Current Urology
Reports
http://www.springerlink.com/content/511756m02x4n133m/
Volume 8, Number 6
(2007), 467-471, DOI: 10.1007/s11934-007-0050-4
Testosterone, diabetes mellitus, and the
metabolic syndrome
Abstract
Metabolic syndrome is characterized
by insulin
insensitivity, central obesity dyslipidemia, and hypertension. It is recognized
as a risk factor for cardiovascular disease in men; by the time metabolic
syndrome is diagnosed, however, most men already have entrenched cardiovascular
disease. A reliable early warning sign is needed to alert physicians to those
at risk for metabolic syndrome and cardiovascular disease. Low serum testosterone
level has emerged as a reliable prognosticator of metabolic syndrome in men
whose testosterone deficiency is genetic (Klinefelter syndrome), iatrogenic
following surgery for testicular cancer, pharmacologically induced by
gonadotropin-releasing hormone during prostate cancer treatment, or a natural
consequence of aging. One third of men with type 2 diabetes mellitus are now
recognized as testosterone deficient. Emerging evidence suggests that
testosterone therapy may be able to reverse some aspects of metabolic syndrome.
“In on pivotal 2005 study, Laakxonen et at measured
hormone
levels in 702 Finnish men without evidence of diabetes or MetS at baseline and
after 11 years of regular follow-up. Of
the original cohort, 57 men had diabetes and 127 with the lowest serum
testosterone levels developed on or more MetS manifestations…. [Another
study found] higher levels of serum
testosterone and sex hormone-binding globulin (SHBG) in these middle-aged and
aging men conferred a protective benefit against METS development….a finding
that was surprisingly independent of baseline insulin level, body weight, and
body fat.”
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
American Diabetes Association, Diabetes Care
doi: 10.2337/diacare.27.5.1036 Diabetes Care May
2004 vol. 27 no. 5 1036-1041
Testosterone and Sex Hormone–Binding
Globulin Predict the Metabolic Syndrome and Diabetes in Middle-Aged Men
Abstract
OBJECTIVE—In men, hypoandrogenism is associated
with
features of the metabolic syndrome, but the role of sex hormones in the
pathogenesis of the metabolic syndrome and diabetes is not well understood. We
assessed the association of low levels of testosterone and sex hormone–binding
globulin (SHBG) with the development of the metabolic syndrome and diabetes in
men.
RESEARCH DESIGN AND METHODS—Concentrations of
SHBG and
total and calculated free testosterone and factors related to insulin
resistance were determined at baseline in 702 middle-aged Finnish men
participating in a population-based cohort study. These men had neither
diabetes nor the metabolic syndrome.
RESULTS—After 11 years of follow-up, 147 men
had developed
the metabolic syndrome (National Cholesterol Education Program criteria) and 57
men diabetes. Men with total testosterone, calculated free testosterone, and
SHBG levels in the lower fourth had a severalfold increased risk of developing
the metabolic syndrome (odds ratio [OR] 2.3, 95% CI 1.5–3.4; 1.7, 1.2–2.5; and
2.8, 1.9–4.1, respectively) and diabetes (2.3, 1.3–4.1; 1.7, 0.9–3.0; and 4.3,
2.4–7.7, respectively) after adjustment for age. Adjustment for potential
confounders such as cardiovascular disease, smoking, alcohol intake, and
socioeconomic status did not alter the associations. Factors related to insulin
resistance attenuated the associations, but they remained significant, except
for free testosterone.
CONCLUSIONS—Low total
testosterone and SHBG levels independently predict development of the metabolic
syndrome and diabetes in middle-aged men. Thus, hypoandrogenism is
an early marker for disturbances in insulin and glucose metabolism that may
progress to the metabolic syndrome or frank diabetes and may contribute to
their pathogenesis.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
This subject is thinly researched with a lack of appropriate
population studies. However based on animal studies and 1 trial, there is a
positive effects of estrogen in the brain.
