Low Testosterone in Men
Diagnosis
Video Lesson
Experts you'll learn from
Former President, ASRM
Professor, Urology
Weill Cornell Medicine
Vice President, ASRM
Vice Chair, Clinical Urology
Northwestern University Feinberg
Written Lesson
Normal vs. Low Testosterone Levels
According to guidelines from the American Urological Association (AUA) and the European Association of Urology (EAU), a diagnosis of hypogonadism can be made if a patient shows signs and symptoms along with consistently low total testosterone levels on at least two separate morning blood tests done under fasting conditions.
Cut-off values for diagnosis also vary by organization and geographic location, with most studies utilizing a lower limit between 200—325ng/dL total testosterone. The AUA recommends a lower limit of 300ng/dL total testosterone in diagnosing hypogonadism. Below are the normal ranges of total and free testosterone in men based on age.
Prevalence of Hypogonadism
Determining the prevalence of hypogonadism in the general population has yielded varied results, ranging from as low as 2% to as high as 40%. This variation depends on factors such as the age of participants and the criteria used to define low testosterone levels. For instance, a study by McBride et al. in 2016 estimated the prevalence to be approximately 7% in men under 40 years and 38% in men over 45 years when the minimum total testosterone level was set at 300 ng/dL.
In the Massachusetts Male Aging Study conducted between 1987 and 1997, hypogonadism was defined as having at least three signs or symptoms and a total testosterone level less than 200 ng/dL, or having at least three signs or symptoms and a total testosterone level between 200 and 400 ng/dL, with free testosterone levels less than 8.91 ng/dL. Based on these guidelines, the study estimated the prevalence of symptomatic hypogonadism as between 6—12%, as shown in the table below.
Signs & Symptoms
The signs and symptoms associated with hypogonadism can be categorized into sexual, physical, and psychological manifestations. The timing of onset greatly influences the severity of the phenotype with earlier onset associated with the most pronounced effects.
In cases where hypogonadism begins in utero the effects can be profound, impacting sexual differentiation and reproductive function including underdeveloped or ambiguous external genitalia. During puberty, hypogonadism may manifest as delayed or incomplete development of secondary sexual characteristics, such as sparse facial and body hair, underdeveloped genitalia, and delayed growth spurts. Interestingly, some young men with low testosterone levels have no symptoms whatsoever. For them, their existing, albeit low, testosterone level is the highest they have ever experienced, so they feel normal. Men who have a dramatic or sudden drop in testosterone levels are most likely to notice symptoms.
In adulthood, symptoms can include reduced libido, erectile dysfunction, infertility, decreased muscle mass and strength, increased body fat, gynecomastia, decreased bone density, fractures, fatigue, depression, and cognitive impairment. These symptoms are systemic and can vary in specificity, making diagnosis and management challenging. Therefore, a comprehensive evaluation of signs, symptoms, and laboratory findings is crucial for accurate diagnosis and appropriate treatment of hypogonadism.
Below are some of the typical signs and symptoms linked with late onset hypogonadism as described by the EAU. The specificity of a symptom indicates how well it points to a specific disease. The more specific a symptom is, the clearer it points to a distinct cause, while less specific symptoms, which can show up in various conditions, can make diagnosis trickier.
A 2010 New England Journal of Medicine study conducted by Wu et al. sought to characterize symptoms associated with low testosterone. The primary aim was to identify specific threshold levels of both total and free testosterone where, if a patient’s levels were to fall below them, the prevalence of these symptoms would notably increase. A summary of some results from this study are outlined in the table below. It’s important to note that for an individual patient, the referenced cut-points for testosterone levels cannot be used to interpret whether symptoms are occurring because of low testosterone alone.
Below is a flow chart of the stepwise approach doctors use to assess patients who show signs and symptoms of testosterone deficiency.
Who Should Be Tested
Low testosterone can affect various aspects of life with diverse effects ranging from reduced sex drive and erectile problems to physical changes like hair loss and hot flashes. Some men might experience fertility problems while others may notice physical and psychological issues such as feeling down, struggling with memory and focus, and weight gain. Moreover, it can impact muscle strength, endurance, and even lead to enlarged breast tissue.
