Individuals with increased blood viscosity have been known to be at an increased risk for thrombotic complications such as stroke, myocardial infarction, deep vein thrombosis, stroke, and pulmonary embolism 203–208. This dose-dependency was noted in another study , which compared the effects of transdermal versus intramuscular testosterone. There appears to be a direct relation between testosterone dosage and the incidence of erythrocytosis with testosterone gel . In the past, low T was typically treated with testosterone replacement therapy (TRT). Also, some symptoms, such as fatigue, sleep problems, and depression, can be caused by many underlying conditions that have nothing to do with testosterone. Depending on the cause and age when low T first appears, symptoms can differ. The primary goal in treating patients with TD is symptom improvement by achieving physiological levels of testosterone. Studies have shown that application of standardized albumin levels leads to very little variation in calculated free testosterone and is clinically acceptable23. The percentage of free 3 H-T is multiplied by the total testosterone to calculate the FT of the sample. Low Serum Testosterone and Mortality in Older Men There is an inverse linear relationship between total testosterone and BMI, and free testosterone concentrations also decrease with increasing BMI. The concentrations of C-reactive protein in these patients are twice as high as those in eugonadal type 2 diabetics, whose C-reactive protein levels are already elevated compared with non-diabetics. Analysis of gonadotropin levels demonstrates that the hypogonadism in type 2 diabetes is mostly hypogonadotropic (secondary) hypogonadism (40). 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. 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. Even men with normal serum testosterone levels may require or request exogenous testosterone therapy because of other constitutional symptoms.53 Patients on long-term androgen therapy require follow-up of their PSA, hematocrit, and liver enzymes about every 6 to 12 months. In pre-pubertal hypogonadal boys, testosterone replacement therapy will initiate puberty and induce development of secondary sexual characteristics. This raises some concern about an increasing trend among some practitioners of combining testosterone replacement therapy with aromatase inhibitors. A recent study showed that testosterone increases muscle mass but aromatization to estradiol is necessary for decrease in fat mass and improvement in sexual function suggesting that estradiol in men will be necessary for these functions. Studies have shown that testosterone may have a threshold effect on some parameters such as sexual function but there appears to be a dose-related response to testosterone treatment for muscle mass, fat mass and hemoglobin and hematocrit 26,27. For all hypogonadal men, replacement of testosterone is indicated except in patients where fertility is desired (Table 1) or when there are contraindications (Table 2). In contrast, other studies have found increased cardiovascular mortality in patients with testosterone deficiency (19). The Massachusetts Male Aging Study (10), an observational cohort study conducted on healthy men aged 40 to 70 years from the Boston area, estimated that the prevalence of androgen deficiency (total testosterone Many men with low testosterone levels have no symptoms, and many men with symptoms who receive treatment and reach goal testosterone levels have no improvement in their symptoms. Therefore, for the management of testosterone levels, it is important to maintain a normal body weight by smoking cessation and frequent strength exercise. TRT is thought to have a minimal effect on serum prostate-specific antigen (PSA) levels in men with benign prostatic hyperplasia and in men with treated prostate cancer. Replacing testosterone to physiologic levels is not thought to cause new prostate cancer or accelerate growth or spread of localized prostate cancer (2). This is thought to be a physiologic rate of growth due to the normalization of serum testosterone. Because any systemic illness can temporarily decrease levels of testosterone, FSH, and LH, secondary hypogonadism should be confirmed by measuring these levels again at least 4 weeks after resolution of the systemic illness. Free testosterone levels can be calculated based on SHBG, albumin, and testosterone values; there are calculators available online. Neither weight loss nor serum total testosterone increase were maintained after supervised weight loss intervention ended (45). Only 6 patients (1.9%) had a macroadenoma, all of whom had total testosterone concentrations of 104 ng/dL (3.6 nmol/L) or less. To minimize phlebotomies and expedite the evaluation, we recommend ordering early morning, fasting serum total testosterone, SHBG, and gonadotropins at the first clinic visit. Measurement of serum total testosterone concentrations was repeated twice 3 months later after the patient had returned to baseline health. Further studies to help establish more accurate and uniform methods of assessing free testosterone concentrations and to determine its clinical utility for the diagnosis of hypogonadism are needed. You may become pre-diabetic, or see your cholesterol levels rise, says Danielle McDevitt, M.D., a physician who specializes in hormones. A guy in his 20s with healthy genes and no chronic ailments will have a higher testosterone level than a 55-year-old with ongoing medical issues. Guidelines cannot include evaluation of all data on emerging technologies or management, including those that are FDA-approved, which may immediately come to represent accepted clinical practices. The mission of the Panel was to develop recommendations that are analysis-based or consensus-based, depending on Panel processes and available data, for optimal clinical practices in the treatment of muscle-invasive bladder cancer. Findings are similar to the previously cited pharmacokinetic study (750 mg in 3 mL) in which one patient in 130 (438 It is notable that similar findings have also been observed with other oil-based testosterone preparations that are currently most often self-administered at home (typically with lower volumes of injection).445 The cut-off of 300 ng/dL was chosen based on the mean total testosterone levels cited in the best available literature with a view to maximizing the potential benefit from prescribing testosterone while minimizing the risks of such treatment. Likewise several large population-based and observational studies have established an inverse relationship between serum testosterone levels and risk of developing CVD and CVD-related or diabetes-related mortality Khaw et al. 2007; Corona et al. 2010; Ohlsson et al. 2011; Haring et al. 2013; Muraleedharan et al. 2013. Therefore, some experts recommend treatment for clearly symptomatic men even if serum testosterone levels are ‘low-normal’ and free testosterone levels are low Morgentaler et al. 2014. These findings lead to the proposal of diagnostic criteria for symptomatic hypogonadism to include the presence of three sexual symptoms combined with a total testosterone level lower than 11 nmol/l or free testosterone lower than 220 pmol/l in those with equivocal total testosterone levels (8–11 nmol/l). Currently, there is not enough evidence to clearly state