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Testosterone Administration in Older Men
Tes t o s t e ro n e A d m i n i s t r a t i o n i n Older M en Alvin M. Matsumoto,
MD
a,b,
*
KEYWORDS Hypogonadism Aging Diagnosis Testosterone Treatment KEY POINTS In older men, consider the potential contribution of comorbidities and medications on clinical manifestations and their impact on the diagnosis and management of male hypogonadism. The goals of testosterone treatment in older hypogonadal men should be patient-centered and include potential improvements in quality of life and functional status. The choice testosterone formulations in older men is based both on pharmacologic considerations and patient preferences. In older hypogonadal men, appropriate monitoring of efficacy and safety should be performed during testosterone administration.
INTRODUCTION
The only indication for testosterone (T) administration in older men is replacement therapy for male hypogonadism, which is defined as a syndrome consisting of symptoms and signs of androgen deficiency in the presence of consistently low serum T levels.1 Male hypogonadism is common, occurring in 2% to 6% of communitydwelling middle-aged to older men and its prevalence and incidence increases with age.2–4 Compared with young hypogonadal men, the diagnosis and optimal management of male hypogonadism in older men presents greater challenges. Clinical manifestations of androgen deficiency in older adults are nonspecific, and serum T levels decline progressively with increasing age, such that an increasing proportion of men have T levels in the hypogonadal range with age.5,6 Both symptoms and signs of androgen deficiency and low T levels may be caused or modified by comorbid illnesses that occur commonly as men age and by medications that are taken more frequently by older men.7,8 As result, there is an increasing likelihood of a
Geriatric Research, Education and Clinical Center and Clinical Research Unit, VA Puget Sound Health Care System, 1660 South Columbian Way (S-182-GRECC), Seattle, WA 98108, USA; b Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA * VA Puget Sound Health Care System, 1660 South Columbian Way (S-182-GRECC), Seattle, WA 98108. E-mail address: [email protected] Endocrinol Metab Clin N Am 42 (2013) 271–286 http://dx.doi.org/10.1016/j.ecl.2013.02.011 0889-8529/13/$ – see front matter Published by Elsevier Inc.
endo.theclinics.com
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overdiagnosis of male hypogonadism and subsequent inappropriate use of T administration and inadequate response to treatment in older men. Therefore, it is important to use a systematic, holistic clinical approach to the diagnosis and management of older men with clinical findings and low serum T levels that could be caused by androgen deficiency. In older men, the approach should include the following elements: Considering the potential contribution of comorbidities and medications on clinical manifestations and their impact on the diagnosis and management of male hypogonadism Setting patient-specific or patient-centered goals of treatment, including improvements in quality of life and functional status Choosing T formulations based both on pharmacologic considerations and patient preferences Using appropriate monitoring for efficacy and adverse effects during T therapy Before initiating T treatment, endocrinologists should consider the following questions in older men with hypogonadism: Has the diagnosis of hypogonadism been established and, if so, what is the cause of hypogonadism? Should older men with hypogonadism be treated with T replacement therapy? What T formulation should be used for treatment in older men? What monitoring is appropriate in older men treated with T? DIAGNOSIS
The Endocrine Society clinical practice guidelines recommend that the diagnosis of male hypogonadism be made only in men with symptoms and signs of androgen deficiency and consistently low serum T levels (on at least 2 occasions).1 For endocrinologists in a referral practice, it is not uncommon for older patients to be referred with a “presumptive diagnosis” of hypogonadism based on a single low total T level without complete consideration of the clinical manifestations of androgen deficiency and without an evaluation to determine the cause of hypogonadism. Therefore, it is important for an endocrine specialist to ask first whether a diagnosis of hypogonadism has been established and to investigate its cause. Clinical Diagnosis
The clinical manifestations of hypogonadism may be classified into 3 domains: sexual, behavioral, and physical (Box 1). In the European Male Ageing Study, although sexual symptoms were nonspecific (ie, they occurred in men with normal T levels as well as those with low T levels), decreased frequency of sexual thoughts (low libido) and morning erections, and erectile dysfunction (ED) were found to cluster most strongly with low T levels.4 These findings suggested that compared with behavioral and physical manifestations, sexual symptoms were more prominently associated with hypogonadism in older men. The clinical diagnosis of male hypogonadism in adults is challenging because the symptoms and signs of androgen deficiency (including sexual symptoms) are nonspecific and, in older men, age-associated comorbid illness and/or medications may produce some of the same symptoms as androgen deficiency. For example, depression may cause diminished libido and sexual activity, ED, diminished energy and vitality, depressed mood, irritability, difficulty concentrating, and sleep disturbance. Heart disease, type 2 diabetes mellitus, and use of antihypertensive or cardiovascular
Testosterone Administration in Older Men
Box 1 Clinical manifestations of androgen deficiency Sexual Diminished libido and sexual activity Reduced morning erections ED Infertility, small testes Behavioral Diminished energy and vitality Depressed mood, irritability Difficulty concentrating Increased sleep, hot flashes, and sweats Physical Gynecomastia Reduced male hair Decreased muscle bulk, strength, and activity Low bone mineral density [BMD], osteoporosis
medications that are common in older men may cause diminished libido and sexual activity, ED, diminished energy and vitality, and depression. The clinical manifestations of androgen deficiency in older men also may be less prominent than in young hypogonadal men. Young men with classical severe hypogonadism (eg, due to idiopathic hypogonadotropic hypogonadism) demonstrate most if not all of the symptoms and signs of androgen deficiency. In older men with hypogonadism, the manifestations may be less prominent, in large part because androgen deficiency may be less severe. Older men who undergo androgen deprivation therapy to induce medical castration (eg, with gonadotropin-releasing hormone agonist treatment) for prostate cancer, however, develop classical symptoms and signs similar to those demonstrated by young men with severe hypogonadism. Finally, it is important to appreciate that prior T treatment may attenuate some manifestations of androgen deficiency (eg, male body hair) for some time after cessation of therapy and that often prominent manifestations of comorbid illness may mask or take clinical precedence over those of androgen deficiency. Biochemical Diagnosis
If a patient’s clinical presentation suggests androgen deficiency, male hypogonadism is confirmed if serum T levels are consistently low. Biochemical confirmation of male hypogonadism is often difficult, however, because (1) T measurements in various immunoassays are highly variable and may be inaccurate; (2) circulating T levels exhibit circadian and day-to-day biologic variability; (3) clinical conditions that alter sex hormone–binding globulin (SHBG) and, therefore, total T levels occur commonly, particularly in older men; and (4) T levels may be suppressed transiently with illness, nutritional deficiency, and certain medications.1 Because endocrinologists rely on hormone measurements to confirm diagnoses, it is essential that they use the most accurate, precise, and reliable assays available to make clinical decisions. Practitioners should be aware that various T immunoassays
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differ considerably in absolute levels measured and in accuracy. The extreme variability in T assays was highlighted in a recent comparison of T measurements made on the same external quality control sample in different immunoassays that reported T levels that ranged from 160 ng/dL to 508 ng/dL (ie, from the hypogonadal to eugonadal range).9 Therefore, T assay variability may affect an endocrinologist’s ability to confidently confirm the biochemical diagnosis of hypogonadism. In addition to assay variability, serum T levels also exhibit a circadian variability with highest values in the morning.10,11 Circadian variability of T levels is blunted in older men. In one study, however, more than half of men over 65 years who had low T levels in the afternoon were found to have repeatedly normal T levels in the morning,12 supporting guideline recommendations to measure serum T levels in the morning. There is also considerable day-to-day biologic variability in T levels,13 and a single low T level may be normal on repeat testing in up to 30% to 35% of men.14 Therefore, it is important that T levels be measured on at least 2 occasions and be consistently low to confirm the diagnosis of hypogonadism prior to considering T treatment. Compared with younger individuals, older men are more likely to have clinical conditions or take medications that decrease or increase SHBG concentrations (Box 2) and, therefore, decrease or increase total T levels, respectively, without altering free T levels.1 With regard to the diagnosis of hypogonadism, conditions that lower SHBG and total T levels without affecting free T levels, such as obesity, are particularly noteworthy. In men with a high prevalence of obesity and comorbidity, more than 60% of men who had low total T levels were reported to have normal free T levels.15 Total T levels less than 350 ng/dL were not sufficiently sensitive to exclude hypogonadism and, except when levels were less than 150 ng/dL, total T had low specificity for the biochemical diagnosis of hypogonadism (defined as low calculated free T <34 pg/mL). Therefore, if conditions that alter SHBG levels are present or suspected or if total T levels are close to the lower limit of the normal reference range, it is recommended that accurate measurements of free T (eg, calculated free T or free T by equilibrium dialysis) be used to confirm the diagnosis of hypogonadism.1 Finally, T levels may be suppressed transiently during and sometime after an acute illness and/or nutritional deficiency or while taking certain medications (eg, opioids or glucocorticoids).1 Therefore, before T treatment is considered, it is important to Box 2 Causes of alterations in sex hormone–binding globulin Causes of decreased SHBG Moderate obesity, type 2 diabetes mellitus Glucocorticoids, progestins, and androgens Nephrotic syndrome Hypothyroidism Acromegaly Causes of increased SHBG Aging Anticonvulsants and estrogens Liver disease (hepatitis and cirrhosis) Hyperthyroidism HIV disease
Testosterone Administration in Older Men
