Testosterone is the main androgen secreted by the testes, and the testes are the major source of circulating androgens in males. Testosterone is present in the body in 3 forms: free testosterone (FT), albumin bound testosterone, and testosterone bound to serum hormone binding globulin (SHBG). Albumin bound testosterone readily dissociates to FT. SHBG tightly binds the testosterone it carries and this form is not bioavailable. Testosterone levels are controlled by interaction of the testicular-pituitary-hypothalamic axis. Primary hypogonadism is failure of the testes to produce testosterone and is accompanied by elevated LH and/or FSH. Causes of primary hypogonadism include, but are not limited to, Klinefelter syndrome (KS), cryptorchidism, some types of chemotherapy, radiation to the testes, trauma, torsion, infectious orchitis, human immunodeficiency virus (HIV) infection, anorchia syndrome, and myotonic dystrophy. Secondary hypogonadism is disruption of the testicular-pituitary-hypothalamic pathway. These patients will typically have low or normal LH and FSH levels. Causes of secondary hypogonadism include hyperprolactinemia; severe obesity; iron overload syndromes; the use of opioids, glucocorticoids, or androgen-deprivation therapy with gonadotropin-releasing hormone agonists; androgenic–anabolic steroid (AAS) withdrawal syndrome; idiopathic hypogonadotropic hypogonadism; hypothalamic or pituitary tumors or infiltrative disease; head trauma; and pituitary surgery or radiation. In other cases, the decline in gonadal function, as may occur gradually with aging, may not be a clearly pathological process. This process is known as LOH.1 As men age, their serum concentrations of total testosterone (TT) gradually decrease. Furthermore, SHBG increases with age, thus the normal course of aging is to further decrease the total bioavailable testosterone.
Testosterone products have been approved by the FDA for replacement therapy in men with primary or secondary hypogonadism caused by specific, well-recognized medical conditions. On the basis of this replacement use, the FDA has required only that testosterone products reliably bring low serum testosterone concentrations into the normal range, defined as the concentrations seen in healthy young men. The FDA has not mandated that clinical trials show improvements in signs or symptoms of hypogonadism in order for a testosterone product to be approved.2
Testosterone prescriptions for men have increased substantially in recent years. One study found that in 2011, 3.7% of the men 60 years or older were taking some form of testosterone.3 Yet, as many as 25% of the 11 million men over the age of 40 who were prescribed such treatment had not undergone testosterone testing in the 12 months prior to beginning an androgen.4 This increase in prescribing may be due to direct to consumer marketing for “low testosterone syndrome” as well as conflicting prescribing guidelines.5
The actual prevalence of low serum testosterone in aging men is not known with certainty. Important cross-sectional and longitudinal studies have reported different prevalence rates of hypogonadism in men. The differences may be in part due to different definitions of hypogonadism adopted by these studies. Variables include low testosterone level definition, clinical symptoms used for the diagnosis of hypogonadism, the population studied, and the inclusion or exclusion of comorbid conditions in older men.6
The Hypogonadism in Males (HIM) study estimated the prevalence of hypogonadism [TT < 300 ng/dl] in men aged ≥ 45 years visiting primary care practices in the U.S. Of 2162 patients, 836 were hypogonadal, rendering a prevalence rate of 38.7%. Odds ratios for having hypogonadism were significantly higher in men with hypertension (1.84), hyperlipidemia (1.47), diabetes (2.09), obesity (2.38), prostate disease (1.29), and asthma or chronic obstructive pulmonary disease (1.40) than in men without these conditions.7
In a report from the European Male Aging Study (EMAS), 2966 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.8 The combination of low serum testosterone (< 317 ng/dL) and 3 sexual symptoms, was seen in only 2.1% of men (n=63). More severe hypogonadism (serum testosterone concentration < 230 ng/dL) was seen in 27 of the 63 (0.9%) 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, and 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 than when it was in the 230 to 317 ng/dL range. This data supports the concept of a low testosterone syndrome in middle-aged and older men, but only in a small percentage of men.
Symptoms of testosterone deficiency are varied and can occur with a myriad of other illnesses. Symptoms and signs suggestive of androgen deficiency include low libido, decreased morning erections, loss of body hair, low bone density, gynecomastia, and small testes. Symptoms and signs such as fatigue, depression, loss of motivation, decline in cognitive function, anemia, reduced muscle strength, and increased fat mass are not specific to, and not directly correlated to, specific levels of testosterone. It is difficult to ascertain which condition caused the other. For example, obesity is strongly associated with a decrease in testosterone. This relationship is complex and likely to be bidirectional. Obesity can give rise to low testosterone, insulin resistance, the metabolic syndrome, and cardiovascular changes. Hypogonadism can also promote fat accumulation, insulin resistance, the metabolic syndrome, and cardiovascular changes. While treatment with testosterone has been reported to improve some of these conditions, it is equally valid that weight loss will not only improve the comorbidities but will also increase the serum testosterone. The appropriate treatment for such functional declines in serum testosterone is not testosterone therapy but reversing the underlying condition. The most logical approach is lifestyle modification, weight reduction, and good treatment of comorbid diseases.9,10
The laboratory diagnosis of testosterone deficiency is a challenge. Serum testosterone levels are subject to variation— diurnal, seasonal, and age-related. Illness and certain medications, such as opiates and glucocorticoids, can temporarily affect testosterone concentrations through central and peripheral effects.11 When low testosterone is suspected, serum TT is initially measured, sometimes followed by measurement of FT. Additional laboratory tests may be required to characterize the etiology of hypogonadism as primary or secondary. In certain clinical situations, genetic testing is also appropriate to identify etiology.