that the benefits of testosterone-replacement therapy outweighs the risks of testosterone-replacement therapy in aging males. One limitation of this trial is that it is not powered to fully assess potential risks of prostate cancer and cardiovascular events. The long-term benefits and risks of testosterone-replacement therapy will become clearer when the effects of testosterone are studied on all health-related outcomes over an extended period of time. Two small studies have reported no significant prostate-specific antigen (PSA) rise or prostate cancer recurrence in a total of 17 men, following radical prostatectomy in men with undetectable PSA 216, 217. The bioavailable fractions of testosterone are composed of both the albumin-bound and the free testosterone. The important factors that need to be considered in testosterone measurement are (1) types/forms of testosterone to be measured, (2) time of measurement, and (3) frequency of measurement. Symptoms and signs suggestive of hypogonadism (Table 2) include loss of vitality, visceral obesity, decreased muscle mass and strength, osteopenia and bone pain, and mood changes and depression 1, 2, 5. A number of diagnostic inventories or questionnaires exist for recognizing symptoms of testosterone deficiency. Lifestyle choices and comorbid conditions may also lead to lowered levels of testosterone. Aging, liver disease, hyperthyroidism, and anticonvulsant use all increase SHBG level and therefore decrease the bioavailable levels of testosterone8. However, solid evidence linking testosterone insufficiency to health-related outcomes in older men is just beginning to emerge, and even less information is available on testosterone and mortality. Furthermore, they can be used to identify high-risk men for LowT screening. While this is beyond the scope of the present study, future investigations into these pathways and mechanisms are warranted. In a study directly comparing the pharmacokinetics of 2 doses of SQ testosterone enanthate injected weekly (50 or 100 mg) and 1 concentration of IM testosterone enanthate injected once (200 mg), the IM testosterone achieved the highest peak testosterone (mean 2,261 ng/dL) followed by SQ 100 mg (1,345 ng/dL) and SQ 50 mg (622 ng/dL).437 The time-to-peak level was slightly faster with IM testosterone (33 hours) compared to SQ 100 mg (36 hours) and SQ 50 mg (45 hours). The pharmacokinetics of short-acting testosterone therapy depends on the dose, interval, and method of delivery (SQ versus IM). One of the oral alternatives for testosterone therapy is the 30 mg sustained-release muco-adhesive buccal pellet applied to the upper gums above the incisor teeth twice daily.432 However, the increase in size of the prostate needs to carefully monitored, and the patient needs to be made aware that there might be increased voiding symptoms during treatment (2,4,9,79,89). Prostate volume does, however, increase during testosterone therapy usually in the first 6 months, but this is usually to the normal volume seen in eugonadal men. As a result of the concerns about prostate cancer it is important to monitor PSA levels and perform a DRE regularly during the course of treatment. Testosterone should NOT be used in individuals with significant cardiovascular diseases and prostate cancer. Therefore, it appears that testosterone effects in older men may be heavily dependent on pre-existing comorbidities and risk factors. Meanwhile, comorbidities such as obesity and diabetes mellitus were relatively high in testosterone clinical trials. Increasing rates of testosterone prescriptions in men over the past decade have warranted evaluation of the multi-organ effects of testosterone replacement therapy. Current knowledge dictates that the presence of testosterone is crucial for the development of prostatic hyperplasia, and chemical or surgical castration has been reported to result in reduced prostate volume . Conditions requiring measurement of serum testosterone (as suggested by the Endocrine Society) (2) None of these symptoms is unique to hypogonadism, so one or more of these symptoms must be combined with a low testosterone concentration for the diagnosis to be made. There are a number of symptoms and signs related to low testosterone concentrations that indicate a diagnosis of hypogonadism. Some experts discourage the measurement of free testosterone because of the limitations discussed above, and these experts recommend focusing on the interpretation of total testosterone concentrations in conjunction with SHBG concentrations (7). Serum testosterone has a circadian rhythm with highest concentrations in the morning, and the normal range of serum testosterone is based on early morning blood samples. In patients with a protracted systemic illness lasting more than a few weeks, serial measurements of testosterone over several months are helpful; a pattern of increasing serum testosterone suggests that the HPT axis might fully recover. Although this man's initial serum total testosterone concentration was very low, he had a recent severe illness, (hospitalization for pneumonia 2 weeks prior to the initial testosterone measurement). The equilibrium dialysis is the reference method for the measurement of free testosterone concentrations . Bioavailable testosterone is measured by the ammonium sulfate precipitation method. However, there is a growing concern about the accuracy of automated immunometric assays especially for measurements in the low testosterone concentration range 36–38. The normal reference range for TT in adult men is approximately 300–1000 ng/dL. The rest of the testosterone is bound to sex hormone-binding globulin (SHBG), and this portion is not available for use by most target organs 21, 27–29. Regarding diabetes, it is well known in urology that androgen deprivation therapy for patients with prostate cancer increases insulin resistance,40,41 and indeed, the serum total testosterone level is inversely related to the insulin concentration and insulin resistance in men.42 Several epidemiological studies in men have shown that a close association between a low serum testosterone level and type 2 diabetes mellitus (T2DM) has been reported.43-45 Recently, it was reported that about a third of men with T2DM present with LOH.46 However, the more interesting finding than that of a close relationship between low serum testosterone level and T2DM in cross-sectional studies is the fact that a low serum testosterone level is a precursor for the incidence of insulin resistance and T2DM, as shown in longitudinal studies of healthy men.47-49 When the efficacy of TRT for diabetes is considered, three recent large RCTs consistently showed a significant decrease in insulin resistance,50-52 although testosterone-induced changes in glucose metabolism still appear inconsistent and less pronounced than would be expected. We previously reported that the International Index of Erectile Function-5 score for erectile function increased significantly with increases in serum testosterone in a study of 130 men with symptoms of sexual dysfunction.10 The fundamental importance of testosterone at most levels of the pathways that serve penile erection, from the cortex through the midbrain and spinal cord to the smooth muscle cells and endothelial function, gives the consideration of testosterone status a significant place in the management