How to help the aging male? Current approaches to hypogonadism in primary care

Abstract

Hypogonadism is a common condition which occurs more frequently in older men. It is characterized by low testosterone (T) and is associated with symptoms which are often nonspecific. A key symptom is low libido, but it can also be associated with erectile dysfunction, reduced muscle mass and strength, increased body fat, reduced bone mineral density and osteoporosis, reduced vitality, and depressed mood. Hypogonadism is linked with a variety of comorbid conditions including erectile dysfunction, metabolic syndrome, diabetes, obesity, and osteoporosis. However, the condition is often underdiagnosed. T supplementation in hypogonadism is associated with a range of benefits including improved sexual function, increased lean body mass and/or reduced fat mass, and improved bone mineral density. A variety of T supplementation formulations are available. Although there is no evidence of increased risk of initiating prostate cancer with T supplementation, it is contraindicated in men with prostate cancer. It is important that primary care physicians are aware of both the signs and symptoms of hypogonadism, the monitoring and testing that is required and the merits and advantages of the various T preparations to ensure optimal management of the condition with a treatment approach that best suits patients’ needs.

Keywords::

• Hypogonadism
• late-onset hypogonadism
• testosterone deficiency
• testosterone supplementation

Hypogonadism

What is hypogonadism?

Hypogonadism, as defined by Endocrine Society Clinical Practice Guidelines, is a clinical syndrome resulting from failure of the testis to produce physiological levels of testosterone (T) and a normal number of spermatozoa due to disruption of the hypothalamic-pituitary-testicular axis [1]. Hypogonadism is thus in general defined as the presence of low T levels and hypogonadal symptoms.

Late-onset hypogonadism

Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age, as recognized by the International Society of Andrology (ISA), the International Society for the Study of the Aging Male (ISSAM), the European Association of Urology (EAU), European Academy of Andrology (EAA), and American Society of Andrology (ASA). It is characterized by symptoms and a deficiency in serum T levels below the young healthy adult male reference range. LOH may adversely affect quality of life and the function of multiple organ systems [2].

There are no generally accepted lower limits of normal T, however, it is generally agreed that total testosterone (TT) >12 nmol/l (350 ng/dl) does not require substitution, whereas serum TT <8 nmol/l (230 ng/dl) will usually benefit from T supplementation. However, Zitzmann et al. [3] has shown that some symptoms may occur above the 12 nmol/l threshold; e.g., the prevalence of loss of libido or vigor started to increase below T levels of 15 nmol/l. Furthermore, some studies have shown benefits of T supplementation in men with TT >12 nmol/l; e.g., in men with TT <15 nmol/l [4] or in men with TT ≤13.9 nmol/l [5].

For TT of 8–12 nmol/l, repeating the TT measurement with sex hormone-binding globulin (SHBG) to calculate free testosterone (FT) or measuring FT by equilibrium dialysis may be helpful [2]. In addition, a European Male Aging Study (EMAS) report showed that LOH can be defined by the presence of at least three sexual symptoms (decreased frequency of morning erection, decreased frequency of sexual thoughts, and erectile dysfunction (ED)) associated with a TT <11 nmol/l (320 ng/dl) [6].

How common is hypogonadism?

Studies suggest an overall prevalence of hypogonadism in the region of approximately 5% based on T levels and symptoms. Thus, using diagnostic criteria for androgen deficiency comprising both signs/symptoms and TT and calculated FT, data from 1691 men (aged 40–69 years) in the Massachusetts Male Aging Study (MMAS) showed an overall prevalence of hypogonadism of 6% [7]. In 1475 men from the Boston Area Community Health Survey, the prevalence of androgen deficiency (again defined by both clinical symptoms and T levels) in men aged 30–79 (mean 47.3) years was 5.6% [8]. Analysis of the prevalence of LOH in the EMAS study population showed that 4.1% of subjects had a TT <8.0 nmol/l and 17.0% had a TT <11 nmol/l. If the definition of LOH is considered to include at least three sexual symptoms (decreased frequency of morning erection, decreased frequency of sexual thoughts, and ED) associated with a TT <11 nmol/l and a FT <220 pmol/l, the overall prevalence of LOH was 2.1%. However, it should be remembered that healthy nonobese men seldom develop hypogonadism and that prevention of disease and frailty, with optimal lifestyle (physical, mental activity, and healthy food) may delay the occurrence of hypogonadism.

Comorbid conditions

Hypogonadism is associated with the presence of a number of comorbidities and is also associated with the risk of developing a series of medical conditions. The effect of T therapy in these conditions in terms of efficacy and improvement in underlying disease is still a matter of investigation.

ED

ED is multifactorial and with increasing age is predominantly associated with vascular disease and endothelial dysfunction. However, adequate T concentrations are important for normal sexual function and lower levels affect the central nervous system (with decreased libido, sexual fantasies, and centrally derived spontaneous erections) and peripheral penile erectile mechanisms. ED is also a known symptom of hypogonadism [9] and T supplementation may normalize sexual function. Studies suggest that a high proportion of men (~52%) aged 40–70 years have some degree of ED [10] and that approximately 10% of men with ED also have lower than normal T levels [11].