Medical associations have varied guidelines regarding who should undergo testing of serum testosterone levels. While some guidelines suggest screening for some symptoms while others do not, broadly speaking, physicians will screen patients who have unexplained anemia, involuntary loss of muscle mass and strength as well as bone density loss, loss of libido, erectile dysfunction, fewer and decreased morning erections, or unexplained depression. Some doctors may also screen patients with infertility, HIV, or who have a history of chronic opioid or glucocorticoid use for low testosterone.
Impact on Fertility
Studies have shown a correlation between low T and reduced success with fertility but there remains work to be done in this arena. For example, one study conducted by DiGuardo and colleagues on men in Belgium between 2009 and 2017 found that although abnormal semen parameters were more likely to be observed in men with low total testosterone compared with those with normal testosterone levels, the results were not statistically significant.
Another study by Trussell and colleagues published in 2019 in Fertility and Sterility investigated male partners of infertile couples undergoing intrauterine insemination (IUI). The study revealed a significant association between low total testosterone levels and abnormal sperm morphology (size and shape). Moreover, the findings suggested that lower total testosterone was also linked to a reduced live birth rate in follow-ups among the couples.
Since low testosterone can be related to abnormal sperm production, the most recent guidelines for the evaluation and management of male infertility recommend measurement of serum testosterone for men with oligospermia, which is sperm concentration less than 15 million sperm/mL. Treatment of infertile men with low testosterone is typically focused on enhancing the man’s testosterone production with medications such as selective estrogen receptor modulators, aromatase inhibitors, or hCG, as discussed below.
Evaluating Testosterone Levels
Testosterone is primarily transported attached to proteins rather than freely circulating in the blood. The active form called free testosterone (FT) represents only about 3% of the total in circulation. Some testosterone loosely binds to a protein called albumin, making it potentially active and easily available to be in the free form. However, when it binds tightly to another protein called sex hormone binding globulin (SHBG), it becomes unavailable to interact with cells throughout the body. Total testosterone (TT) encompasses all forms present in the blood, including bound and unbound testosterone, while bioavailable testosterone (BT) includes both free and loosely bound testosterone, representing the hormone accessible for cellular action.
Several tests are accessible for gauging testosterone levels and deciphering their significance, each with its own set of tradeoffs concerning availability, simplicity of execution, cost, accuracy, and reproducibility. Your physician will typically assess your total testosterone levels to provide a broad understanding of your overall production status. Blood samples for these tests should be taken in the morning because testosterone follows a circadian production pattern, reaching its peak in the morning and declining throughout the day. Additionally, since food intake may affect testosterone levels, it's advisable to conduct the test under fasting conditions. Since bioavailable testosterone is difficult to measure, many practitioners evaluate levels based on total testosterone alone.
Interpreting Test Results
In general, a clinically significant low testosterone level is considered to be below about 300ng/dL. Many clinical guidelines differ on whether there's a specific threshold for diagnosing low testosterone and consider repeating blood tests to confirm a low reading since testosterone levels and its measurement is highly variable in the laboratory.
Diagnosing low testosterone involves evaluating both a person's symptoms and specific test results to gauge the overall impact on their health. Typically, a healthcare provider will assess signs and symptoms suggestive of hypogonadism and confirm with at least two low serum total testosterone levels taken in the morning. However, guidelines reflect a wide series of different evaluation approaches, even considering geographic location. For instance, the Canadian Medical Association does not mandate a repeated measure of serum testosterone if the initial test indicates a low level. Below are the testosterone thresholds recommended by various global organizations.
Additional Testing
In addition to evaluating total testosterone levels, individuals suspected of hypogonadism may require further testing to thoroughly assess their condition. Assessing levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) can offer valuable insights into the functioning of both the pituitary gland and testes.
