A Deep Dive: The Indications, Contraindications, and Maybes When Prescribing Testosterone Replacement Therapy

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Endocrine Society Clinical Endocrinology Update 2022 is a hybrid meeting for the first time and will offer attendees a variety of refresher courses on the latest diagnosis and treatment recommendations for various endocrine conditions. Endocrine News talks with Arthi Thirumalai, MBBS, about her two sessions that detail treating low testosterone in men, risk factors, controversies, and comorbidities.

This year’s Endocrine Society’s always highly anticipated Clinical Endocrinology Update (CEU) symposium takes place on a hybrid basis (live, in Miami, Fla, and online) from Thursday, September 8 through Saturday, September 10. At CEU 2022, leading experts will present new findings and how these translate to the point of care.

Endocrine News once again provides an advance peek into select presentations. In the topic area of Male Reproduction, Arthi Thirumalai, MBBS, section head of Endocrinology at Harborview Medical Center, and endocrinologist at the UW Medicine Diabetes Institute and the Lipid Clinic at South Lake Union, and a University of Washington assistant professor of medicine and metabolism, endocrinology and nutrition in Seattle, will present two talks, both on the many questions surrounding testosterone replacement therapy in patients with comorbid conditions, especially diabetes, as low testosterone is associated with insulin resistance. These talks are certainly topical — the prevalence of hypogonadism among males with diabetes is reported to be 25% – 30% and can predispose males to adverse cardiometabolic outcomes.

According to the Endocrine Society’s Facts & Figures on Reproduction and Development, “Symptoms of androgen deficiency may include decreased energy, mood, muscle mass and strength, erectile function, bone density, and libido. Erectile dysfunction, low libido, and lack of morning erections are the symptoms that are most specific for male hypogonadism.”

Trick or Treatment?

For the first talk, “Cardiometabolic Disorders and Low Testosterone in Men: Cases Studies of When to Treat,” she will be exploring what the literature says about testosterone in the context of cardiometabolic disorders. For patients with diabetes, obesity, or metabolic syndrome, for example, is there any evidence to support checking testosterone levels in these patients or treating low testosterone levels that may or may not be consistent with hypogonadism? And how do testosterone levels affect these patients? “Many physicians will check testosterone levels in everybody with diabetes and everybody with obesity or a fatty liver, and the question then really is, is it a cause or effect — is it an association or is it a cause of that disorder?” she explains.

“Is treating low testosterone beneficial, harmful, or neutral? That’s where I would like to go with this talk, because there are trials of treating people with diabetes with testosterone and treating people with cardiometabolic disease with testosterone; does that help . . . or not?”

Arthi Thirumalai, MBBS, section head, Endocrinology, Harborview Medical Center; endocrinologist, UW Medicine Diabetes Institute and the Lipid Clinic at South Lake Union; assistant professor of medicine and metabolism, endocrinology, and nutrition, University of Washington, Seattle, Wash.

This presentation will start off with a review of the epidemiology of low testosterone in patients with cardiometabolic disorders. How testosterone levels affect these patients often depends on the severity of their condition. But the question remains, is a low testosterone value contributing to their symptoms and worsening their chronic illness? On the other hand, perhaps the patient has multiple factors contributing to a low level, such as medication, and the low serum testosterone is associated with those factors. In either case, would raising that level by treating with testosterone replacement therapy actually affect the disease itself? “Is treating low testosterone beneficial, harmful, or neutral?” asks Thirumalai, “That’s where I would like to go with this talk, because there are trials of treating people with diabetes with testosterone and treating people with cardiometabolic disease with testosterone; does that help . . . or not?”

Thirumalai will be discussing approaches to actual patient cases: “Do you go hunting for low testosterone? Do you wait for symptoms? What symptoms would clue you in to treating versus not treating?” For example, she explains, some physicians might say that a patient with chronic diabetes who also has osteoporosis should be checked and treated even though he does not have the traditional symptoms of low libido or decrease in energy levels. Then, too, most patients with diabetes have erectile dysfunction — is that symptom sufficient to warrant testing for low testosterone?

Attend “Cardiometabolic Disorders and Low Testosterone in Men: Cases Studies of When to Treat” from 1:25 p.m. to 2:10 p.m. on Thursday, September 8th to learn how Thirumalai will address these and related clinical questions.

