hypogonadism in men with type 2 diabetes

IntroductionThere is increasing evidence that asignificant number of men with type2 diabetes have clinically relevanthypogonadism. The diagnosis andtreatment of testosterone deficiencyin diabetes has been controversial.The biochemical assessment oftestosterone status has been con-founded by difficulties in the inter-pretation of assays and which assaysto use. This review addresses theseproblems in the light of recent scien-tific and clinical evidence from bothepidemiological studies and pilotstudies using physiological testos-terone replacement therapy (TRT)on clinical benefits, which includeglycaemic control and erectile dys-function as well as the generalimprovement in well-being and qual-ity of life.

HypogonadismHypogonadism is defined as a clinicalcondition comprising both symptomswith or without signs and biochemi-cal evidence of testosterone defi-ciency. The symptoms are non-spe-cific and include reduced or loss oflibido, reduction in the strength oferections, fatigue, reduced physicalstrength and endurance, mood dis-turbance such as irritability, grumpi-ness, depression, and impaired cog-nitive function and spatial awareness(Table 1). It is recognised that thesesymptoms are non-specific and mayoccur in any man with type 2 diabetesindependent of androgen status. Inparticular, erectile dysfunction is verycommon with up to 70% of diabeticmen having this complaint. If, how-ever, the presence of symptoms isassociated with low testosterone lev-els, further evaluation is indicated.The clinical signs of hypogonadismas in hypothyroidism are usually only

manifest in the more overt cases andinclude fine wrinkling of facial skin,eunuchoid body habitus, loss of sec-ondary sexual hair and gynaecomas-tia. The keys to making a diagnosisare an understanding of the clinicalguidelines and biochemical testsavailable which are described below.A diagnosis of hypogonadism is sup-ported by the presence of osteopae-nia or osteoporosis as assessed bybone mineral density. Once a diagnosis of hypogonadism has been established then treatment withTRT should be considered, providedthere are no contraindications.

The causes of hypogonadism areclassified traditionally into primary(testicular failure) and secondaryhypogonadism (hypothalamic andpituitary disorders) – listed in Table 2.Primary hypogonadism is associatedwith elevated gonadotrophin levels,whereas secondary hypogonadism isassociated with low gonadotrophins.More recently, it has become estab-lished that hypogonadism can occurwith normal gonadotrophin levels(normogonadotrophic or mixedhypogonadism). This type of hypogo-

nadism is associated with obesity andageing and will be discussed later inthis review.

The most common form of classi-cal hypogonadism is Klinefelter’s syn-drome. It has been shown that 75%of men with this condition are undi-agnosed in the general population.1Furthermore, men with Klinefelter’shave a higher risk of developingmetabolic syndrome and type 2 dia-betes than the normal population.2

There are two major sets of clini-cal guidelines for the diagnosis andmanagement of hypogonadism. Jointguidelines for the diagnosis andtreatment of men with late-onsethypogonadism (LOH) – testosteronedeficiency associated with ageing –have been produced by theInternational Society for Andrology,the International Society for theStudy of the Aging Male (ISSAM)and the European Association forUrology.3 They recommend that atotal testosterone in the presence ofsymptoms <8nmol/L requires substi-tution and >12nmol/ does not. Insymptomatic men with a total testos-terone between 8 and 12nmol/L,

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Pract Diab Int June 2007 Vol. 24 No. 5 Copyright © 2007 John Wiley & Sons 269

Hypogonadism in men with type 2 diabetesTH Jones*

ABSTRACTRecent studies demonstrate a high prevalence of hypogonadism in men with metabolicsyndrome and type 2 diabetes. Men with low testosterone levels have a higher mortalityrate. Diagnosis and treatment with testosterone replacement can lead to improvement inwell-being and quality of life. Early studies of testosterone replacement therapy haveshown a benefit on glycaemic control, insulin resistance, visceral adiposity andcholesterol. Low testosterone levels are associated with the presence and the degree ofatherosclerosis in carotid, coronary and aortic vessels. Furthermore, testosteronereplacement therapy in testosterone deficient men with erectile dysfunction converts overhalf of PDE5 inhibitor non-responders to responders. This review presents the up-to-dateevidence in relation to testosterone, and discusses the importance of criteria to make adiagnosis of hypogonadism in diabetic men. Copyright © 2007 John Wiley & Sons.

