The diagnosis of "hypogonadism" sounds simple - low testosterone. In fact, its setting requires compliance with a number of rules, without which it is easy to get a false result and either miss the disease or prescribe unnecessary treatment. The editors analyze step by step how testosterone deficiency is diagnosed according to modern guidelines.
Symptoms: what should alert
Hypogonadism is a clinical syndrome, i.e. symptoms and laboratory confirmation are required for diagnosis. The guidelines of the Endocrine Society divide the signs into more specific and less specific: the former more convincingly indicate testosterone deficiency, the latter occur in many other conditions.
| More specific signs | Less specific signs |
|---|---|
| Decreased libido and sexual activity | Fatigue, decreased energy |
| Rarer spontaneous morning erections | Depressed mood, irritability |
| Gynecomastia | Deterioration of concentration and memory |
| Reduction of body hair, less shaving | Sleep disturbance, drowsiness |
| Small or reduced testicles | Decrease in muscle mass and strength |
| Infertility, low bone mineral density, hot flashes | Increase in fat mass |
The large European EMAS study (Wu et al., NEJM 2010) in men aged 40–79 years showed that three sexual symptoms were most reliably associated with low testosterone: infrequent morning erections, decreased sexual desire, and erectile dysfunction. The authors proposed to define late-onset hypogonadism as a combination of these three symptoms with total testosterone below 11 nmol/L and free testosterone below 220 pmol/L.
Questionnaires such as ADAM or AMS are sometimes used for screening, but they have low specificity: many men with a "positive" questionnaire have normal testosterone. Therefore, the questionnaire can be a reason for the analysis, but not a substitute for it.
The doctor also pays attention to circumstances that increase the likelihood of hypogonadism: pituitary disease, radiation, HIV infection, long-term use of opioids or glucocorticoids, use of anabolic steroids, type 2 diabetes, osteoporosis, or minor trauma fractures.
How testosterone should be tested
The level of testosterone fluctuates during the day, depends on food intake, sleep, acute illnesses and stress. Therefore, the rules of blood sampling are not a formality, but a condition of authenticity.
- Blood is taken in the morning — usually between 7:00 a.m. and 10:00–11:00 a.m., when hormone levels are highest.
- Fasting: Glucose intake lowers testosterone levels, so fasting is recommended.
- Not during or immediately after an acute illness, not after a night shift or a sleepless night.
- The result is confirmed by repeated measurement on another day.
- It is preferable to use a laboratory with a certified (standardized) method.
The method of analysis is also important. An Endocrine Society position statement (Rosner et al., 2007) addressed the inaccuracy of some direct immunochemical methods in the low range. Liquid chromatography with tandem mass spectrometry is considered the gold standard, and standardization of assays through CDC programs has improved the comparability of results.
For harmonized analyses, Travison et al (2017) defined a reference range for total testosterone in healthy, nonobese men aged 19–39 years as approximately 264–916 ng/dL (approximately 9.2–31.8 nmol/L). It is this range that the Endocrine Society uses.
Free testosterone and SHBG
In the blood, most of the testosterone is bound to proteins — sex hormone-binding globulin (GHB) and albumin. Only a few percent circulates in free form. Free and weakly bound fractions with albumin are considered biologically active.
When SHBG levels are altered, total testosterone can be misleading. SHBG decreases with obesity, insulin resistance, type 2 diabetes, nephrotic syndrome, and androgens; increases with age, with hyperthyroidism, liver diseases, HIV, taking some anticonvulsant drugs.
Therefore, with borderline total testosterone or suspicion of a change in SHBG, the guidelines recommend determining free testosterone. The reference method is equilibrium dialysis, but it is expensive and not available everywhere. In practice, calculation according to the Vermeilen formula is often used based on total testosterone, SHBG and albumin.
Direct analog immunoassays for free testosterone, still offered by some laboratories, are considered imprecise and guidelines do not recommend relying on them. If the form says "free testosterone", it is worth clarifying the method by which it was obtained.
Primary or Secondary: Finding the Cause
Having confirmed low testosterone, the doctor determines LH and FSH. The further diagnostic path depends on their level.
- High LH and FSH — primary hypogonadism: the testicles do not respond to the signal. The causes are Klinefelter's syndrome (confirmed by karyotyping), orchitis, trauma, the effects of chemotherapy, cryptorchidism.
- Low or “normal” LH and FSH—secondary hypogonadism: pituitary or hypothalamic problem. Next, prolactin, ferritin (hemochromatosis), and other pituitary hormones are determined.
- MRI of the pituitary gland according to Endocrine Society guidelines is appropriate for severe secondary hypogonadism (total testosterone below 150 ng/dL), elevated prolactin, signs of other hormonal deficiencies, or neurological symptoms.
It is important to distinguish between organic and functional hypogonadism. Functional is associated with obesity, diabetes, chronic disease, opioid or anabolic steroid use, and is potentially reversible once the cause is removed.
When hypogonadism is confirmed, the consequences are additionally evaluated: bone mineral density (densitometry), a general blood test, and in the presence of infertility, a spermogram.
Diagnostic traps
The most common trap is a diagnosis based on a single test taken at any time of the day. Studies show that a significant proportion of men with a low first result have a normal level when repeated in the morning.
The second is an examination during an acute illness, after surgery or during a diet with a sharp deficit of calories. In such conditions, testosterone is temporarily reduced, and treatment of the "number" does not make sense.
The third is the influence of drugs. Opioids, glucocorticoids, anabolic steroids, GnRH agonists inhibit the axis. Instead, against the background of taking testosterone or stimulants, the analysis reflects the effect of the drugs, and not their own function.
The fourth is ignoring SHBG in obese men. Their total testosterone is often low due to low SHBG, while free testosterone may be normal. Without an assessment of free testosterone, such patients are at risk of being prescribed unnecessary treatment.
Editorial conclusion
Hypogonadism is diagnosed by a combination of symptoms and consistently low morning testosterone, confirmed repeatedly. The method of analysis, the time of sampling and the condition of the patient critically affect the result.
LH and FSH help distinguish the primary form from the secondary, and SHBG and free testosterone help to avoid errors in men with obesity or altered protein metabolism. Only after that, treatment is discussed.
We also advise you to read "Testosterone replacement therapy: indications and contraindications", "Testosterone gels, injections, implants: comparison of forms" and "When to consult an endocrinologist after the course".
References
- Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715â1744.
- Wu FCW, Tajar A, Beynon JM, et al. Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010;363(2):123â135.
- Travison TG, Vesper HW, Orwoll E, et al. Harmonized reference ranges for circulating testosterone levels in men of four cohort studies in the United States and Europe. J Clin Endocrinol Metab. 2017;102(4):1161â1173.
- Rosner W, Auchus RJ, Azziz R, et al. Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab. 2007;92(2):405â413.
- Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666â3672.
- Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423â432.
- Corona G, Goulis DG, Huhtaniemi I, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males. Andrology. 2020;8(5):970â987.
