Epidemiology and Prevalence of Male Hypogonadism 

The prevalence of hypodgonadism rises with age, ranging from 9% for men in their 50s to 91% of those in their 80s in a major epidemiologic study of generally healthy people (13).  This study measure hypogonadism prevalence in terms of both total T (<325 ng/dL [11.3 nmol/L) and free T index (total T/sex-hormone-binding globulin [SHBG], <0.153 nmoL/nmoL).  The latter measures the proportion of T that is bioavailable rather than bound to SHBG. 


The Hypogonadism in Men (HIM) study of men > or equal to 45 years old (N=2165) who visited a primary care provider's office found the rate of hypogonadism (total T ,300 ng/dL [10.4 nmol/L])  was 38.7%.  Yet only 3.7% of all subjects were being treated for hypogonadism, suggesting that many cases had not been detected (14).  In this study, the mean age was 60.5 years (range, 45-96 years) and the majority of visits (61.6%) were for routine care.  Also, a significant percentage of the men being treated for hypogonadism had inadequate levels of testosterone, indicated the nee for continue follow-up. 


Although hypogonadism is more common among men with certain comorbidities, the decline in T seen with age appears unrelated to illness.  Free T fell by 1.4% per yer in men aged 39 to 70 (n=1709) (15).  T levels among men with one or more comorbid conditions (eg, obesity, cancer, coronary heart disease, hypertension, diabetes, prostate problems) remained 10% to 15% lower. 


A larger prospective population-based study (N= 1896 nondiabetic Finnish men, 42 to 60 years old at baseline) found that T was associated with the metabolic syndrome and some of its elements (insulin and glucose concentrations, TG) as well as with a marker of inflammation (CRP), and iron stores (6). Men with free T in the lowest tertile of the cohort were 1.7 times more likely to have the metabolic syndrome after adjustment for age and BMI (6). 


Low T is associated with abdominal obesity, which in turn promotes development of insulin resistance, but some data suggest a more direct role of testosterone deficiency.  Perhaps it is not surprising that healthy men with low T (N=25, mean 291 ng/dL or 10.1 nmol/L) have significantly higher fasting and 2-hour plasma insulin levels than those with T in the normal range (N=25, mean, 570 ng/dL or 19.8 nmol/L), suggesting insulin resistance (21).  More recently, a study of 70 men, 20 to 60 years old, also found that total T and SHBG levels were significantly and inversely correlated with insulin levels and insulin resistance (HOMA-IR) (22). 


Risks Associated With Testosterone 


All-cause and CV death

Epidemioogic studies have identified significant associations between T levels and all-cause cardiovascular (CV) death in general populations of men greater than or equal to 40 years old (17-19). 


A larger (2314 men, aged 40 to 79 years) longer (average 7 year follow up) nested case-control study found that every 173 ng/dL) (6-nmol/L) increase in serum T was associated with a 21% lower risk of all-cause death (or .79, 95% CI, .69 to .91 P <.01) and CV death (or .79, 95% CI, .64-.97, P=.02) after excluding deaths within the first 2 years and controlling for multiple variables (age, body mass index [BMI], systolic blood pressure (SBP), cholesterol, cigarette smoking, diabetes, alcohol intake, physical activity, social class, education, and SHBG)(18).  Subjects had no cardiovascular disease (CVD) at baseline. 


The Rancho Bernardo study (N= 794 men, aged 50 to 91 years, average foll up 11.8 years, but up to 20 years) also found that total and bioavailable T were inversely related to risk of death.  Men in the lowest quartile of total T (,241 ng/dL [8.4 nmol/L]) were 44% more likely to die during the follow up period compares to those in the highest quartile (.370 ng/dL [12.8 nmol/L]) independent of age, BMI, waist-to-hip ration, alcohol use, current, smoking, and exercise (HR 1.44, 95% CI, 1.12-1.84) (19).  Additional adjustment for prevalent diabetes, CVD, or the metabolic syndrome had minimal effect on the strength of this association (19).  Low total T also predicted increase risk of death due to CV (HR 1.38, 95% CI, 1.02-1.85) and respiratory disease (HR2.29, 95% CI, 1.25-4.20) (19). 