Type 2 diabetes

T is frequently low in men with type 2 diabetes (T2D) and the majority have symptoms of hypogonadism [12]. The prevalence of hypogonadism in men with T2D has been estimated at 33–50%, making it a candidate for the most common complication of male T2D [13,14]. Conversely, in men with low T, the risk of T2D is increased [3]. In the Hypogonadism in Males (HIM) study, a man with T2D was approximately twice as likely to be hypogonadal compared with a man without T2D [15]. Indeed, serum T should be measured in men with T2D with symptoms suggestive of T deficiency [2]. Hypogonadism, ED, and T2D mellitus often occur together in the same patient; in one study, >70% of men with both T2D mellitus and low T reported ED [12].

Obesity

Numerous studies have established a close relationship between obesity and low T [2,16] and there is an inverse linear relationship between TT and body mass index (BMI); FT also decreases with increasing BMI. There is also an inverse relationship between serum TT and FT and visceral fat mass [14]. Indeed LOH is more often associated with obesity and poor health than with aging per se [17]; in patients with increased visceral fat (waist circumference >94 cm) both T and SHBG should be measured.

Metabolic syndrome

Many components of the metabolic syndrome (obesity, hypertension, dyslipidemia, impaired glucose regulation, and insulin resistance) occur in hypogonadal men [2]. Indeed, data suggest that the metabolic syndrome predisposes to development of hypogonadism in middle-aged men [18]. For example, in the HIM study [15], Odds ratios for having hypogonadism were significantly higher in men with hypertension (1.84), hyperlipidemia (1.47), diabetes (2.09), and obesity (2.38) vs. men without these conditions. Conversely, lower T and SHBG levels are considered risk factors for metabolic syndrome in men [19].

The Testim^® Registry in the United States (TRiUS) is a large, 12-month observational cohort registry (n = 849 registrants), established to quantify symptoms and comorbidities of hypogonadism in real-world clinical settings and evaluate the effect of T supplementation [20]. The most common comorbid conditions and cardiovascular risk factors included: smoking, metabolic syndrome, hypertension, dyslipidemia, and coronary artery disease. Weak but statistically significant inverse correlations were noted between TT and sexual dysfunction, fasting glucose, systolic blood pressure, BMI, and Framingham risk scores. Patients with obesity or metabolic syndrome had significantly lower TT, particularly among younger and middle-aged patients. Androgen deficiency may play a central role in the various pathologies encompassing the components of the metabolic syndrome, including T2D, insulin resistance, obesity, and ED.

Osteoporosis

T is also positively associated with bone mineral density (BMD), but the relationship is weaker than that of estradiol [14,21,22]. Hypogonadism is also a secondary cause of osteoporosis [23]. While there appears to be evidence of an association between hypogonadism and osteoporosis, there does not appear to be an established causal link [14].

HIV

There is a high prevalence of low T levels in HIV-infected men; 20–25% of HIV-infected men on highly active antiretroviral therapy have low T [1,24–26].

Depression

Levels of TT appear to be lower in depressed than in nondepressed individuals. Levels of TT have been found to be particularly low in men with severe and treatment-resistant depression [27].

Cerebrovascular and cardiovascular disease

Low T concentration is associated with an increased risk of vascular disease while high T levels are, on the contrary, a risk-reducing factor for cardiovascular events (defined as a composite endpoint of coronary heart disease events and cerebrovascular events) [28].

Hypogonadism incidence increases with age

Circulating T in men declines progressively from the third decade [16,29,30]. Consequently, the prevalence of hypogonadism increases with age but, of course, varies according to the diagnostic criteria. In the US HIM study in 2162 men ≥45 years who were visiting primary care practices, the overall prevalence of hypogonadism (TT <300 ng/dl (10.4 nmol/l) or current androgen treatment) was 38.7% [15]. Prevalence varied with age; in this study in men aged at least 45 years, for every 10-year increase in age, a patient’s risk of hypogonadism increased by 17% [15]. The Baltimore Longitudinal Study on Aging (n = 890), using TT criteria <11.3 nmol/l (325 ng/dl), showed an incidence of hypogonadism rising from 12% for men in their 50s, to 19, 28, and 49% for men in their 60s, 70s, and 80s, respectively [31]. Again, in MMAS prevalence increased with age: 4.1, 4.5, and 9.4% for men in their 40s, 50s, and 60s, respectively. After an average 8.8-year follow-up, overall prevalence was 12.3% (7.1, 11.5, and 22.8% for men aged 48–59, 60–69, and 70–79 years, respectively) [7]. In the Boston Area Community Health Survey, while prevalence increased with age, it was significantly greater for men in their 70s (18.4%) vs. men <70 years (3.1–7.0%) [8]. Finally, in EMAS the incidence of LOH increased with age from 0.1% for men in their 40s, to 0.6, 3.2, and 5.1% for men in their 50s, 60s, and 70s, respectively [6].

