Effective Date: September 19, 2018
Revised Date: October 27, 2022
This protocol reviews the appropriate use of serum testosterone testing in men and women aged ≥ 19 years. This document is intended to direct primary care practitioners and to help constrain inappropriate test utilization, particularly as it pertains to “wellness” and “anti-aging” practices. This protocol expands on the guidance provided in the associated BC Guideline.ca – Hormone Testing – Indications and Appropriate Use.
Testosterone testing for pediatric and transgender* patients is out of scope of this protocol. For information and guidance on testosterone testing for transgender people, refer to Gender-affirming Care for Trans, Two-Spirit, and Gender Diverse Patients in BC: A Primary Care Toolkit, produced by Trans Care BC at the Provincial Health Services Authority.
Symptom Assessment
Timing and Frequency
Unsupported Indications
The testosterone tests available in British Columbia are:
MSP Cost of Tests1
Test | Cost |
---|---|
Testosterone – total | $15.81 |
cBAT (includes SHBG) | $29.37 |
Current to April 1st, 2022.
Circulating testosterone exists in three forms: free, weakly bound to albumin, and strongly bound to SHBG. Serum total testosterone measures all three forms. Bioavailable testosterone is the sum of free testosterone and albumin bound testosterone. In BC, all bioavailable and free testosterone results are calculated rather than directly measured. Calculated bioavailable testosterone (cBAT) and calculated free testosterone are derived from the same calculation, which utilizes both the measured total testosterone and measured SHBG concentrations. Although the two parameters may be reported separately, cBAT and calculated free testosterone are functionally and diagnostically equivalent (and therefore redundant) – as such, only cBAT will be referenced in the remainder of the guideline. Reference ranges for serum total testosterone and cBAT are method and age dependent and are determined by each laboratory independently.
Patients should use the same lab for initial and follow up testosterone tests because reference ranges are lab-dependent,2 meaning that results from different labs may not be comparable. For more information about the different forms of testosterone in plasma and their measurement, refer to BCGuidelines.ca – Hormone Testing Guideline Appendix A: Testosterone Testing and Measurement in BC.
Routine biochemical screening for testosterone deficiency (hypogonadism) in asymptomatic men is not recommended. A decision to test must be guided by the medical history and clinical examination. In the case of isolated, or non-specific symptoms only, a comprehensive general assessment is required to exclude potential alternative explanations3 and to guide further investigations.
When an untreated male patient is investigated for hypogonadism and is incidentally discovered to have a high total testosterone, hypogonadism is ruled out. Incidental discovery of a modest elevation total testosterone in the context of an investigation for hypogonadism does not necessarily warrant investigation.
In the case of follow up of a previously ordered, relatively low, testosterone measurement, in a minimally symptomatic man, refer to Appendix A: Differential Diagnosis of Hypogonadism in Men (PDF, 95KB) and Appendix B: Medications that May Alter Testosterone Levels in Men and Women (PDF, 95KB) for conditions and medications associated with changes in testosterone concentration.
Late onset hypogonadism (LOH), defined as hypogonadal symptoms in a male over 65 years of age, with associated serum testosterone concentrations less than 6-8 nanomoles (nmol) per litre,10 and the symptoms identified in Table 1: Symptoms and signs of testosterone deficiency in men, in order of specificity, below.
LOH is frequently associated with obesity and type 2 diabetes mellitus (T2DM).3 The long-term outcome of treating the hypogonadal symptoms associated with this condition are uncertain, and there are unclear cardiovascular safety concerns. However, addressing the underlying conditions (obesity and T2DM) associated with LOH through significant weight loss (10% of total body weight or greater)11 will increase the serum testosterone concentration, improve the hypogonadal symptoms, and benefit the long-term cardiovascular outcomes and cognitive function in this patient. Therefore, treatment of the causes
of the late onset hypogonadism (which offers the opportunity to improve morbidity and mortality) should be prioritized over the biochemical recognition, and symptomatic treatment, of the hypogonadism itself.3
There are many non-specific somatic and psychological symptoms associated with hypogonadism (refer to the “Supportive” and “Not specific” columns in Table 1: Symptoms and signs of testosterone deficiency in men, in order of specificity, below). Any one of these findings in isolation, including erectile dysfunction,4 is insufficient grounds to order a testosterone test.