Practical Diabetes Int 2007; 24(5): 269–277

KEY WORDStestosterone; hypogonadism; type 2 diabetes; glycaemic control; insulin resistance;cardiovascular risk factors; erectile dysfunction; atherosclerosis

T Hugh Jones, BSc, MD, FRCP, ConsultantPhysician & Endocrinologist, BarnsleyHospital NHS Foundation Trust, and Honorary Professor of Andrology, Universityof Sheffield, UK

*Correspondence to: Professor TH Jones,Robert Hague Centre for Diabetes andEndocrinology, Barnsley Hospital NHSFoundation Trust, Gawber Road, BarnsleyS75 2EP, UK; e-mail: [email protected]

Received: 29 April 2007Accepted: 30 April 2007

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Hypogonadism in men with type 2 diabetes

trials of therapy can be considered.The American Endocrine Society’sguidelines recommend that levels<10.4nmol/L are consistent with adiagnosis of hypogonadism.4

Testosterone: assays andinterpretationTestosterone has a circadian rhythmwith serum levels reaching a peakbetween 0600–0800h and a nadirbetween 1800–2000h. Clinically, it isstrongly recommended that bloodshould be taken before 1100h.Testosterone levels in a significantnumber of normal men can reachhypogonadal levels in the late after-noon and early evening. The diurnalrhythm is lost with age in some, butnot all, men. It is recommended thattestosterone be measured on at leasttwo or, in borderline cases, three sep-arate occasions. Testosterone levelscan be lower in the presence of inter-current infections and can be higherthe morning after sexual intercourse.

In the serum, testosterone is pres-ent in three major fractions (the pro-portion of which varies between sub-jects) which together comprise thetotal testosterone that is routinelymeasured in clinical practice: (1)2–3% free, (2) 20–40% bound toalbumin, and (3) 60–80% bound tosex hormone binding globulin(SHBG); (Figure 1). Testosterone

bound to SHBG is tightly bound andonly dissociates slowly, and is consid-ered to be biologically inactive.Testosterone bound to albumin isweakly bound and readily dissociates,and is available to the tissues. Thefree plus the albumin bound testos-terone is known as the bioavailable orbiologically active testosterone.

In states of insulin resistance –such as obesity, metabolic syndromeand type 2 diabetes – SHBG levelstend to be lower as a result of inhibi-tion of hepatic release of the carrierprotein. In a large study5 of healthymen, subjects with lower levels oftotal testosterone were shown to havehigher insulin and markedly reducedSHBG levels compared to those withhigher normal levels. Importantly,there was no difference between thebioavailable testosterone levels ineach group demonstrating that theassociation between total testos-terone and insulin could beexplained by the negative correlationbetween SHBG and plasma insulin,and this did not affect the biologi-cally active testosterone fraction. Alow SHBG, therefore, can lead tolower total testosterone levels and,consequently, can complicate thediagnosis of hypogonadism in menwith obesity, the metabolic syndromeand type 2 diabetes. It is also impor-tant to recognise, however, that only

a small proportion of subjects – e.g.in type 2 diabetes – have very lowSHBG levels.6 Another confoundingfactor, that does affect SHBG, is age-ing which is associated with a rise inlevels. A recent report shows thatatorvastatin but not simvastatincauses a lower total but not free orbioavailable testosterone. Thereforemen with borderline hypogonadismon atorvastatin require assessment offree or bioavailable testosterone.7

Measurement of free (by equilib-rium dialysis method) or bioavailabletestosterone neutralises the effect ofSHBG, and is helpful in borderlinecases and in those with low or lownormal SHBG. Unfortunately, theseassays are time consuming and arenot readily available for routine clini-cal use at present. Free and bioavail-able testosterone can be calculatedmathematically by validated equa-tions if the total testosterone andSHBG levels are known.8,9 The meas-urement of free testosterone levelsusing current radioimmunoassays isnot recommended, as these levels arepartly SHBG dependent.

Epidemiological studies intype 2 diabetesSeveral studies have consistentlyreported that testosterone levels arelower in men with diabetes when com-pared to matched healthy con-trols.6,10–15 These studies, which arelisted in Table 3, have mainly meas-ured total testosterone. A significantstudy published in 200415 demon-strated that one third of men with type2 diabetes had below normal levels offree testosterone measured using thegold standard method of equilibriumdialysis. Until recently, no studies haveassessed and compared hypogonadalsymptoms with testosterone levels. AUK study of 355 men with type 2 dia-betes6 has reported that 14% withbioavailable testosterone <2.5nmol/Land 17% with total testosterone<8nmol/L had levels below the nor-mal ranges and a positive symptomscore (ADAM – Androgen Deficiencyin the Aging Male questionnaire). Afurther 25% had borderline low totaltestosterone levels (8–12nmol/L)and, in all, 42% had calculated freetestosterone levels in the hypogonadalrange – all with symptoms. One thirdof the hypogonadal men had classical

270 Pract Diab Int June 2007 Vol. 24 No. 5 Copyright © 2007 John Wiley & Sons

Table 1. Symptoms, signs and other clinical findings of testosteronedeficiency

• Reduced or loss of libido • Reduced quality and frequency of erections, particularly nocturnal

erections• Changes in mood with depressed mood and irritability• Reduced intellectual activity, cognitive function, spatial orientation• Reduced motivation• Fatigue, reduced physical strength and endurance• Sleep disturbances• Hot flushes and sweats• Subfertility

• Decrease in lean body mass with reduced muscle volume and strength• Increased visceral fat• Decreased body hair and skin alterations• Gynaecomastia• Reduced bone mineral density (BMD) with loss of height, osteopaenia,

osteoporosis and fracture risk• Mild anaemia

NB. Most commonly only symptoms are present. Only in the more severe and long-standing hypogonadism are signs and changes in BMD found.

