Given the relative non-specificity of symptoms associated with low testosterone, a need exists to define a total testosterone threshold to guide clinicians in the diagnosis and management of the testosterone deficient male. The Panel believes that total testosterone <300 ng/dL is the proper threshold value to define low testosterone. This will increase clinicians' confidence regarding the risk-benefit ratio of testosterone therapy, explicitly place a higher value on maximizing true benefit, and reduce clinically inefficacious testosterone therapy. To support this threshold, a series of RCTs of testosterone therapy were evaluated, all of which used a cutoff of total testosterone <350 ng/dL as inclusion criterion. Across these studies, the median baseline total testosterone was 249 ng/dL, with interquartile ranges of 233 - 283 ng/dL.

A number of medical societies (e.g., American Society of Andrology, Endocrine Society, European Association of Urology, European Academy of Andrology, International Society of Andrology, International Society for the Study of the Aging Male) have used various thresholds to define low total testosterone, ranging from 230-350 ng/dL. Large-scale population studies that have attempted to quantify the prevalence of testosterone deficiency have also established 250-350 ng/dL (concurrent with certain symptoms and signs) as the threshold for the diagnosis of testosterone deficiency.^4-8

Establishing total testosterone thresholds for a diagnosis of testosterone deficiency is challenging considering the heterogeneity that exists in the testosterone deficiency literature. There is a great deal of variability across studies with respect to the forms of testosterone measured (total versus free), the assays utilized to measure testosterone, the time of day when the sample is obtained, and the number of testosterone measurements taken. The most accurate testosterone measurements are obtained in the early morning and on more than one occasion, which is not uniform across testosterone trials. 

The Panel recommends that clinicians use the same laboratory with the same method/instrumentation for serial total testosterone measurement. Where possible, clinicians should use LCMS to measure total testosterone levels to maximize accuracy and limit CV between tests in men undergoing testing, particularly in men with very low total testosterone levels. The Panel recognizes that not all laboratories use LCMS technology, and immunoassays may be the only measurement tool available to clinicians.

Some authorities have advocated that free testosterone should be the primary measure used to define testosterone deficiency. This is based on the concept that the free testosterone fraction is believed to be the most biologically active component. Although direct measurement of free testosterone has a generally good correlation with equilibrium dialysis, it is not reliable because of high CV. Given that the direct method for free testosterone measurement is also time-consuming and labor intensive, calculation derived free testosterone measurement is more commonly used, however there is considerable variation in total testosterone assays as well as the clinical conditions that affect serum albumin and SHBG, all of which impact this measurement.

The Panel does not recommend using free testosterone measurements as the primary diagnostic method for testosterone deficiency. Total and free testosterone are not to be considered interchangeable measures as there is no clear data that point to consistent thresholds between the two measures below which deficiency symptoms are observed and above which therapeutic benefits occur.^{15, 16} An analysis of 3,219 men (mean age 58 years) who had a single morning testosterone measurement suggested that using a free testosterone level added no value to the diagnosis of testosterone deficiency when the total testosterone level was <231 ng/dL. When total testosterone was between 230-317 ng/dL, the authors suggested that a free testosterone measurement may be helpful in diagnosis.⁸ Free testosterone also has a place in the diagnosis of testosterone deficiency in highly symptomatic patients with total testosterone levels in the low/normal or equivocal range.¹⁷

The Panel recognizes that in clinical practice there are men who have total testosterone levels >300 ng/dL who are highly symptomatic and who have anecdotally experienced symptom/sign improvement with testosterone therapy. The Panel urges clinicians to use their clinical judgment in the management of such patients. One strategy is to further evaluate patients using adjunctive tests, which might strengthen an argument for a short-term trial of testosterone therapy. Such tests are discussed in Appendix C.

There are inherent challenges in testosterone measurement due to the health status of patients at the time of testing, circadian rhythms in testosterone production, intra-individual variability, and inconsistencies in the assays themselves. To ensure accuracy and precision, it is necessary to obtain at least two serum total testosterone measurements in an early morning fashion to diagnose patients with low testosterone. If a patient's first test is <300 ng/dL and the second test is normal, then the clinician should use his or her judgment to determine if a third test is to be used as a control.

At this time, there is no definitive evidence indicating what the optimal time interval should be between the two separate tests. Likewise, while some literature suggests that food ingestion might affect testosterone levels, the evidence is particularly weak, and the Panel does not recommend that clinicians insist on fasting prior to testing.

Circadian Rhythm. Among men with traditional (10p.m. to 6a.m.) sleep patterns, peak testosterone values occur around 3-8a.m., with 32-39% of the diurnal total decline occurring within the first 30 minutes of waking.^18-23 Older men experience diurnal blunting and more stability in testosterone levels throughout the day, while younger men undergo greater variation. Total testosterone values obtained at 4p.m. in men aged 30-40 years were 20-25% lower than measurements takes at 8a.m., while men aged 70 years experienced only a 10% decline between the two time points.²³

Intra-individual Testosterone Variability. Intra-individual testosterone variability is significant. Repeat measures can fluctuate 65-153% between tests, depending upon the assay utilized,²⁴ however using 2 or 3 measures can reduce this variability by 30-43%, respectively. To minimize these effects, two morning draws for testosterone are recommended before any clinical intervention.

Acute Illness. Acute illnesses should be considered when measuring testosterone levels, the presence of which can affect the accuracy of the test and lead to artificially decreased testosterone measurements. In a small study of young men with acute respiratory infections, mean total testosterone levels declined by 10%, with some cohorts experiencing reductions of up to 30%.²⁵

Total testosterone <300 ng/dL alone does not define testosterone deficiency. The diagnosis of testosterone deficiency must include the presence of symptoms and/or signs associated with low testosterone in combination with documented low total testosterone levels. Clinicians should make note of any patient-reported symptoms, particularly those listed in Table 5 and conduct a physical examination to assess patients for signs related to low testosterone. Making a diagnosis of testosterone deficiency in the absence of signs and/or symptoms increases the likelihood of making a false diagnosis and reduces the potential benefit of testosterone therapy. Clinicians should refrain from measuring testosterone levels in patients who are asymptomatic, do not exhibit signs related to low testosterone, or do not have any comorbid conditions that are associated with low testosterone.

A challenge in making the diagnosis of testosterone deficiency is that many of the symptoms reported by patients are non-specific and might be related to conditions other than low testosterone. Patients complaining of changes in mood (e.g., irritability, depression), decreased ability to focus, decreased intellectual function, perceived decrease in strength and physical function, loss of muscle mass (sarcopenia), increased fat mass (especially centrally-located visceral fat), erectile dysfunction ([ED], including absence of nocturnal/early morning erections), or decreased sex drive may exhibit these symptoms secondary to chronic stress, chronic fatigue, or depression rather than due to low testosterone levels.

Fatigue (especially afternoon fatigue) may be associated with low testosterone levels, but it is a symptom that is non-specific and can be attributed to other conditions. A meta-analysis of 4 observational studies involving 4,426 men, showed that men with low testosterone levels had a higher prevalence of fatigue than men with normal testosterone levels (OR=1.46; CI 1.16, 1.98).^26-29 While significant heterogeneity was not detected in this analysis, the thresholds used to define low testosterone varied among the studies. Those that used <350ng/dL as a cut-off to define low testosterone did not detect a significant association between reported fatigue and testosterone level (p=0.547),²⁹ but studies that used a lower cut-off found this correlation to be stronger.^26-28 A study of 203 men with documented type 2 diabetes (mean age 61.4 years) found that patients who had total testosterone <231 ng/dL (n=73) were significantly more likely (p=0.02) to report fatigue on the Androgen Deficiency in the Aging Male (ADAM) questionnaire than men who had total testosterone >231 ng/dL (n=130).²⁸ Similarly, a cross-sectional analysis of 355 diabetic men found that 68% of men (49/71) who had total testosterone <231 ng/dL and 64% of men (70/109) with testosterone 231-346 ng/dL reported fatigue on the ADAM questionnaire, while only half of men with total levels >346 ng/dL reported fatigue.²⁷ 

Men who have been diagnosed with depression are more likely to have low testosterone than men who are not depressed (OR=1.81; CI: 1.48, 2.32)^30-34 however, a meta-analysis of 7 observational studies that compared the prevalence of depression between men with low testosterone and men with normal testosterone did not detect a significant difference between the two groups (OR=1.23; CI: 0.92,1.63).^{1, 35-40} This is partly due to the subjective nature of depressive symptoms and the fact that the symptoms of depression can overlap with those associated with other conditions. Studies whose primary endpoint was to measure the association between depression and low testosterone found that men with low testosterone have a significantly higher incidence of depression as well as a shorter time to onset of depression. This is particularly pronounced in older men with low testosterone, who are 3-times more likely to have increased risk of depression when compared to men with normal testosterone (HR=3.2; CI 1.7, 5.9). After adjustment for age and comorbidities, low testosterone levels remained a statistically significant predictor of the age of onset of depression (HR=2.1, CI 1.3, 3.2; p=0.002).³⁹

ED (organic in nature) is a symptom that may be associated with low testosterone. The Panel recognizes that ED is often correlated with medical conditions that are themselves associated with low testosterone (e.g., low sex drive, diabetes, obesity) and that the presence of these comorbidities makes it difficult to isolate the association between low testosterone and ED or definitively state that low testosterone is an independent predictor of ED. The scientific literature examining the relationship between ED and low testosterone is further limited by the variability in, or absence of, the definition of ED, incomplete vascular comorbidity information, as well as variability in the thresholds used to define low testosterone.   Despite the methodological limitations, individual studies have shown a link between low testosterone levels and ED. The Panel recognizes ED as a symptom associated with low testosterone levels and clinicians are advised to measure total testosterone in all such patients.

Point estimates that measure the difference in testosterone levels between men with and without ED may appear statistically significant, but these estimates are not always clinically meaningful. Pooled analysis of 29 studies indicates that men with ED have lower testosterone levels than men without ED (mean difference = -47ng/dL; CI: -69, -25.52);^{37, 41-68} however, this difference, while significant, is negligible and does not provide the clinician with clinically relevant discrimination between these populations.

There does appear to be a trend towards lower total testosterone and a diagnosis of ED. The European Male Aging Study (EMAS)⁸ studied 3,369 men (mean age 59 years) and culled data on their sexual, physical, and psychological symptoms along with morning total testosterone measurements. Adjusted logistical regression showed an inverse relationship between total testosterone and the presence of ED, with a probability of experiencing ED increasing as total testosterone levels decreased. Specifically, the odds ratio for developing ED in men with total testosterone <317ng/dL was 1.64 (CI: 0.93, 2.80) compared to 1.94 (CI: 1.20, 1.83) in men with total testosterone <231ng/dL. An analysis of 625 men in the Massachusetts Male Aging Study (MMAS)⁶ used a single question to define ED and also showed an increase in ED risk as total testosterone levels decreased. However, after accounting for confounding variables (e.g., age, body mass index [BMI], comorbidities, depression), the study found that testosterone levels had no effect on the likelihood of having ED (OR=0.99; CI: 0.11, 1.11).

Other symptoms that may be associated with low testosterone include gynecomastia, history of infertility/difficulty conceiving, visual field changes (bitemporal hemianopsia), and anosmia.

Clinicians should conduct a targeted physical exam to examine patients for signs that are associated with low testosterone. This  assessment should include evaluation of general body habitus; virilization status (examination of body hair patterns and amounts in androgen dependent areas); BMI or waist circumference; evaluation for gynecomastia; testicular evaluation including size, consistency and masses; and presence of varicoceles.

Men who are obese (BMI ≥30) or who have increased waist circumference (>40 inches) should have their testosterone levels checked.⁶⁹ Although obesity is a confounding factor and is often associated with other conditions (e.g., diabetes), obesity is also associated with low testosterone levels. Obese men are almost five times more likely to have low testosterone than men who are not obese (OR=4.89; CI: 2.35, 10.17).^{43, 70-73} Unadjusted baseline measurements of 1,687 middle-aged men who were classified as normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9) or obese (BMI >30) showed that nearly a third of overweight/obese subjects had low total testosterone (<300 ng/dL) compared to 6.4% of men who were of normal weight.⁷¹ Another study in younger men (aged 19-24 years) with ED indicated that there was a statistically significant difference (p<0.001) in the prevalence of low testosterone between men who were stratified to BMI <27 (non-obese) and BMI >27 (obese).⁴³ A study in 225 men found that BMI was associated with low testosterone; specifically, there was a 2.2 fold increase in the odds of low testosterone for every 5-point increase in BMI.⁷⁴

Recent studies have explored the association between varicocele and low testosterone levels, and while there is no definitive evidence that varicocele presence is a cause of low testosterone, accumulating data suggest that ligation surgery might increase serum testosterone levels. A systematic review found that varicocele ligation results in significant improvement in testosterone levels in some men, with a mean improvement of approximately 100 ng/dL. At this time, identification of the optimal patient (based on age, varicocele grade, baseline testosterone level) has not been defined.⁷⁵

Gynecomastia is a benign enlargement of the male breast tissue that can occur at times of male androgen/estrogen change (alteration in testosterone/estradiol [E2] ratio), infancy, adolescence, or old age, and may be a sign of low serum testosterone. Male breast growth can be classified as pharmacological (associated with risperidone, cimetidine, anti-androgens, digoxin, clomiphene, methadone, marijuana, chlorpromazine), physiological (occurring in the neonatal period and at puberty), and pathological (in association with testosterone deficiency, testicular tumors, hyperprolactinemia, Klinefelter syndrome [KS], HIV disease, or cirrhosis). Histologically, the male breast contains both glandular and fatty tissue, and although gynecomastia may result from proliferation in either or both, proliferation of only the fatty tissue is termed pseudogynecomastia. Only 1% of male breast enlargement is caused by malignancy,⁷⁶ however with any enlargement of the male breast, the possibility of carcinoma should be considered.

