Management of Testosterone Deficiency in Men (Guidelines - Part 1)

Introduction

Testosterone deficiency (TD) in men remains a topic of debate and controversy because of gaps and inconsistencies in our understanding of the condition. Yet information linking TD to serious comorbidities and increased mortality has been accumulating,[1-3] and enough is known about TD to argue that it merits greater clinical attention and concern. This is especially true in primary care settings where patients with TD-associated symptoms are likely to be seen first, and where under-recognition and skepticism of TD as a clinical entity persist.

One of the clearest findings of TD research is the association of testosterone decline with aging.[1,4] The aging of the population in the United States and other countries all but guarantees TD and its associated morbidities will increase in prevalence and burden in primary care offices. This column, the first in a series on TD and its management, discusses findings and prevailing views on the definition, prevalence, risks, and barriers to clinical recognition of TD. Upcoming columns will address screening and workup for TD, treatment considerations, and monitoring of treatment responses.

Defining TD

Clinical practice guidelines on testosterone deficiency in men recognize that the condition is both a biochemical and clinical state, suspected on the basis of symptoms but confirmed by laboratory findings. The Endocrine Society, whose most recent clinical practice guidelines were published in 2010,[5] defines TD as a clinical syndrome resulting from failure of the testes to produce physiologic levels of testosterone and a normal number of spermatozoa; this is caused by disruption at 1 or more levels of the hypothalamic-pituitary-gonadal (HPG) axis.[5,6] Recommendations reflecting the views of the International Society of Andrology (ISA), International Society for the Study of the Aging Male (ISSAM), European Association of Urology (EAU), European Academy of Andrology (EAA), and American Society of Andrology (ASA) define TD as a clinical and biochemical syndrome associated with advancing age and characterized by symptoms and a deficiency in serum testosterone levels.[7] Although there is general agreement among guidelines on the common symptoms of TD (Table 1), consensus is lacking regarding biochemical parameters.

Table 1. Symptoms and Signs Suggestive of Testosterone Deficiency in Men[5,7-9]
More Specific Signs and Symptoms
– Reduced libido
– Erectile dysfunction (ED)
– Reduced intensity of orgasm and genital sensation
– Osteoporosis or low bone mineral density
– Decreased spontaneous erection
– Oligospermia or azoospermia
– Very small or shrinking testes
– Hot flushes, sweats
– Breast discomfort, gynecomastia
– Loss of pubic and axillary hair, reduced shaving
Less Specific Signs and Symptoms
– Decreased energy or vitality, increased fatigue
– Depressed mood
– Reduced muscle mass and strength
– Poor concentration and memory
– Sleep disturbance; increased sleepiness
– Mild anemia
– Increased body fat, body mass index
– Diminished physical or work performance

For example, consider serum total testosterone (TT), the most widely used measurement for establishing biochemical TD. The Endocrine Society suggests that symptoms of TD correspond to the lower limit of normal for young men, or <300 ng/dL, and that this may be an appropriate defining point for TD.[5,6] The ISA/ISSAM/EAU/EAA/ASA recommendations propose 230 ng/dL as the point below which patients will usually benefit from testosterone repletion.[7] Consensus is also lacking on parameters for free testosterone, which guidelines say should be measured when TT is nondiagnostic or lacks specificity (eg, in cases of obesity, alcoholism, or human immunodeficiency virus [HIV]).

Prevalence of TD

A clear reading on the prevalence of TD in middle-aged and older men has been difficult to establish because studies have differed in design, population, and definition of TD. Some are not true prevalence studies in that they define TD only biochemically. However, while key studies have arrived at different numerical conclusions, they present an overall picture of TD increasing with age and associated with comorbidities including diabetes and metabolic syndrome.

The Hypogonadism in Males (HIM) study[1] is an example of a biochemical prevalence study. This was a cross-sectional study of 2162 men aged 45 years and older who had visited a primary care office for any reason, not necessarily for TD-associated complaints, in 2003 and 2004. Based on a TT of <300 ng/dL, 39% of the men were defined as being hypogonadal; for every 10-year increase in age, the risk of hypogonadism increased by 17% (Figure). By extrapolating to national census data, the HIM authors estimated that 13.8 million men (39%) aged 45 and older who visit a primary care physician in the United States might be biochemically testosterone deficient.


