Male Hypogonadism: The Korean Society of Men's Health and Aging Position Statement (original) (raw)

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Copyright © 2025 Korean Society for Sexual Medicine and Andrology

Review

Received October 25, 2024; Revised December 11, 2024; Accepted December 19, 2024.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The Korean Society of Men's Health and Aging (KSMHA) acknowledges the necessity for an updated statement on testosterone therapy driven by evolving clinical practices and new research findings. The primary purpose of this position statement is to provide a tailored, evidence-based framework that aligns with international best practices while addressing the unique needs of the Korean population. Additionally, this statement addresses the growing recognition of both organic and functional hypogonadism, particularly given the rising rates of obesity and metabolic syndrome, which affect testosterone levels and overall health. The position statement addresses key areas, including the clinical and laboratory diagnosis of male hypogonadism, with a focus on appropriate cut-off values for testosterone levels in Korean men, and provides guidance on assessing treatment outcomes. In this statement, we present an objective position on testosterone therapy based on recent studies that have carefully evaluated its effectiveness and safety. By providing a tailored framework for the management of male hypogonadism, KSMHA aims to enhance patient care and align Korean practices with global standards.

Keywords

Clinical effectiveness; Diagnosis; Hypogonadism; Safety; Testosterone; Therapy

INTRODUCTION

In 2006, the Korean Society of Men's Health and Aging (KSMHA)'s ‘Hormonal Treatment Recommendations for Late-Onset Male Hypogonadism’ marked a significant milestone as the first guideline proposed in Korea for the management of late-onset hypogonadism (LOH) in males [1]. This recommendation was initially based on joint guidelines proposed in 2005 by the International Society of Andrology (ISA), the International Society for the Study of the Aging Male (ISSAM), and the European Association of Urology (EAU) [2]. It covered the diagnosis, treatment, and follow-up of LOH and was adapted to the Korean context by the academic committee, which consolidated discussions from the 2006 KSMHA annual meeting. However, this recommendation has not been officially revised or updated.

In contrast, international academic organizations such as the International Society for Sexual Medicine (ISSM), American Urological Association (AUA), Endocrine Society (ES), ISSAM, and EAU have continuously revised and updated guidelines for male hormone therapy [3, 4, 5, 6]. Countries including Canada, Australia, Italy, and the United Kingdom have also developed and periodically updated their national guidelines, tailoring recommendations to their specific contexts [7, 8, 9, 10]. These efforts provide clinicians with a robust evidence-based framework for the evaluation and management of male patients with hypogonadism. Unfortunately, due to the lack of updated domestic guidelines incorporating the latest knowledge, Korean clinicians often face the inconvenience of referring to treatment recommendations from overseas academic societies.

Significant changes over the past two decades have highlighted the necessity of updating these guidelines. Updates encompass several aspects, including terminology used, the diminished diagnostic value of questionnaires, contraindications to testosterone (T) therapy, and up-to-date consensus on the effectiveness and safety of T therapy across various organ systems. These changes emphasize the need for a revised, comprehensive position statement that reflects the current state of scientific evidence and clinical best practices.

Over the past decade, landmark randomized controlled trials (RCTs) have provided crucial insights that should inform new guidelines. The National Institutes of Health-supported Testosterone Trials (T-Trials) have provided comprehensive data on the safety and efficacy of T therapy. Following these, the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) study and the Testosterone for the Prevention of Type 2 Diabetes (T4DM) trial provided additional data regarding T therapy-related cardiovascular (CV) disease diabetes, erectile function, libido, and prostate diseases.

This position statement is not intended as a guideline but rather as a summary of the published literature, emphasizing the safety and efficacy of T therapy. This statement aims to enhance the diagnosis, treatment, and management of hypogonadism by incorporating the latest research and international guidelines. These efforts will not only improve patient outcomes but also equip healthcare providers with the knowledge and tools needed to deliver high-quality care. The implementation of these updated guidelines is expected to standardize care, reduce complications, and improve the overall health and well-being of men with hypogonadism in South Korea.

TERMS AND DEFINITIONS

The terminology used to describe deficiencies in T production has evolved significantly over time. In 2002, the ISSAM introduced the term “LOH” to describe a clinical and biochemical syndrome associated with advancing age [11]. However, in 2006, Dr. Morales suggested “testosterone deficiency syndrome (TDS)” as a more appropriate term, arguing that it better reflects the condition's basis on low T levels and associated symptoms rather than age alone [12]. This term has been adopted by organizations such as the ISSM and AUA in their recent guidelines [3, 4].

Currently, the ES and the EAU continue to use “male hypogonadism” in their guidelines [5, 6]. “Male hypogonadism” is a well-established medical term that describes insufficient T production and is consistent with other endocrine deficiencies such as hypothyroidism, hypoparathyroidism, and hypopituitarism. This term provides a clear and comprehensive framework for understanding endocrine pathology. In contrast, the term “TDS” emphasizes the coexistence of low T levels with associated symptoms, making it particularly practical for clinical diagnosis and management. TDS is valuable for identifying candidates for T therapy and monitoring therapeutic responses by focusing on the symptomatic aspects of the condition.