Table 5: Symptoms and Signs Associated with Testosterone Deficiency

Anemia. It is believed that as many as one-third of older men have unexplained anemia,⁷⁷ and data from observational studies indicate that there is a significant association between low testosterone levels and reduced hemoglobin (Hb) levels. As such, all patients who have a history of unexplained anemia should have their testosterone tested. A meta-analysis of 10 studies showed that men with baseline low testosterone levels had significantly lower Hb values than men with normal testosterone (mean Hb difference: -0.65 mg/dL; CI -0.95, -0.36).^{26, 78-87} The significance of the relationship was independent of thresholds used to define low testosterone among the studies (196 ng/dL - 300 ng/dL) or study population, which included patients with spinal cord injury, diabetes, renal failure, and heart disease. A linear regression model run on cross-sectional data from EMAS that controlled for age, BMI, smoking status, and other comorbidities found that men who had moderate (231 ng/dL-317 ng/dL) and severe (<231 ng/dL) testosterone deficiency had significantly lower Hb as compared to testosterone replete patients.⁸

Bone Density Loss. While it has been estimated that more than one third of men over the age of 50 years with testosterone deficiency have bone density loss,^{88, 89} the evidence linking low testosterone levels to osteopenia/osteoporosis in older men is not definitive. Aging is associated with reduced bone mineral density (BMD), which can lead to risk of fractures.⁹⁰ Given the larger implications for men's health, particularly in elderly patients, the Panel recommends that men who present with low-trauma bone fractures (LTBF) have their testosterone measured. Clinicians might also consider obtaining a bone densitometry (DEXA) scan to establish a baseline measurement (Appendix C). Although a meta-analysis of 3 observational studies in elderly men (aged 60-74 years) showed no significant difference in BMD in patients who had  low testosterone levels compared to those who had normal levels (mean difference -0.19 g/cm², CI: -0.44, 0.05),^{26, 90, 91} serum E2 levels were found to be associated to BMD.^{88, 90} One study of 162 men aged 65-88 years who had total testosterone levels <300 ng/dL did find that low testosterone levels were a significant independent predictor of BMD loss after controlling for age, weight, height, and BMI (p<0.05).⁹¹ The association between low testosterone and BMD might extend to younger men as well. A retrospective review of 399 men (mean age 37 years) with a mean total testosterone of 308 ng/dL found that 35% of patients had BMD at osteopenic levels and 3% had osteoporosis. BMD increased in patients treated with testosterone therapy leading the authors to conclude that younger testosterone deficient men may benefit from having routine DEXA scans performed, particularly those with concomitant low E2 and low BMI.⁸⁹ 

Diabetes. Patients who have diabetes have been shown to have significantly lower testosterone levels than men who are not diabetic, and the American Association of Clinical Endocrinologists (AACE) recommends that men with type 2 diabetes be evaluated for testosterone deficiency.⁶⁹ A meta-analysis of 52 studies that compared testosterone levels in diabetic men and non-diabetic men showed a significant reduction in testosterone values in men who had diabetes (mean difference -73.57 ng/dL; CI: -84.20, -62.67).^{20, 54, 64, 92-137} The patient populations across studies had a high degree of heterogeneity and contained testosterone measurements taken at baseline that were unadjusted, which is problematic in diabetes analysis given that obesity is a potentially confounding factor. Another meta-analysis of 37 studies¹³⁸ found that diabetic men had significantly lower testosterone values than those who did not have diabetes; individual studies with adjusted point estimates also support this outcome.^{97, 133, 139} A multivariate logistic regression model from one study of 1,089 men who had total testosterone <300 ng/dL and type 2 diabetes identified diabetic neuropathy as an independent risk factor for low testosterone.⁹⁴ Corona et al. likewise found that the prevalence of low testosterone levels (defined as total testosterone of <300 ng/dL) was 24.5% in diabetic men as compared to 12.6% in the rest of the sample (p<0.0001), a difference that remained significance after adjustment for age and BMI.¹⁰⁷

Chemotherapy. A meta-analysis of 5 studies that examined the effects of chemotherapy on testosterone levels indicates that men with a history of chemotherapy have significantly reduced serum testosterone when compared to men who do not have such a history (mean difference -109.22 ng/dL; CI: -209, -8.69).^140-144 Although some of studies included in the analysis did not show a significant difference in testosterone levels in chemotherapy patients as compared to controls, the age of the patients might have been a contributing factor.  One study involving 1183 testicular cancer survivors (mean age 44 years) who underwent either surgery, radiotherapy, or two different chemotherapy protocols found that the odds of a testosterone deficiency diagnosis after treatment was over 7-times greater in the low-dose chemotherapy group (cisplatin 850 mg) and over 4-times greater in the high-dose chemotherapy group (cisplatin >850 mg) as compared to the controls (adjusted OR=7.9 and adjusted OR=4.8, respectively).¹⁴²

Testicular Radiation Therapy. Men who have had exposure of their testes during radiation therapy, either through direct or scatter radiation, are possibly at risk for low testosterone and the Panel recommends total testosterone measurement in such patients. While Leydig cells are less radiosensitive than germ cells, radiation exposure to the testis can impair testosterone production. Two studies^{145, 146} included in the evidence report that was developed in the support of this guideline suggest a link between radiation (in rectal cancer and prostate cancer patients) and low testosterone levels, however the studies are limited by heterogeneity in study populations, heterogeneity in radiation delivery, and the presence of confounders such as chemotherapy exposure. Conversely, a recent study exposing patient testes to radiation (3 patients 17Gy and 4 patients 24Gy) demonstrated normal testosterone levels up to 3 years after radiation exposure.¹⁴⁷

HIV. Men who are seropositive for HIV have been shown to have a higher rate of testosterone deficiency than the general population.³⁷ Cohort studies in HIV infected men have estimated the rate of testosterone deficiency in this group ranges from 17-38%,^{37, 148, 149} while population-based studies have estimated the rate of testosterone deficiency much lower.^{6, 37, 87} It was once thought that gonadal dysfunction in HIV infected men is caused by virus-induced reduction in Leydig cells, but in the post-antiretroviral therapy era, it is postulated that the etiology of testosterone deficiency can be attributed to malnutrition, cytokine activity, opportunistic infections/acute illnesses, or the HIV medications themselves.^{37, 148} HIV infected men who are testosterone deficient have also been shown to have concomitant elevated HbA1c levels (p=0.016) and are at higher risk for CVD (p=0.004) when compared to HIV+ patients who have normal testosterone levels.¹⁴⁸  Patients who are seropositive for HIV should have their testosterone levels measured given the co-morbidity risks as well as evidence culled from placebo-controlled randomized trials that indicates that HIV+ men respond favorably to testosterone replacement therapy^150-152 in absolute terms; QoL indicators; and muscle strength, size, and volume.

Chronic Narcotic Use. Men who have a history of chronic narcotic use are at an increased risk of opioid-induced androgen deficiency, which is characterized by low testosterone levels.⁴² A meta-analysis of 7 studies showed that men who were on opioid treatment for non-cancer related pain for at least 30 days had a significant reduction in testosterone levels (-117.11 ng/dL; CI -176.17, -58.04)^{42, 153-158} when compared to patients who were opioid-free.

Male Infertility. Testosterone deficiency is prevalent in men presenting for an infertility evaluation.¹⁵⁹  The testes contain germ cells that produce spermatozoa and Leydig cells that produce testosterone; any pathology of the testes can result in infertility and testosterone deficiency, conditions that frequently co-exist. A survey of 120 patients who were treated for infertility at the University of Illinois-Chicago found that the incidence of testosterone deficiency was 45% in men with non-obstructive azoospermia, 42.9% in men with oligospermia, and 16.7% in men with obstructive azoospermia.¹⁵⁹

Pituitary Disorders. Pituitary dysfunction may be a significant cause of testosterone deficiency. The pituitary gland sits in the sella turcica below the cerebrum and plays a critical role in testosterone physiology by producing luteinizing hormone (LH), which targets the Leydig cells in the testes stimulating them to produce testosterone. Serum testosterone and the downstream hormone E2 are involved in the feedback mechanism to the hypothalamus and pituitary to suppress LH production. In homeostasis, LH levels are typically low. With worsening Leydig cell function, there is a reduction in the feedback mechanism resulting in elevation of LH levels (hypergonadotropic hypogonadism). In conditions where LH is not produced in normal amounts (hypogonadotropic hypogonadism), testosterone deficiency may also result. The most common clinical causes of pituitary-associated hypogonadotropic hypogonadism include prolactinoma, pituitary radiation, pituitary removal, hemochromatosis/iron overload and certain parasellar processes. Functioning prolactinomas result in hyperprolactinemia, suppressing LH production and leading to low testosterone levels. The contemporary management of functioning prolactin secreting tumors is the use of medications, such as bromocriptine and cabergoline. Large pituitary tumors, functioning or non-functioning, may require surgical extirpation because of mass effect. Radiation to the brain that exposes the pituitary gland can also result in pituitary dysfunction and low testosterone. The hypothalamic-pituitary unit is highly radiosensitive. Thus, pituitary dysfunction can develop after radiation therapy for sellar, parasellar, and extrasellar neoplasms (e.g., craniopharyngiomas, meningiomas, germinomas, chordomas, hemangio-pericytomas, pituicytomas, gliomas), head and neck tumors, and following total body irradiation for systemic malignancies. Depending upon the radiation dose, delivery modality, and underlying tumor type, LH deficiency rates in patients whose pituitary gland has been exposed to radiation is 10-96%.¹⁶⁰

Chronic Corticosteroid Use. Men who have a history of chronic corticosteroid use have been shown to be at risk for low testosterone levels. An analysis of 3 studies with highly homogeneous populations showed that corticosteroid users had a significant reduction in testosterone levels when compared to men who were not on steroid therapy (-85.22 ng/dL; 95 CI: 105.17, -65.27).^161-163 In particular, men who are on long-term corticosteroid therapy are more likely to have a diagnosis of low testosterone (OR=1.82; CI: 1.15, 2.86).^162,250 In one study, 36 long-standing rheumatoid arthritis (RA) patients (mean duration of disease 17 years) aged 38-75 years were followed for 6 months to determine the effect of prednisone on testosterone levels. At the end of follow-up, RA patients who were on 5-10 mg of prednisone/day had a mean testosterone level of 356 ng/dL, which was a statistically significant difference from testosterone levels measured in healthy controls (409 ng/dL; p<0.05).¹⁶²  However, another study in 99 men with RA returned conflicting results: 74 men taking 5 mg/day of prednisone (with a cumulative dose of 8,633 mg) had an average total testosterone of 461 ng/dL, which was lower than those men who were not on steroid treatment (n=25; 545 ng/dL), but the difference was not statistically significant (p<0.06).¹⁶³

Varicocele. It is notable that the above conditions are included in the current guideline because they are both associated with low testosterone and have relevance to testosterone management.  For example, bone mineral density is both associated with testosterone, and treating low testosterone may improve bone mineral density.  There are other conditions which are associated with low testosterone but are not necessarily considered direct symptoms or definitively improve testosterone with subsequent treatment.  One such example is with the presence of varicoceles.  Although very limited data suggest that varicoceles (particularly grades II and III) may be associated with low testosterone, it is not clear if the treatment of varicoceles improves symptoms in non-infertile populations and with long-term durability.^{164, 165}  Given that infertile men likely represent a distinct cohort which is already recommended to undergo screening for low testosterone, the addition of varicocele as an independent trigger for screening was not felt to be sufficiently justified by the current data.   

Screening questionnaires are not an appropriate tool to identify candidates for testosterone therapy. Their role in diagnosing testosterone deficiency is unclear, and they should not be used at the expense of a full patient evaluation, including laboratory testosterone measurement.