Comorbidities and cardiovascular risk factors 

Multiple studies have reports that low T raises risk of certain medical comorbidities and CV risk factors.  Baseline total T in the Rancho Bernardo study was inversely associated with weight, BMI, waist to hip ration, systolic and diastolic blood pressure, fasting glucose and serum insulin, homeostasis model assessment insulin resistance (HOMA-IR), triglycerides (TG) and C-reactive protein (CRP) (P,.01 for all) (19).  The HIM study found that a higher proportion of untreated hypogonadal men (total T<300ng/dL [10.4 nmol/L]) reported a history of obesity, hypertension, hyperlipidemia, and diabetes (P<.001 for all conditions) (14).  Asthma/chronic obstructive pulmonary disease (COPD) also was significantly more common among hypogonadal than eugonadal men (p=.013). 


Relative risk of aortic atherosclerosis in men (n= 504, aged greater than or equal to 55 years, follow for 6.5 years) was inversely related to total T (P=.04 for trend, adjusted for covariates) and bioavailable T (P =.004, adjusted for covariates) in the Rotterdam study, a population-based prospective cohort study (20).  Men in the second and third highest tertile of total and bioavailable T were protected against atherosclerotic progression compared to those in the lowest tertile (p =.02 for trend)(20). 


Yet the association of T with death does not appear to always operate through many risk factors and comorbidities, as the link between low T and shorter survival remains significant after adjustment for such covariaties in multiple studies (17-19).  Possible explanations might include a rapid and separate association of the development of inflammatory cytokines and insulin resistance with the induction of hypogonadism (eg, withdrawing testosterone therapy in men with known hypogonadism).  Both of these factors are related to CVD. 


Metabolic Syndrome, Diabetes, Insulin Resistance 

Studies also link T to risk for metabolic syndrome and diabetes.  Definitions and criteria for the metabolic syndrome differ but generally it can be characterized by the presence of any three of five conditions: elevated blood sugar/insulin resistance, enlarge waist circumference or BMI, hypertension, elevated TG levels, low high-density lipoprotein (HDL)-cholesterol levels.  Metabolic syndrome and diabetes both are associated with increased risk for CVD. 


Analysis of data from the MMAS (N= 950 men, aged 40-70 years at baseline) demonstrates that in men who are neither overweight nor obese (BMI < 25 kg/m2), a decrease of 170 ng/dL (5.9 nmol/L) in total T was associated with approximately a 40% increased risk of developing the metabolic syndrome (3).  Another population-based study (N = 702, mean age 51.3 years) found that total T  <450 ng/dL (15.6 nmol/L) was associated with a 70% increased risk of developing the metabolic syndrome and nearly 2 fold higher risk of diabetes over an 11 year period after adjustment of several covariates (age, presence of CVD, smoking, alcohol use, waist or waist-to-hip ration, insulin, glucose, and TG concentrations; SBP, use of antihypertensive medication) (4). 


Conversely higher total T, bioavailable T, and SHBG appeared to protect against development of the metabolic syndrome among 400 communicty based men aged 40 to 80 years old (5).  Each standard deviation (SD) (153 ng/dL or 5.3 nmol/L) increase in total T was associated with a 57% reduced risk of the metabolic syndrome (5).  Total T also was inversely related to elements of the metabolic syndrome.  Each SD increase in total T (153 ng/dL, or 5.3 nmol/L) was associated with a 38% reduced risk for high waist girth, and 37% reduced risk for both low HDL and high fasting glucose levels (5). 


