Uncovering the problem, evaluating the role of therapy

John H. MacIndoe, MD



CME learning objectives

To review the prevalence and causes of hypogonadism in men
To become familiar with screening strategies for hypogonadism and the criteria needed to establish the diagnosis
To understand the effects of aging on gonadal function in men
The author discloses no financial interests in this article and no unlabeled uses of any product mentioned.



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This is the third of three articles on men's health.

Preview: In addition to its relatively uncommon congenital causes, testosterone deficiency in men occurs in a diverse range of clinical conditions. Even healthy men are now known to begin experiencing progressive yet subtle declines in testosterone secretion after age 30. Diagnosis can be challenging, and testosterone replacement therapy does not alleviate all symptoms in all men. Nevertheless, some men can get relief with intramuscular long-acting testosterone esters, transdermal testosterone patches, or transdermal testosterone gel. MacIndoe JH. The challenges of testosterone deficiency: uncovering the problem, evaluating the role of therapy. Postgrad Med 2003;114(4):51-62



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Like any other endocrine deficiency state, a subnormal testosterone level causes metabolic changes that produce both short-term and long-term consequences (table 1). Until recently, it was generally held that testosterone deficiency was a relatively uncommon problem. It was thought to be limited to men with congenital causes of hypogonadism, such as Klinefelter's syndrome or Kallmann's syndrome, or to sporadic instances of testicular failure resulting from large pituitary tumors or gonadal injury. However, it is now clear that marked testosterone deficiency also may develop in a variety of other clinical situations, including HIV infection, morbid obesity, severe illness, and psychologic stress, or as a side effect of some medications (eg, glucocorticoids, certain chemotherapy agents). At least one report (1) indicated that moderate head trauma may be a common but previously unrecognized cause of isolated pituitary gonadotropin failure.

Table 1. Some reported effects of testosterone deficiency in men
Loss of bone, increased fracture risk
Loss of skeletal muscle and strength
Increased fat mass
Reduced libido
Reduced erectile function
Infertility
Increased insulin resistance and risk of diabetes
Reduced sense of well-being
Fatigue
Reduced stamina
Depression
Reduced cognition


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In addition, it is now well established that testosterone secretion begins to decline even in healthy men after age 30. This phenomenon has been popularly referred to as male menopause or andropause. The extent to which this decrease in biologically active testosterone results in reduced physiologic function remains ill-defined and likely varies among men. Nevertheless, most experts agree that in symptomatic patients, serum testosterone values that fall below those seen in healthy young men are consistent with hypogonadism.

To clarify the current level of understanding of andropause and its proper diagnosis and management, the Endocrine Society recently brought together a group of experienced physicians to form the Andropause Consensus Panel. The group met in 2000 and 2001 to develop consensus-based guidelines in these areas. Summaries of its conclusions are available through the Endocrine Society (2,3). Another recent andropause review (4) is available through Massachusetts General Hospital.

Diagnosis
Detection of hypogonadism in men is often challenging. Although the clinical signs are readily identified in men who have not undergone puberty, they are far less apparent in men who have lost testicular function after reaching sexual maturity. This is largely because many testosterone-dependent physical features, such as muscle mass, beard, and genital development, are maintained long after the onset of testicular failure. Thus, the currently accepted criteria are both the presence of hypogonadal symptoms and laboratory evidence of a subnormal serum testosterone level.

Uncovering the symptoms
The most common symptoms of testosterone deficiency in men (eg, loss of libido, sexual dysfunction, fatigue, loss of stamina, depressed mood) are vague and not specific for hypogonadism. Furthermore, men as a group interact with the healthcare system far less often than women, and when they do visit the physician's office, they often do not volunteer such complaints unless directly questioned about them.

Physicians can minimize the chance of missing these complaints by routinely asking about libido, sexual function, and stamina in their systems assessment. An alternative is to use a simple questionnaire that patients can fill out in the waiting room.