confirm that low T levels were not measured during these situations and, if they were, to repeat a biochemical evaluation after complete recovery from illness and nutritional deficiency and discontinuation of offending medications. Etiology
When serum T levels are repeated to confirm that they are low, they are usually measured in conjunction with serum gonadotropin, luteinizing hormone and folliclestimulating hormone, measurements to ascertain whether is hypogonadism is (1) primary hypogonadism due to a disorder of the testes (characterized by low T with elevated gonadotropin levels), (2) secondary hypogonadism due to a disorder of the pituitary and/or hypothalamus (characterized by low T with low or inappropriately normal gonadotropin levels), or (3) combined primary and secondary hypogonadism (characterized by low T with mid-normal to slightly high gonadotropin levels).1 Subsequently, it is important to pursue the cause of hypogonadism because, with treatment or discontinuation of a medication, some functional causes of hypogonadism may be reversible and not necessarily require T treatment. From the standpoint of management, it is useful to classify the cause of hypogonadism as having organic or functional origins (Box 3). Organic causes of hypogonadism are due to congenital, developmental, destructive, or pathologic conditions of the hypothalamic-pituitary-testicular axis that are not reversible. Most causes of primary and some causes of secondary hypogonadism are organic. Functional causes of hypogonadism are due to nondestructive suppression of the hypothalamic-pituitarytesticular axis by conditions that are potentially reversible, if they can be treated or if offending medications can be discontinued and, therefore, may not require T treatment. Many causes of secondary and combined primary and secondary hypogonadism are functional. T TREATMENT Considerations Before Staring T Treatment
Once clinical hypogonadism is diagnosed in older men, several issues need to be considered before T treatment is started:
The severity of clinical and biochemical androgen deficiency The contribution of comorbidities and medications to clinical manifestations Treatment of potentially reversible functional causes of hypogonadism Potential clinical benefits and risks of T treatment Patient-centered goals of T treatment Contraindications and precautions to T treatment
Severity of androgen deficiency
The severity of clinical and biochemical hypogonadism affects the decision to start T replacement therapy. Older men with reduced libido, spontaneous erections and energy, ED, and loss of male body hair associated with very low serum total T levels and free T levels and very high gonadotropin levels (primary hypogonadism) are more likely to treated with T than men with isolated ED or poor energy, low end of normal to slightly low total T levels and free T levels, and normal gonadotropin levels. Contribution of comorbidities and medications
In older men, treatment of comorbidities (eg, depression) or discontinuation of medications (eg, antihypertensive medications that might cause fatigue, low libido, and ED)
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Box 3 Organic and functional causes of hypogonadism Organic causes Primary Klinefelter syndrome Cryptorchidism, myotonic dystrophy, and anorchia Chemotherapy, irradiation, and orchidectomy Orchitis Secondary Pituitary tumor Hypopituitarism (tumor, infiltrative, destructive, and surgical) Hemochromatosis Idiopathic hypogonadotropic hypogonadism and Kallmann syndrome Functional causes Secondary Hyperprolactinemia Opioids, central nervous system–active medications Nutritional deficiency and excessive exercise Morbid obesity and sleep apnea Anabolic steroids, progestins and and estrogens Combined primary and secondary Chronic systemic illness Organ failure (renal, liver, heart, and lung) Aging Alcohol abuse Glucocorticoids
that might contribute to clinical manifestations should be considered before starting T treatment. Treatment of functional causes of hypogonadism
Treatment of potentially reversibly functional causes of hypogonadism that might improve or resolve clinical and biochemical androgen deficiency should also be considered before initiating T treatment (eg, discontinuing medications that cause hyperprolactinemia or dopamine agonist treatment of hyperprolactinemia; discontinuing opioids, glucocorticoids, central nervous system–active medications, or progestins; correction of nutritional deficiency; weight reduction program or surgery for morbid obesity; continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BPAP] therapy for obstructive sleep apnea [OSA]; or withdrawal from alcohol dependence). Although these functional causes of hypogonadism are potentially reversible with treatment, in many instances, the etiologic condition cannot be treated or managed in a reasonable time frame (eg, chronic opioid or glucocorticoid treatment of certain comorbid conditions), so that T treatment of these functional causes of hypogonadism should be considered.
Testosterone Administration in Older Men
Potential benefits and risks of T treatment
As with any therapeutic modality, practitioners should consider the potential benefits and risks of T treatment (Box 4),1 the patient-specific goals of T therapy, and presence of contraindications or precautions to T treatment (Table 1)1 prior to initiating T therapy. Unfortunately, long-term controlled trials of the effects of T treatment in older men on clinically meaningful outcomes, such as fractures, frailty, dementia, diabetes mellitus, cardiovascular events, prostate cancer, and mortality, are not available to guide clinical practice. Based on current evidence, the potential benefits of T treatment include improvements in sexual function and activity, energy and vitality, and mood (see Box 4).1,16 Therefore, T treatment has the potential to significantly improve symptoms of androgen deficiency and consequently the quality of life in older hypogonadal men. Although a reduction in the risk of fractures has not been investigated and improvement in physical function has not been demonstrated consistently in previous studies, increase in BMD and muscle strength with T treatment1 has the potential to contribute to fracture reduction by conventional osteoporosis therapies and improve functional status in older men with hypogonadism. The most common short-term risk of T treatment is erythrocytosis or increase in hematocrit17; other risks are uncommon (see Box 4). As a consequence of increased monitoring for prostate cancer (eg, DRE and PSA levels) during T therapy, there is an increased likelihood of detecting an abnormality during monitoring that may result in a prostate biopsy that may be associated with physical discomfort or psychological distress; thus, this is a potential risk of T treatment.17 Patient-centered treatment goals
T treatment should be considered in older men if the potential benefits outweigh the risks of T therapy. Consistent with patient-centered care, it is critical to discuss patient-specific goals of therapy with each patient before initiating T treatment in older men with hypogonadism. A patient’s treatment goals may differ from those of a practitioner. Identification of patient-specific goals and expectations is particularly important for older men with borderline hypogonadism (ie, men with limited clinical manifestations of androgen deficiency [eg, isolated ED] and low total T levels but Box 4 Benefits and risks of testosterone treatment Benefits Increased sexual function and activity Improved energy and vitality Improved mood Increased BMD Increased muscle strength Risks Erythrocytosis Formulation-related adverse effect Increased prostate biopsy (related to monitoring) Gynecomastia (uncommon) Increased OSA (rare)
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Table 1 Contraindications to testosterone treatment Contraindications
Concern
Active or metastatic prostate cancer Estrogen receptor–positive breast cancer
Stimulation of cancer growth Stimulation of cancer growth
Precautions
Concern
Unevaluated prostate nodule/induration or high prostate-specific antigen (PSA)a High hematocrit or poorly controlled hypoxic conditionb Severe, untreated OSA Severe lower urinary tract symptoms (LUTS)c Severe or poorly controlled CHF or edematous conditiond
Increased prostate cancer risk Increased risk of erythrocytosis; cardiovascular riske Increased OSA; cardiovascular riske Increased risk of urinary retention Worsening of CHF or edema from fluid retention
a
PSA >4 ng/mL or >3 ng/mL in men at higher risk for prostate cancer (eg, African American, family history of prostate cancer, or abnormal digital rectal examination [DRE]). b Hematocrit >50% (dependent on regional normal male range); poorly controlled hypoxic conditions, such as severe chronic obstructive pulmonary disease, restrictive lung disease, or OSA. c International Prostate Symptom Score (IPSS) >19. d Edematous conditions, such as congestive heart failure (CHF), hepatic cirrhosis, and nephrotic syndrome. e Increased erythrocytosis and worsening OSA may increase the risk of cardiovascular adverse events.
low-normal to slightly low free T levels). Often there are other causes for a patient’s symptoms and alternative treatments to T therapy (eg, phosphodiesterase type 5 inhibitors for ED) in these borderline cases, and it is reasonable to not treat these men with T. If T treatment is considered, however, a suggested approach is to identify specific treatment goals with a patient, discuss alternative treatment options, lower a patient’s expectation of improvement in symptoms in response to T treatment, treat with T replacement for a limited prescribed period of time (eg, 6 months), and discontinue T treatment if there is no clinical response. Contraindications and precautions to T treatment
Metastatic prostate cancer is initially an androgen-dependent malignancy that regresses with androgen deprivation and may be stimulated by increased T levels, such as occurs initially during luteinizing hormone-releasing hormone agonist therapy without androgen receptor blockade or with T treatment.18–20 Short-term controlled studies of T treatment have not demonstrated an increased incidence of prostate cancer in T treated older men.17 However, sufficiently powered, long-term controlled studies, however, have not been conducted to assess the effect of T treatment on the risk of prostate cancer. Therefore, the risk of prostate cancer, most importantly, of high-grade prostate cancer, during T treatment is at present not known. A recent 6-month randomized, placebo-controlled trial of T treatment in older men with impaired mobility and low T levels who also had a high baseline prevalence of cardiovascular disease was stopped because of an increased number of cardiovascular events in T-treated men,21 particularly in men who achieved high serum T levels.22 In a similar, 6-month, randomized, placebo-controlled trial of T treatment in frail and near-frail older men23 and a recent meta-analysis of T treatment trials,17 no increase in cardiovascular events was reported with T treatment. As with prostate cancer, however, sufficiently powered, long-term controlled trials of T treatment have not been conducted to assess the risk of T on cardiovascular events.