Contemporary assay techniques to assess TT include immunoassays (IA) and mass spectrometry (MS). Currently, the most accurate method for determining the TT to differentiate eugonadal from hypogonadal males is liquid chromatography-tandem MS. Despite the recognition of MS as a reference technique, the reliability of results depends upon regular calibration maintenance, which is labor intensive and limits the ability to achieve consistently high throughputs without deterioration. Few studies discussing testosterone supplementation report details on specifics of the testing modality itself.12
FT is measured either through direct assays or indirectly via several different published calculations. The equilibrium dialysis is the gold standard for the direct measurement of FT concentrations. This method is very complex and is typically only available in reference laboratories. Universally accepted methods of calculating FT do not exist. The calculations of FT are limited by assumptions made for the equilibrium dissociation constants for the binding of SHBG and testosterone, and albumin and testosterone. In addition, there is no agreed standard for determining the SHBG.
Furthermore, results of testosterone measurements are affected by patient factors, such as glucose intake, triglyceride (TG) levels, medications taken, and initial processing of a sample. Pre-analytical factors include various technical factors, such as types of collection tubes used to obtain samples, sample centrifugations, intermediate storage, and environmental conditions of sample transport. For example, storage of serum or plasma in collection tubes following centrifugation can affect the results of measured testosterone after processing; storage in ethylenediaminetetraacetic acid (EDTA) can adversely affect SHBG measurement and thereby affect the calculation of FT.
All of the above makes analysis of testosterone deficiency treatment very difficult. From a clinical aspect, the same result should be obtained if blood was drawn from the same patient, at the same time, and sent to different laboratories, a scenario that is not common at present.12
Definition of Low Testosterone
In healthy males, the circadian rhythm causes testosterone levels to change throughout the day. Testosterone levels are highest in the morning and start to decline by 10 am. Because levels are suppressed by glucose ingestion,13 the evaluation of primary hypogonadism should be undertaken with a fasting TT level performed in the morning before 10 am. Clinicians should use an accurate and reliable method, optimally, an assay that has been certified by an accuracy-based standardization or quality control program [e.g., Centers for Disease Control and Prevention (CDC) Hormone Standardization Program for Testosterone]. If this level is below 280 ng/ml further testing is warranted, with at least 2 separate serum testosterone levels taken on 2 different days at least 1 month apart, preferably using the same laboratory with the same method/instrumentation for measurement. It is important to confirm low TT concentrations, because 30% of men with an initial TT concentration in the hypogonadal range have a normal TT concentration on repeat measurement.14 Some have suggested establishing age-adjusted normal values and recommend not defining hypogonadism in older men until serum levels are below 200 ng/dL, rather than 280 ng/dL. In men with 200-300 ng/dL and who have a condition that alters sex hormone binding globulin (obesity, type 2 diabetes mellitus), FT should be obtained using either equilibrium dialysis or estimating it using an accurate formula. If the FT is normal there is no need for testosterone therapy.15
Medications such as glucocorticoids and opioids can affect testosterone levels, as can acute or subacute illness. Therefore, testosterone levels should not be measured while a patient is receiving these medications, and testing should wait until a patient has recovered from being ill. If a low testosterone level is confirmed on 2 occasions, testing of LH and FSH should be performed.14 Elevated LH/FSH confirms primary hypogonadism and the potential need for replacement hormone. Two testosterone determinations which are low, along with normal or low LH and FSH levels, confirms secondary hypogonadism. Only patients with low testosterone associated significant symptoms should be considered for treatment.15
Potentially reversible pituitary disease or chronic diseases such as hemochromatosis, should be assessed with further testing. A comprehensive examination should evaluate for medications or chronic diseases known to cause decreased energy, memory problems, impotence, and mental health problems as these issues should be treated first. For example, Viana Jr., et al.16 conducted a small retrospective review of 153 non obese men with obstructive sleep apnea (OSA) and found a significant association between OSA severity, oxygen desaturation index (ODI), and a reduced testosterone level in 3 men > age 50. The significant association of low TT levels with high apnea-hypopnea index (AHI) values suggest that gonadal dysfunction is a consequence of OSA rather than a primary condition independent of the hypothalamic-pituitary-gonadal axis.