One instrument, the Androgen Deficiency in Aging Males (ADAM) questionnaire (5), has been developed and validated by a group of Canadian physicians (see box at the end of this article). The questionnaire has a sensitivity of 88% for detecting hypogonadism but a specificity of only 60% because of a significant overlap in similar response patterns from eugonadal men with depression. Interestingly, a more recent report suggests that testosterone may be an effective treatment for major depressive disorder in some eugonadal middle-aged men, which raises further questions about the relationship between testosterone and mood (6).

Laboratory confirmation
Confirmation of hypogonadism requires the demonstration of a subnormal level of circulating testosterone. The next step is to identify the source of the problem as either the testis itself (primary hypogonadism) or the hypothalamic-pituitary complex (secondary, or central, hypogonadism).

Because young and middle-aged men exhibit higher testosterone secretion in the morning than in the evening, total testosterone values are evaluated in the morning on at least two different days. Laboratory values consistently below the lower limit of normal (usually 200 ng/dL [6.9 nmol/L]) are considered confirmatory. However, a number of men who have true hypogonadism have total testosterone values in the lower end of the normal range.

Total testosterone values measure three different circulating forms of the hormone, all in equilibrium. About 40% of circulating testosterone is tightly bound to sex hormone-binding globulin. A second form, which is totally unbound, or free, represents about 2% of total testosterone. The remaining fraction is loosely bound to albumin and, like free testosterone, is thought to be available for biologic activity. Both free and albumin-bound testosterone can be measured together and expressed as the level of bioavailable testosterone, or free testosterone can be measured separately.

Laboratory confirmation becomes an important issue when clinical situations arise that are associated with abnormal sex hormone-binding globulin production. The most common situations involve the presence of excess estrogen, a potent stimulator of hepatic sex hormone-binding globulin synthesis, and include both morbid obesity and normal aging. As excess estrogen increases the circulating levels of sex hormone-binding globulin, the newly formed protein binds up free and loosely bound testosterone, which leads sequentially to a decline in bioavailable testosterone, an increase in secretion of luteinizing hormone, and a rise in testosterone production to restore normal bioavailable testosterone levels.

In patients with normal gonadal function, this sequence of events raises the total testosterone level. However, in patients who have inadequate testosterone production, the total testosterone value remains largely unchanged but with a disproportionate level of tightly bound testosterone and a low level of bioavailable testosterone. As it turns out, most cases of hypogonadism in men result from inadequate ability of the hypothalamic-pituitary axis to secrete luteinizing hormone (ie, secondary, or central, hypogonadism). Consequently, symptomatic patients may have normal levels of total testosterone and luteinizing hormone, suggesting that gonadal function is normal. Further testing of free testosterone or bioavailable testosterone in such patients is required to identify the deficiency.

Finally, it is clear that testosterone secretion declines with age. This decline is commonly intensified by illness. Using longitudinal cross-sectional data from the Massachusetts Male Aging Study, Feldman and associates (7) recently reported that the total testosterone level drops by 0.8% per year in men aged 40 to 70 years and that free testosterone and bioavailable testosterone values decline by about 2% annually over the same period. However, data on the same subjects over time revealed an even more pronounced annual decline in total testosterone (1.6%) and free testosterone or bioavailable testosterone (2% to 3%) (7). Most experts agree that in symptomatic patients, serum levels of free testosterone or bioavailable testosterone that fall below those seen in healthy young men are consistent with a diagnosis of hypogonadism.

Further workup
Having confirmed the presence of testosterone deficiency, the next step is to determine the general location of the problem. If most cases of adult hypogonadism resulted from a defect in the testis, pituitary luteinizing hormone levels would be a sensitive indicator of early hypotestosteronemia. Certainly this type of response is true of hypothyroid cases in which thyrotropin values rise long before thyroxine levels drop below normal. However, the decreases in testosterone observed in most hypogonadal men are the result of inadequate pituitary luteinizing hormone secretion. Because current serum assays are unable to consistently distinguish between normal and subnormal pituitary secretion, luteinizing hormone values even in severely hypogonadal men may be reported to be within the normal laboratory range.

