Clinical Practice Guidelines on Diagnosis and Treatment of Hypogonadism – important issues

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.

Key Points

  • Medical associations / societies publish clinical practice guidelines on the diagnosis and treatment of hypogonadism, to help guide physicians in the management of hypogonadal men.
  • Because of lack of scientific data on several issues related to hypogonadism and its diagnosis and treatment, guidelines recommendations inevitably contain an element of opinion, which is why there are contradictions between some recommendations issued by different guidelines.
  • Guideline recommendations should not be interpreted as commandments or laws that should be blindly followed. In the real-life clinical setting, it is critical for practicing physicians to use their own clinical judgment in the management of hypogonadal men, many of whom deviate from the “example patient” that guidelines describe.
  • When making the diagnosis of hypogonadism, confusion is particularly common regarding the diagnostic testosterone thresholds and what is meant by “low testosterone”.
  • The Endocrine Society states that weight loss can treat hypogonadism. However, several studies refute this by showing that the small elevation in testosterone levels after weight loss in not enough to alleviate symptoms of testosterone deficiency and its symptoms.

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.

Guideline Recommendations
Screening
AUA
2018
Clinicians should refrain from measuring testosterone levels in patients who are asymptomatic, do not exhibit signs related to low testosterone, or do not have any comorbid conditions that are associated with low testosterone.
BSSM
2017
Screen for TD in adult men with consistent and multiple signs of TD

Screen all men presenting with ED, loss of spontaneous erections, or low sexual desire

Screen for TD in all men with type 2 DM, BMI > 30 kg/m2, or waist circumference > 102 cm

Screen for TD in all men on long-term opiate, antipsychotic, or anticonvulsant medication
EAU
2017
Screen for TD only in adult men with consistent and multiple symptoms and signs suggestive of TD:

Clinical symptoms and signs suggestive for androgen deficiency:

  • Obesity, especially visceral obesity
  • Metabolic syndrome
  • Insulin resistance and type 2 diabetes
  • Gynecomastia
  • Decrease in lean body mass and muscle strength
  • Reduced testis volume
  • Infertility
  • Decrease in bone mineral density (osteoporosis) with low trauma fractures
  • Mild anemia

Young men with testicular dysfunction and men older than 50 years of age with low testosterone should additionally be screened for osteoporosis.

Sexual symptoms:

  • Reduced sexual desire and sexual activity
  • Erectile dysfunction
  • Fewer and diminished nocturnal erections

Cognitive and psychological symptoms:

  • Hot flushes
  • Changes in mood, fatigue and anger
  • Sleep disturbances
  • Depression
  • Diminished cognitive function
ICSM
2015
Men presenting with the following conditions should be screened for low T:

  • Sexual symptoms including decreased libido, erectile dysfunction, and decreased frequency of morning erections.
  • Clinical conditions associated with insulin resistance (obesity, type 2 DM, MetS) should be screened for TD because it is often comorbid.
  • Infertility
  • Osteoporosis and height loss or low trauma fractures likely indicate low T because asymptomatic low T can negatively contribute to these conditions and can be corrected with TTh.
  • HIV-associated weight loss.
  • Long-acting opioid use.
  • High doses of glucocorticoid use.

Screening for low T is not recommended in the absence of TD symptoms in all other populations, although they are potentially associated with an increased prevalence of low T (cardiovascular diseases, chronic pulmonary diseases, end-stage renal diseases, cirrhosis, rheumatoid arthritis, and cancer) because of the lack of evidence of benefit resulting from TTh in non-symptomatic individuals.
ISSM
2015
Screening for TD in the general population is not recommended.

Systematic screening for TD should be undertaken in men with obesity, type 2 diabetes and the “metabolic syndrome.”

Screening for TD should be undertaken in men who report symptoms or signs typically associated with TD, particularly sexual dysfunctions.
ES
2018
We recommend against routine screening of men in the general population for hypogonadism.

