madman
Super Moderator
* Treating physicians should aim to prescribe the minimal required dosing to improve serum T and hypogonadal symptoms.
* Clinical experience supports raising tT into the upper third of the normal range for patients who do not respond symptomatically at lower levels.64
* A patient’s hematocrit should be measured at baseline and thereafter followed to ensure they are not developing polycythemia (hematocrit levels 54% or greater) during TTh (Table 4).6,8,17,65–67
* Established risk factors for TEs in patients with polycythemia vera include advanced age, TE history, and elevated hematocrit. Likewise, secondary polycythemia or erythrocytosis is a relatively common side effect of TTh and may be associated with thromboembolic events.8,44,68–70 More specifically, a positive family history of venous thromboembolism (VTE) requires further analysis to exclude a condition of congenital undiagnosed thrombophilia-hypofibrinolysis.71 Moreover, lower baseline hematocrit (48%-50%) should be carefully evaluated before TTh, especially in high-risk men such as those with chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea syndrome (OSAS). A
* As a whole, these findings imply that the optimum hematocrit is subgroup specific and depends on the many factors impacting blood rheology.77Thereof, a hematocrit level 54% or greater should require TTh withdrawal, dose reduction (concentration or application frequency), drug holiday, change of formulation, and/or blood donation/phlebotomy depending on the clinical situation to avoid any potential cardiovascular complications.
* Overall, T levels affect libido, erectile function, and ejaculatory function in men with the greatest effect appearing to be on libido. Conversely, TTh has a modest and variable effect in improving erectile function (mostly mild ED) in hypogonadal men.
* 5) Combination TTh and hCG
There are some men who simply do not tolerate complete withdrawal of TTh. For these men, a combined approach of lowering TTh dosing and adding hCG has been suggested. Although literature is scant on the efficacy of this approach, it is a well-established off-label clinical practice. The dosing must be titrated to maintain FSH levels in the detectable range and check frequent semen analyses to guide therapy. Usual dosing regimens include hCG 3 times a week, ranging from 750 to 2000 IU. Subcutaneous or intramuscular T injections of either T enanthate or cypionate will range from 50 to 100 mg weekly. Elevating weekly injections into the 150–200 mg range, which is often used as weekly dosing for unopposed TTh, will likely suppress FSH and spermatogenesis.207 Given the off-label nature of this approach and the lack of systematic reviews or clinical trials proving safety and efficacy, one should pause prior to prescribing this combination therapy.
6) Testosterone nasal gel
* Although the spermatogenic preservation mechanism is unknown, it is most likely the short-acting nature of intranasal T that is responsible for this effect. Given these data, intranasal T may play a role in TTh as a primary agent in men actively trying to conceive or as a recovery agent in men on long-acting TTh.213 Overall, in consideration of the scarcity of available data and their results, which have made the product extremely controversial in terms of clinical use, with authoritative expert opinion, this ICSM 2024 Panel decides not to issue recommendations regarding the use of the same in real-life daily clinical practice.
* It can now be reasonably stated that TTh does not increase the risk of developing PCa.
* It must be added that since 15% of men with low serum T and PSA <4.0 ng/mL have biopsy-detectable PCa, approximately 1 in 7 men receiving TTh has undiagnosed PCa.222,223 The absence of increased rates of PCa among men receiving TTh in these various trials argues strongly that TTh does not cause rapid or aggressive growth of existing PCa.
==============
Male hypogonadism, also known as testosterone deficiency (TD), is a prevalent clinical condition combining low concentrations of circulating testosterone (T) and specific signs and symptoms associated with impaired hormone production.
This consensus paper is aimed to provide the International Consultation for Sexual Medicine (ICSM) 2024 recommendations (Boxes 1 and 2) concerning work-up management strategies for male hypogonadism diagnosis (Box 1) and testosterone therapy (TTh) (Box 2) in the everyday real-life clinical setting.
========
Methods
A comprehensive literature search was performed using Google and PubMed database for English-language original and review articles, either published or e-published with focus on research from but not limited to the last 10 years, mostly covering the whole literature on male hypogonadism published since the last 2015 consultation with the goal to support or repeal previous recommendations. Available studies were collected and analyzed by all panel members; the various topics have been subdivided among experts, and finally discussed with 2 panel chairs (M.K., A.S.). This paper was then developed as an authoritative, comprehensive, all-encompassing consensus document highlighting state-of-the-art knowledge, based on the peer-reviewed medical literature and expertise of worldwide experts on major topics concerning diagnosis of male hypogonadism, treatment options, T impact toward cardiovascular, metabolic, sexual and reproductive health and prostate cancer (PCa). The first draft of the manuscript was then circulated to all the members for further review to address possible conflicts or disagreements. Thereafter, a modified Delphi method was used for making recommendations on management strategies for male hypogonadism in the everyday real-life clinical setting. In this context, recommendations have been dichotomized into strong versus weak statements according to the quality of the evidence for each statement,1 the cost-effectiveness ratio between advantages and disadvantages in favor of patients’ management, and the overall agreement versus disagreement of the committee’s experts toward a specific statement. After different meetings and adequate general discussion during ICSM in Madrid (from June 28 to 29, 2024; International Consultation on Sexual Medicine (ICSM) - ISSM), the final manuscript was approved by all the authors.
============
Diagnosis and definitions of male hypogonadism
Signs and symptoms of male hypogonadism
Questionnaires to screen for male hypogonadism
When digital rectum examination is necessary?
