Testosterone deficiency in the aging maleRecent years have seen an increasing interest in the study of the aging male, with a particular interest in the problem of whether so-called rejuvenating hormones and, more specifically, androgens can improve quality of life, counteract androgen replacement therapy in the aging male skeletal muscle loss and strength, prevent falls and fractures, prolong independent living, and reduce the dependence on medical care. Almost a decade has elapsed androgen replacement therapy in the aging male the first studies on androgen supplementation in elderly men were published 12 and, in the view of the persisting controversies concerning this problem as well as the increasing public interest for rejuvenating hormones, it may be indicated to evaluate critically the clinical relevance of the relative androgen deficiency androgen replacement therapy in the aging male elderly males, the diagnostic criteria of androgen deficiency, as well as the risks and benefits of androgen supplementation in elderly men. Male hormone replacement therapy implies, of course, that elderly men have a significant deficit in male hormone. Therefore, the first question to be answered is whether the common occurrence of the age-associated decline of testosterone levels is inherent to the aging process and occurs also in healthy men or whether the observed decline is the consequence of intercurrent disease, obesity, stress, relative physical inactivity, medications, etc. Moreover, the circadian rhythm of plasma T levels, with higher levels in the morning than in the evening, is generally lost in elderly men 3. This is in clear distinction to the situation in postmenopausal women who all tren vs anavar fat loss clearly decreased estradiol levels. It is important to mention that this decrease, observed in cross-sectional studies, has now been confirmed by longitudinal studies 5 — 9.
Androgen replacement therapy in the aging male--a critical evaluation. - PubMed - NCBI
Recent years have seen an increasing interest in the study of the aging male, with a particular interest in the problem of whether so-called rejuvenating hormones and, more specifically, androgens can improve quality of life, counteract progressive skeletal muscle loss and strength, prevent falls and fractures, prolong independent living, and reduce the dependence on medical care.
Almost a decade has elapsed since the first studies on androgen supplementation in elderly men were published 1 , 2 and, in the view of the persisting controversies concerning this problem as well as the increasing public interest for rejuvenating hormones, it may be indicated to evaluate critically the clinical relevance of the relative androgen deficiency in elderly males, the diagnostic criteria of androgen deficiency, as well as the risks and benefits of androgen supplementation in elderly men.
Male hormone replacement therapy implies, of course, that elderly men have a significant deficit in male hormone. Therefore, the first question to be answered is whether the common occurrence of the age-associated decline of testosterone levels is inherent to the aging process and occurs also in healthy men or whether the observed decline is the consequence of intercurrent disease, obesity, stress, relative physical inactivity, medications, etc.
Moreover, the circadian rhythm of plasma T levels, with higher levels in the morning than in the evening, is generally lost in elderly men 3. This is in clear distinction to the situation in postmenopausal women who all have clearly decreased estradiol levels. It is important to mention that this decrease, observed in cross-sectional studies, has now been confirmed by longitudinal studies 5 — 9.
However, the androgen deficiency in elderly men is generally moderate; therefore, some authors have suggested the term partial androgen deficiency in the aging male PADAM.
Others, in analogy with the term menopause in women, use the term andropause, although distinct from women in menopause, elderly men retain their reproductive capacity. Although the decrease in F T levels occurs in healthy elderly men, it is evident that sequelae of intercurrent disease 10 , medication, environmental, psychosocial, and socioeconomic factors accelerate this age-associated decrease.
Recently, the important role of abdominal obesity in the age-associated decrease of T levels has been stressed 10 — Androgens have many physiologic actions, but does the age-associated decrease in F T levels have clinical significance, and does it indicate hypogonadism?
Evidence for the clinical significance could be provided by the eventual similarity between signs and symptoms of aging and androgen deficiency, respectively, in young men, the existence of a significant correlation between symptoms and F T levels, and the eventual beneficial effect of androgen supplementation in elderly men with low T levels.
Similarity of signs and symptoms of aging and androgen deficiency, respectively, in young men. The age-associated decrease in muscle mass and strength, energy and work capacity, body hair, and hematopoiesis; the decrease in sexual drive and activity, bone mass, and cognitive function; the decline of memory and of the sense of general well being; the difficulties in concentration; and the increase in abdominal fat mass are reminiscent of the symptomatology of androgen deficiency.
