LE Magazine May 2003
Effects of testosterone on coronary
vasomotor regulation in men with coronary heart disease.
BACKGROUND: The increased incidence of coronary artery
disease in men compared with premenopausal women suggests a
detrimental role of male hormones on the cardiovascular
system. However, testosterone has direct relaxing effects on
coronary arteries in animals, as shown both in vitro and in
vivo. The effect of testosterone on the human coronary
circulation remains unknown. METHODS AND RESULTS: We studied
13 men (aged 61+/-11 years) with coronary artery disease. They
underwent measurement of coronary artery diameter and blood
flow after a three-minute intracoronary infusion of vehicle
control (ethanol) followed by two-minute intracoronary
infusions of acetylcholine (10(-7) to 10(-5) mol/L) until peak
velocity response. A dose-response curve to three-minute
infusions of testosterone (10(-10) to 10(-7) mol/L) was then
determined, and the acetylcholine infusions were repeated.
Finally, an intracoronary bolus of isosorbide dinitrate (1000
microgram) was given. Coronary blood flow was calculated from
measurements of blood flow velocity using intracoronary
Doppler and coronary artery diameter using quantitative
coronary angiography. Testosterone significantly increased
coronary artery diameter compared with baseline (2.78+/-0. 74
mm versus 2.86+/-0.72 mm [P=0.05], 2.87+/-0.71 mm [P=0.038],
and 2.90+/-0.75 mm [P=0.005] for baseline versus testosterone
10(-9) to 10(-7) mol/L, respectively). A significant increase
in coronary blood flow occurred at all concentrations of
testosterone compared with baseline (geometric mean [95% CI]:
32 [25, 42] versus 36.3 [27, 48] inverted question markP=0.006
inverted question mark, 35.3 [26, 47] inverted question
markP=0.029 inverted question mark, 36.8 [28, 49] inverted
question markP=0.002 inverted question mark, and 37 [28, 48]
inverted question markP=0.002 inverted question mark mL/min
for baseline versus testosterone 10(-10) to 10(-7) mol/L,
respectively). No differences existed in coronary diameter or
blood flow responses to acetylcholine before versus after
testosterone. CONCLUSIONS: Short-term intracoronary
administration of testosterone, at physiological
concentrations, induces coronary artery dilatation and
increases coronary blood flow in men with established coronary
artery disease.
Circulation 1999 Oct
19;100(16):1690-6
Testosterone and other anabolic
steroids as cardiovascular drugs.
There has been much interest in the effect of sex hormones
on cardiovascular risk factors and as a therapeutic modality
in both men and women. In this article, testosterone is
considered as a possible therapy for cardiovascular disease.
It has been shown that the level of serum testosterone
decreases in men as they age. Healthy men with low
testosterone levels have increased cardiovascular risk
factors, including high fasting and two-hour plasma glucose,
serum triglycerides, total cholesterol and low-density
lipoprotein (LDL) cholesterol, and apo A-I lipoprotein.
Injections of testosterone to raise the levels to midnormal
range have been shown to decrease total cholesterol and LDL
cholesterol, while increasing high-density lipoprotein (HDL)
cholesterol. Testosterone affects the clotting system by
increasing thromboxane A (2) receptor activity and platelet
aggregability. Testosterone has also been shown to augment the
fibrinolytic system and antithrombin III activity. In men,
testosterone has been shown to have antianginal effects, and
endogenous levels have an inverse relationship to systolic
blood pressure. Testosterone can be given in oral, injectable,
pellet and transdermal patch forms. There may be a role in
administering testosterone to return men to normal physiologic
range who have low serum levels. This treatment increases the
risk of prostatic cancer, benign prostatism, erythrocytosis
and edema. No long-term studies of the effects of long-term
testosterone replacement have been undertaken, so it is
difficult to recommend this treatment as yet, but it is being
considered as a therapy for augmenting skeletal muscle
strength in patients with congestive heart failure.
Am J Ther 1999
May;6(3):167-74
The association of low plasma testosterone level with
coronary artery disease in Chinese men.
