Testosterone replacement therapy: who to evaluate, what to use, how to follow, and who is at risk?

Hospital Practice

ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20

Testosterone Replacement Therapy: Who to Evaluate, What to Use, How to Follow, and Who is at Risk? A. Afiadata MD & Pamela Ellsworth MD To cite this article: A. Afiadata MD & Pamela Ellsworth MD (2014) Testosterone Replacement Therapy: Who to Evaluate, What to Use, How to Follow, and Who is at Risk?, Hospital Practice, 42:5, 69-82 To link to this article: http://dx.doi.org/10.3810/hp.2014.12.1160

Published online: 30 Jun 2015.

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Testosterone Replacement Therapy: Who to Evaluate, What to Use, How to Follow, and Who is at Risk?

DOI: 10.3810/hp.2014.12.1160

A. Afiadata, MD 1 Pamela Ellsworth, MD 2 1 University of Massachusetts Medical School, Worcester, MA; 2Professor of Urology, Department of Urology, University of Massachusetts Memorial Medical Center, Worcester, MA

Abstract

Background: Hypogonadism, defined as a low serum testosterone in the presence of signs and symptoms, is common, particularly in aging men. Testosterone supplementation therapy (TST) is the standard treatment for male hypogonadism. It has been demonstrated to have a significant impact on the signs and symptoms of hypogonadism, but there are concerns about the increase in TST and its potential adverse effects, particularly cardiovascular effects. Objective: This review presents health care providers with current information regarding the prevalence and impact of hypogonadism, as well as the diagnosis, evaluation, and treatment of hypogonadism. The beneficial and potential adverse effects are reviewed with a discussion on the current cardiovascular controversy. Methods: We reviewed current and “landmark” articles in the English-language literature pertaining to hypogonadism, its prevalence, etiologies, presentation, evaluation, and treatment. Results: Authorities in the field have offered guidelines and recommendations regarding the diagnosis, evaluation, and management of hypogonadism. Although there is a consensus as to the definition of hypogonadism as the presence of a low serum testosterone with signs and symptoms of hypogonadism, there is variability in the definition of “low testosterone.” Various testosterone formulations exist, differing in route and frequency of administration as well as in side-effect profiles. Testosterone supplementation therapy should be continued in individuals demonstrating an improvement in signs and symptoms, which may take 3 months to a year for maximum response. Individuals treated with TST require monitoring for adverse effects. Further studies are needed to determine the impact of TST on cardiovascular health. Conclusion: Hypogonadism is common, particularly in aging men. Symptomatic individuals who have no contraindications to TST should be offered treatment. A careful assessment of treatment response after adequate titration and duration of therapy as well as monitoring for adverse effects is essential in treating patients for hypogonadism. Although hypogonadism is associated with increased all-cause and cardiovascular–related mortality, controversy exists regarding the impact of TST on cardiovascular risk, highlighting the need for further studies. Keywords: testosterone replacement therapy; hypogonadism; cardiovascular risk; monitoring

Correspondence: Pamela Ellsworth, MD, Department of Urology, University of Massachusetts Memorial Medical Center, 55 Lake Avenue North, Worcester, MA 01605. Tel: 508-334-0133

Hypogonadism and Testosterone Supplementation Therapy:The Dilemma

Testosterone supplementation therapy (TST) is the standard treatment therapy for men with hypogonadism. Hypogonadism in the traditional sense results from a disturbance of the hypothalamic-pituitary-testicular axis, resulting in decreased testosterone and a

© Hospital Practice, Volume 42, Issue 5, December 2014, ISSN – 2154-8331 69 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


A. Afiadata and Pamela Ellsworth

syndrome of loss of muscle mass and body hair, decreased libido, fatigue, and other signs and symptoms.1 However, testosterone levels gradually decline with age and in the presence of chronic diseases, obesity, and smoking. With the aging of the Western populations and the dramatic increases in obesity and diabetes, there may be an increasing number of men with hypogonadism. There is controversy concerning the need to treat such men, particularly those aged . 65 years, and about the safety of testosterone treatment.2–5 Such concerns have been supported by recent studies demonstrating an increase in testosterone testing and use of testosterone therapies over the past decade, particularly in the United States. Of concern is the substantial use of TST in men without recent testing and in US men with normal levels.6 Recent studies suggest that the use of testosterone has increased in the United States,7 the United Kingdom,8 and other countries.9,10 Furthermore, the safety of TST in certain populations has been questioned, and the US Food and Drug Administration (FDA) is now officially investigating the potential that even FDA-approved testosterone products increase the risk of serious adverse cardiovascular outcomes in men with cardiovascular disease (CVD). Additionally, the US Endocrine Society notes that a fuller assessment of the risks and benefits of testosterone treatment in older men with declining levels of the hormone is needed.

range).”11 Hypogonadism is classified based on the location of the defect in the hypothalamic-pituitary-testicular axis. The primary (testicular) cause is that resulting from defects at the level of the testis, whereas the secondary (central) cause results from defects of the hypothalamus or pituitary (Table 1). Hypogonadism may also result from defects affecting both the testis and the pituitary.1 There is variability regarding the lower limit of the “normal” testosterone range, with estimates ranging from 200 to 350 ng/dL. In addition, there is variability in assay results between laboratories, making it difficult to apply common reference ranges to results from different testing facilities.12 Furthermore, there is no agreed-upon standard population in whom “normal” levels have been established. In addition, many reference ranges have been determined in populations of healthy, younger men that may not be applicable to older men who may experience normal, natural decreases in testosterone as they age or that are related to chronic diseases.6 Lastly, the level of testosterone deficiency at which adverse signs/symptoms occur is not well established and may vary among individuals.13

Materials and Methods

Table 1. Primary and Secondary Causes of Hypogonadism

A comprehensive literature review regarding hypogonadism was conducted. The focus was on current guidelines and recommendations by thought leaders regarding diagnostic investigations and different treatment modalities, as well as on recent studies regarding the cardiovascular controversies surrounding TST. The literature search involved PubMed, other electronic databases, and other sources.

