the metabolic syndrome ( mets ) was first described by kylin , a swedish physician , in 1923 as a clinical association between hypertension and gout .
he described it as  syndrome x  which is a constellation of insulin resistance , hyperglycemia , hypertension , low high - density lipoprotein cholesterol ( hdl - c ) , and increased very - low - density lipoprotein ( vldl ) and triglyceride ( tg ) levels .
it is considered the main threat for public health in the 21 century with its associated risk of cardiovascular disease .
several definitions for mets have been put forward by different expert bodies such as world health organization ( who ) , european group for study of insulin resistance ( egir ) , national cholesterol education program ( ncep ) , american association of clinical endocrinologist ( aace ) , national heart , lung , and blood institute / american heart association , and international diabetes federation ( idf ) . in 2005 idf
the main emphasis is on central obesity defined by waist circumference : waist circumference ( wc ) in europids 94 cm and in asians > 90 cm .
and there should be two or more of the following four factors : elevated tg 1.7
mmol / l ( 150 mg / dl ) , reduced hdl - c < 1.03 mmol / l ( < 40 mg / dl ) , elevated blood pressure ( bp ) systolic 130 mmhg , diastolic 85 mmhg ( or treatment ) , and dysglycemia ( raised fasting plasma glucose , fbg 5.6 mmol / l ( 100 mg / dl ) ( or type 2 diabetes mellitus , dm ) . a new joint statement from a number of professional organizations such as idf , the national heart , lung , and blood institute ( nhlbi ) , who , the international atherosclerosis society , and the american heart association ( aha ) has identified specific criteria for the clinical diagnosis of the metabolic syndrome .
patients with three of the five criteria ( elevated wc , elevated tgs , reduced hdl - c levels , elevated bp and elevated fbg levels ) are considered to have ms .
prevalence of mets : it is estimated that around 20 - 25% of the world 's adult population have the metabolic syndrome . in the united states
the prevalence of mets is 34.5% based on the ncep definition and 39.0% based on idf definition . even in children and adolescents it has been reported in up to 9% . in north india
the prevalence of mets was reported to range from 31.6% to 49.2% of the urban population using ncep atp iii / modified ncep atp iii guidelines.[1518 ] two studies from urban north india reported the prevalence of mets ranging from 35.8% to 38.5% by ncep atp iii criteria , 45.3% by modified ncep atp iii criteria and 39.5% to 47.4% by idf criteria . in south
india the prevalence has been reported in the range of 18.3 - 41% using ncep atp iii guidelines . in an urban population of south india
the prevalence of mets ranges from 18.3% by ncep atp iii criteria , 23.2% by who criteria and 25.8% by idf criteria .
another two studies showed a prevalence of 29.7 - 41.3% using idf guidelines . using who criteria a higher prevalence of 46.4%
the prevalence is reported in the range of 19.5 - 35.2% using different criteria . in a rural population of central india
it is seen in around 9% by modified atp iii criteria . in sub - himalayan region of eastern india ,
abdominal obesity has been associated with low t in both cross - sectional and longitudinal studies , and low t concentration correlates with greater visceral fat accumulation .
testosterone normally inhibit adipocyte development but in states of low t there is greater fat mass .
visceral obesity causes increased inflow of free fatty acids into the liver and perturbs metabolism .
obesity is associated with increased inflammatory cytokine production , as well as increased aromatization of t to estradiol in peripheral fat tissue .
both of these factors then decrease the pituitary production of gonadotropins , which , in turn , decreases testicular production of t. the increased level of leptin in obese individuals may interfere with luteinizing hormone / human chorionic gonadotropin stimulation of androgen production , thereby decreasing t levels .
testosterone deficiency leads to increased fat deposition resulting in insulin resistance . in states of low t muscle biopsy
as up to 70% of the body 's insulin sensitivity is accounted by muscle , low t leads to insulin resistance .
hyperinsulinemia , as encountered in insulin resistance , might impair t secretion by the leydig cell may be directly since there are insulin receptors on the leydig cell .
it has also been found in obese men that there is an attenuated pulse amplitude of luteinizing hormone ( lh ) while the lh pulse frequency is unaffected , thus producing a less strong stimulation of testicular t production .