The incidence rate and mortality of coronary heart disease
(CHD) is obviously higher in men than in women, which may be
related to the influence of plasma lipoprotein metabolism by
endogenous sex hormones. We determined plasma testosterone
(TTT), estradiol, total cholesterol (TC), triglyceride (TG),
high density lipoprotein-cholesterol (HDL-C), HDL2-C, HDL3-C,
apolipoprotein (Apo) AI, Apo B100 and lipoprotein (a) [Lp(a)]
in 201 subjects, among them 102 patients with CHD and 99
healthy subjects. It was found that, mean plasma TTT levels in
patients with CAD (252+/-125 ng/ml) was significantly lower
than in the healthy subjects (412+/-309 ng/ml). There was a
negative association between plasma TTT level and plasma TG
level (r=-0.239; P<0.001) and Lp(a) (r=-0.163, P<0.05),
and a positive association between plasma TTT level and HDL-C
(r=0.301, P<0.001) and HDL3-C (r=0.328, P<0.001). The
results in the present study suggest that low plasma TTT level
may be a risk factor for CHD, which may relate to the
influence of plasma lipoprotein metabolism by endogenous
testosterone.
Int J Cardiol 1998 Jan
31;63(2):161-4
Decreased serum testosterone in men
with acute ischemic stroke.
Serum levels of total and free testosterone and 17
beta-estradiol were determined in 144 men with acute ischemic
stroke and 47 healthy male control subjects. Blood samples
from patients were drawn a mean of three days after stroke
onset and also six months after admission in a subgroup of 45
patients. Initial stroke severity was assessed on the
Scandinavian Stroke Scale and infarct size by computed
tomographic scan. Mean total serum testosterone was 13.8 +/-
0.5 nmol/L in stroke patients and 16.5 +/- 0.7 nmol/L in
control subjects (P = .002); the respective values for free
serum testosterone were 40.8 +/- 1.3 and 51.0 +/- 2.2 pmol/L
(P = .0001). Both total and free testosterone were
significantly inversely associated with stroke severity and
six-month mortality, and total testosterone was significantly
inversely associated with infarct size. The differences in
total and free testosterone levels between patients and
control subjects could not be explained by 10 putative risk
factors for stroke, including age, blood pressure, diabetes,
ischemic heart disease, smoking and atrial fibrillation. Total
and free testosterone levels tended to normalize six months
after the stroke. There was no difference between patients and
control subjects in serum 17 beta-estradiol levels. These
results support the idea that testosterone affects the
pathogenesis of ischemic stroke in men.
Arterioscler Thromb Vasc Biol 1996
Jun;16(6):749-54
SAMe
S-adenosylmethionine improves
depression in patients with Parkinson's disease in an
open-label clinical trial.
We report a pilot study of S-adenosylmethionine (SAMe) in
13 depressed patients with Parkinson's disease. All patients
had been previously treated with other antidepressant agents
and had no significant benefit or had intolerable side
effects. SAMe was administered in doses of 800 to 3600 mg per
day for a period of 10 weeks. Eleven patients completed the
study, and 10 had at least a 50% improvement on the 17-point
Hamilton Depression Scale (HDS). One patient did not improve.
Two patients prematurely terminated participation in the study
because of increased anxiety. One patient experienced mild
nausea, and another two patients developed mild diarrhea,
which resolved spontaneously. The mean HDS score before
treatment was 27.09 +/- 6.04 (mean +/- standard deviation) and
was 9.55 +/- 7.29 after SAMe treatment (p < 0.0001).
Although uncontrolled and preliminary, this study suggests
that SAMe is well tolerated and may be a safe and effective
alternative to the antidepressant agents currently used in
patients with Parkinson's disease.
Mov Disord 2000 Nov;15(6):1225-9
Rapidity of onset of the
antidepressant effect of parenteral S-adenosylmethionine.
A possible method of reducing the delay in antidepressant
response is to use S-adenosylmethionine (SAMe), a naturally
occurring compound that appears to have a rapid onset of
effect in the treatment of depression. In this open,
multicenter study, 195 patients were given 400 mg of SAMe,
administered parenterally, for 15 days. Depressive symptoms
remitted after seven and 15 days of treatment with SAMe, and
no serious adverse events were reported. Further studies with
a double-blind design are needed to confirm this preliminary
indication that SAMe is a relatively safe and fast-acting
antidepressant.
Psychiatry Res 1995 Apr
28;56(3):295-7
Role of S-adenosylmethionine in the treatment of depression:
a review of the evidence.
