subnormal testosterone concentrations in the men are associated with a two to three times elevated risk of cardiovascular events and death in two early studies.Short-term studies of tes-tosterone therapy in hypogonadal men with type2diabetes have demonstrated an increa in insulin nsitivity and a decrea in waist circumference.However,the data on the effect of tes-tosterone replacement on glycemic control and cardiovascular risk factors such as cholesterol and C-reactive protein concentrations are inconsistent.As far as xual function is concerned,testos-terone treatment increa
s libido but does not improve erectile dysfunction and thus,phospho-diestera inhibitors may be required.Trials of a longer duration are clearly required to definitively establish the benefits and risks of testosterone replacement in patients with type2diabetes and low testosterone.(J Clin Endocrinol Metab96:2643–2651,2011)
S ubnormal free testosterone concentrations in asso-ciation with inappropriately low LH and FSH con-centrations and a normal respon to GnRH of LH and FSH in type2diabetes were first described in2004(1). The abnormalities were independent of the duration and verity of hyperglycemia[glycosylated hemoglo-bin(HbA1c)].Magnetic resonance imaging in the hy-pogonadal patients showed no abnormality in brain or the pituitary(1).This association of hypogonadotropic hypogonadism(HH)with type2diabetes has now been confirmed in veral studies and is prent in25–40% of the men(2–5).In this context,it is important that The Endocrine Society now recommends the measure-ment of testosterone in patients with type2diabetes on a routine basis(6).The obrvations were recently extended to younger patients with type2diabetes be-tween the ages of18and35yr who had HH at a rate of 33%when the usual normal range for middle age was employed,whereas the rate was58%when age-specific normal range for free testosterone for the young was em-ployed(7).With the advent of more specific liquid chro-matography tandem ma
ss spectrometry assay for measur-ing total testosterone,the reference ranges for total and free testosterone have recently been revid downward. Using this methodology,in our most recent study,we have found that29%of men with type2diabetes have sub-normal free testosterone concentrations,as measured by equilibrium dialysis(8);25%had HH,whereas4%had hypergonadotropic hypogonadism.
Type2diabetic men with low testosterone levels have also been found to have a high prevalence of symptoms suggestive of hypogonadism such as fatigability and erectile dysfunction(2).In all of the above studies,total testosterone and free testosterone concentrations were
ISSN Print0021-972X ISSN Online1945-7197
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Copyright©2011by The Endocrine Society
doi:10.1210/jc.2010-2724Received November19,2010.Accepted July8,2011.Abbreviations:BMD,Bone mineral density;BMI,body mass index;CRP,C-reactive protein; HbA1c,glycosylated hemoglobin;HH,hypogonadotropic hypogonadism;HOMA-IR,ho-meostasis model asssment for insulin resistance;PSA,prostate-specific antigen.
卫生间反味怎么办J Clin Endocrinol Metab,September2011,96(9):2643–dojournals2643
inverly related to body mass index(BMI)and age. However,the prence of low testosterone concentra-tion was not entirely dependent upon obesity becau 25%of nonobe patients(31%of lean and21%of overweight)also had HH(1).HH is relatively rare in type1diabetes and,therefore,is not a function of di-abetes or hyperglycemia per (9).Thus,in view of the inver relationship between BMI and testosterone con-centrations in both type1and type2diabetes,HH is probably related to insulin resistance(1,4,9).Previous studies have shown that hypogonadism is associated with upper abdominal adiposity,insulin resistance,and the metabolic syndrome(10,11).Treatment of systemic insulin resistance by rosiglitazone leads to a modest in-crea in testosterone concentrations in men with type 2diabetes(12),without the restoration of testosterone concentrations to normal.