although there are a number of publications showing the association of t and mets in females,[4556 ] in this review we will restrict to the association in males . the frequency of mets is increased with declining tertiles of total t ( tt ) . and an inverse relationship for circulating t , bioavailable t , sex - hormone binding globulin ( shbg ) , and dehydroepiandrosterone sulphate ( dhea - s ) is also seen with mets .
the quebec family study found higher levels of t reduced the risk of metabolic syndrome and increased insulin sensitivity . in a finnish study of 1896 nondiabetic middle - aged men , free t and shbg were 11% and 18% lower in men with mets .
men with metabolic syndrome at baseline are at an increased risk of developing hypogonadism based on an 11-year follow - up . in another finish study of 702 middle - aged men who had neither diabetes nor the metabolic syndrome , after 11 years of follow - up
after adjustment for age men with total t , calculated ft , and shbg levels in the lower fourth had a severalfold increased risk of developing the metabolic syndrome and diabetes . in a population - based sample of 462 older italian men with mean age of 75 years ,
after adjusting for multiple confounders , including age , smoking , alcohol intake , and physical activity , tt was found to be negatively associated with mets .
the massachusetts male aging study has demonstrated that low t levels in a nonobese population were found to predict the later onset of the metabolic syndrome particularly among men with a bmi < 25 kg / m . in the baltimore longitudinal study of aging of 618 healthy caucasian adult men with a mean age of 63 years alone
total t and shbg were inversely related to the development of mets over a mean follow - up period of 5.8 years .
a cross - sectional study from australia involving 2502 community dwelling men aged 50 - 70 years without known diabetes reported that men with hypogonadotrophic hypogonadism have a high prevalence of metabolic syndrome .
the risk of metabolic syndrome increased for total t<20 nmol / l , shbg<50 nmol / l , and free t<300 pmol / l . in study of health in pomerania ( ship ) , which is a population - based prospective cohort of adults aged 20 - 79 years without baseline mets , after a median follow - up time of 5.0 years 47.8% developed mets . with increasing number of mets components t levels decreased .
testosterone in the lowest quartile predicted mets particularly among men aged 20 - 39 years .
data from the third national health and nutrition examination survey showed that after adjustment for age , race / ethnicity , smoking status , alcohol intake , physical activity level , ldl -c , crp , and insulin resistance , men with lower total testosterone were more likely to have metabolic syndrome than men with higher t ( p<0.001 for linear trend ) .
similarly , men with lower shbg were more likely to have metabolic syndrome than men with higher shbg ( p=0.02 for linear trend ) . in a study of 63 males with mets total and calculated ft and shbg were significantly lower in cases with mets than controls .
hypogonadism was seen in 30% cases with mets compared to 3.1% in controls [ table 1 ] . the various studies which reported the difference in the serum testosterone level in normal subjects and those with mets in a meta - analysis of 20 studies , patients with mets showed significantly lower
comparison of data using ncep atp iii criteria and other mets classifications reveals the same .
lower baseline t was demonstrated among patients with incident mets compared to controls in longitudinal studies . in another meta - analysis of 52 observational studies comprising
22,043 men and 7839 women , endogenous tt and ft levels were lower in men with mets and higher in women with mets .
similarly , men with higher tt levels had a lower mets risk whereas higher tt levels increased the risk of mets in women . in both sexes , higher shbg levels were associated with a reduced risk .
although various studies have shown that lower t levels may be associated with mets and type 2 dm , both conditions associated with cardiovascular disease , reverse causation has to be considered , as systemic illness may result in reduced t levels .
thus , the strength of these associations and the likely direction of causation need to be carefully considered .
in the telecom study , there appeared to be an association of t and cardiovascular risk factors in healthy , nondiseased adult men .
serum tg , tc , ldl - c , apolipoprotein b , fasting , and 2-hour plasma insulin were higher and serum hdl - c was lower in men with lower serum t levels .
total and ft and shbg were inversely associated with concentrations of insulin , glucose , tg , c - reactive protein ( crp ) , and crp - adjusted ferritin and positively associated with hdl - c .
