Your activity: 6 p.v.

Approach to older men with low testosterone

Approach to older men with low testosterone
Author:
Peter J Snyder, MD
Section Editors:
Alvin M Matsumoto, MD
Kenneth E Schmader, MD
Deputy Editor:
Kathryn A Martin, MD
Literature review current through: Dec 2022. | This topic last updated: May 04, 2020.

INTRODUCTION — As men age, their serum concentrations of testosterone decrease. This decline is gradual and of a modest degree, but because many of the changes of aging are similar to those of hypogonadism due to known disease, the decline in testosterone has been postulated to be a cause of these changes of aging. Recent studies show that raising the testosterone levels of older men with low testosterone has some benefits, but no study yet has enrolled enough men and treated and observed them for long enough to determine the risk of this treatment.

The decline in testicular function with aging, its possible consequences, and the results of increasing testosterone levels in older men are reviewed here. Testosterone treatment of male hypogonadism due to known disease is discussed separately. (See "Testosterone treatment of male hypogonadism".)

AGE-RELATED ENDOCRINE CHANGES — Both cross-sectional and longitudinal studies demonstrate a decline in serum testosterone concentration, an increase in sex hormone-binding globulin concentration (SHBG), and a decrease in free testosterone with age.

Serum total testosterone — Several cross-sectional studies show a decline of serum total testosterone concentration with increasing age [1,2]. In one, the European Male Aging Study (EMAS), of 3220 men ages 40 to 79 years, the serum total testosterone concentration fell 0.4 percent per year [1]. In a second study, a gradual decline in testosterone concentration was seen after age 35 years, with a more marked decline after age 80 years [2].

A study using serum samples from four population-based studies (EMAS, Framingham Heart Study, Osteoporotic Fractures in Men [MrOS], Male Sibling Study of Osteoporosis) of men from ages 19 to 79 that were assayed and standardized against gold-standard measurements performed at the Centers for Disease Control and Prevention (CDC), age-specific harmonized reference ranges were generated. This study demonstrated that the lowest 2.5th percentile values decreased considerably with age, but the 50th percentile value decreased much less and the 97.5th values not at all [3]. For example, the 2.5th percentile model estimate for all men and nonobese men 19 to 39 years was 229 ng/dL and 264 ng/dL, respectively, and that for all men 70 to 79 years was 119 ng/dL, whereas the values for the 50th percentile were 507 and 446 ng/dL and for the 97.5th percentile were 902 and 902 ng/dL, respectively.

Longitudinal studies also show a decrease in testosterone with increasing age, and in three of them, the decrease was greater than that in cross-sectional studies [4-6]. In 890 men participating in the Baltimore Longitudinal Study of Aging, serum testosterone decreased at a fairly constant rate, independent of other clinical variables [6]. In the Massachusetts Male Aging Study, longitudinal assessment also showed a decrease in total testosterone with increasing age but a greater decrease in free testosterone [4,5].

Another feature of testosterone with increasing age is a loss of circadian rhythmicity. Whereas young men exhibit a prominent increase in the morning, peaking at approximately 8 AM, older men show a very dampened increase (figure 1) [7].

Serum sex hormone-binding globulin — SHBG concentrations increase gradually as a function of age, as shown in the EMAS [1]. The clinical implication, because SHBG binds testosterone with high affinity, is that with increasing age, less of the total testosterone is free (ie, biologically active). SHBG, however, is lower at all ages in obese men than in nonobese men [1].

Serum free testosterone — The serum free testosterone concentration decreases with increasing age to a greater degree than the total testosterone; the values in 75 to 79-year-old men were approximately 30 percent less than those in 40 to 44-year-old men [1].

Effects of obesity and comorbid conditions — The total testosterone levels in obese men are lower than those in men of normal weight of the same age, partly due to a lower level of SHBG in obesity, but partly due to hypogonadotropic hypogonadism, since their free testosterone levels are also lower those of nonobese men and their luteinizing hormone (LH) levels are not higher (figure 2) [1]. Total and free testosterone levels are lower in men who have one or more comorbid conditions than in men of the same age who have none and their LH levels are not higher, suggesting that they also have hypogonadotropic hypogonadism [1].

