Clinical practice guidelines on diagnosis and treatment of hypogonadism – important issues
The diagnosis and management of hypogonadism (also known as testosterone deficiency) can be challenging. Several medical societies regularly publish clinical practice guidelines on hypogonadism and testosterone therapy, with the aim to help clinicians diagnose and treat men who present with signs and symptoms of testosterone deficiency.
The main medical associations / societies that recently published new guidelines on the diagnosis and treatment of testosterone deficiency are:
- American Urological Association (AUA) 20181
- The British Society for Sexual Medicine (BSSM) 20172
- The European Association of Urology (EAU) 20173
- The International Society of Sexual Medicine (ISSM) 20154
- International Consultation for Sexual Medicine (ICSM) 20155
- The Endocrine Society (ES) 20186
Here we summarize the similarities and differences between the recommendations provided by these guidelines on issues related to the diagnosis and treatment of testosterone deficiency. Widespread confusion is particularly common regarding what is meant by “low testosterone”. Most guidelines recommend the diagnostic testosterone threshold of 12 nmol/L (~350 ng/dL) and suggest that levels below this is considered low testosterone. However, it is acknowledged that in clinical practice there are men who have total testosterone levels above 12 nmol/L (~350 ng/dL) who are highly symptomatic and who have experienced symptom/sign improvement with testosterone therapy.1 Support for this comes from physician experts with long clinical experience of diagnosing and treating testosterone deficiency, who all agree that symptoms should be the primary consideration in the diagnosis of testosterone deficiency.7
In the commentary below we highlight important issues and share the practices of expert clinicians who have decades of clinical experience in successfully diagnosing and treating men with hypogonadism. Our goal is to help clinicians who face diagnostic and/or treatment dilemmas to make well informed decisions, and to provide guidance on issues that are not addressed by the guidelines.
What is known about hypogonadism and clinical guidelines
Hypogonadism (also known as testosterone deficiency) is a well-established and significant medical condition.1-5 It is a syndrome associated with advancing age and comorbidities, and is diagnosed by presence of inadequate testosterone levels combined with characteristic symptoms and signs.1-5 Hypogonadism can adversely affect multiple organ systems and result in significant deterioration in health status, sexual dysfunction and decreased quality of life.1-5
Clinical practice guidelines are a set of recommendations that intend to assist doctors and patients in making decisions about appropriate health care, and improve the quality of medical treatment.8,9 However, it is important to keep in mind that because of lack of definitive medical research data on various health issues, there are often contradictions between recommendations issued by different guidelines – even those that address the same medical condition, such as hypogonadism and its treatment.
In the table below we summarize recommendations issued by the main clinical guidelines on the diagnosis and treatment of hypogonadism. In the following commentary we highlight especially important issues that doctors and hypogonadal men should know.
Table: Recommendations for the diagnosis and treatment of hypogonadism from the main clinical guidelines.
What is meant by low testosterone levels?
The main point of agreement between all guidelines is that the diagnosis of hypogonadism requires symptoms that are indicative of testosterone deficiency, combined with measured low testosterone levels. The lack of agreement is about how to define low testosterone levels.
When interpreting testosterone levels in men it is important to keep in mind that different intra-individual thresholds exist for various symptoms and signs, and there is substantial inter-individual variability in testosterone thresholds for the same symptom or sign.10 The rigid application of a specific testosterone level threshold for all individuals as the primary instrument to diagnose hypogonadism – as is implied by all current clinical guidelines – therefore lacks a scientific foundation and is discouraged.10
The lack of association between the symptoms and the most commonly used blood tests points to the paramount importance of symptoms. An emphasis and reliance on total testosterone levels alone hinders the clinician’s ability to effectively treat testosterone deficiency.11 Indeed, several leading scientists, who are also expert physicians with a long clinical practice experience of diagnosing and treating men with hypogonadism, point out that they rely more on symptoms than testosterone levels when making the diagnosis of hypogonadism.7
The laboratory determination of testosterone levels consistent with a diagnosis of hypogonadism is complicated by the availability of several testosterone assays (laboratory measurement techniques) and different reference ranges.12 In a survey of 25 laboratories, there were 17 and 13 different sets of reference values for total and free testosterone, respectively; the low reference value for total testosterone ranged from 4.5 to 12.1 nmol/L (130 to 450 ng/dL) – a 350% difference - and the upper value ranged from 16.8 to 40 nmol/L (486 to 1593 ng/dL) – a 325% difference.12 The consequence of this is that a man may have his testosterone level categorized as “low” by one laboratory and “normal” by another. In another survey of 120 laboratories, the lower reference value for total testosterone ranged from 5.5 to 10.4 nmol/L (160 to 300 ng/dL) and the mean upper reference value ranged from 25.2 to 39.2 nmol/L (726 to 1130 ng/dL).13
Diagnostic testosterone thresholds
Nevertheless, to help doctors make the diagnosis of hypogonadism, as shown in the table, guidelines have published the recommended diagnostic testosterone threshold of 12 nmol/L (or ~350 ng/dL). For the reasons outlined above, this is intended as a guideline when making that diagnosis, not as a rule to be strictly followed.
