Symptoms to Diagnosis

An obese 48-year-old man with progressive fatigue and decreased libido

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A 48-year-old man presents to his primary care physician because of progressively decreasing energy and gradual decline in both libido and erectile function for the past 18 months. He has noticed decreased morning erections as well. He rates his libido at 3 to 4 on a scale of 10 for the past 6 months. He also reports poor motivation, depressed mood, impaired concentration, and sleep disturbances. He reports no hair loss, headache, or dizziness, and no decrease in shaving frequency. Review of his systems is otherwise unremarkable.

He has had dyslipidemia for 3 years and is not known to have hypertension or diabetes. His medications include atorvastatin, vitamin E, and multivitamins.

He is married with 3 children and does not wish to have more. He works as a software engineer and leads a sedentary lifestyle. He is a nonsmoker and occasionally drinks alcohol on the weekends.

On physical examination, he is alert and oriented and appears well. His height is 5 feet 10 inches (178 cm), weight 230 lb (104 kg), and body mass index (BMI) 32.8 kg/m2. His blood pressure is 115/83 mm Hg and pulse rate is 82 beats per minute and regular. Findings on cardiovascular and pulmonary examination are normal. He has large fatty breasts but without palpable glandular tissue.

Table 1. Results of initial laboratory testing
Abdominal examination reveals central obesity—waist circumference 48 inches (122 cm)—without tenderness or organomegaly. There are no striae.

Genitourinary examination reveals normal hair distribution, a normal-sized penis, and slightly soft testes with testicular volume of 18–20 mL bilaterally.

His primary care physician suspects that he has low testosterone and orders some basic laboratory tests; the results are normal except for a low total testosterone level (Table 1).

FURTHER TESTING

1. Which of the following tests should his physician order next?

  • Repeat total testosterone measurement
  • Free testosterone measurement by commercial assay
  • Calculated free testosterone
  • Bioavailable testosterone measurement
  • Serum inhibin B measurement

This patient presents with several nonspecific symptoms. But collectively they suggest testosterone deficiency (hypogonadism).

Table 2. Symptoms and signs of postpubertal male hypogonadism
Symptoms and signs of low testosterone vary according to age of onset. Prepubertal onset is associated with incomplete or delayed puberty, no development of secondary sexual characteristics, eunuchoid features, and small penis and testes. Postpubertal onset is associated with a wide array of symptoms (Table 2). Most manifestations of low testosterone are nonspecific, such as fatigue, impaired concentration, and sleep disturbance.1

Together, erectile dysfunction, low libido, and decreased morning erections strongly suggest hypogonadism.2 Loss of body hair and decreased shaving frequency are specific symptoms of hypogonadism; however, they require years to develop.3 Gynecomastia can also occur due to loss of the inhibitory action of testosterone on breast growth and a relative increase in estradiol. This occurs more in primary hypogonadism, due to the increase in luteinizing hormone (LH), which stimulates the remaining Leydig cells to secrete estradiol rather than testosterone.4

Table 3. Conditions in which screening for hypogonadism may be indicated in men
Screening for hypogonadism in men may be warranted in several conditions, even without clinical manifestations of low testosterone (Table 3).5–10

To diagnose hypogonadism in men and to start treatment for it, current guidelines recommend that the patient should have clinical features as well as laboratory evidence of low testosterone.5,6

Measuring testosterone: Total, free, bound, and bioavailable

Testosterone, a steroid hormone, circulates in the serum either as free testosterone or bound to several plasma proteins, mainly sex-hormone binding globulin (SHBG) and albumin.

Total testosterone includes both the free and bound fractions, whereas bioavailable testosterone includes both free and the portion bound to albumin, which has low affinity and can dissociate and be used at the tissue level.11

Low levels of total testosterone do not necessarily reflect a hypogonadal state, as a man with altered SHBG levels or binding capabilities can have low total but normal free testosterone levels and no manifestations.12 Several conditions can alter the levels of SHBG, including obesity, diabetes, aging, thyroid dysfunction, and others.5,13

Because our patient is obese, his total testosterone level is not a reliable indicator of hypogonadism, and repeating its measurement will not add diagnostic value.

Therefore, an alternative measurement should be used to accurately reflect the testosterone levels. From a physiologic point of view, bioavailable testosterone is the active form of testosterone and is the most accurate to be measured in a patient with hypogonadism. Nevertheless, because of technical difficulties in its measurement and lack of evidence correlating bioavailable testosterone with the clinical picture of hypogonadism, it is recommended that the level of free testosterone be used.5

The gold standard for direct measurement of serum free testosterone is equilibrium dialysis, but this is expensive and time-consuming.14 Commercial assays for free testosterone exist but have been deemed unreliable.14,15 It is recommended that free testosterone be measured by equilibrium dialysis or calculated using equations based on total testosterone, SHBG, and albumin levels.5 These equations are reliable and give results very close to the values obtained by equilibrium dialysis.15 Therefore, in our patient, it would be suitable to calculate the free testosterone level next.

Serum levels of free testosterone vary according to several factors. Diurnal variation of testosterone has been established: levels are highest in the morning and decline throughout the day.16 Food decreases testosterone levels.17 In addition, there is considerable day-to-day variation.18 Therefore, at least 2 readings of fasting morning testosterone on 2 separate days are recommended for the diagnosis of hypogonadism.5

Inhibin B is a hormone produced by Sertoli cells in the testes in response to follicle-stimulating hormone (FSH) stimulation. In turn, it acts as negative feedback, together with testosterone, to inhibit FSH release from the pituitary. Inhibin B has been shown to reflect spermatogenesis in the testes and therefore fertility.19 Inhibin B levels were found to be low in patients with central hypogonadism, due to less FSH release; however, they did not correlate with testosterone levels.20

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