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hypogonadism with 26% having pri-mary hypogonadism and 10% second-ary hypogonadism. The remaining64% had low testosterone levels with gonadotrophins within the nor-mal range, i.e. normogonadotrophichypogonadism. The prevalence ofsymptoms of hypogonadism were,however, similar in diabetic men with normal and low testosterone levels. This does confirm the non-specificity of hypogonadal symptomsin diabetic men.

Low testosterone: a riskfactor for metabolicsyndrome and diabetesThere is now convincing evidencefrom longitudinal population studiesthat a low free testosterone or abioavailable testosterone are inde-pendent risk factors for the subse-quent development of both the metabolic syndrome and type 2 dia-betes. Five separate studies – theMassachusetts Male Aging Study(MMAS),16 MRFIT,17 NHANES III,18

the Rancho Bernardo Study19 and aFinnish study20 – have all shown thatlow levels of free testosterone orSHBG independently predict thedevelopment of the metabolic syn-drome and diabetes. Importantly, two of the studies (MMAS,21

NHANES III18) have found that theincreased risk for metabolic syn-drome and diabetes is also relevantfor initially non-obese men.

It is also known that men withKlinefelter’s syndrome, the most com-mon cause of classical primary hypog-onadism, have an increased risk ofdeveloping diabetes. Kennedy’s syn-drome is a genetic condition associ-ated with a relatively insensitive andro-gen receptor which is associated withthe development of diabetes, provid-ing further evidence of a link betweenandrogen status and diabetes.

A recent large population studyof 73 196 men treated with andro-gen deprivation therapy for prostatecarcinoma reported an increasedrisk of incident diabetes, myocardialinfarction and cardiovascular dis-ease.22 Other studies have foundandrogen deprivation for prostatecancer leads to elevation of fastingand postprandial glucose andinsulin, and vascular stiffness.23 Indiabetic men treated for prostate


Primary or hypergonadotrophic hypogonadism

Congenital• Klinefelter’s syndrome (47 XXY)• Noonan’s syndrome (male Turner’s syndrome, 45 X0)• Reifenstein’s syndrome (defective androgen receptor)• Congenital anorchidism• Other syndromes: 5-alpha reductase deficiency, myotonic dystrophy,

cryptorchidism • Rare genetic syndromes (47 XYY syndrome, dysgenetic testes, androgen

receptor defects)Acquired• Trauma • Testicular torsion• Orchitis (mumps or bacterial)• Radiation treatment or chemotherapy• Alcohol abuse• Varicocoele• Haemochromatosis • Liver cirrhosis• Human immunodeficiency virus infection• Orchidectomy

Secondary or hypogonadotrophic hypogonadism

Inherited• Kallmann’s syndrome• Isolated hypogonadotrophic hypogonadism• Prader-Willi syndrome• Lawrence-Moon-Bardet-Biedl syndrome • Isolated gonadotrophin deficiency• Familial cerebellar ataxia• Fertile eunuch syndromeAcquired• Hypopituitarism• Pituitary tumour• Hyperprolactinaemia• Cushing’s syndrome• Intracranial neoplasm (e.g. craniopharyngioma, meningioma, metastases)• Haemochromatosis, transfusion siderosis• Head injury• Granulomatous disease (e.g. sarcoidosis, tuberculosis, histiocytosis)• Hypophysitis• Drug abuse (opiates)• Vasculitis• Radiation

Hypogonadism associated with other causes

• Cardiovascular disease• Obesity• Metabolic syndrome• Type 1 and type 2 diabetes• Human immunodeficiency virus• Chronic renal failure• Congestive cardiac failure• Malnutrition• Liver disease

Table 2. Classification of hypogonadism, and hypogonadism associatedwith other causes

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cancer there is deterioration in theirdiabetes and an increased insulindose is required.24

Effect of TRT on insulinsensitivity/resistanceTestosterone replacement therapyimproves insulin sensitivity in menwith hypogonadism.5 Testosteroneadministration to middle-aged obesemen has also been shown to reduceinsulin levels and insulin resistance.25

The association between hypogo-nadism and insulin resistance has alsobeen reported in men undergoingchemical castration for treatment ofprostate cancer, as described above.Two studies in men treated withGnRH agonists, anti-androgens or acombination of both, have shown arise in insulin levels and visceral fatbut no change in glucose. A similarstudy in men treated with surgical cas-tration had an increase in both fastingand postprandial glucose and post-prandial insulin. Animal studies havealso demonstrated beneficial effectsof testosterone on insulin sensitivityand glycaemic control. (See Kapoor etal.26 for review.)

