Late-Onset Hypogonadism in Men: A Modern Approach to Treatment
Age and Testosterone
Late-onset hypogonadism is defined as an age-related clinical and biochemical syndrome characterized by typical symptoms and reduced serum testosterone concentrations, which may significantly impair quality of life and the function of multiple organ systems [1]. It is a mixed form of hypogonadism that develops as a result of declining testicular function (the primary hypogonadism component) and impaired function of the hypothalamic-pituitary-gonadal axis (the secondary hypogonadism component).
Hypogonadism is further aggravated by obesity, comorbid chronic diseases, chronic organ failure, severe acute conditions, alcoholism, and the use of medications such as opioids and corticosteroids. Hypogonadism is considered a risk factor for various chronic diseases and mortality in men. Reduced testosterone concentrations lead to decreased bone mineral density (BMD) and the development of osteoporosis. In men with hypogonadism, fat mass increases, and metabolic syndrome and insulin resistance develop. Studies have shown that men with androgen deficiency are more likely to develop cardiovascular diseases and have higher all-cause and cardiovascular mortality [2].
Testosterone levels decline with age, even in healthy men. Testosterone concentrations below the normal range are found in 2.1–12.8% of middle-aged men, while symptomatic androgen deficiency occurs in 2.1–5.7% of men aged 10–79 years [2]. In the context of an aging population, this health issue affecting older men is being investigated worldwide, with considerable attention devoted to testosterone replacement therapy and the continuous improvement of clinical practice guidelines.
In this article, we present selected aspects of the latest testosterone therapy guidelines and highlight several important clinical challenges.
Clinical Manifestations
Androgen deficiency is associated with a wide range of clinical signs and symptoms, including reduced testicular size, regression of secondary sexual characteristics, decreased lean body mass and muscle strength, impaired fertility, increased visceral fat, gynecomastia, and anemia.
Psychological and autonomic disturbances are also characteristic, including declining cognitive function, mood disorders, depression, persistent fatigue, poor sleep quality, and hot flashes. The most common symptoms of hypogonadism in older men are reduced sexual desire, activity, and satisfaction, erectile dysfunction, decreased overall physical performance, and mood changes [2].
Diagnosis
Both the European Association of Urology (EAU) and the Endocrine Society, in their testosterone therapy guidelines updated in 2018, agree that hypogonadism should be diagnosed in patients who exhibit symptoms and signs characteristic of androgen deficiency and have consistently and unequivocally low serum testosterone concentrations. These guidelines do not recommend routine screening of all men for hypogonadism [2, 3].
Laboratory diagnosis of hypogonadism begins with the measurement of total serum testosterone. Blood samples should preferably be collected in the morning between 7:00 and 11:00 AM, ideally after fasting. The latest guidelines particularly emphasize that testing and repeat measurements should be performed using the same reliable method, such as mass spectrometry, in the same laboratory [2, 3].
Low testosterone concentrations measured on 2 separate mornings are considered sufficient evidence to support the diagnosis. However, a difference greater than 20% between the 2 measurements should raise concerns about the reliability of the results [2].
Various studies have established approximate lower limits of normal serum testosterone concentrations ranging from 9.2 to 12.1 nmol/L for total testosterone and 243 µmol/L for free testosterone. In uncertain cases, when the patient's total testosterone concentration is close to the lower limit of normal, measurement of free testosterone and sex hormone-binding globulin concentrations is recommended to confirm the diagnosis [2, 3].
Benefits of Testosterone Replacement Therapy
Testosterone replacement therapy (TRT) is recommended for patients with symptomatic hypogonadism. Its aim is to restore physiological testosterone concentrations and alleviate symptoms caused by androgen deficiency.
Oral preparations, intramuscular injections, transdermal patches or topical formulations, and subcutaneous testosterone-releasing implants are used for testosterone therapy. These formulations differ in their pharmacokinetics, fluctuations in testosterone concentrations, formulation-specific adverse effects, costs, and administration schedules. Therefore, treatment is selected individually, taking into account not only the pharmacological effects of the medication but also the patient's preferences and ability to adhere to the treatment regimen [2, 3].