Benefits and Risks
March 2015, at the joint meeting of the Bone, Reproductive, and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the U.S. FDA, experts mandated that package labeling for testosterone must state that “the efficacy and safety for testosterone therapy in age-related hypogonadism have not been established,” and that there is biological plausibility for so-far weak cardiovascular safety signals and “the potential signal for increased cardiovascular and stroke risk”. They reiterated the original FDA approval which indicated that testosterone is approved as replacement therapy only for men who have confirmed low testosterone due to disorders of the testicles, pituitary gland, or brain that cause a condition called hypogonadism. The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone. This FDA instruction has specifically made testosterone treatment of aging-related, idiopathic and metabolic hypogonadism “off-label”.2
The multicenter Testosterone Trials (TTrials),17 published in 2016, were a coordinated set of 7 double-blind placebo-controlled trials at 12 U.S. academic centers to assess the 1-year efficacy of testosterone versus placebo gel in 788 men, 65 years or older with hypogonadism who had self-reported and objective impairment of sexual and physical function and/or vitality, and an average of 2 morning serum testosterone concentrations < 275 ng/dL. The initial dose of the gel (5 g daily) was adjusted at months 1, 2, 3, 6, and 9, to keep the serum testosterone concentration within the normal range for young men. To allow the results to be widely applicable to older men with low testosterone, they included men with comorbid conditions, unless those conditions might have exposed the men to excessive risk. Thus, they excluded men with a history of prostate cancer and those whose risk (using the Prostate Cancer Risk Calculator) of any prostate cancer was > 35% and that of high-grade prostate cancer was > 7%. They also excluded men whose lower urinary tract symptoms were moderately severe, as judged by an International Prostate Symptom Score > 19. They excluded men with any cancer and those with severe cardiac, renal, or hepatic disease. The enrollees participated in 1 or more of 3 main trials (the Sexual Function Trial [n = 470], the Physical Function Trial [n = 390], and the Vitality Trial [n = 474]). They could also participate in any of the other trials for which they qualified.17
Significantly, over 51,000 men were screened to enroll the 790 men who met inclusion criteria (only 1.5% of those screened). The median pretreatment testosterone concentration was 232 ng/dL. After 1 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 median serum testosterone concentration of the men treated with testosterone increased from unequivocally low at baseline to mid-normal for young men by month 3 and remained at that level during the 12 months of treatment. Of the 394 men in the testosterone arm, 301 required 504 adjustments of the dose at months 3, 6, and/or 9 to maintain the testosterone level within the target range. The levels of TT did not change in the men who used placebo gel. Of the 788 enrollees, 689 participated in more than 1 of the 3 main trials, and many also participated in 1 or more of the other trials.
Inclusion in the Sexual Function Trial required self-reported decreased libido, a score of 20 or less on the sexual desire domain range (0-33) of the Derogatis Interview for Sexual Functioning in Men-II, and a partner willing to have intercourse at least twice a month. Primary outcome was change in baseline in the score for sexual activity with secondary outcomes of erectile function and sexual desire. Testosterone therapy was associated with a moderate improvement in sexual function, including sexual activity, sexual desire (libido), and, to a lesser extent, erectile function. Sexual activity was assessed by the Psychosexual Daily Questionnaire which assesses 12 types of sexual activity, from flirting to intercourse. Testosterone treatment, compared with placebo, substantially increased sexual activity, of all types, about 4 times a week. The clinical significance of the effect of testosterone on libido was judged by the responses to the Patient Global Impression of Change question, in which 20% of men treated with testosterone reported that their sexual desire was “much better” than before treatment compared with 10% of men treated with placebo. These results are also consistent with another 16 week placebo-controlled study of a different testosterone gel in 751 men with a mean age of 55 years who had low testosterone levels.18
Testosterone has long been recognized to stimulate the growth of muscles and increase muscle strength, resulting in greater muscle development during puberty in men than in women. Administration of testosterone to older men also increases muscle mass and, in some studies, increases muscle strength.19 Inclusion in the Physical Function Trial required self-reported difficulty in walking or climbing stairs and a gait speed of at least 1.2 m per second on the 6 minute walk test. Men who were not ambulatory were excluded. Primary outcome was increased distance in the 6 minute walk test. There was no significant difference between the testosterone- versus placebo-treated groups in walking distance on a 6 minute walk test in the 390 men who were enrolled in the physical function trial, but testosterone did improve walking distance by a small amount when all 788 men were included. In 2 trials reported while the TTrials were in progress, testosterone treatment of moderately frail older men improved muscle strength but did not clearly or consistently improve physical performance.19-21
Many physicians believe that testosterone improves mood, although data is inconsistent because few trials used validated questionnaires. Low certainty evidence demonstrated a small improvement in quality of life as measured by the Aging Males’ Symptoms (AMS) scale, however, this change might have been driven solely by improvement in sexual function which is an AMS subscale.8,22 The Vitality Trial enrolled men who had self-reported low energy and scored less than 40 on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. This questionnaire has been validated for assessing energy vs. fatigue in many different diseases. Testosterone, compared with placebo, did not substantially increase vitality, as determined by an increase of ≥ 4 points on the FACIT-Fatigue scale for the 474 men enrolled in this trial (the primary outcome), although it was statistically significant for all 788 TTrials men. The effect of testosterone on mood (determined using the positive and negative affect scales), and depressive symptoms (determined using the Patient Health Questionnaire) was statistically significant. The magnitude of each of these effects, however, was small.