low tt and ft levels were associated with high levels of insulin , glucose , and tg and low levels of hdl - c . in the tromso study , t levels
were inversely associated with anthropometrical measurements with the lowest levels of total and free t found in men with the most pronounced central obesity .
total t was inversely associated with systolic blood pressure , and also men with hypertension had lower levels of both total and free t. furthermore , men with dm had lower t levels compared to men without a history of dm , and an inverse association between t levels and hba1c was found .
a strong association of mets with sex hormones was observed for tg higher than 150 mg / dl and wc more than 102 cm and a modest with hypertension .
increased odds of low hdl - c < 40 mg / dl were observed with lower tt levels and shbg but not with ft . further adjusting for bmi , observed associations of sex hormones and mets were attenuated but remained statistically significant with the exception of the associations observed with hypertension .
total t was positively associated with hdl - c but not with other components of mets .
log shbg is positively associated with hdl - c , negatively associated with tg and wc , but not associated either way with bp or bg levels .
bioavailable t was significantly associated with abdominal obesity and marginally associated with high blood pressure .
tt was also shown to be associated with all except hypertension , and free t was associated only with wc and tg . in a study of middle - aged japanese men ,
t was significantly related to the mets parameters of obesity ( wc and bmi ) , hypertension , dyslipidemia , insulin resistance , and adiponectin .
there are studies from special groups of patients where hypogonadism is a feature due to pharmacotherapy , which strengthens opinion that t deficiency is a risk factor for the development of mets and type 2 dm , and is an independent cardiovascular risk factor .
a small study showed that initiation of gnrh agonist or antiandrogen therapy in 22 men with prostate cancer led to increases in serum insulin , arterial stiffness , and fat mass over the subsequent 3-month period .
braga - basaria et al . evaluated 58 men , including 20 with prostate carcinoma undergoing androgen deprivation therapy for at least 12 months .
the prevalence of mets was higher in the androgen deprivation group compared with the nonandrogen deprivation group and control groups .
men in the androgen deprivation group had a higher prevalence of abdominal obesity and hyperglycemia .
androgen - deprived men also had elevated tg compared with controls but the prevalence of hypertension and low hdl levels were similar .
a longitudinal study followed a large population of 73,196 men with loco - regional prostate cancer followed for a median of 4.55 years .
those treated with androgen suppression therapy were more likely to develop diabetes , ischemic heart disease , myocardial infarction , and sudden death from cardiovascular disease compared with those patients untreated or treated with other modalities .
similarly , a study of 396 men with prostate cancer undergoing androgen - deprivation therapy showed worsening glycemic control with an increase in hba1c and an increased incidence of new onset of diabetes .
another study has shown increased risk of mets with chemotherapy compared with radiotherapy for testicular cancer .
metabolic syndrome was positively associated with cumulative cisplatin , bleomycin , and etoposide doses but not with cumulative vinblastine dose .
logistic regression using a backward stepwise model with all four chemotherapy agents and age included , revealed cumulative cisplatin dose as significant variables .
one of the earliest studies reporting the effect of trt on obesity was by rebuffescrive et al . in 1991 in a small group of 11 men where it was found that waist - hip ratio decreased in 9 out of 11 men after 6 weeks of testosterone replacement .
recently , there have been a number of studies published investigating the effect of trt in men primarily with type 2 dm and mets .
marin and colleagues were the first to report a significant reduction in diastolic blood pressure after trt in obese middle - aged men , along with a reduction in visceral fat , fbg , tg , and total cholesterol . in a study of 122 men receiving treatment with parenteral t undecanoate over 15 months
, both systolic and diastolic blood pressure decreased . a single - blind randomized study of t administration to men with mets and recent onset of dm established also beneficial effects of testosterone on blood pressure over and above the effects of diet and exercise . in men with osteoporosis intramuscular
t for 6 months showed significant reduction in diastolic blood pressure along with total cholesterol , tgs , and hdl - c .
reported a study of 48 type 2 diabetic men with symptoms of androgen deficiency in an open - label , randomized treatment undertaken over 3 months .
