Androgen deficiency in aging men is a condition in which low levels of testosterone in an older man is associated with a decreased in sexual satisfaction or decline in a feeling of general well-being. Cross-sectional and longitudinal studies have demonstrated that testosterone levels at the rate of approximately 1% per year after the age of 30 years. Because of the increased of sex hormone-binding globulin (SHBG) levels with aging, there is an even greater decline in the free of bioavailable testosterone levels with aging.
The Pathophysiology Of Late-Onset Hypogonadism
In young men, the most common form of hypogonadism is testicular failure characterized by a decrease in testosterone and an increase in luteinizing (LH). In older people, testosterone levels decreases, but rarely to the level seen in primary hyogonadism in young men. The decrease is associated with only a small increase in LH, except late in life. The prevalence of hypogonadism has been estimated to be between 2% to 5% at 40 years of age and 30% to 70% by 70 years of age. It is estimated that at least 5 million men in the United States have hypogonadism, with less than 10% receiving hormone replacement.
The causes of late-life hypogonadism are multifactorial. Defects have been shown to occur at the level of gonadotrophin-releasing hormone (GnRH) pulse generator in the hypothalamus, the pituitary, and the testes. With aging, there is a decrease in Leydig cells and the testicular response to stimulation with human chorionic gonadotrophin. The negative feedback of testosterone at the pituitary level increases with aging. There is a decrease pulse generation of GnRH, with the pulses being generated more chaotically. It is the combination of these factors that leads to the age-related decline in testosterone level. In addition, with aging the normal circadian rhythm of testosterone secretion is lost.
Testosterone circulates in a free form and bound to albumin, and SHBG. In general, it is believed that the testosterone that is free and bound to albumin is available to tissues (bioavailable), whereas that bound to SHBG is not capable of entering tissues. With the aging, an increase in SHBG decreases the amount of bioavailable testosterone.
Biochemical Determination Of Testosterone
Many authorities believe that especially with the older person, free of bioavailable (albumin-bound + free) testosterone should be obtained.
Testosterone And Sexuality
In general, it is believed that the testosterone is a primary driver of libido. People with a low libido, generally have lower testosterone levels than those with a normal libido, but there is a marked overlap in testosterone levels in people with normal and abnormal libido. Hajjar and colleagues showed that testosterone replacement leads to a marked increase in libido. A meta-analysis has confirmed that testosterone increase enthusiasm for sex and sexual activity.
Testosterone levels are particularly low in people with diabetes mellitus and a low libido, and erectile dysfunction is commonly associated with diabetes.
The prevalence of erectile dysfunction (ED) is difficult to estimate because of the assumed under reporting of the problem. Various age-dependent estimates have been made from population-based studies. Pinnock and colleagues reported that erections inadequate for intercourse affected 3% of men in their 40s, and increased to 64% of men in their 70s, based on an Australian community sample. In another Australian sample of consecutive male attendees to general medical practices, Chew and coworkers reported the prevalence of complete ED to be 2% of men in their 40s, and 50% of men in their 70s. Data on the incidence of ED form the Massachusetts Male Aging Study reported an increase from 12.4 cases per 1000 man-years for men in their 40s to 29.8 per 1000 man-years for men in their 50s, and 46.4 per 1000 man-years for men in their 60s.
Associations between serum testosterone levels and ED have not been clear in epidemiologic studies. Serum free-testosterone concentrations correlate with impaired relaxation of cavernous endothelial and corporeal smooth muscle in response to vasoactive challenge, independent of age. Factors that may be associated with both ED and low T levels include determinants of health (age, education, occupation, and ethnicity), behavioral and lifestyle (quality of life, alcohol intake, smoking, diet, and physical activity), clinical (diabetes, heart disease, hypertension, and drug therapies), and psychological factors, including depression and anxiety. There is a strong positive relationship between ED and cardiovascular risk factors and depression (the probability of ED is 90% in men who have severe depression, but only 25% in men who have mild depression). The causal relationship is unclear and possibly occurs through mechanisms involving reduced testosterone levels. A longitudinal study of the evolution of ED, associated factors, and comorbidities will provide this much needed data.
Prostate volume was not significantly related to circulating testosterone levels, but increase with increasing age and body mass index and decrease with increasing levels of SHBG in African Americans men. Neither elevated testosterone nor dihydrotestosterone predisposes men to BPH.
In animal studies, androgen deprivation alters the functional responses and structure of erectile tissue. Penile tissue possesses high concentrations of locally synthesized androgens and thus androgen-dependent functions need not reflect circulating androgen levels. It is well documented in rats that testosterone is required for adequate function of nitric oxide synthase, which produces nitric oxide necessary for relaxation of cavernosal endothelial and corporeal smooth muscle resulting in erection.