Several validated questionnaires are used as screening tools to identify men at high risk for testosterone deficiency, but there is an absence of concordance among the questionnaires as to what symptoms are related to low testosterone or to what extent these symptoms improve with treatment. The validation studies for each questionnaire use a distinct total testosterone cut-off for defining low testosterone; however, total testosterone has been shown to correlate poorly with most questions.^{164, 165}

The validated instruments include ADAM, Quantitative ADAM, Aging Male Survey (AMS), MMAS, and the ANDROTEST.^{10, 166, 167} Specificities and sensitivities vary greatly amongst these tests making them ill-suited for screening or for use as a surrogate for testosterone laboratory testing. Higher sensitivities and lower specificities have been reported for the AMS and ADAM, with a sensitivity/specificity of 81%/19% and 97%/39%, respectively, for each questionnaire; while the MMAS and ANDROTEST exhibit lower sensitivities and higher specificities, with a sensitivity/specificity of 60%/53% and 71%/65%, respectively.¹⁰

LH, which is routinely measured by immunoassay, may help to establish the etiology of testosterone deficiency and can be an important factor in determining if adjunctive tests should be ordered (Appendix C - refer to the Appendix C section in the left menu).  A low or low/normal LH level points to a secondary (central) hypothalamic-pituitary defect, (hypogonadotropic hypogonadism), while an elevated LH level indicates a primary testicular defect (hypergonadotropic hypogonadism).¹⁶⁸ In men with hypogonadotropic hypogonadism, the yield from adjunctive tests (e.g., prolactin measurement, pituitary imaging, iron studies) is increased. However, the literature at this time fails to define the LH level below which such adjunctive testing is warranted.

Hypogonadotropic hypogonadism can result from a number of conditions, including congenital abnormalities (e.g., Kallman syndrome), as well as pituitary or suprasellar tumors, pituitary infiltrative disorders (e.g., hemochromatosis, tuberculosis, sarcoidosis, histiocytosis), medications (i.e., chronic narcotic exposure), hyperprolactinemia, prior head trauma, pituitary apoplexy, and severe chronic illness. In the event that a patient may have hypogonadotropic hypogonadism, adjunctive tests should be ordered.

Hypergonadotropic hypogonadism, which is not a contraindication to begin testosterone therapy, can result from a number of conditions, including congenital abnormalities (KS being the most common), iatrogenic causes (e.g., bilateral orchiectomy, testicular radiation, chemotherapy), testicular trauma, infection, or autoimmune damage. In some cases, the etiology is obvious (e.g., iatrogenic causes), in others, a karyotype may be warranted to establish a diagnosis of KS (47, XXY).¹⁶⁹ In other cases, it may not be possible to establish a definitive etiology.

Testosterone deficient patients with low or low/normal LH levels can be considered candidates for SERM use as a treatment for testosterone deficiency, particularly those wishing to preserve their fertility.¹⁷⁰ However, an LH level below which SERM response is optimized is not firmly established. 

In patients who have low total testosterone and low or low/normal LH levels (hypogonadotropic hypogonadism), serum prolactin should be measured to screen for hyperprolactinemia (Appendix C).^{168, 169} If a patient has elevated prolactin levels, prolactin measurement should be repeated to ensure that the initial elevation was not spurious. Men with total testosterone levels of <150 ng/dL in combination with a low or low/normal LH should undergo a pituitary MRI regardless of prolactin levels, as non-secreting adenomas may be identified.¹⁷¹

Hyperprolactinemia is an uncommon condition^{172, 173} but it is a well-established cause of secondary (central) testosterone deficiency and can lead to infertility, decreased libido, sexual dysfunction, and gynecomastia. Medications, most commonly dopamine antagonists (but also anti-psychotics, anti-emetics, proton pump inhibitors, calcium channel blockers, opiates, and selective serotonin reuptake inhibitors) may cause hyperprolactinemia.¹⁷³ Chronic medical conditions, such as hypothyroidism, renal failure, and cirrhosis are associated with hyperprolactinemia as well.¹⁷⁴ 

Persistently elevated prolactin levels can indicate the presence of pituitary tumors such as prolactinomas,¹⁷⁵ the most common functioning pituitary tumor. Current literature fails to support any specific level of prolactin elevation that is predictive of prolactinomas, however any persistent elevation in prolactin level may be associated.  While prolactin levels generally parallel tumor size, most are typically associated with prolactin levels above 250 mg/L,¹⁷⁵ although levels can exceed 1,000 mg/L.¹⁷⁶ Milder elevations in prolactin can be seen with prolactinomas as well as with other pituitary or parasellar tumors or infiltrative processes.^{176, 177}

Patients should be referred to an endocrinologist for further evaluation if the etiology for hyperprolactinemia cannot be established. An evaluation for a prolactinoma in such patients is imperative because these benign tumors can be effectively managed using medications, such as bromocriptine or carbergoline. Furthermore, the identification of other pituitary tumors or processes may have important clinical implications for the patient beyond testosterone deficiency.¹⁷⁸

Given the enzymatic conversion of testosterone to E2 by aromatase, it is not uncommon for E2 levels to increase while patients are on testosterone therapy.¹⁷⁹ Men who present with breast symptoms should have their E2 measured (Appendix C) and those with elevated E2 measurements (>40 pg/mL), should be referred to an endocrinologist. For men who develop gynecomastia/breast symptoms while on treatment (e.g., breast pain, breast tenderness, nipple tenderness), a period of monitoring based on clinical judgment should be considered, as breast symptoms sometimes abate.

Clinicians should be aware that symptomatic gynecomastia or other breast symptoms are an uncommon side effect in men on testosterone therapy. In randomized, placebo-controlled trials involving testosterone therapy this has been a rarely reported adverse event. Among all of the studies included in the evidence report for this guideline, only 3 returned gynecomastia events.^180-182 In one multi-center study across 16 sites, 227 men (19-68 years, untreated for low testosterone in the preceding four weeks) were given either 50mg of testosterone gel (n=73), 100 mg of testosterone gel (n=78), or a testosterone patch (n=76). After 180 days of treatment, only 1 patient in the 50mg gel arm, 3 patients in the 100mg gel arm, and no patients in the testosterone patch arm were found to have gynecomastia. Of these four men, two were known to have pre-existing gynecomastia.¹⁸⁰ 

Another multi-center study compared the effectiveness and risks of transdermal and IM testosterone in 66 men aged 22-65 years old. At the end of the 24-week trial, there was only 1 new case of gynecomastia in the transdermal group; 4/9 pre-existing cases either resolved or improved. In the IM testosterone group, there were no new cases of gynecomastia, and one patient with pre-existing gynecomastia had gynecomastia resolution.¹⁸¹

Finally, a randomized trial of 76 men (mean age 50.6 years), who had at least 1 ejaculatory dysfunction symptom and at least 2 testosterone tests <300 ng/dL, were put on 2% transdermal testosterone (60 mg daily) solution for 16 weeks. There was only 1 reported case of gynecomastia in the treatment arm (n=35) at follow up compared to no cases in the placebo group (n=35).¹⁸²

Men diagnosed with testosterone deficiency who are interested in preserving their current fertility should undergo testicular exam to evaluate testicular size, consistency, and descent and have their serum follicle-stimulating hormone (FSH) measured to assess their underlying reproductive health status (Appendix C).¹⁸³ Most of the testis is composed of reproductive tissue, such as germ cells and Sertoli cells, and it is common for men with reduced testicular volume to also have impaired sperm production.¹⁸⁴

FSH, a pituitary gonadotropin, targets the Sertoli cells within the testes and is a key regulator of spermatogenesis.^{187, 188}  Based on the hypothalamic-pituitary-gonadal feedback mechanisms, normal spermatogenesis is typically associated with an FSH level in the low/normal range.¹⁷¹ Elevated FSH levels in the setting of testosterone deficiency (hypergonadatropic hypogonadism) is typically indicative of impaired spermatogenesis, and in such patients, clinicians should consider fertility testing, such as semen analysis.¹⁷¹ Patients who have severe oligospermia (sperm concentration <5 million sperm per mL) or non-obstructive azoospermia should be offered reproductive genetics testing consisting of karyotype testing and Y-chromosome analysis for microdeletions.¹⁸⁵ The management of such patients is best conducted by a reproductive urologist.

Polycythemia, sometimes called erythrocytosis, is generally defined as a hematocrit (Hct) >52%. It is categorized into primary (life-long), often related to genetic disorders; and secondary (acquired), which is attributed to polycthemia vera, living at high altitude, hypoxia (e.g., chronic obstructive pulmonary disease, obstructive sleep apnea, tobacco use), paraneoplastic syndromes, and testosterone therapy.^{187 188}

Prior to commencing testosterone therapy, all patients should undergo a baseline measurement of Hb/Hct (Appendix C). If the Hct exceeds 50%, clinicians should consider withholding testosterone therapy until the etiology of the high Hct is explained.¹⁸⁷ While on testosterone therapy, a Hct ≥54% warrants intervention. In men with elevated Hct and high on-treatment testosterone levels, dose adjustment should be attempted as first-line management. In men with elevated Hct and low/normal on-treatment testosterone levels, measuring a SHBG level and a free testosterone level using a reliable assay is suggested. If SHBG levels are low/free testosterone levels are high, dose adjustment of the testosterone therapy should be considered. Finally, men with elevated Hct and on-treatment low/normal total and free testosterone levels should be referred to a hematologist for further evaluation and possible coordination of phlebotomy.

Androgens have a stimulating effect on erythropoiesis and elevation of Hb/Hct is the most frequent adverse event related to testosterone therapy.^189-191 During testosterone therapy, levels of Hb/Hct generally rise for the first six months, and then tend to plateau.^{192, 193}   

Among 5 randomized, placebo-controlled trials that evaluated Hb and Hct levels in men (mean baseline testosterone <300 ng/dL) using either gel, solution, or IM testosterone therapy for 12 weeks to 1 year, a significant increase in the incidence of elevated Hct was observed in those using testosterone (OR=6.46; CI: 1.86, 22.40) compared to those on placebo.^194-201 The calculated odds ratio belies the number of polycythemia events in absolute terms; 19 events in 1,094 patients occurred in the treatment arm as compared to 1 event in 1,093 patients in the placebo group.

While the incidence of polycythemia for one particular modality of testosterone compared to another cannot be determined, trials have indicated that injectable testosterone is associated with the greatest treatment-induced increases in Hb/Hct. In the current meta-analysis of RCTs, long-acting IM testosterone resulted in a mean increase in Hb levels of 1.4 mg/dL compared to 1.6 mg/dL with short-acting IM testosterone, 0.9 mg/dL with transdermal preparations, and 0.7 mg/dL with topical patches.^{150, 182, 194-196, 201-218}  This is likely due to the high and sometimes supra-physiological levels of testosterone that occur in the early days after injection.²¹⁹ A retrospective comparative series involving 175 men with testosterone deficiency who used different modalities of testosterone therapy reported that 19% of men receiving IM testosterone experienced polycthemia compared to 12.5% with testosterone pellets and 5.4% with gels.²²⁰

It is unclear if the risk of polycythemia is greater in men with comorbid disorders that predispose to hypoxia, such as chronic obstructive pulmonary disease or obstructive sleep apnea.¹⁸⁸ It is also currently unknown if rates of polycthemia are associated only with short-acting injectable agents or occur with equal frequency when using the longer-acting testosterone undecanoate.²²¹

In 2013, the AUA published the Early Detection of Prostate Cancer Guideline,²²² which makes no specific statements about PSA screening in men with testosterone deficiency or in men on testosterone therapy. It is the opinion of this Panel that serum PSA levels 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. 

