In primary care practice, it is not unusual to encounter male patients in their 50s or older who report having loss of libido, erectile dysfunction, fatigue, and depression.
Such signs and symptoms may signal an age-related decline in androgen levels, which commonly begin after age 40.
The term andropause refers to a state of lowered androgen levels.
Androgens are a group of hormones that include testosterone, dehydroepiandrosterone, and androstenedione, among others.
There is undeniable evidence that aging results in a lowering of androgen levels.
Testosterone is produced by fetal testes as early as the first trimester.
Levels in adult males peak at about age 20 years and gradually decline thereafter.
Total testosterone declines at the rate of 3.82 nmol/L (110 ng/dL) per year, typically after age 40.
Levels of bioavailable testosterone decline much more dramatically.
Bioavailable testosterone is thought to be the "active" component of androgen acting directly at the cellular level.
It consists of free testosterone and that loosely bound to sex hormone-binding globulin (SHBG).
Binding with SHBG increases with the aging process and hence decreases the available free testosterone.
On the basis of total testosterone measurements, 20% of men older than 55 years are hypogonadal.
However, when bioavailable testosterone levels are measured, 50% of men older than 50 years are defined as hypogonadal.
Overall, the impact of aging on testosterone is negative.
Hypogonadism (i.e., low testosterone level) that occurs with aging is the result of both primary gonadal failure and hypothalamic-pituitary failure.
Primary hypogonadism involves a decrease in the number of Leydig's cells, reduction of testosterone production, and decreased secretion of testosterone in response to the stimulation of human chorionic gonadotropin.
Because the decline in androgens is gradual, the term androgen decline in aging males (ADAM) has been used to describe this phenomenon.
Alternatively, partial androgen decline in aging males has also been suggested because the androgen deficiency in older men is generally moderate and not a complete deficiency.
Symptomatic hypogonadism is sometimes referred to as the andropause syndrome.
As in menopause, symptoms may be present or absent in andropause.
Transitory symptoms include mood changes (e.g., decreases in energy level and feeling of well-being) and changes in sexual function.
Potential long-term effects of hypogonadism include osteoporosis, muscle atrophy, and cognitive changes.
In the study involving 302 men (most older than 60 years), the dominant symptoms were loss of libido and erectile dysfunction (46%), fatigue (41%), and memory loss (36%).
The correlation of symptoms to levels of testosterone is highly variable and is the subject of ongoing investigation on relative hypogonadism.
Androgen Levels and Androgen Deficiency
Bone Mineral Density
With aging, there is an exponential increase in bone fracture rate, which shows a clear association with the age-related decrease of bone mineral density.
In view of the significance of sex steroids in the maintenance of bone mineral density at all ages, the question whether the partial androgen deficiency in aging males plays an important role in the decrease of bone mineral density is pertinent.
Some studies find a significant, although weak, correlation between androgen levels and bone mineral density at some but not all bone sites; others are unable to establish a correlation.
There are some recent large-scale studies of several hundreds of elderly men; they demonstrated that bone densities at the radius, spine and hip are correlated with levels of bioavailable testosterone.
Interestingly, the correlation with levels of bioavailable estradiol was much more prominent, probably pointing to the significance of estrogens in men, also in old age.
Levels of bioavailable testosterone correlated with all regions of proximal femur bone mineral density and total body bone mineral density, after adjustment for age.
In summary, the relevance of androgens (both in their own right and as precursors for the formation of estrogens) in age-associated osteopenia seems clear on the basis of these recent large-scale studies.
The aging process seriously affects body composition.
Aging is almost universally accompanied by an increase in abdominal fat mass and a decrease of muscle mass.
Androgens have a substantial impact on muscle mass and on fat distribution, and therefore the relationships between these signs of aging and testosterone levels have been researched.
Several studies have convincingly documented an inverse correlation between abdominal fat mass and free testosterone levels.
This correlation appeared to be independent of age.
