Are Declining Testosterone Levels A Major Risk Factor for Ill-Health in Aging Men?

B. B. Yeap

April 08, 2009

Testosterone, Cardiovascular Risk and Mortality in Aging Men

Erectile dysfunction is a marker for impaired endothelial function and underlying vascular disease and its presence predicts increased incidence of subsequent cardiovascular disease events^[96,97,98] (Table 3). This association between erectile dysfunction and cardiovascular risk is complex as erectile dysfunction commonly coexists with conditions that are associated with increased risk of cardiovascular disease, namely obesity, metabolic syndrome and Type II diabetes, which are also associated with lower testosterone levels.^{[80,81,97,99]} Thus, lower testosterone levels are associated with higher body mass index (BMI), and with increased prevalence and incidence of metabolic syndrome and Type II diabetes in middle-aged and older men.^{[10,11,13,14,19,100,101,102,103,104,105,106,107]} In addition, lower testosterone levels are associated with surrogate markers for cardiovascular disease, including less favorable carotid intima medial thickness,^{[108,109,110]} ankle/brachial index as a measure of peripheral arterial disease^[111] and calcific aortic atheroma.^[112] Thus, lower testosterone levels, erectile dysfunction and conditions associated with higher cardiovascular risk appear to be interrelated.^[113,114] The direction of causation is debatable as marked obesity predisposes to type II diabetes and atherosclerosis, and may reduce LH pulse amplitude and testicular responses to LH.^[115,116] However, testosterone therapy increases lean body mass and reduces fat mass, thus modulating insulin resistance and risk of metabolic syndrome.^[66,117,118] Testosterone may also exhibit antiatherogenic effects at the tissue level, whether mediated by classical or nonclassical pathways.^{[119,127,128]} The key question is whether testosterone therapy reduces the risk of cardiovascular disease distinct from any effects on erectile dysfunction. Trials of testosterone therapy generally have not been designed or adequately powered to detect effects on clinically significant cardiovascular events.^{[16,64,65,66,119,120]} Although randomized controlled trial data are lacking, there are observational data which support a relationship between low testosterone and fatal cardiovascular events. Lower testosterone levels have been associated with increased overall and cardiovascular-related mortality in middle-aged and older men.^{[121,122,123]} However, other studies have not shown a clear relationship between lower testosterone and higher mortality.^[124,125] In the Caerphilly study, a higher ratio of cortisol to testosterone was associated with ischemic heart disease but this was attenuated after adjustment for components of the insulin-resistance syndrome.^[124] By contrast, in the Massachusetts Male Aging Study, higher free testosterone was significantly associated with ischemic heart disease mortality.^[125] Finally, data are lacking as to whether higher testosterone levels predict reduced incidence of combined nonfatal and fatal major cardiovascular events.^[126] Thus, although lower testosterone levels are associated with higher cardiovascular risk and to an extent with mortality in aging men, randomized controlled clinical trials of adequate size and duration are needed to determine whether testosterone therapy will reduce morbidity and mortality from cardiovascular disease in hypogonadal or eugonadal men.

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Abstract and Introduction
Testosterone Levels Decline as Men Grow Older
Testosterone and Cognitive Function in Older Men
Testosterone, General Health and Quality of Life in Aging Men
Testosterone and Sexual Health in Aging Men
Testosterone, Cardiovascular Risk and Mortality in Aging Men
Can the Age-related Decline in Testosterone Levels Be Prevented?
Conclusions
References