Change in gonadotropins — As men age, serum gonadotropin concentrations increase, follicle-stimulating hormone (FSH) more than LH, but the rise is not so great as one would expect from the fall in testosterone, suggesting that the fall in testosterone with aging is due to both secondary and primary hypogonadism.

In the EMAS, the fall in testosterone with age was associated with an increase in LH, suggesting a degree of primary hypogonadism [1], but the fall in testosterone with obesity alone (without aging) was not, suggesting that the effect of obesity was mediated by hypogonadotropic hypogonadism.

Effects on spermatogenesis — Sperm production does not appear to change dramatically with increasing age. Testicular size, which reflects primarily the volume occupied by the seminiferous tubules, was somewhat smaller (mean volume 20.6 mL) in 114 older men than in 42 young men (29.7 mL) [8]. Ejaculated sperm density in 20 fathers ages 24 to 37 years old was slightly lower than that in 22 grandfathers ages 60 to 88 years old, but percent motility was greater in the younger group, resulting in a similar total number of motile sperm in the two groups [9].

In 1174 men recruited for studies of erectile function, the oldest quartile, who were aged 56 to 80 years, had similar semen characteristics to the youngest quartile, aged 45 to 47.8 years [10].

ARE THERE CONSEQUENCES OF AGE-RELATED FALL IN TESTOSTERONE? — No clinical consequences of the decline in serum testosterone with age are known with certainty, but several parallels between the effects of aging and those of hypogonadism due to pituitary or testicular disease suggest that the decline in serum testosterone might be a cause of several effects of aging. The parallels include a decline in libido and sexual activity, decreased muscle mass and strength, depressed mood, decreased bone mineral density (BMD), and anemia. (See "Clinical features and diagnosis of male hypogonadism".)

Hypogonadism is actually uncommon in older men. In a report from the European Male Aging Study (EMAS), 2,966 men aged 40 to 79 were evaluated to determine if men with a low serum testosterone concentration for no apparent reason other than age develop the typical signs and symptoms of male hypogonadism due to known pituitary or testicular disease [11]. The combination of low serum testosterone (<317 ng/dL [11 nmol/L]) and three sexual symptoms, was seen in only 2.1 percent of men (n=63). More severe hypogonadism (serum testosterone concentration <230 ng/dL [8 nmol/L]) was seen in 27 of the 63 (0.9 percent) hypogonadal men.

The hypogonadal men tended to be older and more obese, and in proportion to their testosterone deficiency they had significantly lower:

Hemoglobin

Heel bone mineral density

Muscle mass

Poorer general health

Severe hypogonadism was also associated with insulin resistance and the metabolic syndrome. The associations were stronger when the serum testosterone concentration was <230 ng/dL (8 nmol/L) than when it was in the 230 to 317 ng/dL range (8 to 11 nmol/L). These data support the concept of a low testosterone syndrome in middle-aged and older men, but only in a small percentage.

EVALUATION FOR POSSIBLE HYPOGONADISM IN OLDER MEN

Who to test — Older men who have symptoms (eg, decreased libido, depressive mood), physical findings (eg, decreased body hair), or laboratory findings (eg, anemia, low bone mineral density [BMD]) of low testosterone should be evaluated in the same way as younger symptomatic men. (See "Clinical features and diagnosis of male hypogonadism".)

Biochemical testing

The initial test should be a serum testosterone measurement early in the morning, fasting. If the result is low, the test should be repeated at least once, preferably twice.

Testosterone should be measured in a laboratory that performs the assay by liquid chromatography and tandem mass spectroscopy and that participates in the Center for Disease Control and Prevention (CDC)'s accuracy-based testosterone Hormone Standardization (HoSt) program or uses an immunoassay that participates in the HoSt program. In a study using sera from four population studies and a harmonized testosterone assay, the lower limit (2.5th percentile) for nonobese men 19 to 39 years was 264 ng/dL [3].