Symptoms of hypogonadism

Diagnosis is challenging since symptoms and signs are nonspecific [32] and modified by age, comorbid illness, severity and duration of androgen deficiency, variation in androgen sensitivity, and previous T therapy [1].

Currently, diagnosis of treatable hypogonadism requires the presence of symptoms and signs suggestive of T deficiency [2]. The symptom most associated with hypogonadism is low libido [2]. Other symptoms include: ED, decreased muscle mass and strength, increased visceral or abdominal body fat, decreased BMD and osteoporosis, decreased vitality, depressed mood [2], and decreased spontaneous erections [1]; ≥1 of these symptoms must be corroborated with a low serum T [2]. Waist circumference measurement may also be useful as it reflects abdominal fat. T levels are inversely associated with visceral (or intra-abdominal) adiposity [33,34]. Indeed, there appears to be a regulatory role for T in counteracting visceral fat accumulation [35]. A list of symptoms for which T should be measured, and also less specific symptoms for which T measurement should be considered, is shown in Table I [1]. In a recent community-based study of three cohorts of men from the Framingham Heart Study (second and third generation), EMAS, and the Osteoporotic Fractures in Men Study (MrOS), in all three cohorts, men with low TT (348.3 ng/dl (12.1 nmol/l)) or FT (70.0 pg/ml (243 pmol/l)) were more likely to have at least one of the following: diabetes, sexual symptoms (EMAS only) or physical dysfunction [36].

Table I.  Symptoms for which testosterone should be measured and less specific symptoms for which testosterone measurement should be considered.

Symptoms and signs suggestive of androgen deficiency in men

A. More specific symptoms and signs

• Incomplete or delayed sexual development, eunuchoidism

• Reduced sexual desire (libido) and activity

• Decreased spontaneous erections

• Breast discomfort, gynecomastia

• Loss of body (axillary and pubic) hair, reduced shaving

• Very small (especially <5 ml) or shrinking testes

• Inability to father children, low or zero sperm count

• Height loss, low trauma fracture, low bone mineral density

• Hot flushes, sweats

B. Other less specific symptoms and signs

• Decreased energy, motivation, initiative, and self-confidence

• Feeling sad or blue, depressed mood, dysthymia

• Poor concentration and memory

• Sleep disturbance, increased sleepiness

• Mild anemia (normochromic, normocytic, in the female range)

• Reduced muscle bulk and strength

• Increased body fat, body mass index

• Diminished physical or work performance

Reproduced from Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95(6):2536–2559 [1], with permission from The Endocrine Society. Copyright 2010, The Endocrine Society.

Who is at risk of hypogonadism?

Conditions associated with a higher risk of developing hypogonadism include: obesity, cardiovascular disease, inflammatory and rheumatic disease, hypertension, hyperlipidemia, diabetes, prostate disease, asthma or chronic obstructive pulmonary disease [15], and past history of male infertility [1]. There is considerable evidence linking the metabolic syndrome to androgen deficiency [19]. Indeed a recent meta-analysis of available cross-sectional data showed that metabolic syndrome was significantly associated with an overall lower TT [37]. It should also be noted that treatment with opioids and corticosteroids are risk factors for the development of hypogonadism [1].

Consequences of hypogonadism

The consequences of low T present significant health risks, including falls and fractures associated with brittle bones and decreased muscle strength, as well as serious impact on quality of life. Sarcopenia with low T is a factor in the frailty of old age [38] and severe sarcopenia is an independent risk factor for development of physical disability [39]. Men with a T deficiency also often have anemia [40]. Furthermore, endogenous T concentrations appear to be inversely related to mortality due to all causes, cardiovascular causes, and cancer [28,41,42].

Diagnosis of hypogonadism

When should I suspect the diagnosis?

General screening for hypogonadism is not recommended, but several groups with a high prevalence of low T should have their T measured (Table II) [1]. In some chronic diseases (e.g., T2D, end-stage renal disease, and chronic obstructive lung disease), T measurement may be indicated by symptoms (e.g., sexual dysfunction, unexplained weight loss, weakness, or mobility limitation). In other conditions (e.g., pituitary mass, HIV-associated weight loss, low trauma fracture, or use of medications that affect T production), T measurement may be indicated irrespective of symptoms [1].

Table II.  Conditions in which there is a high prevalence of low testosterone levels and for which we suggest measurement of serum testosterone levels.

• Sellar mass, radiation to the sellar region, or other diseases of the sellar region

• Treatment with medications that affect testosterone production or metabolism, such as glucocorticoids and opioids

• HIV-associated weight loss

• End-stage renal disease and maintenance hemodialysis

• Moderate to severe chronic obstructive lung disease

• Infertility

• Osteoporosis or low trauma fracture, especially in a young man

• Type 2 diabetes mellitus

Reproduced from Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95(6):2536–2559 [1], with permission from The Endocrine Society. Copyright 2010, The Endocrine Society. In chronic diseases (e.g., diabetes mellitus, chronic obstructive lung disease, end-stage renal disease), testosterone measurement may be indicated by symptoms (e.g., sexual dysfunction, weakness, mobility limitation, unexplained weight loss). In some other conditions (e.g., HIV-associated weight loss, low trauma fracture, a pituitary mass, treatment with medications that affect testosterone production), testosterone measurement may be indicated regardless of symptoms.