Testosterone Administration in Older Men
The prevalence and incidence of both prostate cancer and cardiovascular disease increase with aging and, as discussed previously, there is uncertainty regarding the effects of T treatment on the natural history of these common, age-associated conditions. Thus, there remain concerns that T treatment in older men may increase the risk of prostate cancer and cardiovascular events. Given this concern and lack of longterm clinical outcome studies of T treatment in older men, it is important to discuss the potential short-term benefits and risks of T therapy and the uncertainty regarding long-term benefits and risks (ie, informed consent, whether formal or informal) when considering T treatment in older men. Because T may stimulate the growth of androgen-dependent malignancy, T treatment is contraindicated in men with active or metastatic prostate cancer (see Table 1).1 Administered T is aromatized endogenously to estradiol and both T and estradiol levels increase during T treatment. Therefore, T treatment is also contraindicated in men who have breast cancer, particularly if it is estrogen receptor positive. According to The Endocrine Society clinical practice guidelines,1 men who are found to have a prostate nodule or induration on DRE or who have a consistently high PSA level (>4 ng/mL or >3 ng/mL in men at higher risk for prostate cancer) should undergo a urologic evaluation before starting T treatment (see Table 1). It is important to repeat serum PSA measurements if they are found high on initial testing because values may normalize spontaneously. The concern in older hypogonadal men is that institution of T treatment may stimulate growth of undiagnosed prostate cancer, although there is no evidence for this. Although uncommon, T treatment may worsen OSA.24–26 Hypoxemia associated with OSA may cause erythrocytosis and cardiovascular morbidity, such as hypertension, edema, and arrhythmias. Therefore, men with untreated, severe OSA should be treated (eg, with CPAP or BPAP) or surgery before starting T therapy. In men with benign prostatic hyperplasia (BPH) who are bothered by persistently severe LUTS, treatment with pharmacologic agents (eg, a-adrenergic receptor antagonist or 5a-reductase inhibitor therapy) or surgery should be considered before starting T therapy.1 T treatment may increase fluid retention, and it should be used with caution in men with severe, uncontrolled edematous conditions, such as CHF, hepatic cirrhosis, or nephrotic syndrome.1 T Formulations
If, after a discussion of benefits and risks of T, both patient and physician decide to start T therapy and there are no contraindications to T, a decision regarding which T formulation to use needs to be made. Several T formulations are available for T replacement therapy (Table 2).1 Intramuscular or transdermal T formulations, however, are used most often for T replacement therapy for hypogonadal men. The choice of a specific T formulation to use is based both on pharmacologic considerations and patient preferences (eg, related to convenience and cost) in older men with hypogonadism. Because of uncertainties regarding the long-term risks of T therapy in hypogonadal men, The Endocrine Society clinical practice guidelines recommend a therapeutic goal in the lower part of the normal range for young men (400–500 ng/dL).1 In older men, the clearance of T is reduced so that the dosage of T required to achieve normal T levels may be less in older than in young hypogonadal men.27 Compared with transdermal T, the usual therapeutic dosages of intramuscular T enanthate or cypionate (200 mg every 2 weeks or 100 mg every week) result in higher average T levels and more frequent erythrocytosis.28 Therefore, it is advisable to initially use a lower dosage (eg, 150 mg every 2 weeks or 75 mg every week) of intramuscular T or to use
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Table 2 Testosterone formulations Formulation
Advantages
Disadvantages
IM T enanathate or cypionate 150–200 mg IM every 2 wk or 75–100 mg IM every week T undecanoated 1000 mg every 10–14 weeks
Long-standing use Effective Reliable Inexpensive (self-injection) Some flexibility in dose Less fluctuation in T levels Convenient
IM injections every 1–2 wk (inconvenience and discomfort) Occasional symptomatic fluctuations in T levels Higher T levels and more erythroctyosis vs transdermal T Large volume (4 mL) injection Not self-injectable Not removable
Transdermal T gel (1%) 50a–100 mg Daily to shoulders, upper arms T gel (1.62%) 40.5b–81 mg Daily to shoulders, upper arms T gel (2%) 40c–70 mg Daily to thighs T solution 60e–120 mg to Underarms T patch (adhesive) 4f–6 mg (1–2 Patches) nightly
Effective Relatively steady T levels (T gels and solution) Circadian T variation (T patch) Ease and convenience (no injections) Less erythroctyosis vs IM injections
Daily application More variable T absorption and lower T levels vs IM T Dose titration, 2 patches often needed Skin irritation/rash (T patch > gel or solution), skin dryness or stickiness; odor; poor adhesion of T patch with excessive hair or sweating Contact transfer of T (gels and solutions) Expensive
Transbuccal T tablet 30 mg bid placed between cheek and gums
Relatively steady T levels
Twice-daily application Only single dosage Gum irritation, poorly tolerated initially Expensive
Implanted pellet Relatively steady T levels over 3–6 mo T pellet 2–6 75-mg Pellets implanted subcutaneously every 3–6 mo
Orald T undecanoate 40–80 mg 2 or 3 Times daily with meals
a
Ease (oral)
May be adjusted down to 25 mg daily. May be adjusted down to 20.25 mg daily. May be adjusted down to 20 mg daily. d Not available in United States. e May be adjusted down to 30 mg. f May be adjusted down to 2 mg patch. b c
Surgical implantation Large number of pellets Extrusion, bleeding, and infection (uncommon) Not removable, if adverse effect of T Infrequent use 2 to 3 Times daily with meals Variable T absorption, lower T levels, and variable clinical response vs other T formulations High dihydrotestosterone levels (unclear clinical consequence)
Testosterone Administration in Older Men
a transdermal T formulation initially in older men. Occasionally, when using transdermal T formulations, it may be difficult achieve adequate T levels and there may be greater variability in T levels so that monitoring of T levels during therapy is critical during transdermal T therapy. Intramuscular T formulations more reliably achieve adequate T levels but cause fluctuating T levels (levels above normal shortly after an injection, which fall to the lower end of the normal range or to low levels before the next injection) that may be associated with noticeable fluctuations in symptoms (eg, libido or energy).1 In contrast, transdermal T results in more stable T levels than intramuscular T formulations. Because subcutaneous T pellets release T over several months and are not removable, they are less desirable for the treatment of older men who might develop prostate cancer while on therapy. Outside the United States, a longer-acting intramuscular formulation, testosterone undecanoate, is available; it is given at a dosage of 1000 mg every 10–14 weeks. This formulation produces less fluctuations in T levels and symptoms, but it requires a 4 mL intramuscular injection that can’t be self-administered and is not removable. Oral androgen formulations (eg, methyltestosterone) available in the United States should not be used for T replacement therapy because they are not effective and have the potential for liver toxicity. Oral T undecanoate, which is available countries outside the United States, produces highly variable T levels and clinical responses. In addition to these pharmacologic considerations, the choice of a specific T formulation may be influenced by patient preferences.1 Intramuscular T injections may be uncomfortable, need to be given every 1 to 2 weeks, and may be inconvenient for older men who are not able to self-inject or do not have a spouse or housemate to administer injections. Therefore, they may be less desirable than transdermal T formulations. Alternatively, some transdermal T formulations may cause skin rash, irritation, dryness, or stickiness or have a disagreeable odor, and T patches may adhere poorly in men with excessive hair or sweating. T gels and solutions have a potential risk of transferring T to a child or female partner with prolonged skin contact. Therefore, these formulations require thorough hand washing after application and covering of the application site with clothing; also, residual T at the application site may be washed off several hours after application. Finally, transdermal T formulations are more expensive than intramuscular T injections. The need for a minor surgical procedure for subcutaneous implantation of T pellets, twice-daily application of buccal T tablets and possible gum irritation, and 2 or 3 times daily administration of T undecanoate with a meals (for adequate T absorption) make these formulations less desirable for older men with hypogonadism. Monitoring Efficacy
Because the evidence base for the efficacy of T treatment is based on short-term studies, the prevalence of prostate cancer and cardiovascular disease increases with aging, and the effect of T therapy on the natural history of these conditions is uncertain, it is important to monitor the efficacy and safety of T treatment shortly after starting T therapy (ie, within the first 6 months, in addition to subsequent regular monitoring during T treatment) (Table 3).1 The efficacy of T treatment is monitored by self-reported improvement of symptoms and measurement of serum T levels, initially at 3 to 6 months after starting T and subsequently on an approximately yearly basis, relative to baseline assessments. It is expected that some sexual and behavioral symptoms of androgen deficiency, such as reduced libido and energy, will improve by 3 months and be maintained by 6 months of T therapy. Physical manifestations of androgen deficiency (such as loss
