Cognitive function. Cognitive function decreases with aging. Most of the age-related changes in cognition are associated with vascular and/or degenerative diseases that cause anatomic changes in the central nervous system. The possibility that an age-related fall in T causes functional changes in cognition is of great interest. In a study involving 407 men aged 50 to 91 years at baseline and followed for an average of 10 years, Moffat and colleagues showed that higher free T indices were associated with better scores on visual and verbal memory, visuospatial functioning, and visuomotor scanning, and a reduced rate of decline in visual memory (Moffat et al., 2002). On the other hand, men classified as hypogonadal had significantly lower scores on measures of memory and visuospatial performance and a faster decline in visual memory. Of course, changes in the CNS could cause hypogonadism rather than be caused by hypogonadism. In another study by Barrett-Conner and associates, low estradiol and high total and bioavailable T levels predicted better performance on several tests of cognitive function in older men (Barrett-Connor et al., 1999). T could exert its actions through androgen receptors that could modulate serotonin, dopamine, calcium, and acetylcholine signaling pathways. Androgen also increases neurite arborization facilitating intercellular communication. T can be aromatized in the brain to estrogen, and thus some of the effects of T may be mediated through its conversion to estradiol. Most of the effects of androgen on cognitive function are thought to be domain-specific. For example, observations that men outperform women in a variety of visuospatial skills suggest that androgens might enhance these skills. Some, but not all, of the trials found better verbal memory and spatial cognition in the T-treated men compared with placebo-treated men, but no better scores on other cognitive domains (Cunningham et al., 1990; Janowsky et al., 2000; Kenny et al., 2002).
Mood and depression. It is estimated that two million older Americans are depressed (NIMH, 2003). Depression increases with aging, in part due to diseases associated with aging. Although depression is not a part of the aging process, medical diseases associated with aging such as stroke, diabetes, and heart disease reduce physical activity and contribute to depression. It is estimated that 80% of older adults with depression improve when they receive therapy with an antidepressant medication, psychotherapy, or both (NIMH, 2003). T may have a beneficial effect on mood and depression, as it is known to modulate the serotonin and dopamine pathways.
Androgens appear to improve positive aspects of mood and reduce negative aspects of mood such as irritability in young, hypogonadal men, and some improvements in mood usually are observed in clinical trials involving mostly middle-aged men (Wang et al., 1996).
Libido. T also appears to be essential for development and maintenance of libido or sexual desire. Males with congenital hypogonadotropic hypogonadism have minimal libido. This is increased by therapy that increases their T levels. Reduced libido also is observed in men with acquired hypogonadism, and clinical trials with replacement doses of T in young and middle-aged men usually show improved libido.
Bone strength decreases with aging. Men undergo a gradual loss in bone mass beginning in their 30s. It is estimated that two million men in the United States have osteoporosis and that one in eight men over age 50 will have an osteoporosis-related fracture (NIAMS, 2003). Risk factors for osteoporosis include family history of osteoporosis, smoking, excessive alcohol intake, physical inactivity, poor nutrition, vitamin D deficiency, inadequate calcium intake, hypogonadism, and use of some medications (e.g., glucocorticoids, anti-convulsants).
Osteopenia and osteoporosis are common in males with congenital causes of hypogonadism, and severe T deficiency occurring later in life also results in bone loss. For example, androgen deprivation therapy for prostate cancer has been shown to result in rapid bone loss, osteopenia, and osteoporosis (Smith, 2003). Although less severe T deficiency in aging men appears to increase osteopenia and osteoporosis, population-based studies suggest that estrogen levels are better correlated with loss of BMD in men (Greendale et al., 1997; van den Beld et al., 2000). Estrogen is very important in bone development in males as illustrated by individuals with aromatase deficiency (Maffei et al., 2004). Males with inactivating mutations of the aromatase gene develop osteopenia and osteoporosis that improve with estradiol therapy. Estrogen also plays a major role in bone metabolism of older males (Khosia et al., 1998).
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