Colleagues randomized 32 hypogonadal men (total T<346 ng/dL [12nmol/L]) with newly diagnosed type 2 diabetes to diet and exercise alone or diet and exercise combined with testosterone gel therapy (.50 mg once daily)(7).  Mean age in the lifestyle changes-only group was 57.3 (standard error [SE] 1.4); mean age in the lifestyle change plus T group was 55.9 (SE 1.5).  All subjects met the criteria for the metabolic syndrome as defined by the National Cholesterol Education Program Adult Treatment Panel III (ATP III) as well as the more stringent International Diabetes Federation (IDF); this definition includes stricter limits for waist circumference (greater than or equal to 37 rather than 40 inches for European men) and fasting plasma glucose (greater than or equal to 100 mg/dL rather than 110 mg/dL)(23).  Subjects had never received insulin or other glucose lowering therapy, either before or during the trial, and had a mean hemoglobin A1C of 1.5 (7).


Patients were contacted at least twice a week to encourage adherence to the exercise and diet regimen.  At 52 weeks, both groups showed improvement from baseline on multiple measures including serum T concentration, glycemic control, insulin levels and sensitivity, and high-sensitivity CRP.  The group receiving T plus diet and exercise improved significantly more on all those paramteres compared to the subjects randomized to diet and exercise alone (P< .001 for all between group comparisons).  More than 80% of the testosterone group showed conversion from the metabolic syndrome according to ATP III criteria, versus 31% of the diet and exercise alone group.  At study end, serum prostate-specific antigen (PSA) concentrations were equivalent between groups, an indication of treatment safety. 


Additionally, TRT reversed the metabolic syndrome nearly two-thirds of the subjects.  By the end of the study, 37.5% of those treated with T still met the IDF criteria for metabolic syndrome.  These data support the therapeutic value of testosterone, when combined with beneficial lifestyle changes, for diabetes and the metabolic syndrome in hypogonadal men.  


Diagnosis and Treatment

Several professional societies have issued guidelines for the diagnosis and treatment of hypogonadism (2,8).  All require clinical signs and symptoms of hypogonadism (physical, psychological, and sexual) as well as persistently low T levels as criteria for diagnosis (2,8).  


The first step toward recognition of low T is the suspicion of the disease.  If patients report at least one of the manifestations of hypogonadism, then consider asking about other symptoms.  patients with chronic comorbid conditions associated with hypogonadism should be questioned about symptoms of low T, as should patients who present for other, unrelated disorders.  because hypogonadism has been linked to diabetes, international and European guidelines advise measuring serum T in men with diabetes and obesity and symptoms that suggest T deficiency (2).  


Some evidence suggests that certain symptoms are associated with specific T levels and that symptoms accumulate as T levels fall (24).  In a population of 434 men aged 50 to 86 years old presenting at an andrological outpatient department, prevalence of loss of libido or vigor began to increase when testosterone levels fell (T,432 ng/dL [15 nmol/L]).  Depression and type 2 diabetes were more likely to be present at even more lower levels of testosterone (T <288 ng/dL [10nmol/L]; P<.001).  Erectile dysfunction became more common at an even lower threshold of testosterone (T,230 ng/dL [8nmol/L]; P=.003). 


Laboratory Testing

Measurement of serum total T is the most widely accepted laboratory criteria for hypogonadism (2).  Free testosterone, indicating the fraction that the body can actually use, provides a more accurate measure.  Advantages of measuring total serum T, however, include lower cost and the fact that practitioners are generally more accustomed to its use. 


Some authors recommend that samples should be collected between 7 AM and 11 AM (2).  Others disagree, based on studies that show little variation in serum T over daytime hours in men older than 40 years (25,26). 


The numerical value of low serum T varies with guidelines and laboratory but is defined as below the normal reference range for a healthy young adult male (2).  There is no consensus regarding the lower limit of normal T.  However, guidelines from a group of European and international medical societies state that men with levels >350 ng/dL (12.1 nmol/L) usually do not require T therapy while those with levels <230 ng/dL (8nmol/L) usually will benefit from such treatment (2).  For men with levels in between, internation guidelines and vise repeated serum total T measurement along with measuring SHBG to allow for calculation of free T (2).  A free T level <.225 nmol/L (65ng/dL) lends support to use of T therapy, especially in obese men (2).  If the T level is normal, then consider other causes for the presenting signs and symptoms. 