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Efficacy Monitoring
Frequency
Management
Clinical improvement and maintenance of improvement Self-reported symptoms and physical examination
Baseline, 3–6 mo, then yearly
If no clinical improvement or worsening of symptoms by 6 mo or physical manifestations by 1 y Assess proper administration of and compliance with T treatment Assess contribution of comorbidities and medications Check T level at nadir after IM T or any time after other T formulations, and if levels low, increase T dosage In the absence of these explanations, consider stopping T treatment
Baseline, 3–6 mo, then yearly Serum T level depending on clinical change IM T at midinterval or nadir if worsening symptoms Transdermal T—after 1 wk T gel/solution—anytime T patch—3–12 h after applied
Adjust T dosage to achieve mid-normal to low-normal T level
BMD Dual-energy x-ray absorptiometry
Baseline, then 1–2 y If osteoporosis is present at baseline, calcium, vitamin D and depending on other risks factors conventional osteoporosis treatment (eg, bisphosphonates) for bone loss and fracture
Safety Monitoring
Frequency
Management
Hematocrit
Baseline, 3–6 mo, then yearly
If hematocrit >54%, stop T Check T level at nadir after IM T or any time after other T formulations and, if levels high, decrease T dosage Evaluate for hypoxic conditions, such as OSA and treat appropriately, and consider restarting T treatment at a reduced dosage
LUTS, PSA, and DRE LUTS by IPSS
Baseline, 3–6 mo, then as per standard of care
If IPPSS >19, PSA increase >1.4 in any 12-mo period, or abnormal DRE (new nodule or induration), consider appropriate treatment (eg, a-blocker for LUTS) and/or urologic consultation
Gynecomastia Baseline, 3–6 mo, then yearly Self-reported breast pain, tenderness, or enlargement and physical examination
If new or worsening symptomatic gynecomastia, consider reducing T dosage
Induction or worsening of OSA Daytime somnolence, witnessed apnea, snoring
Baseline, 3–6 mo, then yearly
If new or worsening symptomatic OSA, consider sleep study and institution of CPAP or BPAP therapy or adjustment of CPAP or BPAP, respectively
Formulation-related adverse reaction
Baseline, 3–6 mo, then yearly
If adverse effect, consider switching T formulation
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Table 3 Monitoring during testosterone treatment
Testosterone Administration in Older Men
of body hair, muscle bulk and strength, and BMD) should improve by 6 months and continue to improve over the next year or 2. If no clinical improvement or worsening of symptoms occurs, proper use and compliance with T treatment should be reviewed, worsening of comorbid illness or change in medications that might contribute to worsening of symptoms assessed, and serum T levels measured to determine whether adequate T levels (in midrange to lower end of the normal range) are achieved with the initial dosage regimen of T. Men on intramuscular T injections should be asked whether there is a noticeable worsening of symptoms (eg, decreased libido, energy, or vitality) just before their next injection. If this is the case, serum T measurement should be performed at the time when T levels are at their nadir, and if T levels are below the normal range, shortening the interval between T injections should be considered (eg, from every 2 weeks to every 10 days). Because absorption of T is variable and unpredictable, measurement of T levels is essential in men using transdermal T formulations. After at least 1 of week of treatment, T levels can be measured anytime after application of T gel or solution and 3 to 12 hours after application of a T patch.1 If symptoms of androgen deficiency improve initially but improvement is not sustained or if there is no clinical improvement by 6 months of therapy in the presence of mid-normal T levels and in the absence of problems with T administration, compliance, or change in comorbidities or medications, discontinuation of T treatment should be considered. Because physical manifestations may take longer to improve than sexual or behavioral symptoms of androgen deficiency, the assessment of clinical improvement and decision to continue with T therapy should be made at or after 1 year. Because fracture reduction has not been demonstrated with T treatment, hypogonadal older men with osteoporosis should receive calcium, vitamin D, and, if appropriate, conventional osteoporosis treatment (eg, bisphosphonates).29 T treatment does improve BMD, however, which probably contributes to fracture reduction. Therefore, in older hypogonadal men with osteoporosis, it is reasonable to monitor BMD by dual-energy x-ray absorptiometry scan at baseline and after 1 to 2 years of T therapy.1 Safety
The stimulatory effect of T on hematocrit and, therefore, the risk of significant erythrocytosis on T treatment is greater in older compared with younger men.30 Older men with hypogonadism should have hematocrit monitored initially at 3 to 6 months and then yearly during T therapy.1 If significant erythrocytosis (eg, hematocrit >54%) occurs, T treatment should be discontinued, T levels should be measured, and an evaluation should be performed for conditions that may cause hypoxia (eg, OSA or chronic lung disease) and, therefore, induce erythrocytosis. If T levels are found to be high or if a hypoxic condition is identified and treated appropriately, it is possible to consider restarting T treatment at a lower dosage. Prostate gland growth and development and early advanced prostate cancer are androgen dependent. The incidence of both BPH and prostate cancer increases with age as does the incidence of male hypogonadism that may in some cases require T treatment. The effect of T administration on the natural history of BPH and prostate cancer, however, is not known. In the absence of this knowledge and because of concerns related to the potential risk of T therapy in these common age-associated conditions, The Endocrine Society clinical practice guidelines recommend monitoring for LUTS and prostate cancer.1 These guidelines recommend that older men should have LUTS assessed by self-report or, preferably, a standardized questionnaire, such as the IPSS; PSA level; and DRE at baseline and 3 to 6 months after starting T and then according to the standard of care in the practitioner’s community or as
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recommended by existing guidelines that the practitioner uses. If older men on T therapy develop severe LUTS (IPSS score >19), a PSA level greater than 1.4 ng/mL in any 12-month period, or an abnormal DRE (new nodule or induration), appropriate treatment (eg, a-adrenergic receptor antagonists for LUTS) and/or a urologic consultation should be considered. These recommendations for PSA monitoring are controversial, however, particularly given recent findings that PSA screening results in overdiagnosis of prostate cancer and does not prevent mortality.31,32 Because there is uncertainty related to the effect of T treatment on the natural history and prognosis of prostate cancer, however, monitoring to detect an initial change in PSA from baseline within 3 to 6 months after initiation of T treatment is not equivalent to PSA screening in the general population and is a reasonable and conservative approach for older men on T treatment. At baseline and at each follow-up visit, monitoring for gynecomastia, OSA, and formulation-specific adverse reaction should performed. New or worsening gynecomastia (breast pain, tenderness, and/or enlargement) is uncommon but, if it occurs, a reduction in T dosage should be considered. Induction or worsening of OSA is also uncommon and usually associated with higher-dosage T treatment.24 Older men on T treatment should be asked about new or worsening daytime somnolence (as a result of disrupted sleep associated with frequent episodes of oxygen desaturation due to apnea), witnessed apnea episodes, and excessive, loud snoring. If new, these symptoms should prompt a formal sleep study, and if OSA is documented, institution of CPAP or BPAP therapy should be considered. If a formulation-specific adverse reaction occurs, switching to another T formulation should be considered. REFERENCES
1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95(6):2536–59. 2. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab 2007;92(11):4241–7. 3. Araujo AB, O’Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2004;89(12):5920–6. 4. Wu FC, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med 2010;363(2):123–35. 5. Gray A, Feldman HA, McKinlay JB, et al. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991;73(5):1016–25. 6. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86(2):724–31. 7. Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab 2010;95(4):1810–8. 8. Travison TG, Araujo AB, Kupelian V, et al. The relative contributions of aging, health, and lifestyle factors to serum testosterone decline in men. J Clin Endocrinol Metab 2007;92(2):549–55. 9. Wang C, Catlin DH, Demers LM, et al. Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid
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10.