The Journal of Clinical
Endrocrinology & Metabolism Doi: 10.1210/jc.82.2.638 February
1, 1997 vol.
82
no.
2 638-643
Estrogen Replacement Therapy Decreases
Hyperandrogenicity and Improves Glucose Homeostasis and Plasma Lipids in
Postmenopausal Women With Noninsulin-Dependent Diabetes Mellitus1
Abstract
Hyperandrogenicity in women is closely associated with insulin resistance
and a risk factor for cardiovascular disease and noninsulin-dependent diabetes
mellitus (NIDDM). Therefore, 25 postmenopausal women with NIDDM and sex
hormone-binding globulin values less than 60 nmol/L, as an indicator of a
moderate hyperandrogenicity, were treated with 2 mg 17-β-estradiol orally for 3
months in a double-blind, cross-over, placebo-controlled trial. During the last
16 days of active treatment, 1 mg norethisterone acetate was added for 10 days
for endometrial protection.
Blood glucose, glycosylated hemoglobin, insulin, c-peptide, lipoprotein
profile, sex steroid hormones, GH, and insulin-like growth factor I (IGF-I)
were measured, and insulin sensitivity was determined by the euglycemic
hyperinsulinemic clamp method. All metabolic measurements were taken at
baseline and after 68 days of active or placebo treatment.
Estradiol treatment, compared with the placebo
period, was followed by a marked increase of sex hormone-binding globulin and a
decrease of free testosterone. Blood glucose, glycosylated hemoglobin,
c-peptide, total cholesterol, low-density lipoprotein cholesterol, and IGF-1
decreased significantly (P < 0.01–P < 0.001), whereas
high-density lipoprotein cholesterol rose (P < 0.001).
In conclusion, estrogen replacement therapy in postmenopausal women
with
NIDDM ameliorated hyperandrogenicity, and this was
accompanied by marked improvements in glucose homeostasis and lipoprotein
profile.
^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
Low
testosterone was associated with 2.3 higher rate of mortality. This was a low
dose, as is currently
marketed. Unfortunately the level of the
treated with testosterone group is no given here. In the full text, 60 patients
received TRT
(testosterone replacement therapy) for one year, and 51 for more than 2
years. Thus those treated few received
treatment for the duration of the study.
If so there would surely had been an even greater divergence between the
tow groups.
http://www.eje-online.org/content/169/6/725.abstract
EJE-13-0321v1, 159/6/725
2013 European Society of
Endocrinology, Made
available on line 9/2/13
Testosterone deficiency is associated with
increased risk of
mortality and testosterone replacement improves survival in men with type 2
diabetes
Abstract
Objective Men with type 2
diabetes are known to have a high prevalence of testosterone deficiency. No
long-term data are available regarding testosterone and mortality in men with
type 2 diabetes or any effect of testosterone replacement therapy (TRT). We
report a 6-year follow-up study to examine the effect of baseline testosterone
and TRT on all-cause mortality in men with type 2 diabetes and low testosterone.
Research design
and methods A
total of 581 men with type 2 diabetes who had testosterone
levels performed between 2002 and 2005 were followed up for a mean period of
5.8±1.3 S.D. years. Mortality rates were compared between total
testosterone >10.4 nmol/l (300 ng/dl; n=343)
and testosterone ≤10.4 nmol/l (n=238).
The effect
of TRT (as per normal clinical practise: 85.9% testosterone gel and 14.1%
intramuscular testosterone undecanoate) was assessed retrospectively within the
low testosterone group.
Results Mortality was
increased in the low testosterone group (17.2%) compared with the normal
testosterone group (9%; P=0.003)
when controlled for covariates. In the Cox regression model,
multivariate-adjusted hazard ratio (HR) for decreased survival was 2.02 (P=0.009, 95% CI
1.2–3.4). TRT (mean duration 41.6±20.7 months; n=64)
was
associated with a reduced mortality of
8.4% compared with 19.2% (P=0.002) in the
untreated group (n=174). The multivariate-adjusted
HR for decreased
survival in the untreated group was 2.3
(95% CI 1.3–3.9, P=0.004).