If the testosterone results are consistently low, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) should be measured to determine if the hypogonadism is primary or secondary. (See "Clinical features and diagnosis of male hypogonadism", section on 'LH and FSH'.)

If secondary, other pituitary hormonal deficiencies should be evaluated. (See "Clinical features and diagnosis of male hypogonadism", section on 'Pituitary function testing'.)

If the hypogonadism is secondary and of moderate severity (eg, <200 ng/dL) and/or associated with other hormonal deficiencies, magnetic resonance imaging (MRI) of the sella area should be ordered.

TESTOSTERONE THERAPY

Potential candidates for therapy — Whether or not older men who have low testosterone for no discernable reason other than age will benefit from testosterone treatment is controversial. In contrast, there is general agreement that older men who have unequivocally low testosterone due to known hypothalamic-pituitary or testicular disease should be treated with testosterone as younger men. In 2015, the US Food and Drug Administration (FDA) directed manufacturers of testosterone products to state in their labels that these products are approved only for men with low testosterone due to known causes [12].

However, other expert groups argue that there may be a role for testosterone therapy in selected patients. Our approach is similar to the Endocrine Society Clinical Practice Guidelines for testosterone therapy in adult men with testosterone deficiency, which were updated in 2018 [13].

We suggest offering testosterone on an individualized basis to older men who have symptoms and conditions suggestive of testosterone deficiency and who have consistently and unequivocally low serum testosterone levels after explicit discussion of the potential risks and benefits.

In contrast, we recommend against routinely prescribing testosterone to older men with low testosterone levels in the absence of symptoms and conditions of androgen deficiency (or symptoms without unequivocally low testosterone levels).

As with hypogonadism due to known disease, testosterone treatment should not be initiated until further evaluation if the patient has a prostate nodule, a prostate-specific antigen (PSA) >4 ng/mL or >3 ng/mL in men at increased risk of prostate cancer (eg, African American men or those who have a first-degree relative with diagnosed prostate cancer), or a hematocrit >48 percent.

The same testosterone preparations available for younger men can be used for older men. (See "Testosterone treatment of male hypogonadism".)

Monitoring treatment — If testosterone treatment is prescribed, we recommend monitoring the serum testosterone level during treatment. The author of this topic suggests using a target value in older men that is in the low-normal range for young men (eg, 300 to 400 ng/dL [10.4 to 13.9 nM]) to lower the risk of testosterone-dependent diseases.

PSA should be repeated three to six months after initiation of testosterone treatment to determine if it has increased more than 1.4 ng/mL above baseline or to >4 ng/mL. If the increase is reproducible, the patient should be referred for urologic evaluation.

Hematocrit should be measured three to six months after initiation of treatment and at least once a year thereafter because testosterone stimulates erythropoiesis. A high value can occur because of an excessive dose of testosterone or unmasking of a secondary cause.

Previous efficacy data — Data from five randomized, placebo-controlled trials including over 500 older men [14-20] during the 1990s showed some beneficial effects of testosterone treatment in older men, but the results were not consistent, possibly because of enrolling men who were not clearly hypogonadal, not increasing the serum testosterone to normal, insufficient duration of treatment, and/or not choosing clinically important outcomes. A committee of the Institute of Medicine (now the National Academy of Medicine) reviewed these and other trials and concluded that there was insufficient evidence to conclude that testosterone treatment of older men has any well-established benefit. The committee recommended that a coordinated set of randomized, placebo-controlled clinical trials should be performed to determine if testosterone does have any benefit [21]. The Testosterone Trials (TTrials) were designed to implement this recommendation.

The Testosterone Trials

Design — The multicenter TTrials were a coordinated set of seven placebo-controlled clinical trials to test the one-year efficacy of testosterone on sexual function, physical function, vitality, cognitive function, anemia, bone density, and cardiovascular risk factors in older men with symptoms of hypogonadism and consistently low testosterone [22].