Who should undergo T measurements
Sexual symptoms
Insulin resistance and diabetes
============
Treatment options
Purposes of testosterone therapy
The primary goals of TTh are to mitigate the negative signs and symptoms of male hypogonadism and improve quality of life (QoL) while achieving eugonadal (normal) serum T levels.7,61
============
Available treatment formulations
=============
Testosterone levels during treatment and dose adjustment
Treating physicians should aim to prescribe the minimal required dosing to improve serum T and hypogonadal symptoms. Recognizing the variations in normal ranges among the various laboratories, the current recommendations are to target correction of serum levels to the mid-normal reference range for tT in young men.59,61,63,64
Patients without significant symptomatic improvement and serum tT levels measured below the mid-normal range can be considered for dose escalation to improve clinical efficacy.63 Clinical experience supports raising tT into the upper third of the normal range for patients who do not respond symptomatically at lower levels.64 Patients with satisfactory resolution of their symptoms, but serum tT below the recommended target range, typically do not require dose adjustment.6 Dose reduction should be prescribed in patients with serum tT concentrations consistently measuring above the normal range while on treatment.6
============
Treatment monitoring
After initiating TTh, patients should have regular monitoring for response to treatment and adverse events. Table 4 summarizes an evidence-based monitoring schedule for patients on TTh according to the authoritative opinion of this ICSM Panel.
Adjustments to treatment dose and delivery can be made based on patient response, adverse events, and bloodwork results. Testosterone levels (±gonadotropins) should be measured to determine adherence and absorption of treatment. The recommended timing of tT measurement relative to the last treatment dose will vary depending on the T formulation (ie, mid-cycle for injectables), and patients should be counseled appropriately to ensure accurate interpretation of results and response to treatment.
A patient’s hematocrit should be measured at baseline and thereafter followed to ensure they are not developing polycythemia (hematocrit levels 54% or greater) during TTh (Table 4).6,8,17,65–67 In this context, it is relevant to outline that polycythemia vera is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells and is associated with an increased risk of thrombotic events (TEs). Established risk factors for TEs in patients with polycythemia vera include advanced age, TE history, and elevated hematocrit. Likewise, secondary polycythemia or erythrocytosis is a relatively common side effect of TTh and may be associated with thromboembolic events.8,44,68–70 More specifically, a positive family history of venous thromboembolism (VTE) requires further analysis to exclude a condition of congenital undiagnosed thrombophilia-hypofibrinolysis.71 Moreover, lower baseline hematocrit (48%-50%) should be carefully evaluated before TTh, especially in high-risk men such as those with chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea syndrome (OSAS). Accordingly, the Framingham Heart Study showed that hematocrit levels 48% or greater represented a condition associated with increased risk of coronary artery disease (CAD) and mortality and was associated with cardiovascular disorders.65 Thereof, despite it has been recently demonstrated that short TTh does not worsen global coagulation, thus suggesting that the treatment can be safely prescribed to men diagnosed with hypogonadism,72 these patients need to be carefully counseled prior to TTh initiation and throughout TTh itself (Table 4).
Non-univocal data have depicted that natives living at high altitudes (HAs) (ie, above 3500 m) seem to be associated with an apparent increased risk of developing stroke, probably linked to the presence of polycythemia and other associated factors such as increased blood viscosity.73 Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by relative hypoventilation and secondary excessive erythrocytosis.74 However, the pathogenesis of high-altitude polycythemia (HAPC) is still not fully understood. Previous data showed that native men at HAs are not adequately adapted if they have elevated T levels;75 elevated serum T seems to be responsible for, or at least associated with, chronic mountain sickness. In addition, T administration increases sleep apnea in men.76 Therefore, these panel experts recommend that a lower baseline hematocrit (48%-50%) should be carefully evaluated before TTh in men at HAs.76
As a whole, these findings imply that the optimum hematocrit is subgroup specific and depends on the many factors impacting blood rheology.77Thereof, a hematocrit level 54% or greater should require TTh withdrawal, dose reduction (concentration or application frequency), drug holiday, change of formulation, and/or blood donation/phlebotomy depending on the clinical situation to avoid any potential cardiovascular complications.
Finally, prostate-specific antigen (PSA) testing and DRE should be performed to monitor prostate health in accordance with the evidence-based guidelines for PCa screening.6,8,35,48,63 While discontinuation of TTh may be advised while investigating a PSA elevation, significant increases in PSA while on TTh should be investigated irrespective of the use or TTh discontinuation.
===========
Testosterone and diabetes, obesity, and MetS
In conclusion, there is now clear evidence that TTh in hypogonadal men with MetS, prediabetes, and T2DM is beneficial for general and cardiometabolic health, mortality, and sexual health. Very recent findings from the TRAVERSE RCT confirmed that TTh alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism.57
The efficacy of TTh varies between patients as diabetes is a complex condition, and many have multiple co-morbidities. The heterogeneous nature of diabetic individuals also differs in duration of disease, degrees of insulin resistance and beta-cell function, age, co-morbidities, and the response to glucose-lowering medication including insulin. All of these factors may influence the response to TTh. In diabetes, it is also important to recognize that the effect of TTh on symptom improvement can take as long as 12 months. Although data are not unequivocal, the treatment of ED may require a combination of TTh and a PDE5I due to the presence of vascular disease or other causality.112,116–119
==============
Hypogonadism and cardiovascular health
Endogenous T levels and CVD risk
In summary, a number of observational studies have shown significant associations between male hypogonadism and increased mortality rates, particularly related to cardiovascular and all-cause mortality. Although considering the inevitable heterogeneity among observational studies, the most updated systematic review involving prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up to July 2019, with bridge searches to March 2024, at 2-stage random-effects IPD meta-analyses found that men with baseline tT concentrations below 7.4 nmol/L (<213 ng/dL) had higher all-cause mortality, and those with tT concentrations below 5.3 nmol/L (<153 ng/dL) had a higher CVD mortality risk.128
--------------------
TTh and cardiovascular disease risks
The ICSM 2024 Panel points out that it is important to note that the TRASVERSE trial has limitations. First, patients have been enrolled without checking out for COVID-19 at the entrance, which has been recently associated with male hypogonadism and severe clinical outcomes.53However, Pencina et al. recently outlined that in men with hypogonadism and CVD or increased risk of CVD belonging to the TRAVERSE trial, baseline and pre-COVID-19 on-treatment tT, dihydrotestosterone, and E2 levels were similar in those who developed COVID-19 and those who did not; however, COVID-19 attenuated the treatment response to TTh.152
Second, the target T range used in the TRAVERSE trial may have been too low to detect certain benefits or harms (median T levels achieved ~350 ng/dL) as normal physiological serum T levels for men range from 300 to 1000 ng/dL. It is generally recommended to maintain tT levels in the mid-normal range, which is often achieved with TTh injections rather than gel. Additionally, since TTh is often required for long-term treatment, further studies are needed to determine its long-term safety and efficacy.