Screening questionnaires (e.g., the aging male symptom (AMS) score and androgen deficiency in aging men (ADAM)) for hypogonadism have been proposed. Both the AMS and ADAM questionnaires have shown high sensitivity (e.g., ADAM 97%, AMS 83%) but low specificity (ADAM 30%, AMS 39%) [43] and have identified males with hypogonadism needing treatment. While these help strengthen the diagnostic criteria and clinical requirement for symptoms in addition to low serum T [44], they are limited by the variability in symptoms and are not recommended for diagnosis because of low specificity [2]. However, the AMS may be valid for follow-up. Since LOH is a clinical and biochemical syndrome, symptoms must be corroborated with a low serum T level [2].

What should I look for on examination?

As well as assessing medical history, patients at risk or suspected of having hypogonadism should have a thorough physical and biochemical examination [2].

Medical history

Physicians should identify major medical problems, medications, toxic exposures, fertility problems and developmental milestones, and investigate family/relationship problems (e.g., sexual problems). Clinicians should ask specifically about issues such as low libido, impotence, fatigue, impaired concentration, sexual dysfunction, and frequency of morning erections [45,46]. Evidence of other endocrine deficiencies (e.g., central hypothyroidism or secondary adrenal insufficiency), visual field disturbances, headaches, or seizures may be associated with pituitary tumors or other central disorders.

Physical examination

This should assess the amount and distribution of body hair (including beard growth, axillary, and pubic hair); presence and degree of breast enlargement; size and consistency of the testes; abnormalities in the scrotum; size of the penis [46,47]. Although the prostate should be examined, it may be enlarged in older men, despite a low T [47]. Weight, height, BMI, and waist circumference should also be measured since symptoms and signs potentially indicative of androgen deficiency in men include height loss, reduced muscle bulk and strength, and increased body fat and BMI [1].

Laboratory testing

This is essential to confirm a clinical diagnosis and to differentiate primary from secondary hypogonadism. Transient T decreases (e.g., due to acute illnesses) should be excluded. Morning (0700–1100 h) TT should be measured [1] and low T confirmed by repeat measurements. Mass spectrometry is increasingly recognized as the method of choice for serum T evaluation. A TT >12 nmol/l (350 ng/dl) generally does not require substitution while TT <8 nmol/l (230 ng/dl) will usually benefit from T supplementation (Figure 1). If TT is between 8 and12 nmol/l, a repeat measurement of TT with SHBG should be performed to calculate FT. There are no generally accepted lower limits of normal for FT for the diagnosis of hypogonadism, however, FT <225 pmol/l (65 pg/ml) can provide supportive evidence for T treatment.

Figure 1.  Suggested algorithm for the diagnosis and treatment of late-onset hypogonadism (based on International Society of Andrology, International Society for the Study of the Aging Male, European Association of Urology, and American Society of Andrology recommendations [2], and The Endocrine Society Guidelines [1]). FSH, follicle-stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone-binding globulin; T, testosterone.

General laboratory variables (especially hematocrit and RBC count) should also be determined before T administration and should be monitored frequently.

Primary or secondary hypogonadism?

Primary (hypergonadotropic) hypogonadism is caused by testicular failure, characterized by low serum T and high luteinizing hormone and follicle-stimulating hormone concentrations. It can result from testicular injury, tumor, infection, genetic defects affecting testicular development (e.g., Klinefelter syndrome), chemotherapy, radiotherapy or alcohol abuse [14].

Secondary (hypogonadotropic) hypogonadism involves defects in the hypothalamus or pituitary which produce low T because of insufficient stimulation of the Leydig cells. It is associated with low or low-normal follicle-stimulating hormone and luteinizing hormone. In secondary (but not primary) hypogonadism, fertility can be restored by suitable gonadotropin stimulation. Secondary hypogonadism can be caused by hypothalamic and pituitary disorders or lesions, hyperprolactinemia, and Kallmann syndrome, certain medications and illnesses.

LOH is regarded as a mixed type of hypogonadism combining both primary and secondary testicular failure and reflecting disturbances of both the hypothalamus/pituitary and gonads. These disturbances produce low T concentrations, variable gonadotrophin levels (depending on the predominant primary or secondary failure) and impaired spermatogenesis [48].

Diagnostic tests

Measurement of serum luteinizing hormone can help differentiate primary from secondary hypogonadism. If prolactin is elevated, imaging of the sella turcica should be considered. In primary testicular failure of unknown etiology, a karyotype should be obtained to exclude Klinefelter syndrome, especially when testicular volume is <6 ml. In men being evaluated for infertility, ≥2 seminal fluid analyses should be obtained, while in those with severe androgen deficiency or low trauma fracture, measurement of BMD by dual-energy X-ray absorptiometry scanning is indicated [1].

