Elsevier

Metabolism

Volume 86, September 2018, Pages 69-78
Metabolism

Male Reproductive Endocrinology
Testosterone replacement therapy: For whom, when and how?

https://doi.org/10.1016/j.metabol.2018.03.007Get rights and content

Highlights

  • Testosterone replacement therapy should only be offered to men with documented androgen deficiency

  • Men with late-onset hypogonadism should be treated on an individualized basis

  • The goals of TRT are to restore testosterone levels to mid-normal range for young healthy adults and alleviate the symptoms

  • Regular monitoring is essential in order to assess efficacy and safety

Abstract

The finding of low circulating testosterone level in men is relatively frequent. The symptoms of hypogonadism are very frequent in the aging men. However, the diagnosis of hypogonadism is often neglected and the opportunity to replace low testosterone in older men is highly debated. The aim of this narrative review is to summarize the steps necessary to formulate a proper diagnosis and to guide toward an individualized treatment. While universally recognized the need to treat the young adults with known causes of pituitary or testicular failure, there are controversies on the cost-benefit of treating testosterone deficiency in older men. Discrepancies among the several available guidelines do not help to clarify the scenario, however, the recent larger clinical trials have shed some light on the fact that testosterone treatment carries some benefit, that is not free from risks. We provide an updated review of the diagnostic hallmarks, the several treatment modalities, with their advantages and disadvantages, and how to individualize and monitor treatment in order to maximize the benefits and minimize the risks. The treatment of male hypogonadism can no longer be downgraded and must become part of the cultural baggage of the endocrinologist.

Introduction

Hypogonadism in men is the clinical syndrome that results from failure of the testis to produce adequate levels of testosterone (T) (androgen deficiency) and sperm cells [1]. Classical hypogonadism resulting in markedly reduced T levels due to identifiable congenital or acquired disorders at the testicular (primary hypogonadism), hypothalamic-pituitary (secondary hypogonadism) or combined levels is universally accepted indication for testosterone replacement therapy (TRT) [1,2].

In addition to the classical causes of T deficiency, several cross-sectional and longitudinal studies have demonstrated a gradual decline in T levels with increasing age, at an average rate of 1–2% per year, which varies in different individuals and is affected by adiposity, medications and chronic disease [[3], [4], [5], [6], [7]]. Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age and characterized by symptoms suggestive of androgen deficiency and a decline in serum testosterone levels below the young healthy adult male reference range [8]. Identification of LOH has potentially broadened the spectrum of men that might benefit from TRT, although the cost-benefit of treating LOH has been questioned and it is still under debate.

In recent years, the availability of new T formulations in combination with aggressive direct-to- consumer advertising (DTCA) marketing strategies and wider recognition of LOH have contributed to increased T testing and prescribing, in western countries [9]. Especially in the USA, sales of T preparations have quadrupled from 2000 to 2011, although the number of low testosterone levels revealed in laboratory testing has remained constant [9]. It appears that T preparations have been increasingly prescribed and consumed for symptoms without documented androgen deficiency. Symptoms such as fatigue, loss of libido, erectile dysfunction and depression can also be caused by diseases other than hypogonadism and will not necessarily improve under TRT especially if T levels are only marginally reduced [2]. Moreover, a few recent studies have raised concerns about the cardiovascular safety of TRT [[10], [11], [12]]. At least part of these currently discussed adverse effects of TRT, might be caused by improper prescribing [2]. Therefore, it is crucial to have clearly-defined criteria for initiating TRT in order to maximize the clinical benefits and minimize the side-effects of this treatment. All guidelines agree that the presence of symptoms of T deficiency and subnormal T serum levels are both necessary for the diagnosis of hypogonadism and initiation of TRT [1,8,13].

The aim of the present review is to provide updated evidence on TRT in adult males, focusing on indications for TRT, available T formulations, possible adverse effects and proper monitoring of men receiving this therapy.

Section snippets

Adults With Classical Hypogonadism

Disorders that can cause primary or secondary hypogonadism are listed in Table 1 [14,15]. Combined primary and secondary hypogonadism may occur with sickle cell disease, thalassemia, alcoholism, glucocorticoid treatment, hemochromatosis, DAX-1 mutations and in older men [16]. TRT should be administered only when the diagnosis of hypogonadism is firmly established as evidenced by the presence of compatible symptoms and signs and a subnormal morning (07:00–11:00 AM) serum testosterone

TRT Preparations

The principal goals of TRT are to restore normal T serum levels, avoiding supraphysiological or subnormal concentrations and to alleviate the clinical manifestations of androgen deficiency [82]. This is best accomplished by using natural T, and not synthetic androgens, since the full spectrum of androgen actions can only be achieved after aromatization of T to estradiol and 5α-reduction to dihydrotestosterone (DHT) [2]. However, natural T, when orally administered, is absorbed well by the

Contraindications to TRT and Potential Adverse Effects

Current guidelines recommend against initiating TRT in men with:

  • known prostate cancer (locally advanced or metastatic) [1,13,26]

  • breast cancer [1,13,26]

  • prostate nodule/induration or PSA > 4 ng/mL or PSA > 3 ng/mL and high risk for prostate cancer without further urological evaluation [1,26]

  • severe lower urinary tract symptoms (LUTS) with an International Prostate Symptom Score (IPSS) > 19 [1,26]

  • hematocrit > 50% [1] or according to EAU > 54% [13]

  • untreated severe sleep apnea [1,26]

  • uncontrolled or

Monitoring of TRT

The purpose of monitoring is to assess the efficacy and safety of TRT. Unfortunately, TRT is frequently prescribed without proper patient follow-up, as recent studies have demonstrated [9,11,12].

Conclusions

In the past, the diagnosis and treatment of the hypogonadism was confined to specialized centers with a special interest in andrology or urology. Previous approaches were mainly biased by the fact that there were few evidence-based data. The core of knowledge consisted of small clinical trials, personal experience and expert recommendations. In the recent 20 years, a revolution has occurred. Many different testosterone preparations have reached the market. This impulse prompted more rigorous

Disclosures

CT has nothing to declare.

AMI has been occasional consultant and has received unconditional grants from Novartis, Shire and IBSA, outside the current work.

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