This finding has clinical relevance: the amount of visceral fat is highly significantly associated with an increased risk of cardiovascular disease, impaired glucose tolerance and non-insulin-dependent diabetes mellitus.
Whether the abdominal, and more specifically visceral, obesity is the consequence of the low testosterone levels, or, vice versa, whether visceral obesity induces low plasma levels of testosterone, is not yet clear.
It is clear, however, that visceral obesity leads to a decrease of testosterone levels, mainly via a decrease in SHBG levels; hyper-insulinemia associated with visceral obesity suppresses SHBG levels, leading, in the first instance, to higher quantities of free testosterone, which are subsequently rapidly metabolized since the half-life of free testosterone in the circulation is short (15-20 mm).
In morbid obesity (body mass index > 35 kg/m2), there is also a decrease of free testosterone.
There is an impressive age-associated decline in muscle mass (12 kg between the age of 20 and 70 years).
This loss of muscle mass is a major contributor to the age-associated decline in muscle strength and of fatigue.
Maximal muscle strength shows a correlation with muscle mass, independent of age.
This is again related to the occurrence of falls, fractures and the consequent limitations on independent living.
The correlation between testosterone levels and muscle mass appears stronger than the correlation with muscle strength.
It must be concluded that the correlation between testosterone levels and muscle mass is readily demonstrable whereas the relation with muscle strength is apparently less firm and could not be demonstrated in all studies.
Factors other than androgens, such as growth hormone, probably play a significant role.
Premenopausal women suffer significantly less from cardiovascular disease than men, and traditionally it has been thought that the relationship between sex steroids and cardiovascular disease is predominantly determined by the relatively beneficial effects of estrogens and by the relatively detrimental effects of androgens on lipid profiles.
Nevertheless, the vast majority of cross-sectional studies in men are not in agreement with this assumption; they show a positive correlation between free testosterone levels and those of high-density lipoprotein (HDL) cholesterol and a negative correlation between free testosterone and with fibrinogen, plasminogen activator inhibitor-146 and insulin levels as well as with coronary heart disease, but not with cardiovascular mortality.
Recent research shows that the effects of sex steroids on biological systems other than lipids, such as fat distribution, endocrine/paracrine factors produced by the vascular wall (such as endothelins, nitric oxide), blood platelets and coagulation, must also be considered in the analysis of the relationship between sex steroids and cardiovascular disease.
Premenopausal women, in comparison to men, are protected against cardiovascular disease, this protection being ascribed to the cardioprotective effects of estrogens.
It is, then, paradoxical that, in cross-sectional studies of men, elevated levels of estrogens and relatively low levels of testosterone appear to be associated with coronary disease and myocardial infarction.
Some studies in aging men have shown results that seem to contradict the overall notion that androgens, by their action on lipid profiles, increase the risk for coronary artery disease.
In a study of geriatric male patients who had suffered a myocardial infarction, it was found that these patients had testosterone levels at a low threshold level.
These studies suggest the intriguing possibility that, in spite of the overall negative effects of androgens on lipid profiles, a lower-than-normal androgen level in aging men is associated with an increase of atherosclerotic disease.
The explanation may lie in the fact that a complex of risk factors for cardiovascular disease, termed syndrome X or the metabolic syndrome (comprising hypertension, insulin resistance, hypertriglyceridemia and visceral obesity), is associated with low testosterone levels.
The first a result of studies in which testosterone was actually administered to mildly hypogonadal aging men did not indicate negative effects on lipid profiles.
Administration of testosterone enanthate (100 mg per week) for 3 months to 13 healthy elderly men (with low serum total and non-sex hormone binding globulin-bound testosterone levels) decreased total and low-density lipoprotein (LDL) cholesterol without affecting levels of HDL cholesterol.
Age-related changes in sexuality
Reliable studies on the relationships between androgens and psychological functions are of rather recent date.
There is now solid evidence that androgens stimulate sexual appetite.
With regard to erectile function, the situation is somewhat less certain.
