Editor’s note: This is the second of two articles on hypogonadism in men and focuses on the appropriate use of testosterone therapy. The first article, published last month, focused in more detail on the differential diagnosis of hypogonadism.
As men age, testosterone production gradually decreases. In our increasingly aged population, clinicians will continue to see an increase in the number of men with seemingly nonspecific symptoms of aging that are possibly due to low serum testosterone (eg, low energy level, depressive symptoms, erectile dysfunction, decreased libido). These clinical symptoms, coupled with low serum testosterone, may adversely affect quality of life and life expectancy. Testosterone replacement therapy (TRT) may improve symptoms and quality of life. Given the nonspecific nature of these symptoms, accurate diagnosis and treatment of clinically significant low testosterone with a goal of symptom and quality of life improvement can prove challenging.
These challenges in diagnosis and treatment result in a lack of standardized nomenclature. The terms male menopause and andropause, although popular, are the least helpful, as they have few correlates with the better-defined female menopause. Late-onset hypogonadism implies a well-defined, later age of decline, which is inaccurate since the decline in serum testosterone in men begins in middle age and is gradual. Testosterone deficiency syndrome implies a set of specific and well-defined symptoms. Androgen deficiency in the aging male (ADAM) and Androgen deficiency in the older male are common terms specifying an age cohort (> 40 years old) and an abnormal laboratory value without mention of symptoms. While all these terms have their limitations, we will primarily use ADAM in this discussion.
PREVALENCE OF LOW TESTOSTERONE
Serum testosterone levels begin to decline in men in their mid-40s, with an approximately 1% to 2% decline annually and a marked decline after age 60.1
Araujo and colleagues2 studied the prevalence of androgen-deficient men, with androgen deficiency defined as at least three signs or symptoms and either a total testosterone less than 200 ng/dL or a total testosterone 200 ng/dL to 400 ng/dL with a free testosterone less than 8.91 ng/dL. The overall prevalence of low testosterone on initial measurement was 6%, which doubled to 12% with repeat measurement.
Serial measures are important: one study that followed untreated men over 15 years found normal testosterone on serial measures in 50%.3 In a multicenter cross-sectional study, 11.8% of men had low testosterone and low or normal luteinizing hormone (LH) levels (secondary hypogonadism/hypothalamic-pituitary failure), with 2% of patients with low testosterone and elevated LH (primary hypogonadism/testicular failure).4
CLINICAL PRESENTATION AND DIAGNOSIS
A biochemical diagnosis of low testosterone is dependent on accurate measurement. Testosterone release is diurnal, with the highest levels in the early morning, and often has week-to-week variability. Thus, it is important to collect blood in the early morning and to confirm a diagnosis of low testosterone with at least one repeat measurement several days later, including LH assessment. LH levels will help differentiate primary hypogonadism from secondary hypogonadism, which may alter diagnosis and treatment in certain patients, with secondary hypogonadism associated with pituitary dysfunction, and primary hypogonadism associated with aging.4
Testosterone binds in the bloodstream to sex hormone-binding globulin (SHBG), and this bound form is generally considered biologically inactive, although there are in vitro and animal studies suggesting SHBG-bound androgen may indeed have biological activity. 5,6 “Bioavailable” testosterone is active and includes both free testosterone and testosterone bound to albumin.
There is no general agreement on the acceptable normal range of testosterone, with variability within the literature and between laboratories. “Normal” total testosterone levels have ranged from more than 280 ng/dL to more than 350 ng/dL (12 nmol/L).7,8 Similarly, there is no generally accepted lower limit of normal, although some studies report a threshold level of testosterone less than 230 ng/dL (8 nmol/L) as “abnormal.” Values between these two upper and lower limits are considered “borderline.”7,8 These intermediate or borderline values coupled with clinical symptoms of testosterone deficiency syndrome or ADAM should be considered abnormal.
When total testosterone is borderline, measurement of free or bioavailable testosterone (free plus albumin-bound) should be considered. Total testosterone is typically measured using automated immunoassay platforms, with method-related differences leading to significant variability in measurement accuracy and precision. This variability is seen most dramatically in those with low total testosterone.9 However, the variability of total testosterone measurements is substantially smaller among mass spectrometry assays than among immunoassays. 10
The gold standards for free testosterone measurement are centrifugal ultrafiltration and equilibrium dialysis.9 However, these techniques are laborious and usually unavailable in local laboratories. Calculated free testosterone values using total testosterone and SHBG are most commonly used and are sufficiently accurate for clinical practice.11
Free testosterone levels can be diagnostic when total testosterone levels do not correspond with clinical presentation. However, the clinical utility of free testosterone is difficult to assess due to the variability among laboratory assays and a lack of consensus on threshold parameters. A threshold free testosterone level of more than 225 pmol/L (65 pg/mL) is generally considered normal.7,8 Before starting a patient on TRT, measurement of hemoglobin and prostate-specific antigen (PSA) and digital rectal examination of the prostate (if age is > 39) are essential.
Prolactin levels are recommended when low testosterone is confirmed, especially in patients at high clinical risk for hyperprolactinemia. Once hyperprolactinemia is identified, Endocrine Society guidelines recommend excluding medication use, renal failure, hypothyroidism, and parasellar tumors as possible causes of elevated prolactin levels.12
Low testosterone values should be treated only in patients with clinically significant symptoms that are likely to be caused by the low testosterone itself. Symptoms associated with age-related decline in testosterone that may improve with TRT include low libido,13,14 low energy,14 depressed mood,15–17 low muscle mass, osteoporosis, and hot flashes. Men with erectile dysfunction have also shown a significant improvement with TRT compared with placebo, but with a variable overall response independent of normalization of testosterone. 18,19 This is likely due to the multifactorial nature of erectile dysfunction, including vascular, neurologic, psychogenic, and endocrinologic causes.
Screening questionnaires have been developed for symptoms of low testosterone, but their clinical utility is unclear. The ADAM questionnaire is used as a screening tool for low testosterone but not to monitor response to TRT, and it is highly nonspecific.20 The Aging Male Symptom Scale questionnaire includes psychological, somatovegetative, and sexual components and is used both to screen for low testosterone and to measure outcomes.21 However, a recent observational study comparing the ability of these questionnaires to assess clinical symptoms revealed a low sensitivity and a low specificity to detect androgen deficiency in men with a total testosterone level less than 300 ng/dL.22 Overall, the current data do not conclusively support the use of hypogonadism questionnaires for screening.
The patient history when evaluating for ADAM should include evaluation of sexual and constitutional symptoms as described above and in Table 1. In addition, a history of traumatic, medical, or surgical events that could affect testosterone production should be obtained, including cryptorchidism, scrotal, inguinal, or abdominal surgery, pituitary surgery or radiation, prior issues with infertility, timing of puberty, history of renal or hepatic failure, chemotherapy (for cancer or autoimmune diseases), and prior use of anabolic steroids or opiates.
A complete physical examination should include assessment of virilization, gynecomastia, and the genitalia, including the size, position, and volume of the testes. The size and consistency of the prostate should be assessed on digital rectal examination.