Clinical background [return to contents]

Male hypogonadism is a clinical syndrome resulting from decreased testosterone and/or sperm production due to abnormalities of the testis or the hypothalamic-pituitary unit.1 Prevalence estimates vary depending on the approach used to make the diagnosis. Three types of hypogonadism have been described with organic or functional causes as described below. This Clinical Focus discusses the important role that laboratory testing plays in the diagnosis and management of adult male hypogonadism. This information is not intended as medical advice. Test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

Epidemiology

In the United States, hypogonadism is estimated to affect about 5.4% of men2; however, reported estimates vary depending on the diagnostic approach taken, which should be based on clinical and biochemical features (ie, the syndromic approach) and not based on features of one or the other.1 The prevalence can be as high as 24% when the diagnosis is made using only the clinical approach and 29% using only the biochemical approach,3 contrasting with 2% to 12% using a strictly applied syndromic approach.3-6

Types and causes of hypogonadism

Types of hypogonadism include primary, secondary, and combined1:

• Primary hypogonadism (hypergonadotropic hypogonadism) is caused by abnormalities of the testis and is characterized by decreased testosterone and spermatogenesis and increased gonadotropins (follicle stimulating hormone [FSH] and luteinizing hormone [LH]).
• Secondary hypogonadism (hypogonadotropic hypogonadism) is caused by abnormalities of the hypothalamus and/or pituitary and is also characterized by decreased testosterone concentrations and impaired spermatogenesis, but gonadotropins are decreased or in-range.
• In combined hypogonadism, gonadotropin levels are variable depending on whether primary or secondary hypogonadism predominates.

When hypogonadism is diagnosed in men, additional diagnostic evaluation is recommended to determine the cause(s), which are classified as either organic or functional (Table 1).1 Organic causes include congenital, structural, or destructive disorders that permanently affect the hypothalamus, pituitary, or testis. The clinical presentation of organic hypogonadism is usually severe, and testosterone supplements are almost always necessary.7

Table 1. Organic vs Functional Causes of Hypogonadism

Functional causes of male hypogonadism include comorbidities associated with aging, some medications and drugs of abuse, excessive exercise, organ failure, and renal, endocrine, sleep, and systemic disorders (Table 1).1 These causes lead to the suppression of gonadotropins and testosterone, but to a lesser degree than organic causes; suppression by functional causes is potentially reversible upon removal of the cause (eg, liver transplantation in terminal liver failure, weight loss in obesity and weight gain in anorexia nervosa, and stopping medications affecting the hypothalamus, pituitary, or testes).1

In general, patients with functional hypogonadism present with milder symptoms compared to those with organic hypogonadism. Furthermore, severe symptoms (Table 2)8 only occur in (1) the most advanced forms of functional hypogonadism, such as those caused by chronic use of opioids or other drugs affecting the hypothalamic-pituitary-testicular axis, and (2) patients affected by functional hyperprolactinemia, who develop significant low testosterone over a long time.

The clinical presentation of hypogonadism depends, in part, on when it occurs. Typical signs and symptoms of peripubertal hypogonadism include incomplete or delayed puberty, small testes, reduced libido, erectile dysfunction, scanty steroid-dependent pubic and axillary hair, and lack of temporal recession of the hairline (Table 2).8

If hypogonadism occurs after puberty, the clinical presentation depends on the degree and duration of testosterone deficiency.

A classic scenario of abrupt testosterone lowering occurs in patients undergoing androgen deprivation therapy for prostate cancer. These individuals develop sudden and complete testosterone deficiency and experience an immediate reduction of libido and erectile function, low energy, hot flashes, insomnia, depression, and changes in body composition.

However, most men who develop hypogonadism after puberty undergo a gradual decrease in serum testosterone levels; their symptoms develop over a more extended period, and their primary and secondary sexual characteristics do not regress to prepubertal levels for several months to years. Also, testicular size does not decrease significantly, unless the patient is affected by primary hypogonadism.

Table 2. Symptoms and Signs of Hypogonadism in Men

Laboratory testing for diagnosis and management of hypogonadism

Biochemical diagnosis of male hypogonadism is based on laboratory testing that indicates unequivocally and consistently low serum testosterone concentrations.1,9 Laboratory testing is an absolute requirement in the diagnosis of men with suspected hypogonadism, especially when conditions associated with a high prevalence of low testosterone are present (Tables 1 and 2).1,8 However, routine screening for male hypogonadism in the general population is not recommended.1

Laboratory testing for hypogonadism is not always as straightforward as simply measuring total testosterone (TT) levels. Conditions associated with changes in sex hormone binding globulin (SHBG) can also help identify individuals requiring specific laboratory testing.1 If TT is near the lower limit of normal or alterations in SHBG are suspected (Table 3)1 such that TT is affected, guideline recommendations include measuring free testosterone (FT).1

Table 3. Conditions Associated with Changes in SHBG

For men with hypogonadism who have started testosterone replacement therapy (TRT), laboratory testing involves monitoring testosterone, hematocrit, prostate-specific antigen (PSA), and bone mass density (BMD).1 Testosterone can cause secondary erythrocytosis (ie, increase in hematocrit), which can lead to an increased risk of cardiovascular disease.10 PSA levels are also increased in hypogonadal men who are receiving TRT. Monitoring estradiol levels may be helpful in the assessment of BMD in men with osteoporosis who are receiving TRT.11

The Endocrine Society does not recommend TRT for men with hypogonadism who are planning fertility in the near future, or those who have breast or prostate cancer, elevated hematocrit, or untreated severe obstructive sleep apnea.1 Nor do they recommend offering TRT to men who experienced a cardiovascular episode in the last 6 months or who are affected by poorly controlled congestive heart failure1; however, recent publication of findings from the TRAVERSE trial has established that TRT does not increase cardiovascular risk for at least 2 years after starting TRT.12 In summary, physicians should discuss the benefits and risks with patients before prescribing TRT.

