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The Nuances, Controversies, and Challenges of Diagnosing and Managing Hypogonadism

March 27, 2019
Authors: Alexandra Clark, MD, Division of Endocrinology, VA Pittsburgh Healthcare System, clinical assistant professor, Division of Endocrinology and Metabolism,University of Pittsburgh and R. Harsha Rao, MD, chief, Division of Endocrinology and Metabolism, VA Pittsburgh Healthcare System, professor of Medicine, Division of Endocrinology and Metabolism,University of Pittsburgh
We currently live in a society that values very simple solutions to complex medical or aging-related problems, providing fertile ground for advertising initiatives1 focused on the promise of a quick fix or immediate satisfaction. A prime example of this type of marketing platform is the promotion of “Low T” or hypogonadism. Consumers are led to believe that they are affected by this specific syndrome and that treatment with Testosterone Replacement Therapy (TRT) will be a magic key able to unlock their previous feelings of youth and vitality. Unbranded direct-to-consumer advertising for “Low T” represents a highly successful “disease-awareness” campaign2 that is now considered a template for “how to sell a disease”.3 In 2014, the United States Food and Drug Administration (FDA) changed its testosterone labeling to emphasize the restriction of the indication to pathological causes, specifically excluding age-related testosterone decline as a reason for TRT. Nevertheless, the damage wrought by poorly regulated advertising continues to play a major role in driving the prescribing of TRT in the United States. As a result, patients present to their health care providers with preconceived notions of diagnosis and treatment, leading to a sometimes antagonistic refusal to accept reasoned advice to the contrary. This is particularly problematic because the diagnosis of potential androgen deficiency (AD) or hypogonadism is both nuanced and controversial, with considerable debate regarding the costs versus benefits of TRT.   

The Nuances of Diagnosing Hypogonadism

The diagnosis of AD rests on both symptoms and laboratory data. Symptoms associated with hypogonadism such as low libido, erectile dysfunction, decreased energy, depressed mood, poor concentration, sleep disturbance, reduced muscle bulk and strength, increased body fat, and/or increased BMI are nonspecific. These symptoms can be associated with other medical comorbidities, including undiagnosed sleep apnea, obesity, or even just the natural aging process. Obtaining a testosterone level in order to assist with the diagnosis of hypogonadism has not been standardized, though the most recent Endocrine Society Clinical Practice Guidelines4 go a long way to clarify this issue. The guidelines recommend total testosterone (TT) concentrations be obtained in the morning, fasting, and using an accurate and reliable method with confirmation of the results. Liquid chromatography–tandem mass spectrometry (LC/MS/MS) assays as opposed to immunoassays for TT offer higher specificity, sensitivity, and precision, so this assay is preferred if available.4 Yet another nuance of diagnosing hypogonadism is deciding whether the TT concentration is an accurate assessment of the body’s available testosterone concentration. The TT concentration includes sex hormone binding globulin (SHBG)-bound testosterone, albumin-bound testosterone, and free testosterone. The biologic activity of a hormone is dependent upon the concentrations of the free rather than protein-bound hormone in plasma.5 Testosterone is tightly bound to SHBG, making it unavailable for use by the body, while testosterone is loosely bound to albumin, allowing it to dissociate and become biologically available for action in the tissues. Free testosterone in combination with albumin-bound testosterone is termed bioavailable testosterone and is available for use by the body.

Conditions that lower SHBG, of which there are many, can lower TT concentrations to below the normal range, although bioavailable and free testosterone concentrations might remain within the normal range. This is particularly important given the increasing prevalence of obesity and type 2 diabetes, both of which can lower SHBG levels as well as have symptoms that mimic those associated with hypogonadism. To make matters worse, there is no universally accepted testosterone concentration cut-off below which a person is considered to definitively have hypogonadism.   

Off-label Prescribing of TRT

The FDA released a safety announcement in 2015 against the habitual recommending and prescribing of TRT for “no reason other than age, even if symptoms seem related to low testosterone.”6 Despite this, testosterone products increasingly are being prescribed to treat a controversial condition termed late-onset hypogonadism (LOH), andropause, and/or partial androgen deficiency of the aging male.7 This syndrome is diagnosed in men who, for no discernible reason other than older age, obesity, or ill health, have serum testosterone concentrations below the normal range for healthy young men and report one or more of the following symptoms: muscle weakness or wasting, mood, behavior and cognition-related symptoms, and sexual function or libido impairment.1 In contemporary societies, individuals are required to be increasingly competitive in all areas of their personal and working life often with their much younger counterparts,1 so the promised ability of TRT to delay or reverse aging is extremely appealing despite its modest symptomatic benefits in practice.8   

