Editor’s note: This article on the differential diagnosis of hypogonadism in men is the first of two articles. The second, to be published next month, focuses on the appropriate use of testosterone therapy.
A 54-year-old man is referred for evaluation of low testosterone. He had seen his primary care physician for complaints of diminished libido and erectile dysfunction for the past year and worsening fatigue over the past few years. He has not been formally diagnosed with any medical condition. His serum testosterone level is 180 ng/dL (reference range 249–836 ng/dL).
On physical examination, he is obese (body mass index 31 kg/m2) with a normal-appearing male body habitus, no gynecomastia, and normal testicles and prostate gland.
How should this patient be evaluated?
LOW TESTOSTERONE HAS MANY CAUSES
Male hypogonadism, ie, failure of the testes to produce adequate amounts of androgen or sperm, has become a common clinical finding, particularly in the older population. This is more likely the result of an increase in awareness and detection of the disorder by physicians rather than a true increase in prevalence.
The finding of a low serum testosterone value needs to be confirmed and thoroughly evaluated before starting treatment. It is important to determine whether the cause is a primary (hypergonadotropic) testicular disorder or secondary to a hypothalamic-pituitary process (hypogonadotropic or normogonadotropic).
THE HYPOTHALAMIC-PITUITARY-GONADAL AXIS
Testosterone production is under the control of luteinizing hormone (LH), whereas sperm production is under the control of follicle-stimulating hormone (FSH) (Figure 1). Both of these pituitary hormones are regulated by the pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH).
Testosterone (produced by Leydig cells) and inhibin B (produced by Sertoli cells within the seminiferous tubules) result in negative feedback inhibition of gonadotropin (LH and FSH) secretion. Testosterone and estradiol (produced by aromatization of testosterone) act at both pituitary and hypothalamic sites and are the principal regulators of LH secretion.1,2 Inhibin B is the major regulator of FSH secretion in men,3 but steroid feedback also occurs.2,4
TO FOLLOW UP A LOW TESTOSTERONE, CONFIRM THE VALUE NEAR 8 am
If a testosterone value is found to be low, it is important to determine the time that the sample was obtained. Serum testosterone levels follow a diurnal rhythm, at least in younger men, with values near 8 am being, on average, 30% higher than the trough levels later in the day.5–7 The timing of the diurnal variation may be different in night-shift workers, who may require assessment at a more appropriate time of the day (ie, upon awakening).
Another factor affecting testosterone levels is the patient’s health status at the time of testing. Values obtained in the hospital during an acute illness should be repeated once the event has resolved, as testosterone values decrease considerably in this setting.8 Even in outpatients, particularly in men over age 60, one must be sure that the low testosterone level was not obtained during a period of decompensation of one of the many comorbidities seen in these patients, such as coronary artery disease, congestive heart failure, or uncontrolled diabetes.
If an 8 am testosterone value is low, it is reasonable to obtain at least one confirmatory testosterone level on another day, near 8 am, in the next few weeks, when the patient is in good health. Confirming the testosterone level is important, particularly since commercially available testosterone assays are not well standardized and some are frankly unreliable.9,10 A repeat confirmatory level should always be performed by a reliable reference laboratory. If the testosterone level is still low, further evaluation is warranted.
TOTAL TESTOSTERONE VS BIOAVAILABLE TESTOSTERONE VS FREE TESTOSTERONE
Of the total circulating testosterone, 60% is bound to sex hormone-binding globulin (SHBG), 38% is bound to albumin, and only 2% is free. All of these fractions can be measured to assess for testosterone deficiency.
Free testosterone is the biologically active form of this hormone and, thus, the free testosterone level is considered to be a better representation of the true testosterone status. However, some clinicians believe that bioavailable testosterone (testosterone loosely bound to albumin + free testosterone) is a better reflection of the true level of the active hormone than the level of free testosterone alone.
There are situations in which the total testosterone level is low but bioavailable or free testosterone levels are normal. The level of total testosterone is affected by alterations in the levels of SHBG and albumin. A reduction in the level of SHBG can result in low total serum testosterone levels in patients with obesity or type 2 diabetes (states of insulin resistance), and also in cachexia, malnutrition, advanced cirrhosis, acromegaly, hypothyroidism, and nephrotic syndrome. SHBG can also be low in patients taking glucocorticoids, progestins, or androgenic steroids.11 In these settings, checking the level of free testosterone (the active hormone), bioavailable testosterone, or both, by a reliable reference laboratory, may be more appropriate.9,10
But regardless of which measurement is chosen, all testosterone levels—especially bioavailable and free testosterone values—should be interpreted with caution if they are not measured at a reliable reference laboratory.9,10 Interested readers may wish to see the US Centers for Disease Control and Prevention (CDC) Hormone Standardization Program Web site (www.cdc.gov/labstandards/hs.html) for more details, including a list of CDC-certified laboratories.