Testosterone has long been known to stimulate erythropoiesis, which explains why normal men have higher hemoglobin levels than normal women. Before the availability of erythropoietin, testosterone was actually used to treat anemia. The goal of the Anemia Trial was to determine whether testosterone treatment for older men with low testosterone and unexplained mild anemia (hemoglobin < 12.7 g/dL) would increase their hemoglobin by ≥ 1.0 g/dL and correct the anemia. Those with severe anemia (hemoglobin < 10.0 g/dL) were excluded. Of the 788 men enrolled in the TTrials, 126 were anemic at baseline. Of these, 64 were found to have a known cause of the anemia, such as iron, B12, or folate deficiencies or inflammation. The other 62 were considered to have unexplained anemia of aging. In the men with unexplained anemia, testosterone treatment, compared with placebo, substantially increased the hemoglobin concentration by ≥ 1.0 g/dL (54% vs. 15% of men) and corrected the anemia (58.3% vs. 22.2% of men). In the men with anemia of known cause, testosterone also substantially increased the hemoglobin concentration by ≥ 1 g/dL (52% vs. 19%) and corrected the anemia (60% vs. 14.8%). The magnitude of the effect was modest, with a mean increase in hemoglobin to greater than baseline of 0.8 to 1.1 mg/dL at months 6 to 12. Testosterone-treated men were nearly 4 times as likely to have hematocrit > 50% as placebo-treated men (OR = 3.69, 95% CI, 1.82-7.51).
With this benefit, comes a risk, particularly with testosterone ester injections. More men in the testosterone group experienced erythrocytosis (hemoglobin ≥ 17.5 g/dL) (7 versus 0). This is of concern because the risk of venous thromboembolic disease is directly related to hematocrit. Standard labeling of testosterone products in the U.S. has information about the risk of venous thromboembolism (VTE) as a consequence of the erythrocytosis. In a meta-analysis of 3 placebo-controlled clinical trials that enrolled a total of 1543 participants, erythrocytosis occurred in 16 men in the testosterone arms compared with 1 man in the placebo arms.
Previous studies of the effect of testosterone on bone in men who were severely hypogonadal showed marked increases in areal bone mineral density (aBMD) by dual energy x-ray absorptiometry and estimated bone strength using magnetic resonance imaging (MRI). The 211 men in the Bone Trial underwent assessment of volumetric bone mineral density (vBMD) and bone strength by quantitative computed tomography (QCT) scanning at baseline and 12 months. After 12 months, testosterone significantly increased mean lumbar spine trabecular vBMD by 8.5% more than placebo (P ≤ 0.001; (7.5% versus 0.8%)), as well as lumbar peripheral and hip trabecular and peripheral vBMD and mean estimated strength of spine trabecular bone (11% versus 2.4%).23
Overall men with low TT levels may be at increased risk for cardiovascular disease as seen by elevated cardiovascular risk markers, but studies often lack clinical data indicating presence or absence of preexisting cardiovascular disease or other cardiovascular risk factors.24 Furthermore, it is not known whether improving the testosterone level to that of a healthy male, improves or worsens cardiovascular disease risk. A retrospective national cohort study of 8709 men with low testosterone (< 300 ng/dL) who underwent coronary angiography in the Veterans Affair (VA) system between 2005 and 2011, found an increased risk of MI and stroke in the patients receiving testosterone therapy. Among 1223 patients receiving testosterone therapy, 67 died, 23 had MIs, and 33 had strokes. At 3 years after coronary angiography, the Kaplan-Meier estimated cumulative percentages with events were 19.9% in the no testosterone therapy group vs. 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% (95% CI, −1.4% to 13.1%).25 A systematic review and meta-analysis of 27 placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events found the effect of testosterone therapy varied with source of funding. Overall in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events.26 The Cardiovascular Trial performed serial coronary computed tomographic angiography (CCTA) on 165 men at baseline and after 12 months of therapy. The primary trial endpoint was % change in noncalcified coronary plaque volume over the 12-month treatment period. In addition to the entry requirements to the TTrial itself, participants had to have a normal baseline renal function [estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m2]. Men were excluded if their weights were greater than 300 pounds, they had known allergy to iodinated contrast medium, they were unable to breath-hold for 10 seconds, they had a prior diagnosis of tachycardia or irregular heart rhythm, or they had undergone coronary artery bypass graft surgery. Total noncalcified plaque at baseline showed a slight but nonsignificant trend toward lower plaque volume with higher serum testosterone concentrations (P = 0.12). One year of testosterone therapy was