Measurement of serum testosterone
Three forms of testosterone are found in serum: sex hormone-binding globulin (SHBG)-bound (60%-70% of total), albumin-bound (20%-30% of total), and free (1%-3% of total). SHBG-bound testosterone is not biologically active because of the strong binding between the two. Only albumin-bound and free testosterone are available to tissues and are therefore called bioavailable testosterone.
A total measurement detects all three types and is the current standard. The normal physiologic range is not well defined, but the reference range for total testosterone is currently considered to be 300-1,000 ng/dL.4 Normal ranges vary by lab; interpretation of these values should be limited to an individual lab’s report for normal range. In addition, serum testosterone levels vary from hour to hour, and periodic decreases falling below the normal range can occur in otherwise healthy men. In younger men, circulating testosterone levels are highest during the early morning (to accurately diagnose a low level, serum should be drawn before 10 am). The circadian release of testosterone becomes blunted as men age, and the early morning level shows less variation. To avoid an inappropriate diagnosis, tests should be repeated in younger patients with subnormal testosterone levels, especially those with no definite signs or symptoms of testosterone deficiency.
When low testosterone levels are identified, additional testing is needed to rule out possible causes other than age-related hypogonadism (Table 1). Guidelines issued by the American Association of Clinical Endocrinologists (AACE) and other groups recommend the following laboratory determinations: luteinizing hormone, follicle-stimulating hormone (appropriate for studying infertility), prolactin-1, estradiol levels (especially in men with a high BMI), and serum transferrin saturation.4,5 According to the ACCE, patients with exceedingly low total testosterone levels (<150 ng/dL) may be candidates for pituitary imaging even in the absence of other signs or symptoms.
The threshold total testosterone values to be used when making a diagnosis of hypogonadism are in dispute. The wide variability in testosterone levels in men is one difficulty,6 as is the variation in values among labs. There is probably no single, broadly applicable threshold, and this becomes more of a challenge since there is a lack of consensus regarding guidelines for treatment goals. To consider hypogonadism a reasonable diagnosis, there should be a documented low testosterone level with a consistent report of symptoms that are attributed to low testosterone. As a general practice guideline, starting testosterone replacement is acceptable when there are consistent symptoms and the total testosterone level is within one standard deviation above the lab’s lowest threshold.
The signs and symptoms commonly attributed to testosterone deficiency are difficult to separate from the age-related decline of other hormones. No age-related population studies have been done to evaluate the similarity, and many “hypogonadal” symptoms are nonspecific. These concerns take on greater significance when total testosterone levels are near the threshold value. In such cases, the total testosterone level may not be a satisfactory marker of testosterone activity, and measurements of free testosterone or SHBG-bound testosterone may be helpful. These levels are again lab-dependent and viewed in the context of an individual patient. If there is ongoing concern regarding the correct diagnosis, referral to an andrologist or endocrinolgist would be appropriate.
Who needs treatment
Men with symptomatic testosterone deficiency and a total testosterone level <300 may be candidates for testosterone replacement therapy, although no specific recommendations have been established. The typical treatment candidate has a validated low total testosterone level and consistent symptoms of testosterone deficiency, especially sexual function complaints. The benefits of testosterone therapy in men with testosterone deficiency include improvements in libido, sexual function, and quality of life; maintenance of cognitive function; prevention of bone mineral density (BMD) loss and osteoporosis; and possibly reductions in risk factors for cardiovascular disease.4 In older men with low-normal serum testosterone levels, recent evidence suggests that testosterone therapy increases lean body mass but has no beneficial effects on functional mobility, muscle strength, cognitive function, or BMD.7
Since consistent follow-up is required, the ideal candidate for replacement therapy is motivated and shows evidence of the “typical” hypogonadal symptoms. In some cases, a family member may be able to substantiate that there has been a decline in one or more domains of function. There is no upper age limit that prevents offering replacement therapy as a treatment option.
Testosterone therapy has several potential adverse effects—most notably, it may encourage growth of the prostate or prostate cancer. There is no evidence that testosterone triggers the actual development of prostate cancer or that the risk for developing prostate cancer while on testosterone replacement is greater.8 Testosterone therapy also causes erythrocytosis in a substantial minority of patients, although no thromboembolic events have been reported.8 This therapy may also be associated with sleep apnea and adverse changes in serum lipid levels.8,9
Testosterone therapy is contraindicated in patients who have prostate cancer or male breast cancer and in those who are at high risk for developing either disease (which includes those with high prostate-specific antigen [PSA] levels). Sleep apnea, polycythemia, and severe benign prostatic hyperplasia-related voiding complaints are relative contraindications to testosterone therapy. Elevated prolactin levels and severe bladder outlet obstruction should be treated and controlled before initiating testosterone therapy.10
How to treat
The goal of testosterone therapy for age-related hypogonadism is to restore levels to within the normal physiologic range.11 A reasonable target for replacement is a value that is mid-range on the total testosterone lab test used for diagnosis. Several delivery methods will achieve this goal, including transdermal gels and patches, IM depot injections, buccal formulations, and subcutaneous implants (Table 2). Because of concerns regarding potential hepatotoxicity, oral testosterone therapy is not available in the United States.
Of these agents, transdermal gels have become the most commonly used because of their effectiveness and convenience in application. Patient preference is a critical factor in determining the choice of agent, although this is influenced in many cases by insurance coverage. Most patients are satisfied if their treatment relieves their symptoms, but ease of use and fragrance of the gel are considerations for some.
All patients receiving testosterone therapy require regular follow-up and monitoring. The AACE recommends monitoring at three- to four-month intervals during the first year of therapy and at six- to 12-month intervals thereafter. Monitoring should assess both efficacy (symptomatic improvement, serum testosterone level) and safety (PSA tests, liver studies).
Patients receiving testosterone therapy should undergo digital rectal examination and assessment of prostate-related symptoms every 6-12 months. Severe prostatic symptoms (e.g., urinary frequency or urgency) mandate further assessment before testosterone therapy is continued. PSA levels should be measured at baseline and quarterly during the first year of treatment, then every six months thereafter. A PSA >4.0 ng/mL, an increase in PSA >1.4 ng/mL in a 12-month period after beginning replacement, or a PSA velocity >0.4 ng/mL, based on the PSA after six months of treatment, are widely accepted standards for urologic referral and/or prostate biopsy.4 Monitor men with a high BMI closely because testosterone replacement can lead to elevations in their estradiol.
Serum testosterone levels require assessment at every follow-up visit. The timing of the assessment may be important depending on the formulation used: for depot injections, the level should be measured approximately halfway through the interval between injections, while patients using transdermal patch systems should be assessed four to eight hours after application. Timing is less critical for transdermal gels, which provide relatively constant testosterone levels. Regardless of the delivery method, a dose increase warrants consideration if serum testosterone levels are below the physiologic range or if the patient is not experiencing satisfactory symptom relief.
Ms. Quallich is the andrology nurse practitioner in the Department of Urology at the University of Michigan Health System in Ann Arbor.
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7. Emmelot-Vonk MH, Verhaar HJ, Nakhai Pour HR, et al. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA. 2008;299:39-52.
8. 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.
9. Darby E, Anawalt BD. Male hypogonadism: an update on diagnosis and treatment. Treat Endocrinol. 2005;4:293-309.
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All electronic documents accessed June 10, 2009.