Classical vs. non-classical hypogonadism

Classical hypogonadism comprises men with very low serum T concentrations generally associated with specific medical disorders [49]. Guidelines suggest T administration irrespective of age and etiology if the diagnostic criteria for hypogonadism are fulfilled, and also in older men with signs/symptoms that occur in normal aging that are suggestive of hypogonadism in combination with “low” T based on normative values for young men [49] (non-classical hypogonadism).

Testosterone supplementation

Benefits of T supplementation

T supplementation in hypogonadal men has been associated with a range of benefits. T shows beneficial effects on sexual function with most studies showing that T increases sexual awareness and arousal, erectile function, and frequency of spontaneous erections [50]. ISA, ISSAM, EAU, EAA, and ASA recommendations consider men with ED and/or diminished libido and documented T deficiency as candidates for T therapy [2]. In hypogonadal men (morning serum TT ≤400 ng/dl (13.9 nmol/l)) with a lack of response to sildenafil monotherapy, T gel administered as adjunctive therapy to sildenafil 100 mg produced significantly enhanced erectile function vs. adjunctive placebo. Improvements in orgasmic function, overall satisfaction, total International Index of Erectile Function (IIEF) score, and percentage of IIEF responders, were also observed with adjunctive T gel [5]. These findings are corroborated by a small study in tadalafil-refractory patients receiving combined T gel/tadalafil treatment [51]. In another study in sildenafil nonresponders with T2D, a combination of oral T undecanoate and sildenafil was associated with improvement in erections, a significant increase in IIEF scale and increased sexual contacts [52]. Some studies have also suggested that T supplementation may also have a beneficial effect on lower urinary tract symptoms [53–55].

There is also strong evidence to show that T has a beneficial effect on body composition with increases in lean body mass and/or reduced fat mass [50]. Secondary benefits for muscle function, metabolic, and cardiovascular disease are suggested but require confirmation by large-scale studies [2].

The effects of T supplementation on glycemic control in T2D are much less certain. Some studies show favorable effects on insulin sensitivity while others show no changes after androgen administration [1]. In a trial in aging men with low normal bioavailable T, 6 months of T therapy produced significant improvements in body composition without a change in whole-body insulin sensitivity [56]. The TIMES2 study [57] showed that over 6 months, transdermal T was associated with beneficial effects on insulin resistance and other variables in hypogonadal men with T2D and/or metabolic syndrome; however, methodological issues limit the conclusions that can be drawn from this trial.

ISA, ISSAM, EAU, EAA, and ASA recommendations consider it premature to recommend T for metabolic syndrome or T2D without evidence of hypogonadism. In men with hypogonadism and T2D and/or metabolic syndrome, T for traditional hypogonadal symptoms may have other unproven benefits on metabolic status [2].

T has beneficial effects on BMD in hypogonadal men; however, fracture data are not yet available and require further investigation [2]. While some studies have suggested an improvement in cognitive function and/or mood with T supplementation, overall, the evidence is weak and/or inconsistent [50]. Finally, T may also have beneficial effects on mortality. In a case-control study (n = 11,606), a 6 nmol/l increase in T was associated with lower risks of total (~14% lower risk) and cardiovascular (17% lower risk) mortality [41]. Also, in a recent observational study of 1031 male veterans with low T, mortality in T-treated men was significantly lower than in untreated men (10.3 vs. 20.7%, p < 0.0001). After multivariable adjustment, T treatment was associated with a reduced mortality risk (hazard ratio 0.61, p = 0.008) [58].

Testosterone therapy – potential risks

Adverse events (AEs) associated with T include erythrocytosis, acne and oily skin, reduced sperm production and infertility, and growth of metastatic prostate cancer (PCa) [1]. Early detection of subclinical PCa (an increase in prostate-specific antigen during T therapy), however, may be beneficial since it may predict, very early, a growing (or developing) PCa. Increased hematocrit may increase the risk for a thromboembolic event [47]. However, a single measurement may not be sufficient as hematocrit elevation can be the result of dehydration e.g., due to insufficient fluid intake on a hot day. Repeated hematocrit values >54% should be followed by treatment which may include therapeutic phlebotomy, low-dose aspirin, and/or reduction of T dose. Uncommon AEs include gynecomastia, male pattern balding (familial), growth of breast cancer, and induction or worsening of obstructive sleep apnea [1]. A recent review of available clinical trial data indicate that the use of T in middle-aged to elderly men does not increase cardiovascular risk nor does it unfavorably modify cardiovascular risk profile [59].