Men over age 65 years (n = 788) with low serum testosterone (<275 ng/dL [9.54 nmol/L] early in the morning on two occasions) and symptoms and objective evidence of sexual dysfunction, physical dysfunction, and/or reduced vitality were assigned to receive testosterone or placebo gel with balancing by minimization for one year and participated in one or more of three main trials (the sexual function [n = 470], physical function [n = 390], and vitality [n = 474] trials). They could also participate in any of the other trials for which they qualified.

Benefits — Over 51,000 men were screened to enroll the 790 men who met inclusion criteria (only 1.5 percent of those screened). The median pretreatment testosterone concentration was 232 ng/dL. After one year of testosterone gel therapy, average serum testosterone concentrations increased into the mid-normal range (approximately 500 ng/dL) for men ages 19 to 40 years. The following results were reported:

Sexual functionTestosterone therapy was associated with a moderate improvement in sexual function, including sexual activity (figure 3), sexual desire (libido), and, to a lesser extent, erectile function [23]. The effect on sexual activity and sexual desire was likely of clinical significance because the effect sizes were 0.45 and 0.44, respectively, and participants who were treated with testosterone were significantly more likely than those treated with placebo to respond on a Patient Global Assessment of Change question that their sexual desire was better during treatment than before. The magnitude of rise in serum testosterone and estradiol concentrations was associated with the magnitude of improvement in sexual desire and sexual activity, but not erectile function.

Physical function – There was no significant difference between the testosterone- versus placebo-treated groups in walking distance on a six-minute walk test in the 390 men who were enrolled in the physical function trial, but testosterone did improve walking distance when all 788 men were included [22].

Vitality (as assessed by Functional Assessment of Chronic Illness Therapy-Fatigue Scale in the vitality trial) did not differ in testosterone- versus placebo-treated men enrolled in the vitality trial (but testosterone improved vitality [energy] slightly when subjects from all three main trials were included) [22]. However, men receiving testosterone reported better mood and lower severity of depressive symptoms when compared with placebo.

Cognitive function – A subgroup of 493 men in the TTrials met criteria for age-associated memory impairment (AAMI), based on subjective memory complaints and objective memory performance lower than younger men [24]. After 6 and 12 months, there were no differences in changes from baseline in testosterone- and placebo-treated men in test scores for memory and other cognitive functions (delayed paragraph recall, visual memory, executive function, or spatial ability), but testosterone improved executive function when all subjects from all three main trials were included.

Anemia – Among the 788 men enrolled in all three trials, 126 were anemic (hemoglobin ≤12.7 g/dL) at baseline, 64 associated with a known cause, such as iron deficiency, and 62 with unexplained anemia [25]. After 12 months of testosterone treatment, more men with unexplained anemia in the testosterone group had increases in hemoglobin of 1 g/dL or more (54 versus 15 percent in the placebo group) and normal hemoglobin values (58 versus 22 percent in the placebo group) (figure 4). Similar results occurred in men who had anemias of known cause (figure 5). This effect of testosterone replacement is consistent with the known stimulatory effect of testosterone on erythropoiesis.

Bone density – A subgroup of 211 men underwent assessment of volumetric bone mineral density (vBMD) and bone strength by quantitative computed tomography (QCT) scanning at baseline and 12 months [26]. After 12 months, testosterone significantly increased mean lumbar spine trabecular vBMD (7.5 versus 0.8 percent), as well as lumbar peripheral and hip trabecular and peripheral vBMD (figure 6), and mean estimated strength of spine trabecular bone (11 versus 2.4 percent), as well as lumbar peripheral and hip trabecular and peripheral bone (figure 7).