A pilot double-blind placebo con-trolled crossover study of TRT (threemonths each of treatment and ofplacebo) in hypogonadal men withtype 2 diabetes has demonstrated asignificant improvement in insulinresistance as assessed by HOMA-IR (-1.73).27 Furthermore, there wereimprovements in fasting blood glucose (mean -1.58mmol/L) and

HbA1c (-0.37%). The mean HbA1c atbaseline in the study was 7.28%(range 5.8–9.4%). Ten patientsincluded in the study were on insulintherapy (these were not assessed forinsulin resistance). Five of these sub-jects, in addition to an improvementin HbA1c, reduced their insulin dosesby a mean of 7±1.9 units as they weredeveloping hypoglycaemia when ontestosterone as opposed to placebo. Anon-blinded study has also shown animprovement in HbA1c in a poorlycontrolled group treated over sixmonths where the study investigatorsobserved a mean fall in HbA1c of1.8% (from 10.4 to 8.6%).28

ObesityThe INTERHEART study has clearlydemonstrated that visceral adiposityis a major independent risk factor forcardiovascular disease.29 In turn, vis-ceral fat is an essential component ofthe metabolic syndrome which is acondition with an increased risk ofcardiovascular mortality. Visceral fatis more metabolically active than sub-cutaneous fat. Furthermore, bloodfrom visceral fat drains directly to theliver resulting in a higher exposure ofthe liver to free fatty acids and henceincreasing hepatic insulin resistance.

Total testosterone levels are lowerin men with obesity; however, not allmen with obesity are hypogonadal.The HERITAGE Family Study foundlow total testosterone and SHBG but normal free testosterone levelsdemonstrating that subjects did not

have clinical hypogonadism.30 TheSan Antonio Heart Study, however,for example found that BMI as well aswaist:hip ratio is inversely related toboth total and free testosterone.31 Inour study,6 we found men – especiallyin the younger group of less than 40years old – to have a low incidence ofsymptoms with low total testosteronebut normal bioavailable testosterone.These findings demonstrate that it iscritically important to evaluate eachpatient individually before making adiagnosis of hypogonadism.

Changes in total and free testos-terone due to obesity may bereversible with weight loss.32 This has,however, only been demonstrated insmall studies, but does imply that menwithout an underlying medical causefor their hypogonadism apart fromobesity could initially be challengedwith a regimen of diet and exercise.

It is well established that physio-logical TRT in hypogonadal menimproves body composition with areduction in fat free mass and anincrease in lean mass.33 The benefi-cial effects on body composition cantake up to two years to maximise.TRT over three months in hypogo-nadal men with type 2 diabetes doesimprove waist circumference but didnot show a significant change in over-all percent body fat or BMI.27

Many questions arise from thesefindings including whether low testos-terone levels are a cause or a conse-quence of obesity. A hypothesisknown as the Hypogonadal-ObesityCycle first described by Cohen in1999 goes some way to providing a sci-entific basis to explain this phenome-non.34 We have recently extended thehypothesis to include the effects ofadipocytokines and have called it theHypogonadal-Obesity-AdipocytokineCycle (Figure 2).

Visceral fat has a high activity ofthe enzyme aromatase, whichmetabolises testosterone to oestra-diol. The normal testis produces5–6mg of testosterone per day onaverage. Increasing visceral fat vol-ume would in turn increase aro-matase content resulting in moretestosterone being converted tooestradiol and a lowering of circulat-ing testosterone levels. Testosterone isknown to inhibit the enzyme lipopro-tein lipase, which is the major regula-


Figure 1. Different fractions of circulating testosterone

Free + albumin bound =bioavailable testosterone

60–80% bound toSHBG

20–40%bound toalbumin

2–3%free

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tor of triglyceride uptake intoadipocytes.35 A fall in testosterone levels leads to greater activity oflipoprotein lipase, causing increasedtriglyceride storage and proliferationof adipocytes, with this in turn exacer-bating insulin resistance. The greateramount of adipocytes then drive thecycle leading to a further reduction inthe circulating testosterone level.

The normal homeostatic responseof the body would be to increaseluteinising hormone (LH) releaseand pulsatility to stimulate the testesto produce more testosterone. Thisresponse is blocked by the actions of oestradiol and adipocytokines.Clomiphene, which blocks theinhibitory effect of oestradiol on thehypothalamic-pituitary axis, producesan increase in LH production inobese men. Leptin is the cytokinereleased by adipocytes and is stronglypositively correlated with adipose tissue mass. In normal circumstances,leptin stimulates the hypothalamic-pituitary axis to release LH; however,in human obesity the hypothalamusbecomes resistant to leptin.36

Leptin also directly inhibits the effect of gonadotrophins on thetestis.37 In addition, the pro-inflamma-tory adipocytokines interleukin-6 (IL-6) and tumour necrosis factoralpha (TNF-α) are well known to suppress the hypothalamic-pituitary-testicular axis.