We recognize that both terms reflect their strengths. TDS is acknowledged for its practical applications in clinical settings, particularly in diagnosing and managing patients undergoing T therapy. Meanwhile, “male hypogonadism” remains a precise and longstanding descriptive term suitable for academic and clinical discussions within the broader scope of endocrinology. The decision to use both terms underscores our commitment to providing a comprehensive and accurate framework for understanding and managing hypogonadism in adult males. While TDS offers a practical approach for clinical application, “male hypogonadism” is consistent with traditional medical terminology. In this position statement, for convenience, we will match the term “male hypogonadism” with the term “TDS” and will use only the term “male hypogonadism” from now on.

DIAGNOSIS AND TREATMENT

Recent clinical guidelines agree that a clinical diagnosis of male hypogonadism should be made only when patients present with low total testosterone (TT) levels and associated symptoms or signs. This approach aligns with the current position. Despite the availability of several questionnaires, including the Androgen Deficiency in Aging Males and Aging Males' Symptoms questionnaires, their use for diagnosing male hypogonadism is currently not recommended. However, these questionnaires lack specificity and cannot reliably define candidates for T therapy or monitor symptom responses in patients undergoing T therapy [13, 14]. The diagnosis of hypogonadism is particularly challenging because its symptoms and signs are nonspecific and vary widely among individuals. Common symptoms include decreased libido, erectile dysfunction (ED), reduced frequency of morning erections, fatigue, depression, and loss of muscle mass. In addition to these symptoms, certain clinical conditions and risk factors are frequently associated with hypogonadism, including obesity, type 2 diabetes mellitus, metabolic syndrome, osteoporosis, HIV-associated weight loss, chronic opioid use, and long-term glucocorticoid therapy [15]. Given these considerations, the KSMHA recommends T screening in men with the abovementioned symptoms, clinical conditions, or risk factors.

There are notable differences in the biochemical cut-off values for low TT levels among the current guidelines. Determination of the cut-off value for low TT is vital for making a diagnosis, and various organizations have proposed different thresholds for this purpose. Different approaches have been considered when establishing Korea's T-cut-off value, mirroring those employed in the prevailing guidelines. For instance, adhering to the ES approach, which utilizes the 2.5th percentile value, yields a 2.59 ng/mL cut-off for Korean men. This determination was drawn from a study of 8,367 middle-aged Korean men in their 40s and 50s [16]. Alternatively, when considering the thresholds associated with specific sexual symptoms, as recommended by the British Society for Sexual Medicine (BSSM) and the ISSM, a cut-off of 2.61 ng/mL is established. This value stems from a study that focused on 1,895 Korean men aged 40 to 80 years and considered the presence of sexual symptoms [17]. Based on evidence-based outcomes observed in the Korean population, it is advisable to consider a cut-off value of approximately 2.6 ng/mL as the designated Korean cut-off. However, setting a cut-off value as low as 2.59 or 2.61 ng/mL poses a difficulty, as it is significantly lower in comparison to the 3.0 to 3.5 ng/mL values recommended by other prominent organizations such as the AUA, EAU, ES, ISSM, ISSAM, and BSSM (Table 1) [4, 5, 6, 8, 15, 18]. This discrepancy raises concerns about whether such a low cut-off would be appropriate and beneficial for clinical practice in Korea. Addressing this issue seems to necessitate conducting a meta-analysis of Korean studies that have examined the effects of T therapy. This approach would allow us to suggest a new evidence-based cut-off value that maximizes the potential benefits of T therapy while minimizing the associated risks. Such a cut-off value would align more closely with international standards while being tailored to the specific needs and outcomes observed in the Korean population. Given that the TT cut-off value for Koreans differs from that used by other organizations, it is recommended that if a patient presents with convincing clinical symptoms and biochemical results showing low borderline TT levels (less than 3.5 ng/mL), treatment can be initiated for 3 to 6 months. In such cases, attempting T therapy to determine whether the symptoms are alleviated is reasonable.

Meanwhile, when faced with a borderline TT level or a discrepancy between symptoms and TT levels, it is important to consider additional tests such as luteinizing hormone (LH), sex hormone-binding globulin (SHBG), and prolactin (PRL) levels or to calculate free T. In obese or elderly patients, it is essential to measure SHBG levels to calculate free T. For suspected secondary hypogonadism, measurement of LH, follicle-stimulating hormone (FSH), and PRL is recommended.

Achieving an optimal therapeutic level is the key goal of T therapy. This study aimed to increase and maintain serum T levels within the normal range. For this, KSMHA recommends an optimal therapeutic TT level within the range of 4.2 to 6.3 ng/mL based on a previous study [16]. Serum T levels should be measured 3 to 6 months after the initiation of therapy and annually thereafter. In addition, improving symptoms while achieving the optimal therapeutic level of T therapy is essential. The treatment durations required to observe improvements in specific symptoms varied. Previous trials have shown significant improvements in symptoms over different timeframes, such as erectile function and low sex drive (within 3–6 weeks), anemia (within 3–6 months), bone mineral density (BMD) (within 6–24 months), lean body mass (within 12–16 weeks), and depressive symptoms (within 3–6 weeks) [19, 20]. Therefore, each symptom requires an adequate and appropriate evaluation period for outcome measurements. The therapeutic effects of T on symptoms should be assessed 3, 6, and 12 months after initiating T therapy. There is consensus that T therapy should be discontinued if symptoms do not improve despite achieving adequate therapeutic levels. Notably, serum T levels do not always directly correlate with symptom improvement.