A recent study investigated the prevalence of low tes-tosterone concentrations in a large number of obe and diabetic men(mean age,60yr;range,45–96yr)(13);44% of diabetic and33%of age-matched nondiabetic men had subnormal free testosterone concentrations,respectively. Forty percent of obe men and50%of obe diabetic men had subnormal free testosterone concentrations.Thus, obesity is associated with a high prevalence of hypogo-nadism,and the prence of diabetes adds to that risk. Possible Pathophysiological Mechanisms Underlying HH in Type2Diabetes
没有山根的鼻子Role of estradiol
Becau testosterone and androstenedione in the male can be converted to estradiol and estrone,respectively, through the action of aromata in the menchymal cells and preadipocytes of adipo tissue,it has been suggested that excessive estrogen cretion due to aromata activity in the obe may potentially suppress the hypothalamic cretion of GnRH(14).This hypothesis was examined in a recent study that compared the estradiol concentrations in240type2diabetic men with and without HH(8).Total estradiol concentrations were measured by immunoassay, and free estradiol concentrations were calculated using SHBG.Total and free estradiol concentrations in men with HH were significantly lower than in tho without HH(8).To confirm the findings,total estradiol concen-trations were measured in a subt of102men by the liquid chromatography tandem mass spectrometry assay,and free estradiol concentrations were measured by equilib-rium dialysis.Estradiol concentrations were25%lower in men with HH.Free estradiol concentrations were directly related to free testosterone concentrations,irrespective of age or BMI.The diminished availability of the substrate, testosterone,may therefore be the major determinant fac-tor of estradiol concentrations in the men.A study in elderly men(European Male Ageing Study)has also found lower estradiol concentrations in hypogonadal men(15). Thus,it appears that the low testosterone co
ncentrations in HH of diabetes,as in aging,are not the conquence of estradiol-dependent suppression of the hypothalamo-hy-pophyal-gonadal axis.Furthermore,HH in type2dia-betic men with a normal weight is not likely to be associ-ated with incread estradiol concentrations(1).
Role of insulin resistance
The lective deletion of the insulin receptor from neu-rons in mice leads to a reduction in LH concentrations by 60–90%and low testosterone concentrations(16).The animals respond to GnRH challenge by normal or supra-normal relea of LH.In addition,the animals had atro-phic miniferous tubules with markedly impaired or ab-nt spermatogenesis.In addition,it is known that the incubation of hypothalamic neurons with insulin results in the facilitation of cretion of GnRH(17,18).Thus,in-sulin action and insulin responsiveness in the brain are necessary for the maintenance of the functional integrity of the hypothalamo-hypophyal-gonadal axis.
Role of inflammatory mediators
TNF-␣and IL-1have been shown to suppress hypo-thalamic GnRH and LH cretion in experimental animals and in vitro(19,20).It is therefore relevant that C-reactive protein(CRP)concentrations are markedly incread in hypogonadal type2diabetic men compared wi
th men with type2diabetes and normal testosterone(6.5vs.3.2 mg/liter)(21).The data were confirmed by another study from Australia in which the median CRP concen-tration in type2diabetic patients with low total testos-terone was7.7mg/liter compared with4.5mg/liter in men with normal testosterone(4).Free testosterone concen-trations were inverly related to CRP concentrations(rϭϪ0.27;Pϭ0.02).It is thus possible that inflammatory mediators may contribute to the suppression of the hypo-thalamo-hypophyal axis and the syndrome of HH in type2diabetes.The prence of inflammation may also contribute to insulin resistance becau veral inflamma-tion-related mediators,such as suppressor of cytokine sig-naling-3,IB kina,and c-Jun N-terminal kina-1in-terfere with insulin signal transduction(22,23)and contribute to insulin resistance.The mediators are also known to be incread in obesity(24).蒙马特遗书
In summary,it is likely that there are veral interlinked causative mechanisms underlying HH in men with type2 diabetes.It should also be noted that human chorionic
2644Dandona and Dhindsa Hypogonadism in Type2Diabetes J Clin Endocrinol Metab,September2011,96(9):2643–2651日本神话故事
gonadotropin-induced testosterone cretion by Leydig cells is inverly related to insulin nsitivity(
as measured by hyperinsulinemic euglycemic clamp)among men with varying degrees of gluco tolerance(25).Thus,the lesion resulting in hypogonadism in obesity and type2diabetes may occur at veral levels of the hypothalamic-pitu-itary-gonadal axis.However,the abnce of an increa in gonadotropin concentrations indicates that the pri-mary defect in type2diabetes and obesity is at the hy-pothalamo-hypophyal level.
What Comes First:Hypogonadism or Type 2Diabetes?
