Andropause
Testosterone levels in men are known to decline at a rate of 1% per year after aged 30 years.6 About 20% of men aged ≥ 60 years and 50% of men aged ≥ 80 years have low (hypogonadal) total testosterone levels.7 The clinical diagnosis of hypogonadism, however, is made on the basis of signs and symptoms consistent with androgen deficiency and a low serum morning testosterone level measured on serum on multiple occasions.8
Specific clinical signs and symptoms (“A” list) consistent with androgen deficiency include low libido and sexual activity; diminished spontaneous erections; gynecomastia; reduced facial, axillary, or pubic hair; small (≤ 5 mL) testes; inability to father children; loss of height, fractures, or other signs of bone loss; and hot flashes and night sweats.9
Less specific signs and symptoms (“B” list) of androgen deficiency include a decrease in energy or motivation, feelings of sadness or depression, poor concentration or memory, trouble sleeping, increased sleepiness, mild anemia, reduced muscle bulk or strength, increased body fat, and diminished physical performance.9
Making the clinical diagnosis of hypogonadism is challenging, because the clinical symptoms have a high prevalence in the older male population and overlap with many nonendocrine diseases. Testosterone replacement therapy has been associated weakly, but consistently, with improved sexual function,10-12 bone mineral density,13,14 fat free mass,13,14 strength,15,16 lipid profiles,17,18 insulin resistance,17,18 and with an increased time to ST segment depression during stress testing.19,20
Laboratory Evaluation
Serum total testosterone circulates in 3 forms: free testosterone, sex hormone-binding globulin (SHBG)-bound testosterone, and albumin-bound testosterone. Free testosterone is the most bio-available testosterone but represents only 2% to 3% of total testosterone.21 Whether total testosterone or free testosterone measurements most closely correlate with symptomatic androgen deficiency is a matter of debate.21 A total testosterone level is an appropriate screening test in young, healthy, and lean men for whom SHBG levels are presumably normal. However, a free or bioavailable testosterone level should be considered for men when there is a high likelihood of conditions that can affect SHBG levels.
Conditions that can decrease SHBG (and may result in a low total testosterone reading even when the free fraction may be normal) include obesity, metabolic syndrome, type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, chronic glucocorticoid use, and the use of progestins and anabolic steroids.21 Conditions that can increase SHBG (and may result in a normal total testosterone level in patients with hypogonadism, as they have low levels of free testosterone) include aging, cirrhosis, anticonvulsant use, hyperthyroidism, catabolic conditions, and HIV.21
Related: Effect of Statins on Total Testosterone Levels in Male Veterans
Serum testosterone levels generally peak in the early morning, followed by a progressive decline over the course of the day until they reach a nadir in the evening.21 Although it has been debated that morning testosterone levels are not necessary in older men due to a blunting of the circadian rhythm, many men aged 65 to 80 years who have low T in the afternoon will have normal testosterone levels when retested in the morning.22,23 Readings below a reference range of 280 ng/dL to 300 ng/dL on at least 2 different occasions support a diagnosis of hypogonadism.9
Follicle stimulating hormone (FSH) and luteinizing hormone (LH) laboratory tests may be ordered following confirmation of a low testosterone level. Prolactin levels and iron saturation can help evaluate for the presence of hyperprolactinemia and hemochromatosis, respectively. Primary hypogonadism due to testicular failure is diagnosed with high FSH, high LH, and low testosterone levels. Secondary hypogonadism due to hypothalamic or pituitary failure is diagnosed with low FSH, low LH, and low testosterone levels.
Hypothalamic or pituitary suppression from a nonendocrine condition may result in functional hypogonadotropic hypogonadism (FHH), which can be identified with low (or normal) FSH; low (or normal) LH; and low testosterone levels. Hypogonadotropic hypogonadism has been associated with depression, obesity, stress, and physical exertion; and FHH may also be associated with the use of multiple drugs and drug classes (spironolactone, anabolic and corticosteroids, ketoconazole, ethanol, anticonvulsants, immunosuppressants, tricyclic antidepressants, selective serotonin reuptake inhibitors, antipsychotics, and opioids).24,25 Even statin therapy has been associated with FHH.26,27 Testosterone levels will often recover if or when modifiable factors for FHH are corrected.28
Although there is no consensus on an absolute number that defines a low testosterone level, concern exists that there are economic incentives to raise the bar for normal and thereby increase the potential market for testosterone-raising products.29 Many commercial avenues for the treatment of low T do not follow the standards of the established medical community. Some websites suggest screening for low T with total and free testosterone levels for all men aged > 40 years. Others advise men to consider TRT if they have a total testosterone level of < 500 ng/dL or a free testosterone level that is not in the upper one-third range for men aged 21 to 49 years.30 Of even greater concern, Baillargeon and colleagues reported that 25% of all new androgen users had not had their testosterone levels measured in the 12 months before starting treatment.31 In another study, 40% of men who initiated TRT did not have a baseline measurement.32