In summary, the KSMHA recognizes the complexity and variability in diagnosing and treating hypogonadism in Korean men. While the current international guidelines provide useful frameworks, the KSMHA acknowledges the need for tailored approaches that reflect the unique biochemical and clinical characteristics of the Korean population. The society advocates a cautious but proactive approach to T therapy, particularly in cases where patients exhibit borderline TT levels and compelling clinical symptoms. Recognizing the lower TT cut-off values suggested for Koreans, the KSMHA emphasizes the importance of personalized treatment plans that prioritize patient outcomes while minimizing risks. The society also underscores the need for further research, including meta-analyses of existing Korean studies, to establish more precise and evidence-based guidelines. By recommending treatment initiation in appropriate cases and regularly monitoring therapeutic outcomes, the KSMHA aims to optimize the management of male hypogonadism and ultimately improve the quality of life of affected men in Korea.

The KSMHA recommendations for the diagnostic step and subsequent initiation of T therapy are summarized in Table 1.

FUNCTIONAL HYPOGONADISM

Organic (also known as classical) hypogonadism caused by genetic and anatomical defects, such as Klinefelter syndrome and Kallmann syndrome, can affect the hypothalamic-pituitary-gonadal (HPG) axis and alter gonadotropin levels [21]. In contrast, T levels may decrease without significant changes in the HPG axis following several health conditions such as obesity, diabetes, medication use, and systemic illnesses [22]. Unlike primary (testicular dysfunction) and secondary hypogonadism (pituitary/hypothalamic failure), functional hypogonadism (FH) may describe a late-onset hypogonadal status with reversible causes.

1. Characteristics of FH

Unlike organic hypogonadism, FH does not have recognizable intrinsic HPG axis pathology. Obesity and other comorbidities may mildly suppress the HPG axis, and FH can be reversed if the underlying cause is eliminated or treated [22]. The characteristics of FH, in contrast to organic hypogonadism, are described in Table 2 [23].

The FH can be defined in two ways. First, FH is a hypogonadism characterized by decreased androgen production and consistent clinical symptoms and signs of androgen deficiency [24]. Second, organic hypogonadism should be ruled out; hence, gonadotropin levels should be within the reference ranges. A clinical study suggested that LH levels range from 2 to 7 IU/L and FSH levels range from 2 to 10 IU/L [25].

2. Management of FH

1) Reversing underlying conditions

Repeat testing revealed that T levels normalized in 30% of the men with initially low T levels [24]. It suggests that day-to-day variations in T levels and temporary suppression of the HPG axis exist. Obesity is a major factor that suppresses the HPG axis and causes FH. A meta-regression analysis showed that a greater loss of body weight was associated with a higher T increase [26]. EAU guidelines also recommend weight loss and physical activity for improvement in T levels [5]. The treatment of underlying conditions with lifestyle modifications is considered first-line therapy [27]. The concept of FH suggests that hypogonadism is linked to lifestyle and systemic health issues rather than primary testicular failure. Considering the high prevalence of comorbidities such as obesity, recognizing and understanding FH may guide clinicians in clinical practice. FH can be considered after ruling out the organic causes of hypogonadism by emphasizing the role of modifiable risk factors and underlying health conditions.

2) T replacement in the FH

The TRACK_9 study showed the effect of the intramuscular administration of T undecanoate (1,000 mg) on FH [25]. During the 9-year observation period, patients with FH showed notable improvements in metabolic parameters and in the aging male symptom score (AMS) and International Index of Erectile Function (IIEF) questionnaire scores. Considering the CV safety revealed in the TRAVERSE trial [28], T replacement could be considered a therapeutic option in patients with FH.

T THERAPY AND SEXUAL FUNCTION

Therapy has shown a consistent and significant impact on sexual activity and libido. Data from several RCTs, including the T-Trials and TRAVERSE studies, support these findings. The T-Trials demonstrated that sexual activity, as measured by the Psychosexual Daily Library (PDQ-Q4) score, increased significantly with T treatment compared to placebo. The mean difference in the change from baseline between participants assigned to the T and those assigned to the placebo was 0.58 (p<0.001) among men enrolled in the Sexual Function Trial and 0.62 (p<0.001) across all T-Trials participants [29]. Similarly, the TRAVERSE Sexual Function Study, the largest randomized placebo-controlled study on the effects of T therapy on sexual function, further validated these findings. In this study, testosterone-treated men exhibited a significant increase in the frequency of daily sexual activity compared with the placebo group, with a nearly 50% increase in their overall sexual activity. This study also reported sustained improvements in sexual desire over 24 months [30]. These results align with those of previous meta-analyses, which have consistently indicated that T supplementation improves sexual function, particularly in terms of libido and overall sexual activity [31, 32]. Based on this evidence, the KSMHA endorses the view that T therapy is beneficial for enhancing libido and overall sexual function in men with hypogonadism.