Figure. Age-specific prevalence of biochemically defined testosterone deficiency (TD), defined as total testosterone <300 ng/dL or current testosterone therapy. For every 10-year increase in age, risk of TD increased by 17% (95% confidence interval [CI], 1.08-1.27).

The prevalence was much lower in the Massachusetts Male Aging Study (MMAS), which assessed TD symptoms and biochemistry in a population-based random sample of 40- to 70-year-old men.[10] In this study (N = 1491), TD was defined by the presence of at least 3 signs or symptoms of TD plus a TT level of <200 ng/dL; or signs/symptoms plus TT of 200 to 400 ng/dL plus free testosterone <8.91 ng/dL. The prevalence of TD was estimated to be between 6% and 12%. An analysis of the later Boston Area Community Health Study (BACH) data (2002-2005) (N = 1475) used a somewhat stricter definition of symptomatic TD and estimated its prevalence at 5.6% nationwide among men aged 30 to 79 years.[11] Of these men, they estimated that 87.8% were not being treated for TD.[12]

The European Male Aging Study (EMAS) took a uniquely stringent approach to defining TD in a random sample of 3369 men aged 40 to 79 years.[4] The list of qualifying TD symptoms was whittled down based on the strength of each symptom’s association with low levels of TT (<317 ng/dL) and free testosterone (<6.34 ng/dL). The 3 symptoms that made the final cut were sexual: poor morning erection, low sexual desire, and erectile dysfunction (ED). Defined by these symptoms and biochemical evidence, the prevalence of hypogonadism was estimated at 2.1% overall, increasing from as little as 0.1% in men aged 40 to 49 to 5% in men aged 70 to 79. Prevalence also rose in line with increasing body mass index and increasing number of comorbidities.[4] Like EMAS, the HIM study noted a higher TD prevalence in men with comorbidities, most significantly in those who were obese or had diabetes, hypertension, rheumatoid arthritis, hyperlipidemia, or osteoporosis. The risk of having low testosterone levels was 2.4 times higher for obese men, 2.1 times higher for men with diabetes, 1.8 times higher for men with hypertension, and 1.5 times higher for those with hyperlipidemia.[1]

As epidemiologic research continues in middle-aged and older men, the wide disparities in prevalence figures should begin to narrow. Meanwhile, more specific findings regarding TD in younger men are appearing. At the 2011 annual meeting of the American Urological Association (AUA), expert panelists named obesity and diabetes as comorbidities in younger men, but added others such as chronic opiate use, steroid abuse, stress, and possibly genetic factors (report on file, Practicing Clinicians Exchange). Long-term opiate use and chronic pain are comorbidities of TD being seen with increasing frequency in primary care settings.[13]

Also discussed at the AUA annual meeting was the biologic potential of testosterone therapy to interfere with spermatogenesis, a particular concern in younger men being treated for TD (report on file, Practicing Clinicians Exchange). Use of a low dose of human chorionic gonadotropin (hCG) in conjunction with testosterone replacement was discussed as a way of protecting spermatogenic function while improving testosterone levels.[14,15]

Presenting Symptoms

Symptoms of TD are essential to the diagnosis, even though they are individually nonspecific and may be affected by the patient’s age, comorbid illnesses, duration of TD, previous testosterone therapy, and other factors. The symptoms of TD itemized in clinical practice guidelines are shown in Table 1.[5,7] According to the guidelines, any of these symptoms, even those considered “less specific,” should raise suspicion of TD and prompt the clinician to measure testosterone levels.