PSA Response to Testosterone Therapy. PSA secretion is an androgen dependent phenomenon, and the rise of PSA levels in patients on testosterone therapy is primarily dependent upon baseline total testosterone levels. The literature indicates that men with lower baseline testosterone levels are more likely to experience PSA level increases. The Testim Registry in the United States followed PSA changes in men without prostate cancer who were on testosterone therapy. Participants (N=451) received 5-10g of 1% testosterone gel daily for 12 months. Patients were divided into 2 groups: A (n=197 with total testosterone <250ng/dL) and B (n=254 with total testosterone ≥250 ng/dL). In group A but not group B, baseline PSA levels correlated significantly with total testosterone levels (r=0.2; p<0.01). At the end of follow-up, PSA increased significantly in group A (21.9% change; 0.19±0.61 ng/mL; p=0.02) but not in group B (14.1% change; 0.28±1.18 ng/mL; p=0.06) with the greatest PSA change observed after one month of treatment.²²³

A meta-analysis of 9 RCTs that compared PSA changes in men who were treated with testosterone therapy to men who were on placebo showed that there was no difference in the risk of elevated PSA during or after the study period (OR=1.71; CI: 0.98, 3.00).^{197-199, 216, 217, 224-230} While these RCTs were not powered to detect an increase in PSA as a primary or secondary endpoint, each trial measured PSA at baseline, intermittently throughout treatment, and at the end of study. Across all 9 studies, 2,601 men (mean range 55-74 years) with testosterone <350 ng/dL (mean range 225-303 ng/dL) were randomized to placebo (n=1,165) or treatment with transdermal or IM testosterone (n=1,414) for a period of 12 weeks to 3 years. Of the nine trials, six did not detect a statistically significant difference in PSA values between the treatment and placebo arm at the end of study, while small increases in PSA elevations, defined as the number of men who had PSA elevated to >4 ng/mL or PSA increases ≥0.75 ng/mL from baseline at any time point, were found in three studies.^{227, 229, 230} A nested case-control study by Svartberg identified 2/19 men on treatment versus 1/19 men on placebo who had reportable increases of PSA during treatment (p <0.01), none of whom required cessation of testosterone therapy.²³⁰ Kaufman et al. found that 17/234 men on testosterone therapy compared to 0/40 men on placebo had reportable PSA increases, with all 17 men discontinuing treatment. Seven of these men stopped therapy based upon a single elevated PSA value even though the second PSA test was not elevated. One subject from the testosterone group was diagnosed with prostate cancer, which was deemed possibly treatment related.²²⁷ Finally, the Snyder Testosterone Trials reported that 23 men in the treatment arm (n=395) and 8 men in the placebo arm (n=395) had PSA increases >1.0 ng/dL during treatment, although p values were not reported. Only one man in the treatment group was diagnosed with prostate cancer during the study period; two more who had been on treatment and one on placebo were diagnosed in the following year.²²⁹ 

A 2005 meta-analysis by Calof et al.¹⁹⁰ pooled data from 19 RCTs to determine the number of all-cause prostate events in men who were on exogenous testosterone treatment compared to men who were on placebo. A total of 651 men (mean age 62.9 years) received oral, transdermal, or IM testosterone or placebo (n = 433) for a period of 12 weeks to 3 years. PSA levels at baseline did not differ between study arms (1.3 ng/mL) however, at the end of the study, more men in the testosterone group (57.1/1,000 patient years) reported PSA levels elevated to >4 ng/mL or PSA increases ≥1.5 ng/mL than in placebo-treated men (41.6/1000 patient years), a difference that was not significantly significant.

Elevated PSA Level Pre-Testosterone Therapy. 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 two PSA levels at baseline that raise suspicion for the presence of prostate cancer, a more formal evaluation, potentially including reflex testing (e.g., 4K or phi), and prostate biopsy with/without MRI, should be considered before initiating testosterone therapy.

PSA Testing in Men on Testosterone Therapy. Patients with testosterone deficiency who maintain testosterone levels in the normal range while on testosterone therapy should have their PSA levels tested, utilizing a shared decision-making approach, in accordance with the AUA's Early Detection of Prostate Cancer Guideline. Specifically, the AUA does not recommend routine PSA testing in men 40-54 years of age unless they are at higher risk (e.g., positive family history, African American race), at which point decisions regarding PSA testing should be individualized. In men 55-69 years of age, biennial PSA testing should be considered.

Currently available literature has consistently shown that low testosterone levels are associated with an increased incidence of major adverse cardiac events (MACE), such as myocardial infarction, stroke, and possible cardiovascular-related mortality. Furthermore, low testosterone levels are also associated with an increased prevalence of certain atherosclerotic CVD (ASCVD) risk factors. Testosterone deficient patients should be informed that low testosterone levels place them at risk for these major cardiovascular events and clinicians should assess all testosterone deficient patients for ASCVD risk factors, both fixed (e.g., older age, male gender) and modifiable (e.g., dyslipidemia, hypertension, diabetes, current cigarette smoking). The presence of ASCVD risk factors is not a contraindication to starting testosterone therapy; however, the optimization of modifiable risk factors in such patients using lifestyle and medical management strategies is recommended and may be best addressed by the patient's primary care provider. 

A meta-analysis of 7 observational studies indicated that men with low testosterone, as compared to men with normal testosterone, have an increased risk of myocardial infarction (OR=1.33; CI 1.12, 1.59);^{1, 79, 231-235} a pooled analysis 12 studies demonstrated an increased risk cerebrovascular accidents (OR=1.41; CI: 1.12, 1.59);^{79, 82, 231, 232, 234, 236-242} a meta-analysis of observational studies by Arujo et al. showed that men who reported lower (or low) testosterone levels had an increased risk of cardiac event-related death (RR = 1.25; CI: 0.97, 1.60) as well as all-cause mortality (RR=1.35; CI: 1.13, 1.62).²⁴³

Thirty-three studies that compared men with low testosterone to those with normal testosterone showed that testosterone deficient men were at significantly greater risk of having hypertension (OR=1.59; CI: 1.43, 1.77). ^{1, 7, 27, 28, 35, 40, 82, 231, 232, 234, 237, 239, 240, 244-263} Twenty-one studies indicated that men with low testosterone, as compared to men with normal testosterone levels, had significantly increased odds of having dyslipidemia (OR=1.34; CI: 1.12, 1.86). ^{7, 37, 40, 83, 231, 234, 237, 240, 247-250, 254-256, 258, 259, 262-265} 13 studies comparing the prevalence of obesity and 62 studies comparing BMI values showed that low testosterone patients are nearly twice as likely to be obese (OR=1.94; CI: 1.53, 2.47)^{27, 28, 148, 248-250, 254, 256-258, 266-268} and have higher BMI (OR=1.97; CI: 1.62, 2.31).^{1, 7, 26, 28, 38, 74, 78, 79, 81-86, 90, 101, 103, 107, 148, 233, 235, 237-242, 245, 247, 249, 251, 255, 257, 260, 262-265, 267-289} as compared to men with normal testosterone levels.

The ability of testosterone to independently predict future cardiovascular-related events remains controversial, with available data demonstrating mixed results after controlling for confounders.^{292 293} However, the predictive ability is less relevant given the strong association of testosterone to multiple cardiovascular risk factors.  As such, low testosterone is likely better considered as a covariate with these comorbid conditions rather than as an independent observation.  Similarly, regardless of its independent predictive ability, the presence of low testosterone remains strongly associated with cardiovascular disease and should lead clinicians to consider additional evaluations in this high-risk cohort.   

The main purpose of testosterone therapy is to return patients to normal physiological testosterone levels and provide relief of symptoms or signs. In trials, patients with low testosterone have demonstrated statistically significant improvements in erectile function, anemia, BMD, lean body mass, and depressive symptoms.

Erectile Function. ED is one of the primary reasons that men seek testosterone treatment. Two well-powered studies, Brock-Maggi (N=715)^{197, 198} and Snyder (N= 790)²²⁹ showed statistically significant mean improvements in the erectile function domain score of the International Index of Erectile Function (IIEF) of 2.64 and 2.80, respectively. In the pooled results of 6 trials,^{197, 198, 229, 290-295} which included Brock-Maggi and Snyder, a mean 1.32 (CI: 0.38, 2.26) point improvement was seen in the Erectile Function Domain Score in men on testosterone therapy. ^{1-89, 10}These results are consistent with other meta-analyses,²⁹⁶ yet methodological flaws in the study design may underestimate the true rate and magnitude of improvement in erectile function. Study limitations included failure to report baseline erectile function, failure to identify a population of men with isolated ED, study population heterogeneity, and inconsistent inclusion criteria across studies. Study duration was also short, with only one study performed for 52 weeks.²²⁹ This may underestimate the true benefits of therapy as long-term prospective data suggest ongoing and slowly progressive improvements in erectile function occurring up to three years after treatment initiation.²⁹⁷

While on testosterone therapy, patients with ED and testosterone deficiency often observe one or a combination of the following events: improved nocturnal erections, improved ease of attaining erections (even if non-functional), and improved ability to achieve a penetration hardness erection. While the Panel is unable to quantify what percentage of men with ED and testosterone deficiency experience clinically meaningful improvements in erectile function (in contrast to statistically significant improvements) or the ability to achieve a functional erection, it is clear that some men will have improvement in erectile function with testosterone therapy. At the present time, there are insufficient data available to predict which men with ED are most likely to respond to testosterone therapy.  

Sex drive. Sex drive (sexual desire) is a complex aspect of sexual function and is difficult to objectively measure. The sexual desire domain of the IIEF is a commonly used standardized tool that can assess libido despite its limitations and narrow scope. A total of 3 RCTs demonstrated a non-significant mean improvement of 0.4 points (CI -0.6, 1.4) on the 10-point desire domain of the IIEF.^{197, 198, 290, 292} However, a larger RCT evaluating the impact of testosterone therapy on the Derogatis Interview for Sexual Functioning in Men-II (DISF-M-II) score of sexual function reported that those men in the treatment arm of the sexual function sub-cohort were more likely to show improvement in desire when compared to those on placebo.²²⁹ However, when the entire trial study population was measured for overall sexual function, which included measures of both desire and erectile function, improvements in 10/12 measures of sexual activity were relatively mild (+0.2 on testosterone versus -0.1 on placebo). These findings support the concept that sexual function represents a multidimensional condition that cannot be easily captured using subjective sexual function questionnaires. Improvements in sex drive were also assessed in another meta-analysis performed by Bolona et al.²⁹⁸  Using a variety of measures, the authors demonstrated improvement with a pooled effect of 1.31 (31% increase in sex drive) among men treated with testosterone, with greater improvements noted among men with lower baseline testosterone levels.

Anemia. Patients with anemia, both unexplained and explained, can increase their Hb and/or Hct levels while on testosterone therapy. In the 14 unique RCTs that included measures of Hb/Hct, ^{3, 5, 7, 15-32}men on testosterone therapy compared to placebo demonstrated a mean 1.2 g/dL increase in Hb (3.2% increase in Hct).^{77, 182, 194, 195, 204-206, 208, 210-214, 216-218, 299-303} Subset analyses based on duration of testosterone therapy showed that men treated for >3 months versus men treated for ≤3 months increased Hb by 1.2 compared to 0.2, respectively, although this failed to achieve statistical significance (p=0.22). In a trial with a 3-year follow-up, results demonstrated that mean Hct and Hb values increased significantly in the treatment arm (p < 0.001) but were unchanged in the placebo group.²⁹⁹ In a subset analysis in men with baseline anemia, 52-54% (explained 52%, unexplained 54%) increased their Hb by 1.0 g/dL on testosterone therapy compared to 15-19% (explained 19%, unexplained 15%) on placebo.⁷⁷ At study completion, 58% of testosterone therapy patients were no longer considered anemic compared to 22% with placebo.

Bone Mineral Density. An increase in BMD is an important potential benefit of testosterone therapy for men who might be at risk for LTBF. Given the link between LTBF and morbidity and mortality in older men, evaluating bone density is an important step in the assessment of patients with testosterone deficiency. An analysis of 6 studies^{15, 33-37} showed that BMD increased significantly (0.41 g/cm²; CI 0.11, 0.72) in men on testosterone therapy compared to those on placebo.^{230, 299, 304-307} Another RCT evaluated the effect of testosterone therapy in men with low baseline testosterone and osteoporosis/osteopenia who had a prior fracture.³⁰⁸ At 24 months, men on testosterone therapy demonstrated an approximate 3-4% increase in BMD in the lumbar spine and femoral neck over those on placebo. Whether the changes in both these studies represent a clinically meaningful improvement is unclear. As with other symptoms, the duration of testosterone therapy likely has a significant impact on overall bone density benefits. One trial with three years of follow-up showed near linear, time-dependent improvements in BMD.²⁰² These findings are similar to other prospective, controlled data, which report an estimated 5% per year increase in BMD in men on testosterone therapy.³⁰⁹ Declining bone density may necessitate additional medical intervention, such as weight bearing exercise, calcium, vitamin D, or bisphosphonate medications. Furthermore, additional testing, such as parathyroid hormone, calcium, and vitamin D levels, may be required. If baseline DEXA demonstrate bone density loss, imaging should be repeated one to two years after testosterone initiation. DEXA should be repeated sooner should any LTBF occur. If normalized, subsequent serial imaging can be performed in two to five years.