Adverse events

Coronary artery plaque – In a substudy of 170 men, one year of testosterone therapy was associated with a greater increase than placebo in noncalcified coronary artery plaque volume, as measured by coronary computed tomographic angiography (CCTA) [27]. There was also a significantly greater increase in total plaque volume in the testosterone group but no change in the coronary calcification score in either group. Of note, 50 percent of the study subjects had severe atherosclerosis at baseline on CCTA. Major limitations of the study were the use of CCTA (a surrogate outcome for atherosclerosis) and the small size and short duration of the trial. However, the findings do raise serious concerns about testosterone use in older men.

Erythrocytosis – More men in the testosterone group experienced erythrocytosis (hemoglobin ≥17.5 g/dL) (7 versus 0) [22]. The incidence of major adverse cardiovascular events and other adverse events was otherwise similar with testosterone and placebo.

Prostate outcomes – In the same set of trials, testosterone therapy that increased serum testosterone concentrations from moderately low (approximately 230 ng/dL [7.97 nmol/L]) into the midnormal range (approximately 500 ng/dL [17.3 nmol/L]) increased serum PSA concentrations to a small degree [28]. Only 2.5 percent of men experienced an increase above baseline of ≥3.4 ng/mL, A confirmed PSA >4.0 ng/mL occurred in 1.9 percent of men on testosterone and 0.3 percent on placebo.

Four prostate cancers were diagnosed during the 12 months of treatment and the 6 months of follow-up; three in the testosterone arm (two of which were high-grade prostate cancer) and one in the placebo arm.

The TTrials, in short, demonstrated that testosterone treatment of symptomatic older men with unequivocally low testosterone levels is efficacious in improving sexual function, walking, mood, depressive symptoms, anemia, and bone density, all to modest degrees. Testosterone treatment, however, did not improve vitality or cognitive function and was associated with an increase in noncalcified coronary artery plaque volume. Although testosterone treatment was not associated with increased risks of clinical cardiac events or prostate cancer, a much larger and longer trial would be needed to assess these risks with greater certainty.

Other data — In a meta-analysis of four trials of 1779 patients [29], testosterone therapy was associated with a small improvement in some measures of sexual function (sexual desire, erectile function, and sexual satisfaction), but it had no effect on mood or energy. There was an increased risk of erythrocytosis, but no significant effect on lower urinary tract symptoms.

Potential harmful effects — There are theoretical and other reasons to think that testosterone treatment of older men with low testosterone might exacerbate certain diseases. For example, the prostate gland is testosterone dependent, so it is reasonable to wonder if raising the serum testosterone concentration will increase the risk of prostate cancer or benign prostatic hyperplasia. Erythropoiesis is also testosterone dependent, so raising the testosterone level, especially to supraphysiologic levels, can cause erythrocytosis. Some epidemiologic studies have shown a larger number of cardiovascular events in men treated with testosterone, but others have not. (See "Testosterone treatment of male hypogonadism", section on 'Venous thromboembolism' and "Testosterone treatment of male hypogonadism", section on 'Cardiovascular risks'.)

Prostate cancer — Prostate cancer is partly testosterone dependent [30]. This dependency is illustrated by the current practice of treating men who have metastatic and locally advanced prostate cancer by lowering their serum testosterone concentrations with drugs that decrease testosterone synthesis and/or its action [31]. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

In the few clinical trials of testosterone in older men, few cases of prostate cancer occurred [14,16,17,22], but these trials, involving at most 788 men, had too little statistical power to state that testosterone treatment does not increase the risk of prostate cancer (see 'The Testosterone Trials' above). It has been estimated that a trial would require 6000 men randomized to receive testosterone or placebo for five years each to determine if testosterone increases the incidence of prostate cancer by 30 percent [21].

In a 2010 meta-analysis of 51 randomized trials of testosterone therapy in men designed to look at the primary endpoints of mortality, cardiovascular events and risk factors, prostate outcomes, and erythrocytosis, testosterone treatment was not associated with increased incidence of prostate cancer, need for prostate biopsy, or other prostate outcomes when compared with the placebo/nonintervention group [32]. Results were the same when analyzed by subject age (less than or greater than age 65 years). However, as the study authors emphasize, the number of subjects studied and the quality of the observations were not adequate to say that testosterone does not result in worse prostate outcomes. (See "Testosterone treatment of male hypogonadism".)