Definition of Hypogonadism

The Endocrine Society defines hypogonadism in men as “a clinical syndrome that results from failure of the testis to produce physiologic levels of testosterone (androgen deficiency) and a normal number of spermatozoa due to disruption of $ 1 level of the hypothalamic-pituitary-testicular axis.”1 The diagnosis of androgen deficiency is becoming more common with the increasing life expectancy and growing aging population. “Late-onset hypogonadism (also referred to as age-associated testosterone deficiency) is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels (below the young healthy male reference 70

Prevalence of Hypogonadism

The prevalence of hypogonadism ranges from 12% to 49%, increasing with age. Estimates of the prevalence differ

Primary (Testicular) Causes

Secondary (Central) Causes

• Undescended testes • Klinefelter’s syndrome • XX male • Male pseudohermaphrodite • Androgen resistance states (eg, receptor defect, 5α-reductase deficiency) • Noonan’s syndrome

• Aging • Infections • Medications • Trauma, radiation • Kallmann’s syndrome

• Idiopathic hypogonadotropic hypogonadism • Orchidectomy • Pituitary tumors • Congenital and acquired anorchidism • Craniopharyngioma • Bilateral torsion of the testes • Hyperprolactinemia • Inborn errors of testosterone • Isolated gonadotropinsynthesis releasing hormone deficiency • Bilateral orchitis • Isolated luteinizing hormone deficiency • Systemic diseases (eg, HIV, • Systemic diseases hemochromatosis, cancer, (eg, hemochromatosis, liver cirrhosis) sarcoidosis, tuberculosis, HIV) • Gonadal toxins (eg, chemotherapy • Prader-Willi syndrome and radiation) • Bardet-Biedl syndrome • Anorexia nervosa • Underweight Abbreviation: HIV, human immunodeficiency virus.

© Hospital Practice, Volume 42, Issue 5, December 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Testosterone Replacement Therapy

according to the definition used. Several epidemiologic studies have been performed; most of these studies reveal a high prevalence, and a positive correlation with aging.14–16 The Baltimore Longitudinal study, which involved 890 men with an average age of 53.8, estimated the incidence of hypogonadism to be approximately 12% in men aged . 50 years, 19% . 60 years, 28% . 70 years, and 49% . 80 years. This study defined androgen deficiency as a total testosterone level , 325 ng/dL.14 The Hypogonadism in Males (HIM) study conducted by Mulligan et al15 looked at 2165 men in the United States and found a crude prevalence of hypogonadism in men aged $ 45 years to be 38.7%. Their definition of hypogonadism was total testosterone , 300 ng/dL. A later study of 1475 men aged 30 to 79 years conducted in the Boston area showed a crude prevalence of symptomatic androgen deficiency of 5.6%. The Massachusetts Male Aging Study (MMAS) noted an overall prevalence of 12.3% for hypogonadism among men aged 40 to 70 years, with total testosterone , 200 ng/dL or $ 3 symptoms of androgen deficiency with a total testosterone between 200 and 400 ng/ dL.16 All of these studies have demonstrated an age-related increase in the prevalence of hypogonadism.

Causes of Hypogonadism

Testosterone production is controlled by the hypothalamicpituitary-testicular axis. The hypothalamus secretes gonadotropin-releasing hormone, which stimulates the pituitary to release luteinizing hormone (LH), which in turn stimulates the production of testosterone by the Leydig cells. Testosterone feeds back on the hypothalamus to modulate the release of gonadotropin-releasing hormone. When the etiology is either hypothalamus or pituitary (central) based, it is referred to as secondary hypogonadism, and primary hypogonadism when the problem is from the testis (testicular; Table 1). Primary (testicular) causes of hypogonadism are characterized by a low testosterone level and elevated gonadotropin and LH levels, whereas secondary causes are associated with low testosterone and low gonadotropin and LH levels. In aging men, the type of hypogonadism is often either secondary or mixed. Declining testosterone levels may be the result of several factors: (1) a decline in Leydig cell function, (2) a decline in pituitary/hypothalamic axis function with loss of circadian rhythm, (3) increase in sex hormone–binding globulin (SHBG) levels, and (4) the effects of altered cardiometabolic and inflammatory markers.17 Certain conditions are associated with a higher prevalence of low testosterone: sella mass or history of radiation or other

disease affecting the sella region; treatment with medication that affects testosterone production or metabolidonesm, such as glucocorticoids or opioids; HIV-associated weight loss; end-stage renal disease and hemodialysis; moderate to severe chronic obstructive lung disease; infertility; osteoporosis or low trauma fracture; and type 2 diabetes mellitus. One should consider screening for low testosterone in individuals with such conditions, particularly if there are coexistent symptoms of hypogonadism.18

Signs and Symptoms

The signs and symptoms of hypogonadism vary with the age of onset, duration of androgen deficiency, androgen sensitivity, and prior history of testosterone therapy.17 Comorbid conditions may also affect the signs and symptoms.19 Signs and symptoms suggestive of hypogonadism include decreased libido, loss of vitality, visceral obesity, decreased muscle mass and strength, loss of bone mineral density, infertility, hot flashes/sweats, reduced body hair, gynecomastia, mood changes, and depression.17,20–22 Nonspecific symptoms that may be attributed to hypogonadism include decreased energy and motivation, poor concentration and memory, sleep disturbance, reduced muscle bulk and strength, mild anemia, increased body fat, and decreased physical or work capacity.17,20–23 The European Male Aging Study noted that the combination of erectile dysfunction, poor morning erections, and low sexual desire had a syndromic association with decreased testosterone levels.23