Consideration for hypogonadal men’s symptoms / signs and response to a therapeutic testosterone therapy trial are key to successful management of men with testosterone deficiency. Most guidelines recommend that total testosterone should be measured in the morning. If patients are symptomatic and total testosterone is in the low-normal range, calculating free testosterone from total testosterone and SHBG (a binding protein in the blood which makes bound testosterone unavailable for tissues) is recommended. There are online free testosterone calculators that are easy to use, for example https://www.nebido.com/hcp/tools/free-testosterone-calculator
Weight loss as a treatment of hypogonadism
A second issue that merits clarification is the possible contribution of weight loss to elevation of testosterone levels in testosterone deficient men (most of whom are obese). The Endocrine Society (ES) 2018 in particular states that weight loss is an “easy” way to treat hypogonadism.6 It is common knowledge that achievement – and importantly – maintenance of weight loss, is not an easy task. Furthermore, while it is well documented that obesity contributes to the development of hypogonadism, and that weight loss can increase testosterone levels, the amount of weight loss that can be realistically achieved and maintained with diet and exercise is in most cases not large enough to translate into sustained symptomatic improvement.
This was shown in a study of the Diabetes Prevention Program, which examined the effect of an intensive lifestyle intervention on changes in testosterone and mood among middle-aged men.14 While the intensive lifestyle intervention, which resulted in a weight loss of 8 kg after 1 year, increased testosterone from 11 nmol/L to 12 nmol/L (about a 10% increase), there were no significant improvements in mood. This is not surprising considering that the testosterone elevation was quite small, despite the intensive lifestyle intervention. In the EMAS study, spontaneous resolution of secondary hypogonadism was accompanied by a 45% increase in testosterone levels (from 9.2 nmol/L at baseline to 13.3 nmol/L), but this was still not sufficient to drive improvements or resolution of sexual symptoms.15
It seems like a 2-fold increase of testosterone levels into the mid-normal physiological range is required for symptomatic improvements, as has been demonstrated in randomized controlled trials of testosterone therapy showing improvements in sexual function16, physical strength17, and depressive symptoms.18 This is supported by a notable RCT of diet+exercise vs diet+exercise+testosterone treatment, showing that only testosterone treated patients had improvements in hypogonadal symptoms.19 Hence, weight loss alone does not necessarily cause resolution of symptoms related to testosterone deficiency (hypogonadism).
It is critical be aware of that it is unknown below what testosterone level men develop symptoms of Hypogonadism (testosterone deficiency) and adverse health outcomes.10 Reference ranges and suggested testosterone thresholds for what constitutes “low testosterone” can assist in the interpretation of testosterone measurements, but have important limitations and should not be construed as criteria to provide a definitive diagnosis of hypogonadism.
Guideline recommendations reflect “ideal” practices for management of a “typical patient”. Due to lack of scientific evidence, variability in laboratory reporting and assays, and inter-individual variability in androgen sensitivity and feedback set-points, at times these recommendations may not be the best approach for practicing clinicians who provide care for men in real life circumstances.
The 2018 AUA guideline acknowledges this. While stating a reasonable threshold for low testosterone to support the diagnosis, they do recognize that in real life (as opposed to strictly controlled studies) there are men who have testosterone levels above the suggested diagnostic thresholds who are highly symptomatic and who have experienced symptom relief/resolution with testosterone therapy.1 Therefore, the 2018 AUA guideline urges doctors to use their clinical judgment in the management of such patients.1 This individualized patient care approach is also recommended by physician experts with long clinical experience of diagnosing and treating hypogonadism, who all agree that symptoms should be the primary consideration in the diagnosis of testosterone deficiency.7 The BSSM guideline recommends a therapeutic trial of testosterone therapy for at least 6 months for symptomatic men, even if their testosterone level is not unequivocally low, and underscores that maximum effects are seen beyond 12 months of treatment with testosterone.2 This means that adherence to longer term testosterone treatment is critical for achievement of therapeutic benefits.