Although the Endocrine Society's 2006 clinical practice guideline on men with androgen deficiency symdromes identifies total T   < 300 ng/dL (10.4 nmol/L) as the lower limit for healthy young men (8), a 2007 Endocrine Society position statement evaluating assays for total and free T set the bar slightly higher.  That paper characterizes serum T <200 ng/dL (6.9 nmol/L) diagnostic for hypogonadism, levels of 200-320 ng/dL as equivocal, and levels of >320 ng/dL (11.1 nmol/L) as normal (27).  In men with equivocal values, measurement of free or bioavailable T can clarify the diagnosis.  Free T <6.5 ng/dL or bioavailable T <150 ng/dL (5.2 nmol/L) points to a diagnosis of hypogonadism (27). 


The Endocrine Society recommends repeat measurement of morning T.  Measurement of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels at the same time as the repeat T assessment to useful for determining whether hypogonadism is primary (testicular high LH and FSH) or secondary (pituitary-hypothalamic, low or normal LH and FSH) (8).  Other guidelines advise measuring LH when the clinician suspects secondary hypogonadism and total T <150 ng/dL (5.2 nmol/L) (2).  


With variations in major clinical guidelines available from authoritative sources, how should a practitioner decide which to use?  While both guidelines discussed here are valid, consider that the more recent international consensus statement has the benefit of updated data.  Also, its algorithm may be more useful as it accounts for factors such as patient age, variations among laboratories, and the various assays used for total T. 


Hormone levels supporting secondary hypogonadism warrant testing serum prolactin and iron saturation or ferritin levels to rule out hyperprolactinemia and hemochromatosis, respectively.  An MRI will rule out pituitary and/or hypothalamic tumor or infiltrative disease (8).  Seminal fluid analysis should be performed if fertility is an issue (8).  Patients with normal T, LH, and FSH levels on the repeat test should return for follow-up evaluation of signs and symptoms. 


Treatment

Standards differ as to the threshold for offering TRT; some authorities suggest 200 ng/dL and some 300 ng/dL (8).  The latest consensus statement notes a general agreement that therapy is not usually required for men with total T levels > or equal to 350 ng/dL (12 nmol/L) (2).  Some regard precise cutoff points as arbitrary, however, and factor symptomatology into the treatment decision, based on their clinical judgment and the knowledge that men with total T levels in the low-normal range may demonstrate favorable responses to TRT (28,29).  Prior to beginning T therapy, it is important to assess a man's risk for prostate cancer (2).  This involves at minimum, measuring PSA level and performing a digital rectal exam (DRE) (2,8).  If the PSA and the DRE are abnormal, evaluation of the prostate by a urologist is indicated.  The Endocrine Society recommends further urological investigation prior to starting TRT if examination detects a palpable prostate nodule or induration, or if PSA is > 3 ng/mL (8). 


Goals and Potential Benefits of Therapy 

The goal of therapy is not only to achieve and maintain mid-normal range eugonadal serum T levels but also to treat the individual patient's signs and symptoms of hypogonadism (2,8).  In studies of hypogonadal men, TRT has been linked to improved body composition (reduced fat mass, increased lean body mass) and increased bone mineral density (BMD), libido and erectile function.  Data suggests that T may improved mood as well as muscle and grip strength (2,8,30-33).  It is important to remember that low libido and/or erectile dysfunction can be related to comorbidities (eg diabetes, the metabolic syndrome, peripheral vascular disease, bladder outlet obstruction, hyperprolactinemia) or medications even in the presence of T deficiency (2), although trial of testosterone therapy may still be warranted. 