Evaluation of Hypogonadism

The evaluation of hypogonadism involves a history, physical examination, and laboratory evaluation to confirm the presence of a low serum testosterone as well as the signs and symptoms of hypogonadism. In addition, the evaluation should focus on determining the etiology of the hypogonadism, as it may direct the treatment. Several questionnaires have been developed to help identify aging men with hypogonadism, including the following: (1) the Androgen Deficiency in Aging Male (ADAM) questionnaire, (2) the Aging Male Survey (AMS), and (3) the Massachusetts Male Aging Study (MMAS) questionnaire.17,24,25 Although highly sensitive, they are not very specific and thus have limitations.17 Miwa et al26 demonstrated that symptoms related to partial androgen deficiency of aging men as evaluated by the AMS scale are not significantly related to serum total or free testosterone. Chen et al27 demonstrated significant correlation between the results of the AMS and ADAM questionnaires and total and free testosterone, but when late-onset




hypogonadism was defined as total testosterone , 300 ng/dL and free testosterone , 5 ng/dL, the sensitivity and specificity of the AMS scale were 54.0% and 41.2%, respectively, compared with 78.7% and 14.8% for the ADAM questionnaire. The MMAS questionnaire has been demonstrated to have a sensitivity of 59.9% and a specificity of only 42.9% for low free testosterone in men aged $ 40 years.28 Although the International Index of Erectile Function (IIEF) is the most widely used questionnaire for diagnosis and assessment of treatment outcome of sexual dysfunction, it has shown only a weakly positive correlation between total testosterone levels and all IIEF domains except sexual desire, where no correlation was noted.29

History and Physical Examination

The patient’s overall health should be assessed, with an emphasis on a history of systemic illnesses; use of medications that may affect testosterone production (eg, opiates, high-dose glucocorticoid therapy), as well as recreational drugs; and a history of eating disorders and excessive exercise, which can lower testosterone levels transiently. The patient should be asked about changes in sexual function, ejaculate volume, and libido. Testicular failure may be the result of testicular trauma, cryptorchidism, mumps orchitis, toxic exposures, or chemotherapy or radiation treatment. Prior anabolic steroid use should be considered in young men seeking treatment for symptomatic hypogonadism, as it is the most common cause of profound hypogonadism (testosterone # 50 ng/dL).30 A history of anosmia or hyposmia, midline defects, or cryptorchidism may be suggestive of Kallmann’s syndrome or other types of hypogonadic hypogonadism.31 The physical examination should focus on evaluating the amount and distribution of body hair (ie, axillary and pubic hair, and beard growth) and the presence and degree of gynecomastia. In addition, the testes should be carefully examined. The testicular size should be evaluated with a Prader orchidometer or calipers. Scrotal ultrasound is indicated if a mass is palpable on testicular examination; otherwise, it is not necessary in the evaluation of hypogonadism.31 Adult testes are usually between 20 and 30 mL in volume and 4.5 to 6.5 cm long by 2.8 to 3.3 cm wide. The consistency of the testis should also be assessed. Small, firm testes suggest prepubertal damage, whereas small, soft testes suggest postpubertal damage.31 The presence/absence of varicocele(s) should also be noted. Penile size should be assessed. The length of the penis in adult men varies from 10 to 17 cm and the width in the flaccid state is . 3 cm.31 72

Laboratory Evaluation

Testosterone levels should be measured by a reliable assay on $ 2 occasions.1 Radioimmunoassays are the most commonly used testosterone assays, and they involve the use of a radioactively labeled antigen bound to an antibody. This technique is simple, has a fast turnaround time, and is inexpensive, but it can overestimate the level of testosterone, particularly with testosterone levels , 300 ng/dL. A method related to radioimmunoassay is enzyme-linked immunosorbent assay. The newest method is tandem mass spectrometry following liquid chromatography. Tandem mass spectrometer quantifies the amount of a compound in a sample by monitoring the mass/charge ratio of parent and product ions of testosterone and determines the quantity of testosterone in the sample. It is more sensitive and accurate than immunologic methods.32 It is currently recommended that a serum total testosterone level should be obtained in the morning, before 10 to 11 a m., as serum testosterone levels exhibit a circadian variation with peak values in the morning. However, a recent study of 266 hypogonadal men from 4 new drug applications noted that, in general, baseline testosterone concentration in hypogonadal men fluctuated , 100 ng/dL over a 12- to 24-hour period pretreatment.33 Circadian variation is blunted with aging.34 If the total testosterone level is low (, 250 ng/dL) or low normal (250–350 ng/dL), then it should be repeated (Figure 1). Thirty percent of men with an initial mildly low testosterone level will have a normal testosterone level on repeat evaluation.35 A free or bioavailable testosterone level, measured using an accurate and reliable assay, is recommended in men in whom the total testosterone concentration is near the lower limit of the normal range, and in whom alterations of SHBG are suspected. Factors that can affect SHBG include aging, obesity, diabetes mellitus, thyroid disease, kidney disease, liver disease, HIV, and use of steroids and anticonvulsants.1 The majority of testosterone circulates bound to SHBG and albumin. Approximately 0.5% to 3% of testosterone circulates unbound or free.1 Lastly, some studies have suggested an impact of seasonal variation on testosterone levels. Smith et al,36 in a review of the evidence for seasonal variation of testosterone in men, noted that currently reproducible data demonstrating season patterns of testosterone is limited, with some studies suggesting its effects and others failing to replicate these results. Free testosterone level can be measured accurately by equilibrium dialysis, whereas bioavailable testosterone is measured by ammonium sulfate precipitation.1 Both free and bioavailable testosterone levels may be calculated from




Figure 1. Flowchart for the assessment of symptoms of hypogonadism.

