Male Hypogonadism

Medical Experts

Contributor

Doyle

Kelly Doyle, PhD, DABCC, FAACC

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Special Chemistry and Endocrinology, ARUP Laboratories

Contributor

Straseski

Joely A. Straseski, PhD, MS, MT(ASCP), DABCC, FAACC

Professor of Pathology (Clinical), University of Utah

Head of Clinical Operations for Clinical Chemistry, Toxicology, and Biochemical Genetics; Medical Director, Endocrinology; Co-Director, Automated Core Laboratory, ARUP Laboratories

Male hypogonadism is defined as a failure, in individuals with testes, to produce either a normal concentration of testosterone or a normal number of spermatozoa. Signs and symptoms vary from highly specific (eg, incomplete sexual development and very small testes) to nonspecific (eg, decreased energy, mild anemia, and depressed mood). Hypogonadism is caused by one or more defects along the hypothalamic-pituitary-testicular axis. Hypogonadism may be either primary (resulting from defects in the testes) or secondary (resulting from defects in the hypothalamus or pituitary gland). Hypogonadism may also be categorized as organic (or classical) hypogonadism or functional (or late onset) hypogonadism. The former results from permanent dysfunction of the testes, hypothalamus, or pituitary gland, whereas the latter may be reversible if the underlying condition is treated.

A diagnosis of hypogonadism requires both clinical signs or symptoms of testosterone deficiency and consistently low testosterone concentrations, as demonstrated by laboratory testing. Testosterone therapy should not be considered unless both of these conditions are met.

Quick Answers for Clinicians

What is functional hypogonadism, and which laboratory tests must be performed before prescribing testosterone therapy for this diagnosis?

Compared with primary hypogonadism, functional hypogonadism is associated with a later age of onset, more modest decreases in testosterone concentrations, and subtler clinical presentations. The signs and symptoms of late-onset hypogonadism may be very nonspecific (eg, reduced libido, decreased energy, sleep disturbance, and increased body fat).

Research indicates that there has been an increase in testosterone prescriptions in the United States and that many adult cisgender males who are prescribed testosterone therapy do not have their testosterone concentrations checked or do not meet the criteria to be diagnosed with testosterone deficiency. Both signs and symptoms of testosterone deficiency and consistently low serum testosterone concentrations are needed for a diagnosis of functional hypogonadism.

Is general population screening for hypogonadism recommended?

No, general population screening for male hypogonadism is not recommended. Low testosterone concentrations alone do not establish a diagnosis of hypogonadism, and the benefits and risks of testosterone therapy in asymptomatic individuals with unexpectedly low testosterone concentrations are unclear. Instead, testing for hypogonadism should be limited to symptomatic individuals or those presenting with medical issues that may be associated with lower testosterone concentrations (eg, infertility, pituitary mass, use of opioids or glucocorticoids, and withdrawal from anabolic-androgenic steroids).

Should standardized testosterone assays be used for the diagnosis of male hypogonadism?

Reference intervals for testosterone assays vary widely between laboratories and methods. Standardization is important because it improves the accuracy and precision of laboratory testing for the diagnosis of diseases such as male hypogonadism. The CDC provides an accuracy-based standardization program for some hormone testing, which includes total testosterone. To receive certification, an assay must meet certain performance criteria. Ideally, total testosterone testing should be conducted using a CDC-certified assay. For a list of certified assays, refer to the CDC’s hormone standardization website.

Free testosterone assays are not included in the CDC’s standardization program. For these tests, laboratories should establish their own reference intervals for free testosterone as calculated or as measured by equilibrium dialysis.

For guidance in selecting an appropriate ARUP test, please refer to the Testosterone Tests Comparison table.

Indications for Testing

Testing for hypogonadism should be performed in individuals with testes who present with signs and symptoms of testosterone deficiency or who have conditions associated with testosterone deficiency (eg, infertility, pituitary mass, use of opioids or glucocorticoids, and withdrawal from anabolic-androgenic steroids).

Highly specific signs and symptoms include incomplete or delayed sexual development, loss of body hair, and testicular volume <6 mL. Suggestive signs and symptoms include reduced libido, gynecomastia, infertility, low bone mineral density, and eunuchoid body proportions. These signs and symptoms may vary depending on the age of onset of testosterone deficiency and are generally more severe in individuals with prenatal testosterone deficiency than in those with postpubertal testosterone deficiency.

For individuals primarily concerned with infertility, refer to the ARUP Consult Infertility topic.

Laboratory Testing

Diagnosis

The diagnosis of hypogonadism is established by laboratory confirmation of low testosterone in patients with signs and symptoms suggestive of hypogonadism.

Testosterone

Total testosterone is the initial test for hypogonadism in individuals with testes. The preferred testing method is immunoassay for adult cisgender males and mass spectrometry for prepubertal individuals or anyone for whom low testosterone concentrations would be expected. Total testosterone should be measured twice on two different specimens taken on two separate mornings when the patient has fasted. To ensure accurate comparison, both specimens should be tested using the same laboratory and method.