Benign prostatic hyperplasia — The testosterone dependency of benign prostatic hyperplasia has been known for over 100 years and is the basis for one current medical treatment: use of the 5-alpha-reductase inhibitors, finasteride and dutasteride, to block the conversion of testosterone to dihydrotestosterone, its active metabolite within the prostate [33]. In the meta-analysis noted above, testosterone therapy had no adverse effect on lower urinary tract symptoms or other prostate outcomes [32]. In the TTrials of 788 men treated for one year, the number of men whose International Prostate Symptom Score increased above 19 (moderately severe) was similar in the testosterone and placebo groups (testosterone 27, placebo 26) [22]. The number of men observed and duration of the observations are not sufficient to say that testosterone does not worsen lower urinary tract symptoms. (See "Medical treatment of benign prostatic hyperplasia".)

Sleep apnea — Data from a small number of men with hypogonadism suggest that even physiologic replacement of testosterone increases sleep apnea [34-36], a condition to which older men are already prone. In contrast, in the meta-analysis described above [37], the frequency of sleep apnea did not differ between testosterone- and placebo-treated men.

Erythrocytosis — Testosterone treatment of older men, especially with long-acting testosterone esters in doses that have been commonly employed, causes erythrocytosis. In one retrospective trial of 45 men whose average age was 71.8 years and who had relatively low serum bioavailable testosterone concentrations, treatment with 200 mg of testosterone ester (enanthate or cypionate) caused an increase in hematocrit to >52 percent in 11 of them (24 percent) [38].

In the trial described above in which men were randomized to receive testosterone enanthate 200 mg/two weeks alone or with finasteride, 14 of 46 men developed an elevated hemoglobin [17].

Even in the TTrials, in which testosterone and hemoglobin levels were monitored at least every three months, the dose of testosterone adjusted accordingly, and the incidence of erythrocytosis was relatively low, the seven men who developed erythrocytosis were all in the testosterone group.

The potential significance of this adverse effect is that in the Framingham Heart Study, men who were in the highest quintile (46 to 70 percent) with regard to hematocrit had greater overall mortality and cardiovascular mortality than those in the middle two quintiles [39].

Serum lipids — Both oral and intramuscular administration of high doses of testosterone have been shown to decrease high-density lipoprotein (HDL) cholesterol concentrations in young hypogonadal men and in men receiving gonadotropin-releasing hormone (GnRH) antagonists, respectively [40,41]. In a meta-analysis of 10 studies of intramuscular testosterone esters and plasma lipids in hypogonadal men, a small, dose-dependent decrease was seen in total cholesterol, low-density lipoprotein (LDL) cholesterol, and HDL [42]. In the TTrials, testosterone was associated in small decreases in both LDL and HDL cholesterol [43].

Cardiovascular risk — Data on the risk of cardiovascular complications with testosterone therapy have been conflicting, with some epidemiologic studies suggesting no increase in cardiovascular events in older men, while others suggest a possible increase in cardiovascular events in some men who take testosterone. Although this issue remains unclear, the FDA issued a safety announcement on March 3, 2015, stating that it was requiring manufacturers of testosterone products to change its labeling of these products to include a warning of possible increased risk of heart attacks and strokes associated with testosterone use [12]. This issue is discussed in detail separately. (See "Testosterone treatment of male hypogonadism", section on 'Cardiovascular risks'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Testosterone therapy in men" and "Society guideline links: Male infertility or hypogonadism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Androgen replacement in men (The Basics)" and "Patient education: Low testosterone in men (The Basics)")

SUMMARY AND RECOMMENDATIONS

Serum total testosterone concentrations fall slightly with increasing age, and free testosterone concentrations fall more, although still modestly. (See 'Serum total testosterone' above.)

Older men who have symptoms, physical findings, or other findings suggestive of hypogonadism should be evaluated for low testosterone, just as younger men. (See 'Who to test' above.)