Abbreviations: AM, morning; DM, diabetes mellitus; FSH, follicle-stimulating hormone; LH, luteinizing hormone; T4, thyroxine.

total testosterone, SHBG, and albumin.1 Free testosterone is a reliable index of unbound testosterone, and the calculation of free testosterone from total testosterone and immunoassayable SHBG is a simple and rapid method that yields values comparable to those obtained by equilibrium dialysis.37 An online calculator, to determine free and bioavailable testosterone is available at www.issam.ch. If the serum total testosterone or free or bioavailable testosterone is low, the serum LH and follicle-stimulating hormone (FSH) level should be tested to determine whether it is primary (testicular) or secondary (pituitary-hypothalamic) in etiology.1 For those individuals with low LH and FSH, further evaluation may include serum prolactin and iron saturation, pituitary function testing, and magnetic resonance imaging of the sella turcica (Figure 1).1 Anabolic steroid use will lead to a low serum testosterone level and suppressed LH and FSH levels and should be considered, particularly in young men. In men with primary testicular failure of unknown etiology, a serum karyotyping may be useful to assess for Klinefelter syndrome, particularly in those men with small testes bilaterally (, 6 mL volume). Furthermore, men being evaluated for fertility should have $ 2 semen analyses performed. Those men with severe androgen deficiency or a low trauma fracture should have a

dual-energy x-ray absorptiometry scan obtained to evaluate bone mineral density.1

Treating Hypogonadism

It is recommended that only symptomatic men with low testosterone be treated, with the goal of inducing and maintaining secondary sex characteristics, and improving sexual function, the sense of well-being, and bone mineral density.1 There is consensus that patients with a serum total testosterone level , 8 nmol/L (230 ng per 100 mL) will usually benefit from testosterone therapy. If the serum testosterone is between 8 and 12 nmol/L, it may be helpful to check a free testosterone by repeating the testosterone with SHBG to calculate free testosterone or to check free testosterone by equilibrium dialysis, and treating if the free testosterone is low. For individuals with a total testosterone level . 12 nmol/L (350 ng per 100 mL), treatment is not recommended.11 Testosterone therapy may be used with caution in men with a history of prostate cancer treated with definitive therapy (radical prostatectomy, radiation therapy, brachytherapy) and deemed free of disease.38–43 Coward and Carson38 reviewed 5 studies evaluating the use of TST after definitive therapy for prostate cancer and noted that biochemical recurrence occurred in 2 of the 147 patients (1.4%). Thus, the authors




concluded that TST is an option in men who have received definitive therapy for prostate cancer, the timing of which needs evidence-based data, but Coward and Carson typically wait $ 6 months after definitive therapy. Pastuszak et al44 performed a retrospective review of 103 hypogonadal men with prostate cancer treated with testosterone therapy after radical prostatectomy compared to 49 nonhypogonadal men with prostate cancer treated with radical prostatectomy who were evaluated for . 36 months. The authors noted a significant increase in the prostate-specific antigen (PSA) in the high-risk and non–high-risk patients treated with testosterone. Prostate cancer recurrence was noted in 4 of the men receiving testosterone therapy and in 8 of the nonhypogonadal patients. Despite the lack of apparent risk of prostate cancer recurrence, the authors recommended that a vigorous surveillance protocol be used with TST in hypogonadal patients with a history of prostate cancer. When treating male hypogonadism, it is important to review the benefits and risks and ensure that the patient has no contraindications to testosterone replacement therapy (TRT; Table 2). Testosterone supplementation therapy may impair spermatogenesis and lead to azoospermia in 40% of patients. Concomitant use of low-dose human chorionic gonadotropin (500 IU intramuscular every other day) in conjunction with TST was shown to maintain semen parameters in hypogonadal men on TST over a mean follow-up of 6.2 months.45 A variety of testosterone formulations exist, each with unique modes of administration, frequency of administration, and unique side effects. The cost of the different formulations may vary considerably (Table 3). Aromatase inhibitors have been demonstrated to increase testosterone levels in men with hypogonadism and have been proposed as an attractive alternative to TST due to the effects on testosterone and the ease of use, which entails oral administration. However, the long-term effects of use in hypogonadal men are not well known, and the role of estrogen in men with hypogonadism and sexual dysfunction is not well defined.46 Finkelstein et al13 reported an important role of estrogen in the regulation of sexual function in men on TST, as dramatic declines in libido were noted in conjunction with decreased levels of serum estrogen.13 Ramasamy et al47 evaluated the quality of libido in men on TST with serum testosterone levels . 300 ng/dL and , 300 ng/dL as well as estradiol levels . 5 ng/dL and # 5 ng/dL, and noted that on multivariate analysis only estradiol at serum levels . 5 ng/dL (OR = 2.13, P = 0.04) were associated with greater libido. As a result of these findings, Ramasamy et al recommend the judicious use of aromatase inhibitors for indications such as gynecomastia. 74

Table 2. Treating Hypogonadism: TRT Benefits

Risk/Adverse Effects

Relative Contraindications

Maintain secondary sex characteristics Improve sexual function Improve sense of well-being

Erythrocytosis

History of prostate cancer

Acne and oily skin

History of breast cancer

Detection of subclinical prostate cancer Growth of metastatic prostate cancer Decreased sperm production and fertility

Hematocrit . 50%

Improve bone mineral density Improve body composition

Untreated severe obstructive sleep apnea Severe lower urinary tract symptoms (American Urological Association’s International Prostate Symptom Score . 19) Poorly controlled heart failure Men desiring fertility

Abbreviation: TRT, testosterone replacement therapy.