As mentioned previously, the most common cause of reduced testosterone secretion in otherwise healthy men is aging, and at least in men younger than 70 years, this seems to result from a blunted luteinizing hormone response to subnormal serum testosterone levels. However, because it is uncommon for total testosterone values to decrease below 150 ng/dL (5.2 nmol/L) from andropause alone, total testosterone values below this level that are associated with normal or low luteinizing hormone levels may reflect more serious underlying problems in the hypothalamic-pituitary axis. Thus, it is generally recommended that such patients be further evaluated with magnetic resonance imaging (MRI) of the head, with thin cuts through the sella.

In summary, a clinical diagnosis of testosterone deficiency requires the presence of appropriate symptoms and subnormal serum testosterone values confirmed by either a consistent morning total testosterone value below 200 ng/dL (6.9 nmol/L) or a free testosterone or bioavailable testosterone value below the normal range for a 40-year-old man. (The latter normal range varies by laboratory.) Most hypogonadal men have a low or normal luteinizing hormone value, signifying a pituitary source for the deficiency. If such patients have total testosterone values below 150 ng/dL, they should be further evaluated with an MRI of the head to rule out a pituitary or hypothalamic lesion. Patients with less severely depressed total testosterone levels should be considered for testosterone replacement therapy without further workup.

Treatment
Currently, there is little evidence that testosterone deficiency directly affects mortality in men. Nevertheless, the potentially significant reduction in quality of life (see table 1) supports the need to consider testosterone replacement in selected patients. Safe and effective testosterone replacement therapy can be provided through intramuscular long-acting testosterone esters, transdermal testosterone patches, or transdermal testosterone gel. Use of oral 17-alpha alkylated androgens should be avoided because of the consistently deleterious effects of these preparations on low-density and high-density lipoprotein cholesterol levels and, less commonly, on hepatic function. Sublingual or buccal preparations avoid these problems but require frequent use throughout the day to maintain therapeutically effective levels of circulating testosterone. Subcutaneous testosterone pellets last for several months per application but are not widely used in the United States.

Intramuscular testosterone esters (cypionate [Depo-Testosterone] or enanthate [Delatestryl]), the least expensive option for testosterone replacement therapy, are initiated at doses of 200 mg every 14 days or 100 mg every week. Thereafter, the dose or frequency of injections can be adjusted so that the total testosterone value immediately preceding the next injection falls within the low-normal to mid-normal range. One potential disadvantage of this regimen is that blood testosterone levels often rise to values well above 1,000 ng/dL (34.7 nmol/L) during the first few days following injection and then fall over time until the next dose. The resulting cyclic fluctuations in serum testosterone levels have been associated with mood swings in some men. Furthermore, the supraphysiologic testosterone values attained early after each injection have been linked to a greater frequency of testosterone-related side effects than occur with other testosterone replacement regimens.

Nonscrotal transdermal testosterone patches (Androderm, Testoderm TTS) are applied daily and are available in a 2.5-mg (Androderm) and a 5-mg (Androderm and Testoderm TTS) dose. Blood testosterone levels rise to peak values within 4 to 6 hours after application, then decrease slightly to remain within the physiologic range over the next 18 to 20 hours. Applying a patch after showering at night can reproduce diurnal testosterone levels similar to those seen in younger men, in whom morning values are somewhat higher than evening ones. The most common side effect reported is skin irritation. Its frequency seems to increase with age in men over age 50. It often can be prevented or reduced by rubbing triamcinolone cream (Aristocort, Atolone, Kenacort) into the skin before application of the patch.

Another transdermal delivery system is testosterone gel (AndroGel, Testim) that is applied to nonscrotal skin daily. These preparations are generally available in a 5-mg dose, and serum testosterone can be monitored 2 to 4 weeks after starting or changing a dose.

Sexual dysfunction resulting from testosterone deficiency appears to resolve as testosterone concentrations rise into the lower half of the normal range, but positive effects on bone and muscle may require higher circulating levels. Therefore, serum total testosterone should be monitored monthly during the initiation of transdermal testosterone replacement therapy and the dosage adjusted upward until testosterone levels above 500 ng/dL (17.4 nmol/L) are achieved (3).