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chromatography-tandem mass spectrometry. J Clin Endocrinol Metab 2004; 89(2):534–43. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab 1983;56(6): 1278–81. Plymate SR, Tenover JS, Bremner WJ. Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men. J Androl 1989;10(5):366–71. Brambilla DJ, Matsumoto AM, Araujo AB, et al. The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. J Clin Endocrinol Metab 2009;94(3):907–13. Brambilla DJ, O’Donnell AB, Matsumoto AM, et al. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin Endocrinol (Oxf) 2007;67(6):853–62. Swerdloff RS, Wang C, Cunningham G, et al. Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men. J Clin Endocrinol Metab 2000;85(12):4500–10. Anawalt BD, Hotaling JM, Walsh TJ, et al. Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism. J Urol 2012;187(4):1369–73. Bolona ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebocontrolled trials. Mayo Clin Proc 2007;82(1):20–8. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95(6):2560–75. Chrisp P, Sorkin EM. Leuprorelin. A review of its pharmacology and therapeutic use in prostatic disorders. Drugs Aging 1991;1(6):487–509. Fowler JE Jr, Whitmore WF Jr. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 1981;126(3):372–5. Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol 1990;144(6):1479–80. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363(2):109–22. Basaria S, Davda MN, Travison TG, et al. Risk factors associated with cardiovascular events during testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci 2013;68(2):153–60. Srinivas-Shankar U, Roberts SA, Connolly MJ, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebocontrolled study. J Clin Endocrinol Metab 2010;95(2):639–50. Liu PY, Yee B, Wishart SM, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab 2003; 88(8):3605–13. Sandblom RE, Matsumoto AM, Schoene RB, et al. Obstructive sleep apnea syndrome induced by testosterone administration. N Engl J Med 1983;308(9):508–10. Schneider BK, Pickett CK, Zwillich CW, et al. Influence of testosterone on breathing during sleep. J Appl Physiol 1986;61(2):618–23. Coviello AD, Lakshman K, Mazer NA, et al. Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin
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29. 30.
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suppression receiving graded doses of testosterone. J Clin Endocrinol Metab 2006;91(11):4669–75. Dobs AS, Meikle AW, Arver S, et al. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab 1999;84(10):3469–78. Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97(6):1802–22. Coviello AD, Kaplan B, Lakshman KM, et al. Effects of graded doses of testosterone on erythropoiesis in healthy young and older men. J Clin Endocrinol Metab 2008;93(3):914–9. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360(13):1310–9. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360(13): 1320–8.
MD
a,b,
*
KEYWORDS Hypogonadism Aging Diagnosis Testosterone Treatment KEY POINTS In older men, consider the potential contribution of comorbidities and medications on clinical manifestations and their impact on the diagnosis and management of male hypogonadism. The goals of testosterone treatment in older hypogonadal men should be patient-centered and include potential improvements in quality of life and functional status. The choice testosterone formulations in older men is based both on pharmacologic considerations and patient preferences. In older hypogonadal men, appropriate monitoring of efficacy and safety should be performed during testosterone administration.
INTRODUCTION
The only indication for testosterone (T) administration in older men is replacement therapy for male hypogonadism, which is defined as a syndrome consisting of symptoms and signs of androgen deficiency in the presence of consistently low serum T levels.1 Male hypogonadism is common, occurring in 2% to 6% of communitydwelling middle-aged to older men and its prevalence and incidence increases with age.2–4 Compared with young hypogonadal men, the diagnosis and optimal management of male hypogonadism in older men presents greater challenges. Clinical manifestations of androgen deficiency in older adults are nonspecific, and serum T levels decline progressively with increasing age, such that an increasing proportion of men have T levels in the hypogonadal range with age.5,6 Both symptoms and signs of androgen deficiency and low T levels may be caused or modified by comorbid illnesses that occur commonly as men age and by medications that are taken more frequently by older men.7,8 As result, there is an increasing likelihood of a
Geriatric Research, Education and Clinical Center and Clinical Research Unit, VA Puget Sound Health Care System, 1660 South Columbian Way (S-182-GRECC), Seattle, WA 98108, USA; b Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195, USA * VA Puget Sound Health Care System, 1660 South Columbian Way (S-182-GRECC), Seattle, WA 98108. E-mail address: [email protected] Endocrinol Metab Clin N Am 42 (2013) 271–286 http://dx.doi.org/10.1016/j.ecl.2013.02.011 0889-8529/13/$ – see front matter Published by Elsevier Inc.
endo.theclinics.com
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overdiagnosis of male hypogonadism and subsequent inappropriate use of T administration and inadequate response to treatment in older men. Therefore, it is important to use a systematic, holistic clinical approach to the diagnosis and management of older men with clinical findings and low serum T levels that could be caused by androgen deficiency. In older men, the approach should include the following elements: Considering the potential contribution of comorbidities and medications on clinical manifestations and their impact on the diagnosis and management of male hypogonadism Setting patient-specific or patient-centered goals of treatment, including improvements in quality of life and functional status Choosing T formulations based both on pharmacologic considerations and patient preferences Using appropriate monitoring for efficacy and adverse effects during T therapy Before initiating T treatment, endocrinologists should consider the following questions in older men with hypogonadism: Has the diagnosis of hypogonadism been established and, if so, what is the cause of hypogonadism? Should older men with hypogonadism be treated with T replacement therapy? What T formulation should be used for treatment in older men? What monitoring is appropriate in older men treated with T? DIAGNOSIS
The Endocrine Society clinical practice guidelines recommend that the diagnosis of male hypogonadism be made only in men with symptoms and signs of androgen deficiency and consistently low serum T levels (on at least 2 occasions).1 For endocrinologists in a referral practice, it is not uncommon for older patients to be referred with a “presumptive diagnosis” of hypogonadism based on a single low total T level without complete consideration of the clinical manifestations of androgen deficiency and without an evaluation to determine the cause of hypogonadism. Therefore, it is important for an endocrine specialist to ask first whether a diagnosis of hypogonadism has been established and to investigate its cause. Clinical Diagnosis
The clinical manifestations of hypogonadism may be classified into 3 domains: sexual, behavioral, and physical (Box 1). In the European Male Ageing Study, although sexual symptoms were nonspecific (ie, they occurred in men with normal T levels as well as those with low T levels), decreased frequency of sexual thoughts (low libido) and morning erections, and erectile dysfunction (ED) were found to cluster most strongly with low T levels.4 These findings suggested that compared with behavioral and physical manifestations, sexual symptoms were more prominently associated with hypogonadism in older men. The clinical diagnosis of male hypogonadism in adults is challenging because the symptoms and signs of androgen deficiency (including sexual symptoms) are nonspecific and, in older men, age-associated comorbid illness and/or medications may produce some of the same symptoms as androgen deficiency. For example, depression may cause diminished libido and sexual activity, ED, diminished energy and vitality, depressed mood, irritability, difficulty concentrating, and sleep disturbance. Heart disease, type 2 diabetes mellitus, and use of antihypertensive or cardiovascular
Testosterone Administration in Older Men
Box 1 Clinical manifestations of androgen deficiency Sexual Diminished libido and sexual activity Reduced morning erections ED Infertility, small testes Behavioral Diminished energy and vitality Depressed mood, irritability Difficulty concentrating Increased sleep, hot flashes, and sweats Physical Gynecomastia Reduced male hair Decreased muscle bulk, strength, and activity Low bone mineral density [BMD], osteoporosis
medications that are common in older men may cause diminished libido and sexual activity, ED, diminished energy and vitality, and depression. The clinical manifestations of androgen deficiency in older men also may be less prominent than in young hypogonadal men. Young men with classical severe hypogonadism (eg, due to idiopathic hypogonadotropic hypogonadism) demonstrate most if not all of the symptoms and signs of androgen deficiency. In older men with hypogonadism, the manifestations may be less prominent, in large part because androgen deficiency may be less severe. Older men who undergo androgen deprivation therapy to induce medical castration (eg, with gonadotropin-releasing hormone agonist treatment) for prostate cancer, however, develop classical symptoms and signs similar to those demonstrated by young men with severe hypogonadism. Finally, it is important to appreciate that prior T treatment may attenuate some manifestations of androgen deficiency (eg, male body hair) for some time after cessation of therapy and that often prominent manifestations of comorbid illness may mask or take clinical precedence over those of androgen deficiency. Biochemical Diagnosis
If a patient’s clinical presentation suggests androgen deficiency, male hypogonadism is confirmed if serum T levels are consistently low. Biochemical confirmation of male hypogonadism is often difficult, however, because (1) T measurements in various immunoassays are highly variable and may be inaccurate; (2) circulating T levels exhibit circadian and day-to-day biologic variability; (3) clinical conditions that alter sex hormone–binding globulin (SHBG) and, therefore, total T levels occur commonly, particularly in older men; and (4) T levels may be suppressed transiently with illness, nutritional deficiency, and certain medications.1 Because endocrinologists rely on hormone measurements to confirm diagnoses, it is essential that they use the most accurate, precise, and reliable assays available to make clinical decisions. Practitioners should be aware that various T immunoassays