However, these symptoms are multifactorial in origin; aging is accompanied by a decrease of almost all physiological functions and, as far as the endocrine system is concerned, by a decrease not only of gonadal and adrenal androgen secretion but also of GH secretion. Moreover, the age-associated decrease in physical activity is partly responsible for the decrease in muscle mass and bone mineral density BMD Hence, it is not surprising that the correlation between aging symptoms and T levels is often rather poor.
Correlation between aging symptoms and F T levels. Whereas the age-associated decrease of BMD with an exponential increase in bone fracture rate with age 14 , 15 is well established, the role of the partial androgen deficiency in aging males in this decrease remains to be established Indeed, available data are equivocal, some studies showing a significant, albeit weak, association between FT levels and BMD at some but not all bone sites 13 , 17 , 18 , whereas others did not find any correlation 19 — Recently, several large-scale studies, involving several hundreds of elderly men 22 — 24 , found bio-T to be significantly associated with bone density at radius, spine and hip; however, the correlation with bioestradiol, the levels of which decline in elderly males, was even stronger, suggesting that part of the androgen effects on bone are at least partially indirect, mediated via their aromatization On the basis of these recent large-scale studies it seems reasonable to accept a role of the decreased T levels in the age-associated osteopenia.
Aging is also accompanied by a increase in abdominal fat mass and a decrease of muscle mass. We 27 as well as Seidell et al. Visceral fat accumulation is highly significantly associated with increased risk of cardiovascular disease, impaired glucose tolerance, and non-insulin-dependent diabetes mellitus syndrome X 30 , Whether the abdominal obesity is the consequence of the low T levels or vice versa is not clear. The age-associated decline in muscle mass 12 kg between 20 and 70 yr of age , which is most pronounced for the fast twitch type II fibers 32 , is a major contributor to the age-associated decline in muscle strength and early onset of fatigue 33 and a strong predictor of falls, fractures, and loss of independent living.
In fact, maximal muscle strength correlates with muscle mass independently of age Whereas van den Beld et al. It should be stressed that although a correlation exists between the lower T concentration and reduced muscle function in older men, T is not the only factor responsible for the age-associated muscle loss. The prevalence of atherosclerosis in men increases spectacularly with aging. Nevertheless, the vast majority of cross-sectional studies show a positive correlation between FT levels and HDL-C 39 — 41 and a negative correlation with fibrinogen, plasminogen activator inhibitor-1 42 , and insulin levels as well as with coronary heart disease 43 , 44 , but not with cardiovascular mortality 45 — However, the correlation between T levels and HDL-C and insulin sensitivity is only observed within the physiologic male concentration range of T 48 , Androgen blockade by GnRH leads to an increase of HDL-C and, to a lesser extent, of total cholesterol, the effect of which is neutralized when T enanthate was injected in parallel, to maintain physiological T concentrations 48 , whereas supraphysiological T levels induce an increase in low density lipoprotein cholesterol LDL-C and a decrease of HDL-C 40 Moreover, it should be realized that, beside the effects on lipids, T has direct effects on several vasoactive factors such as endothelin 50 , prostacyclin, and thromboxane A 2 The inverse correlation between T levels and the severity of coronary artery disease as reported by Phillips et al.
As to the role of the age-associated decline in T levels in the highly negative correlation between sexual desire, arousal, activity, and age, Schiavi 53 reported that men desiring intercourse with a greater frequency than once a week, had higher T levels than men with lower frequency. Moreover they observed 54 that men with the primary diagnosis of hypoactive sexual desire had significantly lower T levels than controls.
Similarly, Pfeilschifter et al. However, other authors 57 , 58 did not observe any correlation between plasma T levels within the normal range and sexual activity. Moreover, it is known that healthy males have much higher T levels than required to maintain sexual function, although Schiavi 53 as well as Bancroft 59 suggested that circulating androgen levels in elderly men might be insufficient to sustain nocturnal penile tumescence and adequate sexual function.
As to erectile dysfunction, which increases dramatically with age, whereas androgens, acting both centrally and peripherally 60 are essential for normal penile erection and T-stimulating nitric oxide synthesis in the corpora cavernosa 60 , 61 , androgen deficiency is rarely the major cause of impotence in elderly males, although it may play a subsidiary role.