=================
Testosterone and sexual function
Overall, T levels affect libido, erectile function, and ejaculatory function in men with the greatest effect appearing to be on libido. Conversely, TTh has a modest and variable effect in improving erectile function (mostly mild ED) in hypogonadal men.
Therefore, the ICSM 2024 Panel considers that TTh can be used as monotherapy only in patients with mild ED and absolute demonstration of hypogonadism; conversely, TTh should not be use as monotherapy for ED but rather in combination therapy with PDE5Is or intracavernosal injections in hypogonadal men to improve overall erectile function, despite the fact that data are not unequivocal. Finally, men presenting with delayed ejaculation should have a serum tT value assessed and TTh should be considered if their serum tT levels are low.
======
Testosterone therapy and less specific signs/symptoms associated with male hypogonadism
Depressive symptoms
Overall, the TRAVERSE trial depicted the attributes of good trial design, thus including the adoption of HIS-Q, a validated, psychometrically robust instrument designed specifically for men with hypogonadism. Therefore, although it is clinically relevant to outline that the cause of hypogonadism was not determined for the enrolled participants, these findings clearly demonstrated that middle-aged and older men with confirmed hypogonadism should be evaluated for depressive symptoms; conversely, TTh alone did not emerge to represent an effective treatment option for most men with clinical depressive disorders.179Therefore, the ICSM 2024 Panel recommends against TTh for the sole purpose of treating depressive symptoms in hypogonadal men (Box 2).
=============
Bone health and fractures
Overall, and unexpectedly, the fracture incidence also appeared to be higher in the TTh group for all other fracture end points.180 The Authors explained that they did not expect those results, according to previous literature data showing TTh to increase areal and volumetric bone mineral density and to improve many structural and mechanical measures of trabecular bone.180 Therefore, the ICSM 2024 Panel recommends against TTh for the sole purpose of reducing fracture risk in hypogonadal men with high fracture risks (Box 2).
===========
Anemia
Despite the fact that the cause of anemia in the enrolled participants was not ascertained, of 815 participants who met eligibility criteria for anemia (namely, 390 in TTh and 425 in placebo group, respectively), the proportion of those who eventually experienced correction of anemia was significantly greater in the TTh group as compared with the placebo-treated group throughout the overall trial duration (omnibus test P = .002). Similar findings were observed for hemoglobin increases greater than 1 g/dL (omnibus test P < .001). Conversely, among those without anemia at baseline, a significantly smaller proportion of participants in the TTh group developed anemia post-randomization compared to placebo group (omnibus test P = .02). Therefore, the authors concluded that in middle-age and older men with confirmed hypogonadism and anemia, TTh was more efficacious than placebo in correcting anemia.181
=========
Fertility preserving strategies in testosterone therapy
In men who desire paternity, gonadotropin therapy should be considered the standard in men with secondary hypogonadism.182,183 Recombinant human chorionic gonadotropin (rhCG) and recombinant LH formulations offer comparable effects to urinary-derived preparations. According to a meta-analysis of the available evidence, hCG should be administered with FSH since combined therapy results in better endocrine and exocrine outcomes.184
Conversely, TTh per se is a very effective inhibitor of spermatogenesis. Men on TTh experience reduced sperm production, frequently to azoospermia, and notice diminished testicular volume (TV). Therefore, the male factor reproductive specialist must take an accurate history and account for any TTh in their patients. Since hypogonadism has become an increasingly prevalent diagnosis and has noted a demographic shift to younger ages, offering spermatogenesis-preserving T modulation is a critical part of any clinician providing men’s health services.185
Thankfully, there are many tools in the andrologist’s tool chest to improve a man’s T and preserve sperm production and TV. Additionally, sperm recovery after TTh is almost universally possible with the right protocol. This section will sketch out a playbook for the practicing male health specialist to offer state-of-the-art, evidence-based hormone therapy to either improve spermatogenesis or recover sperm production in men with a history of TTh.
Exogenous tT not only shuts down LH production by disrupting the negative feedback loop but also stops FSH production as tT inhibits GnRH secretion. Applying the organizational rubric of hypogonadism to primary and secondary hypogonadism, one categorizes TTh as a form of secondary, albeit iatrogenic, hypogonadism. This fact is critical to understanding how to recover a man with a history of TTh use. Whatever the therapy employed, it must stimulate both LH and FSH.
=======
Goals of therapy
The ideal plan to recover a man from TTh will manage his symptomatic relief and expedite spermatogenic recovery and TV. The simplest therapy to recover spermatogenesis in a man withdrawing from TTh is to stop treatment completely and rapidly. Allow the pituitary gland to recover, which, by most estimates, takes anywhere from 3 to 24 months to generate a normal semen analysis.186 Withdrawing a man from exogenous T without a recovery plan may result in numerous side effects, for example, night sweats, weight gain, brain fog, and irritability.