Assessing Response to Testosterone Supplementation Therapy

Miner and Sadovsky48 suggest a 3-month trial of TST before assessing treatment response. This duration does not appear to be associated with a risk of serious adverse effects.49 If the symptoms are not resolved within 3 months of treatment, and laboratory testing demonstrates normal serum total testosterone levels on therapy, the testosterone supplementation therapy should be discontinued and other causes of the symptoms evaluated. The International Society of Andrology, the International Society for the Study of the Aging Male, the European Association of Urology, the European Academy of Andrology, and the American Society of Andrology recommend a trial of therapy for 3 to 6 months to assess the impact on libido and sexual function, muscle function, and body fat. The effects on bone mineral density require a longer duration of therapy before assessing response. If no significant improvement is noted at these intervals, then therapy should be discontinued and other causes of the symptoms should be investigated.11 The Endocrine Society suggests an assessment of symptom response 3 to 6 months after starting TST and then annually thereafter to follow the response, and to assess adverse effects, and to check compliance.1 Saad et al50 performed a literature review to evaluate the onset of the effects of testosterone treatment and the time span until maximum effects are achieved. The authors reported as follows:


Abbreviation: POME, pulmonary microembolism.

150–450 mg every 3–6 months

30 mg every 12 hours

Buccal tablets (Striant) Implantable pellets

Underarm spray (Axiron)

Nasal gel (Natesto)

Gel (Androgel, Testim)

Pellets can become infected

Has to be applied to clean, dry intact skin; avoid swimming or washing the application site 2 hours after application; antiperspirant/deodorant should be applied 2 minutes prior to applying Axiron; side effects much like the topical gels, with risk of secondary exposure Irritation of the gums and alterations in taste

Not recommended for use in patients with chronic nasal conditions or alterations in nasal anatomy; may cause headache, rhinorrhea, epistaxis, nasal discomfort, nasopharyngitis, bronchitis, upper respiratory tract infection, sinusitis, nasal scab

Requires the patient to allow it to dry before putting on clothes or close contact with someone, as the gel may be transferred

Associated with less fluctuation in testosterone levels and symptoms; less likely to cause erythrocytosis l ke the other injectables. Serious POME reactions and anaphylaxis have been reported to occur during or immediately after administration of testosterone undecanoate. These reactions can occur after any injection during the course of treatment, including after the first dose. Following injection of Aveed, patients should be observed for 30 min for symptoms of such reactions and management. Aveed is available only through a restricted program called the Aveed risk evaluation and mitigation strategy because of the risk of POME and anaphylaxis Skin reaction at application site

750 mg injection initially, at 4 weeks, then every 10 weeks

Initially 4 or 5 mg daily, then adjusted based on serum testosterone levels 5–10 g of 1% gel, then adjusted based on serum testosterone levels One pump delivers 5.5 mg, recommended dose is 11 mg (one pump each nostril) intranasally 3 times per day, daily dose 33 mg Initially 60 mg daily (one pump, 30 mg) to each axilla), then adjusted as needed

Fluctuation in mood or libido; pain at injection site; excessive erythrocytosis; and coughing episodes immediately after injection thought to be related to oil embolization Testosterone cypionate is more readily available in the United States

75–100 mg weekly or 150–200 mg every 2 weeks

Intramuscular testosterone: enanthate and cypionate; both are testosterone esters in oil; cypionate is administered within a cottonseed oil suspension, whereas enanthate is delivered in a sesame oil suspension Intramuscular testosterone: undecanoate, Aveed

Transdermal patches (Androderm)

Adverse Effects/Limitations

Dose Used: Adult

Formulation

Table 3. Different Formulations of Testosterone


Ten 75 mg pellets: low cost

30 tabs (30 mg each): moderate cost

1 bottle (90 mL) of 30 mg/1.5 mL (1800 mg total): high cost

Varies depending on manufacturer but it is a more expensive formulation: high cost Approved May 29, 2014

30 patches of 4 mg: moderate cost

Not yet available in pharmacies; recently approved by FDA

For 1000 mg enanthate or cypionate: low cost

Cost





Effects on sexual interest appear after 3 weeks, plateauing at 6 weeks, with no further increments expected beyond. Changes in erections/ejaculations may require up to 6 months. Effects on quality of life manifest within 3–4 weeks, but maximum effects take longer. Effects on depressive mood become detectable after 3–6 weeks with a maximum after 18–30 weeks. Changes in fat mass, lean body mass, and muscle strength occur within 12–16 weeks, stabilize at 6–12 months, but can marginally continue over years. Effects on bone are detectable already after 6 months while continuing for at least 3 years.