Table 1. Studies of Testosterone and Cognitive Function in Older Men
Reference	First author	Study	n	Sample	Results
^[21]	Moffat SD	L	407	50-91 years	Higher ratio TT/SHBG associated with better memory and visuospatial functioning, and reduced rate of longitudinal decline in visual memory
^[22]	Barrett-Connor E	(L)	547	59-89 years	Higher testosterone levels predicted better performance in several tests of cognitive function
^[23]	Yaffe K	X	310	73±7.1 years	Higher bioavailable testosterone associated with better cognitive test scores
^[24]	Thilers PP	X	1107	35-90 years	Higher free T associated with better visuospatial ability and memory
^[25]	Muller M	X	400	40-80 years	Higher testosterone associated with memory and processing capacity
^[26]	Yeap BB	X	2932	70-89 years	Higher free testosterone associated with better cognitive function
^[27]	Hogervorst E	X	112 vs 98	AD vs controls	Men with AD had lower ratio TT/SHBG vs age-matched controls
^[28]	Moffat SD	L	574	32-87 years	Higher TT/SHBG predicted reduced incidence of AD
^[29]	Fonda SJ	X	981	48-80 years	No relationship between TT or free T and working memory, attention, spatial relations
^[30]	Yonker JE	X	450	35-80 years	Lower free T associated with higher performance in spatial visualization
^[31]	Martin DM	X	1046	35-80 years	Higher free T and TT associated with poorer verbal memory and executive performance but faster processing speed
^[32]	Burkhardt MS	X	45	> 55 years	Higher free T associated with better cognition in non-APOE ε4 carriers and with poorer executive function, working memory and attention in ε4 carriers
^[33]	Cherrier MM	I	19	52-76 years with prostate cancer	Androgen suppression and blockade benefited verbal memory but worsened spatial ability
^[34]	Salminen EK	I	26	65±6.7 years with prostate cancer	Androgen deprivation resulted in visuomotor slowing and slowed reaction times in attentional domains
^[35]	Almeida OP	I	40	44-83 years with prostate cancer	Discontinuation of anti-androgen therapy improved verbal memory but not visuospatial abilities
^[36]	Hogervorst E	R			90 references
^[37]	Beauchet O	R			64 references
^[38]	Cherrier MM	I	32	21-46 years	Levonorgestrel reduced testosterone levels and verbal memory
^[39]	Maki PM	I	15	66-86 years with TT > 8.3 nmol l^-1	Intramuscular testosterone decreased verbal memory
^[40]	Lu PH	I	16	AD	Testosterone improved quality of life assessed by caregivers
^[41]	Cherrier MM	I	12	34-70 years, TT < 10.4 nmol l^-1	Transdermal testosterone improved verbal memory, DHT improved spatial memory
^[42]	Cherrier MM	I	15 and 17	AD and MCI, not hypogonadal	Intramuscular testosterone improved verbal and spatial memory and constructional ability
^[43]	Cherrier MM	I	60	50-90 years	Intramuscular testosterone improved spatial memory, improvement in verbal memory with testosterone blocked by anastrozole

Abbreviations: AD = Alzheimer's disease; DHT = dihydrotestosterone; free T = free testosterone; MCI = mild cognitive impairment; SHBG = sex hormone-binding globulin; TT = total testosterone.
Study type: X = cross-sectional; L = longitudinal; I = interventional study; R = review or meta-analysis.

