New Testosterone Treatment Guidelines 'Useful but Not Gospel'

March 17, 2018

CHICAGO, Illinois — The Endocrine Society has issued an updated clinical practice guideline on testosterone therapy in men with hypogonadism, but experts here today at ENDO 2018: The Endocrine Society Annual Meeting stressed that the new recommendations are "a broad roadmap" on how to approach the diagnosis and treatment of hypogonadism, but not necessarily a definitive path to follow.

The availability of new information from some of the largest randomized trials of testosterone, recent improvements in testosterone measurement, combined with the growing public interest in issues related to men's health has encouraged the Endocrine Society's initiative to update its testosterone treatment guideline, which was last released in 2010.

"In a reflection of the growing attention paid to men's health issues, men's health clinics have mushroomed" all over the United States, said Shalender Bhasin, MD, of Brigham and Women's Hospital in Boston, Massachusetts, who is chair of the guidelines task force.

"Yet recent surveys indicate many men are prescribed testosterone treatment without an appropriate diagnostic workup or monitoring plan. Some men receiving testosterone therapy do not have adequately documented hypogonadism, while others who have hypogonadism are not receiving the needed treatment."

Testosterone therapy is recommended for hypogonadal men to correct symptoms of testosterone deficiency. Men who are otherwise healthy do not need to be screened for hypogonadism.

The guideline calls for avoiding testing and treating healthy men for whom the risks and benefits of testosterone therapy are unclear.

And when it is determined that testosterone therapy is required, "We recognize variations in disease treatment must be individualized," and based on shared decision-making between the physician and patient, Bhasin told attendees.

"I use the 'hum and haw' policy at least 3 times before picking up the prescription pad," he added.

And Bradley Anawalt, MD, University of Washing Medical Center, Seattle, moderator of the session in which the recommendations were presented, emphasized that "the guidelines are not a set of rigid rules. They are useful, but not gospel."

The new clinical practice guidelines were published online today in the Journal of Clinical Endocrinology & Metabolism, the Endocrine Society's journal. The panel that developed the recommendations included a cardiologist, primary care expert, and member of the European Academy of Andrology.

First Do No Harm, No Routine Prescription for Those 65 Years and Older

"The panel worked by consensus," and there were only two topics on which there were "nuanced disagreements," which were prostate monitoring and treatment of older men, Bhasin told delegates.

And in areas "where evidence is weak, we were guided by safety concerns and the principle of first do no harm," he added.    

The guidance was developed based on systematic reviews and meta-analyses, but only "a handful of trials were" considered, including the testosterone trials, as the criteria for inclusion were strict, he noted.

High-quality efficacy data from large controlled trials has enabled a stronger treatment recommendation for men with organic hypogonadism. "We recommend testosterone therapy in hypogonadal men to induce and maintain secondary sex characteristics and correct symptoms of testosterone deficiency," explained Bhasin, noting that it is well-established that testosterone significantly improves libido, erectile function, and sexual activity compared with placebo. There are also benefits in correcting unexplained and explained anemia and volumetric density of the spine and hip, but no difference in terms of energy or mood.

Safety concerns include a significantly higher frequency of erythrocytosis (hematocrit > 54%).

However, the panel recognizes that there is a lack of long-term randomized controlled trial data on the effects of testosterone replacement therapy on major adverse cardiovascular events (MACE) and prostate cancer, he noted, although there is "no clear evidence that testosterone replacement therapy increases the risk of MACE or prostate cancer."

Nevertheless, this has led to a "more guarded suggestion" in older men.

The recommendation is against routine prescription of testosterone therapy to all men 65 years or older with low testosterone concentrations. The scientific evidence for this recommendation has grown stronger since the 2010 guideline was released.

In men older than 65 years who have symptoms or conditions suggestive of testosterone deficiency (such as low libido or anemia), and consistently and unequivocally low morning T concentrations, "we suggest that clinicians offer testosterone therapy on an individual basis after explicit discussion of the potential risks and benefits," Bhasin observed.

There are also special sections in the new guideline on the increasing prevalence of androgen deficiency associated with opioid use and androgenic-anabolic specific withdrawal hypogonadism, he explained.

"Twenty percent of testosterone prescriptions in the VA system are now for men using opioids chronically," he noted. "Ascertaining a history of opioid or anabolic steroid use" is therefore of paramount importance, and there is "greater emphasis on the workup."

Diagnosis: Lab Accuracy of the Utmost Importance

For diagnosis, there is now a strong emphasis on ensuring the use of accurate assays, especially liquid chromatography-mass spectrometry (LC-MS)/MS assays, "which have become more widely available since the last guideline was issued," Bhasin continued.

It is also important for physicians to ensure that the laboratories they use for testosterone assays are certified by the Center for Disease Control Hormone Standardization (HoSt) program or another accuracy-based certifying program (as opposed to peer-based, which is less stringent), he stressed.

Harmonized reference ranges should be used for total testosterone, and there needs to be a better understanding of testosterone's binding to sex hormone-binding globulin and greater emphasis on free testosterone determination than in the previous 2010 guideline.

The panel set a harmonized testosterone reference range of 264–916 ng/dL (9.2–33 nmol/L).