Sexual symptoms are appropriately at the top of the list of “more specific” TD symptoms. Indeed, loss of libido is sometimes considered the hallmark of TD. Primary care clinicians might argue that fatigue is the most common presenting symptom, but fatigue and low libido often go hand in hand. Most patients with TD come to the attention of physicians because of the presenting problem of ED, a condition with implications beyond the obvious quality-of-life issues. In particular, ED and/or TD may be the harbingers of cardiovascular disease.[16,17]

Evidence linking ED with cardiovascular disease is not new. In 2005, a report based on data from the Prostate Cancer Prevention Trial described ED as a strong predictor of cardiovascular events in men aged 55 years and older and encouraged clinicians to investigate cardiovascular disease in men this age if ED is present.[18] Testosterone deficiency is associated with ED and increased cardiovascular risk.[2,5,11] Yet, in guidelines on hormonal testing in evaluation of ED, the American College of Physicians takes no position for or against testosterone measurement.[19] Many experts would disagree with this stance and instead recommend testing of testosterone as a routine and indispensable part of the ED workup,[20] especially in men with diminished libido or fatigue and an inadequate response to phosphodiesterase-5 inhibitors.

Presenting symptoms in the context of screening and workup for low testosterone will be discussed in detail in a later column.

Barriers to Recognition of TD

Judging by the number of prescriptions for testosterone therapy, diagnoses of TD are increasing. Between 1999 and 2004, prescriptions for the most popular forms of testosterone replacement increased by approximately 200%, most notably among men younger than age 65 but also in older men.[21] Nevertheless, many men with TD symptoms go undiagnosed or receive a diagnosis and treatment only after multiple visits to a clinician. A study of a random sample of community-based men aged 30 to 79 years found that, of those who met the criteria for TD, only 12.2% were being treated, despite access to healthcare.[12] A survey of physicians from several global regions concluded that 35% of testosterone-deficient men are not receiving treatment.[22] An Internet survey of men with TD, reported at the 2009 meeting of the Endocrine Society, indicated that 36% of the men saw 2 physicians, 9% saw 3 physicians, and 9% saw 4 physicians before receiving a diagnosis.[23] What explains these findings? Key barriers to recognition of TD include the following:
  • Lack of consensus on the definition of TD. Lack of consensus may be a valid point with respect to biochemical thresholds and ranges for defining TD, but there is agreement that TD can be appropriately identified through evaluation of symptoms and abnormal biochemistry.
  • Lack of confidence in diagnostic tests. The Endocrine Society acknowledges that, among other shortcomings, assays for TT vary over 3 orders of magnitude, depending on a patient’s age, gender, and coexisting diseases. Most assays have adequate sensitivity in men but are “relatively inaccurate,” and the manner in which most assays are performed is “decidedly unsatisfactory.”[24] The most widely accepted tests are mass spectrometry and equilibrium dialysis, which are expensive tests.
  • Nonuse of screeners. Although validated questionnaires are available to assess clinical manifestations of TD,[25] they are not widely used in primary care offices. Most are too lengthy and are used mainly in research. This practice gap is one reason that some men suffering from depression, for example, are treated with psychotropic drugs when the etiology of their depression is TD. Shorter, more practical screeners for TD are being developed.[26]
  • Nonspecificity of signs and symptoms. Clinicians and patients alike may attribute TD symptoms to other conditions, most commonly normal aging, ie, a natural decline. Yet, these symptoms, no matter how vague, may be having a profound impact on the patient’s quality of life and well-being, and should be explored as part of overall health management.
  • Perception that TD is difficult to manage. This perception is based on the lingering but unsupported belief that testosterone therapy increases the risk of prostate cancer and must, at a minimum, be intensively monitored with prostate-specific antigen (PSA) testing. A 2007 survey of physicians worldwide found that responders showed a “very powerful” fear of inducing prostate cancer with use of testosterone therapy; 68% of respondents (especially those based in Europe) associated therapy with greater risks than benefits.[22] While it is true that the long-term outcomes of testosterone therapy are not well defined, therapy has never been proved to cause development or progression of prostate cancer. To the contrary, some findings suggest TD is the riskier condition with respect to cancer. Testosterone replacement even for men with a history of treated prostate cancer is no longer considered unusual.[27,28] The Endocrine Society recommends initial PSA testing and digital rectal examination for all patients when testosterone therapy is being considered. If all factors are normal, these tests should be repeated at 3 months, but thereafter repeated only in accord with standard screening recommendations.[5]
Comorbidities