Treatment – contraindications

While T can stimulate growth and aggravate symptoms in locally advanced/metastatic PCa, there is no evidence that it increases PCa/benign prostatic hypertrophy risk [2]. Nevertheless, T is contraindicated in men with prostate/breast cancer and is relatively contraindicated in those at high risk of developing PCa. It is unclear whether localized low-grade (Gleason score <7) PCa represents a relative or absolute contraindication. Men with significant erythrocytosis (hematocrit >52%), untreated obstructive sleep apnea, or untreated severe congestive heart failure, should not start T treatment without prior resolution of the comorbid condition [2]. Severe lower urinary tract symptoms (International Prostate Symptom Score >21) due to benign prostatic hypertrophy is a relative contraindication, although after successful treatment of lower urinary tract obstruction, this contraindication is no longer applicable. Age is not a contraindication to initiate T therapy in LOH [2]. Individual assessment of comorbidities (as possible causes of symptoms) and potential risks vs. benefits of T treatment is particularly important in elderly men.

Men successfully treated for PCa who have symptomatic hypogonadism are potential candidates for T therapy after a prudent interval if there is no evidence of residual cancer. Risks/benefits must be clearly discussed with and understood by patients and follow-up must be particularly careful [2,60].

Available treatments

A variety of T formulations and routes of administration are available (injections, patches, gels, tablets, pellets, implants, and solutions); the advantages and disadvantages of these are summarized in Table III. Treatment can be individualized according to patient preference, dosing and monitoring requirements, AEs, and cost [47]. Ideally, selection of a preparation should be a joint decision between an informed patient and physician [2].

Table III.  Clinical pharmacology of some testosterone formulations.

Formulation	Regimen	Pharmacokinetic profile	Advantages	Disadvantages
T enanthate or cypionate	150–200 mg IM q 2 weeks or 75–100 mg/week	After a single IM injection, serum T levels rise into the supraphysiological range, then decline gradually into the hypogonadal range by the end of the dosing interval	Corrects symptoms of androgen deficiency; relatively inexpensive, if self-administered; flexibility of dosing	Requires IM injection; peaks and valleys in serum T levels
1% Testosterone gel^a	Available in sachets, tubes, and pumps 5–10 g T gel containing 50–100 mg T q d	Restores serum T and E2 levels to the physiological male range	Corrects symptoms of androgen deficiency, provides flexibility of dosing, ease of application, good skin tolerability	Potential of transfer to a female partner or child by direct skin-to-skin contact; skin irritation in a small proportion of treated men; moderately high DHT levels
Transdermal testosterone patch	1 or 2 patches, designed to nominally deliver 5–10 mg T over 24 h applied q d on non-pressure areas	Restores serum T, DHT, and E2 levels to the physiological male range	Ease of application, corrects symptoms of androgen deficiency	Serum T levels in some androgen-deficient men may be in the low-normal range; these men may need application of 2 patches daily; skin irritation at the application site occurs frequently in many patients
Buccal, bioadhesive, T tablets	30 mg controlled release, bioadhesive tablets bid	Absorbed from the buccal mucosa	Corrects symptoms of androgen deficiency in healthy, hypogonadal men	Gum-related adverse events in 16% of treated men
T pellets	3–6 pellets implanted subcutaneously; dose and regimen vary with formulation	Serum T peaks at 1 m and then is sustained in normal range for 3–6 m, depending on formulation	Corrects symptoms of androgen deficiency	Requires surgical incision for insertions; pellets may extrude spontaneously
17-α methyl T	This 17-α alkylated compound should not be used because of potential for liver toxicity	Orally active		Clinical responses are variable; potential for liver toxicity; should not be used for treatment of androgen deficiency
Oral T undecanoate^b	40–80 mg orally bid or tid with meals	When administered in oleic acid, T undecanoate is absorbed through the lymphatics, bypassing portal system; considerable variability in the same individual on different days and among individuals	Convenience of oral administration	Not approved in the USA; variable clinical responses, variable serum T levels, high DHT:T ratio
Injectable long-acting T undecanoate in oil^b	European regimen 1000 mg IM, followed by 1000 mg at 6 weeks and 1000 mg q 10–14 weeks	When administered at a dose of 750–1000 mg IM, serum T levels are maintained in the normal range in a majority of treated men	Corrects symptoms of androgen deficiency; requires infrequent administration	Requires IM injection of a large volume (4 ml); cough reported immediately after injection in a very small number of men
Testosterone in-adhesive matrix patch^b	2 × 60 cm^2 patches delivering approximately 4.8 mg T/d	Restores serum T, DHT, and E2 to the physiological range	Lasts 2 d	Some skin irritation

Adapted from Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM; Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95(6):2536–2559 [1], with permission from The Endocrine Society. Copyright 2010, The Endocrine Society.

bid, twice daily; DHT, dihydrotestosterone; E2, estradiol; IM, intramuscular; q d, every day; q week, every week; T, testosterone; tid, three times daily.

^aIn some countries, the following preparations are available: Tostran 2% gel (20 mg T/g; one press of the canister piston delivers 0.5 g of gel containing 10 mg T), Androgel 1.62% (20.25 mg T/1.25 g), Axiron 2% topical solution (30 mg T/1.5 ml), Fortesta (2%; 10 mg T/0.5 g). ^bThese formulations are not approved for clinical use in the USA, but are available outside the USA in many countries. Physicians in countries where these formulations are available should follow the approved drug regimens.