Lean Body Mass. In men with testosterone deficiency, testosterone therapy results in increased lean muscle mass and reduced fat mass, but no overall changes in BMI. Based on analyses of 12 studies, lean body mass increased by a mean 1.9 kg with trial durations ranging from 12-156 weeks.^{195, 199, 200, 203, 206, 217, 226, 230, 301, 302, 305, 310} Although there were an insufficient number of studies to confirm statistically significant differences between groups, benefits appeared to be dose- and duration-dependent. Studies reporting optimal testosterone levels yielded a mean 2.2 kg increase in lean body mass compared to a non-significant 0.8 kg increase when suboptimal levels of testosterone were achieved. Similarly, studies of ≤3 months' duration reported non-significant improvements (0.8 kg) compared to 2.1 kg with >3 months. Although fat mass was only indirectly assessed (via lean body mass), other meta-analyses have confirmed reductions in adiposity by an estimated 1.6-1.8 kg.^{138, 311, 312} Meta-analyses have also consistently demonstrated increases in lean muscle mass with testosterone therapy but have reported inconsistent outcomes on overall BMI.^{138, 311-314}

Depressive Symptoms. The impact of testosterone therapy on improving depressive symptoms has been reported in nine RCTs using various assessment measures, including the Hamilton Rating Scale for Depression, Beck's Depression Inventory, and Patient Health Questionnaire-9 questionnaires.^{210, 213, 225, 230, 315-319}  Overall, results demonstrated mild improvements in depressive indices with no impact on anxiety. Duration of studies and mode of administration did not appear to impact outcomes. Four trials included patients with either baseline major depression or dysthymia.^{213, 316-318} Although results showed significant improvements in men receiving testosterone therapy (-0.63; CI -1.13, -0.13), results were not different when compared to those without baseline depression, suggesting improvements in mood regardless of baseline status. The rate of remission was also higher in a statistically significant manner among dysthymic men receiving testosterone therapy (53%) compared to placebo (19%).^{317, 318}

Testosterone therapy has demonstrated indeterminate benefits for several symptoms that are associated with testosterone deficiency, including cognitive function, measures of diabetes, energy, fatigue, lipid profiles, and QoL measures. Despite the absence of definitive evidence, the Panel recommends that patients with these symptoms be counseled regarding the possibility of improvement on testosterone therapy.

Cognitive Function. A total of four RCTs assessed the impact of testosterone therapy on various measures of cognitive function.^{225, 230, 315, 320}  Mean age of participants in the trials ranged from 69-72.5 years, and two included men with no baseline cognitive impairments.^{230, 315}  Trial duration ranged from 24 weeks to 3 years. Overall, only one of the trials (N=22) demonstrated a significant improvement in a single measure of verbal memory, with no other changes in cognition noted.²²⁵ In the largest RCT, men with subjective or objective memory impairments (severe impairments excluded) experienced no changes in visual memory, executive function, or spatial ability after one year of treatment.³²⁰ Clinical experience and the medical literature demonstrate a link between the total absence of testosterone (castrate testosterone levels) and cognitive dysfunction, such as men on androgen deprivation therapy (ADT) for prostate cancer, which suggests there is a threshold effect in the link between testosterone deficiency with cognitive deficiency, with very low levels of testosterone being required to see cognitive changes.

Diabetes. Despite clinical experience that some men with testosterone deficiency and diabetes improve glycemic control with testosterone therapy, nine RCTs that assessed the impact of testosterone therapy on measures of diabetes demonstrated that there were no significant differences in HbA1c levels between those who were treated with testosterone and controls.^{182, 199, 200, 206, 230, 302, 306, 321, 322} While these data overall suggest that testosterone therapy has minimal to no impact on measures of diabetes, other meta-analyses outside of the evidence report have reported conflicting results. Grossman et al.³²³ performed a review of seven RCTs including men with diabetes or metabolic syndrome and demonstrated no significant changes in HbA1c, consistent with the Panel's current findings. Another meta-analysis of RCTs performed by Cai³²⁴ concluded that testosterone therapy in diabetic men improved fasting glucose levels (mean difference -1.1 points), fasting serum insulin levels (mean difference -2.73), and HbA1c (mean difference -0.87). Other meta-analyses that have included observational studies with less stringent inclusion criteria have demonstrated variable improvements in fasting glucose, insulin resistance, and HbA1c levels.^{138, 325, 326}

Energy and Fatigue. Men who seek medical care for possible testosterone therapy often present with non-specific symptoms, such as low energy and fatigue, which can be manifestations of other conditions, such as chronic stress, chronic fatigue, and depression. There are conflicting results in the literature as to whether testosterone therapy has a significant impact on these symptoms. Three RCTs that evaluated the impact of testosterone therapy on patients who had low energy or fatigue demonstrated that there were minimal to no benefits in men with testosterone deficiency.^{197, 225, 319} Brock et al. studied 636 men who were evaluated with a validated testosterone deficiency energy diary over a 16-week period.¹⁹⁷ Among those treated with testosterone, energy scores were not improved in a statistically significantly manner compared to placebo (+2.9 points; mean baseline score 50, transformed range 0-100). A second large RCT by Snyder et al.³¹⁹ used the Functional Assessment of Chronic Illness Therapy-Fatigue scales (range 0-52) in 474 men treated with testosterone for 12 months. Compared to placebo, no significant changes were noted with testosterone therapy, including when the data were evaluated as a continuous or dichotomous (≥4 point change) variable. However, when patients were requested to assess their global impression of change regarding energy level, men receiving testosterone were significantly more likely to rate changes as a little or much better compared to placebo (approximately 15% more in testosterone cohort). These findings highlight the limitations of standardized questionnaires in the assessment of energy. In both trials, scores in the placebo cohort increased by a relatively large amount (placebo: 6.7-7.4 points versus treatment: 8.0-10.6 points), highlighting the significant placebo effect.

Lipid Profiles. Several meta-analyses have evaluated the impact of testosterone therapy on lipid profiles. Overall, the effects of testosterone on lipid profiles are uncertain, with potential benefits limited to minor reductions in triglycerides and total cholesterol, if any. Using very lenient study selection criteria (all types of trials, including observational), Corona et al.³²⁵ identified improvements in total cholesterol, triglycerides, and high-density lipoproteins (HDL). A similar meta-analysis of only RCTs demonstrated no changes in total cholesterol or triglycerides in men who were on testosterone as compared to those on placebo. When only RCTs of men with baseline total testosterone values <350 ng/dL were included, improvements were identified with total cholesterol (-10.9 mg/dL) and triglycerides (-7.0 mg/dL), but not HDL.³²⁶ It is unlikely that these changes represent clinically meaningful differences. Using stricter criteria for inclusion (only RCTs), Cai et al.³²⁴ demonstrated minor improvements in triglycerides (-13.5 mg/dL) among testosterone treated men in 4 RCTs of men with testosterone deficiency. No differences were identified in total cholesterol, low-density lipoproteins, or HDL. Older meta-analyses from 2007 and 2005 similarly demonstrated no impact of testosterone on lipid profiles.^{312, 327}

Quality of Life. The impact of testosterone therapy on QoL in men with testosterone deficiency is challenging to quantify due to variable study methodology and inherent limitations with standardized questionnaires. Included studies had significant heterogeneity with the populations themselves, methods of assessment, study durations, baseline population characteristics, and number of participants, leading the Panel to conclude that there is currently insufficient evidence to determine if testosterone therapy impacts QoL in a meaningful way. Overall, seven studies reported no benefits on QoL in men using testosterone therapy compared to placebo,^{199, 205, 212, 225, 226, 230, 303, 318} while five studies demonstrated improvements.^{203, 317, 319, 328, 329}

While the vast majority of healthy men with normal testosterone levels will recover sperm production after cessation of exogenous testosterone,^{330, 331} there are no high-quality reports detailing the recovery of spermatogenesis for either testosterone deficient or infertile males who have used exogenous testosterone.³³² Liu et al. analyzed data from 30 contraception studies in which semen analyses were assessed monthly in 1,549 healthy men placed on exogenous testosterone as a possible contraceptive.³³¹ The probability of recovery of sperm concentration to >20 million/mL was 67% within 6 months, 90% within 12 months, 96% within 16 months, and 100% within 24 months. Patients who had shorter treatment duration,  were on shorter-acting testosterone preparations, and had higher sperm concentrations and lower LH levels at baseline had better spermatogenesis recovery. Men were eligible for inclusion in the study if they had testosterone in the normal range, an unremarkable reproductive history and physical exam, and 2 semen samples with a sperm concentration of ≥20 million/mL. Given the reproductive profile of the study population, the spermatogenesis results might not be generalizable to patients with testosterone deficiency.³³²

A study of 66 males who presented with infertility while on exogenous testosterone therapy revealed several interesting findings.³³³ The authors used a total motile sperm count (TMSC) of 5 million as the benchmark for spermatogenesis recovery. In this population, exogenous testosterone was stopped and combination high-dose hCG and SERM therapy was initiated. Patients had repeat semen testing at 6 and 12 months. The authors found that 65% of patients with azoospermia at presentation achieved a TMSC > 5 million at 12 months on salvage therapy compared to 92% of patients with cryptozospermia at presentation (rare sperm in the ejaculate), who achieved a TMSC > 5 million at 12 months. Increasing patient age and increasing duration of prior exogenous testosterone use both significantly reduced the likelihood of reaching the 5 million TMSC benchmark. While the lack of a baseline semen analysis before commencement of the initial exogenous testosterone therapy is a possible weakness of this study, the methodology mirrors the clinical scenario for a large percentage of men starting exogenous testosterone with no prior semen testing.

For men already on exogenous testosterone who are planning future reproduction, testosterone cessation should occur in advance of initiation of any effort to conceive. While two-thirds of males in the contraceptive studies recovered sperm in the ejaculate within 6 months of exogenous testosterone therapy cessation, 10% failed to do so until the second year.³³¹ Patients need to be made aware of the highly variable time course to recover sperm in the ejaculate and the variable degree to which spermatogenesis returns after stopping exogenous testosterone.^{331, 333} Wenker et al. showed that some infertile men may never recover spermatogenesis after use of exogenous testosterone, and this important risk needs to be discussed with patients before starting treatment.³³⁴ Intratesticular testosterone levels can be maintained by the simultaneous administration of low dose hCG with exogenous testosterone.³³⁵ To date, a single study of 26 patients has assessed this combination therapy approach in terms of effects on semen parameters and found that the concurrent administration of low dose hCG and exogenous testosterone can preserve spermatogenesis in select patients.³³⁶ In this study, no patient became azoospermic, and 35% of the patients conceived with their partner while on combination therapy.

Males with KS merit special mention. This is a relatively common condition that affects approximately 1:500 males and is characterized by hypergonadotropic hypogonadism. Patients with KS are often prescribed exogenous testosterone to treat signs and symptoms associated with low testosterone. In addition to exogenous testosterone monotherapy, a number of other regimens have been used to treat low testosterone in these men, including AI monotherapy, hCG monotherapy, SERM monotherapy, and various combinations of these classes of drugs.^337-339  Patients with KS frequently have low levels of testosterone production and high levels of aromatase activity, which leads to increased aromatization of testosterone to E2, resulting in decreased testosterone:E2 (T:E) ratios.³⁴⁰ The aim of hormonal therapies in these individuals is to both optimize intrinsic testosterone production and decrease conversion of testosterone to E2. Decreasing E2 levels diminishes E2's negative feedback on LH production at the hypothalamus and pituitary gland.³⁴⁰ Ramasamy et al. reported that both baseline and post-treatment T:E ratios have prognostic significance in azoospermic males with KS because at both of these time points, T:E ratios > 10:1 are associated with a higher likelihood of sperm retrieval on microscopic testicular sperm extraction.³³⁸

The relationship between testosterone therapy and the development of prostate cancer has been debated. The controversy surrounding prostate cancer and testosterone stems from the work of Dr. Charles Huggins who discovered that treating metastatic prostate cancer patients with ADT resulted in cancer remission,³⁴¹ suggesting that the presence of testosterone would lead to an increased likelihood of prostate cancer development. However, an analysis of Huggins' original paper reveals that this assumption was based on a single patient who was cancer and androgen therapy naïve at study onset. The other men in the study already had metastatic disease at the time of testosterone initiation. Since Huggins' work, subsequent research has failed to definitively link testosterone therapy to a progression of prostate cancer in the untreated patient or recurrence in the treated patient.

While the FDA retains a warning regarding the potential risk of prostate cancer in patients who are prescribed testosterone products ("patients treated with androgens may be at increased risk for prostate cancer"), there is accumulating evidence against a link between testosterone therapy and prostate cancer development. A meta-analysis of 7 RCTs showed that there was no significant increase in the rate of a prostate cancer diagnosis in older, testosterone deficient men who were treated with testosterone compared to placebo (OR=1.00; CI: 0.36, 2.87).^{194-198, 202, 203, 211, 215-217, 229, 315} Upon study entry, enrollees did not have a prostate cancer diagnosis, had no history of prostate nodules, or a PSA level > 4.0 ng/mL. Men who were taking medication known to affect androgen production and/or testosterone were likewise excluded. Across all 7 studies, 2,508 men (range of mean ages 55-74 years) with total testosterone levels <350 ng/dL (mean range: 232-303ng/dL) were treated with either transdermal or IM testosterone for a period of 12 weeks to 3 years. At the end of follow-up, 10 men who were on testosterone treatment (n=1,372) were diagnosed with prostate cancer, compared to 9 men in the placebo arm (n=1,136). Some of the cancers were detected during the treatment phase, while others were detected during post-study follow-up.²²⁹ It was noted by some authors that it was difficult to implicate testosterone as the etiology since biopsies were taken at the end of study, and it was possible that the cancer was present throughout the trial²¹¹ or age-related.²¹⁵ Prostate cancer incidence was the primary endpoint in only one of the seven studies,²¹¹ while the balance of the trials were powered to measure physical strength, BMD, or sexual function, with prostate events recorded as adverse outcomes.