Becau even young men with type2diabetes and patients with newly discovered type2diabetes have a high prev-alence of HH and obesity is associated with HH,it is pos-sible that HH precedes diabetes.Several epidemiological studies have shown that low testosterone at baline ap-proximately doubles the odds of development of type2 diabetes(26–28).The data,however,are more consistent with total testosterone than with free testosterone(29). It is possible that low SHBG concentrations may medi-ate a portion of this association.SHBG polymorphisms that lead to lower SHBG concentrations are strongly predictive of the development of type2diabetes, whereas tho that lead to higher SHBG concentrations are protective(30,31).
Does Hypogonadism Matter?Possible Conquences of Hypogonadism in Type2 Diabetes
It is well accepted that low testosterone concentrations are associated with symptoms such as fatigue,lack of libido, and erectile dysfunction.Recent studies have described pathophysiological effects of subnormal testosterone con-centrations beyond tho related to xual health,as dis-cusd below.
Symptoms of xual dysfunction
Cross-ctional studies have found a high prevalence of low libido(64%),erectile dysfunction(74%),and fatigue (63%)in hypogonadal men with type2diabetes(2).How-ever,the prence of the symptoms was similarly high in eugonadal men with type2diabetes as well(48,65,and 57%,respectively).The treatment of erectile dysfunction with phosphodiestera-5inhibitors such as sildenafil in men with type2diabetes is known to be not as effective as that in nondiabetic subjects(32).Cardiovascular dia
Recent evidence from longitudinal obrvational stud-ies shows that low testosterone concentration is prospec-tively associated with an increa in the incidence of car-diovascular events.Laughlin et al.(33)prospectively followed794elderly men(mean age,71yr)for20yr in a community tting.The hazard ratio for men in the lowest quartile of bioavailable testosterone was1.44for all-cau mortality
and1.36for cardiovascular mortality.Another prospective study[Osteoporotic Fracture in Men(MrOS) Swedish cohort(34)]that included3014men(mean age, 75yr;mean follow-up,4.5yr)showed a65%incread risk of mortality in men with low free testosterone(Ͻ6.1 ng/dl).Subnormal free testosterone concentrations are as-sociated with a69%incread risk of stroke or transient ischemic attack(35).Many cross-ctional,retrospective, ca-control and smaller studies have also demonstrated an association of low testosterone with incread mortal-ity(36–38).However,the relationship between cardio-vascular mortality and low testosterone was not en in two longitudinal studies(39,40).The studies were done in relatively younger populations(mean ages,52and55 yr)and had much lower mortality rates,which can pos-sibly explain the lack of an association(39,40).
A recent study in930men with coronary artery dia reported that a low testosterone at baline was associated with incread mortality after7yr of follow-up(21vs. 12%)(41).Only one study has looked at the association between subnormal testosterone concentrations and car-diovascular mortality specifically in men with type2di-abetes(42):in153men with type2diabetes and known coronary artery dia,subnormal free testosterone con-centration at baline incread cardiovascular mortality by three times over2yr.
Insulin nsitivity
HH in men with type2diabetes is associated with a higher BMI(3–4kg/m2),12%more sc fat mass(measured by dual-energy x-ray absorptiometry),and higher waist-to-hip ratio compared with eugonadal men with type2 diabetes(1,2,43).In one study involving type2diabetic men from the United Kingdom,74%of hypogonadal men were obe compared with54%of eugonadal men(2).As of yet,no study has measured visceral,im,or hepatic fat content in type2diabetic men with and without HH. Many studies have documented that hypogonadism is as-sociated with insulin resistance(reviewed in Refs.44and 45).No study has compared the insulin resistance in type 2diabetic men with subnormal or normal testosterone concentrations.
J Clin Endocrinol Metab,September2011,96(9):2643–dojournals2645
Hematocrit
Hypogonadal type2diabetic men have a lower hemat-ocrit than tho with normal testosterone concentrations (21).The prevalence of normocytic normochromic ane-mia in such patients is38%compared with3%in tho with normal testosterone concentrations.A large study (464men)also found a direct correlation between free testosterone concentrations and hemoglobin in men with type2diabetes and renal insufficiency(46).Testoster-one regulates erythropoiesis(47).Howe
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ver,it has not yet been determined whether the association of anemia with hypogonadism in men with type2diabetes is causal or is condary to other confounding factors such as inflammation.In the men,hemoglobin is positively related to testosterone but negatively related to CRP concentrations(21).