This hypothesis would explain thenormogonadotrophic hypogonadismdescribed above. The hypothalamic-pituitary-testicular axis would not beable to respond adequately to the lowandrogen state induced by obesity asa result of the effects of raised oestra-diol and relevant adipocytokine lev-els found in the obese condition.

Testosterone and lipidsThe majority of cross-sectional stud-ies have shown that low testosteronelevels are associated with a pro-atherogenic lipid profile – high totaland LDL cholesterol and triglyc-erides and low HDL cholesterol (seeJones et al.38 for review). Some stud-ies, however, have not shown such arelationship. A meta-analysis ofreported studies demonstrates thatTRT in hypogonadal men reducestotal and LDL cholesterol, but causesa small but significant lowering of

HDL cholesterol.39 There appears tobe a difference in the effect of testos-terone on HDL cholesterol withshort-term studies of younger menshowing a fall in HDL cholesterol butno effect in older men. An initial fallin HDL cholesterol may be as a resultof increased metabolism due to shut-tling of cholesterol to the liver. Inpopulation studies, there is a positivecorrelation of testosterone with HDLcholesterol,40 which holds true formen with type 2 diabetes.41

Two short-term studies – one inwhich the majority of hypogonadalmen had coronary heart disease, and the other of hypogonadal dia-betic men – have found that TRTreduces total cholesterol by a meanof 0.4mmol/L but had no significanteffect on the rest of the lipid pro-file.27,42 The majority of these sub-jects were on statin therapy.

HypertensionThere is no clear effect of TRT onblood pressure. The majority of stud-ies have found no effect; however,some studies have demonstrated asmall fall in diastolic pressure,whereas others have shown a rise. Astudy in men with diabetes found no effect.27

CoagulationLow levels of testosterone are associ-ated with a hypercoagulable state(see Jones et al.38 for review). Inhypogonadism, levels of plasminogenactivator inhibitor type 1 (PAI-1),Factor VII and fibrinogen are all neg-atively correlated with testosteronelevels, whereas tissue plasminogenactivator (tPA) is positively corre-lated. In men with angina unselectedfor testosterone levels, no adverseeffects of testosterone on tPA or PAI-1 activity were detected.43 No studieshave been performed in men withdiabetes. Testosterone therapy in asmall proportion of men can result in an increased haematocrit.Testosterone dose reduction nor-malises the haematocrit.

Testosterone and theinflammatory stateThe pro-inflammatory cytokines,which are involved in atherogenesis,are TNF-α, IL-1 and IL-6, whereas IL-10 and adiponectin are atheroprotec-tive. Testosterone is known to have animmunosuppressive effect on theimmune system (see Jones et al.38 forreview). Testosterone levels arereduced in states of inflammation,infection and trauma as a result of


Study Population No. Testosterone Outcomefraction studied

Ando et al.10 Diabetic 41 TT TT in diabetic menHealthy 47

Barrett-Connor Diabetic 110 TT TT in diabetic menet al.11 Healthy 875

Barrett-Connor12 Diabetic 44 TT, BT TT, BT in diabeticHealthy 88 men

Zietz et al.13 Diabetic 155 FT FT in diabetic menHealthy 155

Andersson Diabetic 46 TT TT in diabetic menet al.14 Healthy 11

Dhindsa et al.15 Diabetic 103 FT FT in 33%

Kapoor et al.6 Diabetic 355 TT, BT, FT TT, BT, FT in 42%

TT = total testosterone; FT = free testosterone; BT = bioavailable testosterone.

Table 3. Cross-sectional studies of testosterone levels in men with type 2diabetes

↓

↓

↓

↓

↓

↓

↓

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the suppressive action of inflamma-tory cytokines on the hypothalamic-pituitary axis, described above.Testosterone also does have a directaction on inhibiting cytokine produc-tion from lymphocytes.44

In men with hypogonadism andcoronary heart disease, testosteronetherapy reduced serum TNF-α andIL-1β but not IL-6 levels and raisedlevels of IL-10.42 In hypogonadalmen with type 2 diabetes, baselinetestosterone inversely correlates withIL-6 and C-reactive protein (CRP)levels.45 This finding has also beenobserved in other studies in non-dia-betic men. In the study of diabetic

men, testosterone replacement hadno effect on TNF-α, IL-6 or CRP lev-els. Testosterone did reduce serumleptin and adiponectin levels.45 Thiseffect may potentially be mediatedvia a reduction in adipose tissue.Similar effects of testosteronereplacement in these men have beenshown in non-diabetic hypogonadalmen. Adiponectin is atheroprotec-tive and the fall in the level of thiscytokine is opposite to the effects oftestosterone on other components ofthe atherogenic cytokine profile.This was a short-term study and mayreflect initial reduction in fat mass.Longer-term studies are needed

to determine if adiponectin levelsremain low or rise.