T injections and gels are the most common routes of T supplementation. Oral agents (except oral T undecanoate which is absorbed via the lymphatics) should not be used because of liver toxicity associated with first-pass metabolism. A non-alkylated oral T, available since the 1970s, has shown improvements in quality of life in men with T deficiency [61]. Since 2003, T undecanoate has been available in a new bioequivalent formulation with castor oil and propylene glycol laurate, improving storage conditions [62,63]. Injectable agents benefit from infrequent administration intervals, however, traditional agents often display peak and trough fluctuations in T levels [1,50]. The improved pharmacokinetic profile of the relatively new T undecanoate injection avoids such T fluctuations [64]. While topical gel or transdermal preparations are easy to administer and can minimize T fluctuations, patches are often associated with skin irritation while gels have the potential for contact transmission to partners/children. Buccal tablets also avoid first-pass metabolism but can cause gum-related AEs. Implants of T pellets provide long-term T release but require surgical incision and can extrude spontaneously [1,50].

As the development of AEs during treatment requires rapid discontinuation, short-acting preparations may be preferred over long-acting ones for initial treatment of patients with LOH [2].

Injections

Traditionally, injectable T esters generated supranormal T levels shortly after administration with rapid declines, often to subnormal levels, in the days before the next injection [64,65]. T enanthate intramuscular injections may also produce dose-dependent increases in total and free 17β-estradiol levels [66].

The development of the long-acting injectable T undecanoate may offer an improved pharmacokinetic profile and less frequent dosing schedule (four times annually) which might increase convenience and aid compliance [64,67]. T undecanoate injection can reverse the effects of hypogonadism on bone, muscle, metabolic parameters, and sexual function. However, T undecanoate has been shown to significantly increase levels of hemoglobin and hematocrit [68,69]. There have also been concerns raised by the US Food and Drug Administration regarding very rare but serious AEs, including post-injection anaphylactic reaction and pulmonary oil microembolism [70].

Gels

Gels can be applied directly to non-scrotal skin once daily [71] and show rapid absorption, providing a reservoir for sustained T release and allowing T levels to remain reliably within the normal range over 24 h. Gels can provide rapid improvements in sexual activity and mood [72]. With T gel, there are significant improvements in body composition (increased lean body mass, decreased fat mass) and BMD of the lumbar spine over 12 months and improvement in sexual function was maintained over the long term [73].

Gels show a generally good tolerability profile (e.g., McNicholas & Ong [74]; Miner & Sadovsky [71]) and ease of dose titration. They also allow self-application, usually to the upper arms, shoulders or abdomen, are easy to apply and quick to dry. In addition, gels may offer advantages over patches. Two randomized trials comparing pharmacokinetic data after 90 days’ treatment found that T gel was superior to a T patch in normalizing serum T in patients with hypogonadism [75,76].

Recent real-world data from TRiUS showed that 12 months’ treatment with T gel in hypogonadal patients resulted in increased TT and FT levels and significantly improved sexual function [77]; it also produced statistically significant improvements in waist circumference, fasting blood glucose, and blood pressure in patients positive for metabolic syndrome [78].

Are all gels the same?

Various T gel formulations are available in various parts of the world (e.g., AndroGel (Abbott Laboratories, Illinois, USA), Testogel (Laboratoires Besins International/Bayer, Paris, France/Leverkusen, Germany), Testim™ (Auxilium Pharmaceuticals, Inc. Pennsylvania, USA; marketed by Ferring in Europe under license from Auxilium Pharmaceuticals, Inc.), Tostran (ProStrakan, Galashiels, UK), Fortesta (Endo Pharmaceuticals, Pennsylvania, USA); however, they are not interchangeable. A topical T solution is also available for underarm administration via an applicator (Axiron (Lilly, Indiana, USA)).

For example, a pharmacokinetic comparison of AndroGel and Testim™ showed a lack of bioequivalence, with Testim™ tending to achieve higher serum T levels than AndroGel and providing greater bioavailability (Figure 2; [79]). Thus, estimates of the maximum serum concentration after dosing (Cmax) for TT, dihydrotestosterone, and FT were 30, 19, and 38% greater, respectively, following the application of Testim^™ compared with AndroGel. Similarly, AUC_0–24 (area under the serum concentration vs. time curve from zero to 24 h) estimates for TT, dihydrotestosterone, and FT were 30, 11, and 47% greater, respectively, following the application of Testim^™ compared with AndroGel. It has been suggested that the enhanced absorption of T with Testim^™ may reflect the increased emollient qualities of this formulation due to inclusion of a pentadecalactone [79].

Figure 2.  Mean testosterone following a single dose of Testim™ or AndroGel. Reproduced from Marbury E, Hamill R, Bachand T, Sebree T, Smith T. Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formulation, Testim, compared to AndroGel [79], with permission from John Wiley & Sons, Ltd. Copyright © 2003 John Wiley & Sons, Ltd.