Long-term studies utilizing injectable testosterone undecanoate have demonstrated continued improvement in a variety of symptoms of hypogonadism during follow-up ranging from 9 months to 5 years, supporting a longer duration of treatment than 3 months to assess treatment response.51–55 It is recommended that the total testosterone level be maintained between 350 and 700 ng/dL during treatment.1,17,56–58 In patients who are not responding to testosterone supplementation, we recheck the serum testosterone level, and if it is at the lower end of the therapeutic range, we increase the dose, reassess symptom response, and check serum testosterone level again at the higher dose. We typically do not exceed the level of 700 ng/dL; however, in patients on the injectable formulations, such levels may occur shortly after administration of testosterone cypionate and enanthate. Thus, timing of the assessment of treatment response may vary with the symptom being assessed and should not be performed until titration is completed. The time to check serum testosterone varies with the testosterone formulation being used. For men receiving the injectable formulations, the serum testosterone level should be checked 1 week after injection, with the aim of achieving a level between 400 and 700 ng/dL.1 Injectable testosterone undecanoate (Aveed, Endo Pharmaceuticals, Malvern, PA), is associated with fewer fluctuations in testosterone level and “roller coaster” effects of traditional parenteral testosterone. Its plasma testosterone levels are nearly always in the normal range as are its metabolic products.59 Patients using the gel formulation usually have constant blood levels of testosterone; hence, the time for measurement is not critical. On the other hand, the patch formulation tends to have peak serum testosterone within 4 to 8 hours after application.31

Testosterone Supplementation Therapy Monitoring

Once testosterone therapy is initiated and a decision made to continue therapy, the patient must be monitored over 76

the long-term for adverse effects related to TRT.60–62 The patient should be asked about side effects such as acne, fluid retention, snoring suggestive of sleep apnea, male pattern baldness, and gynecomastia. The patient’s lipid profile and hematocrit should be followed during TST. Liver function tests are not adversely affected by the current FDA-approved formulations of testosterone. A baseline serum hematocrit should be obtained prior to starting TST and rechecked 3 to 6 months later. Testosterone supplementation therapy in older men is associated with a significantly higher risk of hematocrit . 50%.62 A hematocrit . 54% is considered worrisome, and TST should be discontinued until the hematocrit returns to a safe level, and then can be resumed at a lower dose. If the patient is symptomatic or at high risk for complications related to the polycythemia, then phlebotomy is employed. The role of routine phlebotomy is not established. The risk of developing polycythemia varies with the formulation used. Intramuscular TST has been demonstrated to have a stronger association with polycythemia than topical use.63 In patients receiving subcutaneous testosterone pellets, the trough serum testosterone level predicts the development of polycythemia.64 For men aged . 40 years who have baseline PSA . 0.6 ng/mL, it is recommended to perform a digital rectal examination and check the PSA level prior to initiation, at 3 to 6 months, and then follow the American Urological Association guidelines for prostate cancer screening.1 Further investigation is warranted if there is an increase in serum PSA level . 1.4 ng/mL within any 12-month period, or an abnormal digital rectal examination, or an American Urological Association’s International Prostate Symptom Score . 19, or a PSA velocity of . 0.4 ng/mL/year.1 Although most formulations of TST are associated with a favorable effect on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, the use of injection therapy, particularly if associated with supraphysio logic testosterone levels, may adversely affect HDL levels, and thus monitoring of lipids is recommended with TRT.65 Fernandez-Balsells et al66 performed a systemic review and meta-analysis that supported the association between testosterone treatment and decrease in HDL cholesterol. In diabetic patients, the metabolic effects of androgens may decrease the blood glucose and lower insulin requirements. C-17–substituted derivatives of testosterone, such as methandrotestosterone, have been reported to decrease anticoagulant requirements in patients receiving oral anticoagulants, which requires close monitoring. Coadministration of androgens and oxyphenbutazone may lead to increases in levels of oxyphenbutazone.67




Testosterone Supplementation Therapy and the Heart: Friend of Foe?

Several studies have demonstrated that low testosterone is a risk factor for CVD (Table 4). Corona et al,68 using a search database restricted to data from January 1969 to January 2011, performed a meta-analysis evaluating hypogonadism as a risk factor for cardiovascular mortality in men, and demonstrated that lower testosterone and higher E2 (estradiol) levels independently correlated with an increased risk of CVD and cardiovascular mortality in cross-sectional surveys. In longitudinal studies, low testosterone predicted overall and cardiovascular mortality, but there was no association between testosterone and E2 and CVD incidence.68 The MMAS found that men with low total testosterone levels were almost twice as likely to die from all causes and CVD, compared with men with normal total testosterone level. The age-adjusted hazard ratios for men with total testosterone , 200 ng/dL versus men with a total testosterone of 410 to 509 was 1.93 or 2-fold for all mortalities (P = 0.93) and 1.93 or 2-fold for CVD-related death (P = 0.028).69 The Epic Study in Norfolk, England, was a nested casecontrol study comparing 825 men without CVD at baseline and who died in the follow-up period of up to 10 years, with 1489 men who remained alive. After controlling for confounders, the baseline testosterone levels were noted to be inversely related to deaths resulting from all causes, CVD, and malignancy. The authors noted that the risk of cardiovascular mortality varied with the testosterone level and that an increase of 6 nmol/L in testosterone was associated with a multivariate adjusted odds ratio of 0.81 (P , 0.010) for

overall mortality.70 The Rancho Bernardo Study demonstrated that men whose total testosterone were in the lowest quartile (, 8 nmol/L) were 40% more likely to die from all causes than were those with higher levels (hazard ratio [HR], 1.4; P = 0.002), after adjusting for age, body mass index, waist/ hip ratio, alcohol use, current smoking, and exercise. They also noted that low total testosterone predicted an increased risk of cardiovascular mortality (HR, 1.38).71 Shores et al72 and the Rotterdam study73 demonstrated strong associations between low total testosterone and mortality. A Swedish study followed 3014 men for 4.5 years and found that men with total testosterone levels in the lowest quartile (, 336 ng/dL) had a 2-fold higher mortality than the other quartiles.74 A Norwegian study demonstrated a 24% increase risk in mortality for men with a free testosterone in the lowest quartile (, 16 pg/mL).75 Corona et al76 evaluated the association between total testosterone level and major coronary events. They noted that men with a total testosterone of , 230 ng/dL had a significantly increased incidence of fatal major adverse coronary events (HR, 7.1; 95% CI, 1.8–28.6) at 4.5 years after adjusting for age and chronic disease.76 An Australian study showed that low free testosterone and raised SHBG and LH were associated with all-cause and cardiovascular deaths (HR, 1.62; 95% CI, 18.2–24.8).77 Maggio et al,78 in the 6-year Chianti study, suggested that a decline in T levels is a strong independent predictor of mortality in men. More recently, prospective data from the European Male Aging Study was evaluated to assess the relationship of late-onset hypogonadism to mortality. The study demonstrated that severe late-onset hypogonadism