associated with a greater increase than placebo in noncalcified coronary artery plaque volume, as measured by CCTA, although there was no change in the coronary calcification score in either group. Several cardiovascular biomarkers were also evaluated (total cholesterol, high density lipoprotein (HDL), TG, low density lipoprotein (LDL), glucose, insulin, hemoglobin A1C (HbA1c), D-dimer, C-reactive protein (CRP), Troponin) at baseline, 3 months, and 12 months. Testosterone treatment, compared to placebo, significantly decreased total cholesterol, HDL, and LDL from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin. Testosterone did not change TG, D-dimer, CRP, glucose, or HbA1c more than placebo.27 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. Testosterone treatment of 1 year for older men with low testosterone was not associated with more cardiovascular events; however, the number of men and the duration of treatment were not sufficient to draw definitive conclusions about the risks.28
Tao, et al.,29 conducted a review of 8 published clinical trials of 170 patients in the testosterone supplementation group to determine whether testosterone treatment would benefit patients with congestive heart failure (CHF). Information on exercise capacity, hemodynamic parameters, electrocardiogram indicators, muscle strength, echocardiography guidelines, and laboratory indexes were collected to assess clinical outcomes. They found that testosterone did not significantly improve exercise capacity, ejection fraction, systolic blood pressure, diastolic blood pressure, or high sensitivity CRP in men with CHF.
Finkle, et al.,30 conducted a cohort study of the risk of acute non-fatal MI following an initial testosterone prescription (N = 55,593) in a large health-care database. They compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the 1 year prior to the initial prescription (pre-prescription interval) (post/pre). Among men aged 65 years and older, they observed a 2-fold increase in the risk of MI in the 90 days after filling an initial testosterone prescription. The risk declined to baseline in the 91 to 180 days after initial testosterone prescription among those who did not refill their prescription. Among younger men with a history of heart disease, they observed a 2 to 3-fold increased risk of MI in the 90 days following an initial testosterone prescription and no excess risk in younger men without such a history. Among older men, the 2-fold increased risk was associated with testosterone prescription regardless of cardiovascular disease history, although this analysis was based on relatively small numbers of MI cases in each subgroup. Taken together, the evidence supports an association between testosterone therapy and risk of serious, adverse cardiovascular related events–including non-fatal MI.
While several studies have investigated the association between testosterone and the risk of arterial thrombosis, limited information is available regarding its risk of VTE, outside of the known increased risk of VTE due to testosterone induced erythrocytosis. A systematic review of randomized clinical trials (RCTs) looked at this question. In all, 2636 men were randomized to testosterone, and 2414 men to placebo. Sample sizes ranged from 101 to 790 men, and testosterone duration from 3 to 36 months. Five studies had a high risk of bias, largely driven by unclear randomization and outcome assessment. When data were pooled across RCTs, testosterone therapy was not associated with VTE compared with placebo (RR: 1.03, 95% CI: 0.49-2.14; I(2): 0%; low-quality evidence). Similar estimates were obtained for deep vein thrombosis and pulmonary embolism outcomes. Their systematic review suggests that testosterone is not associated with an increased risk of VTE. However, estimates were accompanied by a wide 95% CIs, and a clinically important increased risk cannot be ruled out.31
Prostate volumes and PSA increase in response to testosterone treatment. Because benign prostatic hypertrophy (BPH) is a testosterone dependent disease, there are theoretical concerns that testosterone treatment may increase the incidence of BPH and worsen urinary outflow obstruction. Calof, et al.,32 performed a meta-analysis of RCTs to determine the risks of adverse events associated with testosterone replacement in older men. Of the 417 studies identified, 19 met the inclusion criteria: testosterone replacement for at least 90 days, men ≥ 45 years old with low or low-normal testosterone level, RCT, and medically stable men. In the 19 studies, 651 men were treated with testosterone and 433 with placebo. The combined rate of all prostate events was significantly greater in testosterone-treated men than in placebo-treated men (OR = 1.78, 95% confidence interval [CI], 1.07-2.95). Rates of prostate cancer, PSA > 4 ng/ml, and prostate biopsies were numerically higher in the testosterone group than in the placebo group, although differences between the groups were not individually statistically significant.
