Testosterone deficiency, popularly known as “low T”, has entered the center stage in both the lay and medical communities. However, how is testosterone deficiency (a.k.a. hypogonadism) diagnosed? What is the testosterone level threshold below which you can say you have low T? What are the references ranges for healthy men?
Here you will find out what the medical guidelines say, what critical information they are ignoring, what you should point out to your doctor if he/she doesn’t think you have low T…
What do current clinical practice guidelines say about how to diagnose testosterone deficiency?
The Endocrine Society clinical practice guideline recommends making a diagnosis of testosterone deficiency only in men with consistent symptoms and signs, who also have unequivocally low blood testosterone levels. They recommend testosterone therapy for men with symptomatic androgen deficiency, with the goal to improve their sexual function, sense of well-being, muscle mass and strength, and bone mineral density.
The Endocrine Society clinical practice guideline is against starting testosterone therapy in patients with:
– Prostate cancer or prostate-specific antigen (PSA) greater than 4 ng/ml or greater than 3 ng/ml in men at high risk for prostate cancer (such as African-Americans or men with first-degree relatives with prostate cancer without further urological evaluation).
– Hematocrit greater than 50%.
– Severe lower urinary tract symptoms with International Prostate Symptom Score (IPSS) above 19,
– Uncontrolled heart failure.
When testosterone therapy is instituted, we suggest aiming at achieving testosterone levels during treatment in the mid-normal range with any of the approved formulations, chosen on the basis of the patient’s preference, consideration of pharmacokinetics, treatment burden, and cost. Men receiving testosterone therapy should be monitored.
What are the testosterone reference ranges for men?
The normative reference ranges for total and free testosterone levels in healthy young men vary among assays and laboratories. While variation between laboratories for the same testosterone assay (analytical method) is negligible, it should be noted that reference intervals for testosterone levels (as well as LH and FSH) differ widely and significantly between assays.
In some laboratories, the lower limit of the normal range for total testosterone level in healthy young men is 280–300 ng/dl (9.8–10.4 nmol/liter), and the lower limit of the normal range for free testosterone level (measured by the equilibrium dialysis method) is 5–9 pg/ml (0.17–0.31 nmol/liter).
According to the medical guidelines, clinicians should use the lower limit of the normal range for healthy young men established in the specific assay that is used.
However, it should be noticed that many assays have established testosterone reference ranges that were compiled from small convenience samples of subjects [3-6], and frequently used unreliable laboratory analytics based on the immunoassay technique , whose accuracy, particularly in the low range, has been questioned.[2, 8-19] Importantly, the immunoassay technique, which is the most widely used method for measuring total testosterone levels, overestimates true levels and has very limited accuracy at levels below 300 ng/dl. Another study found that over 60% of the samples tested (with testosterone levels within the adult male range) measured by most commercial assays had a spread of up to +/- 20% of those reported by LC-MS (liquid chromatography mass spectrometry) , which is the gold standard testosterone analytical method.[19, 20]
Table 1 shows the most recently published reference ranges for total and free testosterone levels, established in a large population of healthy young men aged 19-40 years  and older men aged 70-89 years , using the gold standard LC-MS analytical method.
|Total testosterone (ng/dL)men 19-40 years||Free testosterone (pg/mL) men 19-40 years||Total testosterone (ng/dL)men 70-89 years||Free testosterone (pg/mL) men 73-79 years|
|Highest end of normal range||1322||266||Data not available||Data not available|
|Lowest end of normal range||292||55||Data not available||Data not available|
|Reference limit for low-T||348||70||184||30|
|Reference limit for high-T||1197||230||739||91|
* To convert total testosterone from nanograms per deciliter (ng/dL) to nanomoles per liter (nmol/L), multiply concentrations in ng/dL by 0.0347
* To convert free testosterone from picograms per milliliter (pg/mL) to picomoles per liter (pmol/L), multiply concentrations in pg/mL by 3.47
The first thing to note when comparing the reference ranges between young and older men is the dramatic decline testosterone levels. Total testosterone levels in older men are about 40-50% lower than that of younger men. Free testosterone levels drop even more with age. This data confirms findings from previous studies which have shown that as men get older, levels of free (or bio-available) testosterone decline at a faster rate than total testosterone levels.[23-26]
According to the approach used for defining reference limits for biological parameters [27, 28], total and free testosterone values below the 2.5th percentile (approximately 2 SD [standard deviations] below the mean) are deemed low. For total and free testosterone in young men, this corresponds to 348 ng/dL and 70 pg/mL, respectively. The same applies to defining the high end of the reference limit (approximately 2 SD above the mean). For total and free testosterone, this corresponds to 1197 ng/dL and 230 pg/mL, respectively.