Table 4. Studies Demonstrating Improved or No Change in Cardiovascular Morbidity and Mortality With TRT Investigator Haddad et al, 2007

93

Shores et al, 201294

Calorf et al, 200562

Muraleedaran et al, 201395

Study Design

Result/Conclusion

Systematic review and meta-analysis of randomized placebo-controlled trials Observational study using a clinical database that included 7 Veterans Affairs medical centers in the Pacific Northwest to evaluate association between TRT and mortality in men with low testosterone levels

TRT use in men was not associated with important cardiovascular events. Mortality in TRT-treated men was 10.3% compared to 20.7% in untreated men (P , 0.0001) with a mortality rate of 3.4 deaths per 100 person-years for TRT-treated men compared with 5.7 deaths per 100 person-years for untreated. TRT was associated with decreased risk of death after multivariable adjustment including age, body mass index, testosterone level, medical morbidity, diabetes, and coronary heart disease. The frequency of cardiovascular events was not significantly different between the TRT and placebo groups.

Meta-analysis of randomized clinical trials to determine risks of adverse events associated with TRT in older men (age $ 45 years) Prospective study involving 587 men with type 2 DM followed for 5.8 years

Mortality rate in the untreated group was 17.2% compared to 9% in the treated group (P = 0.001).

Abbreviations: DM, diabetes mellitus; TRT, testosterone replacement therapy. © Hospital Practice, Volume 42, Issue 5, December 2014, ISSN – 2154-8331 77 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.



(testosterone , 8 nmol/L) is associated with substantially higher risks of all-cause and cardiovascular mortality. Compared with eugonadal men, the mortality was 2-fold higher in men with testosterone level , 8 nmol/L (HR, 2.3; 95% CI, 1.2–4.2) and 3-fold higher in those with 3 sexual symptoms (irrespective of serum testosterone; compared with asymptomatic men; HR, 3.2; 95% CI, 1.8–5.8).79 Testosterone replacement therapy has been shown to have a favorable impact on risk factors for CVD. Most studies have demonstrated a favorable impact of TRT on cholesterol, LDL, and triglycerides, with variable effects on HDL.50,80–87 Low-dose TRT in men with chronic stable angina reduced exercise-induced myocardial ischemia after 4 weeks of treatment.88 A later study demonstrates improvement continuing . 12 months.89 However, despite the association of low testosterone, CVD, and mortality, and despite improvements in several risk factors for CVD as well as exercise tolerance, the data on the risks of cardiovascular events with TRT is controversial (Tables 4 and 5).90−95 More recently, in response to 2 recent studies, both of which have design limitations (Table 5),90−92 the FDA posted an alert regarding CVD risks with testosterone therapy. The FDA stressed that testosterone formulations are approved for men with low testosterone levels and associated medical conditions, and that patients should not stop taking testosterone therapy unless they first consult with their physician. Physicians need to consider the risk/benefit profile when considering prescribing testosterone therapy for a patient and follow the prescribing information in the drug labels of FDA-approved testosterone products.

Testosterone Supplementation Therapy and Erectile Dysfunction

The association between androgens and sexual function in aging men is controversial. Up to 35% of men presenting with erectile dysfunction have reduced or borderline circulating androgen levels.96–100 Experimental studies have demonstrated that testosterone deficiency is associated with a marked decrease in nitric oxide synthetase activity and protein expression, which are factors important in normal erectile function.101–103 Despite experimental studies supporting a role of testosterone in normal erectile function, results of studies using TST for men with erectile dysfunction are conflicting. Isidori et al104 performed a meta-analysis evaluating the effects of TST on the different domains of sexual life. The authors noted that in men with an average testosterone level at baseline , 12 nmol/L, TST moderately improved 78

the number of nocturnal erections, sexual thoughts and motivation, number of successful intercourses, scores of erectile function, and overall sexual satisfaction, whereas TST had no effect on erectile function in eugonadal men compared to placebo. Bolona et al105 performed a systematic review and meta-analysis of randomized placebo-controlled trials to measure the effect of testosterone use on sexual function in men with sexual dysfunction and varying testosterone levels. Results of the review of 17 trials that enrolled patients with low testosterone levels demonstrated (1) a moderate but not significant and inconsistent effect of testosterone on satisfaction with erectile function, (2) a large effect on libido, and (3) no significant effect on overall sexual satisfaction. More recently, Alhathal et al106 performed a systematic review evaluating the synergetic effect of testosterone and phosphodiesterase-5 inhibitors in hypogonadal men with erectile dysfunction. The review focused on studies that evaluated combination therapy of testosterone and phosphodiesterase type-5 inhibitors in patients with low or low-normal testosterone levels who failed monotherapy with phosphodiesterase type-5 inhibitors. The authors noted that the studies were heterogenous and suffered from methodological problems and variable results. However, 8 of the 10 studies that reported varying improvement in IIEF domains after combination therapy (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) showed an increase in the erectile function domain from an average of 13 ± 1.8 at baseline to an average of 20.25 ± 3.9 posttreatment, with an overall efficacy of 34% to 100%. The prevalence of erectile dysfunction in aging men, coupled with increasing age-related risk factors, highlights the importance of searching for other signs of hypogonadism in this population, prior to prescribing TST. We typically screen for other signs and symptoms in men with erectile dysfunction. If other signs and symptoms are present, we obtain a serum testosterone at the time of the initial evaluation. If no other signs and symptoms are present, we often obtain a serum testosterone level, but hold off on treating with TST, unless the patient fails phosphodiesterase type-5 inhibitors. In those patients failing phosphodiesterase type-5 inhibitors with a low serum testosterone (# 300 ng/dL), we typically add TST if there are no contraindications and reevaluate the patient’s erectile function. If there is no significant improvement in erectile function and the patient has no other signs or symptoms of hypogonadism, then we do not routinely continue TST.