Major depression remains difficult to treat, despite the
wide array of registered antidepressants available. In recent
years there has been a surge in the popularity of natural or
alternative medications. Despite this growing popularity,
there is limited evidence for the effectiveness of many of
these natural treatments. S-adenosylmethionine (SAMe) is one
of the better studied of the natural remedies. SAMe is a
methyl donor and is involved in the synthesis of various
neurotransmitters in the brain. Derived from the amino acid
L-methionine through a metabolic pathway called the one-carbon
cycle, SAMe has been postulated to have antidepressant
properties. A small number of clinical trials with parenteral
or oral SAMe have shown that, at doses of 200 to 1600 mg/d,
SAMe is superior to placebo and is as effective as tricyclic
antidepressants in alleviating depression, although some
individuals may require higher doses. SAMe may have a faster
onset of action than do conventional antidepressants and may
potentiate the effect of tricyclic antidepressants. SAMe may
also protect against the deleterious effects of Alzheimer's
disease. SAMe is well tolerated and relatively free of adverse
effects, although some cases of mania have been reported in
bipolar patients. Overall, SAMe appears to be safe and
effective in the treatment of depression, but more research is
needed to determine optimal doses. Head-to-head comparisons
with newer antidepressants should help to clarify SAMe's place
in the psychopharmacologic armamentarium.
Am J Clin Nutr 2002
Nov;76(5):1158S-61S
Open trial of S-adenosylmethionine
for treatment of depression.
Nine depressed inpatients completed trials with
S-adenosylmethionine. Seven showed improvement or remission of
their symptoms. As in European studies, no side effects were
seen except the apparent induction of mania in two patients
with bipolar disorder.
Am J Psychiatry 1984
Mar;141(3):448-50
The antidepressant potential of oral
S-adenosylmethionine.
S-adenosylmethionine (SAMe), a naturally occurring brain
metabolite, has previously been found to be effective and
tolerated well in parenteral form as a treatment of major
depression. To explore the antidepressant potential of oral
SAMe, we conducted an open trial in 20 outpatients with major
depression, including those with (n = 9) and without (n = 11)
prior history of antidepressant nonresponse. The group as a
whole significantly improved with oral SAMe: seven of 11
non-treatment-resistant and two of nine treatment-resistant
patients experienced full antidepressant response. Side
effects were mild and transient.
Acta Psychiatr Scand 1990
May;81(5):432-6
The influence of S-adenosylmethionine
(SAMe) on prolactin in depressed patients.
Twenty subjects entered a double-blind placebo-controlled
trial of SAMe in depression. Prolactin concentrations were
measured before and after 14 days treatment. There was a
highly significant fall in prolactin concentrations in the
SAMe-treated group.
Int Clin Psychopharmacol 1987
Apr;2(2):97-102
S-adenosylmethionine in the treatment
of Alzheimer's disease.
Patients with Alzheimer's disease (AD) have an apparent
abnormality possibly representing an increase in the average
fluidity of their cell membranes. Changes in membrane fluidity
of similar magnitude to those observed in AD have been noted
to lead to marked alterations in cell function. Therefore, the
changes in fluidity observed in AD may be related to the
symptoms of that disorder, representing either an underlying
cause of dysfunction or cellular attempts to compensate for
dysfunction in AD. To test these possibilities, we
administered S-adenosylmethionine (SAMe), an agent shown to
increase membrane fluidity in animals, to patients with AD.
Treatment with SAMe led to marked increases in membrane
fluidity. However, it produced neither improvement nor
worsening of symptoms. The results imply that while SAMe may
be useful for other conditions associated with altered
membrane fluidity (such as normal aging), changing membrane
fluidity per se is not likely to lead to marked changes in
symptoms in AD.
J Clin Psychopharmacol 1988
Feb;8(1):43-7
C-reactive protein
Risk of cardiovascular disease in
relation to achieved office and ambulatory blood pressure
control in treated hypertensive subjects.
Objective: We investigated the prognostic impact of 24-hour
blood pressure control in treated hypertensive subjects.
Background: There is growing evidence that ambulatory blood
pressure improves risk stratification in untreated subjects
with essential hypertension. Surprisingly, little is known on
the prognostic value of this procedure in treated subjects.
Methods: Diagnostic procedures including 24-hour noninvasive
ambulatory blood pressure monitoring were undertaken in 790
subjects with essential hypertension (mean age 48 years)
before therapy and after an average follow-up of 3.7 years
(2,891 patient-years). Results: At the follow-up visit, 26.6%
of subjects achieved adequate office blood pressure control
(<140/90 mm Hg), and 37.3% of subjects achieved adequate
ambulatory blood pressure control (daytime blood pressure
<135/85 mm Hg). Months or years after the follow-up visit,
58 patients suffered a first cardiovascular event. Event rate
was lower (0.71 events/100 person-years) among the subjects
with adequate ambulatory blood pressure control than among
those with higher blood pressure levels (1.87 events/100
person-years) (p = 0.0026). Ambulatory blood pressure control
predicted a lesser risk for subsequent cardiovascular disease
independently of other individual risk factors (RR 0.36; 95%
confidence intervals: 0.18 to 0.70; P = 0.003), including age,
diabetes and left ventricular hypertrophy. Office blood
pressure control was associated with a nonsignificant lesser
risk of subsequent events (RR 0.63; 95% confidence intervals:
0.31 to 1.31; P = NS). In-treatment ambulatory blood pressure
was more potent than pre-treatment blood pressure for
prediction of subsequent cardiovascular disease. Conclusions:
Ambulatory blood pressure control is superior to office blood
pressure control for prediction of individual cardiovascular
risk in treated hypertensive subjects.