Initial evaluation should be measurement of the serum testosterone in the early morning, fasting, by liquid chromatography-tandem mass spectroscopy in a laboratory that participates in the Centers for Disease Control and Prevention (CDC)'s testosterone Hormone Standardization (HoSt) program. If the result is low for young men (eg, less than 229 ng/dL), the measurement should be performed twice more. (See 'Biochemical testing' above.)

If the testosterone is unequivocally and reproducibly low, we suggest measurement of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to determine if the hypogonadism is primary or secondary. If secondary, we suggest assessment of other pituitary hormones. If the patient has multiple pituitary hormonal deficiencies and/or if the testosterone is less than 200 ng/dL, we suggest magnetic resonance imaging (MRI) of the sella. (See 'Biochemical testing' above.)

We suggest offering testosterone on an individualized basis to older men who have symptoms and conditions suggestive of testosterone deficiency and who have consistently and unequivocally low serum testosterone levels after explicit discussion of the potential risks and benefits (Grade 2B). (See 'Potential candidates for therapy' above.)

In contrast, we suggest against routinely prescribing testosterone to older men with low testosterone levels in the absence of symptoms and conditions of androgen deficiency (or symptoms without unequivocally low testosterone levels) (Grade 2B). (See 'Potential candidates for therapy' above.)

For those with unequivocally and reproducibly low testosterone due to an identifiable primary or secondary cause, we suggest treatment as for a younger man with hypogonadism (Grade 2B). (See 'Potential candidates for therapy' above.)

The expected benefits of testosterone treatment, based on recent results from the Testosterone Trials (TTrials), are increased sexual interest and activity, slight improvement in walking, slight improvement in mood, increased hemoglobin, and markedly increased bone mineral density (BMD). No change in energy or cognition is expected. (See 'The Testosterone Trials' above.)

No trial yet has been large enough or long enough to determine if testosterone increases the risk of prostate cancer or benign prostatic enlargement. If a digital rectal examination shows a prostate nodule or the prostate-specific antigen (PSA) is >4 ng/mL or >3 ng/mL in men at increased risk of prostate cancer (eg, African American men or those who have a first-degree relative with diagnosed prostate cancer), the patient should be referred for urologic evaluation before prescribing testosterone. (See 'Prostate cancer' above and 'Benign prostatic hyperplasia' above.)

Testosterone increases red blood cell production, which could cause an elevated hematocrit. Hematocrit should be measured before beginning treatment and evaluated if it is above 48 percent in a hypogonadal man. The measurement should be repeated after three to six months of treatment and at least once a year thereafter. (See 'Erythrocytosis' above.)

No clinical trial of testosterone has been large enough or long enough to determine its cardiovascular risk, but the US Food and Drug Administration (FDA) has not approved testosterone treatment for older men who have low testosterone but no known pituitary or testicular disease. (See 'Cardiovascular risk' above.)