Table 1: Symptoms and signs of testosterone deficiency in men, in order of specificity5, 6
Specific to testosterone deficiency | Supportive of testosterone deficiency | Not specific to testosterone deficiency |
---|---|---|
|
|
|
Adapted from Bhasin 20106 and Bhasin 20185
Serum total testosterone is the initial test of choice. Specimens must be collected in the morning,8 preferably before 10:00AM, or within 3 hours of waking, and preferably in a fasting state.5, 9 Testing should occur when the sleep-wake pattern is stable (e.g., not during shift changes or jetlag). Testing of serum total testosterone should be performed when patients are clinically well; do not test during acute illness or hospitalization.
If the total testosterone level is below the lab-specific lower limit of normal (approximately 8 nmol/L in younger men (<30 years), and 6 nmol/L in older men (>50 years)),10–13 and a diagnostic question remains, cBAT (which includes SHBG) can be used to confirm or rule out hypogonadism. Total testosterone is determined in large part by the carrier protein SHBG, the latter of which can vary markedly between individuals.10 That is, low SHBG can cause low testosterone, and this situation can be clarified with cBAT. See Table 2: Conditions associated with alterations in SHBG concentrations in men and women, for a list of conditions that may impact SHBG.
Decreased SHBG Concentrations | Increased SHBG Concentrations |
---|---|
|
|
α Particularly common conditions associated with alterations in SHBG levels
Note that testosterone is characterized by variable secretion. Healthy adult males will experience fluctuations in testosterone levels due to biologic variation (10-15%) meaning that two successive measurements on the same individual are expected to differ by up to, but typically not more than, 30%.
In BC it has been observed that men frequently receive prescriptions for testosterone replacement without first having a serum testosterone test to confirm low levels.15 This practice is not appropriate, as biochemical confirmation of a low for age serum total testosterone (or cBAT) is necessary to confirm the clinical impression of hypogonadism. In the absence of this biochemical confirmation, a re-visitation or verification of the original empiric diagnosis will be very difficult since prolonged androgen therapy will result in suppression of the hypothalamic pituitary gonadal axis for as long as 18 months.
While specific investigation is beyond the scope of this protocol, it is important to establish the etiology of hypogonadism, after biochemical confirmation of the clinical diagnosis, and before initiating testosterone replacement. Refer to Appendix A: Differential Diagnosis of Hypogonadism in Men (PDF, 95KB) and Appendix C: Hypogonadism Investigation Algorithm (PDF, 95KB) for guidance on initial investigation and testing.
Prior to initiating testosterone replacement, the following baseline tests are recommended: hematocrit, prostate-specific
antigen (PSA), and digital rectal exam (DRE).7 Other contraindications to testosterone replacement should be considered. These are discussed in detail elsewhere.5,7 Occasionally the cause of hypogonadism is congenital/pituitary/hypothalamic in nature and if there are pre-existing risk factors (e.g., cranial irradiation, hemochromatosis), referral to endocrinology is recommended. Refer to Appendix C: Hypogonadism Investigation Algorithm (PDF, 95KB) for more information.
Consider referral if uncertain. Indications for referral to specialists are outlined in Table 3: Indications for consideration of referral to an endocrinologist, urologist, or obstetrician/gynaecologist as appropriate below.
Monitor men receiving androgen replacement by repeating the hematocrit, PSA test, and DRE at three and six months after initiation, then annually if stable.7 Some recommend that PSA testing after one year is not necessarily obligatory.5 Men receiving stable androgen replacement can be tested with serum total testosterone testing annually.5, 7
Blood collection timing by route of administration:5
Total testosterone testing is indicated to confirm adequacy of androgen deprivation therapy (ADT) in men with prostate carcinoma. Only tandem mass spectrometry is sufficiently sensitive to accurately measure the low total testosterone seen in men rendered chemically castrate for treatment of prostate carcinoma.16 In BC, testosterone analysis by tandem mass spectrometry is available upon request and should be specifically indicated on the requisition. Testosterone should be tested three months after initiating ADT, and in the event of any increase in PSA levels.