However, the effect of T therapy on erectile function presents a more complex picture with conflicting data. Data from the TRAVERSE study revealed that both the testosterone and placebo groups experienced an increase in their IIEF-5 scores, with no significant differences observed between the two groups [30]. These findings suggest that T therapy may not have a notable effect on erectile function itself [2]. In contrast, T4DM and T-Trials reported modest improvements in erectile function with T therapy [29, 33]. Recent meta-analyses reflect this inconsistency, with some studies indicating a modest benefit while others reporting minimal improvement [31, 32, 34].

The KSMHA recognizes that, although T therapy may offer some improvement in erectile function, its effect is generally less than that observed with phosphodiesterase type 5 inhibitors. Moreover, T therapy is not considered an effective monotherapy for ED [35, 36]. The impact of T on erectile function seems to be indirect, potentially exerting a protective effect against age- and comorbidity-related decline in erectile function rather than directly enhancing erectile function. Therefore, when considering T therapy for ED, clinicians should consider baseline erectile function and the presence of any contributing comorbidities such as diabetes and obesity. The stance of the KSMHA is that while evidence supporting direct therapeutic effects on ED is insufficient, T therapy may offer indirect benefits by improving the underlying health conditions that contribute to ED.

T THERAPY AND PROSTATE

Among the various side effects of T therapy, its safety concerning prostate cancer is a major concern. Most clinical guidelines recommend T therapy for patients with metastatic or locally advanced prostate cancer. However, there is growing support for offering T therapy to symptomatic men with a history of treated localized low-risk prostate cancer, provided there is no evidence of active disease, as indicated by prostate-specific antigen (PSA) levels, digital rectal examination, and imaging studies [37, 38]. For instance, the BSSM and the EAU recommend this approach, while the ES takes a more conservative stance, advising against T therapy in men with a palpable prostate nodule, induration, or a PSA level ≥4 ng/mL [5, 6, 8]. The AUA and ISSM suggest that T therapy should be considered on a case-by-case basis for patients with prostate cancer [3, 4]. Recent RCTs mentioned above in this article have further clarified the impact of T therapy on prostate cancer outcomes. In the TRAVERSE study, the incidence of high grade or any prostate cancer was nearly identical between the testosterone and placebo groups, suggesting no significant increase in the risk of prostate cancer with T therapy [39, 40]. Similarly, the T4DM trial and T-Trial reported no significant differences in prostate cancer rates between testosterone-treated and placebo groups [29, 33]. Based on this evidence, the KSMHA acknowledges that T therapy does not increase the risk of prostate cancer in hypogonadal men. For patients with a history of prostate cancer, especially those with low-risk localized disease and no signs of active disease, T therapy should be considered under close monitoring.

Historically, the 2006 KSMHA guidelines recommended against T therapy in patients with severe lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH), particularly in those with high International Prostate Symptom Scores (IPSS) or clinical signs of bladder outlet obstruction due to BPH. However, recent meta-analyses have not found significant differences in LUTS between patients treated with T and those receiving a placebo [41, 42, 43]. These findings support the hypothesis that T therapy does not exacerbate LUTS/BPH. Nonetheless, recent RCTs have provided a nuanced picture. In the T4DM trial, the number of BPH-related hospital admissions was higher in the testosterone group than in the placebo group (8 vs 3); however, this difference was not statistically significant [33]. Similarly, the TRAVERSE study reported a slightly higher incidence of urinary retention, invasive surgical procedures for BPH, and pharmacological treatment in the testosterone group than in the placebo group, but this difference was not statistically significant [39, 40]. It is important to note that these studies excluded patients with severe LUTS, as indicated by an IPSS score >19, limiting the generalizability of the findings.

Given these mixed results, the KSMHA recognizes no current evidence to discourage T therapy in patients with hypogonadal LUTS/BPH. However, its potential impact on severe LUTS remains unclear, and further research is necessary. Therefore, the KSMHA advises that T therapy should be approached cautiously in patients with severe LUTS/BPH, and clinicians should consider each patient's baseline symptoms and comorbidities.