Symptom improvement should be noted within 3 to 6 months after initiating therapy (although BMD response is slower).  If a patient fails to respond in that time, discontinue TRT and investigate whether other factor might account for his symptoms (2). 


Options in Testosterone Replacement Therapy 

Several delivery formulations are available for TRT.  Once daily topical application is available through transdermal gel or a skin patch.  The gel provides longer half-life and is associated with lower rates of skin irritation that the patch (34-37).  The testosterone in the gel can be transferred to others through close, skin-to-skin contact.  Clinicians should counsel patients to cover the application area with clothing and wash prior to skin contact, particularly with a woman or child (8).  The T buccal system is administered twice daily to the inner cheek or gym surface.  it release T in a pattern similar to that of endogenous secretion (33).  Food and beverages do not affect pharmacokinetics, although oral side effects, including gingivitis and inflammation were reports by 16% of users in one study (38).  


Intramuscular (IM) injections are assocated with wide fluctuations in circulating T levels.  Testosterone typically exceeds normal eugonadal levels within the first few days after the injection, then falls to hypogonadal levels before the next injection is due (33). Such fluctuations can result in corresponding swings in mood, energy level, and sexual function (33).   Injection-site reactions and gynecomastia are common, occurring in one-third and one-quarter to one-third subjects, respectively (33).  In contrast, subcutaneous T implants (T pellets/depot T) maintain steady, normal serum T levels for 3 to 6 months (33,39,40). 


A newer formulation of T undecanoate in castor oil is available as an intramuscular injection in China, South America, and Europe but not in the US.  Its long half-life allows for injection (1000 mg) once every 10 to 14 weeks following a loading dose (41).  Oral T undecanoate has been impractical due to first-pass hepatic metabolism and erratic lymphatic absorption necessitating a fatty meal, and is not approved in the US. 


Risks of Testosterone Replacement Therapy 

TRT is associated with dermatologic reactions such as acne, oily skin, and erythema, and with breast tenderness (8,42).  Erythrocytosis can develop, especially in older men receiving T by injection (2).  Clinically significant polycythemia occurs rarely; risk factors include age, COPD, sleep apnea, and a history of smoking (42).  Lower-extremity edema can occur during the first few months of therapy but usually resolves (42). 


TRT is contraindicated when evidence suggests that it could worsen underlying conditions (2,8).  One of the greatest concerns of clinicians regarding the safety of testosterone therapy is the historical fear that raising serum testosterone may cause an occult prostate cancer to grow (43).  Prominent review, however, have failed to find support for this traditional view (1,44) and a large longitudinal study found no relationship between serum androgen concentrations and the risk for prostate cancer (45).  This topic is covered in greater depth below. 


Evaluation and Monitoring 

Prior to starting therapy, clinicians should question patients about voiding symptoms, any history of obstructive sleep apnea, and heart failure.  Significant problems in these areas warrant referral to the appropriate specialist before treatment is started.  Prostate evaluation (DRE and PSA measure) should be performed at baseline, 3 months, and thereafter annually or at the frequency recommended for the patient's age (1,8). 


Patients should be evaluated at 1 to 2 months to determine efficacy and safety of treatment and whether dosage adjustment is needed (1).  Follow-up visits at 3 months and annually should include measuring testosterone, assessing whether symptoms have abated, and evaluating for adverse events.  Patients should be examined for and questioned about any side effects specific to the T formulation that they use; eg, skin reactions to topical prepartions, mood fluctuations in those receiving IM injections, and gum reactions in response to buccal testosterone tablets (8).  Additionally, monitor for urinary symptoms, sleep apnea, and gynecomastia (1).  


Initial, 3 month, and annual laboratory testing should include hematocrit to monitor for erythrocytosis (8).  Authorities variously recommend that therapy should not be initiated if hematocrit is >50% (8) or >52% (2).  If hematocrit rises to >54% during treatment, then therapy should be interrupted until hematocrit returns to a safe level.  A reduction in testosterone dosage may be warranted when reinitiating treatment.  In patients with osteoporosis or low trauma fracture, measure BMD of the hip, lumbar spine, and femoral neck at baseline and 1 to 2 years following T initiation (8).  