========
Available treatments
As detailed, post-TTh discontinuation goals are to recover spermatic function and TV in men previously on TTh and/or preserve testicular function in TTh naïve men. Men with a history of anabolic unprescribed TTh, prescribed TTh, and men with no previous history of TTh will likely respond to the following treatment options, although dosing may vary based on etiology of hypogonadism.
1) Human chorionic gonadotropin
2) Recombinant or urinary-derived FSH
3) Aromatase Inhibitors
4) Selective Estrogen Receptor Modulators
5) Combination TTh and hCG
There are some men who simply do not tolerate complete withdrawal of TTh. For these men, a combined approach of lowering TTh dosing and adding hCG has been suggested. Although literature is scant on the efficacy of this approach, it is a well-established off-label clinical practice. The dosing must be titrated to maintain FSH levels in the detectable range and check frequent semen analyses to guide therapy. Usual dosing regimens include hCG 3 times a week, ranging from 750 to 2000 IU. Subcutaneous or intramuscular T injections of either T enanthate or cypionate will range from 50 to 100 mg weekly. Elevating weekly injections into the 150–200 mg range, which is often used as weekly dosing for unopposed TTh, will likely suppress FSH and spermatogenesis.207 Given the off-label nature of this approach and the lack of systematic reviews or clinical trials proving safety and efficacy, one should pause prior to prescribing this combination therapy.
=========
6) Testosterone nasal gel
Testosterone nasal gel (Natesto) is an FDA-approved intranasal delivery vehicle for TTh administered 2–3 times daily.208–210 Curiously, it appears to have no adverse effects on spermatogenesis.211 In fact, intranasal T may have a protective effect on spermatogenesis. Small studies demonstrate that men converted from long-acting TTh to Natesto maintain eugonadal serum T levels while recovering spermatogenesis. In 1 study of 27 men, 100% regained normal sperm concentration with mean levels at 50.7 million/mL and 1 subject initiated a pregnancy 4 months after converting to Natesto.212Although the spermatogenic preservation mechanism is unknown, it is most likely the short-acting nature of intranasal T that is responsible for this effect. Given these data, intranasal T may play a role in TTh as a primary agent in men actively trying to conceive or as a recovery agent in men on long-acting TTh.213 Overall, in consideration of the scarcity of available data and their results, which have made the product extremely controversial in terms of clinical use, with authoritative expert opinion, this ICSM 2024 Panel decides not to issue recommendations regarding the use of the same in real-life daily clinical practice.
In conclusion, TTh in men wishing to preserve spermatic function and TV is complex but manageable (Table 5). This therapy aims to restore patients to eugonadal levels while preserving sperm concentration. Although monitoring frequency for these treatments was never postulated in the literature, practitioners should monitor serum tT, E2, LH, and FSH levels at least every 4–6 months to ensure proper dosing, given the average time for sperm parameters improvement in each modality.8,214 Since most testis- and sperm-preserving therapies are off label, a careful, well-documented discussion must take place with the patient prior to initiating therapy. Further, no guidelines will likely be published given the off-label nature of this treatment protocol. Therefore, all therapies will be individualized and adjusted based on clinical results and patient experience.
=======
Testosterone and PCa
It can now be reasonably stated that TTh does not increase the risk of developing PCa.
It must be added that since 15% of men with low serum T and PSA <4.0 ng/mL have biopsy-detectable PCa, approximately 1 in 7 men receiving TTh has undiagnosed PCa.222,223 The absence of increased rates of PCa among men receiving TTh in these various trials argues strongly that TTh does not cause rapid or aggressive growth of existing PCa.
The historical PCa concern that T injections “activated” PCa was originally based on scant evidence from Huggins and Hodges in 1941.224,225 In modern times, it had been assumed that since androgen deprivation causes rapid PCa regression, raising serum T must cause rapid growth. The reason it does not is due to maximal androgenic stimulation of prostate tissue occurring at a relatively low tT concentration of approximately 250 ng/dL or 8.7 nmol/L. This has been described as a saturation effect. Indeed, supraphysiological T concentrations have been shown to have a growth-suppressive effect on androgen-sensitive PCa cell lines.226,227 One study providing contradictory results reported that T levels prior to radical prostatectomy (RP) were predictive of biochemical recurrence (BCR).228
As a further safety point of potential TTh in the real-life setting, recent data from a retrospective cohort study using data from the TriNetX database showed that hypogonadal men with a family history of PCa and treated with TTh did not significantly differ in terms of the risk of PCa diagnosis over 10 years versus comparable-age hypogonadal men who had not received TTh (HR 0.81, 95% CI 0.51–1.28). Similarly, no significant difference was found in the risk of receiving any active treatment for PCa between men who received TTh and those who did not (HR 0.55, 95% CI 0.29–1.03).229
Table 6 details the recommendations for several clinical scenarios for TTh. These apply only to men for whom TTh is indicated due to symptoms/signs and documented low tT values (Table 6).
Men without known PCa and normal PSA
There appears to be strong evidence that TTh does not increase the risk of PCa in this population.
Men without known PCa and elevated PSA or prostate nodule
Initiation of TTh should be deferred until further evaluation of the prostate abnormality with MRI and/or biopsy. If such evaluation fails to identify PCa, it is reasonable to then consider initiating TTh.
Men on active surveillance
Despite reassuring results to date, clinicians should only consider offering TTh to men on active surveillance if both the clinician and the patient understand the limitations of available data and are willing to accept the possible risks.
Men following RP
A consent form is recommended, noting that BCR is a risk following RP with or without TTh.
The 2018 AUA Guidelines on TD addressed the use of TTh following RP as follows: “Testosterone therapy can be considered in men who have undergone radical prostatectomy with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively.”8
The 2024 European Association of Urology Guidelines on Sexual and Reproductive Health made the following recommendation on the use of TTh following RP: “Fully counsel symptomatic hypogonadal men who have been surgically treated for localised prostate cancer (PCa) and who are currently without evidence of active disease considering testosterone therapy, emphasizing the lack of sufficient safety data on long-term follow-up.”16
Men following radiation therapy or brachytherapy
TTh may be reasonably offered to men after achieving a low post-treatment PSA value, usually at 3–6 months. A consent form is recommended.