Another meta-analysis by Calof et al.¹⁹⁰ (2005) pooled data from 19 RCTs to determine the number of all-cause prostate events in men who were on exogenous testosterone treatment as compared to men who were on placebo. Studies were ineligible if they used supra-physiologic levels of testosterone or if participants were using androgens other than testosterone. A total of 651 men (mean age 62.9 years) received oral, transdermal, or IM testosterone, while 433 men received placebo for a period of 12 weeks to 36 months. The treatment and placebo arms did not differ at baseline in terms of age (62.9 years versus 64.4 years, respectively), total testosterone level (320 ng/dL versus 344 ng/dL, respectively), or PSA measurements (1.3 ng/mL in both arms). At the end of study the total number of prostate-related events was significantly greater in the testosterone arm than in the placebo arm (OR=1.79; CI: 1.07, 2.95). The authors conceded that it was not possible to determine if each individual prostate event occurred in unique individuals since the same person might have had more than one event leading to an overestimate in incidence. When individual prostate events were analyzed separately, there was not a statistically significant difference in incidence between the two groups in terms of prostate cancer (OR=1.09), PSA elevation to > 4ng/mL or PSA increase > 1.5 ng/mL during treatment (OR=1.19), any increase in International Prostate Symptom Score (OR=1.08), or acute urinary retention (OR=0.99). 

It is the opinion of this Panel that until there is definitive evidence demonstrating that testosterone therapy is not safe for use in prostate cancer patients, the decision to commence testosterone therapy in men with a history of prostate cancer is a negotiated decision based on the perceived potential benefit of treatment.

Given the increasing incidence of both testosterone deficiency and prostate cancer with advancing age, it is common for the two conditions to co-exist in older men. Product labels for all testosterone formulations explicitly state that their use is contraindicated in men with a history of prostate cancer, which results from Huggins' precept that testosterone therapy feeds prostate cancer cell proliferation.

However, the saturation model introduced by Morgentaler is based on the concept that prostate cancer cells' response to the testosterone level to which they are exposed is not linear in nature. From a clinical standpoint, it dictates that there is a testosterone threshold beyond which prostate cells (benign or malignant) cease responding. In-vitro experiments have shown that prostate cancer cells fail to proliferate in the absence of testosterone; once testosterone is introduced, an initial proliferative response is observed followed by a plateau after a certain testosterone concentration is reached. If the testosterone concentration is increased further, rather than further proliferation, the cells reduce their rate of proliferation.^{343, 344} This phenomenon is known as the bipolar testosterone concept. It is probable that the saturation level varies from patient to patient and likely lies somewhere between 100-200 ng/dL.

Recent RCT data support Morgentaler's theory. Marks et al. studied 44 patients who were randomized to receive 150 mg of IM testosterone enanthate (n = 21) versus placebo (n = 19) for 6 months.²¹¹ While on treatment, patients had blood drawn and prostate tissue biopsied to look at serum and prostatic tissue levels of testosterone. At the end of the study, serum testosterone levels rose in those men receiving testosterone therapy; however, no rise in testosterone levels were seen within the prostate tissue itself. 

Post-Radical Prostatectomy Patients. Testosterone therapy can be considered in those men who have undergone radical prostatectomy (RP) with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively. Currently published studies have not demonstrated an increased risk of biochemical cancer recurrence in post-RP patients who are on testosterone therapy, nor does it define the optimal timing for commencement of testosterone therapy. The literature suggests that post-RP patients who had undetectable PSA levels and were subsequently put on testosterone therapy maintained undetectable PSA levels throughout treatment with no evidence of cancer recurrence.^345-347 Only one study by Pastuszak et al., (2013)³⁴⁸ reported that study subjects experienced biochemical recurrence: 4/103 patients in the treatment group versus 8/49 in the reference group (p=0.02), all of whom were classified as having high-risk prostate cancer at study onset.

Radiation Therapy. There is also a dearth of data evaluating the safety of testosterone therapy in men treated with radiation therapy (RT). Available studies are retrospective in nature but have suggested that post-RT patients (with or without ADT exposure) placed on testosterone therapy do not experience recurrence of prostate cancer. Clinicians should be aware that a period of time should elapse after RT and before initiating testosterone therapy in order to allow the patient adequate time to regain functional endogenous testosterone production. While this period of waiting might preclude the need for testosterone therapy by allowing testosterone to return to normal levels organically, it is possible that men who underwent long courses of ADT may not regain physiological testosterone levels even one year after cessation of ADT.^{349, 350}

The studies conducted in post-RT men who have been placed on testosterone therapy indicate that men experienced either a steady decline in PSA values to <0.1 ng/mL or had non-significant changes in PSA, with no patients exhibiting signs of prostate cancer progression or recurrence.^351-354 One study involving 36 men recorded a single patient as having a transient rise of PSA, but this was followed by a decline, while another patient in the same study did have end-of-study PSA >0.5 ng/mL. At the time of publication, this patient was five years post-implantation and had not undergone any biopsies.³⁵¹ A second retrospective study by Balbontin found that one patient out of the study population (N = 20) did experience a PSA bounce of 2 ng/mL above the nadir, but after a 6 month break from testosterone, PSA levels dropped and did not rise again even after testosterone was re-commenced.³⁵²

A study by Pastuszak et al. (2015)³⁵⁵ found a significant increase in biochemical recurrence in high-risk patients who received testosterone therapy after RT or RT/ADT. All patients in the study (N=48) were stratified according to risk: low (Gleason Score ≤6), intermediate (Gleason Score =7), and high (Gleason Score ≥8). After 40.8 months of testosterone gel, IM injection, or SQ pellets, mean PSA remained unchanged in the low- and intermediate-risk strata (0.00 ng/mL and 0.09 ng/mL, respectively), but those in the high-risk group had significant increases (0.10 ng/mL at baseline versus 0.36 ng/mL at follow-up; p=0.018). Six patients experienced biochemical recurrence, all of whom had intermediate- or high-risk prostate cancer. Three of these men were brachytherapy patients alone, did not cease testosterone therapy, and their PSA values eventually decreased. Three others did stop testosterone in response to the PSA bounce, two of whom had negative prostate biopsies.  

Active Surveillance. There are limited data in men on active surveillance who are candidates for testosterone therapy. There has been a concern that testosterone therapy might cause progression of previously existing, but undiagnosed, prostate cancer or that testosterone might cause high-grade prostatic intraepithelial neoplasias (PIN) to progress into frank carcinoma.

A paper by Rhoden and Morgentaler in 2003 looked at the effect of testosterone in patients who did and did not have PIN.³⁵⁶ A total of 75 men (mean age 59.6 years) who were testosterone deficient (total testosterone <300 ng/dL with ED and/or decreased libido) were followed for 12 months after initiation of testosterone therapy. Men were excluded if they had a history of prostate cancer, had undergone prostate surgery, or were taking finasteride or other drugs that altered PSA. Biopsies at baseline revealed that 55 patients were PIN- and 20 patients were PIN+. Mean PSA was 1.54 ng/mL, which did not differ significantly between the PIN+ and PIN- men at baseline (1.49 ng/mL; 1.53 ng/mL, respectively) or at the end of study (1.82 ng/mL; 1.78 ng/mL). After 12 months of testosterone therapy, 1/20 men in the PIN+ cohort and 0/55 men in the PIN- cohort were diagnosed with cancer, resulting in a cancer rate of 1.3%. The authors of the paper could not attribute the cancer diagnosis to testosterone treatment alone considering prostate cancer develops in as many as one quarter of PIN+ patients within three years.

Another retrospective study (Morgentaler 2011) followed 13 men (mean age 58.8 years) with untreated prostate cancer and testosterone deficiency (total testosterone <350 ng/dL and at least one symptom consistent with testosterone deficiency) who were diagnosed with either Gleason 6 or Gleason 7 cancer.³⁵⁷ All patients received either transdermal testosterone, IM testosterone, or SQ testosterone pellets for a mean 3.1 years. PSA at initial biopsy was 5.5 ng/mL, which decreased to 3.6 ng/mL at 24 months (p = 0.29). An increase in serum PSA of 0.5 ng/mL or greater was found in 3 men while on testosterone therapy, and 4 experienced a decrease of the same magnitude on treatment. Prostate volume did not change in any patients on testosterone therapy. All patients had PSA and digital rectal exams every three months and biopsies annually. Of these, 14 biopsies (54%) revealed no cancer, and no patients required additional biopsy for clinical concerns.³⁵⁷

PSA Monitoring. Prostate cancer patients on testosterone therapy should have their PSA levels monitored on the same schedule as men without testosterone deficiency; however, clinicians may choose to increase the frequency of testing. PSA recurrence in men on testosterone therapy should be evaluated in the same fashion as untreated men. A discussion regarding the benefit of stopping testosterone therapy should include the possibility of a decline in PSA.

The concern about the possible association between testosterone therapy and venothrombolic events (VTE) led the FDA to require pharmaceutical companies to add a warning to their product labeling regarding post-marketing reports of VTE; however, this decision was based on anecdotal cases and not peer-reviewed literature.³⁵⁸ Since the FDA warning in June 2014, four large observational studies^{198, 359-361} have been conducted, none of which showed an association between testosterone therapy and an increased risk of VTE.

One RCT by Maggi et al. followed 715 testosterone deficient men for 12 weeks to evaluate the effects of a 2% transdermal testosterone agent on sex drive and energy. The men in the study had a mean baseline total testosterone of 200 ng/dL and at least 1 symptom associated with testosterone deficiency (low energy or decreased sex drive). At the conclusion of the study, no men who were on testosterone therapy had a major adverse cardiovascular event or VTE, while one patient in the placebo group did.¹⁹⁸ A five-year study by Baillargeon et al. reported that testosterone therapy did not increase the risk of VTE in patients who were on testosterone therapy, independent of the route of testosterone administration or exposure period.³⁵⁹ A retrospective cohort study by Sharma et al. likewise did not detect a significant association between testosterone therapy and risk of VTE,³⁶⁰ and neither did Li et al. who used a cohort and nested case-control analysis and found no significant association between testosterone therapy and incidence of overall VTE in men with testosterone deficiency.³⁶¹

Conversely, a population-based retrospective case-control study utilizing a UK clinical database of 19,215 patients with confirmed VTE showed that there was increased risk of VTE in the first 6 months of testosterone therapy. The risk corresponded to an additional 10 cases per 10,000 person-years, which, while low in absolute terms, raised concern about using testosterone therapy in men who may be at increased risk for VTE prior to commencement of therapy.³⁶²

Current evidence consistently shows that untreated low testosterone levels are associated with an increased risk of MACE; however, studies that measure cardiovascular benefit or harm in men on testosterone therapy have returned inconsistent and controversial results. Until there is definitive evidence proving an association between testosterone therapy and subsequent MACE, the Panel recommends that clinicians counsel patients that the current scientific literature does not definitively demonstrate that testosterone therapy increases risk. Men who are on testosterone therapy should be advised to report the occurrence of any possible cardiovascular symptoms, such as chest pain, shortness of breath, dizziness, or transient loss of consciousness, during routine follow-up visits.

RCTs have failed to categorically define if testosterone therapy increases the incidence of MACE when compared to placebo. Some studies have suggested that testosterone therapy is associated with an increase in MACE^363-366 while others have suggested a decreased risk ^{207, 233, 259, 367, 368} and others a neutral effect.^{190, 191, 202, 327, 369-373} The results and the methodology of these studies have been debated. Thresholds for low testosterone were not universal. There were inconsistently defined end points to categorize severe cardiac events, which included 'softer' endpoints (e.g., edema, tachycardia, hypertension) along with myocardial infarction and stroke.¹⁹⁴ The statistical analysis did not account for confounding factors; the duration of follow-up varied widely, from 12 weeks to 3 years; and many of the trials were not powered to detect cardiac events as primary endpoints, rather they were catalogued as adverse outcomes.

