CEU Preview: Controversies Continue to Confound Testosterone Therapy

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At CEU, experts will take a case-based approach to exploring the controversies involved in testosterone therapy in the session “Case-based Debate of Whether to Start Testosterone Therapy and How to Monitor.”

Despite — or perhaps because of — the huge increase in recent years in men requesting treatment for low testosterone levels, controversies continue to dog many aspects of the treatment.

A Clinical Endocrinology Update session will explore the evidence — and lack thereof — that can lead to perplexing questions in a “lively discussion,” according to Bradley Anawalt, MD, a professor of medicine at the University of Washington in Seattle. He will moderate the session “Case-based Debate of Whether to Start Testosterone Therapy and How to Monitor.”

“Clinicians around the country are faced with a lot of men coming in, saying, ‘I think I have “low T,”’ Anawalt says. Endocrinologists are faced with a quandary of sorting out when the benefits outweigh the risks, as well as how to deal with the Food and Drug Administration’s (FDA) required “black box” warnings that testosterone treatment may increase risk of myocardial infarction and stroke as well as increase the risk of venous blood clots.

Fortunately, the Endocrine Society recently issued a clinical practice guideline which provides a reference and starting point for most treatment. The guideline states clearly that men should be treated only if they have not only consistently low testosterone levels by a validated test, but also symptoms of androgen sufficiency.

Exploring the Difficult Cases

The debate at CEU is designed to explore the kinds of cases that are difficult to address fully in a guideline. At a session on the diagnosis and management of male hypogonadism at ENDO 2018, Anawalt presented a hypothetical case that touches on three of the big controversies. The patient is a 64-year-old man diagnosed with severe primary hypogonadism based on a consistently very low serum testosterone concentration accompanied by elevated gonadotropins (follicle-stimulating hormone and luteinizing hormone). His symptoms and signs include a marked decrease in libido and muscle strength.

“This session will be a deliberate effort to give the clinical audience a bird’s-eye view about how we think, how we wrestle with the difficult questions, what are the data, and what situations really make us squirm. It is intended to allow the clinicians to question dogma, and to think about the patient who is sitting in front of them, and to tailor the management of male hypogonadism to the individual patient” – Bradley Anawalt, MD, professor of medicine, University of Washington, Seattle

His medical history is remarkable for localized prostate cancer (Gleason 7) that was treated with radical prostatectomy six years ago. His surgical margins were clear, and follow-up imaging and serum PSA measurements have shown no sign of recurrence. He has a history of coronary artery disease and lower extremity deep venous thrombosis after an ankle fracture ipsilateral to the thrombosis.

Physical examination:

  • Height 69 inches (175 cm) and BMI 31 kg/m2
  • Blood pressure 130/82 and heart rate 76
  • He has normal secondary sexual characteristics. He has a normal cardiac and pulmonary exam. There is no gynecomastia or nipple discharge. He has a normal penis and his testes are 20 mL bilaterally.
  • Labs: Serum prostate specific antigen (PSA) is undetectable.
  • Bone densitometry (DXA) reveals a T score of -1.5 in the left hip and – 2.2 in the lumbar spine.

Does Testosterone Feed Prostate Cancer?

A first question this case raises is whether his history of prostate cancer precludes treatment with testosterone.

“Prostate cancer was previously considered an absolute contraindication to treatment with testosterone,” according to John Amory, MD, MPH, a professor of medicine and section head of general internal medicine at the University of Washington Medical Center, who will be one of the presenters at the workshop. “This is certainly still the case for someone with untreated or advanced prostate cancer. However, over the last decade this stance has been reconsidered for men with a history of localized prostate cancer status post prostatectomy and an undetectable PSA. Such men can be considered as candidates for treatment if they are hypogonadal and symptomatic with appropriate counseling. Such patients require close monitoring with PSA.”

The 2018 Endocrine Society guidelines say that in cases like this one, involving a patient who has undergone radical prostatectomy, has undetectable PSA, and no detectable residual disease two or more years after surgery, the lack of data from randomized controlled trials precludes making a general recommendation.

Anawalt adds that “the rationale for [treatment] is that there is benefit for testosterone therapy in male hypogonadism — including increased bone density and muscle strength, improved sexual function, and improved sense of well-being — and low risk of stimulating prostate cancer growth in men without evidence of persistent prostate cancer.” And PSA provides a marker of prostate cancer growth that can be followed in these men.

Cardiovascular Complications

The “black box” warning on potential increased risks of cardiovascular events means that the patient’s history of coronary artery disease is another issue to consider. Ten months ago, he was admitted to the hospital for unstable angina. He had EKG, laboratory, and imaging findings consistent with a small inferior myocardial infarction. He began intensive medical therapy and has had no angina since that event.

“This patient should be counseled on the controversy about testosterone replacement therapy and cardiovascular risk,” Anawalt says. “The FDA … advises practitioners to make patients aware of these potential risks when deciding whether to initiate or continue testosterone therapy.” But if the details above were the extent of the patient’s disease, Anawalt would be comfortable in offering treatment.

“Given the uncertainty about the impact of testosterone therapy on the progression of atherosclerosis, counseling is certainly important, and this counseling should include mention of the FDA’s ‘black box’ warning about the potential for increased cardiovascular events,” Amory says. He notes that it would be important to know more details about the patient’s history, such as whether the patient had a coronary catheterization. “Knowledge of how extensive the disease was might factor into the shared decision-making,” he says.

Thromboembolic Considerations

The “black box” warning on the potential increased risk of blood clots, and the patient’s history of deep venous thrombosis after an ankle fracture provide another topic to discuss with the patient and opportunity for shared decision-making, Anawalt and Amory say.

“Given the uncertainty about the impact of testosterone therapy on the progression of atherosclerosis, counseling is certainly important, and this counseling should include mention of the FDA’s ‘black box’ warning about the potential for increased cardiovascular events. Knowledge of how extensive the disease was might factor into the shared decision-making.”  – John Amory, MD, MPH, professor of medicine; section head, General Internal Medicine, University of Washington Medical Center, Seattle

Amory notes that based on this limited information in which the patient apparently “had only a single clot with a clear precipitant (the ankle fracture), he appears to be at lower risk than someone with a history of multiple clots, a recognized clotting disorder, or an unprecipitated clot.”

Which Form of Therapy?

Anawalt would also be willing to offer treatment to this patient, with the choice of therapy governed by the patient’s choice between transdermal testosterone gel and intramuscular injection of testosterone cypionate.

“I prefer the gel for older patients,” Amory says, because in this age group the risk of polycythemia is higher with injections than the 2% risk with gel. “The gel would be my first choice, but if the patient insisted on the injection, that would be okay with appropriate monitoring.”

Anawalt promises the session will include additional controversial cases explored at greater depth than this article allows, with a strong emphasis on audience participation: “This session will be a deliberate effort to give the clinical audience a bird’s-eye view about how we think, how we wrestle with the difficult questions, what are the data, and what situations really make us squirm. It is intended to allow the clinicians to question dogma, and to think about the patient who is sitting in front of them, and to tailor the management of male hypogonadism to the individual patient.”

— Seaborg is a freelance writer based in Charlottesville, Va. He wrote about new research advancing the potential development of the male birth control pill in the June issue.

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