Table 2. Studies of Testosterone and General or Sexual Health in Older Men
Reference	First author	Study	n	Sample	Results
^[45]	Hijazi RA	R			123 references
^[46]	Morley JE	R			55 references
^[47]	Haren MT	R			145 references
^[48]	Finas D	X	24 and 24	> 50 years, ±androgen deficiency	Lower free T associated with poorer QoL (SF-12 Health Survey)
^[49]	Perry PJ	X	81	≥55 years	Bioavailable testosterone not correlated with health and QoL assessments
^[50]	Potosky AL	X	661	≥40 years with prostate cancer	Androgen deprivation therapy associated with impotence and decline in vitality
^[51]	Basaria S	X	38 and 20	Prostate cancer and controls	Androgen deprivation therapy associated with lower BMD, higher fat mass, reduced upper body strength and poorer sexual function and QoL
^[52]	Dacal K	X	96	Prostate cancer	Androgen deprivation therapy associated with lower lean body mass, greater body fat and poorer QoL (SF-36)
^[53]	Spry NA	L	250	Prostate cancer	Intermittent androgen suppression: improved QoL during off-treatment period in parallel with recovery in testosterone levels
^[54]	Baumgartner RN	X	121	65-97 years	Muscle mass associated with ratio of TT/SHBG, physical activity, cardiovascular disease and insulin-like growth factor 1
^[55]	Iannuzzi-Sucich M	X	142	64-92 years	BMI, strength, power and bioavailable testosterone correlated with muscle mass.
^[56]	Schaap LA	X	623	65-88 years	TT levels correlated with muscle strength
^[57]	O'Donnell AB	X	684	55-85 years	Higher TT and bioavailable testosterone associated with increased physical performance
^[58]	Orwoll E	L	2587	65-99 years	Lower bioavailable testosterone levels associated with increased fall risk
^[59]	Fink HA	L	2447	≥65 years	Low TT associated with increased prevalence of osteoporosis on BMD criteria and higher incidence of rapid hip bone loss
^[60]	Meier C	L	609	> 60 years	Lower TT associated with increased incidence of fracture
^[61]	Ferrucci L	L	396	≥65 years	Lower testosterone levels associated with higher risk of developing anemia
^[62]	Penninx BW	X	443	≥65 years	Anemia associated with disability, poorer physical performance and lower muscle strength
^[63]	Mulligan T	X	2162	≥45 years	TT < 10.4 nmol l^-1 in over a third of men visiting primary care practices
^[64]	Gruenewald DA	R			98 references
^[65]	Liverman CT	R			Report by the Institute of Medicine
^[66]	Isidori AM	R			70 references
^[67]	Tracz MJ	R			29 references
^[68]	Svartberg J	X and I	281 and 38	60-80 years	Lower TT associated with higher weight and fat mass, and higher glucose, insulin and triglyceride levels. Intramuscular testosterone reduced fat mass and increased hip BMD
^[69]	Emmelot-Vonk MH	I	237	60-80 years with TT < 13.7 nmol l^-1	Oral testosterone therapy increased lean body mass, decreased fat mass but did not change mobility, muscle strength, cognitive function or BMD
^[70]	Behre HM	I	1700+	Hypogonadal men	Planned open-label observational study of testosterone gel therapy
^[71]	Araujo AB	L	1691	40-70 years	Prevalence of symptomatic androgen deficiency 6.0% at baseline and 12.3% after 8.8 years follow-up
^[72]	Araujo AB	X	1475	30-79 years	Prevalence of symptomatic androgen deficiency 5.6%
^[73]	Travison TG	L	1632	40-70 years	TT associated with libido
^[74]	Morley JE	X	148	23-80 years	ADAM and AMS questionnaires are sensitive (97 and 83%) but not specific (30 and 39%) for diagnosis of hypogonadism in older men
^[75]	Beutel ME	X	263	40-84 years	Low TT associated with reduced motivation and sexual desire in men attending andrological outpatient clinics
^[76]	Zitzmann M	X	434	50-86 years	Loss of libido may be present in men with TT in normal range
^[77]	Johannes CB	L	847	40-69 years	Incidence of erectile dysfunction 2.6% per year and increased with age from 1.2% in men 40-49 years to 4.6% in men 60-69 years
^[78]	Lyngdorf P	X	2210	40-80 years	Prevalence of erectile dysfunction increased with age from 4.5% in men 40-45 years to 52% in men 75-80 years
^[79]	Holden CA	X	5990	40-70+ years	Age-standardized prevalence of erectile dysfunction 21%
^[80]	Ahn TY	X	1570	40-79 years	Prevalence of erectile dysfunction 32.4% (IIEF questionnaire)
^[81]	Selvin E	X	2126	≥20 years	Prevalence of erectile dysfunction 18.4%, related to age and cardiovascular risk factors
^[82]	Chew KK	X	1580	20-99 years	Prevalence of erectile dysfunction 25.1% (IIEF questionnaire)
^[83]	Ahn HS	X	213	31-78 years	Free T correlated with erectile function (IIEF questionnaire)
^[84]	Basar MM	X	348	21-76 years	Free T and DHEAS lower in men with sexual dysfunction (IIEF score)
^[85]	Kupelian V	X	625	55-85 years	TT and bioavailable T were not associated with erectile dysfunction
^[86]	Chiang HS	I	38	Hypogonadal men	Transdermal testosterone gel improved IIEF scores
^[87]	Allan CA	I	60	≥65 years, TT < 15 nM	Transdermal testosterone patches improved sexual desire
^[88]	Isidori AM	R			92 references
^[89]	Swerdloff RS	R			91 references
^[90]	Krause W	R			46 references
^[91]	Aversa A	X	52	Impotence	Low free T may correlate with impaired relaxation of cavernous endothelial and corporeal smooth muscle cells to a vasoactive challenge
^[92]	Traish AM	R			161 references
^[93]	Greco EA	R			53 references
^[94]	Aversa A	R			21 references
^[95]	Shabsigh R	R			55 references

Abbreviations: BMD = bone mineral density; free T = free testosterone; QoL = quality of life; SHBG = sex hormone-binding globulin; TT = total testosterone.
Study type: I = interventional study; L = longitudinal; R = review or meta-analysis; X = cross-sectional.