Conditions in which there is a high prevalence of low testosterone levels and for whom we suggest measuring testosterone levels:

  • Pituitary mass, radiation to the pituitary region, or other diseases of the sellar region
  • Treatment with medications that affect T production or metabolism, such as opioids and glucocorticoids
  • Withdrawal from long-term anabolic steroid use
  • HIV-associated weight loss
  • Infertility
  • Osteoporosis or low trauma fracture
  • Low libido or erectile dysfunction
Diagnosis
AUA
2018
  • Clinicians should use a total testosterone level below 300 ng/dL as a reasonable cut-off in support of the diagnosis of low testosterone.
  • The diagnosis of low testosterone should be made only after two total testosterone measurements are taken on separate occasions with both conducted in an early morning fashion.
  • The clinical diagnosis of testosterone deficiency is only made when patients have low total testosterone levels combined with symptoms and/or signs.
  • Clinicians should consider measuring total testosterone in patients with a history of unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use even in the absence of symptoms or signs associated with testosterone deficiency.
  • The use of validated questionnaires is not currently recommended to either define which patients are candidates for testosterone therapy or to monitor symptom response in patients on testosterone therapy.
BSSM
2017
The diagnosis of TD requires the presence of persistent symptoms suggesting TD plus low levels of TT or FT.

Measure fasting T levels in the morning before 11 AM, acknowledging that, in normal life, non-fasting levels could be up to 30% lower.

Repeat TT assessment on at least 2 occasions by a reliable method; in addition, measure free T in men with levels close to lower normal range (12 nmol/L) or those with suspected or known abnormal SHBG level.

Measure LH serum levels to differentiate primary from secondary TD.

Base decisions on therapy on published action levels rather than laboratory reference ranges.
EAU
2017
The diagnosis of male hypogonadism is based on signs and symptoms of androgen deficiency, together with consistently low serum testosterone levels.

Measure testosterone in the morning before 11.00 hours, preferably in the fasting state. Repeat total testosterone on at least two occasions with a reliable method. In addition, measure the free testosterone level in men with:

  • Total testosterone levels close to the lower normal range (8-12 nmol/L), to strengthen the laboratory assessment.
  • Suspected or known abnormal sex hormone-binding globulin (SHBG) levels.

Measure LH serum levels to differentiate between primary and secondary forms of hypogonadism.
ICSM
2015
The following investigations are recommended in patients with suspected TD from the relevant symptoms and/or physical signs

Step 1. Morning determination of TT.

Step 2. For low-level TT (<12 nmol/L or ~350 ng/dL), we recommend repeating the TT measurement, and measuring LH and prolactin.

In individuals clinically suspected of having TD, SHBG levels should be assessed if TT is low to normal or borderline, especially in obese or older men.

There are no generally accepted lower limits of normal TT. However, it is recommended that:
  1. Symptomatic men with TT < 12 nmol/L or < ~350 ng/dL should be treated with TTh.
  2. A trial of TTh in symptomatic men with TT > 12 nmol/L or > ~350 ng/dL can be considered based on clinical presentation.

Clinical assessment of TD:

Sexual dysfunction, in particular low sexual desire, decreased nocturnal and morning erections and erectile dysfunction are prominent and often the presenting symptoms, especially suggestive of TD when all 3 are associated.

Decreased physical vigor, decreased energy and motivation, fatigue, depressive mood, and sleep disturbances are often present.

Visceral obesity is often observed, and muscle mass and bone mineral density are often decreased.

Hot flushes, and sometimes alterations in cognition and memory, can be associated with TD. Not all manifestations need to be evident simultaneously and their intensity shows marked interindividual variability.

Although the prevalence of TD increases with each decade of life, TD can occur in adult men of all ages.
ISSM
2015
Clinical assessment of TD:

The physician must enquire about and document any symptoms of TD.

The committee does not recommend the use of currently available questionnaire instruments in the assessment of TD.

The physician must identify men who wish to maintain their fertility and testicular volume.

Men with suspected TD must have a physical examination to identify physical signs of TD and comorbid conditions. Digital rectal examination is not essential for the initial assessment of TD, but in men over 40, it must be performed before any treatment for TD is commenced.

Laboratory work-up:

Liquid chromatography-tandem mass spectrometry is preferable, when available, but acknowledges that RIA/IA methods are more accessible for many clinicians and despite their limitations may be used in everyday clinical practice.

Measurement of TT, on a blood sample drawn between 08.00 and 12.00, is recommended as the laboratory investigation of choice in the diagnosis of TD.

If TT is <12 nmol/L (346 ng/dL) on an initial sample, then a second venous blood sample should be drawn between 08.00 and 12.00, after an interval of at least one week, for assays of TT, LH and prolactin.

If total testosterone is ≥12 nmol/L (346 ng/dL) then TD is unlikely and further investigation is not recommended unless persistent, suspicious symptoms and signs are present.

Measurement of SHBG is recommended in older and obese men, or others likely to have an elevated SHBG level, with borderline TT results and persistent, suspicious symptoms and signs.