of most patients with ED. The goal of testosterone therapy is to raise serum testosterone level into the midnormal range (400–700 ng/dL) and resolution or reduction in symptoms of hypogonadism. A symptomatic male with total testosterone between 8 mmol/L and 15 mmol/L can reasonably be offered a trial of therapy. Direct assays, however, may overestimate actual testosterone levels and show limited accuracy at lower testosterone levels18. Due to cost and availability, clinical evaluation of a patient suspected to be testosterone deficient generally begins with total testosterone measurement. The Hypogonadism In Men (HIM) study found the odds ratio for having low total testosterone to be 1.84 for hypertension, 2.09 for diabetes, and 2.38 for obesity11. Acute illness will depress testosterone levels and misrepresent one’s true hormonal status7 Individual study factors, such as the heterogeneity and demographics of the study population, the comorbidities of the study population and how they are controlled in the analysis, and confidence intervals also impact overall study quality. Meta-analyses that are limited to only including RCTs may be restricted to a small number of studies and relevant studies may be excluded that could provide sufficient power to make alternative conclusions. For example, outcomes of meta-analyses using RCTs alone are generally more robust than those that also include cohort studies. When reviewing results from meta-analyses, it is important to recognize that the overall reliability is dependent on the quality of the weakest study included in the analysis. 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. Testosterone replacement therapy increases hematocrit in anemic hypogonadal men in a dose dependent manner 79-81. Gynecomastia may occur with the administration of testosterone because of its conversion to estradiol. Studies of sub-fraction analyses of HDL and efflux of HDL from macrophages are ongoing and the results may clarify the significance of the HDL changes. The decrease in central adiposity and minor improvements in insulin sensitivity and hemoglobin A1C have also been reported in individuals with hypogonadism and metabolic syndrome and/or type 2 diabetes 2,57,58,61-66. Defining age- or symptom-specific T thresholds for diagnosing hypogonadism in aging men has proven a challenging task, as different symptoms appear at different T thresholds with age being an important confounder.6–9 Hypogonadal symptoms tend to be specific to the individual, with not all men experiencing symptoms despite having low T levels. Measurement of total testosterone represents a reasonable initial screening assay for most men with convincing symptoms of testosterone deficiency. Within the first year of therapy monitoring should occur about every 3-6 months and include evaluation of serum testosterone, hemoglobin and hematocrit, PSA and prostate health (by DRE). Lastly, conditions that affect levels of SHBG may ultimately skew the interpretation and significance of the total testosterone measurements. Type 2 diabetes, hypertension and sleep apnea are independent risk factors for declining testosterone levels10. Total testosterone absence of signs and/or symptoms increases the likelihood of making a false diagnosis and reduces the potential benefit of testosterone therapy. 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. 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. 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. If this effort is not successful, then the patient may be offered testosterone replacement therapy. Patients with a history of chronic opiate use and who present with symptoms of hypogonadism should be evaluated. When obese men present with symptoms of hypogonadism, lifestyle changes (e.g., caloric reduction and exercise) should be advised. 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. 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. 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. 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 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. You are prohibited from using or uploading content you accessed through this website into external applications, bots, software, or websites, including those using artificial intelligence technologies and infrastructure, including deep learning, machine learning and large language models and generative AI. In addition, recent, large retrospective studies have suggested TRT in aging hypogonadal men can improve overall mortality Shores et al. 2012; Muraleedharan et al. 2013. A few meta-analyses have shown no increase in cardiovascular adverse effects or mortality with TRT Calof et al. 2005; Fernandez-Balsells et al. 2010; Carson and Rosano, 2012. Yet one must emphasize the data for TRT in men with a history of prostate cancer are without randomized or placebo controlled trials and should be interpreted with caution. The Endocrine Society recommends that the serum testosterone be measured again to confirm the consistency of the low values . The symptoms of hypogonadotropic hypogonadism varies with type (congenital vs. acquired), age at onset, duration (functional vs. permanent) and severity (partial vs. complete). Male hypogonadism increases with age and with multiple co-morbid conditions in several epidemiologic studies 5-7. The prevalence of hypogonadism due to genetic or idiopathic abnormalities in the pituitary or hypothalamus is uncommon in clinical practice except in tertiary referral centers. 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). 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. 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 94 Corona et al. likewise found that the prevalence of low testosterone levels (defined as total testosterone of 107 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. Duration of studies and mode of administration did not appear to impact outcomes. If normalized, subsequent serial imaging can be performed in two to five years. Testosterone replacement therapy leads to increase in DHT levels through conversion by 5 α reductase enzymes. In the meantime until such data are available, clinicians should discuss with and monitor cardiovascular events in older hypogonadal men who will start testosterone treatment. However, such an increase was not noted in another randomized placebo-controlled study on testosterone treatment in frail older men . It is reasonable to convert older adolescents to deficiency receive long-acting testosterone enanthate or testosterone cypionate at a dose that is increased gradually over 18 to 24 months, every 1 to 2 weeks. Older adolescents withtestosterone deficiency receive long-acting testosterone enanthate or testosterone cypionate at a dose that is increased gradually over 18 to 24 months, every 1 to 2 weeks. Although patients with primary hypogonadism may not become fertile with any endocrine therapy, patients with secondary hypogonadism often become fertile with gonadotropin therapy. Clinicians should not prescribe alkylated oral testosterone.Frequently two patches per day may be required to maintain the serum testosterone within the reference range in some men.