During the TTrials, serum testosterone and PSA along with digital prostate exam were monitored at screening, 3, and 12 months. Testosterone treatment was associated with a small but substantially greater increase (P < 0.001) in PSA levels than placebo treatment. Serum PSA levels increased from 1.14 ± 0.86 ng/mL (mean 6 SD) at baseline by 0.47 ± 1.1 ng/mL at 12 months in the testosterone group and from 1.25 ± 0.86 ng/mL by 0.06 ± 0.72 ng/mL in the placebo group. Five percent of men treated with testosterone had an increase ≥ 1.7 ng/mL and 2.5% of men had an increase of ≥ 3.4 ng/ml. A confirmed absolute PSA > 4.0 ng/mL at 12 months was observed in 1.9% of men in the testosterone group and 0.3% in the placebo group. Four men were diagnosed with prostate cancer. These trials had too little statistical power nor were they carried out for a long enough time period to adequately evaluate whether testosterone treatment increases the risk of prostate cancer. Overall, when hypogonadal older men with normal baseline PSA are treated with testosterone, 5% had an increase in PSA ≥ 1.7 ng/mL, and 2.5% had an increase ≥ 3.4 ng/mL.33
In 2 previous epidemiologic studies, low testosterone levels were associated with cognitive impairment.34,35 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. They participated in the Cognitive Function Trial and were evaluated by delayed paragraph recall, as determined by the Wechsler Memory Scale, Revised, Logical Memory II. The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to −26), executive function (Trail-Making Test B minus A; range, −290 to 290), and spatial ability (Card Rotation Test; score range, −80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, −0.07 [95% CI, −0.92 to 0.79]; P = 0.88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (−0.28 [95% CI, −0.76 to 0.19]; P = 0.24), executive function (−5.51 [95% CI, −12.91 to 1.88]; P = 0.14), or spatial ability (−0.12 [95% CI, −1.89 to 1.65]; P = 0.89). 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).36
Serum testosterone levels and insulin sensitivity both decrease with age. Severe testosterone deficiency is associated with the development of insulin resistance. The Testosterone Effects on Atherosclerosis in Aging Men Trial was a placebo-controlled, randomized, double-blind trial. The participants were 308 community-dwelling men, ≥ 60 years old, with TT 100 to 400 ng/dL or FT < 50 pg/mL. A subset of 134 nondiabetic men (mean age, 66.7 +/- 5.1 years) underwent an octreotide insulin suppression test at baseline and at 3 and 36 months after randomization to measure insulin sensitivity. Testosterone administration for 36 months in older men with low or low-normal testosterone levels did not improve insulin sensitivity.37
The TTrials, in short, demonstrated that testosterone treatment of symptomatic older men with low testosterone levels is efficacious in improving sexual function, anemia, and bone density, all to modest degrees. Testosterone therapy was not efficacious in vitality, cognitive function, metabolic syndrome, or cardiovascular disease. Furthermore, testosterone therapy is associated with an increased risk in erythrocytosis, sleep apnea, and acne. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger and longer trial would be necessary to assess these risks with greater certainty.23,38
Where replacement is indicated, the dose of replacement therapy should be the least amount necessary to obtain a serum testosterone in the low normal range. Choice of testosterone regimen requires an understanding of their pharmacokinetics. Native testosterone is absorbed well from the intestine, but it is metabolized so rapidly by the liver that it is virtually impossible to maintain a normal serum testosterone concentration in a hypogonadal man with oral testosterone. The solutions to this dilemma involve modifying the testosterone molecule, changing the method of testosterone delivery, or both.