In most circumstances, measurement or calculation of free or bioavailable testosterone, dihydrotestosterone or CAG repeats are not recommended.
ES
2018
We recommend diagnosing hypogonadism in men with symptoms and signs of testosterone deficiency and unequivocally and consistently low total testosterone, and/or free testosterone levels if total testosterone is borderline low.

Until a harmonized reference range is established, the lower threshold established by the laboratory that is used for blood testosterone measurement may be used. This means that the diagnostic threshold for what is considered “low” testosterone will vary between assays and laboratories.
Testosterone treatment
AUA
2018
Clinicians should adjust testosterone therapy dosing to achieve a total testosterone level in the middle tertile of the normal reference range.

Exogenous testosterone therapy should not be prescribed to men who are currently trying to conceive. In men with testosterone deficiency desiring to maintain fertility, clinicians may use aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators, or a combination thereof.

Testosterone therapy should not be commenced for a period of three to six months in patients with a history of a cardiovascular events.
BSSM
2017
Perform cardiovascular, prostate, breast, and hematologic assessments before start of treatment.

Beyond 6 mo there is evidence of benefit for T therapy in body composition, bone mineralization, and features of metabolic syndrome.

T therapy improves sexual desire, erectile function, and sexual satisfaction.

Decreases in BMI and waist size and improved glycemic control and lipid profile are observed in hypogonadal men receiving T therapy.

Trials of T therapy should be at least 6 months; maximal benefit is often seen beyond 12 months. Offer T therapy to symptomatic men with TD syndrome for treated localized low-risk prostate cancer (Gleason score < 8, stages 1-2, preoperative PSA level < 10 ng/mL, and not starting before 1 y of follow-up) and without evidence of active disease (based on measurable PSA level, DRE result, and evidence of metastatic disease).
EAU
2017
Perform hematological, cardiovascular, breast and prostatic assessment before the start of treatment.

Monitor testosterone, hematocrit, hemoglobin and prostate-specific antigen (PSA) during testosterone treatment.

Offer testosterone treatment cautiously in symptomatic hypogonadal men who have been surgically treated for localised prostate cancer and who are currently without evidence of active disease (i.e. measurable PSA, abnormal rectal examination, evidence of bone/visceral metastasis): treatment should be restricted to those patients with a low risk for recurrent prostate cancer (i.e. Gleason score < 8; pathological stage pT1-2; pre-operative PSA < 10 ng/ mL) and should not start before one year of follow-up.

Assess for cardiovascular risk factors before commencing testosterone treatment and optimize secondary prevention in men with pre-existing cardiovascular disease.

Treat men with hypogonadism and either pre-existing cardiovascular disease, venous thromboembolism or chronic cardiac failure who require testosterone treatment with caution by monitoring carefully with clinical assessment, hematocrit (not exceeding 0.54) and testosterone levels maintained as best possible for age within the mid-normal healthy range.
ICSM
2015
Current commercially available preparations of T (with the exception of the 17α-alkylated preparations) are safe and effective.

The treating physician should have sufficient knowledge and adequate understanding of the advantages and drawbacks of each preparation.

The patient should be given the opportunity to actively participate in the choice of T formulation.
ISSM
2015
The committee recommends that, for most patients, TTh be initiated and monitored by the generalist in urology or family medicine, provided that authoritative clinical guidelines are followed.

TTh is recommended for men with total testosterone <8 nmol/L (231 ng/dL).

A 6–12-month trial of TRT may be offered to men with TT >8 nmol/L (231 ng/dL), but <12 nmol/L (346 ng/dL), and bothersome TD symptoms and/or a substantially elevated SHBG level, once other causes of their symptoms have been excluded. TRT should only be continued where men derive persistent and substantial benefit.

TTh is not recommended for men with TT ≥12 nmol/L (346 ng/dL); those with bothersome TD symptoms and/or a substantially elevated SHBG level, once other causes of their symptoms have been excluded, should be referred for specialist assessment.

The goal of TTh is to restore TT levels to the mid-normal range, approximating the natural, endogenous production, without significant side effects or safety concerns, and alleviating the signs and symptoms associated with TD.

The physician must advise the patient of all appropriate TD treatment options, including the option of not treating TD, and agree with the preferred option with the patient.

Men who wish to maintain their fertility and testicular volume should not be given testosterone and should be referred for specialist management of their TD until an approved non-testosterone treatment is available.