The links between TD and more serious medical conditions are only beginning to be explored. At the very least, it can be said that comorbid illnesses seem to explain some of the decline in testosterone attributed to aging. At most, there are specific conditions that have strong epidemiologic associations with TD (Table 2). A recent analysis of HIM data based on free testosterone levels revealed that 40% of obese men and 50% of obese men with type 2 diabetes (45 years and older) were testosterone deficient.[29] The connection between cardiovascular disease and TD is suggested by TD’s associations with diabetes and metabolic syndrome and such findings as an inverse relationship between testosterone level and aortic atherosclerosis, which was seen among middle-aged and older men in the Rotterdam Study.[30] Low free testosterone also has been associated with abdominal aortic aneurysm in community-dwelling men aged 70 to 88 years.[31] Among men aged 50 to 91 years who were followed for 20 years in the Rancho Bernardo Study, testosterone levels were inversely related to weight, body mass index, blood pressure, fasting plasma glucose, and serum insulin. However relevant these cofactors may have been to mortality, men with TT below the 25th percentile had a 40% higher risk of death independent of obesity, lifestyle choices (eg, exercise, smoking), and age.[2] In another recent study of elderly men (aged 69-80 years), low testosterone and estradiol increased the risk of death over a 5-year period.[3]

Table 2. Risks and Comorbid Illnesses Associated With Testosterone Deficiency[1-3,5,29-31]
– Metabolic syndrome
– Obesity
– Hyperlipidemia
– Hypertension
– Elevated fasting plasma glucose and serum insulin
– Elevated C-reactive protein
– Diabetes mellitus (type 1 or 2)
– Cardiovascular disease (including aortic atherosclerosis)
– Chronic obstructive lung disease
– Inflammatory arthritis
– Low trauma fracture
– End-stage renal disease
– HIV-related weight loss
– Hemochromatosis
– Sellar mass, radiation to the sellar region, or other diseases of the sellar region
– Chronic pain syndrome and treatment with opioids
– Treatment with glucocorticoids
– Radical prostatectomy

The subject of chronic opiate use and its association with TD has not been well examined, although there is a documented increase in therapeutic and recreational use of opioids in the past 10 years.[32] During that time, primary care clinicians have become increasingly familiar with men presenting with symptoms of TD and a history of long-term use of long-acting narcotics, such as oxycodone and morphine. Chronic pain should accordingly be considered fairly high on the list of TD comorbidities. The mechanism of any association with TD is unclear, although suppression of hypothalamic function may be involved.

Another timely discussion of comorbidities at the 2011 AUA meeting concerned TD in association with radical prostatectomy (RP).[33] Although the precise role of the prostate on the HPG axis is not well understood, it may influence testosterone and other hormonal levels after RP. Data from men before and 3 months after undergoing RP showed that TT (but not free or bioavailable testosterone) had declined significantly. This and other emerging comorbidities of TD will be the subjects of more intensive research as the population of at-risk patients continues to expand.

When Should Testosterone Replacement Therapy Be Initiated?

Clinicians should not become too focused on specific numerical thresholds and ranges in defining TD, but instead accept that there are no clear dividing lines between normal and deficient testosterone levels in the blood. The different societies are generally in agreement that (a) TT levels >350 ng/dL do not require treatment; and (b) a trial of testosterone therapy can be considered in men with unquestionably low or borderline low testosterone levels and a consistent clinical picture of TD.[7]

In the United States, most men initiate testosterone replacement therapy with a topical gel. Other formulations and delivery systems include scrotal patches, nonscrotal patches, injections, subdermal pellets, and pills (buccal). These options will be discussed in detail in an upcoming column.