Low T and Prostate Cancer: A New Model. 

Prostate cancer has long been viewed as a contraindication of TRT based in part on early findings linking prostate cancer growth with T administration (46,47).  A 1941 article by Huggins et al reported that T injections caused an "enhanced rate of [prostate cancer] growth" and that reduction of T by castration or estrogen therapy caused prostate cancer regression (46).  However, data were presented for only one intact man with prostate cancer who received T injections. Subsequent studies revealed that T administration was associated with progression of metastatic prostate cancer in castrated, but not in hormonally intact, men (11,47,48). 


Reports of hypogonadal men who received T following prostate cancer treatment find not risk of recurrence associated with the hormone therapy.  In 3 retrospective evaluations of men (N=74) receiving T therapy following radical prostatectomy no detectable rise in PSA was recorded.  These men received T therapy for an average of 3 years (maximum 12 years) and were followed on TRT for an average of 13 to 19 months (maximum 8 years) (49,51).  Review of 31 men who received T following brachytherapy for prostate cancer revealed PSA <1.0 ngmL in all subjects after a median of 5 years, with no evidence of recurrence (52). 


Given the Huggins report that T therapy is associated with prostate cancer growth (46), Morgentaler and colleagues explored whether low T levels are associated with a reduced risk of prostate cancer (53).  Subjects (N = 77 hypogonadal men, median age 58 years) had a normal DRE and PSA ,4.0 ng/mL, but sextant needle biopsy detected prostate cancer in 14%. 


Morgentaler and Rhoden revisited this issue with a larger group of subjects (N= 345).  Again, rate of prostate cancer among hypogonadal men with normal DRE and PSA ,4.0 ng/mL was high, at 15% (52/345) (54).  Lower levels of T were associated with higher risk for prostate cancer (or 2.15, 95% CI, 1.01-4.55, respectively, for lowest vs highest tertile of total T).  These results appear to contradict the traditional view that high testosterone concentration are worrisome for prostate cancer, and low testosterone is protective. 


A review of 7 prospective trials of TRT identified 5 cases of prostate cancer among 461 men (1.1%) followed for 6 to 36 months.  This prevalence rate is similar to that of the general population (1).  A pooled analysis of 18 prospective studies evaluating the link between endogenous sex hormones and prostate cancer risk (3886 men with prostate cancer, 6438 controls) found no association between prostate cancer risk and prediagnostic serum T or free T concentrations (45).  Relative risk for prostate cancer did not differ significantly with the highest and lowest quintile of T or free T. 


Investigators evaluating adverse events associated with TRT performed a meta-analysis of 19 randomized studies including 651 men treated with T, 433 with placebo.  Odds ratio of all prostate events was significantly greater in men receiving T therapy (OR, 1.78, 95% CI, 1.07-2.95).  However, the specific risk for developing prostate cancer or an elevated or increasing PSA (>4ng/mL or 1.5ng/mL increase) did not differ significantly between men who received testosterone compared with men who received placebo (55).  A more recent meta-analysis identified 44 studies related to TRT and prostate cancer that met inclusion criteria None demonstrated an association between testosterone therapy and increased prostate cancer risk in men without prostate cancer or increased Gleason score in men with prostate cancer.  The authors also concluded that testosterone therapy did not have a consistent effect on PSA levels (56).  


Morgentaler and Traish have proposed a model to explain that observations that T in castrated men leads to prostate growth but that endogenous T levels and TRT are not associated with prostate cancer risk in several analyses (9).  Experimental evidence indicates that maximal binding of androgen to the androgen receptors occurs in rats at 60-90 ng/dL and in humans at approximately 120 ng/dL (9,57).  Studies in animal models and in prostate cancer cell lines show that growth occurs with increasing androgen concentrations, but this dose-response curve is present only at relatively low androgen concentrations and is followed by plateau indicating that there is a finite ability of androgens to stimulate prostate cancer growth.  One maximal growth has been achieved, further increases in androgen are unable to stimulate additional growth (9). 