Testosterone testing is indicated for investigation of signs and symptoms of hyperandrogenism in women based on medical history and clinical examination. Testosterone testing is not indicated for the investigation of women with low libido.17
The upper limit of normal for testosterone in women is approximately 2-3 nmol/L, or slightly higher depending on menstrual phase and use of oral contraceptive medications.18 In polycystic ovarian syndrome, total testosterone concentrations are within the normal reference interval or slightly higher. Consequently, testosterone concentrations greater than twice the upper limit of normal (i.e., greater than 5 nmol/L) suggest an alternate etiology, such as an androgen-secreting tumour.
A range of symptoms and signs from hirsutism to virilisation may occur. The Endocrine Society recommends testing for hyperandrogenism in women with hirsutism that is moderate or severe, of rapid onset, or accompanied by menstrual dysfunction, obesity or clitoromegaly.19 Other indications for referral are outlined in Indications for Referral.
Serum total testosterone is frequently normal in women with mild clinical hyperandrogenism (due to androgen suppression of SHBG production). cBAT testing (which includes SHBG) has a better diagnostic yield for testosterone excess in women.20 Repeat serum testosterone testing is not indicated if cBAT is normal. Testing of other androgens is dependent on clinical findings and is beyond the scope of this protocol; for more information refer to the BC Guideline Hormone Testing - Indications and Appropriate Use. For women who have regular menstrual cycles, collection should be performed in the morning on
day 4-10.19
The diagnosis of testosterone excess is based on medical history and physical findings, followed by investigational tests. Polycystic ovary syndrome (PCOS) is the most common cause of hirsutism21 and of excess androgen production in pre-menopausal women.19 It is important to rule out non-classic congenital adrenal hyperplasia, which occurs in 1.5-6.8% of women with hyperandrogenism.22 A history of rapid virilization is suggestive of ovarian or adrenal malignancy and such patients should be immediately referred. For more information refer to Appendix B: Medications that May Alter Testosterone Levels in Men (PDF, 95KB) and Women and Appendix C: Hypogonadism Investigation Algorithm (PDF, 95KB). Complete guidance for the investigation and diagnosis of female hyperandrogenism is beyond the scope of this document. Indications for urgent or non-urgent referral are outlined in Table 3: Indications for consideration of referral to an endocrinologist, urologist, or obstetrician/gynaecologist as appropriate below.
Women receiving treatment for hyperandrogenism: Response to treatment of hyperandrogenism in women is clinical. Therefore, testing serum total testosterone and cBAT in patients treated for hyperandrogenism is not recommended unless a concrete cause has been identified, such as non-classical congenital adrenal hyperplasia or an androgen-secreting tumour.
Women receiving androgen therapy for low libido: Testosterone testing is not useful for monitoring women receiving androgen therapy for low libido unless overuse is suspected or unexpected virilisation has developed.
Men5–7 | Women21, 22 |
---|---|
Confirmed or suspected:
* Some indications may require urgent referral; these are indicated with an asterisk |
Confirmed or suspected:
*Some indications may require urgent referral; these are indicated with an asterisk |
TT Total testosterone
cBAT Calculated bioavailable testosterone
SHBG Sex hormone binding globulin
LOH Late onset hypogonadism
PSA Prostate-specific antigen
DRE Digital rectal examination
PCOS Polycystic ovarian syndrome
T2DM Type 2 diabetes mellitus
This guideline is based on scientific evidence current as of the Effective Date.
The guideline was developed by the Guidelines and Protocols Advisory Committee in collaboration with BC's Agency for Pathology and Laboratory Medicine, and adopted by the Medical Services Commission.
The principles of the Guidelines and Protocols Advisory Committee are to:
Contact Information:
Guidelines and Protocols Advisory Committee
PO Box 9642 STN PROV GOVT
Victoria BC V8W 9P1
Email: hlth.guidelines@gov.bc.ca
Website: www.BCGuidelines.ca
Disclaimer
The Clinical Practice Guidelines (the “Guidelines”) have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.