Individuals suitable for testing [return to contents]

• Men with symptoms, signs, or conditions (Tables 2 and 3)1,8 associated with hypogonadism
• Men who are receiving testosterone replacement therapy

Diagnosing hypogonadism

Initial diagnostic testing for low testosterone involves measuring morning fasting TT.1 Liquid chromatography-tandem mass spectrometry (LC-MS/MS, test codes 15983, 36170) and immunoassays (test codes 873, 30741) are available for TT. While being less expensive to perform, having faster turnaround times, and good analytical performance in the normal to high testosterone range,17 immunoassays lack the sensitivity and specificity required at lower concentrations.1,18

For diagnosing hypogonadism, LC-MS/MS provides a more precise and accurate measurement of TT at lower concentrations than immunoassays,5,6 and is the recommended assay in Endocrine Society guidelines.1 Quest LC-MS/MS assays have been certified by an accuracy-based Centers for Disease Control and Prevention Hormone Standardization Program (CDC HoSt) per Endocrine Society recommendations,1 and have an analytical measurement range of 1.0 to 2,000.0 ng/dL with no cross-reactivity with 30 testosterone-related steroid compounds.

FT should be measured if TT is reported near the lower limit of normal or if alterations in SHBG that affect TT are suspected (Table 3).1 Guidelines recommend measuring FT by LC-MS/MS and an equilibrium dialysis method (test code 36170, preferred) or estimating FT levels using a formula based on measurement of TT by MS, SHBG, and albumin (test code 14966). Note, immunoassay platforms are less accurate when compared to equilibrium dialysis and should not be used to measure FT for a hypogonadism workup.1,19

Initial test results indicating low to normal levels of TT or FT should be confirmed by repeating morning fasting TT and FT.1 See Figure for a diagnostic testing strategy.

Figure. Adult Male Hypogonadism Diagnostic Algorithm
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Identifying causes

If initial and confirmatory testing indicates low testosterone, follicle stimulating hormone (FSH) (test code 470) and luteinizing hormone (LH) (test code 615) should be measured to distinguish between primary and secondary hypogonadism (Figure).1 Most clinical diagnostic laboratories, including Quest, use immunoassays to measure gonadotropins owing to their sensitivity in distinguishing between normal and low levels; however, LH and FSH assays are susceptible to biotin interference that can lead to falsely high or low values.20 Clinicians should stop patient use of biotin supplements for at least 72 hours before testing.1

Causes of primary hypogonadism

If clinically indicated, chromosomal analysis (test code 14596) is recommended to identify Klinefelter syndrome following a diagnosis of primary hypogonadism.1 Most adults with Klinefelter syndrome have testosterone in the low-normal or sub-normal range but some may have very low levels, and some may even have normal levels of testosterone.21,22 Identifying the other causes of primary hypogonadism would be based on patient history or clinical examination (Table 1).1

Causes of secondary hypogonadism

A diagnosis of secondary hypogonadism should be followed up with testing to assess for certain guideline-indicated causes, including hyperprolactinemia and iron overload syndromes.1

Clinicians should measure serum prolactin (test codes 746, 40049) to aid in the diagnosis of hyperprolactinemia, a condition in which increased levels of prolactin interfere with the release of gonadotropin-releasing hormone, thus decreasing testosterone.23

Excess iron in the body causes endocrine dysfunction, particularly on the pituitary axis.24 Secondary hypogonadism caused by iron overload syndromes can be diagnosed using iron saturation assays (test codes 457, 5616, 571, 7573), of which a ferritin test (test code 457) should at least be performed1; however, increased ferritin alone does not indicate iron overload.25

If hypopituitarism is clinically indicated or if imaging reveals abnormalities of the sella turcica (bony structure around the pituitary), other pituitary and/or downstream hormones should be evaluated to help identify the cause of secondary hypogonadism, such as a pituitary tumor (ie, nonfunctioning pituitary adenoma13) or infiltrative/destructive disease of the pituitary.1 Potentially useful tests include morning cortisol (test code 4212), ACTH stimulation (test code 38149), alpha subunit (test code 8658), TSH (test code 866), and free thyroxine (FT4) (test codes 866, 35167).1,13 Similarly, if TSH and FT4 are low, one should rule out the concomitant presence of hypothyroidism and a silent pituitary adenoma causing hypogonadism.13

Monitoring during testosterone therapy

For TRT, Endocrine Society guidelines recommend measuring TT and hematocrit (test code 509) from 3 to 6 months after initiation. TT should be measured midway between injections when using intramuscular testosterone esters (DEPO®) or 2 to 8 hours after application of a transdermal gel.1 Testosterone treatment can lead to secondary erythrocytosis (hematocrit >54%), which is associated with risk of cardiovascular mortality and morbidity.10

Detailed guidelines for monitoring for prostate cancer during TRT are provided by the American Urology Association26 and Endocrine Society.1 PSA (test code 5363) should be monitored after 3 and 12 months from the start of TRT.1

Based on some evidence, guidelines suggest monitoring BMD using dual-energy x-ray absorptiometry after 1 to 2 years of TRT in men with osteoporosis1; however, the method is only suggested given the quality of supporting evidence.8 Monitoring BMD by measuring changes in estradiol (test code 30289) levels during TRT may be considered as estradiol has been shown to be the best predictor of changes in BMD.14