Morgentaler and Traish have reviewed evidence from human studies consistent with this saturation model of androgen effect on prostate cancer (9).  In men with near physiologic to supraphysiolic T levels, administering T has little effect on prostate growth as measured by PSA and prostate volume.  In studies of T administration in hypogonadal men, PSA sometimes rises modestly (approximately 15%), but then levels off or does not differ significantly from that of men randomized to palcebo (9).  In young and older eugonadal men, suppression of endogenous T with a long acting luteinizing hormone releasing hormone agonist, followed by administration of a range of T doses, led to supraphysiologic T levels butt no significant change in PSA values (58,59).  Animal and human data suggest that the saturation point beyond which T will not lead to prostate growth is in the near-castrate range (9). 


Morgantaler has described a case of an 84-year-old man with prostate cancer (PSA 8.1 and 8.5 ng/mL, Gleason 6/10) and a low free T level (.74 ng/dL).  The patient declined prostate cancer treatment but requested TRT.  During 2 years of treatment, his PSA level fell to 5.2 ng/mL at 10 months, rose to 6.2ng/mL at 21 months, then resumed falling to 3.8 ng/mL to 24 months.  The last change follow the addition of dutasteride for voiding symptoms (60).  


Summary

Prevalence of hypogonadism rises with age as T levels fall (13,15).  Symptoms of hypogonadism include reduced libido, fatigue, erectile dysfunction; reduced muscle mass and bone density; depression; irritability; decreased energy, mental clarity and motivation; and anemia (1,8).  Measurement of total T is the most widely accepted laboratory criteria for hypogonadism (2).  When levels are equivocal, repeating total T measurement and assessing SHGB to allow for calculation of free T can make the diagnosis.  Measuring LH and FSH can help determine whether hypogonadism is primary or secondary. (8). 


TRT in hypogonadal men has improved body composition, increased VMD, and improved libido and erectile dysfunction, mood, and strength (2,8,30,33).  Delivery options include transdermal gels and a patch, a buccal bioadhesive tablet, pellets implanted under the skin, and IM injections.  Gels are well tolerated with a lower risk of application site reactions than the transdermal patch.  


T pellets maintain the hormone at normal range for 3 to 6 months but extrusion sometimes occurs.  IM injections are associated with wide swings in T levels, leading to poor tolerability.  Adverse events include skin reactions (erythema, oily skin), breast tenderness, and erythrocytosis. 


Testosterone therapy is generally contraindicated in men with prostate cancer due to concerns about promoting prostate tissue growth or cancer recurrence.  Two leading authorities have proposed a saturation model, to describe the relationship of androgens to prostate tissue growth.  Their review of experimental, epidemiologic, and clinical literature is consistent with the proposal that once androgen receptors are saturated - which appears to occur at near-castration levels - androgens no longer foster prostate cancer growth (9).  Still, although current thought is that testosterone does not cause or promote prostate cancer, all questions have not been fully answered.  Clinicians must therefore carefully review benefits and risks with their patients before proceeding with testosterone therapy for men with a history of prostate cancer. 


Low T is significantly associated with elevated risk for death, obesity, diabetes, hypertension, hyperlipidemia, and asthma/COPD compared to eugonadal men (3,14,17,18).  Increasing evidence links low T to the metabolic syndrome and insulin resistance, significant CV risk factors. 


The association of low T with risk for metabolic syndrome led to speculation about whether T therapy could reverse the metabolic syndrome or its components.  A new study demonstrated that 1 year of T therapy plus diet and exercise reversed the metabolic syndrome in two-thirds of hypogonadal, diabetic men not receiving glucose-lowering treatment (7).  Further study is needed to determine whether TRT can prevent CV events. 


References


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