As table 1 shows, the normal range for both total and free testosterone is large, going all the way up to 1322 ng/dL in young men. This means that there is a lot of room for expression of different health outcomes when contrasting the low end with the high end of the normal range. In other words, it is very likely that being in the low end will have very different health consequences vs. being in the high end.
I will go into more depth in an upcoming article on what is an optimal testosterone level. As you might have guessed, this is a controversial topic that is generating a lot of heated discussions among both researchers and medical professionals.
As stated by the US Endocrine Society, and also by European medical organizations, the diagnosis of testosterone deficiency requires the presence of symptoms and signs suggestive of testosterone.[1, 29] Table 2 lists symptoms and signs suggestive of androgen deficiency in men, according to the Endocrine Society.
TABLE 2. Symptoms and signs suggestive of androgen deficiency in men.
|More specific symptoms and signs of low-T||Other less specific symptoms and signs of low-T|
|Reduced sexual desire (libido) and activity.Decreased spontaneous erections.Loss of body (axillary and pubic) hair, reduced shaving.Very small or shrinking testes.Inability to father children, low or zero sperm count.Low bone mineral density.Hot flushes, sweats.||Decreased energy, motivation, initiative, and self-confidence.Feeling sad or blue, depressed mood, dysthymia.Poor concentration and memory.Sleep disturbance, increased sleepiness.Mild anemia (normochromic, normocytic, in the female range).|
Reduced muscle bulk and strength.
Increased body fat.
Diminished physical or work performance.
Several questionnaires are available to help doctors make a diagnosis of testosterone deficiency according to the current medical clinical guidelines. The Androgen Deficiency in Aging Men (ADAM) and the Aging Male Survey (AMS) questionnaires are two examples.[30, 31] Table 3 shows what you will get asked in the ADAM questionnaire.
Table 3: The Androgen Deficiency in Aging Males (ADAM) questionnaire.
1. Do you have a decrease in libido (sex drive)?
2. Do you have a lack of energy?
3. Do you have a decrease in strength and ⁄ or endurance?
4. Have you lost height?
5. Have you noticed a decreased enjoyment of life?
6. Are you sad and ⁄ or grumpy?
7. Are your erections less strong?
8. Have you noticed a recent deterioration in your ability to play sports?
9. Are you falling asleep after dinner?
10. Has there been a recent deterioration in your work performance?
If the answer is ‘yes’ to question 1 or 7, or at least 3 of the other questions, you might have a low testosterone level.
While the ADAM and AMS questionnaires may be useful rough screening tools to screen for hypogonadism across the adult male lifespan , it should be noted that they (like all other questionnaires) are non-specific, i.e. lack diagnostic accuracy. In other words, a man who doesn’t fulfill the criteria can still have low testosterone levels, and vice versa, a man who does fulfill the criteria can have testosterone levels in the normal range. Therefore, the symptoms and signs related to low testosterone levels are only suggestive, not diagnostic of hypogonadism.
Critical problems with the current diagnostic criteria for testosterone deficiency
1. The assumption that there is a specific testosterone level threshold below which the symptoms appear, and that this threshold is the same for everybody.
2. Neglect of the fact the different symptoms often correspond to difference testosterone levels.
3. Ignorance of the fact that testosterone levels in the higher end of the normal range confer health benefits beyond merely symptomatic relief of classical symptoms and signs.
4. Inordinate focus on total testosterone levels, as opposed to free testosterone levels, and not taking into account influence of too low or too high estradiol (the primary estrogen) levels on men’s health.
Diagnosis and treatment of testosterone deficiency is a controversial topic due to the great inter-individual variability in expression of symptoms and sign related to various testosterone levels, and the lack of clear-cut thresholds at which specific symptoms/signs arise.
In the next article I will start tackling each of the problems with the current diagnostic criteria for testosterone deficiency, and alert you on important issues to bring up at your next doctor visit.
1. Bhasin, S., et al., Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2010. 95(6): p. 2536-59.
2. Bhasin, S., et al., The impact of assay quality and reference ranges on clinical decision making in the diagnosis of androgen disorders. Steroids, 2008. 73(13): p. 1311-7.
3. Sikaris, K., et al., Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J Clin Endocrinol Metab, 2005. 90(11): p. 5928-36.
4. Eskelinen, S., et al., Biochemical reference intervals for sex hormones with a new AutoDelfia method in aged men. Clin Chem Lab Med, 2007. 45(2): p. 249-53.
5. Tennekoon, K.H. and E.H. Karunanayake, Serum FSH, LH, and testosterone concentrations in presumably fertile men: effect of age. Int J Fertil, 1993. 38(2): p. 108-12.