Testing for other hormones such as estradiol and prolactin may be necessary to rule out underlying conditions that could mimic symptoms of hypogonadism. Prolactin testing is also indicated in men with impaired libido. If prolactin levels are significantly elevated, an MRI may be recommended to rule out a pituitary tumor, while testicular ultrasound can help identify any structural abnormalities or tumors within the testes.
This comprehensive approach to testing ensures a detailed understanding of the individual's hormonal profile, facilitating accurate diagnosis and tailored treatment planning for male hypogonadism. Below we provide some details on the various additional tests that your healthcare provider may perform.
Luteinizing Hormone (LH)
Alongside a repeated testosterone test, LH testing will help to determine the underlying cause of the testosterone deficiency and guide treatment. Low or low/normal LH levels are indicative of secondary hypogonadism (issue with the brain) while elevated LH levels point to primary hypogonadism (issue with the testes). If LH levels are very high, a type of chromosomal analysis test called a karyotype may be used to assess for Klinefelter syndrome (KS), a condition characterized by the presence of an extra X chromosome.
Prolactin
The AUA advises assessing prolactin levels if low or normal LH levels are detected or libido is impaired. Elevated prolactin levels, often caused by a pituitary tumor, can suppress LH secretion, resulting in decreased testosterone production. Therefore, evaluating prolactin levels is essential for identifying potential pituitary abnormalities and understanding their impact on testosterone levels. If prolactin levels are found to be persistently elevated and without a known cause, an MRI would be the next step with treatment options depending on the cause.
Follicle Stimulating Hormone (FSH)
Before beginning treatment, patients who wish to preserve their fertility should undergo baseline FSH testing. Elevated FSH levels indicate potential issues with sperm production, in which case a semen analysis will be performed. As with LH, when very high FSH levels are present, a karyotype for KS may be recommended.
Estradiol
Serum estradiol measurement is recommended before commencing treatment for patients who present with breast issues, including gynecomastia (breast enlargement). This will allow your medical provider to monitor and control estrogen levels with medications aimed at inhibiting estrogen production during treatment.
Hemoglobin/Hematocrit (Hb/Hct)
Before starting any therapy aimed at increasing testosterone levels, patients should undergo an assessment of their baseline hemoglobin (Hb) and hematocrit (Hct) levels. This is important because testosterone therapy can potentially lead to an increase in red blood cell levels, and monitoring Hb/Hct levels helps to identify any abnormalities or changes that may occur during treatment.
Prostate-Specific Antigen (PSA)
PSA is a protein produced by the prostate gland. It’s commonly measured through a blood test and is used as a screening tool for prostate cancer and to monitor the progression of the disease. Testosterone therapy has the potential to stimulate prostate tissue growth, which could potentially exacerbate underlying prostate conditions if they are present. For this reason, a PSA test is performed prior to commencement of therapy.
Sex Hormone-Binding Globulin (SHBG)
In men, most testosterone is bound to SHBG, leaving only a small portion free and active. In hypogonadism, SHBG levels may be altered, influencing free and bioavailable testosterone balance. Low SHBG can elevate free testosterone, masking true deficiency, while high SHBG can lower free testosterone, worsening symptoms despite normal total testosterone. Evaluating SHBG alongside total testosterone aids in understanding hormonal status and tailoring treatment. Monitoring SHBG over time helps assess treatment response and optimize therapy for hypogonadism.
HbA1C
While a definitive link between low testosterone and diabetes remains uncertain, individuals with type 2 diabetes face a higher likelihood of hypogonadism. The AUA suggests that middle-aged or older men with low testosterone and factors such as obesity, metabolic syndrome, or chronic corticosteroid use should undergo HbA1c testing. Follow-up is recommended for those showing abnormal HbA1c levels, aiding in the early detection and management of potential diabetes-related complications.
Bone Densitometry
Testosterone deficiency heightens the risk of bone density loss and subsequent fractures. For men with very low testosterone levels or a history of fractures, a dual-energy x-ray absorptiometry (DEXA) scan is used to measure bone mineral density (BMD). This scan helps assess the severity of bone weakening and guides treatment decisions to manage the condition effectively.