The Endocrine Society guidelines emphasize that TRT should not be routinely prescribed to men aged 65 years and older solely because of reduced serum testosterone concentrations, but only when symptoms of androgen deficiency are present. Furthermore, even when TRT is considered for men in this age group, its potential benefits and risks must be carefully weighed [3].
This recommendation is based on safety considerations, including the need to avoid adverse effects of TRT, such as marked erythrocytosis, and the lack of long-term studies investigating the effects of TRT on major cardiovascular events and the development of prostate cancer [3].
The European Association of Urology guidelines recommend that lifestyle modification, weight reduction, and effective treatment of comorbid diseases should be prioritized before initiating TRT to increase endogenous androgen production. TRT should be started only when these measures are ineffective [2].
The following sections describe in greater detail the physiological changes associated with TRT and highlight the safety concerns and certain controversial aspects addressed in the guidelines.
Although TRT has no effect on cognitive function, and evidence regarding its beneficial effects on psychoemotional well-being, including mood disorders, is inconsistent [2, 3], TRT clearly improves sexual function by increasing libido and sexual activity and improving erectile function [3].
However, the European Association of Urology guidelines state that the effectiveness of testosterone in treating erectile dysfunction is limited. Therefore, phosphodiesterase-5 inhibitors are recommended as first-line treatment, with additional exogenous testosterone suggested only when the response to these medications is insufficient [2].
An important consideration when treating older men is that studies have not found TRT to worsen lower urinary tract symptoms (LUTS). Testosterone therapy may therefore be prescribed to men experiencing urinary disturbances [2, 3].
Testosterone therapy has beneficial effects on the musculoskeletal system, reducing body fat, increasing muscle mass and muscle strength, and, most importantly, improving BMD [2, 3].
The European Association of Urology guidelines recommend screening men older than 50 years with hypogonadism for osteoporosis [2]. It is emphasized that testosterone is not intended to treat osteoporosis or prevent fractures in patients at high fracture risk. In such cases, medications specifically indicated for osteoporosis should be prescribed.
In patients without a high risk of fractures, physicians are advised to consider temporarily discontinuing specific osteoporosis treatment and reassessing BMD after 1–2 years of testosterone therapy [3].
TRT has been shown to have a beneficial effect on erythropoiesis and therefore helps correct anemia. This effect is more pronounced in older men. On the other hand, this property of testosterone also causes the most common adverse effect of TRT: erythrocytosis, defined as a hematocrit level greater than 54%. Such an increase in hematocrit is considered a risk factor for cardiovascular mortality.
In addition, cases have been reported in which erythrocytosis during TRT was associated with a higher incidence of venous thromboembolic complications in men without previously diagnosed thrombophilia, although studies have not confirmed an increased incidence of venous thromboembolism (VTE) in healthy men [2].
Thus, erythrocytosis is one of the main safety considerations that must be evaluated before prescribing TRT. The latest guidelines recommend assessing hematocrit and hemoglobin levels before initiating TRT and monitoring these parameters throughout treatment.
In patients who develop erythrocytosis during therapy, TRT should be temporarily discontinued and resumed at lower doses only after hematocrit levels have returned to normal. Therapeutic phlebotomy is also mentioned in the guidelines as an effective measure for reducing TRT-induced erythrocytosis [2, 3].
Testosterone Replacement Therapy and Cardiovascular Risk
Another highly debated aspect of testosterone replacement therapy (TRT) is the risk of cardiovascular events. On the one hand, androgen deficiency and erectile dysfunction are considered independent risk factors for cardiovascular disease and cardiovascular mortality. Some studies have found that men whose testosterone deficiency was corrected with TRT experienced fewer cardiovascular events and episodes of atrial fibrillation than untreated men [2].
Furthermore, the guidelines conclude that there is currently no evidence that replacement therapy maintaining testosterone concentrations within the normal range is associated with an increased risk of major adverse cardiovascular events.