Several 17-alpha alkylated androgens (e.g., methyltestosterone) have been available for oral use for many years. Many endocrinologists who treat male hypogonadism think that these preparations are not fully effective in producing virilization, although no studies have tested these observations. In addition, several reports have described hepatic side effects with these preparations, including cholestatic jaundice, a hepatic cystic disease called peliosis hepatis, and hepatoma. For both of these reasons and because better preparations are available, the 17-alpha alkylated androgens should generally not be used to treat testosterone deficiency.39
An oral form of testosterone undecanoate (Jatenzo®) was approved by the FDA in March 2019. This is an oral softgel that is taken twice daily. Because subjects in the original trial exhibited an increase in mean systolic blood pressure, there is a boxed warning label advising monitoring for new onset hypertension or exacerbation of pre-existing hypertension.40
A nasal testosterone gel (Natesto®) is approved in the U.S. for the treatment of male hypogonadism. The gel is administered into the nostrils via a metered-dose pump applicator. One pump actuation delivers 5.5 mg of testosterone; the recommended dose is 11 mg (2 pump actuations, 1 in each nostril), 3 times daily (total 33 mg/day). One advantage over other formulations is the minimal risk of gel transfer to a partner or child. On the other hand, some men may find the 3 times daily regimen inconvenient, and men with allergies or underlying nasal or sinus pathology may have trouble tolerating the formulation as ≥ 3% of subjects in clinical trials experienced rhinorrhea, epistaxis, nasopharyngitis, sinusitis, and nasal scab.15
Testosterone enanthate and testosterone cypionate are esters of testosterone that have been used for many years for the treatment of testosterone deficiency. Intramuscular (IM) injection of testosterone esters results in their storage in and gradual release from the oil-based vehicle in which they are administered, thereby prolonging the presence of testosterone in the blood. An advantage of these products to some men is freedom from daily administration. The disadvantages are the need for deep IM administration of an oily solution every 1 to 3 weeks and fluctuations in the serum testosterone concentration, which results in fluctuations in energy, mood, and libido in many patients. These fluctuations are more pronounced as the dosing interval is increased.41
An extra-long lasting IM formulation of another ester of testosterone, testosterone undecanoate, is available. The dosing is 750 mg in 3 mL of oil injected only into the buttocks. The initial dose is followed by a second dose 4 weeks later and by subsequent doses every 10 weeks. Data provided by the manufacturer demonstrate that, after the third injection, the average peak serum testosterone value occurs approximately 1 week after an injection and is followed by a gradual decline until the next injection. The serum testosterone concentration at approximately 5 weeks would provide an approximate average for the interdosing period. The extra-long acting preparations have been associated with rare cases of pulmonary oil microembolism (POME) and anaphylaxis (1.5 and 0.4 cases per 10,000 injections, respectively). In the U.S., the drug is available only through a restricted program called the AVEED Risk Evaluation and Mitigation Strategy (REMS) Program. All injections must be administered in an office or hospital setting by a trained and registered health care provider and monitored for 30 minutes afterwards for adverse reactions.42
A formulation of testosterone enanthate for subcutaneous injection by autoinjector (Xyosted®) once a week is now available. A total of 150 patients in a single arm dose blinded 52 week study found 92.7% of patients achieved an average TT concentration of 300 to 1,100 ng/dl (mean ± SD 553.3 ± 127.29) at week 12. Of the patients more than 95% reported no injection related pain. The most frequently reported treatment emergent adverse events were increased hematocrit, hypertension, and increased PSA, which led to discontinuation in 30 men. The dose adjusted subcutaneous testosterone enanthate auto-injector demonstrated a steady serum TT pharmacokinetic profile with small peak and trough fluctuations. The device was safe, well tolerated and virtually painless, indicating that this subcutaneous testosterone enanthate auto-injector offers a testosterone delivery system that is a convenient weekly option to treat testosterone deficiency.43
The skin and oral mucosa are also considered favorable routes for the delivery of testosterone. One transdermal patch (Androderm®) is available in the U.S. It relies upon chemical means to increase the absorption of testosterone across nongenital skin, and it is meant to be worn on the arm or torso. It delivers approximately 2 or 4 mg of testosterone per 24 hours and results in normal serum testosterone concentrations in the majority of hypogonadal men. Skin tolerability problems affects compliance with transdermal patches and can be ameliorated by pretreating the skin with cortisone cream.
Topical agents are administered daily in a low dose such that the risk of supraphysiological or subtherapeutic levels is minimized. Four testosterone gels (Androgel®, Testim®, Vogelxo®, and Fortesta®) and 1 solution (Axiron®) are available. Generic versions of most gels are also now available. Indeed, in series examining the toxicity of topical agents, adverse events are nearly nonexistent when administered by these routes.41 The main disadvantage of the topical agents are their high cost ($100 to $150 per month), as well as the potential risk of inadvertent transfer of hormone to women or children through skin contact. The possibility of skin transfer to another person is very low if the patient follows the package insert directions that include washing hands thoroughly after application and avoiding skin contact until the gel has dried completely.
A subcutaneous testosterone pellet (Testopel®) is available. The manufacturer recommends 3 to 6, 75 mg testosterone pellets every 3 to 6 months. The pellets are surgically implanted into the subdermal fat of the buttocks, lower abdominal wall, or thigh with a trocar under sterile conditions and a local anesthetic. Testosterone pellet implants release testosterone at a steady rate of 1.3 mg/200 mg implant/day (95% CI).44 Adverse events include pellet extrusion, hematoma formation at injection site, infection, and fibrosis. Handelman, et al.,45 conducted a retrospective review of the past 13 years with 973 implant procedures in 221 men. Overall rate of adverse events (108/973, 11.1%) was significantly related to increased numbers of implants (4.2±0.1 vs. 4.0±0.03, P = 0.031) and higher levels of physical activity at work (P = 0.030). The most common adverse effect was extrusion (83/973, 8.5%) which was related to occupational classification (P = 0.033) and increasing work activity (P = 0.044) and occurred more frequently than by chance in multiple (16 vs. 3.3 expected) rather than single (65 vs. 76.1 expected) episodes. Bleeding (22/973, 2.3%) was significantly associated with an increased number of implants (4.5±0.2 vs. 4.0±0.03, P = 0.020) but even in the worst cases (3/22) it was of minor clinical importance. Infection was rare (6/973, 0.6%) but occurred more among thinner men.
