorptiometry,
lipid profile, insulin, leptin, sex steroid hormones and sex
hormone-binding globulin (SHBG) levels were compared at
baseline and one year after the beginning of the study. The
data showed that plasma SHBG levels, but not testosterone
levels, correlated negatively to fasting insulin levels and
positively to HDL-cholesterol in both men and women. Total
leptin levels were significantly lower (P<0.0001) in
post-BPD subjects of both sexes compared to dietary treated
obese subjects. The logarithm of plasma leptin correlated
significantly and positively with insulin but negatively with
SHBG. A step-down regression analysis showed that FFM and
SHBG, but not insulin levels, were the most powerful
independent variables for predicting HDL-cholesterol levels in
morbidly obese patients. The negative relationship between
SHBG levels and CHD risk appears to be mediated by a
concomitant variation in body fatness. Finally, in obese
patients, SHBG levels seem to be an indicator of total
adiposity rather than an index of an altered insulin/glucose
homeostasis.
Atherosclerosis 2002
Apr;161(2):455-62
Effect of intravenous testosterone
on myocardial ischemia in men with coronary artery
disease.
BACKGROUND: Studies on the effect of estrogen on
atherosclerotic coronary artery disease (CAD) risk in women
have produced conflicting results. Similar confusion, but
fewer data, exists on the effect of testosterone on CAD risk
in men. METHODS: We used 99mTc sestamibi single-photon
emission computed tomography (SPECT) myocardial perfusion
imaging to examine the acute effect of intravenous
testosterone in 32 men (mean age, 69.1 +/- 6.4 years) with
provocable myocardial ischemia on standard medical therapy.
Patients performed three exercise (n = 18) or adenosine (n =
16) stress tests during the infusion of placebo or two doses
of testosterone designed to increase testosterone two or six
times baseline. RESULTS: Serum testosterone increased 137 +/-
58% and 488 +/- 113%, and estradiol levels increased 27 +/-
46% and 76 +/- 57%, (P <.001 for all) during the two
testosterone infusions. There were no differences among the
placebo or testosterone groups in peak heart rate, systolic
blood pressure, maximal rate pressure product, perfusion
imaging scores or the onset of ST-segment depression.
CONCLUSIONS: Acute testosterone infusion has neither a
beneficial nor a deleterious effect on the onset and magnitude
of stress-induced myocardial ischemia in men with stable
CAD.
Am Heart J 2002 Feb;143(2):249-56
Testosterone increases blood pressure
and cardiovascular and renal pathology in spontaneously
hypertensive rats.
The objective of this paper was to test the hypothesis that
testosterone (T) raises blood pressure (BP), which is
associated with increased coronary adventitial collagen,
whereas the hemodynamic force of BP increases the coronary
media:lumen ratio. Five treatment groups of spontaneously
hypertensive rat (SHR) were established (n = 8-10 per group):
controls; hydralazine (HYZ); castration; castration + HYZ; and
castration + HYZ + T + captopril. At 12 weeks of age, the
castrate + HYZ group was divided so that the mean BP was the
same in both groups (162 mmHg). Both groups continued to
receive HYZ treatment; however one group received T implants.
Also, at 12 weeks of age the castrate + HYZ + T + captopril
group received T implants. BP in the HYZ group was reduced
compared with controls (192 mmHg vs 218 mmHg, p < 0.01).
Castration lowered BP to 170 mmHg (p < 0.01) compared with
controls. However, T implants increased BP by 15 mmHg (p <
0.02) in the castrate + HYZ group and by 44 mmHg in the
castrate + HYZ + captopril group (p < 0.01). Captopril in
combination with HYZ significantly reduced BP compared with
controls but T replacement increased BP and coronary collagen
deposition in spite of HYZ and captopril treatment.
Blood Press 2000;9(4):227-38
Effect of testosterone replacement on
whole body glucose utilization and other cardiovascular risk
factors in males with idiopathic hypogonadotrophic
hypogonadism.