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.Despite improvements in mood with testosterone-replacement-gel therapy, the beneficial effect from concomitant testosterone-replacement therapy and SSRIs cannot be clearly differentiated 157, 158.While these guidelines do not necessarily establish the standard of care, AUA seeks to recommend and to encourage compliance by practitioners with current best practices related to the condition being treated.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.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.In our clinic, we treat such patients for 3 months with exogenous testosterone to determine whether there is an effect on either the ED or the clinical signs of hypogonadism (if present).Whether the changes in both these studies represent a clinically meaningful improvement is unclear. 9Reassessment of men with high BMI consists of assessment for symptoms and signs of hypogonadism and re-measurement of testosterone. In many men, this assessment can only be validated during management, by monitoring the response to lifestyle measures, optimization of comorbidities, and in selected cases, a trial of testosterone treatment. In such men, the conundrum lies in determining the degree to which the (often nonspecific) clinical symptoms are predominantly due to hypogonadism or instead due to obesity and other chronic systemic disorders that suppress the HPT axis (ie, reverse causality). The terms functional hypogonadism and late-onset hypogonadism suggest that testosterone treatment might be beneficial, a concept that has not been proven. In conclusion, This model provides the reference ranges needed to support research and clinical decision making in males who have symptoms that may be due to hypogonadism. A significant percentage of men over 60 years of age have serum testosterone levels below the lower limits of young male adults (20 to 30 years) 6–9. Hypogonadism in older men is a syndrome characterized by the presence of low testosterone levels and clinical signs and symptoms of hypogonadism. Hypogonadism is a common disorder in aging men with a significant percentage of men over 60 years of age having serum testosterone levels below the lower limits of young male adults. These results were similar for the bioavailable fraction of testosterone and were not explained by overall health status. Adjusted for age, BMI, waist to hip ratio, alcohol use, current smoking, and exercise. The association of low testosterone with all-cause, CVD, and respiratory disease mortality remained significant after excluding deaths that occurred during the first 5 yr of follow-up. The 10-yr weight change, heart rate, number of doctor visits in the past year, number of current medications, and serum creatinine. During an average 11.8-yr follow-up, 538 deaths occurred, a mortality rate of 57.5 per 1000 person-years. There is an association between aging and increased sensitivity to negative feedback by androgens. Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner, the periodicity and amplitude of which determines the pattern of secretion of the gonadotropins, LH and FSH, from the anterior pituitary.20 Decreased production of GnRH by the hypothalamus with aging has been demonstrated in both human and animal studies. Once LH binds to the LH receptors on the Leydig cell, there is the rapid synthesis of the transport molecule, steroid activating receptor (StAR), which actively transports cholesterol across the mitochondrial membrane so that it may initiate the rate-limiting conversion of cholesterol to pregnenolone.12 Pregnenolone then passes from the mitochondria to the smooth endoplasmic reticulum, where the remainder of the enzymatic reactions occurs to synthesize testosterone. Age-related hypogonadism is due to a combination of primary hypogonadism (testicular failure) and secondary hypogonadism (hypothalamic-pituitary axis failure). Clinicians need to be familiar with the various options to measure a patient’s testosterone status and an appreciation for the strengths and limitations of the assays used to determine such measurements. Although many causes of hypogonadism may affect the central (hypothalamus and/or pituitary) and peripheral (testes) components of the HPT axis, the serum gonadotropins indicate the site of the principal dysfunction. Using serum gonadotropins as a pivot in the evaluation of possible hypogonadism is very useful. If he has low or normal serum gonadotropin concentrations, then he should be evaluated for causes of hypothalamic and pituitary dysfunction. Elevated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations would be consistent with primary hypogonadism. The high peak levels can be avoided by administering 750 mg instead of 1000 mg of TU injections .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.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.The meta-analysis study by Isidori et al. reported that moderate improvement in sexual function was noted in men with testosterone levels below 346 ng/dL .The pharmacokinetics data of the testosterone gel applied to the axillae are comparable to the other testosterone gels .Lastly, conditions that affect levels of SHBG may ultimately skew the interpretation and significance of the total testosterone measurements.What constitutes a ‘normal value’ has not been clearly established in older men due to multiple issues including underlying physiologic complexity as previously discussed and inherent variations in laboratory testing. “However, most of these explanations for testosterone deficiency may be attributed to age. Explore Mayo Clinic studies testing new treatments, interventions and tests as a means to prevent, detect, treat or manage this condition. Risks from testosterone therapy are most often due to doses that are too high. For older adults who have low testosterone and symptoms of hypogonadism due to aging, it's less clear how well testosterone replacement works. It is approved in some countries for treatment of testosterone deficiency but is not currently approved in the US. 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. 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. 3 Management of hypogonadotropic hypogonadism due to anabolic steroids abuse Common symptoms include fatigue, reduced muscle mass, low libido, erectile dysfunction, mood changes, and decreased motivation. Our experienced medical team understands that each patient’s needs are unique and require personalized treatment approaches. Although lifestyle changes can make a world of difference, medical treatment options may be necessary. Initial Evaluation of the Impotent Patient The normal range for total testosterone is 300 to 1000 ng/dL (10.5 to 35 nmol/L). Age at onset of testosterone deficiency (congenital, childhood-onset, or adult-onset hypogonadism) dictates the clinical presentation. When primary hypogonadism affects testosterone production, testosterone is insufficient to inhibit production of FSH and LH; hence, FSH and LH levels are elevated. When properly monitored by qualified healthcare providers, testosterone replacement therapy is generally safe for men with clinically diagnosed testosterone deficiency. Discussion and Table 7 If the early morning serum TT level is less than 250 ng/dL, the patient is likely to be hypogonadal.Although small testes are an uncommon finding in older men with newly diagnosed hypogonadism, Klinefelter syndrome, the most common cause of classic organic hypogonadism, is typically characterized by very small testes (≤4 cc