A meta-analysis of RCTs developed in support of this guideline indicate that there is no significant difference in MACE in men on testosterone therapy when compared to placebo. Across all studies, a total of 2,821 men (mean ages 52-74 years) were treated with IM or transdermal testosterone (n=1,555) or placebo (n=1,266) for a period of 16-52 weeks. The trials were not powered to measure MACE as a primary endpoint (outcome measures included efficacy or product, muscle strength, AMS scores, and sex drive); cardiac-related events were categorized as adverse outcomes. The pooled results showed that there was not a statistically significant difference in the incidence of myocardial infarction (OR=0.61; CI: 0.12, 1.68) ^{194-198, 208, 216-218, 226, 229, 328} in men using testosterone therapy compared to men on placebo; 6 RCTs showed there was not an increase in cardiovascular-related mortality (OR=0.54; CI: 0.17, 1.73)^{194-196, 216-218, 226, 229, 328} among testosterone users compared to those on placebo; and 3 RCTs showed an equal likelihood of the incidence of cerebrovascular accident (OR=0.98; CI: 0.27, 2.64)^{194-198, 229} between the placebo and treatment arms.

While seven of the trials in the above analysis showed decreased, but statistically insignificant, odds of having a cardiac event while on testosterone therapy, one trial did show an increased risk. The Basaria Testosterone in Older Men (TOM) trial published in 2014 was a randomized, double-blind, placebo-controlled study that showed that men who received transdermal testosterone (n=106) were significantly more likely to have a cardiac related event than those on placebo (n=103).¹⁹⁴ At the end of 6-months follow-up, there were a total of 23 cardiovascular events (in 9 men) in the testosterone therapy arm compared to 5 events in the placebo arm (p <0.001). Although the study was powered primarily to assess the effect of testosterone therapy on frailty, the TOM Trial was one of the first published studies to indicate that there may be increased cardiovascular risk associated with testosterone therapy. The definition for cardiovascular symptoms, either by self-report or medical chart review, was broadly defined, and some severe adverse events would not have met the classic definition for MACE, (e.g., edema, self-reported syncope, ectopy on electrocardiogram, tachycardia). Although study exclusion criteria included uncontrolled hypertension, unstable angina, myocardial infarction within the past three months, and congestive heart failure, there was a higher rate of hyperlipidemia and statin use at baseline in the testosterone therapy group as compared to the placebo group. The authors noted "the small number of overall events suggests the possibility that differences between the two groups may be due to chance alone."

Another meta-analysis of 26 RCTs by Corona et al. (2014)³⁷² found no causal association between testosterone therapy and MACE (defined as a composite of cardiovascular-related death, non-fatal acute myocardial infarction, and cerebrovascular accident) when compared to placebo (OR=1.01; CI: 0.57, 1.77). Across all studies, men had a mean baseline testosterone of 323 ng/dL, mean age of 59.9 years, and were followed for an average 34 weeks, during which time they were administered either a placebo or one of several testosterone modalities. There were 31 events in the treatment arm (n=1,895) and 20 events in the placebo group (n=1341). Specifically, the OR of acute myocardial infarction was 0.68 (p=0.34), acute coronary syndrome 0.92 (p=0.83), cerebrovascular accident 0.82 (p=0.76), and cardiovascular-related mortality 1.14 (p=0.75). The association between testosterone therapy and MACE remained insignificant when adjusted for baseline testosterone level and trial duration >12 weeks.

Given the conflicting nature of the evidence, the Panel cannot definitively state that there is an association between testosterone therapy and subsequent MACE events nor can it be stated definitely that testosterone therapy is associated with reduced incidence of MACE. In 2014, the FDA added a warning to testosterone product labeling after reviewing five observational studies and two meta-analyses of RCTs that examined the effects of testosterone therapy on MACE. For further information on the testosterone therapy and the risk of MACE, please see Appendix D (in the Appendix D section in the left menu).

Men with testosterone deficiency should be counseled that lifestyle modifications, such as losing weight, or maintaining weight within the recommended range, along with increasing physical activity, has the potential to increase total testosterone levels and/or reduce signs and symptoms associated with testosterone deficiency.^374-377 High BMI coupled with low testosterone could put the patient at risk for a cardiovascular event, and patients who are overweight or obese should be counseled regarding weight loss programs concurrent with testosterone therapy. Clinicians should counsel patients that lifestyle modifications should be undertaken for the benefit of their overall health and that improvements in total testosterone levels might not be clinically meaningful.³⁷⁶ The AACE suggests that significant improvements in testosterone levels do not occur until a patient loses 5-10% of his body weight.⁶⁹

Small non-randomized trials support the concept that weight loss in men who are obese or morbidly obese is associated with an increase in testosterone levels. A 2016 study examined the mean total testosterone changes in 29 morbidly obese men (mean age: 31 years; mean BMI: 56.8) before and after gastric bypass surgery. At baseline, 22 patients had total testosterone <300 ng/dL, and 6 months post-surgery, total testosterone had increased significantly (p ≤ 0.001) with 22 patients (75.9%) showing normalized total testosterone levels.³⁷⁵

Increases in testosterone for patients who lose weight might be cumulative over time. A study of 118 overweight and obese men with normal total testosterone levels (>350 ng/dL) placed subjects on either a low-fat/high-protein or low-fat/high-carbohydrate calorie restricted diet for 52 weeks. At the end of the study, total testosterone increased in both groups with neither group deriving more benefit than the other (p ≥ 0.244). Although increases in total testosterone were noted in the first 12 weeks (p=0.037), the improvement was not significant until weeks 12-52 (p=0.002).³⁷⁴

It is possible that exercise programs coupled with diet may have a greater likelihood of success in achieving increases in total testosterone over calorie-restricted diets alone. Studies that randomized overweight or obese men to diet and exercise programs had significantly greater increases in total testosterone levels than men who underwent calorie reduction or exercise programs alone.^{378, 379} It is also postulated that men who engage in quantitatively more exercise have the greatest increases in serum testosterone from baseline.³⁷⁸

Men with mild testosterone deficiency and whose weight is above the recommended range and/or who are physically inactive should be encouraged to consider low-risk lifestyle modifications followed by reassessment of testosterone levels, signs, and symptoms before deciding to start testosterone therapy. For adults in general, behavior-based interventions have been found to be safe and effective. 

The goal of testosterone therapy is the normalization of total testosterone levels combined with improvement in symptoms or signs. The Panel recommends that clinicians use the minimal dosing necessary to drive testosterone levels to the normal physiologic range of 450-600 ng/dL, which is the middle tertile of the normal range for most laboratories. The Panel recognizes that age-adjustments may be required to define this middle range; however, from a practical standpoint, 450-600 ng/dL represents a viable range for all age-groups. Achieving testosterone levels in this window should ameliorate any symptoms that are genuinely associated with testosterone deficiency.^{168, 380}

The Panel recommends that patients on all modalities of testosterone have their symptoms/signs re-evaluated within three months after the commencement of treatment to determine if dosing adjustments are necessary. While some patients may continue to experience symptom/sign relief after this time point, the majority of men have meaningful improvements within the first three months of therapy. In the event that patients do not experience symptomatic relief after reaching the specified target testosterone levels or remain testosterone deficient in the setting of symptom/sign improvement, testosterone therapy should be stopped. In the uncommon circumstance where men have prior available off-therapy testosterone laboratory data considered reliable (early morning testing, appropriate assay), clinicians may consider titrating testosterone therapy dosing to return patients to their 'baseline' total testosterone level.

The Panel recognizes that it might be difficult to achieve an on-treatment total testosterone level in such a narrow range in every patient, especially those using IM testosterone; however, the suggested range aims to limit the over-treatment of testosterone deficient men who have had physiologically lifelong total testosterone levels in the lower range of normal, while minimizing the under-treatment of men who have had physiologically lifelong total testosterone levels in the upper range of normal. For men with on-treatment testosterone levels that fall below the suggested target range but who have on-treatment amelioration of symptoms, up-titration may be considered in an effort to achieve symptom abolition. For men with on-treatment testosterone levels that fall below the suggested target range but who experience complete resolution of symptoms, there is no need to titrate dosing. For the patients with no or minimal symptoms associated with low testosterone levels, but rather the presence of signs (e.g., BMD loss), clinicians are encouraged to aim for on-treatment total testosterone levels in the 450-600 ng/dL target range and re-evaluate the patients' signs at an appropriate time point after reaching the therapeutic range.

While definitive age-specific reference ranges do not exist, some data suggest that patient age may play a role in setting therapeutic ranges, at least in the elderly population. A community dwelling study of 70-89 year-old healthy men (n=3690) in Perth, Australia established a reference range of 283-454 ng/dL (mean 361 ng/dL)³⁸¹ while other randomized trials of testosterone therapy in older men have achieved on-treatment mean total testosterone levels in the range of 430-600 ng/dL.^{202, 226, 229} The Panel interprets the above data to support the mid-tertile range as a therapeutic target.

The target levels suggested here are physiological (eugonadal) not supraphysiological levels, and the Panel found no data to support the argument for dose escalation into the supraphysiological range in the pursuit of greater efficacy. One trial in healthy older men (age range 60-75 years) who were given graded doses of IM testosterone enanthate (25, 50, 125, 300 and 600 mg weekly) showed that men experience higher rates of serious adverse events when receiving the 300 mg and 600 mg weekly doses (producing nadir testosterone levels in the range of 1,800-3,300 ng/dL).³⁸² Case reports and case series have also linked use of high doses of anabolic steroids with a number of serious adverse events, including cardiovascular issues, coagulation abnormalities, mood disorders (e.g., withdrawal symptoms) and dependence issues.^{383, 384}

Exogenous testosterone therapy has been shown to interrupt normal spermatogenesis and can put patients in severely oligospermic or azoospermic states and should not be used in men trying to conceive.  Normal sperm production depends on a functionally intact hypothalamic-pituitary-gonadal axis with normal secretion of pituitary LH and FSH to support intratesticular testosterone production and spermatogenesis. Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis and intratesticular testosterone production, with dosages of testosterone enanthate 200 mg IM testosterone every week having been shown to decrease intratesticular testosterone levels by 94% within 3 weeks of initiation.³³⁵ Clinicians may offer hCG (250 IU or 500 IU every other day) concurrent with exogenous testosterone, which in a single small study has been shown to maintain baseline levels of intratesticular testosterone.³³⁵

A systematic review of 33 RCT's by Grimes et al. evaluated the effectiveness of testosterone or testosterone plus progestin agents as a contraceptive agent in healthy men.³³⁰ The final analysis suggested that the effects of testosterone alone on spermatogenesis varied widely. The general trend indicated that higher doses of testosterone were more likely to result in azoospermia than lower doses, however a dose-response effect was not consistently seen.

A larger study that examined the contraceptive efficacy of testosterone-induced azoospermia in men was conducted by the WHO Task Force on Methods for the Regulation of Male Fertility.³⁸⁵ A total of 271 healthy, fertile men across 7 countries were given 200 mg IM testosterone enanthate every week for 12 months. During the efficacy phase of the trial, adequate suppression of spermatogenesis occurred in 98% of study subjects (n=390) and 157 men became azoospermic during the 12-month follow-up period (mean time to azoospermia was 120 days). 

The currently available literature does not provide enough evidence to offer clear guidance on the use of testosterone therapy in men with existing, stable atherosclerotic CVD and/or a remote history of a myocardial infarction or a cerebrovascular accident. It is the opinion of the Panel that testosterone therapy, with close monitoring to ensure appropriate dosing and safety surveillance, may be considered in these patients after a three to six month waiting period. Clinicians should counsel patients on the association between low testosterone and the increased risk of cardiovascular events, as well as the ill-defined cardiovascular risks and benefits of testosterone therapy in the testosterone deficient patient.

This recommendation is supported by a recent review of studies that evaluate cardiovascular risk associated with testosterone therapy, most of which have excluded men who had a history of a cardiovascular event within the preceding three to six months.^{194, 229, 386} In the recent Testosterone and TOM Trials,^{194, 229} participants were excluded if they had a myocardial infarction or a cerebrovascular accident within the previous 3 months, had a history of unstable angina, New York Heart Association class III or IV congestive heart failure, a systolic blood pressure >160 mm Hg, or a diastolic blood pressure >100 mm Hg.^{194, 229}

In the absence of long-term RCTs evaluating whether testosterone therapy results in cardiovascular benefit or harm, the decision to use testosterone therapy in such patients should be based on a shared decision-making approach between clinicians and patients.

Given the availability of other approved testosterone therapies, the use of 17-alpha-akylated androgens is not appropriate. Methyltestosterone is an oral androgen modified at the 17-alpha position resulting in decreased first pass hepatic clearance and is approved in the US for treatment of testosterone deficiency. It is rapidly metabolized in the liver; therefore, achieving consistently therapeutic testosterone levels is a challenge. Its use is also associated with liver toxicity, including abnormal liver function tests, cholestasis, and jaundice. One study of 60 patients undergoing long-term therapy of 50 mg methyltestosterone three times a day found that nearly one-third of patients, none of whom had a history of liver disease, returned abnormal liver function tests and/or liver scans.³⁸⁷

Testosterone undecanoate is an oral testosterone analogue that is absorbed via the intestinal lymphatics allowing it to avoid the first pass liver effect. It is approved in some countries for treatment of testosterone deficiency but is not currently approved in the US.