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differ considerably in absolute levels measured and in accuracy. The extreme variability in T assays was highlighted in a recent comparison of T measurements made on the same external quality control sample in different immunoassays that reported T levels that ranged from 160 ng/dL to 508 ng/dL (ie, from the hypogonadal to eugonadal range).9 Therefore, T assay variability may affect an endocrinologist’s ability to confidently confirm the biochemical diagnosis of hypogonadism. In addition to assay variability, serum T levels also exhibit a circadian variability with highest values in the morning.10,11 Circadian variability of T levels is blunted in older men. In one study, however, more than half of men over 65 years who had low T levels in the afternoon were found to have repeatedly normal T levels in the morning,12 supporting guideline recommendations to measure serum T levels in the morning. There is also considerable day-to-day biologic variability in T levels,13 and a single low T level may be normal on repeat testing in up to 30% to 35% of men.14 Therefore, it is important that T levels be measured on at least 2 occasions and be consistently low to confirm the diagnosis of hypogonadism prior to considering T treatment. Compared with younger individuals, older men are more likely to have clinical conditions or take medications that decrease or increase SHBG concentrations (Box 2) and, therefore, decrease or increase total T levels, respectively, without altering free T levels.1 With regard to the diagnosis of hypogonadism, conditions that lower SHBG and total T levels without affecting free T levels, such as obesity, are particularly noteworthy. In men with a high prevalence of obesity and comorbidity, more than 60% of men who had low total T levels were reported to have normal free T levels.15 Total T levels less than 350 ng/dL were not sufficiently sensitive to exclude hypogonadism and, except when levels were less than 150 ng/dL, total T had low specificity for the biochemical diagnosis of hypogonadism (defined as low calculated free T <34 pg/mL). Therefore, if conditions that alter SHBG levels are present or suspected or if total T levels are close to the lower limit of the normal reference range, it is recommended that accurate measurements of free T (eg, calculated free T or free T by equilibrium dialysis) be used to confirm the diagnosis of hypogonadism.1 Finally, T levels may be suppressed transiently during and sometime after an acute illness and/or nutritional deficiency or while taking certain medications (eg, opioids or glucocorticoids).1 Therefore, before T treatment is considered, it is important to Box 2 Causes of alterations in sex hormone–binding globulin Causes of decreased SHBG Moderate obesity, type 2 diabetes mellitus Glucocorticoids, progestins, and androgens Nephrotic syndrome Hypothyroidism Acromegaly Causes of increased SHBG Aging Anticonvulsants and estrogens Liver disease (hepatitis and cirrhosis) Hyperthyroidism HIV disease
Testosterone Administration in Older Men
confirm that low T levels were not measured during these situations and, if they were, to repeat a biochemical evaluation after complete recovery from illness and nutritional deficiency and discontinuation of offending medications. Etiology
When serum T levels are repeated to confirm that they are low, they are usually measured in conjunction with serum gonadotropin, luteinizing hormone and folliclestimulating hormone, measurements to ascertain whether is hypogonadism is (1) primary hypogonadism due to a disorder of the testes (characterized by low T with elevated gonadotropin levels), (2) secondary hypogonadism due to a disorder of the pituitary and/or hypothalamus (characterized by low T with low or inappropriately normal gonadotropin levels), or (3) combined primary and secondary hypogonadism (characterized by low T with mid-normal to slightly high gonadotropin levels).1 Subsequently, it is important to pursue the cause of hypogonadism because, with treatment or discontinuation of a medication, some functional causes of hypogonadism may be reversible and not necessarily require T treatment. From the standpoint of management, it is useful to classify the cause of hypogonadism as having organic or functional origins (Box 3). Organic causes of hypogonadism are due to congenital, developmental, destructive, or pathologic conditions of the hypothalamic-pituitary-testicular axis that are not reversible. Most causes of primary and some causes of secondary hypogonadism are organic. Functional causes of hypogonadism are due to nondestructive suppression of the hypothalamic-pituitarytesticular axis by conditions that are potentially reversible, if they can be treated or if offending medications can be discontinued and, therefore, may not require T treatment. Many causes of secondary and combined primary and secondary hypogonadism are functional. T TREATMENT Considerations Before Staring T Treatment
Once clinical hypogonadism is diagnosed in older men, several issues need to be considered before T treatment is started:
The severity of clinical and biochemical androgen deficiency The contribution of comorbidities and medications to clinical manifestations Treatment of potentially reversible functional causes of hypogonadism Potential clinical benefits and risks of T treatment Patient-centered goals of T treatment Contraindications and precautions to T treatment
Severity of androgen deficiency
The severity of clinical and biochemical hypogonadism affects the decision to start T replacement therapy. Older men with reduced libido, spontaneous erections and energy, ED, and loss of male body hair associated with very low serum total T levels and free T levels and very high gonadotropin levels (primary hypogonadism) are more likely to treated with T than men with isolated ED or poor energy, low end of normal to slightly low total T levels and free T levels, and normal gonadotropin levels. Contribution of comorbidities and medications
In older men, treatment of comorbidities (eg, depression) or discontinuation of medications (eg, antihypertensive medications that might cause fatigue, low libido, and ED)
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Box 3 Organic and functional causes of hypogonadism Organic causes Primary Klinefelter syndrome Cryptorchidism, myotonic dystrophy, and anorchia Chemotherapy, irradiation, and orchidectomy Orchitis Secondary Pituitary tumor Hypopituitarism (tumor, infiltrative, destructive, and surgical) Hemochromatosis Idiopathic hypogonadotropic hypogonadism and Kallmann syndrome Functional causes Secondary Hyperprolactinemia Opioids, central nervous system–active medications Nutritional deficiency and excessive exercise Morbid obesity and sleep apnea Anabolic steroids, progestins and and estrogens Combined primary and secondary Chronic systemic illness Organ failure (renal, liver, heart, and lung) Aging Alcohol abuse Glucocorticoids
that might contribute to clinical manifestations should be considered before starting T treatment. Treatment of functional causes of hypogonadism
Treatment of potentially reversibly functional causes of hypogonadism that might improve or resolve clinical and biochemical androgen deficiency should also be considered before initiating T treatment (eg, discontinuing medications that cause hyperprolactinemia or dopamine agonist treatment of hyperprolactinemia; discontinuing opioids, glucocorticoids, central nervous system–active medications, or progestins; correction of nutritional deficiency; weight reduction program or surgery for morbid obesity; continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BPAP] therapy for obstructive sleep apnea [OSA]; or withdrawal from alcohol dependence). Although these functional causes of hypogonadism are potentially reversible with treatment, in many instances, the etiologic condition cannot be treated or managed in a reasonable time frame (eg, chronic opioid or glucocorticoid treatment of certain comorbid conditions), so that T treatment of these functional causes of hypogonadism should be considered.
Testosterone Administration in Older Men
Potential benefits and risks of T treatment
As with any therapeutic modality, practitioners should consider the potential benefits and risks of T treatment (Box 4),1 the patient-specific goals of T therapy, and presence of contraindications or precautions to T treatment (Table 1)1 prior to initiating T therapy. Unfortunately, long-term controlled trials of the effects of T treatment in older men on clinically meaningful outcomes, such as fractures, frailty, dementia, diabetes mellitus, cardiovascular events, prostate cancer, and mortality, are not available to guide clinical practice. Based on current evidence, the potential benefits of T treatment include improvements in sexual function and activity, energy and vitality, and mood (see Box 4).1,16 Therefore, T treatment has the potential to significantly improve symptoms of androgen deficiency and consequently the quality of life in older hypogonadal men. Although a reduction in the risk of fractures has not been investigated and improvement in physical function has not been demonstrated consistently in previous studies, increase in BMD and muscle strength with T treatment1 has the potential to contribute to fracture reduction by conventional osteoporosis therapies and improve functional status in older men with hypogonadism. The most common short-term risk of T treatment is erythrocytosis or increase in hematocrit17; other risks are uncommon (see Box 4). As a consequence of increased monitoring for prostate cancer (eg, DRE and PSA levels) during T therapy, there is an increased likelihood of detecting an abnormality during monitoring that may result in a prostate biopsy that may be associated with physical discomfort or psychological distress; thus, this is a potential risk of T treatment.17 Patient-centered treatment goals
T treatment should be considered in older men if the potential benefits outweigh the risks of T therapy. Consistent with patient-centered care, it is critical to discuss patient-specific goals of therapy with each patient before initiating T treatment in older men with hypogonadism. A patient’s treatment goals may differ from those of a practitioner. Identification of patient-specific goals and expectations is particularly important for older men with borderline hypogonadism (ie, men with limited clinical manifestations of androgen deficiency [eg, isolated ED] and low total T levels but Box 4 Benefits and risks of testosterone treatment Benefits Increased sexual function and activity Improved energy and vitality Improved mood Increased BMD Increased muscle strength Risks Erythrocytosis Formulation-related adverse effect Increased prostate biopsy (related to monitoring) Gynecomastia (uncommon) Increased OSA (rare)
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Table 1 Contraindications to testosterone treatment Contraindications
Concern
Active or metastatic prostate cancer Estrogen receptor–positive breast cancer
Stimulation of cancer growth Stimulation of cancer growth
Precautions
Concern
Unevaluated prostate nodule/induration or high prostate-specific antigen (PSA)a High hematocrit or poorly controlled hypoxic conditionb Severe, untreated OSA Severe lower urinary tract symptoms (LUTS)c Severe or poorly controlled CHF or edematous conditiond
Increased prostate cancer risk Increased risk of erythrocytosis; cardiovascular riske Increased OSA; cardiovascular riske Increased risk of urinary retention Worsening of CHF or edema from fluid retention
a
PSA >4 ng/mL or >3 ng/mL in men at higher risk for prostate cancer (eg, African American, family history of prostate cancer, or abnormal digital rectal examination [DRE]). b Hematocrit >50% (dependent on regional normal male range); poorly controlled hypoxic conditions, such as severe chronic obstructive pulmonary disease, restrictive lung disease, or OSA. c International Prostate Symptom Score (IPSS) >19. d Edematous conditions, such as congestive heart failure (CHF), hepatic cirrhosis, and nephrotic syndrome. e Increased erythrocytosis and worsening OSA may increase the risk of cardiovascular adverse events.