6. Boyce, M.J., et al., Are published normal ranges of serum testosterone too high? Results of a cross-sectional survey of serum testosterone and luteinizing hormone in healthy men. BJU Int, 2004. 94(6): p. 881-5.
7. Mohr, B.A., et al., Normal, bound and nonbound testosterone levels in normally ageing men: results from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf), 2005. 62(1): p. 64-73.
8. Rosner, W., et al., Position statement: Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab, 2007. 92(2): p. 405-13.
9. Wang, C., et al., Measurement of total serum testosterone in adult men: comparison of current laboratory methods versus liquid chromatography-tandem mass spectrometry. J Clin Endocrinol Metab, 2004. 89(2): p. 534-43.
10. Taieb, J., et al., Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clin Chem, 2003. 49(8): p. 1381-95.
11. Kushnir, M.M., et al., Performance characteristics of a novel tandem mass spectrometry assay for serum testosterone. Clin Chem, 2006. 52(1): p. 120-8.
12. Salameh, W.A., et al., Validation of a total testosterone assay using high-turbulence liquid chromatography tandem mass spectrometry: total and free testosterone reference ranges. Steroids, 2010. 75(2): p. 169-75.
13. Demers, L.M., Testosterone and estradiol assays: current and future trends. Steroids, 2008. 73(13): p. 1333-8.
14. Cawood, M.L., et al., Testosterone measurement by isotope-dilution liquid chromatography-tandem mass spectrometry: validation of a method for routine clinical practice. Clin Chem, 2005. 51(8): p. 1472-9.
15. Vicente, F.B., et al., Measurement of serum testosterone using high-performance liquid chromatography/tandem mass spectrometry. Clin Chem Lab Med, 2006. 44(1): p. 70-5.
16. Gallagher, L.M., L.J. Owen, and B.G. Keevil, Simultaneous determination of androstenedione and testosterone in human serum by liquid chromatography-tandem mass spectrometry. Ann Clin Biochem, 2007. 44(Pt 1): p. 48-56.
17. Turpeinen, U., et al., Determination of testosterone in serum by liquid chromatography-tandem mass spectrometry. Scand J Clin Lab Invest, 2008. 68(1): p. 50-7.
18. Thienpont, L.M., et al., State-of-the-art of serum testosterone measurement by isotope dilution-liquid chromatography-tandem mass spectrometry. Clin Chem, 2008. 54(8): p. 1290-7.
19. Soldin, S.J. and O.P. Soldin, Steroid hormone analysis by tandem mass spectrometry. Clin Chem, 2009. 55(6): p. 1061-6.
20. Vogeser, M. and K.G. Parhofer, Liquid chromatography tandem-mass spectrometry (LC-MS/MS)–technique and applications in endocrinology. Exp Clin Endocrinol Diabetes, 2007. 115(9): p. 559-70.
21. Bhasin, S. and S. Basaria, Diagnosis and treatment of hypogonadism in men. Best Pract Res Clin Endocrinol Metab, 2011. 25(2): p. 251-70.
22. Yeap, B.B., et al., Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men. J Clin Endocrinol Metab, 2012. 97(11): p. 4030-9.
23. Ferrini, R.L. and E. Barrett-Connor, Sex hormones and age: a cross-sectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men. Am J Epidemiol, 1998. 147(8): p. 750-4.
24. Muller, M., et al., Endogenous sex hormones in men aged 40-80 years. Eur J Endocrinol, 2003. 149(6): p. 583-9.
25. Litman, H.J., et al., Serum androgen levels in black, Hispanic, and white men. J Clin Endocrinol Metab, 2006. 91(11): p. 4326-34.
26. Feldman, H.A., et al., Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab, 2002. 87(2): p. 589-98.
27. Solberg, H.E., International Federation of Clinical Chemistry (IFCC), Scientific Committee, Clinical Section, Expert Panel on Theory of Reference Values, and International Committee for Standardization in Haematology (ICSH), Standing Committee on Reference Values. Approved Recommendation (1986) on the theory of reference values. Part 1. The concept of reference values. J Clin Chem Clin Biochem, 1987. 25(5): p. 337-42.
28. Elveback, L., The population of healthy persons as a source of reference information. Hum Pathol, 1973. 4(1): p. 9-16.
29. Wang, C., et al., Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl, 2009. 30(1): p. 1-9.
30. Morley, J.E., et al., Comparison of screening questionnaires for the diagnosis of hypogonadism. Maturitas, 2006. 53(4): p. 424-9.
31. Morley, J.E., et al., Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism, 2000. 49(9): p. 1239-42.