Hormone Biomarkers: Total Testosterone in Men

Optimal Takeaways

Testosterone is the predominant sex hormone in males though it affects both males and females. At physiologically desirable levels, testosterone supports sexual health and function, red blood cell production, muscle integrity, and cardiometabolic health. 

However, low levels are associated with hypogonadism, infertility, cirrhosis, anemia, low muscle mass, fatigue, cardiometabolic disorders, visceral adiposity, rheumatoid arthritis, autoimmune disorders, osteoporosis, mood changes, loss of libido, hot flushes, migraines, and certain drugs including opioids, steroids, and digoxin. Elevated levels can be seen with hyperthyroidism, testosterone resistance, encephalitis, and certain tumors.

Standard Range: Male 250 - 1100 ng/dL (8.67 - 38.14 nmol/L)

The ODX Range: Male 700 - 1100 ng/dL (24.27 - 38.14 nmol/L)

Low levels of total testosterone are associated with andropause or hypogonadism, Klinefelter syndrome, infertility, orchiectomy, cryptorchidism, encephalitis, hepatic cirrhosis, alcohol intake, and certain drugs including digoxin, dexamethasone, ketoconazole, spironolactone, androgens, steroids (Pagana 2021), and chronic opioid use (Bain 2007).

Low testosterone may also be associated with atherosclerosis, osteoporosis, obesity, metabolic syndrome, diabetes (Deng 2019), increased risk of cardiovascular disease (Hitsumoto 2019), chronic migraine (Shields 2019), anemia, hypercholesterolemia, inflammation, arterial wall stiffness, endothelial dysfunction, myocardial damage, increased mortality and decreased exercise capacity (Yoshihisa 2018). Low levels were associated with type 2 diabetes in men, while elevated levels were associated with T2DM in women (O’Reilly 2019).

High testosterone in males is associated with testosterone therapy, encephalitis, adrenal hyperplasia, hyperthyroidism, testosterone resistance, precocious puberty, and testicular, pituitary, adrenal, pineal, or adrenocortical tumors. Medications that may increase testosterone include estrogens, oral contraceptives, anticonvulsants, and barbiturates (Pagana 2021).

Overview

Testosterone is an anabolic steroid hormone produced from cholesterol. It is involved in the development of secondary sex characteristics and spermatogenesis in males (Pagana 2021). However, it has a wide variety of effects in the body in both males and females. Levels may decline with age but significant decreases or increases should be investigated further.

Testosterone stimulates red blood cell production, enhances muscle strength and type I fibers, and significantly affects cardiovascular function and integrity (Yoshihisa 2018). Not surprisingly, low levels are associated with anemia, decreased muscle mass, low energy, fatigue, lethargy, and weakness. Low levels are also associated with rheumatoid arthritis and other autoimmune disorders, osteopenia, osteoporosis, visceral adiposity, insulin resistance, insomnia, hot flushes, mood changes, loss of motivation and self-confidence, decreased libido, and decreased sexual function (Bain 2007).

Most circulating testosterone is bound tightly to sex hormone binding globulin (SHBG), while up to 40% may be bound loosely to albumin, making it more bioavailable. A small percentage circulates in the free, unbound, active form (Clapauch 2008). If SHBG is either low (e.g., in obesity or testosterone treatment) or high (e.g., in aging), free or bioavailable testosterone should be measured for further clinical evaluation (Shea 2014).

Suboptimal levels of testosterone are associated with cardiometabolic and mood disorders. Once total testosterone drops below 250 ng/dL (8.68 nmol/L) in men, all-cause mortality can double (Dudek 2017). The Hypogonadism in Men (HIM) study found that men 45 years or older with diabetes, hyperlipidemia, hypertension, and obesity were significantly more likely to have total testosterone below 300 ng/dL (10.4 nmol/L), as well as significantly lower bioavailable testosterone, free testosterone, and SHBG (Mulligan 2006).

Increased 5-year cardiovascular incidents were observed in community-dwelling men as total testosterone dropped to 501 ng/dL (17.4 nmol/L) or below (Gyawali 2019). The risk was also associated with an increasing SHBG of 46.7 nmol/L or above in this group.