each), is underdiagnosed (by 50% or more), and might not be diagnosed until middle or older age (3).The diagnosis of hypogonadism in human males includes identification of low serum testosterone levels, and hence there is an underlying assumption that normal ranges of testosterone for the healthy population are known for all ages.Many of these studies suggest that there may be even neutral to beneficial effect of testosterone-replacement therapy on the cardiovascular risk factors and adverse cardiovascular complications (e.g., angina) 142, 176–179.If the ED is not reversed, which is common,27,28 but the other aspects of hypogonadism are improved, it may be prudent to keep these men on exogenous testosterone as long as there are no contraindications to its use (Table 3).29–31Therefore, except in older men, a morning (7 to 11 AM) serum total testosterone should be checked initially, if testing is necessary.His symptoms of fatigue and low mood are nonspecific and have low diagnostic value.There is an inverse relationship between serum total and free testosterone levels and visceral fat mass. The diagnosis of late-onset hypogonadism can be less certain in aging men who have comorbid conditions with borderline low testosterone levels. The patient is likely to be hypogonadal if the early morning serum total testosterone level is less than 250 ng/dL. The increases in testosterone levels following testosterone-replacement therapy can increase secretion of sebum 221, 222. A change in testosterone levels through the use of testosterone replacement therapy appears to affect the skin and hair in men. The presence of low testosterone levels with preexisting OSA can further complicate cardiometabolic risk factors. Finding the cause of hypogonadism is an important first step to getting the right treatment. Make a medical appointment if you have symptoms of male hypogonadism. As testosterone decreases, some men have symptoms like those of menopause. Testosterone replacement therapy can treat some types of male hypogonadism. Male hypogonadism is a condition in which the body doesn't make enough of the hormone testosterone or enough sperm or both. SERMs are oral agents that block E2 feedback resulting in increased LH secretion. 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 The overall quantity and quality of studies investigating the use of these alternative agents in males are limited. 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. While SERMs, hCG, and AIs are all categorized as "alternative therapies" to testosterone, they are actually a diverse group of agents. There is no well-defined threshold of total testosterone concentration for determining when to perform sellar imaging.Differences in age, geography, date of initial testing (testosterone immunoassay testing was more commonly used before 2005), comorbid conditions, and baseline and therapeutic testosterone levels across studies introduce heterogeneity in the pooled population.It is important to note that screening questionnaires such as ADAM should never be used in isolation to diagnose clinical hypogonadism.Part of this effort includes the availability of serum-based reference material from pooled sera available from the National Institute for Standards and Technology for testosterone and a hormone standardization program using liquid chromatography/mass spectrometry (LCMS) offered by CDC.Repeat testing 3 months after discontinuation demonstrated a serum total testosterone of 266 ng/dL (9.2 nmol/L), and a serum calculated free T of 77 pg/mL (267 pmol/L). Symptoms and Signs of Male Hypogonadism The estradiol produced by aromatisation also provides negative feedback on the HPG axis, further reducing testosterone. Thus, the degree of hypogonadism is positively correlated to the degree of obesity in obese men (51,52). Utilising data from the NHANES III survey, it was found that men in the lowest free testosterone tertile were four times as likely to have diabetes as those in the highest free testosterone tertile (47). 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. Despite these effects, neither treatment led to significant changes in semen parameters.403 HCG is an LH analog that is usually prescribed to treat a deficiency in LH production. However, despite these limitations, several studies provide important insights into the impact of SERMs, AIs, and hCG on spermatogenesis. Given these pharmacologic and mechanistic differences, combinations of these alternative therapies might, in some instances, be clinically appropriate. Serum Free Testosterone Assessments Moreover, studies, including a substudy of the T-Trials (72), using quantitative CT and high resolution–peripheral quantitative CT have reported that testosterone treatment increases cortical and trabecular volumetric bone density and estimated bone strength (71, 72). Testosterone therapy reduces fat mass by about 1.6 to 4.3 kg (65, 66) but does not consistently improve measures of insulin resistance or glycemic control in men with low serum testosterone and established T2D (69). In agreement with findings of the T-Trials, a meta-analysis of RCTs of 2298 men with a mean age of 60 years and a serum testosterone 62). Pharmacological effect that is reported in men with low and low-normal serum testosterone concentrations. In the following section we will focus on double-blind placebo-controlled RCTs of testosterone treatment in older men with low serum testosterone and no classic cause of HPT axis pathology. At the end of the study, total testosterone increased in both groups with neither group deriving more benefit than the other (p ≥ 0.244). 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. 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. 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. 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 Men with testosterone deficiency who are interested in fertility should have a reproductive health evaluation performed prior to treatment. The diagnosis of low testosterone should be made only after two total testosterone measurements are taken on separate occasions with both conducted in an early morning fashion. The AUA and the Testosterone Panel were committed to creating a Guideline that ensures that men in need of testosterone therapy are treated effectively and safely. The Evaluation and Management of Testosterone Deficiency AUA Guideline provides guidance to the practicing clinician on how to diagnose, treat and monitor the adult male with testosterone deficiency. During the initial workup, if a clear treatable condition that explains androgen deficiency is diagnosed, it should be addressed first (11, 14). Ultradian fluctuations (rhythmic fluctuations of less than a 24-hour period but more than 1 hour) are more pronounced in older men, while circadian variation in testosterone is blunted, but still present, in older men (12). The most common cutoff transitioning from normal to low ranges from 280 ng/dL to 320 ng/dL; the guidelines recommend using 300 ng/dL as the cutoff (11). Testicular volume may be decreased (normal volume 15 to 30 mL, equivalent to the size of a quarter dollar coin). Even the sexual symptoms can be due to many other conditions, including vascular disease, chronic alcohol use, and depressive disorders. To be scientifically accurate, the Panel chose the term testosterone deficiency. Clinicians may use aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators, or a combination thereof in men with testosterone deficiency desiring to maintain fertility. The long-term impact of exogenous testosterone on spermatogenesis should be discussed with patients who are interested in future fertility. The testosterone therapeutic space is relatively unique. For most pharmaceutical products, the usage, dosage, and application is consistent across brands, and identification by chemical compound is sufficient to communicate to the reader when to use a given medication. The AUA has a policy that all pharmaceutical and biological agents are referred to only by their chemical compound formulation in guidelines, white papers, and best practice statements and not by their brand or generic name. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence. To minimize these effects, two morning draws for testosterone are recommended before any clinical intervention.Acute Illness. 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. The Panel does not recommend using free testosterone measurements as the primary diagnostic method for testosterone deficiency. Some authorities have advocated that free testosterone should be the primary measure used to define testosterone deficiency. In addition there are many nonspecific symptoms such as low energy, depressive mood, inability to concentrate and less energy.It is not yet known if the normal PSA reference ranges should be lowered for men with type 2 diabetes.It is currently limited to mainly reference laboratories but serves as the standard in all investigational studies of testosterone measurement.The symptoms of hypogonadotropic hypogonadism varies with type (congenital vs. acquired), age at onset, duration (functional vs. permanent) and severity (partial vs. complete).This patient has nonspecific symptoms and signs of androgen deficiency, and his serum total testosterone is modestly reduced.It would be helpful if health care professionals could identify men with low serum testosterone levels who are likely experiencing symptoms purely from androgen deficiency and would therefore benefit from treatment. With these caveats, the authors also want to reiterate the vast literature of known and proven benefits of testosterone normalization, which must also be carefully considered during the decision of whether or not to offer treatment. To the contrary, for men with identifiable etiologies or primary or secondary hypogonadism, treatment may be warranted regardless of age. In such cases, one should consider continuing TRT until underlying prostate cancer is confirmed because the many causes of hypogonadism, such as MetS, may have a greater mortality risk than prostate cancer that can potentially be mitigated by TRT. It is important in the current medical climate for the clinician to identify a contributing pathologic etiology other than only age-related decreases in serum testosterone to warrant treatment. However, a proportion of older men with low afternoon testosterone levels can have normal morning levels Brambilla et al. 2007; Crawford et al. 2007. This fall in bioavailable testosterone is due to rising SHBG levels with aging, which explains the disproportion between total and bioavailable testosterone levels. The gel formulation is able to produce a steady serum testosterone concentration within the physiological range of adult men. The peak levels of testosterone can be achieved within 2-3 days after administration of testosterone enanthate and cypionate. Individuals with an abnormal digital rectal examination suggestive of cancer, and/or elevated prostate-specific antigen should have a careful evaluation by an urologist before considering treatment. Aging males with a history of severe lower urinary tract obstruction, untreated sleep apnea, prostate cancer, or breast cancer should not be considered for testosterone replacement therapy . Testosterone levels should be measured in the morning to obtain peak testosterone results. While long-term studies are still unavailable on these issues, a smoother, more natural serum testosterone level can be obtained with the patches. Because testosterone levels do not increase beyond normal, the mood swings and aggressiveness that sometimes occur with intramuscular testosterone should not be seen with the transdermal preparations. The nonscrotal transdermal patch (Androderm) also maintains a diurnal serum concentration curve with normal testosterone, estradiol, and DHT levels. When applied prior to bedtime, these transdermal patch systems provide normal testosterone levels with diurnal variations in a physiologic fashion. Besides aggression, there are other side effects from androgen therapy, such as the development of an atherogenic lipid profile, insulin resistance, polycythemia, sleep apnea, fluid retention, acne, and hypertension.49 Supraphysiologic levels of testosterone in the blood lead to increased peripheral aromatization of testosterone to estradiol, and this may produce gynecomastia. Commonly used antihypertensive (β-blockers) and anticholesterol (statins) medications can induce mild to moderate reductions in serum testosterone levels Rosen et al. 1988; Schooling et al. 2013. Aging can blunt diurnal variation Bremner et al. 1983, but fluctuating serum testosterone levels can also be affected by laboratory assay differences in sensitivity, seasonality, triglyceride levels, glucose ingestion, or activity prior to serum laboratory draw Smith et al. 2013; Paduch et al. 2014. Diurnal variation in testosterone levels related to pulsatile release of gonadotropins by the HPG axis results in peak serum testosterone levels during morning hours. Low testosterone levels can lead to a variety of symptoms — like fatigue, depression, and a decrease in sex drive — and require proper diagnosis and management. However, very limited data are available on the effects of prolonged testosterone replacement therapy on lean body mass in healthy older adults. Testosterone has been reported to produce a substantial anabolic effect in young and middle-aged men with hypogonadism . However, the effect and consequences of long-term testosterone replacement therapy, specifically in older men, remain significantly understudied. Similar to the previous study, the LTT group had a significantly higher BMI, waist circumference, and fat percentage than the HTT group in this study. As testosterone is affected by age, Model 1 used only age as the adjustment variable. A total of 14,341 men aged 65–80 years tested from 2012 to 2017 at a hospital in South Korea were included. This study established a hypothesis that low alcohol consumption, smoking cessation status, and a high exercise rate would result in a low testosterone prevalence. Despite many studies on health behavior and testosterone, very few studies have analyzed smoking, alcohol, nutrition, exercise, and body composition simultaneously. However improvement in clinically significant physical function and performance-based measures in older men is less robust Page et al. 2005; Storer et al. 2008; Srinivas-Shankar et al. 2010, and effects are often short lived O’Connell et al. 2011. In general, the benefit of treatment for hypogonadism in older men is unclear due to lack of randomized controlled trials and other quality data. It is common in older men and often progresses