AtherosclerosisSeveral studies have found an associ-ation of low testosterone levels withthe presence of atherosclerosis (seeJones et al.38 for review). Two studieson carotid atherosclerosis (one astudy of diabetic men) and one ofaortic atherosclerosis all demon-strated an inverse relationshipbetween testosterone levels anddegree of atherosclerosis.46–48

Another study showed a similar rela-tionship between testosterone andintima medial thickness (IMT) afterexcluding men with cardiovasculardisease.49 Importantly, the follow upstudy of IMT found that those menwith low testosterone levels at base-line had greatest progression of theirdisease after four years.50

Cross-sectional studies in men withcoronary heart disease have foundeither an association with low testos-terone levels or a neutral effect.38 Aswith several studies, bioavailable orfree testosterone measurement ismore sensitive in identifying differ-ences between the groups. One studywas a case-controlled study comparingmen with significant coronary arterydisease (CAD)(>70% stenosis) withmen with normal angiograms.51

Bioavailable and free testosterone lev-els were lower in men with CAD, butthere was no difference in levels oftotal testosterone.

In animal models, castration accel-erates atherosclerosis, whereas testos-terone replacement protects againstprogression of the disease and insome studies ameliorates plaque formation. The positive benefits oftestosterone on the cardiovascular risk factors described above theoreti-cally should reduce overall risk.Testosterone may also have direct ben-eficial effects on the plaques throughits anti-inflammatory actions. This isan important area for future research.

Testosterone as a vasodilatorTestosterone was first reported astreatment for intermittent claudica-tion in 193952 and angina in 1942.53

More recent studies have clearlyshown that physiological testosteronetherapy improves cardiac ischaemia inmen with chronic stable angina as


Figure 2. The Hypogonadal-Obesity-Adipocytokine Cycle

Adipose tissueTriglyceride

uptake

TNF-αIL-6

Activity of lipoprotein lipase

Increasing abdominal obesity leads to increased activity of the enzyme aromatase,present in adipose tissue, which converts testosterone to oestrogen. The resultinglow testosterone increases lipoprotein lipase enzyme activity and triglycerideuptake leading to increased obesity and insulin resistance. This in turn causesfurther androgen deficiency and visceral fat deposition. Oestradiol produced as aresult of testosterone metabolism by aromatase inhibits the hypothalamic-pituitaryrelease of luteinising hormone (LH). Furthermore, testosterone levels are alsolowered as a result of leptin resistance at the hypothalamo-pituitary level and theinhibitory effect of leptin on the testicular axis. Pro-inflammatory adipocytokinessuch as tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) could alsopotentially inhibit the pituitary axis resulting in low testosterone levels.

Oestradiol

Aromatase

-veResistance

-ve

-ve

-ve

-ve

Insulinresistance

Leptin

Hypothalamo-pituitary axis

LH pulseamplitude

Testis

Testosterone↓

↓

↓

↓

Adipocytes↓

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the suppressive action of inflamma-tory cytokines on the hypothalamic-pituitary axis, described above.Testosterone also does have a directaction on inhibiting cytokine produc-tion from lymphocytes.44

In men with hypogonadism andcoronary heart disease, testosteronetherapy reduced serum TNF-α andIL-1β but not IL-6 levels and raisedlevels of IL-10.42 In hypogonadalmen with type 2 diabetes, baselinetestosterone inversely correlates withIL-6 and C-reactive protein (CRP)levels.45 This finding has also beenobserved in other studies in non-dia-betic men. In the study of diabetic

men, testosterone replacement hadno effect on TNF-α, IL-6 or CRP lev-els. Testosterone did reduce serumleptin and adiponectin levels.45 Thiseffect may potentially be mediatedvia a reduction in adipose tissue.Similar effects of testosteronereplacement in these men have beenshown in non-diabetic hypogonadalmen. Adiponectin is atheroprotec-tive and the fall in the level of thiscytokine is opposite to the effects oftestosterone on other components ofthe atherogenic cytokine profile.This was a short-term study and mayreflect initial reduction in fat mass.Longer-term studies are needed

to determine if adiponectin levelsremain low or rise.

AtherosclerosisSeveral studies have found an associ-ation of low testosterone levels withthe presence of atherosclerosis (seeJones et al.38 for review). Two studieson carotid atherosclerosis (one astudy of diabetic men) and one ofaortic atherosclerosis all demon-strated an inverse relationshipbetween testosterone levels anddegree of atherosclerosis.46–48

Another study showed a similar rela-tionship between testosterone andintima medial thickness (IMT) afterexcluding men with cardiovasculardisease.49 Importantly, the follow upstudy of IMT found that those menwith low testosterone levels at base-line had greatest progression of theirdisease after four years.50

Cross-sectional studies in men withcoronary heart disease have foundeither an association with low testos-terone levels or a neutral effect.38 Aswith several studies, bioavailable orfree testosterone measurement ismore sensitive in identifying differ-ences between the groups. One studywas a case-controlled study comparingmen with significant coronary arterydisease (CAD)(>70% stenosis) withmen with normal angiograms.51

Bioavailable and free testosterone lev-els were lower in men with CAD, butthere was no difference in levels oftotal testosterone.