Transdermal preparations are generally more convenient than other preparations for the patient to use. When dosed properly, they also produce more physiologic testosterone blood levels and cause fewer side effects than injectable testosterone esters. However, these advantages come at a significant cost: monthly treatment is about $10 for injections but well above $100 for either transdermal regimen. Because of cost and the observation that some men do not appear to respond to testosterone replacement therapy, I initiate therapy with testosterone ester injections whenever possible. Once symptomatic improvement has been verified, this delivery method can be continued or switched to a transdermal one.

Side effects
Absolute contraindications for testosterone replacement therapy include a history of breast cancer or prostate cancer or a hematocrit above 55%. Relative contraindications include a hematocrit above 52%, severe obstructive sleep apnea, severe congestive heart failure, or severe urinary obstructive symptoms due to benign prostatic hyperplasia (BPH) (3).

Lipid effects from intramuscular or transdermal testosterone replacement therapy have been relatively minor and inconsistent between studies (8). In contrast, both forms of treatment have been observed to stimulate red blood cell production to the point of frank polycythemia in some patients (9,10). Several reports suggest that these responses parallel the height of the peak serum testosterone concentrations achieved with each testosterone replacement therapy regimen, because they are most commonly seen with the intramuscular testosterone esters (3,11). Elderly men and cigarette smokers of any age are most likely to experience significant hemoglobin changes.

Testosterone replacement therapy also has been infrequently linked to fluid retention and hypertension. These effects generally occur within the first 1 to 3 months of therapy and appear to be more common with intramuscular testosterone.

The prostate gland is a classic androgen target tissue, and concerns have been raised about the possible impact of testosterone replacement therapy on subsequent development of BPH or prostate cancer, or both. Certainly, a history of prostate cancer is an absolute contraindication for testosterone replacement therapy. Prospective trials have not demonstrated deleterious effects of testosterone replacement therapy on either potential complication (3). However, these trials cover fewer than 5 years of follow-up, and prostate diseases are thought to evolve over two or more decades. A true assessment of the potential risks of prolonged testosterone replacement therapy will require longer prospective studies. Because of this uncertainty, a baseline prostate-specific antigen (PSA) test and digital rectal examination should be performed in all candidates for testosterone replacement therapy. A urologist should evaluate patients with an elevated PSA level before testosterone replacement is begun.

Appropriate monitoring of patients receiving testosterone replacement therapy includes a digital rectal examination and the measurement of PSA in men over age 40, a blood pressure reading, and a hematocrit at 3 and 6 months after initiating treatment and annually thereafter. Should abnormal increases in any of these parameters be noted, testosterone replacement therapy should be discontinued and the patient observed to assure a return to normal. Patients who experience a PSA increase greater than 1.5 ng/mL per year, an average increase of greater than 0.75 ng/mL per year over 2 years, or a PSA level greater than 4.0 ng/mL should be evaluated by a urologist.

Although the utility of the digital rectal examination and PSA monitoring for routine prostate screening is being questioned, the use of at least the PSA test in this setting seems justified until more complete data are available concerning the impact of testosterone replacement therapy on prostate health.

Assessing response
Several well-done trials have demonstrated clearly beneficial effects of testosterone replacement therapy on muscle mass, strength, body composition, sexual function, libido, and skeletal mass in men with severe hypogonadism (12,13). However, there are far fewer data regarding patients with more subtle testosterone deficiency. Symptoms of reduced libido and sexual dysfunction that result from hypogonadism should respond to testosterone replacement therapy within a few weeks, whereas strength and energy complaints may take several months to improve. Interestingly, in my experience, a number of patients with well-documented testosterone deficiency do not experience symptomatic improvement despite seemingly adequate replacement therapy.

Because most measurements of testosterone-related physical changes are difficult and imprecise in an office setting and because such changes cannot currently be reliably correlated with overall changes in health status, it is my opinion that testosterone replacement therapy should be considered primarily as a means of improving quality of life through the reduction or elimination of hypogonadal symptoms. At least one study (14) has investigated the design of a quality-of-life survey for this purpose. For this reason and because the long-term risks and benefits in otherwise asymptomatic hypogonadal men remain unknown, I discontinue testosterone replacement therapy after 3 months in patients who experience no symptomatic benefit.