References

  1. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM Study. Int J Clin Pract. 2006;60:762-769.
  2. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68-75.
  3. Tivesten A, Vandenput L, Labrie F, et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94:2482-2488.
  4. Wu FC, Tajar A, Beynon JM, et al; EMAS Group. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363:123-135.
  5. Bhasin S, Cunningham GR, Hayes SJ, et al; Task Force, Endocrine Society. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559.
  6. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2006;91:1995-2010.
  7. Wang C, Nieschlag E, Swerdloff R, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment, and monitoring of late-onset hypogonadism in males. Aging Male. 2009;12:5-12.
  8. American Urological Association. Meeting Highlights 2007. Importance of hypogonadism and testosterone replacement therapy in current urologic practice. Available at: http://www.auanet.org/content/products/auanews/annual-meeting-course-highlights/testosterone07.pdf. Accessed July 7, 2011.
  9. Petak SM, Nankin HR, Spark RF, et al. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update. Endocr Pract. 2002;8:439-456.
  10. 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;89:5920-5926.
  11. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92:4241-4247.
  12. Hall SA, Araujo AB, Esche GR, et al. Treatment of symptomatic androgen deficiency. Arch Intern Med. 2008;168:1070-1076.
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  14. Pakarainen T, Zhang FP, Mäkelä S, Poutanen M, Huhtaniemi I. Testosterone replacement therapy induces spermatogenesis and partially restores fertility in luteinizing hormone receptor knockout mice. Endocrinology. 2005;146:596-606.
  15. Coviello AD, Matsumoto AM, Bremner WJ, et al. Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression. J Clin Endocrinol Metab. 2005;90:2595-2602.
  16. Blute M, Hakimian P, Kashanian J, Shteynshluyger A, Lee M, Shabsigh R. Erectile dysfunction in testosterone deficiency. Front Horm Res. 2009;37:108-122.
  17. Somani B, Khan S, Donat R. Screening for metabolic syndrome and testosterone deficiency in patients with erectile dysfunction: results from the first UK prospective study. BJU Int. 2010;106:688-690.
  18. Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2005;294:2996-3002.
  19. QaseemA, Snow V, Denberg TD, et al; for Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Hormonal testing and pharmacologic treatment of erectile dysfunction: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2009;151:1-12.
  20. Traish AM, Miner MM, Morgentaler A, Zitzmann M. Testosterone deficiency. Am J Med. 2011;124:578-587.
  21. Edelstein D, Dobs A, Basaria S. Emerging drugs for hypogonadism. Expert Opin Emerg Drugs. 2006;11:685-707.
  22. Gooren LJ, Behre HM, Saad F, Frank A, Schwerdt S. Diagnosing and treating testosterone deficiency in different parts of the world. Results from global market research. Aging Male. 2007;10:173-181.
  23. Anderson FW. Men with low testosterone see multiple doctors before being diagnosed: many dissatisfied with current treatment options [press release]. Reuters; June 10, 2009. Available at: http://www.reuters.com/article/pressRelease/idUS122449+10-Jun-2009+PRN20090610. Accessed July 7, 2011.
  24. Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H. Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92:405-413.
  25. Rosen RC, Araujo AB, Connor MK, et al. Assessing symptoms of hypogonadism by self-administered questionnaire: qualitative findings in patients and controls. Aging Male. 2009;2:77-85.
  26. Rosen RC, Araujo AB, Connor MK, et al. The NERI hypogonadism screener: psychometric validation in male patients and controls. Clin Endocrinol. 2011;74:248-256.
  27. Morgentaler A. Testosterone and prostate cancer: what are the risks for middle-aged men? Urol Clin North Am. 2011;38:119-124.
  28. Morgentaler A, Lipshultz LI, Bennett R, Sweeney M, Avila D Jr, Khera M. Testosterone therapy in men with untreated prostate cancer. J Urol. 2011;185:1256-1261.
  29. Dhindsa S, Miller MG, McWhirter ML, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33:1186-1192.
  30. Hak AE, Witteman JC, de Jong FH, Geerlings MI, Hofman A, Pols HA. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab. 2002;87:3632-3639.
  31. Yeap BB, Hyde Z, Norman PE, Chubb SAP, Golledge J. Associations of total testosterone, sex hormone-binding globulin, calculated free testosterone, and luteinizing hormone with prevalence of abdominal aortic aneurysm in older men. J Clin Endocrinol Metab. 2010;95:1123-1130.
  32. Manchikanti L, Fellows B, Ailinani H, Pampati V. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician.2010;3:401-435.
  33. Khera M. Testosterone for penile rehab after radical prostatectomy. Available at: http://clinicaltrials.gov/ct2/show/NCT00848497. Accessed July 7, 2011.

1 comment:

  1. over time,i'v come to always consider depression and cardiovascular dx (artherosclerosis to be precise) topmost n mechanically in my evaluation of patients with erectyle dysfxn. i guess i bn missin out on those with testosterone def. good lord!

    ReplyDelete

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