Bone density
Hypogonadism is associated with a decrea in bone mineral density(BMD)and an increa in fracture rate (48,49).Furthermore,trabecular bone architecture(mea-sured by high-resolution magnetic resonance imaging)de-teriorates much more in hypogonadal men compared with eugonadal men(50).Hypogonadal men usually have lower estradiol concentrations compared with eugonadal men becau testosterone is the substrate for estradiol for-mation by aromatization(15).In epidemiological studies, estradiol concentrations correlate more robustly with BMD than testosterone concentrations in men(51).This is especially true of trabecular bone.However,testoster-one appears to be an independent predictor of cortical bone density(52,53).One study in men with type2dia-betes has shown that free testosterone concentrations are positively associated with BMD in arms and ribs,but not with hip,spine,or total body BMD values(43).Another study has shown a positive relation of lumbar spine BMD with free tes
tosterone concentrations in men with type2 diabetes(54).No study has evaluated the relation between BMD and free estradiol concentrations in the men.It is possible that BMD in men with type2diabetes might relate more strongly to estradiol than to testosterone con-centrations,as has been shown in elderly nondiabetic men. No data are available on the fracture rates of hypogonadal men with type2diabetes.
Prostate-specific antigen(PSA)
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Type2diabetic men have20%lower PSA concentra-tions than nondiabetic men(55).PSA concentrations are lower in hypogonadal than in eugonadal type2diabetic men(0.89vs.1.1ng/ml)(56).It is interesting that the incidence of prostatic carcinoma is lower in men with di-abetes.This is in contrast to the incread incidence of cancer in diabetics in various organs including the co-lon,the kidney,the breast,the endometrium,and the pancreas(57).The diminished incidence of prostate cancer in diabetics may receive a contribution from the high prevalence of HH and low testosterone concentra-tions.However,epidemiological studies do not support a causative role of testosterone in prostate cancer in nondiabetic populations(58).
Should Testosterone Be Measured in
Every Patient with Type2Diabetes? Becau the frequency of subnormal free testosterone con-centrations in type2diabetes is at least25%,we believe that free testosterone concentration should be measured in every patient with type2diabetes.This is consistent with The Endocrine Society guidelines.The prevalence of hy-pothyroidism is between5and8%in this population,and yet we screen every one for this condition.An Androgen Deficiency in Aging Male(ADAM)questionnaire should be administered in every patient with a low testosterone so that the prence of clinical hypogonadism can be estab-lished.One can argue that if the ca for the replacement of testosterone in patients with HH is not proven,as dis-cusd below,is there a ca for measuring its concentra-tions in every patient with type2diabetes?We believe that there is becau,like hypothyroidism,patients may slide gradually into this clinical state without any overt symp-toms that may be revealed through direct questioning.“Asymptomatic”men may realize that they had been symptomatic only after a trial with testosterone.Such pa-tients may potentially benefit from testosterone replace-ment therapy,as discusd below.
Should Men with Type2Diabetes and
Low Testosterone Be Replaced with Testosterone?Issues to Be Considered in View of the Above Data
The Endocrine Society recommends that men with low testosterone and symptoms of androgen deficiency be con-sidered for therapy with testosterone(6).The guidelines do not recommend treatment of asymptomatic men with low testosterone.The Institute of Medicine recommends that more short-term studies in lected populations should investigate the benefits and risks of testosterone therapy.Trials in men with type2diabetes and obesity are important in this regard becau both are commonly as-sociated with hypogonadism.A few studies on testoster-one replacement in type2diabetic men with low testos-terone have emerged and are described below.