Conclusions Low testosterone
levels predict an increase in all-cause mortality during long-term follow-up.
Testosterone replacement may improve survival in hypogonadal men with type 2
diabetes.
From Full
text at http://www.eje-online.org/content/169/6/725.full
Several longitudinal population studies
have
reported that a low testosterone at baseline is associated with an increase in
all-cause mortality (1). Some individual studies
have specifically identified increases in cardiovascular, respiratory and
cancer deaths (2, 3, 4). A
meta-analysis of published research papers with a mean follow-up period of 9.7
years confirmed that low testosterone was associated with increased risk of
all-cause and cardiovascular mortality in community based studies. Men with
specific co-morbidities such as
proven coronary artery disease and renal failure have also found that low
testosterone predicts an increased risk of earlier death than those with the
same condition and are testosterone replete. There is a high prevalence of low
serum testosterone levels and clinical hypogonadism in men with type 2
diabetes. The major cause of death in men with type 2
diabetes is cardiovascular disease (CVD). Low testosterone has in several
studies been linked with CVD (12). There is also evidence
which has shown that the degree of atherosclerosis as assessed by the degree of
carotid intimal media thickness (CIMT) is inversely associated with
testosterone levels (13, 14, 15). One study found that a low
testosterone status was associated with greater progression of atherosclerosis
as assessed by CIMT over a 4-year follow-up period (14). Furthermore, low
testosterone is associated with a pro-inflammatory milieu and testosterone
replacement suppresses circulating cytokines (16, 17). Our
previous study found a high prevalence of symptomatic hypogonadism in men with
type 2 diabetes; 17% had TT <8 nmol/l whereas a
further 25% had testosterone levels between 8 and 12 nmol/l .
Interventional
trials have reported that testosterone replacement improves insulin resistance,
glycaemic control, visceral obesity and lipid profile in the short term (18, 19, 20, 21, 22, 23).
A large multi-centre, randomised, double-blind, placebo-controlled study was
recently undertaken in eight European countries, the TIMES2 study, which showed
that testosterone replacement therapy (TRT) improves certain cardiovascular
risk factors which included insulin resistance, cholesterol, lipoprotein(a),
body fat composition and sexual function in men with type 2 diabetes and/or the
metabolic syndrome (21).
Results
The
mean TT level was 15.7±4.5 nmol/l in
the normal testosterone group as compared with 7.5±2 nmol/l in the low testosterone group (P≤0.001).
The weight (102.1±21.4 (low testosterone) vs 95.2±18.5 kg
(normal testosterone),P<0.001)
and BMI (33.6±6.1 vs 31.2±5.3 kg/m2, P<0.001) were higher in the low
testosterone group and they were more likely to have poorer diabetes control
than the normal testosterone group (HbA1c, 7.5±1.3 vs 7.2±1.4;P=0.002). Both groups were matched
for age, smoking status, pre-existing CVD, statin and ACE inhibitors or ARB
therapy. [See table 1 for HbA1c, age,
statin use etc. at http://www.eje-online.org/content/169/6/725/T1.expansion.html
].
Effect of TRT
Of
the 238 men with low testosterone, 64 patients (27%) received TRT and 174 did
not. Mean duration of TRT was 41.6±20.7 (S.D.) months. A
total of 60 patients received TRT for 12 months or more and 51 had treatment
for 2 years or more. [This entails
that the results significantly under report the benefit of TTT—jk].
Discussion
It
is important to note that all patients treated with testosterone had careful
adjustment of testosterone to achieve levels within the mid to upper normal
range for healthy men. [This is
contradicted by the line above which states that 60 patients received TRT for 1
year, not the duration of the study. It
is unlikely that their level would remain high, since other studies have shown
a return to an even lower level after discontinuation of treatment. Also troubling
is the lack in this article of
the testosterone level for both groups at end of study.—jk]