A prospective study of 618 men with heart failure revealed that those with the lowest testosterone, 300 ng/dL (10.4 nmol/L) or below, had the lowest albumin, total protein, iron, hemoglobin, and VO2 max, as well as the highest ferritin, C-reactive protein, pulse wave velocity, troponin I, and all-cause mortality. Individuals who maintained serum testosterone at a level of 632 ng/dL (21.9 nmol/L) or higher did best (Yoshihisa 2018). Testosterone was found to independently predict all-cause mortality, which increased progressively as testosterone decreased.

Total testosterone of 548 ng/dL (19 nmol/L) or above was associated with the lowest risk of CVD events, including unstable angina, myocardial infarction, stroke, and TIA in a follow-up study of 2,416 men 69-81 years old (Yeap 2018).

In one cross-sectional study of 382 males, low total testosterone was associated with increased whole blood passage time, a cardiovascular risk factor. Individuals presented with traditional risk factors for, but no history of, cardiovascular disease. Low testosterone was also associated with increased BMI, triglycerides, fasting glucose, hemoglobin A1C, HOMA-IR, diabetes, and skin-advanced glycation end products. Researchers recommend maintaining a serum total testosterone of 550 ng/dL (19.1 nmol/L) or above to reduce the risk of primary cardiovascular events (HItsumoto 2019).

Men with chronic migraine had significantly lower levels of testosterone than age-matched controls in a pilot study of 14 migraine sufferers. Researchers note that testosterone is considered neuroprotective (Shields 2019).

Review of data from 1,545 testosterone-deficient men aged 40 or older observed an association between serum testosterone below 300 ng/dL (10.4 nmol/L) and higher BMI (35 or greater), diabetes, heart failure, and angina. The lower serum testosterone was also associated with a low HDL and low physical activity (MET) score (Deng 2019).

A retrospective study that included 70, 541 men revealed a significantly increased risk of type 2 diabetes when testosterone decreased or was at 575 ng/dL (20 nmol/L) or below. The highest risk was observed at testosterone levels below 201 ng/dL (7 nmol/L) (O’Reilly 2019).

Research suggests that as testosterone drops below optimal, specific symptomatology may be observed (Zitzmann 2006, Nieschlag 2020):

Total testosterone                                   Symptoms

• Below 432 ng/dL 15 nmol/L     Loss of libido or vigor (in 41% of subjects)   
• Below 346 ng/dL 12 nmol/L     Obesity, BMI greater than 30
• Below 288 ng/dL 10 nmol/L     Depression, disturbed sleep, difficulty
                                                   concentrating, type 2 diabetes

• Below 230 ng/dL 8 nmol/L      Erectile dysfunction, hot flushes
• Below 225 ng/dL 8 nmol/L      Loss of libido in 90% of subjects
• Below 170 ng/dL 9 nmol/L      Loss of libido in 96% of subjects

Testosterone levels may decrease due to obesity, diabetes, chronic inflammation, and cardiovascular disease (Swee 2019), as well as increased conversion to estradiol via aromatase enzyme (Dudek 2017). If testosterone falls to 175 ng/dL (6 nmol/L) or below, further clinical assessment should be completed to rule out more serious conditions (Giagulli 2020).

However, testosterone therapy may be contraindicated in older men with obesity, diabetes, hypertension, and hyperlipidemia. In a study of 209 men with these comorbidities and total testosterone between 100-350 ng/dL (3.5-12.1 nmol/L), those who received transdermal testosterone gel had significantly more adverse cardiac events than those receiving placebo. Testosterone dosing was adjusted depending on serum testosterone which rose to 1000 ng/dL (34.7 nmol/L) in some cases (Basaria 2010).

Testosterone should be measured in the morning as it peaks (Shea 2014) and repeated to determine an individual’s baseline, as levels can vary throughout the day and from day-to-day (Collier 2010).