It is emphasized that patients diagnosed with hypogonadism who already have cardiovascular disease should receive TRT only after a thorough assessment of their cardiovascular status, electrocardiogram (ECG), and hematocrit, and after optimization of secondary cardiovascular prevention. During treatment, hematocrit (not exceeding 54%) and testosterone concentrations should be monitored regularly, with testosterone maintained within the mid-normal range.
The recommended monitoring schedule for hematocrit and testosterone is at 3, 6, and 12 months of therapy and annually thereafter [2, 3]. TRT should not be prescribed to patients with severe heart failure (class IV), because testosterone increases fluid retention in the body [2], or to patients who have experienced myocardial infarction or stroke within the previous 6 months [3].
The association between testosterone use and the development of male breast cancer is not supported by strong evidence. However, testosterone is thought to potentially stimulate the growth of this hormone-dependent cancer. Therefore, TRT is contraindicated in patients with current or previous breast cancer [2, 3].
Testosterone Replacement Therapy and Prostate Cancer
The risk of prostate cancer remains another subject of considerable debate and uncertainty regarding TRT. The European Association of Urology guidelines state that there is currently no evidence that testosterone therapy causes histological changes in the prostate. Furthermore, testosterone use has not been observed to increase the risk of developing prostate cancer or to result in more aggressive prostate cancer [2].
On the other hand, androgen receptors play an important role in the pathogenesis of prostate cancer, and testosterone administration in patients with metastatic prostate cancer would promote tumor growth. It is therefore clear that TRT is contraindicated in patients with advanced prostate cancer.
The safety of TRT in men with hypogonadism who have previously undergone treatment for prostate cancer is also widely debated. The guidelines indicate that TRT may be cautiously prescribed to men who have undergone surgery for localized prostate cancer and have no evidence of active disease, including changes in prostate-specific antigen (PSA), abnormalities on digital rectal examination (DRE), or distant metastases.
It is recommended that TRT be prescribed only to patients at low risk of recurrence (Gleason score <8, pathological stage pT1–2, preoperative PSA – 1.4 ng/mL during the first 1–2 months of TRT, PSA >4 ng/mL detected at any time, or an abnormal prostate lesion palpated during DRE [4].
Summary
TRT is an important treatment option that can improve quality of life in older men with hypogonadism and alleviate certain symptoms caused by androgen deficiency. However, this therapy may cause adverse effects, has contraindications, and raises safety concerns that remain the subject of debate and require further long-term studies.
At present, treatment should be prescribed only to men with symptomatic hypogonadism. The key to successful management of late-onset hypogonadism lies in careful patient selection, individualized therapy, and close cooperation between the physician and patient.
It is important to establish the patient's expectations, discuss the realistic potential of therapy to alleviate individual symptoms of hypogonadism, carefully evaluate the potential risks of treatment, and closely monitor the patient's condition throughout therapy.
Adomas Ladukas, MD, Resident Physician¹; Ramūnas Tyla, MD²
¹ Vilnius University Faculty of Medicine
² Urology Center, Vilnius University Hospital Santaros Klinikos
References
1. Jones TH. Late onset hypogonadism. BMJ [Internet]. 2009 British Medical Journal Publishing Group;338. Available from: https://www.bmj.com/content/338/bmj.b352.abstract
2. Dohle GR, Arvrer S, Bettocchi C, Jones TH, Kliesch S. EAU Guidelines on Male Hypogonadism 2018. In: European Association of Urology Guidelines 2018 Edition [Internet]. 978-94-92671-01-1: European Association of Urology Guidelines Office; 2018. Available from: https://uroweb.org/guideline/male-hypogonadism/
3. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2018 May 1;103(5):1715–44.
4. New Testosterone Treatment Guidelines ‘Useful but Not Gospel’ – Medscape – Mar 17, 2018.
Jones TH. Late onset hypogonadism. BMJ [Internet]. 2009 British Medical Journal Publishing Group;338. Available from: https://www.bmj.com/content/338/bmj.b352.abstract