to more fulminant primary hypogonadism and need for treatment Tajar et al. 2010. While BMD improves, the effect of testosterone replacement therapy on fracture risk is still unclear. Meta-analysis studies have shown testosterone replacement therapy positively affects bone density and reduces the rate of bone loss 69, 88. A double-blinded placebo-controlled study found that elderly men on testosterone replacement therapy for 6 months improved their lower limb muscle strength (isometric knee extension peak torque) when compared with subjects on placebo . Page et al. found improvements in both hand grip and physical function for hypogonadal men that were on testosterone enanthate treatment . Several studies found testosterone replacement therapy to be beneficial in improving muscle strength in hypogonadal older men. This review provides insight into the mechanisms resulting in the multifactorial nature of acquired androgen-deficiency, and outlines the current controversy regarding testosterone-replacement therapy in aging males. In cases where the total testosterone is equivocal despite consistent symptomatology, assessment of free or bioavailable testosterone may be informative. A diagnosis of male breast cancer or prostate cancer represents absolute contraindications to testosterone replacement therapy. AndroGel and Testim are both gel-based products approved in Canada and provide steady-state, physiologic levels of testosterone. Of note, if prolactin is not elevated, a pituitary lesion has to be relatively large to cause hypogonadotropic hypogonadism, and therefore sellar computed tomography (CT) has sufficient sensitivity.Congenital and childhood-onset hypogonadism are often suspected because of developmental abnormalities or delayed puberty.Most important, these agents have been reported to produce significant long-term hepatic toxicity.44 Oral testosterone does not reproduce the circadian pattern of testosterone production by the testes, nor does it achieve normal physiologic levels of DHT or estradiol.Besides aggression, there are other side effects from androgen therapy, such as the development of an atherogenic lipid profile, insulin resistance, polycythemia, sleep apnea, fluid retention, acne, and hypertension.49 Supraphysiologic levels of testosterone in the blood lead to increased peripheral aromatization of testosterone to estradiol, and this may produce gynecomastia.There are a number of formulations available for testosterone therapy including intramuscular injections, transdermal patches, transdermal gels, buccal patches and subcutaneous pellets.Oral testosterone undecanoate (TU) is available in many parts of the world but is not approved for use in the United States 46, 47.Varicoceles are known to cause intratesticular dysfunction and have a higher prevalence in men with increasing age Canales et al. 2005.Testosterone replacement should only be given to men with a diagnosis of hypogonadism based on persistently low serum testosterone concentrations measured reliably and symptoms that are related with low testosterone. Further large scale longitudinal studies are needed to ascertain the effects of testosterone replacement therapy in men with OSA. Common adverse events of testosterone replacement therapy include development of acne and increased oiliness of skin because of the androgenic effects on sebaceous gland. There are also reports that testosterone replacement therapy improves depression 77,78; however the studies are few and controversial. Aside from symptomatic relief, treating low testosterone can offer other significant health benefits. Further, exogenous testosterone is not recommended for men seeking fertility as sperm production may be reduced. By applying to the underarms there is theoretically less risk of secondary exposure by skin-to-skin contact with another individual. How Testosterone Affects Health A combination of age, genetics, and pre-existing medical conditions determines your testosterone levels. Although the study was not powered to detect cardiovascular events as a primary endpoint, the authors did not detect increased risk in the testosterone group. One study reported comparative pharmacokinetics between IM testosterone enanthate (250 mg every 3 weeks) and IM testosterone undenaconate (1,000 mg every 9 weeks, a dosage that is only available outside the United States).440 Results demonstrated that IM testosterone enanthate achieved trough levels of 239 ng/dL compared to 470 ng/dL with IM testosterone undecanoate at the end of the 10-week cycle. In contrast to topical agents where a percentage of men have difficulty achieving therapeutic levels within standard dosing ranges, injectable testosterone preparations are able to achieve therapeutic levels in almost any clinical scenario. Furthermore, the concept of testosterone 'crash' is well recognized by clinicians, with large differences between peak and trough levels potentially leading patients to become symptomatic towards the end of the cycle despite having therapeutic trough testosterone levels. BMD measurement in a male with osteopenia/osteoporosis or low trauma fracture can be repeated in 1–2 years after testosterone replacement therapy is initiated (2,79). Elevated haematocrit values above 54% require action – usually therapy should be stopped until the values decrease to a safe level. ‡After 3 months, perform in accordance with guidelines for prostate cancer screening, depending on the age and race of the patient. Measuring testosterone levels became easier in the 1970s, and it wasn't long before levels were being checked in men across all age groups. This study has limitations in explaining that obesity and health behavior affect testosterone levels, because this study was carried out as a cross-sectional design. Current smokers had lower testosterone levels than non-smokers by an average of −0.61 ± 0.23 ng/dL . A previous study compared testosterone levels between current smokers, past smokers, and non-smokers in 426 individuals. The total serum testosterone level was measured through blood collection through the median cubital vein. The Endocrine Society recommends 300 ng/dl (10.4 nmol/l) as a good level to consider as the lower limit of normal total testosterone. However, studies of testosterone therapy in men with osteoporosis are limited and none have used fractures as an end-point; so although there is significant evidence of an association between hypogonadism and osteoporosis, there is no established causal link between the two. Low testosterone levels increase fat mass and decrease lean muscle, resulting in increased adipose tissue (52). Treatment options for patients with secondary hypogonadism/hypogonadotropic hypogonadism This review will cover the relationship between testosterone and ED, highlighting what is known and unknown regarding the effect of testosterone on penile function, what to look for in the evaluation of the ED patient suspected of having a lower-than-normal serum testosterone level, and the methods currently available to treat patients with this hypogonadal condition. Testosterone replacement can raise testosterone levels and help ease the symptoms of male hypogonadism. Because of the increase in sex hormone–binding globulin (SHBG) with aging, total testosterone level is a less sensitive indicator of hypogonadism after age 50. Although there are no