low-normal to slightly low free T levels). Often there are other causes for a patient’s symptoms and alternative treatments to T therapy (eg, phosphodiesterase type 5 inhibitors for ED) in these borderline cases, and it is reasonable to not treat these men with T. If T treatment is considered, however, a suggested approach is to identify specific treatment goals with a patient, discuss alternative treatment options, lower a patient’s expectation of improvement in symptoms in response to T treatment, treat with T replacement for a limited prescribed period of time (eg, 6 months), and discontinue T treatment if there is no clinical response. Contraindications and precautions to T treatment
Metastatic prostate cancer is initially an androgen-dependent malignancy that regresses with androgen deprivation and may be stimulated by increased T levels, such as occurs initially during luteinizing hormone-releasing hormone agonist therapy without androgen receptor blockade or with T treatment.18–20 Short-term controlled studies of T treatment have not demonstrated an increased incidence of prostate cancer in T treated older men.17 However, sufficiently powered, long-term controlled studies, however, have not been conducted to assess the effect of T treatment on the risk of prostate cancer. Therefore, the risk of prostate cancer, most importantly, of high-grade prostate cancer, during T treatment is at present not known. A recent 6-month randomized, placebo-controlled trial of T treatment in older men with impaired mobility and low T levels who also had a high baseline prevalence of cardiovascular disease was stopped because of an increased number of cardiovascular events in T-treated men,21 particularly in men who achieved high serum T levels.22 In a similar, 6-month, randomized, placebo-controlled trial of T treatment in frail and near-frail older men23 and a recent meta-analysis of T treatment trials,17 no increase in cardiovascular events was reported with T treatment. As with prostate cancer, however, sufficiently powered, long-term controlled trials of T treatment have not been conducted to assess the risk of T on cardiovascular events.
Testosterone Administration in Older Men
The prevalence and incidence of both prostate cancer and cardiovascular disease increase with aging and, as discussed previously, there is uncertainty regarding the effects of T treatment on the natural history of these common, age-associated conditions. Thus, there remain concerns that T treatment in older men may increase the risk of prostate cancer and cardiovascular events. Given this concern and lack of longterm clinical outcome studies of T treatment in older men, it is important to discuss the potential short-term benefits and risks of T therapy and the uncertainty regarding long-term benefits and risks (ie, informed consent, whether formal or informal) when considering T treatment in older men. Because T may stimulate the growth of androgen-dependent malignancy, T treatment is contraindicated in men with active or metastatic prostate cancer (see Table 1).1 Administered T is aromatized endogenously to estradiol and both T and estradiol levels increase during T treatment. Therefore, T treatment is also contraindicated in men who have breast cancer, particularly if it is estrogen receptor positive. According to The Endocrine Society clinical practice guidelines,1 men who are found to have a prostate nodule or induration on DRE or who have a consistently high PSA level (>4 ng/mL or >3 ng/mL in men at higher risk for prostate cancer) should undergo a urologic evaluation before starting T treatment (see Table 1). It is important to repeat serum PSA measurements if they are found high on initial testing because values may normalize spontaneously. The concern in older hypogonadal men is that institution of T treatment may stimulate growth of undiagnosed prostate cancer, although there is no evidence for this. Although uncommon, T treatment may worsen OSA.24–26 Hypoxemia associated with OSA may cause erythrocytosis and cardiovascular morbidity, such as hypertension, edema, and arrhythmias. Therefore, men with untreated, severe OSA should be treated (eg, with CPAP or BPAP) or surgery before starting T therapy. In men with benign prostatic hyperplasia (BPH) who are bothered by persistently severe LUTS, treatment with pharmacologic agents (eg, a-adrenergic receptor antagonist or 5a-reductase inhibitor therapy) or surgery should be considered before starting T therapy.1 T treatment may increase fluid retention, and it should be used with caution in men with severe, uncontrolled edematous conditions, such as CHF, hepatic cirrhosis, or nephrotic syndrome.1 T Formulations
If, after a discussion of benefits and risks of T, both patient and physician decide to start T therapy and there are no contraindications to T, a decision regarding which T formulation to use needs to be made. Several T formulations are available for T replacement therapy (Table 2).1 Intramuscular or transdermal T formulations, however, are used most often for T replacement therapy for hypogonadal men. The choice of a specific T formulation to use is based both on pharmacologic considerations and patient preferences (eg, related to convenience and cost) in older men with hypogonadism. Because of uncertainties regarding the long-term risks of T therapy in hypogonadal men, The Endocrine Society clinical practice guidelines recommend a therapeutic goal in the lower part of the normal range for young men (400–500 ng/dL).1 In older men, the clearance of T is reduced so that the dosage of T required to achieve normal T levels may be less in older than in young hypogonadal men.27 Compared with transdermal T, the usual therapeutic dosages of intramuscular T enanthate or cypionate (200 mg every 2 weeks or 100 mg every week) result in higher average T levels and more frequent erythrocytosis.28 Therefore, it is advisable to initially use a lower dosage (eg, 150 mg every 2 weeks or 75 mg every week) of intramuscular T or to use
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Table 2 Testosterone formulations Formulation
Advantages
Disadvantages
IM T enanathate or cypionate 150–200 mg IM every 2 wk or 75–100 mg IM every week T undecanoated 1000 mg every 10–14 weeks
Long-standing use Effective Reliable Inexpensive (self-injection) Some flexibility in dose Less fluctuation in T levels Convenient
IM injections every 1–2 wk (inconvenience and discomfort) Occasional symptomatic fluctuations in T levels Higher T levels and more erythroctyosis vs transdermal T Large volume (4 mL) injection Not self-injectable Not removable
Transdermal T gel (1%) 50a–100 mg Daily to shoulders, upper arms T gel (1.62%) 40.5b–81 mg Daily to shoulders, upper arms T gel (2%) 40c–70 mg Daily to thighs T solution 60e–120 mg to Underarms T patch (adhesive) 4f–6 mg (1–2 Patches) nightly
Effective Relatively steady T levels (T gels and solution) Circadian T variation (T patch) Ease and convenience (no injections) Less erythroctyosis vs IM injections
Daily application More variable T absorption and lower T levels vs IM T Dose titration, 2 patches often needed Skin irritation/rash (T patch > gel or solution), skin dryness or stickiness; odor; poor adhesion of T patch with excessive hair or sweating Contact transfer of T (gels and solutions) Expensive
Transbuccal T tablet 30 mg bid placed between cheek and gums
Relatively steady T levels
Twice-daily application Only single dosage Gum irritation, poorly tolerated initially Expensive
Implanted pellet Relatively steady T levels over 3–6 mo T pellet 2–6 75-mg Pellets implanted subcutaneously every 3–6 mo
Orald T undecanoate 40–80 mg 2 or 3 Times daily with meals
a
Ease (oral)
May be adjusted down to 25 mg daily. May be adjusted down to 20.25 mg daily. May be adjusted down to 20 mg daily. d Not available in United States. e May be adjusted down to 30 mg. f May be adjusted down to 2 mg patch. b c
Surgical implantation Large number of pellets Extrusion, bleeding, and infection (uncommon) Not removable, if adverse effect of T Infrequent use 2 to 3 Times daily with meals Variable T absorption, lower T levels, and variable clinical response vs other T formulations High dihydrotestosterone levels (unclear clinical consequence)
Testosterone Administration in Older Men
a transdermal T formulation initially in older men. Occasionally, when using transdermal T formulations, it may be difficult achieve adequate T levels and there may be greater variability in T levels so that monitoring of T levels during therapy is critical during transdermal T therapy. Intramuscular T formulations more reliably achieve adequate T levels but cause fluctuating T levels (levels above normal shortly after an injection, which fall to the lower end of the normal range or to low levels before the next injection) that may be associated with noticeable fluctuations in symptoms (eg, libido or energy).1 In contrast, transdermal T results in more stable T levels than intramuscular T formulations. Because subcutaneous T pellets release T over several months and are not removable, they are less desirable for the treatment of older men who might develop prostate cancer while on therapy. Outside the United States, a longer-acting intramuscular formulation, testosterone undecanoate, is available; it is given at a dosage of 1000 mg every 10–14 weeks. This formulation produces less fluctuations in T levels and symptoms, but it requires a 4 mL intramuscular injection that can’t be self-administered and is not removable. Oral androgen formulations (eg, methyltestosterone) available in the United States should not be used for T replacement therapy because they are not effective and have the potential for liver toxicity. Oral T undecanoate, which is available countries outside the United States, produces highly variable T levels and clinical responses. In addition to these pharmacologic considerations, the choice of a specific T formulation may be influenced by patient preferences.1 Intramuscular T injections may be uncomfortable, need to be given every 1 to 2 weeks, and may be inconvenient for older men who are not able to self-inject or do not have a spouse or housemate to administer injections. Therefore, they may be less desirable than transdermal T formulations. Alternatively, some transdermal T formulations may cause skin rash, irritation, dryness, or stickiness or have a disagreeable odor, and T patches may adhere poorly in men with excessive hair or sweating. T gels and solutions have a potential risk of transferring T to a child or female partner with prolonged skin contact. Therefore, these formulations require thorough hand washing after application and covering of the application site with clothing; also, residual T at the application site may be washed off several hours after application. Finally, transdermal T formulations are more expensive than intramuscular T injections. The need for a minor surgical procedure for subcutaneous implantation of T pellets, twice-daily application of buccal T tablets and possible gum irritation, and 2 or 3 times daily administration of T undecanoate with a meals (for adequate T absorption) make these formulations less desirable for older men with hypogonadism. Monitoring Efficacy