T THERAPY AND CARDIOVASCULAR DISEASES

An RCT conducted in 2010 indicated an elevated risk of CV events in older men with limited mobility who underwent T-gel therapy [44]. The trial was prematurely terminated with 209 male participants (mean age, 74 years) due to the high rate of adverse CV events. Thus, the Food and Drug Administration (FDA) initiated a review of the safety of T's CV. However, retrospective cohort studies have yielded conflicting results. Some studies have indicated that T therapy increases CV risk, while others have suggested a decrease [45, 46, 47]. In contrast to the results of the RCT conducted in 2010, the TRAVERSE study published in 2023 presented a contradictory perspective. This pivotal study was designed to investigate the effect of two years of T therapy on major adverse cardiovascular event (MACE) outcomes. The TRAVERSE study reported a hazard ratio of 0.96 with 95% confidence interval (95% CI), 0.78 to 1.17; p<0.001, suggesting that T therapy was non-inferior to placebo during a mean 22-month follow-up in hypogonadal men with pre-existing CV disease or risk factors [39]. Furthermore, no significant differences were observed in the incidences of secondary (CV-related mortality, non-fatal myocardial infarction, nonfatal stroke, or coronary revascularization) and tertiary (all-cause mortality, hospitalization, or urgent visits for heart failure, peripheral arterial revascularization, and venous thromboembolic events) endpoint events. However, a greater occurrence of non-fatal arrhythmias necessitating intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), and acute kidney injury (2.3% vs 1.5%) were noted among hypogonadal males who received T. Consistent with the TRAVERSE study, the TEAAM, T-Trials, and T4DM studies also reported low MACE rates, with similar outcomes between the T and placebo groups [29, 33, 48]. The 2023 TRAVERSE study provided critical evidence that T therapy, when appropriately administered to men with low T levels, does not significantly increase the risk of MACE in hypogonadal men with CV disease or those at CV risk [39]. This finding addresses previous concerns and influences future clinical guidelines. The KSMHA's stance, taking these considerations into account, is that T therapy may not increase the short-term risk of MACE in hypogonadal men, offering important guidance for clinicians considering this treatment option for their patients.

T THERAPY AND METABOLIC EFFECTS

RCTs on the effects of T therapy on insulin resistance (IR) and glycemic control in men with hypogonadism and type 2 diabetes mellitus have produced conflicting results [49]. While some trials have demonstrated a significant decrease in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and hemoglobin A1c (HbA1c) [50, 51, 52], others have reported no significant impact on these parameters [53, 54, 55].

The T4DM study assessed the potential of T treatment in hypogonadal men to prevent or reverse early type 2 diabetes mellitus beyond the effects of lifestyle modifications [56]. In this study involving men aged 50–74 years with impaired glucose tolerance or newly diagnosed T2D and a waist circumference of 95 cm or higher, T therapy significantly decreased the risk of T2D (relative risk, 0.59) over 2 years compared to placebo. The T4DM study showed that T therapy, alongside lifestyle changes, reduced postprandial 2-h glucose levels by 0.75 mmol/L on the oral glucose tolerance test [33] and decreased the absolute incidence of T2D by 8.6% (55/443, 12.4% in testosterone vs 87/413, 21% in the placebo group) in men at high risk of T2D [33]. However, T did not affect HbA1c levels in T4DM, consistent with previous meta-analyses [57]. The favorable effects on glucose metabolism were found to be independent of baseline T levels. Furthermore, compared to placebo, T was also associated with a significant reduction in fat volume and an increase in skeletal muscle mass and strength. On the other hand, In the TRAVERSE trial, which involved 5,204 participants aged 45 to 80 years with hypogonadism and prediabetes or diabetes, the proportions of men who achieved glycemic remission and changes in glucose and HbA1c levels were similar between the T and placebo groups [58]. The risk of progression from prediabetes to diabetes did not differ significantly between groups.

Based on previous studies, the KSMHA recognizes that there is no conclusive evidence that T therapy benefits patients with prediabetes or diabetes. Therefore, the KSMHA suggests that T therapy should not be used for the treatment or prevention of prediabetes or diabetes in men with hypogonadism.

Multiple prospective studies have used large sample sizes to investigate the effects of endogenous T on lipids. Findings from the San Antonio Heart Study indicated an inverse relationship between T levels and total cholesterol (TC), low-density lipoprotein (LDL), and triglyceride (TG), and a positive correlation with high-density lipoprotein (HDL) levels [59, 60]. Additionally, a longitudinal study from the Study of Health in Germany demonstrated a prospective link between low TT and dyslipidemia [61]. According to T-Trials, T therapy significantly decreased TC (adjusted mean difference, -6.1 mg/dL; p<0.001), HDL (adjusted mean difference, -2.0 mg/dL; p<0.001), and LDL (adjusted mean difference, -2.3 mg/dL; p=0.051) after 12 months [62]. However, the clinical implications of T therapy on dyslipidemia remain unclear because both LDL and HDL levels declined, and there were no statistically significant changes in the cholesterol/HDL ratio or TG levels. In addition, the effect of T on the decreased LDL levels in this trial was smaller than that of statins. These results suggest that more RCT should be conducted, and T therapy does not appear to be a priority therapeutic agent for the treatment of dyslipidemia.

T THERAPY AND BONE

As men age, serum T concentrations and BMD decrease. However, previous studies on the effect of T treatment on bone density in older men have been inconclusive [63, 64]. The recent TRAVERSE study found that T treatment did not reduce the incidence of clinical fractures. In fact, men who received T had a numerically higher clinical fracture incidence compared to those who received the placebo (3.50% vs 2.46%, hazard ratio 1.43; 95% CI, 1.04–1.97) [65]. Fractures predominantly occur at sites such as the wrist, ankle, and ribs, often resulting from trauma, particularly falls. However, the incidence curves for fractures diverged early between the T and placebo groups, with fractures in the T group increasing immediately after the initiation of T therapy, suggesting that the increased risk might be due to behavioral factors, such as increased physical activity [66]. The interpretation of these trial results has limitations owing to the lack of information about falls, bone density, and physical activity.