In animal models, castration accel-erates atherosclerosis, whereas testos-terone replacement protects againstprogression of the disease and insome studies ameliorates plaque formation. The positive benefits oftestosterone on the cardiovascular risk factors described above theoreti-cally should reduce overall risk.Testosterone may also have direct ben-eficial effects on the plaques throughits anti-inflammatory actions. This isan important area for future research.

Testosterone as a vasodilatorTestosterone was first reported astreatment for intermittent claudica-tion in 193952 and angina in 1942.53

More recent studies have clearlyshown that physiological testosteronetherapy improves cardiac ischaemia inmen with chronic stable angina as


Figure 2. The Hypogonadal-Obesity-Adipocytokine Cycle

Adipose tissueTriglyceride

uptake

TNF-αIL-6

Activity of lipoprotein lipase

Increasing abdominal obesity leads to increased activity of the enzyme aromatase,present in adipose tissue, which converts testosterone to oestrogen. The resultinglow testosterone increases lipoprotein lipase enzyme activity and triglycerideuptake leading to increased obesity and insulin resistance. This in turn causesfurther androgen deficiency and visceral fat deposition. Oestradiol produced as aresult of testosterone metabolism by aromatase inhibits the hypothalamic-pituitaryrelease of luteinising hormone (LH). Furthermore, testosterone levels are alsolowered as a result of leptin resistance at the hypothalamo-pituitary level and theinhibitory effect of leptin on the testicular axis. Pro-inflammatory adipocytokinessuch as tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) could alsopotentially inhibit the pituitary axis resulting in low testosterone levels.

Oestradiol

Aromatase

-veResistance

-ve

-ve

-ve

-ve

Insulinresistance

Leptin

Hypothalamo-pituitary axis

LH pulseamplitude

Testis

Testosterone↓

↓

↓

↓

Adipocytes↓

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assessed by exercise treadmill test-ing.54 Furthermore, direct infusion oftestosterone at physiological dosesinto human coronary arteries duringroutine angiography produces a rapiddose dependent increase in arterydiameter and flow.55 Acute adminis-tration of supraphysiological testos-terone prior to an exercise test alsoimproves time to cardiac ischaemia.56

In vitro studies in isolated arteriesfrom several different vascular bedshave established that supraphysiologi-cal doses of testosterone have a rapidonset (within two to three minutes)vasodilator effect (see Jones et al.57 forreview). This action of testosterone isindependent of the endothelium hav-ing a direct effect on vascular smoothmuscle cells (VSMCs) acting as a cal-cium antagonist.58 In isolated VSMCsit has been shown that testosterone atphysiological concentrations inhibitsL-Ca2+ channels in a similar mannerto nifedipine.59

Acute administration of testos-terone to men with chronic heart fail-ure reduces peripheral vascularresistance and improves cardiacindex.60 Two studies, one over threemonths and the second over 12months, have shown that testos-terone therapy in men with moderatechronic heart failure gives animprovement in functional exercisecapacity and symptoms, and main-tains blood pressure.61,62 Studies areunderway to examine the effects oftestosterone on leg blood flow inmen with diabetes with and withoutperipheral vascular disease.

Erectile dysfunctionErectile dysfunction is common inmen with type 2 diabetes with reportsranging between 30–90% prevalence.Atherosclerosis, autonomic neuropa-thy and psychological factors havebeen considered to be the main aetiological factors, each alone or in combination. Testosterone defi-ciency, if present, is a contributoryfactor to erectile dysfunction. Studieshave not detected a significant differ-ence between levels of total testos-terone in men with and without erec-tile dysfunction. However, bioavail-able and free testosterone levels arelower in diabetic men with erectiledysfunction.63 Furthermore, theseverity of erectile dysfunction as

assessed by the International Indexof Erectile Function (IIEF score) cor-relates positively with total, bioavail-able and free testosterone.63 Thisstudy also found that erectile dysfunc-tion was more prevalent in men withhigher waist circumference.

It has been established that menwith erectile dysfunction who do notrespond to PDE5 (phosphodiesterasetype 5) inhibitors have lower testos-terone levels than in responders (6.9 vs 18.6nmol/L).64 Two studieshave demonstrated that testosteronereplacement if hypogonadal converts60% of the non-responders to respon-ders.65,66 These findings underpin the importance of testosterone in thephysiology of the normal erectionand the fact that testosterone statusshould be assessed in this group.