Because the evidence base for the efficacy of T treatment is based on short-term studies, the prevalence of prostate cancer and cardiovascular disease increases with aging, and the effect of T therapy on the natural history of these conditions is uncertain, it is important to monitor the efficacy and safety of T treatment shortly after starting T therapy (ie, within the first 6 months, in addition to subsequent regular monitoring during T treatment) (Table 3).1 The efficacy of T treatment is monitored by self-reported improvement of symptoms and measurement of serum T levels, initially at 3 to 6 months after starting T and subsequently on an approximately yearly basis, relative to baseline assessments. It is expected that some sexual and behavioral symptoms of androgen deficiency, such as reduced libido and energy, will improve by 3 months and be maintained by 6 months of T therapy. Physical manifestations of androgen deficiency (such as loss
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Efficacy Monitoring
Frequency
Management
Clinical improvement and maintenance of improvement Self-reported symptoms and physical examination
Baseline, 3–6 mo, then yearly
If no clinical improvement or worsening of symptoms by 6 mo or physical manifestations by 1 y Assess proper administration of and compliance with T treatment Assess contribution of comorbidities and medications Check T level at nadir after IM T or any time after other T formulations, and if levels low, increase T dosage In the absence of these explanations, consider stopping T treatment
Baseline, 3–6 mo, then yearly Serum T level depending on clinical change IM T at midinterval or nadir if worsening symptoms Transdermal T—after 1 wk T gel/solution—anytime T patch—3–12 h after applied
Adjust T dosage to achieve mid-normal to low-normal T level
BMD Dual-energy x-ray absorptiometry
Baseline, then 1–2 y If osteoporosis is present at baseline, calcium, vitamin D and depending on other risks factors conventional osteoporosis treatment (eg, bisphosphonates) for bone loss and fracture
Safety Monitoring
Frequency
Management
Hematocrit
Baseline, 3–6 mo, then yearly
If hematocrit >54%, stop T Check T level at nadir after IM T or any time after other T formulations and, if levels high, decrease T dosage Evaluate for hypoxic conditions, such as OSA and treat appropriately, and consider restarting T treatment at a reduced dosage
LUTS, PSA, and DRE LUTS by IPSS
Baseline, 3–6 mo, then as per standard of care
If IPPSS >19, PSA increase >1.4 in any 12-mo period, or abnormal DRE (new nodule or induration), consider appropriate treatment (eg, a-blocker for LUTS) and/or urologic consultation
Gynecomastia Baseline, 3–6 mo, then yearly Self-reported breast pain, tenderness, or enlargement and physical examination
If new or worsening symptomatic gynecomastia, consider reducing T dosage
Induction or worsening of OSA Daytime somnolence, witnessed apnea, snoring
Baseline, 3–6 mo, then yearly
If new or worsening symptomatic OSA, consider sleep study and institution of CPAP or BPAP therapy or adjustment of CPAP or BPAP, respectively
Formulation-related adverse reaction
Baseline, 3–6 mo, then yearly
If adverse effect, consider switching T formulation
Matsumoto
Table 3 Monitoring during testosterone treatment
Testosterone Administration in Older Men
of body hair, muscle bulk and strength, and BMD) should improve by 6 months and continue to improve over the next year or 2. If no clinical improvement or worsening of symptoms occurs, proper use and compliance with T treatment should be reviewed, worsening of comorbid illness or change in medications that might contribute to worsening of symptoms assessed, and serum T levels measured to determine whether adequate T levels (in midrange to lower end of the normal range) are achieved with the initial dosage regimen of T. Men on intramuscular T injections should be asked whether there is a noticeable worsening of symptoms (eg, decreased libido, energy, or vitality) just before their next injection. If this is the case, serum T measurement should be performed at the time when T levels are at their nadir, and if T levels are below the normal range, shortening the interval between T injections should be considered (eg, from every 2 weeks to every 10 days). Because absorption of T is variable and unpredictable, measurement of T levels is essential in men using transdermal T formulations. After at least 1 of week of treatment, T levels can be measured anytime after application of T gel or solution and 3 to 12 hours after application of a T patch.1 If symptoms of androgen deficiency improve initially but improvement is not sustained or if there is no clinical improvement by 6 months of therapy in the presence of mid-normal T levels and in the absence of problems with T administration, compliance, or change in comorbidities or medications, discontinuation of T treatment should be considered. Because physical manifestations may take longer to improve than sexual or behavioral symptoms of androgen deficiency, the assessment of clinical improvement and decision to continue with T therapy should be made at or after 1 year. Because fracture reduction has not been demonstrated with T treatment, hypogonadal older men with osteoporosis should receive calcium, vitamin D, and, if appropriate, conventional osteoporosis treatment (eg, bisphosphonates).29 T treatment does improve BMD, however, which probably contributes to fracture reduction. Therefore, in older hypogonadal men with osteoporosis, it is reasonable to monitor BMD by dual-energy x-ray absorptiometry scan at baseline and after 1 to 2 years of T therapy.1 Safety
The stimulatory effect of T on hematocrit and, therefore, the risk of significant erythrocytosis on T treatment is greater in older compared with younger men.30 Older men with hypogonadism should have hematocrit monitored initially at 3 to 6 months and then yearly during T therapy.1 If significant erythrocytosis (eg, hematocrit >54%) occurs, T treatment should be discontinued, T levels should be measured, and an evaluation should be performed for conditions that may cause hypoxia (eg, OSA or chronic lung disease) and, therefore, induce erythrocytosis. If T levels are found to be high or if a hypoxic condition is identified and treated appropriately, it is possible to consider restarting T treatment at a lower dosage. Prostate gland growth and development and early advanced prostate cancer are androgen dependent. The incidence of both BPH and prostate cancer increases with age as does the incidence of male hypogonadism that may in some cases require T treatment. The effect of T administration on the natural history of BPH and prostate cancer, however, is not known. In the absence of this knowledge and because of concerns related to the potential risk of T therapy in these common age-associated conditions, The Endocrine Society clinical practice guidelines recommend monitoring for LUTS and prostate cancer.1 These guidelines recommend that older men should have LUTS assessed by self-report or, preferably, a standardized questionnaire, such as the IPSS; PSA level; and DRE at baseline and 3 to 6 months after starting T and then according to the standard of care in the practitioner’s community or as
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recommended by existing guidelines that the practitioner uses. If older men on T therapy develop severe LUTS (IPSS score >19), a PSA level greater than 1.4 ng/mL in any 12-month period, or an abnormal DRE (new nodule or induration), appropriate treatment (eg, a-adrenergic receptor antagonists for LUTS) and/or a urologic consultation should be considered. These recommendations for PSA monitoring are controversial, however, particularly given recent findings that PSA screening results in overdiagnosis of prostate cancer and does not prevent mortality.31,32 Because there is uncertainty related to the effect of T treatment on the natural history and prognosis of prostate cancer, however, monitoring to detect an initial change in PSA from baseline within 3 to 6 months after initiation of T treatment is not equivalent to PSA screening in the general population and is a reasonable and conservative approach for older men on T treatment. At baseline and at each follow-up visit, monitoring for gynecomastia, OSA, and formulation-specific adverse reaction should performed. New or worsening gynecomastia (breast pain, tenderness, and/or enlargement) is uncommon but, if it occurs, a reduction in T dosage should be considered. Induction or worsening of OSA is also uncommon and usually associated with higher-dosage T treatment.24 Older men on T treatment should be asked about new or worsening daytime somnolence (as a result of disrupted sleep associated with frequent episodes of oxygen desaturation due to apnea), witnessed apnea episodes, and excessive, loud snoring. If new, these symptoms should prompt a formal sleep study, and if OSA is documented, institution of CPAP or BPAP therapy should be considered. If a formulation-specific adverse reaction occurs, switching to another T formulation should be considered. REFERENCES
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