There is good evidence that, whereas nocturnal penile tumescence is androgen dependent, erection in response to visual erotic stimuli is androgen independent Finally there is good evidence for a strong correlation between T levels and cognitive performance such as spatial abilities or mathematical reasoning 64 , 65 , findings which were confirmed in Western and non-Western groups of healthy males Studies addressing correlations between T levels and cognitive functions specifically in elderly man are not available.
As to the role of T in the depressed mood frequently observed in elderly men, whereas data in the literature are rather divergent [for review see Christiansen 66 ], a recent large study by Barrett-Connor et al.
In summary, many aging symptoms in men are suggestive of androgen deficiency and, in fact, there frequently exists a weak correlation of these signs with plasma T levels; many, but not all, studies show the persistence of these correlations after correction for age. Nevertheless, it should be kept in mind that most of the aging symptoms are multifactorial in origin and that the age-associated decrease in GH levels might play an important role in the symptomatology 68 , because symptoms of GH deficiency in young men and the symptoms of aging again show a striking similarity; decrease in muscle mass, increase in abdominal fat, thinning of the skin, asthenia, and adynamia.
Aside from a decrease in the secretion and plasma levels of T, aging is accompanied by a decrease of the plasma levels of the major adrenal androgen, dehydroepiandrosterone sulfate DHEAS. Does this decrease have clinical significance?
Functional parameters of daily living in the oldest males were reported to be lowest in men with the lowest DHEAS levels 72 , whereas data of Abassi et al.
Moreover, it has been reported that men with low DHEAS levels would be at higher risk of cardiovascular mortality within the next 2 yr 74 , 75 , but this has not been confirmed 76 , Diagnosis of androgen deficiency in elderly males. As the clinical symptoms of hormone deficiency in elderly males are rather vague and aspecific and as a substantial number of elderly men have F T levels within the normal range for young adults, we can state that hormone replacement therapy HRT is only warranted in the presence both of clinical symptoms suggestive of hormone deficiency and of decreased hormone levels.
Moreover, eventually present primary causes of the decreased androgen levels should be adequately treated before starting HRT. How do we define hypogonadism in elderly males?
Clinical signs of relative androgen deficiency in elderly men most easy to objectify are a decrease of muscle mass and strength, a decrease of bone mass and osteoporosis, and an increase in central body fat. Other signs such as a decrease in libido and sexual desire, forgetfulness, loss of memory, difficulty in concentration, insomnia, as well as a decreased sense of well being are rather subjective impressions that are more difficult to measure and differentiate from hormone-independent aging.
As to subnormal F T levels, it should be realized that it is still unknown whether the requirements of elderly males are identical with the requirements of younger men. There is some evidence for increased sensitivity to androgens in elderly males, for example, at the level of the feedback system 82 — 85 , whereas several 86 — 91 , but not all 92 , 93 , studies show a decrease of the androgen receptor AR concentration in tissues of elderly animals and men, suggesting a saturation of the receptor sites at a lower T concentration and a decrease of the maximal genomic effect of T.
The latter appear to decline more rapidly in subjects with a lower number of CAG repeats 7. This is possibly the consequence of a higher androgen sensitivity; a large number of CAG repeats as in the Kennedy syndrome are accompanied by androgen resistance and increased T levels.
Moreover, even in the young men, it is not clear whether T concentrations in the normal range are required for full androgenic effects in the different androgen-responsive organs.
It has been reported repeatedly that T levels at half the concentration found in young males, are appropriate for sustaining normal libido and sexual activity In fact, there is no clinically useful biological parameter reflecting androgen activity. It has been suggested that SHBG capacity might be such a parameter 95 but, whereas the decrease of SHBG after T treatment indicates androgen activity, a single basal SHBG level is difficult to interpret; the level is determined by several hormonal and nonhormonal factors, such as GH, insulin, thyroid hormones, obesity, and medications.
It should be realized, finally, that normal hormone levels do not imply per se normal physiological effects; indeed, the interaction of the ligand with the hormone receptor as well as the presence of coactivators and coinhibitors will determine the biological effects.