prospective data on the time frame of HPT axis recovery after an acute systemic illness, clinical experience indicates that the time to recovery is inversely related to the severity and duration of the illness. Assessment for hypogonadism should not be done in men who are acutely unwell (and below their baseline health) or during hospital admission. Most experts prefer to err in underdiagnosing very mild hypogonadism in older men over misdiagnosing eugonadal men as hypogonadal. His symptoms might be due to depression (with a false negative result in the Patient Health Questionnaire-9), atherosclerotic disease of the penile vasculature, obesity, sleep apnea, or some combination of these causes. High-density lipoprotein (HDL) cholesterol levels were also found to decrease in patients that were on oral testosterone therapy 57, 113. The serum testosterone levels rise to supraphysiologic levels for several days and gradually decline over a period of 10 to 14 weeks after administration of TU injection 27, 51–53. Over the past two decades, significant advances have been made in improving the understanding of the pathophysiology of the hypogonadism, the diagnostic methods used to diagnose low testosterone levels, and testosterone replacement therapy. Testosterone replacement in individuals with borderline low or low-normal testosterone levels is yet to be proven effective and may not outweigh the risks. The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel's judgment regarding the balance between benefits and risks/burdens (Table 1 - See button below).However, such an increase was not noted in another randomized placebo-controlled study on testosterone treatment in frail older men .Indeed, regarding the efficacy of TRT in treating ejaculatory dysfunction, a significant improvement in ejaculatory ability was found in depressed men with low testosterone levels who continued to take serotonergic antidepressants.Since the FDA warning in 2015, other studies have failed to demonstrate a risk of cardiovascular events in patients on testosterone therapy.Regarding diabetes, it is well known in urology that androgen deprivation therapy for patients with prostate cancer increases insulin resistance,40,41 and indeed, the serum total testosterone level is inversely related to the insulin concentration and insulin resistance in men.42 Several epidemiological studies in men have shown that a close association between a low serum testosterone level and type 2 diabetes mellitus (T2DM) has been reported.43-45 Recently, it was reported that about a third of men with T2DM present with LOH.46 However, the more interesting finding than that of a close relationship between low serum testosterone level and T2DM in cross-sectional studies is the fact that a low serum testosterone level is a precursor for the incidence of insulin resistance and T2DM, as shown in longitudinal studies of healthy men.47-49 When the efficacy of TRT for diabetes is considered, three recent large RCTs consistently showed a significant decrease in insulin resistance,50-52 although testosterone-induced changes in glucose metabolism still appear inconsistent and less pronounced than would be expected.Implants have been available for many decades but earlier larger sized testosterone pellets frequently extruded and were rarely used in the US, until recently. Addition of a combination of health status markers, HOMA-IR or adiponectin and leptin, also failed to influence results, as did adjustment for estradiol or bioavailable estradiol levels. The influence of testosterone covariates and potential biological mediators was examined by adding variables one by one and in combination to the basic model (age, adiposity, and lifestyle adjusted) and comparing men in the lowest testosterone quartile with those with higher values (Table 4). The median bioavailable testosterone level was 96 ng/dl (no reference range is available). Up to 30% of older men with a low serum testosterone concentration have a normal value on repeat testing (18). Without compelling evidence (eg, specific clinical features, such as very small testes and high serum gonadotropin concentrations), androgen deficiency should not be diagnosed with a single low testosterone concentration because of significant diurnal and day-to-day variation (14). Because the man has had a very low serum testosterone measured, it is incumbent to exclude hypogonadism with an appropriate evaluation (Fig. 1). Furthermore, the AACE statement indicates that ‘men with unequivocally low total and/or free testosterone after thorough diagnostic work-up should be considered for TRT and extra caution should be exercised in the frail elderly’. Lastly, the statement indicated that exogenous testosterone should not be used for hypogonadism without a ‘defined cause’ considered to be a ‘disorder of the testicles, pituitary gland, or brain resulting in hypogonadism’. In fact, more recently, a handful of studies assert potentially worse cardiovascular events and mortality in older hypogonadal men on TRT Basaria et al. 2010; Vigen et al. 2013; Xu et al. 2013; Finkle et al. 2014. However, a PSA rise greater than 0.06 mmol/l within 18 months of therapy may indicate underlying, undiagnosed prostate cancer Coward et al. 2009. The 400-mg doses, while obtaining higher peak values, will not maintain eugonadal levels beyond the 3-week limit. The 17β-hydroxyl esters of testosterone, however, are modifications of aqueous testosterone that are more widely used, can be administered with slow-release injection vehicles, and are more useful for testosterone replacement therapy. These parenteral androgens do not provide the normal circadian pattern of testosterone, and the injections are uncomfortable at times. The most effective of oral agents of testosterone are the 17α alkylated testosterones, such as methyltestosterone. Oral agents for testosterone replacement are clearly convenient and comfortable to use. The measurement of the serum testosterone concentration is usually the most important single diagnostic test for male hypogonadism. The laboratory values for mixed hypogonadism can be varied including cases with low testosterone with mild increases in LH and FSH levels. In a study of men in Hong Kong, the prevalence of symptomatic hypogonadism was 9.5% with an increased prevalence of 16.7% in the older age group (60–64 yrs) . We have reviewed the diagnostic methods as well as benefits and risks of testosterone replacement therapy for hypogonadism in aging men. Patients who are on long-acting SQ pellets require two separate assessments of testosterone to determine the dose and frequency required. 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. 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 stimulation of hematopoiesis has been noted to be influenced by age and appears to be more pronounced in older men 198, 199. It was noted that the intramuscular testosterone raised the hematocrit more than transdermal testosterone. Testosterone-replacement therapy is not recommended for those who still desire fertility. It's not used to treat hypogonadism caused by aging. The lymph system absorbs it, so it might not cause the liver problems seen with other oral forms of testosterone. The U.S. Food and Drug Administration has approved one oral testosterone replacement, testosterone undecanoate (Jatenzo, Tlando, Kyzatrex).