Men with BCR or metastatic disease
TTh in these populations should only be offered under investigational conditions.
The EAU guidelines state that it is an absolute contraindication to use TTh in men with locally advanced or metastatic PCa.16
============
Conclusions
This consensus paper comprehensively discusses relevant clinical aspects and the everyday real-life clinical work-up management strategies from the ICSM 2024 Panel on male hypogonadism. Following the criteria of a modified Delphi method, Panel experts strongly reiterate the need to consider serum tT in patients with symptoms and signs suggestive of male hypogonadism, without unnecessarily screening out male individuals who do not demonstrate significant clinical disorders. The need for a concomitant biochemical diagnosis of hypogonadism with reliable laboratory methods is confirmed, as well as an adequate discussion with patients to explain the usefulness of a TTh and the different available therapy modalities, thus including the risks and benefits of the different TTh types. In this context, the ICSM 2024 Panel confirms that while the benefits deriving from TTh in the field of QoL and sexual function are well established, for other specific conditions (eg, depressive disorders and bone health, cognitive and sleep disorders), the choice must not fall on TTh alone, but area-specific therapies must be the cornerstone of the treatment. For patients with a desire for parenthood, the use of TTh is contraindicated, but there are strategies for recovering spermatogenesis in previously T-replete men. Endogenous testosterone and TTh are not associated with a greater risk of PCa, but it is always necessary to thoroughly discuss any TTh in a patient with symptoms compatible with hypogonadism and previous PCa, before any treatment setting.
* Clinical experience supports raising tT into the upper third of the normal range for patients who do not respond symptomatically at lower levels.64
* A patient’s hematocrit should be measured at baseline and thereafter followed to ensure they are not developing polycythemia (hematocrit levels 54% or greater) during TTh (Table 4).6,8,17,65–67
* Established risk factors for TEs in patients with polycythemia vera include advanced age, TE history, and elevated hematocrit. Likewise, secondary polycythemia or erythrocytosis is a relatively common side effect of TTh and may be associated with thromboembolic events.8,44,68–70 More specifically, a positive family history of venous thromboembolism (VTE) requires further analysis to exclude a condition of congenital undiagnosed thrombophilia-hypofibrinolysis.71 Moreover, lower baseline hematocrit (48%-50%) should be carefully evaluated before TTh, especially in high-risk men such as those with chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea syndrome (OSAS). A
* As a whole, these findings imply that the optimum hematocrit is subgroup specific and depends on the many factors impacting blood rheology.77Thereof, a hematocrit level 54% or greater should require TTh withdrawal, dose reduction (concentration or application frequency), drug holiday, change of formulation, and/or blood donation/phlebotomy depending on the clinical situation to avoid any potential cardiovascular complications.
* Overall, T levels affect libido, erectile function, and ejaculatory function in men with the greatest effect appearing to be on libido. Conversely, TTh has a modest and variable effect in improving erectile function (mostly mild ED) in hypogonadal men.
* 5) Combination TTh and hCG
There are some men who simply do not tolerate complete withdrawal of TTh. For these men, a combined approach of lowering TTh dosing and adding hCG has been suggested. Although literature is scant on the efficacy of this approach, it is a well-established off-label clinical practice. The dosing must be titrated to maintain FSH levels in the detectable range and check frequent semen analyses to guide therapy. Usual dosing regimens include hCG 3 times a week, ranging from 750 to 2000 IU. Subcutaneous or intramuscular T injections of either T enanthate or cypionate will range from 50 to 100 mg weekly. Elevating weekly injections into the 150–200 mg range, which is often used as weekly dosing for unopposed TTh, will likely suppress FSH and spermatogenesis.207 Given the off-label nature of this approach and the lack of systematic reviews or clinical trials proving safety and efficacy, one should pause prior to prescribing this combination therapy.
6) Testosterone nasal gel
* Although the spermatogenic preservation mechanism is unknown, it is most likely the short-acting nature of intranasal T that is responsible for this effect. Given these data, intranasal T may play a role in TTh as a primary agent in men actively trying to conceive or as a recovery agent in men on long-acting TTh.213 Overall, in consideration of the scarcity of available data and their results, which have made the product extremely controversial in terms of clinical use, with authoritative expert opinion, this ICSM 2024 Panel decides not to issue recommendations regarding the use of the same in real-life daily clinical practice.
* It can now be reasonably stated that TTh does not increase the risk of developing PCa.
* It must be added that since 15% of men with low serum T and PSA <4.0 ng/mL have biopsy-detectable PCa, approximately 1 in 7 men receiving TTh has undiagnosed PCa.222,223 The absence of increased rates of PCa among men receiving TTh in these various trials argues strongly that TTh does not cause rapid or aggressive growth of existing PCa.
==============
Male hypogonadism, also known as testosterone deficiency (TD), is a prevalent clinical condition combining low concentrations of circulating testosterone (T) and specific signs and symptoms associated with impaired hormone production.
This consensus paper is aimed to provide the International Consultation for Sexual Medicine (ICSM) 2024 recommendations (Boxes 1 and 2) concerning work-up management strategies for male hypogonadism diagnosis (Box 1) and testosterone therapy (TTh) (Box 2) in the everyday real-life clinical setting.