Because there is no generally accepted cut off value of plasma T for defining androgen deficiency, and in the absence of convincing evidence for an altered androgen requirement in elderly men, we consider the normal range of F T levels in young males also valid for elderly men. Most authors use rather similar values 1 , 2 , 9 , 13 , 97 , It should be mentioned that direct FT assays using a T analog, do not yield a reliable estimate of FT The age-associated decline in F T levels has both a testicular decreased Leydig cell number and central origin, the latter being characterized by a decrease in the amplitude of LH pulses in elderly men.
Hence, many elderly men have normal LH levels and we do not consider an increase in LH levels to be required for the diagnosis of hypogonadism in elderly men As already mentioned, in the absence of a reliable, clinically useful biological parameter of androgen action, these criteria of hypogonadism of the aging men are somewhat arbitrary.
The treatment aims at restoring hormone levels in the normal range of young adults and, more importantly, at alleviating the symptoms suggestive of the hormone deficiency. However, the ultimate goals are to maintain or regain the highest quality of life, to reduce disability, to compress major illnesses into a narrow age range, and to add life to years.
There is no doubt that in young androgen-deficient men T supplementation increases fat free mass and muscle strength and decreases body fat, with improvement of insulin sensitivity 98 — Androgens induce their specific response via the AR, which regulates the androgen-responsive target genes. Following androgen treatment, Sheffield-Moore et al. Androgen administration to healthy older men increased insulin-like growth factor 1 messenger RNA; decreased the concentration of the inhibitory insulin-like growth factor binding protein 4 ; and, increasing protein synthesis 99 , — , induced myotrophic effects in skeletal muscle , Also Urban et al.
A recent study of Snyder et al. Muscle power, defined as the rate of power development is strongly correlated to performance of functional activities such as rising from a chair, stair climbing, etc. As to osteoporosis, all studies show that in hypogonadal men androgen supplementation increases bone mass , , , , although normal adult bone mass is not reached Again, the effects in elderly men are less convincing.
However, neither Orwoll and Klein 14 nor Sih et al. On the other hand, it is evident that morbidity of osteoporosis relates essentially to hip fractures! It may be of interest to mention that in orchidectomized aged rats, the threshold concentration of T, necessary for prevention of loss of both bone and LBM is clearly lower than for prostate and seminal vesicles Whether this applies also to the aged man requires further research, but would explain that the effects of T on BMD of elderly men, are limited to men with clearly decreased F T levels.
Finally, HRT only makes sense when other causes of osteoporosis, such as insufficient calcium or vitamin D intake have been excluded As to the effects of T replacement on sexual activity, the effects in young hypogonadal men are spectacular 98 , , , but supraphysiological doses of T administered to young healthy men for contraceptive purposes did apparently not affect frequency of intercourse, kissing, or fondling Interestingly, Carani et al.
Most authors 98 , , observed that androgen substitution in hypogonadal males improved mood, energy, sense of well being, and friendliness, whereas T levels were negatively correlated with nervousness and irritability. Similarly in elderly males, androgen replacement therapy has been reported to increase the sense of well being 2 , , Androgen supplementation in elderly hypogonadal men improves also spatial cognition 1 , and verbal fluency , , but no effect was seen on memory As to the influence on plasma lipids, atherosclerosis, and cardiovascular disease, it is well known that administration of T to surgically or chemically castrated males, or female to male transsexuals , as well as supraphysiological T levels in men 40 , — induce a decrease of HDL-C and an increase of triglyceride levels.
But administration of mg T im once per week for 6 months to young healthy men resulted in a decrease of total and LDL-C, as well as in a slight, nonsignificant decrease of HDL-C and in a decrease of lipoprotein a levels Most 1 , 2 , , , but not all , studies on androgen replacement in elderly men report a fall in total and LDL-C, with no significant effect on HDL-C and an improvement of insulin sensitivity , — Moreover, a tendency to a fall of arterial blood pressure has been reported The mechanism of this fall in lipids might be related to the decrease in the visceral abdominal fat mass under the influence of androgens, which inhibit lipoproteinlipase activity and increase lipolysis , with improvement of insulin sensitivity and mobilization of triglycerides from abdominal fat tissue