In the absence of significant hypogonadism, testosterone treatment does not have an effect on erectile function but it does improve the response to Viagra. Aversa and colleagues showed that in men who had erectile dysfunction, low free testosterone levels, independent of age, correlated with impaired relaxation of cavernous endothelial and corporeal smooth muscle cells. Moreover, a follow-up study in men who had arteriogenic erectile dysfunction, testosterone levels in the lower quartile of the normal range, and who were nonresponsive to Viagra treatment after six attempts, demonstrated that one month of transdermal testosterone supplementation improved erectile response to Viagra. Several studies have suggested enhanced strength or maintenance of erections following testosterone replacement in older men.
Furthermore, a meta-analysis of the usefulness of androgen replacement for erectile dysfunction showed that testosterone-treated patients improved significantly more that placebo-treated patients and those patients with primary testicular failure responded better to treatment than those with secondary testicular failure.
Skeletal Muscle Mass And Strength
Muscle mass decreases and fat mass increases with increasing age. In the New Mexico Ageing Process Study, the best predictor of loss of muscle and strength (sarcopenia) was free testosterone. Other predictors include age, caloric intake, physical activity, and insulin like growth factor – (IGF) 1. Sarcopenia leads to frailty, an important precursor of subsequent functional deterioration and death. Frailty has been defined objectively by the criteria of weight loss, exhaustion, weakness (grip strength), slow walking speed, and low physical activity. Several hormones are believed to play a role in the pathophysiology of frailty. People who have diabetes mellitus are at high risk for developing premature frailty. Weight loss, which can be because of sarcopenia, anorexia, cachexia, or dehydration, is a hallmark of frailty. In men, obesity, particularly when the fat is distributed within the abdomen (visceral), is associated with low plasma testosterone. Conversely, decreased testosterone levels in men are associated with increased accumulation of visceral fat and are reversible on testosterone administration.
Van de Beld and coworkers are reported inverse cross-sectional associations between total, free, and bioavailable testosterone and total fat mass in 403 community-dwelling men aged 73 to 94 years. Moreover, both total and bioavailable testosterone were positively associated with handgrip strength. Denti and colleagues showed an age-independent, inverse association between SHBG and whole body fat percentage estimated from four skinfold measurements using the Durin-Wormsely and Siri equations in 206 healthy volunteers aged 18 to 95 years. In a longitudinal study it was shown that people who have lost muscle mass but remain obese (sarcopenic obesity) have an extremely high rate of future disability and death. It has been shown that sarcopenia is strongly related to the loss of hormones, such as testosterone and IGF-1, and to mild increases in cytokines, such as TNF-a and IL-6. Other causes of sarcopenia include diminished neuronal input to muscle, decreased food intake (particularly protein and creatine), and peripheral vascular disease.
Low levels of gonadal steroids and changes in the activity of the IGF axis therefore may be markers of the metabolic syndrome associated with increasing age, visceral obesity, impaired glucose tolerance and insulin signaling, and cardiovascular disease, resulting in accelerated frailty and death.
Changes in the IGF/insulin signaling pathway with aging are likely to play a central role in regulation of skeletal muscle mass. Skeletal muscle is responsible for the production of 25% of circulating IGF-1. There are two muscle isoforms, one similar to liver IGF-1 and the other (IGF-IEc) mechanogrowth factor (MGF-1), having local actions on muscle. Exercise (stretch) leads up to regulation of the mRNA for both muscle isoforms and reduced muscle IGF-1 signaling leads to muscle atrophy. Hormones (growth hormone, testosterone, insulin, and vitamin D) and exercise regulate muscle IGF-1. It is the decline in the muscle isoforms of IGF-1 (liver like and MGF) that are likely to contribute most to age-related sarcopenia. Moreover, age-related decline in testosterone and growth hormone may lead to increase myostatin expression and dissociation in IGF-1 autocrine effects on protein synthesis in skeletal muscle.
The mechanisms by which testosterone, growth hormone, IGF-1, and other growth factors interact with receptor activity, myostatin gene expression, and satellite cell function in aged skeletal muscle to influence muscle protein warrant further vigorous research.
Testosterone replacement in young hypogonadal men and supraphysiologic treatment in eugonadal young men have shown to increase muscle mass and strength. In older men who have low bioavailable testosterone or low-normal total testosterone level, intramuscular testosterone increases muscle mass and strength. In the study by Wittert and colleagues it was shown that change in lean mass correlated with change in quadriceps strength from baseline to month 12 in the testosterone but not in the placebo group. Urban and coworkers reported that intramuscular testosterone increases muscle IGF-1 and mRNA. Snyder and colleagues reported an increase in serum IGF-1 in men receiving testosterone by transdermal patch. Bhasin and coworkers have shown that the muscle response to testosterone in young men in relation to dose. The use of muscle function testing in the elderly is confounded by wide variability in most measures. Motivation, tolerance to pain, and potential learning effects may be some of the major factors limiting the ability of these tests to identify differences between the treatment groups in interventional studies. Accordingly, large study groups may be required to determine small treatment benefits.