========
Methods
A comprehensive literature search was performed using Google and PubMed database for English-language original and review articles, either published or e-published with focus on research from but not limited to the last 10 years, mostly covering the whole literature on male hypogonadism published since the last 2015 consultation with the goal to support or repeal previous recommendations. Available studies were collected and analyzed by all panel members; the various topics have been subdivided among experts, and finally discussed with 2 panel chairs (M.K., A.S.). This paper was then developed as an authoritative, comprehensive, all-encompassing consensus document highlighting state-of-the-art knowledge, based on the peer-reviewed medical literature and expertise of worldwide experts on major topics concerning diagnosis of male hypogonadism, treatment options, T impact toward cardiovascular, metabolic, sexual and reproductive health and prostate cancer (PCa). The first draft of the manuscript was then circulated to all the members for further review to address possible conflicts or disagreements. Thereafter, a modified Delphi method was used for making recommendations on management strategies for male hypogonadism in the everyday real-life clinical setting. In this context, recommendations have been dichotomized into strong versus weak statements according to the quality of the evidence for each statement,1 the cost-effectiveness ratio between advantages and disadvantages in favor of patients’ management, and the overall agreement versus disagreement of the committee’s experts toward a specific statement. After different meetings and adequate general discussion during ICSM in Madrid (from June 28 to 29, 2024; International Consultation on Sexual Medicine (ICSM) - ISSM), the final manuscript was approved by all the authors.
============
Diagnosis and definitions of male hypogonadism
Signs and symptoms of male hypogonadism
Questionnaires to screen for male hypogonadism
When digital rectum examination is necessary?
Who should undergo T measurements
Sexual symptoms
Insulin resistance and diabetes
============
Treatment options
Purposes of testosterone therapy
The primary goals of TTh are to mitigate the negative signs and symptoms of male hypogonadism and improve quality of life (QoL) while achieving eugonadal (normal) serum T levels.7,61
============
Available treatment formulations
=============
Testosterone levels during treatment and dose adjustment
Treating physicians should aim to prescribe the minimal required dosing to improve serum T and hypogonadal symptoms. Recognizing the variations in normal ranges among the various laboratories, the current recommendations are to target correction of serum levels to the mid-normal reference range for tT in young men.59,61,63,64
Patients without significant symptomatic improvement and serum tT levels measured below the mid-normal range can be considered for dose escalation to improve clinical efficacy.63 Clinical experience supports raising tT into the upper third of the normal range for patients who do not respond symptomatically at lower levels.64 Patients with satisfactory resolution of their symptoms, but serum tT below the recommended target range, typically do not require dose adjustment.6 Dose reduction should be prescribed in patients with serum tT concentrations consistently measuring above the normal range while on treatment.6
============
Treatment monitoring
After initiating TTh, patients should have regular monitoring for response to treatment and adverse events. Table 4 summarizes an evidence-based monitoring schedule for patients on TTh according to the authoritative opinion of this ICSM Panel.
Adjustments to treatment dose and delivery can be made based on patient response, adverse events, and bloodwork results. Testosterone levels (±gonadotropins) should be measured to determine adherence and absorption of treatment. The recommended timing of tT measurement relative to the last treatment dose will vary depending on the T formulation (ie, mid-cycle for injectables), and patients should be counseled appropriately to ensure accurate interpretation of results and response to treatment.
A patient’s hematocrit should be measured at baseline and thereafter followed to ensure they are not developing polycythemia (hematocrit levels 54% or greater) during TTh (Table 4).6,8,17,65–67 In this context, it is relevant to outline that polycythemia vera is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells and is associated with an increased risk of thrombotic events (TEs). Established risk factors for TEs in patients with polycythemia vera include advanced age, TE history, and elevated hematocrit. Likewise, secondary polycythemia or erythrocytosis is a relatively common side effect of TTh and may be associated with thromboembolic events.8,44,68–70 More specifically, a positive family history of venous thromboembolism (VTE) requires further analysis to exclude a condition of congenital undiagnosed thrombophilia-hypofibrinolysis.71 Moreover, lower baseline hematocrit (48%-50%) should be carefully evaluated before TTh, especially in high-risk men such as those with chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea syndrome (OSAS). Accordingly, the Framingham Heart Study showed that hematocrit levels 48% or greater represented a condition associated with increased risk of coronary artery disease (CAD) and mortality and was associated with cardiovascular disorders.65 Thereof, despite it has been recently demonstrated that short TTh does not worsen global coagulation, thus suggesting that the treatment can be safely prescribed to men diagnosed with hypogonadism,72 these patients need to be carefully counseled prior to TTh initiation and throughout TTh itself (Table 4).
Non-univocal data have depicted that natives living at high altitudes (HAs) (ie, above 3500 m) seem to be associated with an apparent increased risk of developing stroke, probably linked to the presence of polycythemia and other associated factors such as increased blood viscosity.73 Chronic mountain sickness is a maladaptive syndrome that affects individuals living permanently at high altitude and is characterized primarily by relative hypoventilation and secondary excessive erythrocytosis.74 However, the pathogenesis of high-altitude polycythemia (HAPC) is still not fully understood. Previous data showed that native men at HAs are not adequately adapted if they have elevated T levels;75 elevated serum T seems to be responsible for, or at least associated with, chronic mountain sickness. In addition, T administration increases sleep apnea in men.76 Therefore, these panel experts recommend that a lower baseline hematocrit (48%-50%) should be carefully evaluated before TTh in men at HAs.76
As a whole, these findings imply that the optimum hematocrit is subgroup specific and depends on the many factors impacting blood rheology.77Thereof, a hematocrit level 54% or greater should require TTh withdrawal, dose reduction (concentration or application frequency), drug holiday, change of formulation, and/or blood donation/phlebotomy depending on the clinical situation to avoid any potential cardiovascular complications.
Finally, prostate-specific antigen (PSA) testing and DRE should be performed to monitor prostate health in accordance with the evidence-based guidelines for PCa screening.6,8,35,48,63 While discontinuation of TTh may be advised while investigating a PSA elevation, significant increases in PSA while on TTh should be investigated irrespective of the use or TTh discontinuation.