Testosterone replacementtherapyThe last few years have seen signifi-cant advances in testosterone therapywith the key benefit being modes ofdelivery which allow replacement tophysiological levels. The major prob-lems with the older formulations areas follows. Oral testosterone tabletsdo not achieve consistent blood levels as the hormone is rapidlymetabolised by first pass metabolismby the liver and the majority of menhave no or little benefit. Delivery sys-tems have therefore been devised tobypass the liver either with muscularor subcutaneous depot preparations,or by transdermal or transbuccalroutes. Testosterone ester injections

give supraphysiological testosteronelevels after treatment falling to sub-normal levels before the next injec-tion is due, with many men becomingsymptomatic at that time. It is notknown whether these fluctuationshave adverse effects on the body inthe long term. Testosterone implantsalso may cause supraphysiologicallevels and there is a risk of infectionand pellet extrusion at the site ofimplantation. Transdermal patcheshave a high incidence of skin allergy,and serum testosterone levels aremainly in the lower range.

Transdermal gels applied daily,transbuccal tablets twice daily orlong-acting depot testosterone unde-conoate by three-monthly deep intra-muscular injections deliver testos-terone to physiological levels. Inpractice it is usually the patient whodecides the mode of treatment.Usually a younger man will prefer thelong-acting injection and the middle-aged to older man a gel formulation.The advantage of the gel is that treat-ment can be stopped quickly if needbe; however, the injection has theadvantage of infrequent dosing.

Safety and monitoring oftestosterone therapyOne of the primary concerns of TRTis whether or not it causes prostatecarcinoma. There is no evidence inthe medical literature that demon-strates an increased risk of develop-ing this cancer over and above that ofthe general male population.67,68

There are, however, no large long-


Key points

• There is a high prevalence of clinically relevant testosterone deficiency(hypogonadism) in men with type 2 diabetes

• Low testosterone levels in healthy men are an independent risk factor forthe subsequent development of metabolic syndrome and type 2 diabeteseven in non-obese individuals

• The diagnosis of hypogonadism is dependent on assessment ofappropriate markers of testosterone which include calculated free andbioavailable testosterone

• Low testosterone levels are associated with an increased mortality• Pilot studies show that testosterone replacement therapy improves insulin

resistance, glycaemic control and visceral adiposity• Testosterone replacement in hypogonadal men converts the majority of

PDE5 inhibitor non-responders to responders• Exclusion of an occult prostate carcinoma is mandatory prior to

commencing testosterone therapy, as is regular monitoring after treatmenthas been commenced


REVIEW


term studies and many medicalexperts have recommended this.More aggressive forms of prostatecarcinoma are more frequentlyfound in hypogonadal men. It ismandatory, however, to exclude thepresence of a pre-existing carcinomaprior to commencing TRT in menolder than 45 years. This is done bymeasuring prostate-specific antigen(PSA) and performing a digital rectalexamination (DRE). If there is anydoubt, a urology opinion should besought and biopsies taken if indi-cated. Guidelines also recommendthat, once on therapy, PSA and DREshould be repeated every threemonths for the first year and thenyearly thereafter.3,4 The PSA which islow in men with hypogonadism mayrise within the normal range to attaineugonadal levels.67 Studies haveshown no adverse effects on benignprostatic hypertrophy.

The haematocrit should be moni-tored as in some men the level risesabove normal, especially in thosewith respiratory conditions. A lower-ing of testosterone dose is usually suf-ficient to normalise the haematocrit.

SummaryCurrent evidence shows that there is asignificant proportion of men withtype 2 diabetes who have hypogo-nadism. Androgen status in diabeticmen is not routinely considered bythe majority of medical practitioners.An understanding of the diagnosis ofhypogonadism has been confoundedby the role of SHBG, but more recentresearch is helping to clarify the inter-pretation of testosterone measure-ment. Although symptoms of hypogo-nadism are non-specific, especially indiabetic men, the presence of symp-toms should be a trigger to the clini-cian to measure serum testosteronelevels. Firstly, diagnosis and treatmentof hypogonadism improve well-beingand quality of life; this can save mar-riages and jobs. Secondly, early evi-dence shows a benefit on glycaemiccontrol, insulin resistance and othercardiovascular risk factors. Largerand longer-term studies are underwayto investigate these findings further.Thirdly, men with erectile dysfunc-tion who fail to respond to PDE5inhibitors may have a low testosteronelevel and replacement therapy can

help the majority of these men tohave a successful response.

Clearly, further research isrequired to establish the specificroles of TRT in men with diabetes.However, the benefits of treatingmen with hypogonadism are wellestablished. There should be anincreased awareness amongst clini-cians of this condition in diabeticmen, especially as a recent publica-tion has shown that men with lowtestosterone levels have a significantincreased mortality over men withnormal levels.69

Conflict of interest statementThe author has been a member ofadvisory boards and has receivedhonoraria from Ardana BioscienceUK, Bayer Schering Pharma, Ipsenand ProStrakan. He has received nofunding for the preparation of thisarticle.

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