Topical testosterone preparations (e.g., gels, creams, liquids) have the potential to result in transference to others. Populations at increased risk of adverse effects from transference include women and children, however very limited data are available on the true risks of transference with topical agents. Several case reports have identified virilization and precocious puberty in children as well as hyperandrogenism in women following accidental exposure to topical testosterone.^388-391

To address the issue, the FDA includes medication guides with topical testosterone preparations and recommends observing for signs and symptoms of early puberty in children as well as avoiding contact with the unwashed or uncovered areas where the drug has been applied.³⁹² In order to reduce risks, patients are advised to apply the medication only to suggested areas, wash hands after applying, cover the area with clothing after drying, wash the area prior to anticipated skin-to-skin contact, and wash regions of inadvertent contact in women and children.

More recently, a study evaluating the amount of residual testosterone identified on laundered clothing from men using an axilla-applied testosterone liquid reported the presence of 13% of a single axilla dose on 10x10 cm clothing samples.³⁹³ After laundering the clothing with various other materials, as much as 5.8% of a standard dose of one axilla was transferred to other garments. It is unclear if the transferred testosterone remained biologically active. These findings require further follow-up as they demonstrate that transference may hypothetically occur in the absence of skin-to-skin contact.

Low testosterone levels are highly prevalent among males presenting for an infertility workup and testosterone deficiency is commonly found in men who have non-obstructive azoospermia and oligospermia.³⁹⁴ Half of all couples experiencing infertility will have a male factor involved and 30-70% of men undergoing a reproductive workup will have an endocrine abnormality of some type.^{395, 396}  Exogenous testosterone has inhibitory effects on the production of intratesticular testosterone, which is imperative to maintain normal spermatogenesis. For this reason, alternative therapies, including SERMs, AIs, and hCG, are commonly used to promote the endogenous production of testosterone. Each class of alternative therapy has a different mechanism of action: hCG acts as an LH agonist and stimulates Leydig cell production of testosterone, AIs block the conversion of testosterone to E2, and SERMs inhibit the negative feedback of E2 on LH production at the level of the hypothalamus and pituitary gland.

Table 6 (featured below) provides pharmacologic information for SERMs, hCG, and AIs. While SERMs, hCG, and AIs are all categorized as "alternative therapies" to testosterone, they are actually a diverse group of agents. These agents share the common overall treatment effect of increasing intrinsic production of testosterone, but there are substantial differences in pharmacologic characteristics and mechanisms of action between them. Given these pharmacologic and mechanistic differences, combinations of these alternative therapies might, in some instances, be clinically appropriate. 

Clinicians should understand that of these agents, only hCG has been approved by the FDA for use in males, specifically to treat males with hypogonadotropic hypogonadism. The overall quantity and quality of studies investigating the use of these alternative agents in males are limited. However, despite these limitations, several studies provide important insights into the impact of SERMs, AIs, and hCG on spermatogenesis.

Aromatase Inhibitors. Pavlovich et al. reported on the existence of a "treatable endocrinopathy" in a subset of infertile men characterized by low testosterone, elevated E2, and a low T:E ratio.³⁴⁰ The authors hypothesized that treating this condition with AIs would result in improvement in both the T:E ratio and semen parameters. In two separate studies of infertile men with azoospermia or severe oligospermia who were treated with an AI, authors reported improvement in the both the T:E ratio and also semen parameters in oligospermic males.^{337, 340} Reifsnyder et al. subsequently assessed the effect of AI therapy for azoospermic males with T:E ratios < 10:1 and serum testosterone levels <300 ng/dL and found no difference in sperm retrieval rates, pregnancy rates, or live birth rates among patients on AI therapy versus those not on therapy.³³⁹ Ramasamy et al. more specifically studied a cohort of azoospermic males with KS who were treated with alternative therapies, including AIs, prior to microscopic testicular sperm extraction.³³⁸ They reported better rates of successful sperm retrieval for men with higher baseline T:E ratios as well as those with higher preoperative T:E ratios and post-treatment testosterone >250 ng/dL after medical therapy.

Human Chorionic Gonadotropin. hCG is an LH analog that is usually prescribed to treat a deficiency in LH production. Most studies assessing hCG efficacy have been performed in males with congenital/idiopathic hypogonadotropic hypogonadism.^{397, 398} While the literature regarding hCG use in adult males with symptomatic testosterone deficiency is less robust, several important reports are worth discussing. Liu et al. conducted a double-blind, placebo controlled, randomized trial assessing response to hCG therapy in older men (mean age 67 years) with androgen deficiency.³⁹⁹ The authors found a 150% increase in total testosterone level, which they concluded demonstrates that older males retain "testicular responsiveness" to gonadotropin therapy. As mentioned above, combination therapy with low dose hCG has been described as a means to maintain intratesticular testosterone levels³⁹⁴ and preserve spermatogenesis³³⁶ for men on exogenous testosterone. Finally, hCG therapy alone or in combination with SERMs has been shown to facilitate recovery of testosterone production and spermatogenesis in men with a prior history of exogenous testosterone use³³³ or anabolic steroid abuse.³³⁴ Return of sperm to the ejaculate in these men can be highly variable, taking up to two years after cessation of exogenous testosterone in some cases, with some men never experiencing return of sperm.³³⁴

Selective Estrogen Receptor Modulators. SERMs are oral agents that block E2 feedback resulting in increased LH secretion. Taylor et al. reported that clomiphene citrate has outstanding biochemical and clinical efficacy, with increases in serum testosterone similar to those for testosterone gel.⁴⁰⁰ Additionally, these investigators found that clomiphene has a favorable side effect profile and is less expensive than testosterone gel. Two RCTs compared treatment of testosterone deficient males with SERMs versus testosterone versus placebo and found that sperm concentration was maintained (comparable to placebo) for males treated with the SERMs, but was significantly decreased for males on exogenous testosterone.^{401, 402} Finally, Helo et al. conducted a prospective, double-blind, RCT comparing the SERM clomiphene citrate versus the AI anastrozole in infertile males with testosterone deficiency. The authors report that clomiphene resulted in significantly higher serum testosterone levels than anastrozole, but anastrozole resulted in significantly higher T:E ratios than clomiphene. Despite these effects, neither treatment led to significant changes in semen parameters.⁴⁰³

Finally, the clinician should adhere to several "key points" when prescribing these agents:

1. A serum LH level can help guide clinical decision-making after initiation of SERM therapy.
2. If after starting the SERM the testosterone level remains low and the LH level remains low or normal, then dose escalation of the SERM should be considered. This step might increase testosterone levels. 
3. If after starting the SERM the testosterone level is low but the LH level is high, then the patient likely has testicular dysfunction. SERM dose escalation in this case is not likely to increase testosterone levels.
4. AIs should in general not be used for extended periods of time due to concerns regarding loss of BMD.⁴⁰⁴ AIs can significantly suppress E2, which is essential in maintaining bone density.   
5. With regular follow-up and careful titration of AI dosage, E2 can often be maintained in the therapeutic range, thus minimizing the risk of loss of bone density.
6. If AI therapy results in persistently elevated E2 levels, the AI should be discontinued due to lack of clinical efficacy.

While the therapeutic aim of each of these alternative therapies is to increase endogenous testosterone production, clinicians must keep in mind that the benefits of exogenous testosterone therapy in testosterone deficient men cannot be extrapolated to the benefits provided by these alternative therapies. 

In contrast to commercial pharmaceutical manufacturing, which is regulated by the FDA, compounded medications are regulated by state laws and, therefore, vary significantly from one region to another.⁴⁰⁵ While testosterone gels and creams are the most commonly used forms of compounded testosterone therapies and are routinely less expensive than branded forms of testosterone, these preparations by individual pharmacies occur without direct FDA oversight and approval. Considerable variation in dosages and in ingredients results.

In 2001, the FDA performed an analysis of internet-purchased, compounded products following reports of contamination, poor compounding processes, and product toxicity.^{406, 407} Among 29 product samples analyzed, which included testosterone among multiple medications, 31% demonstrated sub-potency ranging from 59-89% below target dose. Similarly, a survey conducted by the Missouri State Board of Pharmacy reported overall failure rates of 20-25% for all compounds tested, with specific samples containing 0-553% of the labeled potency.⁴⁰⁸ A follow-up study by the FDA in 2006 confirmed failure rates of 33%, with potencies ranging from 68-268% of labeling claims.⁴⁰⁹ Overall, the FDA concluded that problems with quality occurred throughout the country and that the issues were directly linked to the compounding practices themselves rather than due to variability in the active pharmaceutical ingredient.

With respect to testosterone specifically, Grober et al. conducted an analysis of compounded testosterone creams/gels from 10 pharmacies in Toronto, Canada.⁴¹⁰ Each pharmacy was given two prescriptions for 50 mg of testosterone, separated by 1 month to assess both intra-pharmacy and inter-pharmacy consistency. Overall, only 50% of Batch One and 30% of Batch Two samples achieved a potency within 20% of the prescribed dose. Two pharmacies provided samples with >20% of the prescribed dose, while one contained only minimal amounts of testosterone.

In addition to issues relating to the reliability of compounded products themselves, appropriate clinical studies on pharmacokinetics are lacking. As such, even if consistent testosterone levels could be achieved, providers issuing prescriptions for compounded testosterone need to consider performing additional monitoring and dose adjustments to ensure appropriate therapeutic levels. 

Patients who have been prescribed testosterone should have regular laboratory testing conducted to confirm that therapeutic levels of testosterone are maintained, especially given the suppression of LH by exogenous testosterone and the subsequent decrease in endogenous testosterone production by the testes. It is the opinion of this Panel that total testosterone should be tested after the commencement of therapy at a time point that allows a patient to be sufficiently established on a dosing regimen before determining if therapeutic levels have been achieved and if dosing alterations are required. For patients on daily medication, the Panel recommends that patients use medication the day of follow-up blood work.

Patients on topical gels, patches, and intranasal formulations should have their testosterone checked between two to four weeks after commencement of therapy. Although steady-state levels are generally reached within days following commencement, a longer interval takes into account the potential decreases in endogenous testosterone production when on exogenous testosterone.

Given the mechanisms of action of anastrozole, clomiphene citrate, and hCG, patients using these medications should wait a longer period before follow-up blood work is performed. The Panel recommends testing no sooner than four weeks after commencement.

Patients on short-acting IM or short-acting SQ pellets (testosterone cypionate or enanthate) should have their testosterone measured after several cycles such that testosterone level equilibration has been achieved. The Panel recommends that this be completed no earlier than three to four cycles. While no data exist on the optimal timing of the blood draw within a cycle, it has historically been recommended that blood draws be conducted mid-cycle. The main driving force behind such a strategy is convenience for patients and clinicians, although such timing has no ability to define peak and trough levels.

Patients who are on long-acting IM testosterone (testosterone undecanoate) should have blood work tested once steady state levels have been achieved. Testosterone undecanoate is typically re-administered at a time point 4 weeks after initial dosing and then every 10 weeks thereafter. As with short-acting IM testosterone injections, the general recommendation is mid-cycle testing, after equilibration, and halfway between the first two 10-week injections.

Patients who are on long-acting SQ pellets require two separate assessments of testosterone to determine the dose and frequency required. The first testosterone measurement should be obtained two to four weeks after initial implant to determine if the number of inserted pellets needs to be increased or decreased to achieve the appropriate therapeutic level. Patients should then be tested after 10-12 weeks.

Patients on testosterone therapy should have serum testosterone levels checked every 6-12 months to ensure maintenance of target levels. Given anecdotal concerns about clomiphene citrate-associated tachyphylaxis, it is recommended that patients using this therapeutic approach have total testosterone measured as outlined previously.

Please refer to Table 7 below for a summary of follow-up testing for men being treated for testosterone deficiency. Testing intervals are the expert opinion of the Panel and are provided as a guide to aid clinicians in the follow-up of such patients.  

If patients achieve target testosterone levels, but do not feel that they have sufficient improvement in their symptoms, clinicians should question whether testosterone deficiency is the etiology of their symptoms. There is no utility in continuing testosterone therapy in men who achieve target testosterone levels without symptom improvement. 

An exception can be made if patients do not have symptoms but have documented BMD loss. In this clinical scenario, an argument can be made to continue testosterone therapy. Similarly, in the event patients have unexplained anemia that improves on testosterone therapy, continuation can be considered even in the absence of other symptom improvement. 

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