testosterone treatment resulted in significant reductions in weight , whr , and percentage body fat compared with no treatment .
fasting blood glucose and postprandial blood glucose levels were also reduced significantly , and hba1c fell by 1.8% ( p<0.05 ) .
this study provides the first evidence that testosterone treatment may offer clinical benefit to men with type 2 diabetes . in the first double - blind placebo - controlled study by kapoor et al . with 24 patients of type 2 dm and clinical diagnosis of hypogonadism ,
t treatment resulted in a significant improvement in the homa - ir index in those patients not on insulin therapy and resulted in insulin dose reduction by an average of 7 units per day in those patients recieving insulin .
statistically significant reductions in both fbg ( 28.4mg / dl ) and fasting insulin were observed , with hba1c falling by 0.4% ( p=0.03 ) .
testosterone treatment also resulted in statistically significant improvement in wc , whr , and total cholesterol although there was no significant effect on hdl - c , ldl - c , tgs , or blood pressure .
heufelder et al . investigated the effects of trt in 32 hypogonadal men with newly diagnosed , treatment - naive type 2 dm with mets in a 52-week single - blind , randomized but not placebo - controlled study , with either diet and exercise advice alone , or diet and exercise advice in conjunction with 50 mg t gel once daily .
compared with diet and exercise alone , t treatment resulted in a statistically significant improvement in hba1c of 0.8% ( p<0.001 ) , with all patients attaining an hba1c of < 7.0% and 87.5% of patients attaining an hba1c < 6.5% .
there was also a statistically significant reduction in the homa - ir index , although the observed treatment - mediated reduction in fpg ( 5.4 mg / dl ) narrowly failed to achieve statistical significance ( p=0.06 ) .
testosterone treatment was associated with a statistically significant reduction in serum tg and a statistically significant increase in serum hdl - c . in another study ,
there were declines in plasma total cholesterol , ldl - c , and tg , whereas plasma hdl - c showed an increase .
a large multicenter , randomized , double - blind , placebo - controlled study undertaken in eight european countries , the times2 ( testosterone replacement in men with metabolic syndrome or type 2 diabetes ) , recruited 220 hypogonadal men diagnosed with either type 2 dm and/or mets ( defined according to the idf criteria ) with no trt within the previous 6 months . insulin resistance ( homa - ir ) improved after 6 and 12 months of therapy .
testosterone therapy was also associated with reductions in the percentage of body fat , tc , and ldl - c and lipoprotein ( a ) after 6 months but there was no significant effect on hdl - c or tg .
one of the earliest studies reporting the effect of trt on obesity was by rebuffescrive et al . in 1991 in a small group of 11 men where it was found that waist - hip ratio decreased in 9 out of 11 men after 6 weeks of testosterone replacement .
recently , there have been a number of studies published investigating the effect of trt in men primarily with type 2 dm and mets .
marin and colleagues were the first to report a significant reduction in diastolic blood pressure after trt in obese middle - aged men , along with a reduction in visceral fat , fbg , tg , and total cholesterol . in a study of 122 men receiving treatment with parenteral t undecanoate over 15 months ,
a single - blind randomized study of t administration to men with mets and recent onset of dm established also beneficial effects of testosterone on blood pressure over and above the effects of diet and exercise . in men with osteoporosis intramuscular t for 6 months showed significant reduction in diastolic blood pressure along with total cholesterol , tgs , and hdl - c .
reported a study of 48 type 2 diabetic men with symptoms of androgen deficiency in an open - label , randomized treatment undertaken over 3 months .
testosterone treatment resulted in significant reductions in weight , whr , and percentage body fat compared with no treatment .
fasting blood glucose and postprandial blood glucose levels were also reduced significantly , and hba1c fell by 1.8% ( p<0.05 ) .
this study provides the first evidence that testosterone treatment may offer clinical benefit to men with type 2 diabetes . in the first double - blind placebo - controlled study by kapoor et al . with 24 patients of type 2 dm and clinical diagnosis of hypogonadism ,
t treatment resulted in a significant improvement in the homa - ir index in those patients not on insulin therapy and resulted in insulin dose reduction by an average of 7 units per day in those patients recieving insulin .