The annual cost in 2016 per beneficiary for testosterone was $2135.32 for the transdermal and $156.24 for the IM formulation, according to paid pharmaceutical claims provided in the 2016 Medicare Part D Drug Claims data.22 The annual cost for Testopel® with insertion is approximately $3133.
Guidelines for the diagnosis of male hypogonadism as well as testosterone treatment and contraindications to testosterone have been developed by the American College of Physicians (ACP) and endorsed by the American Academy of Family Physicians.22 Similar recommendations have been made by the Endocrine Society15 as well as the American Urological Association.14 Testosterone therapy impairs fertility by suppressing pituitary LH secretion (essential for spermatogenesis), as well as shrinks testicular tissue. It is contraindicated in those interested in reproduction.22 Given the possible increase in cardiovascular risk, patients who have had an MI, cardiac revascularization, or a stroke within the past 6 months are not good candidates for replacement therapy. Testosterone is contraindicated in men with thrombophilia. It is prudent to make sure that traditional cardiovascular disease risk factors including smoking, hypertension, hyperlipidemia, and diabetes have been assessed and are appropriately managed in men prescribed testosterone replacement. Because testosterone is aromatized to estradiol, it is contraindicated in men with breast cancer. A man who has a history of prostate cancer should not be treated with testosterone. A possible exception is a hypogonadal man who had a radical prostatectomy for cancer confined to the prostate and has been free of disease and has had an undetectable PSA for at least 2 years. Testosterone treatment should not be initiated if the patient has a prostate nodule or induration, a PSA > 4 ng/mL or > 3 ng/mL in men at increased risk of prostate cancer (e.g., African American men or those who have a first-degree relative with diagnosed prostate cancer), a hematocrit > 48%, untreated severe OSA, or severe lower urinary tract symptoms.15
Due to the risk of erythrocytosis, all patients should undergo a baseline measurement of hemoglobin/hematocrit prior to commencing testosterone therapy. If the hematocrit exceeds 50%, clinicians should withhold testosterone therapy until the etiology is formally investigated. While on testosterone therapy, a hematocrit ≥ 54% warrants intervention, such as dose reduction or temporary discontinuation.15
PSA should be measured prior to the commencement of testosterone therapy in patients over 40 years of age in order to minimize the risk of prescribing testosterone therapy to men with occult prostate cancer. For patients who have an elevated PSA at baseline, a second PSA test is recommended to rule out a spurious elevation. In patients who have 2 PSA levels at baseline that raise suspicion for the presence of prostate cancer, a more formal evaluation, potentially including a prostate biopsy with/without MRI, should be considered before initiating testosterone therapy. Men over age 50 years (or 40 years if they are at high risk) who begin testosterone treatment should be reevaluated for prostate cancer 3 months and 1 year after beginning treatment and thereafter according to the standard of care. PSA should be repeated 3 to 6 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, testosterone should be stopped and the patient referred for urologic evaluation.15
Patients who are treated with testosterone must be monitored to determine that normal serum testosterone concentrations are being achieved. Monitoring should be done 2 to 3 months after initiation of treatment and after changing a dose. The therapeutic goal should be a testosterone value well within the normal range (400 to 700 ng/dL) to lower the risk of testosterone-dependent diseases.
The timing of serum testosterone measurements varies with the preparation that is used:
- Serum testosterone should be measured midway between injections in men who are receiving testosterone enanthate or cypionate.
- The serum testosterone can be measured at any time in men who are using the transdermal patch, with the recognition that the peak values occur 6 to 8 hours after application of the patch.
- Serum testosterone concentrations vary substantially when a gel is used but not in a predictable way. Multiple dose adjustments are needed to maintain serum testosterone. Therefore, the Endocrine Society suggests 2 serum testosterone measurements before making dose adjustments.
After therapeutic levels have been achieved, all patients on testosterone therapy should have serum testosterone levels checked every 6-12 months to ensure maintenance of target levels.14 Clinicians should discuss the cessation of testosterone therapy 3 to 6 months after commencement of treatment in patients who experience normalization of TT levels but fail to achieve symptom or sign improvement. The American Urologic Association nor the Endocrine Society make any recommendations as to ideal type of therapy. Evidence from indirect comparisons suggests no substantial differences in clinical effectiveness, benefits, or harms between IM and transdermal testosterone applications, although very little evidence exists from direct comparisons of the 2 formulations. Because the 2 formulations are similar in terms of benefits and harms but the IM formulation is substantially cheaper ($156.32 vs. $2135.32 per person per year for the transdermal option), the IM application is the preferred testosterone treatment by the American College of Physicians.22 There is no preference stated in guidance from the AUA or Endocrine Society.14,15