Conversely, in the T-Trials Bone Study involving 211 participants, T therapy over 12 months led to increased volumetric bone BMD at the trabecular spine (6.8% [4.8–8.7]) and total hip (1.3% [0.8–1.7]) and increased estimated spine trabecular bone strength (8.5% [6.0–10.9], all p<0.001) [67]. In the T4DM bone sub-study (T4Bone) with 600 participants, T therapy over 2 years resulted in increased areal BMD of the lumbar spine (3.3%; 95% CI, 2.7%–3.9%), total hip (1.9%; 95% CI, 1.2–2.7), and femoral neck (1.7%; 95% CI, 0.8%–2.7%), with all p-values <0.001. In a subgroup of 177 men from the T4Bone study, T therapy significantly increased the total and cortical volumetric BMD, as assessed by high-resolution peripheral quantitative CT [68].

However, these two studies were not specifically designed for individuals with low bone density or osteoporosis. The biochemical mechanism of T therapy on bone architecture, bone strength, or incident fracture in hypogonadal men has not been thoroughly researched, and it has been consistently observed that T therapy increases muscle strength, power, bone density, and estimated bone strength in men with low to low-normal serum T [69]. T therapy should be considered a viable treatment approach to alleviate symptoms associated with hypogonadism and enhance BMD. However, evidence regarding the use of T therapy to prevent bone fractures is lacking.

T THERAPY AND ERYTHROCYTES

Anemia is another concern associated with T deficiency. According to TRAVERSE and T-Trials, T therapy significantly increased hemoglobin, alleviated anemia, and prevented anemia in older hypogonadal men with anemia [70, 71]. Red blood cell count and hematocrit (HCT) increased significantly more in T group compared to the placebo, regardless of anemia presence at baseline [70]. In this context, ‘polycythemia’ or ‘erythrocytosis’ may occur as a potential risk for T-treated hypogonadal men who were not anemic at baseline.

‘Polycythemia’ or ‘erythrocytosis’ has been frequently mentioned as a potential adverse effect of T therapy and is an independent risk factor for MACE and venous thromboembolism (VTE) [72, 73]. The FDA requires manufacturers to include a warning regarding the risk of VTE for T-products [6]. In TRAVERSE, six men had persistent erythrocytosis (HCT >54%) even after adjustment to the lowest dose (20.25 mg) and had to discontinue the trial [70]. In the T-Trial, 6 of 336 (1.8%) non-anemic hypogonadal men experienced an elevation of hemoglobin >17.5 g/dL during T therapy, and this elevation was mostly observed concurrently with the elevation of serum T [71]. Similarly, in T4DM, erythrocytosis occurred more frequently in the T group than in the placebo group. An increase in HCT >54% occurred in 106 of 491 patients (22%) in the T group and 6 of 484 patients (1%) in the placebo group. Additionally, 25 patients in the T group had to stop T therapy [33]. The increase in HCT during T administration and the frequency of erythrocytosis were higher in older men than in younger men [74]. In addition, these effects are related to the T dose and circulating concentration [75]. ES, AUA, and EAU guidelines recommend measuring hemoglobin and HCT at baseline, 3 to 6 months after T therapy initiation, and annually if stable [4, 6]. Similarly, the KSMHA recommends regular HCT monitoring during T replacement therapy at baseline, 3 to 6 months, and annually thereafter, especially in older men. The risk of developing polycythemia is higher with short-acting intramuscular injectable T forms owing to the peak-and-trough nature of their delivery [72, 76]. The selection of T formulations other than the intramuscular route may be an alternative for at-risk populations [76].

If polycythemia develops, T therapy should be temporarily suspended until the HCT returns to normal and then resumed at a lower dose [6]. Therapeutic phlebotomy is an option for managing T therapy-induced erythrocytosis. Multiple national guidelines use elevated HCT levels as a trigger to stop or modulate T therapy, such as the dose and T formulation. Specific cutoffs from various guidelines range from 50% to 55% [4, 6, 7, 77]. Additionally, one study indicated an elevated risk of MACE and VTE among men with polycythemia and HCT levels ≥52% as a result of T therapy [70]. Considering these perspectives, the KSMHA recommends the discontinuation or modification of T therapy when HCT levels reach 50% to 55%.

T THERAPY AND DEPRESSION

T has neurobehavioral, somatic, and metabolic effects that relieve depressive symptoms [78]. Hypogonadal men show a higher incidence of depressive symptoms compared to eugonadal males [79]. An animal model showed that decreased T levels correlate with an increased predisposition to depression and suicidal behavior [80]. In this regard, T therapy is believed to enhance mood by increasing positive emotions. Systematic reviews suggest that T therapy can effectively reduce depressive symptoms in men, especially when administered at higher doses to carefully selected populations [81]. A Korean study showed that 8 months of T therapy improved depressive symptoms [82].