BACKGROUND: Excessive testosterone in males or estrogens in
females could explain their differences in coronary heart
disease event rates. As a contraceptive testosterone is likely
to be used at large scale. The role of testosterone in
increasing the risks of coronary heart disease needs
investigation. AIM: To look at the role of testosterone in
development of insulin resistance and other cardiovascular
risk factors. DESIGN: Prospective, before-after study on 10
male subjects with idiopathic hypogonadotrophic hypogonadism
pre- and post-testosterone replacement therapy; outcome
measures: anthropometry, lipoprotein profile and M value
(whole body glucose disposal rates on standard
hyperinsulinemic euglycemic clamp; at insulin infusion rate:
40 mU x (m-2)). RESULTS: Pre-treatment serum testosterone was
0.43 (0.515) ng x mL(-1), LH was 1.29 (0.08) IU x L(-1), and
FSH was 1.54 (0.08) IU x L(-1). None had glucose intolerance.
After replacement testosterone levels increased to 9.4 ng x
mL(-1) (p=0.0005); weight increase of 5.0 kg (p=0.140), body
mass index increase of 1.2 kg x m(-2) (p=0.28), and the change
in waist to hip ratio (p=0.31) were not statistically
significant. M-value (mg x kg x min(-1)) did not change after
testosterone therapy (5.86 [0.72] vs 5.29 [0.82], p=0.62).
Insulin levels (mU x L(-1)) achieved during the clamps were
89.5 (14.2) before and 146 (32.2) after androgen therapy
(p=0.127). There was no change in glucose area under curve (mg
x min x dL(-1)) (14406 [502.2] vs 12557 [826.5], p=0.312). On
testosterone replacement therapy total and LDL cholesterol
levels (mg x dL(-1)) declined (122.5 [13.4] vs 91.6 [5.0],
p=0.04; 65.9 [9.9] vs 39.4 [7.3], p=0.05); Ratio of total
cholesterol to HDL ratio also decreased significantly
(p=0.05). Changes of serum triglycerides (p=0.25) and HDL
cholesterol (p=0.19) did not attain statistical significance.
CONCLUSIONS: Insulin sensitivity does not decrease on
testosterone replacement therapy of male subjects with
idiopathic hypogonadotrophic hypogonadism. Testosterone
replacement was associated with decrease in other
cardiovascular risk factors.
Horm Metab Res 1998
Oct;30(10):642-5
Testosterone-propionate impairs the
response of the cardiac capillary bed to exercise.
OBJECTIVE: Experimental application of anabolic-androgenic
steroids and exercise training induce cardiac hypertrophy.
This study quantifies for the first time, on microscopical
level, the adaptation of the cardiac capillaries and myocytes
to the concomitant application of testosterone-propionate and
exercise training. METHODS: Female SPF-NMRI mice were studied
over three and six week Experimental groups: (i) sedentary
control (C); (ii) exercise (treadmill running, E); (iii)
testosterone-propionate (TP); and (iv)
testosterone-propionate+exercise (TPE). Morphometric
parameters: 1) papillary muscles: capillary density,
intercapillary distance, number of capillaries around a
myocyte, and minimal myocyte diameter; and 2) left ventricular
wall: capillary density and intercapillary distance. RESULTS:
Papillary muscle: A striking suppression of the
exercise-induced improvement in capillary supply occurs in the
testosterone-propionate+exercise groups over three and six
week Exercise without drugs increases significantly (P <
0.05) the capillary density, shortens significantly (P <
0.05) the intercapillary distance, whereas it increases the
number of capillaries around a myocyte. These alterations are
not observed in the testosterone-propionate treated sedentary
animals; e.g., capillary density after 6 week (mean values +/-
standard deviation, capillaries x mm(-2)): C: 4272 +/- 287, E:
5411 +/- 758, TP: 4221 +/- 364, and TPE: 3997 +/- 397.
Moreover, only in the testosterone-propionate+exercise groups
occurs a mild myocyte hypertrophy after both time periods:
there is a trend toward hypertrophy (P < 0.1) in comparison
with the C groups and a significant hypertrophy (P < 0.05)
in comparison with the E groups. CONCLUSIONS:
Testosterone-propionate profoundly inhibits the
exercise-induced augmented capillarization, whereas (under
training conditions) it leads to a mild myocyte hypertrophy.
The microvascular impairment could trigger an imbalance
between the myocardial oxygen supply and demand, especially
during physical exercise.
Med Sci Sports Exerc 2000
May;32(5):946-53
Continued on Page 2 of 3
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