Evaluating the cardiovascular risk of testosterone replacement therapy in men with late-onset hypogonadism
Siyahian, Shant Armen
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As the major circulating androgen in men, testosterone holds a significant role in the maturation and maintenance of male characteristics. Some of its effects include inducing significant growth of the penis and testes early in development, producing sperm, and contributing to bone mass and muscle strength. Testosterone is synthesized in the testes and released into the circulation where it exerts its effects across the body. Its negative feedback on the hypothalamus and pituitary glands serve as regulation of the hypothalamic-pituitary-testosterone axis. Starting around age 30, testosterone levels have been shown to annually decline approximately 1-2% in men. Decline may eventually lead to a deficiency, presenting as reduced sex drive, erectile dysfunction, low sperm count, or decreased muscle bulk and strength. Many symptoms of testosterone deficiency coincide with old age. Also, the threshold of low testosterone at which symptoms manifest can vary from person to person. For these reasons, diagnosing testosterone deficiency has proven difficult. Nevertheless, certain guidelines have defined late-onset hypogonadism (LOH) as testosterone levels below about 200-300 ng/dl with the simultaneous presentation of at least one related symptom. Increasing diagnosis of late-onset hypogonadism, colloquially known as "Low T", has led to the enormous growth of the testosterone replacement therapy (TRT) market. Testosterone replacement therapy is the administration of either synthetic or endogenous testosterone to restore "above threshold" testosterone levels and improve the negative symptoms associated with deficiency. TRT comes in a wide variety of formulations and its use has risen steeply over the past decade, with a market currently worth around $1.8 billion. Reports estimate that the market for TRT may surpass $5 billion by 2018. However, there is plenty of cause for concern. In its current state, LOH is a loosely defined phenomenon whose treatment with TRT has not been confirmed in the research-standard large, randomized, placebo-controlled, trial. Furthermore, two recent retrospective database studies by Vigen et al. (2013) and Finkle et al. (2014) have reported increases in cardiovascular disease risk and mortality with TRT use in men with LOH. These studies were preceded with a meta-analysis by Xu et al. (2013) reviewing cardiovascular risk of TRT as well as another study measuring TRT effectiveness in elderly men by Basaria et al. (2010), which was prematurely halted due to an unsafe number of adverse events. The four studies above were analyzed and evaluated as the argument against TRT and its potential risk to cardiovascular health. On the other hand, there is plenty of evidence associating low endogenous testosterone levels with adverse effects and the benefits of TRT in treating LOH. This study summarized and evaluated the available evidence of the effects of endogenous testosterone levels and testosterone replacement therapy on cardiovascular health, including coronary artery disease, congestive heart failure, factors of atherosclerosis, and risk factors of cardiovascular disease such as obesity, type 2 diabetes mellitus, dyslipidemia, and inflammatory markers. Additionally, this thesis was written in the midst of a recent controversy concerning the field of TRT. Mainstream reporting on the results of the aforementioned studies by Vigen et al. (2013) and Finkle et al. (2014) led to increasing public concern about the safety of testosterone therapy. The results of these studies were met with heavy criticism by the medical field due to their shortcomings in design and conduct. The consumer rights advocacy group Public Citizen petitioned the FDA to add a black box warning of cardiovascular risk to TRT medications on the market. The Androgen Study Group, a group of medical experts and societies committed to accurate reporting of information about androgens, countered with a letter of their own to the FDA as well as a letter to JAMA requesting that they retract the article by Vigen et al (2013). The FDA is currently evaluating these requests as well as the overall risk of testosterone replacement therapy on cardiovascular health and mortality. The analysis of this thesis proved the argument against testosterone replacement therapy unreliable. The four studies contained significant flaws in methodology, substandard presentation of data, and were initially built upon a weak foundation of evidence. Current evidence shows that low endogenous testosterone levels are associated with increased cardiovascular risk, while the results of testosterone replacement therapy in treating LOH are predominantly positive. Many of these studies are epidemiological in nature, have small sample sizes, and vary in methodology and potential confounding factors. Thus, although the advantages reported for testosterone replacement therapy seems to trend positive, the need for randomized controlled trial(s) still remains. Diagnosis of LOH and prescription of TRT should be approached with caution and on an individualized basis.