Controversy Surrounding TRT and Cardiovascular Outcomes

Two studies9,10 reporting a possible increased risk of heart attacks and strokes in patients using TRT prompted the FDA to issue an advisory in 2015 mandating that all product labeling include a warning of increased cardiovascular (CV) risk from TRT.6 The impact of TRT on cardiovascular outcomes remains controversial with studies reporting widely discrepant results, from higher mortality and heightened CV risk11-13 to improved survival and cardio-protection effect,14,15 with a net neutral impact on meta-analysis.16 However, most studies do not take CV risk profile into account, and they differ widely in how AD is defined. Therefore, it is uncertain whether TRT is beneficial or harmful when AD is established with the appropriate diagnostic criteria and when pre-existing vascular risk is taken into account. Our research at VA Pittsburgh Healthcare System (VAPHS) clarifies this area of uncertainty.   

TRT and Vascular Outcomes at VAPHS  

In a retrospective cohort study of more than 900 men at VAPHS who were prescribed TRT, the two most powerful predictors of vascular events (VEs) on TRT were a history of prior VEs and a lack of diagnostic rigor (DR) in diagnosing hypogonadism, defined as ≥ 1 unequivocally low early AM testosterone (T) by tandem mass spectrometry (Total T < 200 ng/dL, or Free T < 5 pg/mL, or calculated bioavailable T < 100 ng/dL). Kaplan-Meier analysis revealed that the probability of VEs on TRT was increased almost four-fold with a prior VE history (Hazard Ratio [HR] = 3·7) and decreased more than four-fold when TRT was initiated with DR (HR = 0·24). When both nonadherence to DR and prior VE history coexisted, the probability of VEs increased eight-fold compared to TRT initiated with DR in patients without prior VEs (HR = 8·2). The results suggest that TRT is harmful when prescribed to patients with a recent history of VEs or when initiated without DR. However, TRT initiated with DR may be safe in low-risk patients. This study was approved by the VAPHS Institutional Review Board and is currently being submitted for publication.  

Studies of TRT’s impact on outcomes have attempted to answer the relatively straight-forward question: “Is TRT beneficial or harmful?” If the question is reframed to ask the more nuanced question: “When is TRT beneficial, and in whom is it harmful?”, the answer can be found in patient selection and diagnostic rigor. Thus, TRT in low-risk patients with AD diagnosed with appropriate rigor is safe and potentially beneficial, whereas replacing testosterone in low-risk patients without proven AD is a recipe for futility. However, harm is inevitable in high-risk patients exposed to a therapy with potential risk of VEs, like TRT. Those three constructs provide a framework for reconciling the contradictory outcomes studies, from unequivocal benefit through no impact to unequivocal harm. 

The fact that patient selection and diagnostic rigor influence outcomes during TRT has major implications for clinical practice. It provides a blueprint for restricting TRT to patients with a low CV risk profile and AD established with diagnostic rigor, while excluding those with a high CV risk, particularly if they have a history of prior VEs.

The Moral of the Story

Diagnosing and managing hypogonadism is not an easy task. Primary care providers (PCPs) are reported to prescribe the bulk of TRT in the United States, but with far less caution or selectivity than endocrinologists.17 Almost 95 percent of TRT is prescribed in ways that are inconsistent with guideline recommen-dations.17,18 Endocrinologists have the responsibility to lead the way in the standardizing of diagnosis, ultimately making it easier to study hypogonadism.

Given the myriad reports on this topic with variable results, it is also the duty of the endocrine specialist to critically evaluate the data to the best of our ability in order to be able to honestly communicate to our patients the controversies and uncertainties that exist. Attending to our patients’ expectations in relationship to TRT is critically important given the commercial initiatives bombarding them with the promise of a potential “fountain of youth.” Patients and health care providers need to understand that diagnosing hypogonadism is not the end of the story; rather, it may be an indication of an underlying causative disease such as a pituitary or genetic issue which has farther reaching implications. Those with advanced training in endocrinology need to help others appreciate that TRT is not a benign treatment. Even putting aside controversies when it comes to the association of TRT and vascular outcomes, DEA licensing is required for prescribing TRT, and there is potential for requirement of long-term and possibly even lifetime therapy. Given this, we as health care providers need to model prescription appropriateness as this is currently the simplest and most efficacious method1 to challenge the complex environment enveloping TRT.  

Our clinic is proud to foster an environment of health care providers who are unafraid to tackle a controversial and rapidly shifting area of medicine such as hypogonadism. We pride ourselves on being an advocate for our patients as well as a resource and example to the medical community by our adherence to available clinical practice guidelines, and contributing to ongoing investigations to improve the understanding and treatment of hypogonadism.  


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