Conversely, one study indicated a limited impact of T therapy on mood in older men [83]. However, some studies have found that it is ineffective in treating clinical depression and fatigue [29, 84]. In a secondary analysis of T4DM, the effect of T on health-related quality of life and psychosocial function, including depressive symptoms, subjective social status, mastery, and sense of coherence, was assessed. T improved the subjective social status and sense of coherence, but there was no difference between the T group and the placebo in mental and physical function (assessed by the Short Form-12) and depressive symptoms (assessed by the Center for Epidemiological Studies-Depression scale) [85]. In participants enrolled in the TRAVERSE trial, although T therapy improved mood (Hypogonadism Impact of Symptoms Questionnaire; HIS-Q mood domain score) and energy in men with hypogonadism compared to the placebo, regardless of the presence of significant depressive symptoms (PHQ-9 score >4), the statistical significance of the treatment effect was small. Depressive symptoms did not improve in severe or moderately severe (PHQ-9 score ≥15) and late-onset low-graded persistent depressive disorder. T therapy did not significantly improve cognition or sleep quality [86].

There are conflicting results on the potential association between T supplementation and newly diagnosed mental health risks, such as depressive mood and suicide attempts [86, 87]. One study suggested the potential risks of new-onset mental health issues [87]. Along with recent RCTs suggesting ineffective or small effects of T therapy on depression, the KSMHA recommends against prescribing T solely to improve mood.

Recent RCTs, including TRAVERSE, T4DM, and T-Trials, have shared findings on the efficacy and risks associated with T therapy. These findings are shown in Fig. 1 for easier comprehension. For more comprehensive information on the results of recent RCTs, please refer to Supplement Table 1.

Fig. 1
Testosterone effects and safeties summary of recent 3 randomized controlled trials.
TRAVERSE: The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men, T4DM: The Testosterone for Diabetes Mellitu, T-Trials: The Testosterone Trials, LUTS: lower urinary tract symptoms, BPH: benign prostatic hyperplasia.

Meanings of the Names of the Trials are in the following colors: Green: Positive (benefit); Magenta: Neutral (balanced); and Red: Negative (risk).

aSexual function (overall sexual activity, orgasm, libido, satisfaction).

bParticipants who have a high risk of cardiovascular events were excluded.

(In T4DM, defined as having had a stroke or transient ischemic attack in the past 3 years, a major cardiovascular event in the past 6 months, cardiac failure (New York Heart Association class≥II), angina, arrhythmias, blood pressure of 160/100 mmHg or more, personal or family history of thrombophilia, and hematocrit greater than 50%).

(In T-Trials, defined as myocardial infarction or stroke within the previous 3 months, unstable angina, New York Heart Association class III or IV congestive heart failure, a systolic blood pressure >160 mmHg, or a diastolic blood pressure >100 mmHg).

cParticipants with a history or high risk of prostate cancer, severe LUTS, and BPH were excluded (T-Trials excluded: Prior history of prostate cancer, or >upper limit of normal for age-adjusted prostate-specific antigen values, clinical suspicion of malignancy on digital rectal examination [DRE], A score of >19 on the IPSS [Questions 1–7]).

dThe use of testosterone therapy improved mood, as indicated by the Hypogonadism Impact of Symptoms Questionnaire (HIS-Q) mood domain score, irrespective of the presence of significant depressive symptoms (defined as a PHQ-9 score of >4). However, the statistical significance of the treatment effects was small. Notably, there was no observed improvement in depressive symptoms in individuals with severe or moderately severe symptoms (PHQ-9 score ≥15) or those with late-onset, low-grade, persistent depressive disorder.

eThe difference was not statistically significant compared with the placebo, but it is important to note that this does not preclude the existence of any potential risk. Even a small probability of adverse effects warrants further attention. In addition, it is essential to interpret these findings with caution, as the trials excluded high-risk participants.

KOREAN STUDIES

1. Aging and epidemiology

While an earlier cross-sectional study suggested a decline in T levels with age, this study found no significant difference in TT levels between individuals in their 40s and 70s [88]. Subsequent research has produced mixed results, with some studies showing a positive correlation between age and T levels, whereas others have reported a weak negative correlation [89, 90]. Additionally, the clinical setting could affect the findings, as young male adults undergoing bowel preparation during health checkups demonstrated lower T levels than older adults [91]. A short-term longitudinal study did not find a significant decline in TT over a three-year period [92]. In accordance with Western studies, an increase in SHBG and a decrease in free T with age are clear in most Korean studies.

2. Sexual function, prostate health

A nationwide study using a randomly selected registry of primary care clinics found a strong association between decreased libido, ED, and lower serum T levels [17]. Studies have explored the relationship between T and sexual function as well as prostate health. Although a weak positive correlation existed between TT levels and overall sexual function, its relationship with general aging symptoms was less pronounced [93]. Additionally, more severe LUTS and larger transitional prostate volumes were observed in aging men with lower TT levels [94]. However, these results suggest that low T levels may be caused by insufficient sleep due to sleep disorders such as nocturia.

The relationship between low T levels and prostate cancer detection risk was investigated in men who underwent prostate biopsy for histological confirmation of prostate cancer [95]. Notably, men with TT <3.0 ng/mL had a higher propensity for high-grade prostate cancer. This finding is consistent with the meta-analyses of prospective epidemiological studies that found no significant association between T concentration and the risk of prostate cancer [96].