Free testosterone should be assessed in individuals who have a borderline total testosterone concentration (a concentration near the lower limit of the reference interval) or who have protein-binding abnormalities (conditions that either increase or decrease sex hormone-binding globulin [SHBG] activity). Free testosterone should be established by calculation using total testosterone (measured by immunoassay) and the binding constant of testosterone and SHBG. Equilibrium dialysis is the gold-standard method for measuring free testosterone and may be useful in certain situations.

For more information about which testosterone test is appropriate for a particular patient population, see the Testosterone Tests Comparison table.

If low testosterone is confirmed in patients with signs and symptoms suggestive of hypogonadism, then a diagnosis of hypogonadism is established.

Luteinizing Hormone and Follicle-Stimulating Hormone

Assessing the concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) can help differentiate between a diagnosis of primary hypogonadism and secondary hypogonadism. High serum LH and FSH concentrations indicate primary hypogonadism. Low or normal concentrations indicate secondary hypogonadism.

Etiologic Testing

For individuals with primary hypogonadism, consider karyotype testing to assess for Klinefelter syndrome, especially for those with a testicular volume of <6 mL.

For those with secondary hypogonadism, iron saturation and/or serum ferritin testing should be performed to assess for iron overload syndromes such as hemochromatosis, and serum prolactin should be measured to assess for hyperprolactinemia. Imaging of the pituitary gland and testing of other pituitary hormones may also be indicated to assess for hypopituitarism.

Treatment-Related Testing

Testosterone

Testosterone concentration should be assessed 3-6 months after the initiation of therapy, then again at 12 months after the initiation of therapy, and then annually thereafter with the goal of achieving a concentration in the middle of the reference interval. The timing of the test depends on the specific type of testosterone therapy being administered. Total testosterone is the standard test used to monitor testosterone therapy, but free or bioavailable testosterone measurements may be used in individuals with protein-binding abnormalities (conditions that either increase or decrease SHBG activity).

Testosterone Reference Intervals and Standardization

Reference intervals for testosterone assays vary widely between laboratories and methods. The CDC provides an accuracy-based standardization program for total testosterone testing, and, ideally, testosterone testing should be conducted using a CDC-certified assay. A list of CDC-certified assays can be found here.

Free testosterone assays also lack standardization. For these tests, laboratories should establish their own reference intervals for free testosterone as calculated or as measured by equilibrium dialysis.

The recommended testosterone concentrations for diagnosis of hypogonadism and therapeutic goals of testosterone therapy vary by society guideline. The concentrations as recommended by several different societies are listed below.

Testosterone Reference Intervals by Society Guideline
Society	Cutoff for Low Total Testosterone	Borderline Total Testosterone Concentrations^a	Target Interval for Testosterone Therapy
Endocrine Society (2018)	<264 ng/dL <9.2 nmol/L	200-400 ng/dL 6.9-13.9 nmol/L	350-600 ng/dL 14.1-24.5 nmol/L
American Urological Association (2018)	<300 ng/dL <10.4 nmol/L	n/a	450-600 ng/dL 15.6-20.8 nmol/L
European Association of Urology (2018)	<231 ng/dL <8 nmol/L	231-346 ng/dL 8-12 nmol/L	Midnormal^b
International Society for Sexual Medicine (2015)	<231 ng/dL <8 nmol/L	231-346 ng/dL 8-12 nmol/L	Midnormal^b
British Society for Sexual Medicine (2017)	<231 ng/dL <8 nmol/L	231-346 ng/dL 8-12 nmol/L	433-865 ng/dL 15-30 nmol/L
^aFollow-up testing with free testosterone is recommended. ^bNo numerical interval offered. n/a, not available Source: Bhasin, 2018; Mulhall, 2018; Kwong, 2019; Dohle, 2018; Dean, 2015; Hackett, 2017

Hemoglobin and Hematocrit

Because testosterone therapy may increase the risk of polycythemia, hemoglobin and hematocrit should be assessed before initiating therapy. In individuals with a hematocrit of more than 50%, therapy should be postponed until the etiology is investigated. Hematocrit should also be tested 3-6 months after starting treatment, then again 12 months after starting treatment, and then annually thereafter. If hematocrit reaches 54% or higher during treatment, treatment should be temporarily discontinued and then reinitiated with a reduced dose.

Prostate-Specific Antigen

Individuals 55-69 years of age (or 40-69 years of age in high-risk groups) who are pursuing testosterone therapy should participate in shared decision-making to determine if monitoring for prostate cancer is appropriate. For those who elect monitoring, digital rectal examination (DRE) and prostate-specific antigen (PSA) testing should be performed before beginning testosterone therapy and then 3-12 months after starting testosterone therapy. After a year of testosterone therapy, the clinician should follow the standard screening protocol for prostate cancer. For more information, see the ARUP Consult Prostate Cancer topic.

Estradiol

Serum estradiol should be measured in individuals with gynecomastia before beginning testosterone therapy. If elevated, an endocrinologist should be consulted. Testosterone therapy can raise estradiol concentrations, which may in turn lead to gynecomastia or other breast symptoms.