Patients who show a suboptimal response to one T gel may be changed to an alternative brand. In a study of 370 hypogonadal men using T gel (Testim^™ or Androgel), 75 (20%) suboptimally responsive men underwent a brand switch [80]. After switching from AndroGel to Testim, mean TT and FT increased significantly from 311 ng/dl and 10.4 pg/ml, respectively to 484 ng/dl (p < 0.001) and 14.6 pg/ml (p = 0.01), respectively. In contrast, patients switching from Testim™ to AndroGel showed no significant change in TT and FT [80].

The effectiveness of switching from Androgel to Testim^™ was evaluated in two studies in older hypogonadal males [81] or HIV-positive males [82], who failed to experience satisfactory symptom relief after treatment with AndroGel. In both studies, patients who switched to Testim^™ showed significantly greater improvement with regard to erectile function, assessment of problems associated with sex, sexual satisfaction, and treatment satisfaction compared with those continuing treatment on Androgel.

The packaging of gels also differs. For example, some gels (e.g., AndroGel/Testogel) are available as sachets, others as multi-dose pumps (e.g., Tostran, Fortesta, AndroGel 1.62%) and others are supplied in tubes (e.g., Testim™).

Treatment monitoring

Endocrine Society guidelines suggest that patients should be evaluated, and T measured, 3–6 months after treatment initiation and then annually to assess symptom response and tolerability [1]; therapy should aim to raise serum T to the mid-normal range. ISA, ISSAM, EAU, EAA, and ASA recommendations include a periodic hematologic assessment before treatment, at 3–4 and 12 months, and annually thereafter [2]. Dose adjustments and/or periodic phlebotomy may be necessary to keep hematocrit <52–55% [2]. Assessment of BMD at 2-year intervals is also advised. Failure to improve clinical manifestations within a reasonable time interval should result in treatment discontinuation [2].

Formulation-specific AEs should be evaluated at each visit [1]. Thus, for buccal tablets inquiry should be made about alterations in taste, and gums and oral mucosa should be examined for irritation. For injectable testosterone esters, physicians should ask about fluctuations in mood or libido, and, rarely, cough after injections. Patients using patches should be checked for skin reaction at the application site. For gels, patients should be advised to cover application sites with a shirt and to wash the skin before any skin-to-skin contact to avoid possible contact transmission. Finally, users of T pellets should be checked for signs of infection, fibrosis, or pellet extrusion.

Before treatment, PCa risk must be assessed by digital rectal examination and determination of serum prostate-specific antigen. Pre-treatment assessment can be improved by incorporating other risk predictors (e.g., age, family history, ethnicity/race); risk assessment tools include online PCa risk calculators. If the patient/physician considers the risk sufficiently high, further assessment may be desirable. However, pre-treatment prostate ultrasound examinations or biopsies are not recommended as routine requirements. After T initiation, patients should be monitored for prostate disease at 3–6 months, 12 months, and at least annually thereafter. If the PCa risk is sufficiently high (suspicious digital rectal examination finding; increased prostate-specific antigen or as calculated using a combination of risk factors as noted above), transrectal ultrasound-guided prostate biopsies are indicated [2].

Conclusions

Hypogonadism is a relatively common condition, especially in older men, but is under-recognized and undertreated. It therefore is vital that primary care physicians, as well as urologists, as the healthcare professionals who generally see patients first, are aware of the signs and symptoms of hypogonadism to facilitate early diagnosis and treatment. Diagnosis is based on (often nonspecific) signs/symptoms and laboratory measurement of T. Furthermore, hypogonadism is associated with various comorbid conditions (metabolic syndrome, diabetes, etc.) which may also require treatment; although it has yet to be proven that treating low T makes a difference to these comorbidities. While T supplementation is indicated to treat classical hypogonadism, its use in non-classical hypogonadism remains controversial and should be approached on an individual basis. Studies show that T therapy offers many benefits to men with low T. Many T formulations are available although gels and injections are the most common. The benefits and risks of T therapy must be clearly discussed with patients and assessment of potential prostatic disease and other risk factors considered before commencing treatment. In addition, physicians and patients should discuss the various options to ensure a treatment choice which best meets the patient’s needs. Primary care physicians and urologists, thus need to be aware of the advantages/disadvantages of the different T therapies. Moreover, it is important that patients should be carefully monitored before and during T therapy to assess response and to manage any AEs.

Acknowledgment

Medical writing assistance (funded by Ferring Pharmaceuticals) was provided by Tom Lavelle of Bioscript Stirling Ltd. The authors participated in an Advisory Board meeting on testosterone replacement therapy. The meeting was sponsored by Ferring Pharmaceuticals and attendees received an honorarium for their participation in the meeting. The concept for this review paper arose from discussions during the meeting.

Declaration of Interest: Stefan Arver has also consulted as a medical expert for Bayer AG, Ely Lilly, Pfizer Inc., AstraZeneca AB, KaroBio AB, Ferring and lectured in curricula supported by these corporations and also received grants for investigator initiated studies from Bayer. Ignacio Moncada, D. Aled Rees, Heinrich M. Schulte and Bruno Lunenfeld report no conflicts of interest.