Table 3. Studies of Testosterone and Risk of Cardiovascular Disease in Older Men
Reference	First author	Study	n	Sample	Results
^[97]	Esposito K	X	100	Metabolic syndrome	Men with metabolic syndrome had increased prevalence of erectile dysfunction compared with controls
^[98]	Thompson IM	L	4247	≥55 years	Incident erectile dysfunction associated with subsequent cardiovascular events
^[99]	Grover SA	X	3921	40-88 years	Cardiovascular disease and diabetes associated with erectile dysfunction
^[100]	Muller M	X	400	40-80 years	Higher TT and SHBG associated with higher insulin sensitivity
^[101]	Chubb SAP	X	2502	≥70 years	Lower SHBG and TT associated with metabolic syndrome
^[102]	Kupelian V	L	950	40-70 years	Lower TT and SHBG predicted development of metabolic syndrome in men with BMI < 25 kg m^-2
^[103]	Ding EL	R			129 references
^[104]	Selvin E	X	1413	≥20 years	Lower free T and bioavailable testosterone associated with prevalent diabetes
^[105]	Oh J-Y	L	294	55-89 years	Lower TT associated with incident type II diabetes
^[106]	Laaksonen DE	L	702	42, 48, 54 or 60 years	Lower TT and SHBG predicted development of metabolic syndrome and diabetes
^[107]	Grossmann M	X	580 and 69	Type II and type I diabetes	Low TT and free T common in men with diabetes
^[108]	Van den Beld AW	X	403	73-94 years	TT inversely related to carotid intima-media thickness
^[109]	Makinen J	X	239	40-70 years	Androgen-deficient men had higher carotid intima-media thickness
^[110]	Muller M	L	195	≥70 years	Free T inversely related to progression of carotid intima-media thickness
^[111]	Tivesten A	X	3014	69-80 years	Lower free T associated with ankle-brachial index < 0.90
^[112]	Hak AE	X, L	504	≥55 years	Higher TT and bioavailable testosterone associated with reduced prevalence and less progression of abdominal aortic calcification
^[113]	Kapoor D	X	198	Type II diabetes	Free T and bioavailable testosterone lower in men with erectile dysfunction
^[114]	Ma RC-W	L	2306	Type II diabetes	Incidence of coronary heart disease events higher in men with erectile dysfunction
^[115]	Giagulli VA	X	110	20-62 years	Obesity associated with lower SHBG and altered LH secretion
^[116]	Pitteloud N	X	21	25-65 years	Insulin resistance associated with decreased Leydig cell testosterone secretion in response to hCG
^[117]	Allan CA	R			98 references
^[118]	Allan CA	I	60	≥55 years, TT < 15 nM	Transdermal testosterone patches lessened visceral fat accumulation and increased fat-free mass
^[119]	Liu PY	R			405 references
^[120]	Allan CA	R			174 references
^[121]	Shores MM	L	858	> 40 years	Low testosterone predicted increased mortality
^[122]	Khaw K-T	L	825 and 1489	40-79 years, cases and controls	TT at baseline inversely related to mortality from all causes, cardiovascular disease and cancer
^[123]	Laughlin GA	L	794	50-91 years	Lower TT predicted increased mortality from all causes, cardiovascular and respiratory disease
^[124]	Smith GD	L	2512	45-59 years	Higher cortisol/testosterone ratio associated with incident ischemic heart disease
^[125]	Araujo AB	L	1686	40-70 years	Higher free T associated with ischemic heart disease mortality
^[126]	Arnlov J	L	2084	56±12 years	Higher estradiol associated with lower cardiovascular disease risk

Abbreviations: free T = free testosterone; LH = luteinizing hormone; SHBG; sex hormone-binding globulin; TT = total testosterone.
Study type: I = interventional study; L = longitudinal; R = review or meta-analysis; X = cross-sectional.

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