Conclusion
Clear evidence supporting the existence of andropause has not been lost on the public. At the same time, the popular media and, in some instances, the pharmaceutical industry have encouraged the perception that testosterone deficiency may be responsible for the decline in vitality noted by many men who are middle-aged or older. As a result, physicians are receiving more requests for testosterone replacement therapy.

Although this article provides a rational guide to the diagnosis and management of testosterone deficiency, it cannot provide an accurate estimate of the relative benefits and risks of testosterone replacement therapy for an individual patient. The benefits reported have often been based on trials involving small groups of patients for relatively short periods. The National Institute on Aging (15) has clearly outlined these issues and has made a strong argument for large, randomized, prospective, phase 3 trials to provide data about the risks and benefits of testosterone therapy in men who are middle-aged or older.

This risk-benefit uncertainty has created an increasingly vocal disagreement within the medical community about the wisdom of prescribing testosterone replacement therapy. One camp contends that the benefits of testosterone replacement therapy, especially in elderly men, remain unproved and that the potential risk of prostate cancer, although similarly unproved, is not worth taking. The second group is of the opinion that the benefits in symptomatic patients appear to outweigh the risks. This disagreement is outlined in more detail in the December 2002 issue of the Canadian Journal of Urology, in which two articles (16,17) express opposing views on whether urologists should take an active role in the diagnosis and treatment of hypogonadism in the aging male.

Regardless of our individual opinions as physicians, each of us should strongly consider that, whenever possible, the final medical decision maker should be the well-informed patient. Our primary role as physicians should be to provide patients with the best and most balanced information at hand.

Finally, I believe that many chronically ill patients may have undiagnosed but overt testosterone deficiency that contributes significantly to their physical and emotional problems. To address this possibility, we need to develop effective screening procedures for hypogonadism in our offices and weigh the relative advantages and disadvantages of testosterone replacement therapy with our patients.

References
Benvenga S, Campenni A, Ruggeri RM, et al. Hypopituitarism secondary to head trauma. J Clin Endocrinol Metab 2000;85(4):1353-61
Summary of the second annual Andropause Consensus Meeting of the Endocrine Society, Beverly Hills, CA, April 28-30, 2000
Bhasin S, ed. Benefits and risks of treating hypogonadism in the aging male. Endocr Soc Clin Bull Andropause 2002;No. 2
Yialamas MA, Hayes FJ. Androgens and the aging male. Endocrinol Rounds 2003;2(1). Available at: https://www.endocrinologyrounds.org. Accessed Aug 5, 2003
Morley JE, Charlton E, Patrick P, et al. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000;49(9):1239-42
Perry PJ, Yates WR, Williams RD, et al. Testosterone therapy in late-life major depression in males. J Clin Psychiatry 2002;63(12):1096-101
Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study. J Clin Endocrinol Metab 2002;87(2):589-98
Singh AB, Hsia S, Alaupovic P, et al. The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J Clin Endocrinol Metab 2002;87(1):136-43
Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal males: a retrospective analysis. J Clin Endocrinol Metab 1997;82(11):3793-6
Viallard JF, Marit G, Mercie P, et al. Polycythaemia as a complication of transdermal testosterone therapy. Br J Haematol 2000;110(1):237-8
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
Gambineri A, Pasquali R. Testosterone therapy in men: clinical and pharmacological perspectives. J Endocrinol Invest 2000;23(3):196-214
Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol 2000;161(1-2):73-88
Novak A, Brod M, Elbers J. Andropause and quality of life: findings from patient focus groups and clinical experts. Maturitas 2002;43(4):231-7
Advisory Panel on Testosterone Replacement in Men. Report of National Institute on Aging Advisory Panel on Testosterone Replacement in Men. J Clin Endocrinol Metab 2001;86(10):4611-7
Heaton JP. Point: urologists should take an active role in the diagnosis and treatment of hypogonadism in the aging male. Can J Urol 2002;9(6):1677-80
Casey RW. Counterpoint: urologists should take an active role in the diagnosis and treatment of hypogonadism in the aging male. Can J Urol 2002;9(6):1681-3