Table 5. Studies Demonstrating Increased Risk of Adverse Cardiovascular Events With TRT Investigator

Study Design

Results/Conclusions

Finkle et al, 201490

Cohort study of risk of acute nonfatal MI following initial TRT prescription. Compared incidence rate of MI in the 90 days following initial prescription (post-rate) versus rate in 1 year prior to the initial prescription (pre-rate). Also compared pre/post rates in a cohort of men prescribed PDE-V inhibitors. They finally compared TRT pre/post rates versus PDE-V inh bitor pre/post rates.

Vigen et al, 201391

Retrospective national cohort study of men with testosterone level , 300 ng/dL who underwent coronary angiography in the Veterans Affairs system 2005–2011. Objective to assess association between TRT and all-cause mortality, MI, or stroke, and determine whether association is modified by underlying coronary artery disease.

Xu et al, 201392

Systematic review and meta-analysis of placebo-controlled randomized trials of TRT among men lasting $ 12 weeks’ duration reporting cardiovascular-related events.

Basaria et al, 201060

Placebo-controlled trial of TRT with topical testosterone gel in 209 frail elderly men aged . 65 years.

In all subjects, the pre/post prescription RR for TRT prescription was 1.36 (95% CI; 1.03, 1.81). The RR for TRT prescription increased to 2.19 (1.27, 3.77) in men aged $ 65 years, compared with 1.15 (0.83, 1.59) for PDE-V inhibitors. In men aged , 65 years with prior history of heart disease, the RR for TRT prescription was 2.90 (1.49, 5.62), compared with 1.40 (0.91, 2.14) for PDE-V inhibitors. It was concluded that the risk of MI increases following TRT initiation in older men or young men with preexisting heart disease. Limitations of study: difference in length of time to evaluate events 1 year prior to treatment, 90 days on treatment; short-term evaluation may limit assessment of treatment benefit; no laboratory evaluation performed. At 3 years after coronary angiography, Kaplan-Meier was used to estimate cumulative percentages; events occurred in 19.9% of patients in the no-TRT group compared with 25.7% in the TRT group, with an absolute risk difference of 5.8% (95% CI, –1.4 to 13.1). In Cox proportional hazards models, adjusting for the presence of coronary artery disease, TRT use as a time-varying covariate was associated with an increased risk of adverse outcomes (hazard ratio, 1.29; 95% CI, 1.04 to 1.58). There was no significant difference in the effect size of TRT among those with and without coronary artery disease. It was concluded that the use of TRT correlated with increased risk of adverse outcomes. Limitations in study include large number of patients excluded from study, inclusion of women in the study. 27 eligible trials involving 2994 primarily older men with 180 cardiovascular-related events. TRT increased the risk of cardiovascularrelated events (odds ratio, 1.54; 95% CI, 1.09 to 2.18). The risk of cardiovascular-related adverse event on TRT was greater in studies that were not funded by pharmaceutical companies (odds ratio, 0.89; 95% CI, 0.50 to 1.60). TRT increases risk of cardiovascular-related events. Limitations of study: 3 trials included in the review used high doses of testosterone (150 mg) in frail elderly men, 1study classified ankle edema as a cardiac event rather than an expected finding. Study terminated, as there were 23 cardiac events, including 3 deaths in the 106 men in the TRT group compared with 5 in the placebo group. The events included MI, dysrhythmia, and hypertension. Limitations included a greater number of men with more severe cardiac disease in the TRT group and a rapid escalation to higher than manufacturer’s recommended dose, and many events lacked adequate validation.

Abbreviations: MI, myocardial infarction; PDE-V, phosphodiesterase type 5; RR, rate ratio.

Conclusion

Hypogonadism is common and increases with age. It is defined by the presence of symptoms in the setting of a low serum testosterone. The etiology may be related to central or testicular causes, and to mixed causes in elderly men. High-risk individuals may benefit from screening. The goal of testosterone therapy is restoration of a normal serum testosterone level and improvement or resolution of symptoms. Various testosterone formulations exist, and providers must be aware of the unique differences with respect to method of administration, frequency of administration, and side effects. Individuals being treated with

TRT require long-term monitoring and an assessment of treatment response. Testosterone supplementation therapy should be continued in those individuals with improvement in symptoms after a satisfactory trial of TST. Those who fail to respond to TST should undergo further evaluation for other possible causes of the symptoms. The cardiovascular effects of testosterone therapy are controversial and should be considered when evaluating and treating patients for hypogonadism. Similarly, studies evaluating the effects of TST on erectile dysfunction are conflicting, and metaanalyses of such studies are limited due to heterogeneity of study designs. However, it does appear that there may



be some beneficial effect of combination therapy of TST and phosphodiesterase type-5 inhibitor in patients with a low serum testosterone who have failed phosphodiesterase type-5 inhibitor monotherapy.

Conflict of Interest Statement

Pamela Ellsworth, MD, and A. Afiadata, MD, have no conflicts of interest to declare.


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