"It's extremely important to know the lab you are using and hold them to the standard you would like," and "make sure there are no other explanations" for the results you are seeing, another guideline author, Alvin M Matsumoto, MD, of Seattle VA Puget Sound Health Care System, Washington, told attendees.

"This requires talking to the lab and making sure they have quality control. It's important to communicate with the lab director," he stressed.

For monitoring, a patient should be evaluated at 3–12 months after the start of testosterone treatment, and then annually, to assess whether symptoms have responded to treatment and the patient is experiencing any adverse effects.

Testosterone concentrations should be measured 3–6 months after initiating therapy, with the aim of raising serum testosterone to the mid–normal range.

Hematocrit should be checked at baseline, 3–6 months after starting therapy, and then yearly. And bone mineral density of the lumbar spine and/or femoral neck should be measured after 1–2 years of testosterone therapy in hypogonadal men with osteoporosis.

Lack of Long-Term Data, and Effects on CV Events and Prostate Cancer

Bhasin went on to discuss considerations with regard to prostate cancer and cardiovascular disease.

For all men aged 55–69 years and those aged 40–69 years at increased risk for prostate cancer (family history or African American) who choose prostate monitoring, "perform a digital rectal exam [DRE] and check prostate-specific antigen [PSA] before initiating [testosterone] treatment," he urged.

Then check PSA and perform DRE 3–12 months after starting therapy and thereafter in accordance with guidelines for prostate cancer screening, depending on the age and race of the patient.

The time to get a urological consult, Bhasin stressed, is when there is a) an increase in PSA concentration of > 1.4 ng/mL within 1–2 months of starting testosterone treatment, b) a confirmed PSA of > 4 ng/mL at any time, c) detection of a prostatic abnormality on DRE, or d) substantial worsening of lower urinary tract symptoms.

There needs to be "shared decision-making" about screening and monitoring for prostate cancer, he explained.

In terms of cardiovascular disease, the panel determined that "the potential cardiovascular risks or benefits of testosterone replacement therapy in hypogonadal men are not known."

They recommend "not starting testosterone therapy within 6 months of a myocardial infarction or stroke," but another guideline author, Maria A Yialamas, MD, an endocrinologist with a special interest in primary care, from Brigham and Women's Hospital in Boston, Massachusetts, said this recommendation "is based on expert opinion rather than being evidence-based."

Questions from the audience included what to do if a patient on testosterone has a cardiovascular event, and whether to discontinue therapy for major surgery.

Yialamas said, "If someone had a myocardial infarction or was undergoing major surgery, I would probably stop testosterone."

Matsumoto added, "I don't see any harm in stopping testosterone during an acute event, but the more important question is if, and when, do you restart it? In general, I don't think there is any reason not to restart it."

Testosterone Gel Vs Injection, "Sweet Spot" for Testosterone Concentrations

Delegates also wanted to know the pros and cons of different testosterone preparations, such as gel vs injection.

Another panel member, Glenn R Cunningham, MD, Baylor College of Medicine in Houston, Texas, said: "When I talk to a patient, I give them information about the benefits and limitations of each delivery system."

He also noted "cost is a consideration. A lot of insurance companies will give you problems paying for some of these delivery systems."

In addition, there were questions from the floor about the timing of checking testosterone levels.

Matsumoto said, for patients on gel, "It doesn't matter when you test on a gel, although you shouldn't change a dosage based on a single level. Make sure you use 2 or 3 or 4 levels before changing dose."

For those on testosterone injections, normally given every 2 weeks, to see if patients are within the normal testosterone range, "perform a nadir level before the next injection," he recommended, noting that "pharmacokinetics in any one individual are not necessarily consistent."

Finally, Anawalt wondered whether his fellow physicians would pursue the 'sweet spot' of testosterone during therapy; that is, "are you going to be happy for your patient to be at the upper limit, or lower limit, of normal testosterone?"

"Are you going to settle for 'good enough' or are you going to adjust and adjust to get to the 'sweet spot?' "

New Guidance at Odds With That of the ISSM

Finally, in a commentary published online today in JAMA to coincide with the new Endocrine Society guidance, Robert M Sargis, MD, PhD, of the University of Illinois at Chicago, and Andrew M Davis, MD, MPH of the University of Chicago, Illinois, say it "largely agrees with the 2010 Endocrine Society clinical practice guideline."

And despite the harmonized testosterone reference range of 264–916 ng/dL (9.2–33 nmol/L), the new guideline does not suggest "specific testosterone levels at which treatment is likely to be beneficial," they note.

This is in contrast to the International Society for Sexual Medicine (ISSM), which indicates that men with total testosterone of 346 ng/mL or higher are unlikely to have testosterone deficiency and benefit from treatment, while the diagnosis and therapeutic benefit are more likely at levels < 231 ng/dL.

"Regular monitoring for therapeutic response and adverse effects, combined with discontinuing [testosterone] therapy in patients who do not experience clear improvement in symptoms, should increase the likelihood of benefit while limiting expense and potential harm," they conclude.

Disclosures for the guideline authors are listed in the manuscript.

J Clin Endocrinol Metab. Published online March 17, 2018. Full text

JAMA. Published online March 17, 2018. Full text

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