If maintenance of fertility and testicular volume is not important to the patient, TTh is recommended for the treatment of TD.
ES
2018
We recommend testosterone therapy in hypogonadal men to induce and maintain secondary sex characteristics and correct symptoms of testosterone deficiency.

Clinicians can initiate testosterone therapy with any of the approved treatments, based on the patient’s preference, consideration of pharmacokinetics, treatment burden, and cost.

Clomiphene citrate has been used empirically in men with hypogonadotropic hypogonadism; however, neither its efficacy nor its safety has been demonstrated in randomized trials.

We recommend against testosterone therapy in men planning fertility in the near term or in men with breast or prostate cancer, a palpable prostate nodule or induration, a prostate-specific antigen (PSA) level >4 ng/mL, a PSA level >3 ng/mL combined with a high risk of prostate cancer (without further urological evaluation), elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia.

Commentary

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/en/hcp/research/testosterone-tools/free-calculator.php

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).

Concluding remarks

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.

References:

1. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol. 2018.
2. Hackett G, Kirby M, Edwards D, et al. British Society for Sexual Medicine Guidelines on Adult Testosterone Deficiency, With Statements for UK Practice. The journal of sexual medicine. 2017;14(12):1504-1523.
3. Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S. 2017 EAU Guidelines on Male Hypogonadism. Available at http://uroweb.org/wp-content/uploads/18-Male-Hypogonadism_2017_web.pdf (accessed April 1st, 2018).
4. Dean JD, McMahon CG, Guay AT, et al. The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men. The journal of sexual medicine. 2015;12(8):1660-1686.
5. Khera M, Adaikan G, Buvat J, et al. Diagnosis and Treatment of Testosterone Deficiency: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). The journal of sexual medicine. 2016;13(12):1787-1804.
6. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018.
7. Morgentaler A, Khera M, Maggi M, Zitzmann M. Commentary: Who is a candidate for testosterone therapy? A synthesis of international expert opinions. The journal of sexual medicine. 2014;11(7):1636-1645.
8. Murad MH. Clinical Practice Guidelines: A Primer on Development and Dissemination. Mayo Clin Proc. 2017;92(3):423-433.
9. Woolf SH, Grol R, Hutchinson A, Eccles M, Grimshaw J. Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ. 1999;318(7182):527-530.
10. Morgentaler A, Zitzmann M, Traish AM, et al. Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions. Mayo Clin Proc. 2016;91(7):881-896.
11. Morales A, Spevack M, Emerson L, et al. Adding to the controversy: pitfalls in the diagnosis of testosterone deficiency syndromes with questionnaires and biochemistry. The aging male : the official journal of the International Society for the Study of the Aging Male. 2007;10(2):57-65.
12. Lazarou S, Reyes-Vallejo L, Morgentaler A. Wide variability in laboratory reference values for serum testosterone. The journal of sexual medicine. 2006;3(6):1085-1089.
13. Le M, Flores D, May D, Gourley E, Nangia AK. Current Practices of Measuring and Reference Range Reporting of Free and Total Testosterone in the United States. J Urol. 2016;195(5):1556-1561.
14. Kim C, Barrett-Connor E, Aroda VR, et al. Testosterone and depressive symptoms among men in the Diabetes Prevention Program. Psychoneuroendocrinology. 2016;72:63-71.
15. Rastrelli G, Carter EL, Ahern T, et al. Development of and Recovery from Secondary Hypogonadism in Aging Men: Prospective Results from the EMAS. J Clin Endocrinol Metab. 2015;100(8):3172-3182.
16. Corona G, Isidori AM, Buvat J, et al. Testosterone supplementation and sexual function: a meta-analysis study. The journal of sexual medicine. 2014;11(6):1577-1592.
17. Isidori AM, Giannetta E, Greco EA, et al. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005;63(3):280-293.
18. Zarrouf FA, Artz S, Griffith J, Sirbu C, Kommor M. Testosterone and depression: systematic review and meta-analysis. Journal of psychiatric practice. 2009;15(4):289-305.
19. Ng Tang Fui M, Hoermann R, Prendergast LA, Zajac JD, Grossmann M. Symptomatic response to testosterone treatment in dieting obese men with low testosterone levels in a randomized, placebo-controlled clinical trial. Int J Obes (Lond). 2017;41(3):420-426.
G.COM.GM.MH.05.2018.0517

Last updated: 2018
G.MKT.GM.MH.02.2018.0506