A retrospective study investigated the factors affecting T recovery after androgen deprivation therapy (ADT) withdrawal in patients with prostate cancer [97]. A shorter ADT duration was associated with faster and more frequent T recovery to optimal levels after treatment cessation. Factors such as age, SHBG levels, initial T levels, and ADT duration influenced the recovery process.

3. Metabolism

According to the Korean Endocrine Society Registry, hypogonadism in patients with Klinefelter syndrome is often accompanied by obesity and hyperglycemia. The study identified T level as an independent risk factor for these metabolic issues [98]. Similarly, Korean studies revealed a complex interplay between T levels and health in men. Lower T levels have been linked to an increased risk of metabolic syndrome [99]. Studies have also indicated a possible association between low T levels and poor glycemic control in men with diabetes [100, 101]. In addition, reduced T levels have been associated with acute ischemic stroke [102]. However, the relationship between T levels and fatty liver disease remains unclear [103]. However, the association between T and bone health remains unclear. Although FT may influence BMD, TT is not clearly associated with BMD or bone turnover markers [90].

4. T therapy

Testosterone undecanoate has demonstrated efficacy and safety for the treatment of TDS in Korean men [104]. A prospective multicenter study involving 133 patients found that T undecanoate was well-tolerated and effectively increased T levels for up to 24 weeks. In another study of 106 men with low T levels and cognitive impairment, T therapy significantly improved cognitive function in participants with baseline scores <25 [82]. The study shows that T therapy might offer dual benefits to older men by improving both mood and cognitive performance. These findings suggest that T therapy may be a beneficial treatment option for men with TDS and the associated cognitive symptoms.

CONCLUSIONS

1. Summary

The KSMHA developed a position statement addressing the specific needs and characteristics of Korean men with hypogonadism. This statement provides a comprehensive review of the current evidence and offers a tailored approach for the diagnosis and management of male hypogonadism in Korea. First, we emphasized the importance of combining both clinical symptoms and biochemical markers for the diagnosis of male hypogonadism. This approach includes recognizing the challenges in diagnosing hypogonadism, particularly distinguishing between organic and FH, which is influenced by factors such as obesity, metabolic syndrome, and systemic conditions. We recommend T screening for men presenting with specific symptoms or risk factors to ensure an accurate diagnosis. Second, we addressed the variability in the biochemical cut-off values for T, acknowledging that the suggested thresholds for Korean men are lower than those used internationally. We highlight the need for further research to establish an appropriate and evidence-based cut-off value that aligns with international standards and the specific needs of the Korean population. In terms of efficacy, the statement highlights the positive effects of T therapy on various health outcomes. These include improvements in sexual functions, such as increased libido and overall sexual activity, although their impact on erectile function is less pronounced. T therapy also has potential benefits regarding metabolic outcomes, including improved insulin sensitivity and reduced fat mass, making it particularly advantageous for men with metabolic syndrome or T2D. Additionally, T therapy is associated with enhanced bone health, improving BMD in hypogonadal men. Evidence suggests that T therapy may have mood-enhancing effects, potentially alleviating symptoms of depression in men with hypogonadism. With regard to safety, this statement acknowledges the importance of carefully monitoring the risks of T therapy. Current evidence suggests that T therapy does not increase the risk of prostate cancer when appropriately managed. Similarly, T therapy does not appear to increase the risk of CV diseases when prescribed and monitored correctly, even in men with pre-existing CV conditions. However, T therapy is associated with an increased risk of polycythemia, necessitating regular monitoring of HCT levels to mitigate this risk.

2. Limitations and future considerations

Despite the comprehensive nature of this statement, some limitations must be acknowledged. One of the primary challenges encountered during the development of these recommendations was the lack of well-designed studies specifically targeting T therapy in the Korean population. This scarcity of robust data has made it difficult to definitively establish the efficacy and safety of T therapy and critically determine an optimal T cut-off value that ensures effective treatment while minimizing risks. Given these limitations, there is a clear need for additional research, including large-scale cohort studies and RCTs focusing on the Korean population. Such studies will be essential to refine our underst anding of the benefits and risks of T therapy and update this statement. Our ultimate goal was to develop more precise guidelines to provide clinicians with the best possible tools for managing hypogonadism in Korean men, thereby improving patient outcomes and overall health. As new evidence emerges, the KSMHA is committed to revisiting and revising these recommendations to ensure they align with the latest research and international best practices.

3. Highlights

Conflict of Interest:The authors have nothing to disclose.

Funding:Supported by the KSMHA for literature review, writing, and editing.

Author Contribution:

Acknowledgements

Endorsed by the Korean Endocrine Society.

Endorsed by the Korean Society for Sexual Medicine and Andrology.

Endorsed by the Korean Academy of Family Medicine.

The authors would like to thank Du Geon Moon (Department of Urology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea), Moon Jong Kim (Department of Family Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea), Seok Won Park (Department of Internal Medicine, Yongin Severeance Hospital, Yonsei University College of Medicine, Seoul, Korea) for their comments on this study.

The authors also thank Mi Ran Choi (Ajou University School of Medicine) for her support with manuscript preparation, including the tables and figure.

We would like to thank Editage (www.editage.co.kr) for English language editing.

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