J Clin Psychopharmacol 1988
Feb;8(1):43-7
C-reactive protein, interleukin 6, and
risk of developing type 2 diabetes mellitus.
CONTEXT: Inflammation is hypothesized to play a role in
development of type 2 diabetes mellitus (DM); however,
clinical data addressing this issue are limited. OBJECTIVE: To
determine whether elevated levels of the inflammatory markers
interleukin 6 (IL-6) and C-reactive protein (CRP) are
associated with development of type 2 DM in healthy
middle-aged women. DESIGN: Prospective, nested case-control
study. SETTING: The Women's Health Study, an ongoing U.S.
primary prevention, randomized clinical trial initiated in
1992. PARTICIPANTS: From a nationwide cohort of 27,628 women
free of diagnosed DM, cardiovascular disease, and cancer at
baseline, 188 women who developed diagnosed DM over a
four-year follow-up period were defined as cases and matched
by age and fasting status with 362 disease-free controls. MAIN
OUTCOME MEASURES: Incidence of confirmed clinically diagnosed
type 2 DM by baseline levels of IL-6 and CRP. RESULTS:
Baseline levels of IL-6 (P<.001) and CRP (P<.001) were
significantly higher among cases than among controls. The
relative risks of future DM for women in the highest vs lowest
quartile of these inflammatory markers were 7.5 for IL-6 (95%
confidence interval [CI], 3.7-15.4) and 15.7 for CRP (95% CI,
6.5-37.9). Positive associations persisted after adjustment
for body mass index, family history of diabetes, smoking,
exercise, use of alcohol and hormone replacement therapy;
multivariate relative risks for the highest vs lowest
quartiles were 2.3 for IL-6 (95% CI, 0.9-5.6; P for trend
=.07) and 4.2 for CRP (95% CI, 1.5-12.0; P for trend =.001).
Similar results were observed in analyses limited to women
with a baseline hemoglobin A(1c) of 6.0% or less and after
adjustment for fasting insulin level. CONCLUSIONS: Elevated
levels of CRP and IL-6 predict the development of type 2 DM.
These data support a possible role for inflammation in
diabetogenesis.
JAMA 2001 Jul 18;286(3):327-34
Associations of elevated interleukin-6
and C-reactive protein levels with mortality in the
elderly.
PURPOSE: To investigate whether interleukin-6 and
C-reactive protein levels predict all-cause and cause-specific
mortality in a population-based sample of nondisabled older
people. SUBJECTS AND METHODS: A sample of 1,293 healthy,
nondisabled participants in the Iowa 65+ Rural Health Study
was followed prospectively for a mean of 4.6 years. Plasma
interleukin-6 and C-reactive protein levels were measured in
specimens obtained from 1987 to 1989. RESULTS: Higher
interleukin-6 levels were associated with a two-fold greater
risk of death [relative risk (RR) for the highest quartile
(> or = 3.19 pg/mL) compared with the lowest quartile of
1.9 [95% confidence interval, CI, 1.2 to 3.1]). Higher
C-reactive protein levels (> or = 2.78 mg/L) were also
associated with increased risk (RR = 1.6; CI, 1.0 to 2.6).
Subjects with elevation of both interleukin-6 and C-reactive
protein levels were 2.6 times more likely (CI, 1.6 to 4.3) to
die during follow-up than those with low levels of both
measurements. Similar results were found for cardiovascular
and noncardiovascular causes of death, as well as when
subjects were stratified by sex, smoking status, and prior
cardiovascular disease, and for both early (<2.3 years) and
later follow-up. Results were independent of age, sex, body
mass index and history of smoking, diabetes and cardiovascular
disease, as well as known indicators of inflammation including
fibrinogen and albumin levels and white blood cell count.
CONCLUSIONS: Higher circulating levels of interleukin-6 and
C-reactive protein were associated with mortality in this
population-based sample of healthy older persons. These
measures may be useful for identification of high-risk
subgroups for anti-inflammatory interventions.
Am J Med 1999 May;106(5):506-12
Continued on Page 3 of 3
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