References

Bain, Jerald. “The many faces of testosterone.” Clinical interventions in aging vol. 2,4 (2007): 567-76. doi:10.2147/cia.s1417

Basaria, Shehzad et al. “Adverse events associated with testosterone administration.” The New England journal of medicine vol. 363,2 (2010): 109-22. doi:10.1056/NEJMoa1000485

Clapauch, Ruth et al. “Laboratory diagnosis of late-onset male hypogonadism andropause.” Arquivos brasileiros de endocrinologia e metabologia vol. 52,9 (2008): 1430-8. doi:10.1590/s0004-27302008000900005

Collier, Christine P et al. “The significance of biological variation in the diagnosis of testosterone deficiency, and consideration of the relevance of total, free and bioavailable testosterone determinations.” The Journal of urology vol. 183,6 (2010): 2294-9. doi:10.1016/j.juro.2010.02.011

Deng, Chunhua et al. “Analysis of cardiovascular risk factors associated with serum testosterone levels according to the US 2011-2012 National Health and Nutrition Examination Survey.” The aging male : the official journal of the International Society for the Study of the Aging Male vol. 22,2 (2019): 121-128. doi:10.1080/13685538.2018.1479387

Dudek, Piotr et al. “Late-onset hypogonadism.” Przeglad menopauzalny = Menopause review vol. 16,2 (2017): 66-69. doi:10.5114/pm.2017.68595

Giagulli, Vito Angelo et al. “Critical evaluation of different available guidelines for late-onset hypogonadism.” Andrology vol. 8,6 (2020): 1628-1641. doi:10.1111/andr.12850

Gyawali, Prabin et al. “Higher Serum Sex Hormone-Binding Globulin Levels Are Associated With Incident Cardiovascular Disease in Men.” The Journal of clinical endocrinology and metabolism vol. 104,12 (2019): 6301-6315. doi:10.1210/jc.2019-01317

Hitsumoto, Takashi. “Clinical Significance of Low Blood Testosterone Concentration in Men as a Cardiovascular Risk Factor From the Perspective of Blood Rheology.” Cardiology research vol. 10,2 (2019): 106-113. doi:10.14740/cr858

Mulligan, T et al. “Prevalence of hypogonadism in males aged at least 45 years: the HIM study.” International journal of clinical practice vol. 60,7 (2006): 762-9. doi:10.1111/j.1742-1241.2006.00992.x

Nieschlag, E. “Late-onset hypogonadism: a concept comes of age.” Andrology vol. 8,6 (2020): 1506-1511. doi:10.1111/andr.12719

O'Reilly, Michael W et al. “Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort.” Clinical endocrinology vol. 90,1 (2019): 145-154. doi:10.1111/cen.13862

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Shea, Jennifer L et al. “Free testosterone: clinical utility and important analytical aspects of measurement.” Advances in clinical chemistry vol. 63 (2014): 59-84. doi:10.1016/b978-0-12-800094-6.00002-9

Shields, Lisa B E et al. “Testosterone levels in men with chronic migraine.” Neurology international vol. 11,2 8079. 19 Jun. 2019, doi:10.4081/ni.2019.8079

Swee, Du Soon, and Earn H Gan. “Late-Onset Hypogonadism as Primary Testicular Failure.” Frontiers in endocrinology vol. 10 372. 12 Jun. 2019, doi:10.3389/fendo.2019.00372

Yeap, Bu B. “Testosterone and its metabolites: differential associations with cardiovascular and cerebrovascular events in men.” Asian journal of andrology vol. 20,2 (2018): 109-114. doi:10.4103/aja.aja_50_17

Yoshihisa, Akiomi et al. “Relation of Testosterone Levels to Mortality in Men With Heart Failure.” The American journal of cardiology vol. 121,11 (2018): 1321-1327. doi:10.1016/j.amjcard.2018.01.052

Zitzmann, Michael et al. “Association of specific symptoms and metabolic risks with serum testosterone in older men.” The Journal of clinical endocrinology and metabolism vol. 91,11 (2006): 4335-43. doi:10.1210/jc.2006-0401