It has become clear that, in males between 20 and 50 years, approximately 60-80% of the normal physiological levels suffice to maintain sexual function and that increasing testosterone levels above that threshold adds little to sexual functioning.
Whether this holds true for aging men remains to be established.
Investigators have suggested that circulating androgen levels in elderly men might be insufficient to sustain nocturnal penile tumescence and adequate sexual function.
It is evident that a multitude of factors impact on sexual functioning at all ages but certainly in old age.
Testosterone is one of these factors.
Aging is generally associated with a decline in sexual desire, arousal and activity.
The studies on the relationship between testosterone levels and sexual functioning in old age are certainly not unanimous.
Men who desired intercourse with a greater frequency than once a week had higher testosterone levels than men with a lower frequency.
Men with the primary diagnosis of hypoactive sexual desire had significantly lower testosterone levels than controls.
It has also been reported that men with a greater sexual activity had higher bioavailable testosterone levels than men with a lower frequency.
The age-related decrease of androgens may be a factor in the decline in male sexuality.
The relationship between erectile dysfunction and androgens is more difficult to establish.
The occurrence of erectile dysfunction increases dramatically with age.
Physiologically, testosterone acts primarily on the brain, increasing sexual appetite, but animal experimentation shows that androgens stimulate nitric oxide synthesis in the corpora cavernosa.
Erectile dysfunction, particularly when associated with a normal libido, is only rarely explained by androgen deficiency.
Androgens and cognitive performance
There is some evidence to suggest that testosterone may influence performance on cognitive tasks.
The finding that testosterone administration to older men enhances performance on measures of spatial cognition supports this.
The correlation between testosterone levels and cognitive performance, such as on spatial abilities or mathematical reasoning, has been confirmed in western and non-western cohorts of healthy males.
Testosterone has also been associated with general mood-elevating effects.
Some studies have found associations between lowered testosterone levels and depressive symptoms.
Depression is not rare in aging men and impairs their quality of life so the effects that declining levels of androgens may have on mood and on specific aspects of cognitive functioning in aging are well worth researching.
Androgen Supplementation in Elderly Men with Subnormal Testosterone Levels
As indicated above, observational studies of aging provide clues that androgen deficiency might be a factor underlying the clinical signs and symptoms of aging.
Such studies are correlational in nature, and the strength of the correlation might provide evidence for the clinical significance of the correlation.
Intervention studies are required to provide final proof of the clinical relevance of the age-related decline of androgen levels in men.
Beneficial effects of androgen supplementation in elderly males have indeed been reported, but it must be remembered that the number of well-designed and well-controlled studies is still small; the number of patients included in such studies has been limited to a few hundreds.
Thus, conclusions are still preliminary.
Testosterone replacement in young, androgen-deficient men almost never fails to have impressive clinical effects.
Testosterone supplementation induces or restores virilization and sexual functioning, increases free fat mass and muscle strength, and decreases body fat, with improvement of insulin sensitivity.
Androgens induce their specific response via the androgen receptor, which regulates the androgen-responsive target genes.
Following androgen treatment, an increase in androgen receptor mRNA in healthy young men is observed.
In older men, 1 month of androgen treatment increased androgen receptor transcription, although with a return to base-line levels after 6 months.
Androgen administration to healthy older men increased insulin growth factor (IGF)-1 mRNA and decreased the concentration of the inhibitory IgF binding protein 475.
While increasing protein synthesis, androgens produced myotrophic effects in skeletal muscle mass.
Androgen supplementation to elderly men, generally at a dose of 200 mg/2 weeks of testosterone enanthater, led to a significant, albeit often modest, increase in muscle mass (± 2 kg) 55 and/or arm circumference, and generally of grip strength.
Fat mass generally decreased, but not to a large extent.
One study reported that testosterone administration to elderly men increased not only muscle mass but also skeletal muscle strength.
By contrast, the other study noted an increase in lean body mass but without increase in strength of knee extension or flexion, whereas the third one after a 12-week administration of testosterone found neither an increase of lean body mass nor of muscle strength.