Testosterone And Bone
Men fracture their hips approximately 10 years later than women do. Men have a higher mortality rate than women when they fracture their hips. Minimal trauma hip fracture is associated with low testosterone levels. The relationship of testosterone to bone is less clear in men. Several studies have shown that testosterone treatment can increase bone mineral density. The 5-alpha-reductase inhibitor does not block this effect of testosterone. It would seem that aromatization of testosterone to estrogen is the major cause of the positive effects of testosterone on bone. This effect has been demonstrated clearly in people with congenital aromatase deficiency. Testosterone also seems to have direct effects on the osteoblast.
Testosterone And Cognition
Low bioavailable testosterone levels are correlated with poor cognition, especially visual-spatial cognition. Some studies have demonstrated that testosterone replacement may improve visual-spatial cognition.
The SAMP8 mouse has poor cognition, which is attributable to overproduction of amyloid-beta protein associated with increased oxidative damage. The SAMP8 mouse has low testosterone levels. Testosterone replacement in this mouse model of Alzheimer disease improves learning and memory. Testosterone treatment decreases amyloid precursor protein.
Low testosterone levels are associated with an increased likelihood of developing Alzheimer disease. Patients with Alzheimer disease have low testosterone levels in brain tissue compared with controls. Testosterone replacement has been shown to produce small improvements in cognition in people who have Alzheimer disease.
Testosterone And Health-Related Quality Of Life
Heath relates quality of life (HRQOL) is a complex and abstract concept that includes physical, psychological, social, and other domains of functioning specific to a given health condition. It focuses on the ways n which a disease modifies the happiness and satisfaction of an individual. It represents the patient’s viewpoint of the effects of treatment. It generally has several domains, including symptoms, function, emotional stability, social functioning, and general satisfaction with life. In the case of hypogonadism, decreased energy levels and impaired sexual performance appear to be to be the most important quality-of-life areas. Lowering testosterone levels in patients who have prostate cancer results in deterioration in the HRQOL.
Diagnosis Of Hypogonadism In Older Men
The diagnosis of hypogonadism in older men requires the presence of a constellation of signs and symptoms, and a demonstrated low total testosterone or preferably, free or bioavailable testosterone level. Several questionnaires have been developed to help screen for andropause and to provide an objective measure of treatment response. Two of these have excellent specificity: the Saint Louis University ADAM questionnaire and the Aging Male Survey. Unfortunately, neither questionnaire has very good sensitivity. Because of the multiple causes of symptoms similar to the male hypogonadism in older men, it is unlikely that any questionnaire will perform much better.
A simplified algorithmic approach to diagnosing late-life hypogonadism is presented below. This approach is compatible with recent consensus recommendations.
A positive screen for hypogonadism includes a “Yes” response to numbers 1 and 7, or any other 3 questions.
1. Do you have a decreased in libido (sex drive)?
2. Do you have a lack of energy?
3. Do you have a decrease in strength and/or endurance?
4. Have you lost height?
5. Have you noticed a decreased enjoyment of life?
6. Are you sad and/or grumpy?
7. Are your erections less strong?
8. Have you noticed a recent deterioration in your ability to play sports?
9. Are you falling asleep after dinner?
10. Has there been a recent deterioration in your work performance?
Several different methods of testosterone treatments have been developed. Testosterone can be given as injections every 1 to 3 weeks. The major problem with this approach is that the levels of testosterone vary from supraphysiologic to low over each treatment period. This approach has been used successfully, however, for more than 70 years. A long-acting testosterone undecanoate injection has been developed in Asia and Europe and should be available in the United States next year. This treatment is similar to testosterone pellet implant therapy, which can be implanted every 4 to 6 months.
Testosterone patches have a high rate of skin irritation because of alcohol being a part of the vehicle. Hydroalcoholic gels containing 1% testosterone have become popular in the United States. They have a lower rate of skin irritation and a better patient acceptance. Doses vary from 50 to 100 mg of gel daily. Three-year safety data fro this form of treatment have been reported. This study showed continued positive results of treatment on muscle, bone, fat, and libido in men age 19 to 67 years. Two forms of testosterone gel, AndroGel and Testim, are available in the United States.
Testosterone And The Cardiovascular System
Low testosterone levels are correlated with increased atherosclerosis and an increased carotid-intima media thickness. Testosterone decreases angina and decreases ST depression. It has minimal effects on cholesterol. Testosterone improves walking speed in peoples with congestive heart failure. Overall, these small studies suggest a beneficial effect of testosterone on heart disease.
The major side effect of testosterone is an excessive increase in hematocrit. When the hematocrit increases to more than 55, testosterone therapy should be withheld. Testosterone also can be associated with worsening sleep apnea. Testosterone therapy can be associated with the development of gynecomastia related to the aromatization of testosterone to estrogen. Parenteral testosterone administration has minimal deleterious effects on the liver.
Testosterone deficiency occurs commonly in men, as they grow older. This deficiency often is associated with a decline in sexual activity and a loss of muscle mass. Testosterone replacement can reverse many of these effects. At present, no ideal form of testosterone replacement is available.
Testosterone Replacement in older men is a “Quality of Life Issue”.