Extenuating Circumstances

“Difficult Cases in Male Hypogonadism: Treatment of Patients with CV Disease, Prostate Cancer, DVT Risk Factors and DM2 Risk Factors” takes place right on the heels of her first presentation, this one from 2:35 p.m. to 3:05 p.m. on Thursday, September 8. Whereas in the previous talk, hypogonadism was not always established, in this talk, Thirumalai will discuss the cases of patients with confirmed hypogonadism but in whom treatment with potential testosterone replacement therapy is complicated by issues such as acute cardiovascular disease, prostate cancer (or history of prostate cancer), or thromboembolic disease (or at high risk for thromboembolic disease).

“These are patients who would be diagnosed categorically with hypogonadism,” she explains, “but because these are known either black box warnings for testosterone prescription or classical areas of debate in the testosterone world as to whether testosterone therapy is dangerous in these patients or not, I would like to review a case of each one of these and go through what we have in the literature about what are the risks and benefits of testosterone replacement therapy in these scenarios.”

The solutions she is hoping to find there regarding testosterone replacement therapy basically amount to whether there is a safe way to pursue it — are there certain parameters we should be giving clinicians. “This is the situation in which you could consider testosterone replacement therapy versus this is a scenario in which you are probably better off waiting,” she continues. For example, testosterone’s black box warning concerns its potential to increase the risk for venous thromboembolism/deep vein thrombosis (DVT). In a patient who has already had DVT, do you prescribe testosterone to that patient or not? Or, if someone has a known genetic mutation like factor V Leiden, which predisposes them to DVTs, would you prescribe testosterone therapy? Then, with prostate cancer, although current guidelines say that patients with active prostate cancer should not get testosterone replacement therapy, what about patients who recently had prostate cancer and are currently in remission? “The guidelines are vague on that one,” she said, “and it’s more expert opinion than randomized clinical trial data.”

Similarly with cardiovascular disease, there is a long-standing debate over whether testosterone therapy predisposes to increased risk for atherosclerotic events or not. “That data has always been very murky, but increasingly the consensus is going toward that it probably does not cause atherosclerotic events, but, at the same time, what do you do if someone who is on testosterone therapy has a myocardial infarction — do you stop therapy temporarily? Do you restart it later? What do you do if somebody is diagnosed with hypogonadism in the immediate aftermath of a cardiac event — is it okay to do therapy at that time, or do you need to wait? These are the sort of questions I would like to review,” she says.

In addition to the quality-of-life (QOL) reductions that unequivocally low total and free testosterone levels cause, Thirumalai explains that low serum testosterone can also cause anemia, osteoporosis, and other problems as well as worsening existing problems. “There is good literature to support that not treating with testosterone replacement therapy will make a lot of things worse. Bone health will continue to decline, predisposing to osteoporotic fractures, as does oxygen-carrying capacity. We also know that low testosterone increases insulin resistance, so not treating can predispose these patients to developing diabetes later in life.”

“It’s important for not just endocrinologists, but also primary care physicians to be aware of all of these aspects of testosterone replacement therapy. There’s a lot of inappropriate prescribing that happens through clinics that are not run by physicians or by regulated facilities, probably stemming from the fact that if physicians do not feel comfortable having these conversations with their patients, then the patient might then go and seek care in other alternative practices. It’s upon us to be educated about these things so we can have those conversations with our patients.”

Arthi Thirumalai, MBBS, section head, Endocrinology, Harborview Medical Center; endocrinologist, UW Medicine Diabetes Institute and the Lipid Clinic at South Lake Union; assistant professor of medicine and metabolism, endocrinology, and nutrition, University of Washington, Seattle, Wash.

The QOL reductions (like mood changes and energy depletion) themselves can precipitate serious depression. “So, the point really is not, is testosterone therapy beneficial to them?” Thirumalai continues. “The question is, are there certain conditions in which a more detailed risk/benefit discussion needs to be had in those men.”

With testosterone therapy getting so much attention currently, being so widely prescribed and even more widely discussed, Thirumalai’s reviews are critical. “It’s important for not just endocrinologists, but also primary care physicians to be aware of all of these aspects of testosterone replacement therapy. There’s a lot of inappropriate prescribing that happens through clinics that are not run by physicians or by regulated facilities, probably stemming from the fact that if physicians do not feel comfortable having these conversations with their patients, then the patient might then go and seek care in other alternative practices. It’s upon us to be educated about these things so we can have those conversations with our patients.”

Horvath is a freelance writer based in Baltimore, Md. In the June issue, she wrote about new noninvasive obesity treatments.

For more information or to register for CEU 2022, click here.

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