2646Dandona and Dhindsa Hypogonadism in Type2Diabetes J Clin Endocrinol Metab,September2011,96(9):2643–2651
Insulin resistance
Three studies have shown a decrea in insulin resis-tance after testosterone therapy in hypogonadal men with type2diabetes.Kapoor et al.(59)studied the effects of treatment with im testosterone for3months in24hy-pogonadal type2diabetic men in a placebo-controlled, double-blind,crossover trial.Homeostasis model asss-ment for insulin resistance(HOMA)-IR decread by1.73 after testosterone therapy compared with placebo.In an-other trial,32men with the metabolic
syndrome and newly diagnod type2diabetes with total testosterone concentration of less than350ng/dl(12nmol/liter)were prescribed diet and exerci(60).Half of them were also given transdermal testosterone for1yr.Testosterone ther-apy resulted in greater improvements in insulin nsitivity (measured by HOMA-IR;Ϫ0.9)compared with diet and exerci alone.A prospective,randomized,double-blind multicenter trial of transdermal testosterone(3g metered-do2%gel for1yr)therapy in220hypogonadal men with type2diabetes or metabolic syndrome has recently been published[Testosterone Replacement in Hypogo-nadal Men with Either Metabolic Syndrome or Type2 diabetes study(TIMES2)(61)].The primary endpoint of the study was a change in insulin nsitivity,as measured by HOMA-IR.Patients were evaluated every3months.A total of136men in the study had type2diabetes,176men had metabolic syndrome,and92men had both.Testos-terone therapy resulted in a15%(Pϭ0.01)decrea in HOMA-IR at6months and at1yr time-points in men with type2diabetes as well as in tho with metabolic syn-drome.One study in lean hypogonadal type2diabetic men with a mean BMI of24kg/m2did not show any change in insulin nsitivity after treatment with low-do im testosterone(100mg every3wk)for3month(62).This do is inadequate and may account for the lack of effect. It is,however,possible that the change in insulin n-sitivity due to testosterone therapy occurs only in obe, and presumably insulin-resistant,men.Thus,it appears that insulin resistance improves with testosterone ther-apy in obe m
en with type2diabetes.The studies have calculated HOMA-IR to measure insulin resis-tance.This needs to be confirmed by trials that u hy-perinsulinemic-euglycemic clamp methodology.It is also not clear whether the effect is due to a change in body composition or independently of it.
Glycemic control
In three of the above-mentioned studies,glycemic con-trol was also evaluated by measuring HbA1c and fasting gluco.The small study by Kapoor et al.(59)showed a decrea in fasting gluco(28mg/dl)and HbA1c(0.37%) compared with placebo with3months of testosterone re-placement.The trial in men with new ont type2diabetes with transdermal testosterone did show a decrea in HbA1c from7.5to6.3%over a period of1yr(60).This was in conjunction with diet and exerci,but no hypo-glycemic medications.The comparison group in this study was a diet and exerci group.There was a decrea in HbA1c from7.5to7.1%in this group.The mean fasting gluco decread by34and29mg/dl in the testosterone and diet/exerci groups,respectively(Pϭ0.06for com-parison among groups).However,the larger trial (TIMES2)did not show a clear effect of testosterone re-placement on HbA1c(61).Medication changes were not allowed for the first6months of the study.Patients with type2diabetes showed a trend toward improvement in HbA1c at1yr(Ϫ0.4%;Pϭ0.057)but not at6months (Pϭ0.6).Although no changes were
made in patient’s medications for the first6months,the study protocol al-lowed medication changes between6and12months; therefore,no clear conclusions can be made regarding the effect of testosterone therapy on glycemic control from this trial.There were no changes in fasting gluco or in-sulin.Thus,there appears to be a mild decrea in HbA1c with testosterone therapy in men with type2diabetes,but the data are inconsistent and currently testosterone re-placement cannot be recommended for glycemic control. Symptoms and xual dysfunction
In the TIMES2trial,there was an improvement in the International Index of Erectile Function score in the tes-tosterone replacement group,mainly due to an increa in xual desire,but other symptoms did not change.The smaller trial of im testosterone by Kapoor et al.(59)in hypogonadal men with type2diabetes showed an im-provement in symptoms as measured by the ADAM ques-tionnaire.Although there are no specific studies asssing the effect of testosterone replacement on the effectiveness of phosphodiestera IV inhibitors like sidenafil,studies in hypogonadal nondiabetics do show this benefit(63). Body composition and abdominal adiposity Heufelder et al.(60)showed a decrea in waist cir-cumference of14cm in men with new ont type2diabetes treated for1yr with transdermal testosterone,diet,and exerci.The control group that was prescribed only diet and exerci lost5cm.Kapoor et al.(59)showed a de-crea by1.63cm in waist circumferenc
e after im testos-terone treatment.In the TIMES2trial,there was a small but statistically significant decrea in waist circumference (0.8cm)in type2diabetic men treated with testosterone. Significantly,BMI did not change in any of the studies despite the decrea in abdominal girth.
J Clin Endocrinol Metab,September2011,96(9):2643–dojournals2647
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