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Testosterone and diabetes, obesity, and MetS
In conclusion, there is now clear evidence that TTh in hypogonadal men with MetS, prediabetes, and T2DM is beneficial for general and cardiometabolic health, mortality, and sexual health. Very recent findings from the TRAVERSE RCT confirmed that TTh alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism.57
The efficacy of TTh varies between patients as diabetes is a complex condition, and many have multiple co-morbidities. The heterogeneous nature of diabetic individuals also differs in duration of disease, degrees of insulin resistance and beta-cell function, age, co-morbidities, and the response to glucose-lowering medication including insulin. All of these factors may influence the response to TTh. In diabetes, it is also important to recognize that the effect of TTh on symptom improvement can take as long as 12 months. Although data are not unequivocal, the treatment of ED may require a combination of TTh and a PDE5I due to the presence of vascular disease or other causality.112,116–119
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Hypogonadism and cardiovascular health
Endogenous T levels and CVD risk
In summary, a number of observational studies have shown significant associations between male hypogonadism and increased mortality rates, particularly related to cardiovascular and all-cause mortality. Although considering the inevitable heterogeneity among observational studies, the most updated systematic review involving prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up to July 2019, with bridge searches to March 2024, at 2-stage random-effects IPD meta-analyses found that men with baseline tT concentrations below 7.4 nmol/L (<213 ng/dL) had higher all-cause mortality, and those with tT concentrations below 5.3 nmol/L (<153 ng/dL) had a higher CVD mortality risk.128
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TTh and cardiovascular disease risks
The ICSM 2024 Panel points out that it is important to note that the TRASVERSE trial has limitations. First, patients have been enrolled without checking out for COVID-19 at the entrance, which has been recently associated with male hypogonadism and severe clinical outcomes.53However, Pencina et al. recently outlined that in men with hypogonadism and CVD or increased risk of CVD belonging to the TRAVERSE trial, baseline and pre-COVID-19 on-treatment tT, dihydrotestosterone, and E2 levels were similar in those who developed COVID-19 and those who did not; however, COVID-19 attenuated the treatment response to TTh.152
Second, the target T range used in the TRAVERSE trial may have been too low to detect certain benefits or harms (median T levels achieved ~350 ng/dL) as normal physiological serum T levels for men range from 300 to 1000 ng/dL. It is generally recommended to maintain tT levels in the mid-normal range, which is often achieved with TTh injections rather than gel. Additionally, since TTh is often required for long-term treatment, further studies are needed to determine its long-term safety and efficacy.
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Testosterone and sexual function
Overall, T levels affect libido, erectile function, and ejaculatory function in men with the greatest effect appearing to be on libido. Conversely, TTh has a modest and variable effect in improving erectile function (mostly mild ED) in hypogonadal men.
Therefore, the ICSM 2024 Panel considers that TTh can be used as monotherapy only in patients with mild ED and absolute demonstration of hypogonadism; conversely, TTh should not be use as monotherapy for ED but rather in combination therapy with PDE5Is or intracavernosal injections in hypogonadal men to improve overall erectile function, despite the fact that data are not unequivocal. Finally, men presenting with delayed ejaculation should have a serum tT value assessed and TTh should be considered if their serum tT levels are low.
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Testosterone therapy and less specific signs/symptoms associated with male hypogonadism
Depressive symptoms
Overall, the TRAVERSE trial depicted the attributes of good trial design, thus including the adoption of HIS-Q, a validated, psychometrically robust instrument designed specifically for men with hypogonadism. Therefore, although it is clinically relevant to outline that the cause of hypogonadism was not determined for the enrolled participants, these findings clearly demonstrated that middle-aged and older men with confirmed hypogonadism should be evaluated for depressive symptoms; conversely, TTh alone did not emerge to represent an effective treatment option for most men with clinical depressive disorders.179Therefore, the ICSM 2024 Panel recommends against TTh for the sole purpose of treating depressive symptoms in hypogonadal men (Box 2).
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Bone health and fractures
Overall, and unexpectedly, the fracture incidence also appeared to be higher in the TTh group for all other fracture end points.180 The Authors explained that they did not expect those results, according to previous literature data showing TTh to increase areal and volumetric bone mineral density and to improve many structural and mechanical measures of trabecular bone.180 Therefore, the ICSM 2024 Panel recommends against TTh for the sole purpose of reducing fracture risk in hypogonadal men with high fracture risks (Box 2).
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Anemia
Despite the fact that the cause of anemia in the enrolled participants was not ascertained, of 815 participants who met eligibility criteria for anemia (namely, 390 in TTh and 425 in placebo group, respectively), the proportion of those who eventually experienced correction of anemia was significantly greater in the TTh group as compared with the placebo-treated group throughout the overall trial duration (omnibus test P = .002). Similar findings were observed for hemoglobin increases greater than 1 g/dL (omnibus test P < .001). Conversely, among those without anemia at baseline, a significantly smaller proportion of participants in the TTh group developed anemia post-randomization compared to placebo group (omnibus test P = .02). Therefore, the authors concluded that in middle-age and older men with confirmed hypogonadism and anemia, TTh was more efficacious than placebo in correcting anemia.181
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Fertility preserving strategies in testosterone therapy
In men who desire paternity, gonadotropin therapy should be considered the standard in men with secondary hypogonadism.182,183 Recombinant human chorionic gonadotropin (rhCG) and recombinant LH formulations offer comparable effects to urinary-derived preparations. According to a meta-analysis of the available evidence, hCG should be administered with FSH since combined therapy results in better endocrine and exocrine outcomes.184
Conversely, TTh per se is a very effective inhibitor of spermatogenesis. Men on TTh experience reduced sperm production, frequently to azoospermia, and notice diminished testicular volume (TV). Therefore, the male factor reproductive specialist must take an accurate history and account for any TTh in their patients. Since hypogonadism has become an increasingly prevalent diagnosis and has noted a demographic shift to younger ages, offering spermatogenesis-preserving T modulation is a critical part of any clinician providing men’s health services.185
Thankfully, there are many tools in the andrologist’s tool chest to improve a man’s T and preserve sperm production and TV. Additionally, sperm recovery after TTh is almost universally possible with the right protocol. This section will sketch out a playbook for the practicing male health specialist to offer state-of-the-art, evidence-based hormone therapy to either improve spermatogenesis or recover sperm production in men with a history of TTh.