Although muscle strength is an important aspect of muscle function, it is not the most important.
Muscle power, defined as the rate of power development, is a better indicator than muscle strength of performance of functional activities, such as rising from a chair, or stair climbing.
An increase in muscle power, more specifically of the lower limb muscles, would be more meaningful for aging subjects, since it improves their mobility and stability and prevents falls and, hence, fractures.
With regard to bone mass and osteoporosis, all studies of truly hypogonadal men show that androgen supplementation increases bone mineral density, although normal adult bone mass is not attained.
Also, in men with osteoporosis with reasonably normal testosterone levels, testosterone esters (250 mg/2 weeks) still increased bone mineral density.
But the effects in elderly men are less convincing than in young hypogonadal men.
Most studies report an improvement of biochemical indices of bone formation rather than of bone mineral density itself.
The beneficial effects of androgens on bone mineral density of elderly men are limited to men with clearly subnormal testosterone levels.
It is further of note that androgen deficiency is one of the causal factors in osteoporosis and its beneficial effect will only become manifest when other causes of osteoporosis, such as insufficient intake of calcium or vitamin D, have been remedied.
The effects of testosterone replacement on sexual activity in young hypogonadal men are, as a rule, impressive, but there is no dose-effect relationship.
Supraphysiological doses of testosterone administered to young healthy men for contraceptive purposes did not affect the frequency of intercourse, kissing or fondling.
Testosterone enanthate weekly injections to normal men showed a significant increase in sexual interest, awareness and arousability, which were, however, not reflected in modification of overt sexual behavior, which, they suggest, may be more determined by social factors.
However, there is a threshold level of testosterone above, which there is no further enhancement of response.
Testosterone levels were negatively correlated with nervousness and irritability, and several authors have observed that androgen substitution in hypogonadal males improved mood, energy, sense of well-being and friendliness.
These significant correlations with testosterone levels were only observed when testosterone levels were below the normal range, which suggests that, once a minimally adequate testosterone/dihydrotestosterone ratio was achieved, further increase did not further contribute to improvement of mood in elderly males, androgen replacement therapy has been reported to increase the sense of well-being.
Androgen supplementation in elderly hypogonadal men reportedly improves spatial cognition and fluency, but no effect was seen on memory.
There is now solid evidence that statistically a decline of (free) testosterone levels occurs in aging men.
Yet many men will continue to have normal reference values of testosterone, so androgen deficiency in old age is by no means the rule.
But, while a large number of men continue to have normal testosterone levels well into high age, a smaller proportion is androgen-deficient and their quality of life might be improved with androgen supplementation.
The identification of aging men with androgen deficiency remains a difficult problem in routine clinical practice.
Aging men often show clinical signs of hypogonadism (loss of muscle mass/strength, reduction in bone mass and an increase in visceral fat).
These manifestations might indicate androgen deficiency but often-normal plasma testosterone levels are found.
A theoretical question is whether there is an impairment of the biological action of androgens in target organs in old age explaining the discrepancy between signs and symptoms of androgen deficiency in old age on the one hand and the laboratory findings on the other.
In order to let aging testosterone-deficient men benefit from androgen supplementation, their identification should be guided by clinical signs of androgen deficiency: loss of lean body mass and bone mass, increase in (visceral) fat mass, and a decline in psychological and sexual functioning.
These might point to not only a fall but (also) an impairment of the biological action of androgens in target organs.
Meanwhile, a role for estrogens in men has become clear.
Positive effects of estrogens have been noted on bone and the cardiovascular system, and possibly adverse effects on prostate stromal hyperplasia.
The first small-scale studies of androgen supplement administration in aging men were not disappointing.
Risks of prostate and cardiovascular disease are probably lower than anticipated.
For the treatment of postmenopausal women, 'designer estrogens' are being developed; similarly, 'designer androgens' retaining beneficial anabolic effects, with elimination of potentially harmful effects on the prostate and cardiovascular system, could be devised.