  1. Wu FC, Tajar A, Pye SR, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008; 93:2737.
  2. Handelsman DJ, Yeap B, Flicker L, et al. Age-specific population centiles for androgen status in men. Eur J Endocrinol 2015; 173:809.
  3. Travison TG, Vesper HW, Orwoll E, et al. Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe. J Clin Endocrinol Metab 2017; 102:1161.
  4. Travison TG, Araujo AB, Kupelian V, et al. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 2007; 92:549.
  5. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002; 87:589.
  6. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001; 86:724.
  7. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab 1983; 56:1278.
  8. Mahmoud AM, Goemaere S, El-Garem Y, et al. Testicular volume in relation to hormonal indices of gonadal function in community-dwelling elderly men. J Clin Endocrinol Metab 2003; 88:179.
  9. Nieschlag E, Lammers U, Freischem CW, et al. Reproductive functions in young fathers and grandfathers. J Clin Endocrinol Metab 1982; 55:676.
  10. Hellstrom WJ, Overstreet JW, Sikka SC, et al. Semen and sperm reference ranges for men 45 years of age and older. J Androl 2006; 27:421.
  11. Tajar A, Huhtaniemi IT, O'Neill TW, et al. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European Male Aging Study (EMAS). J Clin Endocrinol Metab 2012; 97:1508.
  12. Nguyen CP, Hirsch MS, Moeny D, et al. Testosterone and "Age-Related Hypogonadism"--FDA Concerns. N Engl J Med 2015; 373:689.
  13. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2018; 103:1715.
  14. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 1999; 84:1966.
  15. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age. J Clin Endocrinol Metab 1999; 84:2647.
  16. Kenny AM, Prestwood KM, Gruman CA, et al. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci 2001; 56:M266.
  17. Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004; 89:503.
  18. Page ST, Amory JK, Bowman FD, et al. Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 2005; 90:1502.
  19. Nair KS, Rizza RA, O'Brien P, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006; 355:1647.
  20. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008; 299:39.
  21. Testosterone and aging: Clinical research directions, Liverman CT, Blazer DG (Eds), National Academies Press, Washington DC 2004.
  22. Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of Testosterone Treatment in Older Men. N Engl J Med 2016; 374:611.
  23. Cunningham GR, Stephens-Shields AJ, Rosen RC, et al. Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels. J Clin Endocrinol Metab 2016; 101:3096.
  24. Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA 2017; 317:717.
  25. Roy CN, Snyder PJ, Stephens-Shields AJ, et al. Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA Intern Med 2017; 177:480.
  26. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med 2017; 177:471.
  27. Budoff MJ, Ellenberg SS, Lewis CE, et al. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA 2017; 317:708.
  28. Cunningham GR, Ellenberg SS, Bhasin S, et al. Prostate-Specific Antigen Levels During Testosterone Treatment of Hypogonadal Older Men: Data from a Controlled Trial. J Clin Endocrinol Metab 2019; 104:6238.
  29. Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, et al. The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: A systematic review and meta-analysis of randomized, placebo-controlled trials. J Clin Endocrinol Metab 2018.
  30. Huggins, C, Hodges, CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1:293.
  31. Iversen P, Christensen MG, Friis E, et al. A phase III trial of zoladex and flutamide versus orchiectomy in the treatment of patients with advanced carcinoma of the prostate. Cancer 1990; 66:1058.
  32. Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010; 95:2560.
  33. Gormley GJ, Stoner E, Bruskewitz RC, et al. The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med 1992; 327:1185.
  34. Matsumoto AM, Sandblom RE, Schoene RB, et al. Testosterone replacement in hypogonadal men: effects on obstructive sleep apnoea, respiratory drives, and sleep. Clin Endocrinol (Oxf) 1985; 22:713.
  35. Schneider BK, Pickett CK, Zwillich CW, et al. Influence of testosterone on breathing during sleep. J Appl Physiol (1985) 1986; 61:618.
  36. Liu PY, Yee B, Wishart SM, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab 2003; 88:3605.
  37. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005; 60:1451.
  38. Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab 1997; 82:3793.
  39. Gagnon DR, Zhang TJ, Brand FN, Kannel WB. Hematocrit and the risk of cardiovascular disease--the Framingham study: a 34-year follow-up. Am Heart J 1994; 127:674.
  40. Asscheman H, Gooren LJ, Megens JA, et al. Serum testosterone level is the major determinant of the male-female differences in serum levels of high-density lipoprotein (HDL) cholesterol and HDL2 cholesterol. Metabolism 1994; 43:935.
  41. Bagatell CJ, Knopp RH, Vale WW, et al. Physiologic testosterone levels in normal men suppress high-density lipoprotein cholesterol levels. Ann Intern Med 1992; 116:967.
  42. Whitsel EA, Boyko EJ, Matsumoto AM, et al. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med 2001; 111:261.
  43. Mohler ER 3rd, Ellenberg SS, Lewis CE, et al. The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials. J Clin Endocrinol Metab 2018; 103:681.
Topic 7457 Version 29.0

References