statistically significant reductions in both fbg ( 28.4mg / dl ) and fasting insulin were observed , with hba1c falling by 0.4% ( p=0.03 ) .
testosterone treatment also resulted in statistically significant improvement in wc , whr , and total cholesterol although there was no significant effect on hdl - c , ldl - c , tgs , or blood pressure .
investigated the effects of trt in 32 hypogonadal men with newly diagnosed , treatment - naive type 2 dm with mets in a 52-week single - blind , randomized but not placebo - controlled study , with either diet and exercise advice alone , or diet and exercise advice in conjunction with 50 mg t gel once daily .
compared with diet and exercise alone , t treatment resulted in a statistically significant improvement in hba1c of 0.8% ( p<0.001 ) , with all patients attaining an hba1c of < 7.0% and 87.5% of patients attaining an hba1c < 6.5% .
there was also a statistically significant reduction in the homa - ir index , although the observed treatment - mediated reduction in fpg ( 5.4 mg / dl ) narrowly failed to achieve statistical significance ( p=0.06 ) .
testosterone treatment was associated with a statistically significant reduction in serum tg and a statistically significant increase in serum hdl - c . in another study ,
there were declines in plasma total cholesterol , ldl - c , and tg , whereas plasma hdl - c showed an increase .
a large multicenter , randomized , double - blind , placebo - controlled study undertaken in eight european countries , the times2 ( testosterone replacement in men with metabolic syndrome or type 2 diabetes ) , recruited 220 hypogonadal men diagnosed with either type 2 dm and/or mets ( defined according to the idf criteria ) with no trt within the previous 6 months . insulin resistance ( homa - ir ) improved after 6 and 12 months of therapy .
testosterone therapy was also associated with reductions in the percentage of body fat , tc , and ldl - c and lipoprotein ( a ) after 6 months but there was no significant effect on hdl - c or tg .
there is a strong evidence of a high prevalence of mets in patients with a low t level .
there are reports of high prevalence of t deficiency in patients with type 2 dm .
early interventional studies have shown that trt in hypogonadal men with mets has beneficial effects on central adiposity , insulin resistance , and glycemic control .
there are consistent data regarding beneficial effect on blood pressure , tg , or hdl - c .
furthermore testosterone replacement in several studies has been shown to have a small but significant effect in reducing cholesterol and ldl - c , also important cardiovascular risk factors .
whether low t is just a biomarker of the degree of illness or a contributory factor to the progression of atherosclerosis is unclear .
accumulating evidence now suggests that t deficiency is a risk factor for cardiovascular disease and intervention may ameliorate the process .
there is a need for long - term interventional study to examine the effect of t on cardiovascular disease in men with mets and/or type 2 dm .
 metabolic syndrome ( mets ) or  syndrome x  which is a constellation of insulin resistance , hyperglycemia , hypertension , low high - density lipoprotein cholesterol ( hdl - c ) , and increased very - low - density lipoprotein ( vldl ) and triglyceride ( tg ) levels . 
 it is one of the main threats for public health in the 21st century with its associated risk of cardiovascular disease . 
 this condition affects a major chunk of mankind . 
 international diabetes federation ( idf ) estimated that around 20 - 25% of the adult population of the world has mets . 
 several definitions have been put forward by different expert bodies leading to confusion . to overcome this , 
 joint new statement of many expert group have been issued . 
 serum testosterone ( t ) has been shown to be associated with mets . 
 several studies have shown a higher prevalence of mets in subjects with low testosterone . 
 there are also several studies showing a significant difference in serum t between those with mets and those without . 
 serum t has also been shown to be associated with components of mets and testosterone replacement therapy ( trt ) improves various metabolic and anthropometric parameters in mets . 
 patients with androgen deprivation for treatment of various cancers have also been reported to have higher prevalence of mets . 
 but the evidence of association is not sufficient evidence for the causation of mets by low testosterone and long - term studies are needed to confirm whether t deficiency is the cause or is a feature of mets . 
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Effect of testosterone replacement on components of metabolic syndrome
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