Exogenous tT not only shuts down LH production by disrupting the negative feedback loop but also stops FSH production as tT inhibits GnRH secretion. Applying the organizational rubric of hypogonadism to primary and secondary hypogonadism, one categorizes TTh as a form of secondary, albeit iatrogenic, hypogonadism. This fact is critical to understanding how to recover a man with a history of TTh use. Whatever the therapy employed, it must stimulate both LH and FSH.
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Goals of therapy
The ideal plan to recover a man from TTh will manage his symptomatic relief and expedite spermatogenic recovery and TV. The simplest therapy to recover spermatogenesis in a man withdrawing from TTh is to stop treatment completely and rapidly. Allow the pituitary gland to recover, which, by most estimates, takes anywhere from 3 to 24 months to generate a normal semen analysis.186 Withdrawing a man from exogenous T without a recovery plan may result in numerous side effects, for example, night sweats, weight gain, brain fog, and irritability.
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Available treatments
As detailed, post-TTh discontinuation goals are to recover spermatic function and TV in men previously on TTh and/or preserve testicular function in TTh naïve men. Men with a history of anabolic unprescribed TTh, prescribed TTh, and men with no previous history of TTh will likely respond to the following treatment options, although dosing may vary based on etiology of hypogonadism.
1) Human chorionic gonadotropin
2) Recombinant or urinary-derived FSH
3) Aromatase Inhibitors
4) Selective Estrogen Receptor Modulators
5) Combination TTh and hCG
There are some men who simply do not tolerate complete withdrawal of TTh. For these men, a combined approach of lowering TTh dosing and adding hCG has been suggested. Although literature is scant on the efficacy of this approach, it is a well-established off-label clinical practice. The dosing must be titrated to maintain FSH levels in the detectable range and check frequent semen analyses to guide therapy. Usual dosing regimens include hCG 3 times a week, ranging from 750 to 2000 IU. Subcutaneous or intramuscular T injections of either T enanthate or cypionate will range from 50 to 100 mg weekly. Elevating weekly injections into the 150–200 mg range, which is often used as weekly dosing for unopposed TTh, will likely suppress FSH and spermatogenesis.207 Given the off-label nature of this approach and the lack of systematic reviews or clinical trials proving safety and efficacy, one should pause prior to prescribing this combination therapy.
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6) Testosterone nasal gel
Testosterone nasal gel (Natesto) is an FDA-approved intranasal delivery vehicle for TTh administered 2–3 times daily.208–210 Curiously, it appears to have no adverse effects on spermatogenesis.211 In fact, intranasal T may have a protective effect on spermatogenesis. Small studies demonstrate that men converted from long-acting TTh to Natesto maintain eugonadal serum T levels while recovering spermatogenesis. In 1 study of 27 men, 100% regained normal sperm concentration with mean levels at 50.7 million/mL and 1 subject initiated a pregnancy 4 months after converting to Natesto.212Although the spermatogenic preservation mechanism is unknown, it is most likely the short-acting nature of intranasal T that is responsible for this effect. Given these data, intranasal T may play a role in TTh as a primary agent in men actively trying to conceive or as a recovery agent in men on long-acting TTh.213 Overall, in consideration of the scarcity of available data and their results, which have made the product extremely controversial in terms of clinical use, with authoritative expert opinion, this ICSM 2024 Panel decides not to issue recommendations regarding the use of the same in real-life daily clinical practice.
In conclusion, TTh in men wishing to preserve spermatic function and TV is complex but manageable (Table 5). This therapy aims to restore patients to eugonadal levels while preserving sperm concentration. Although monitoring frequency for these treatments was never postulated in the literature, practitioners should monitor serum tT, E2, LH, and FSH levels at least every 4–6 months to ensure proper dosing, given the average time for sperm parameters improvement in each modality.8,214 Since most testis- and sperm-preserving therapies are off label, a careful, well-documented discussion must take place with the patient prior to initiating therapy. Further, no guidelines will likely be published given the off-label nature of this treatment protocol. Therefore, all therapies will be individualized and adjusted based on clinical results and patient experience.
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Testosterone and PCa
It can now be reasonably stated that TTh does not increase the risk of developing PCa.
It must be added that since 15% of men with low serum T and PSA <4.0 ng/mL have biopsy-detectable PCa, approximately 1 in 7 men receiving TTh has undiagnosed PCa.222,223 The absence of increased rates of PCa among men receiving TTh in these various trials argues strongly that TTh does not cause rapid or aggressive growth of existing PCa.
The historical PCa concern that T injections “activated” PCa was originally based on scant evidence from Huggins and Hodges in 1941.224,225 In modern times, it had been assumed that since androgen deprivation causes rapid PCa regression, raising serum T must cause rapid growth. The reason it does not is due to maximal androgenic stimulation of prostate tissue occurring at a relatively low tT concentration of approximately 250 ng/dL or 8.7 nmol/L. This has been described as a saturation effect. Indeed, supraphysiological T concentrations have been shown to have a growth-suppressive effect on androgen-sensitive PCa cell lines.226,227 One study providing contradictory results reported that T levels prior to radical prostatectomy (RP) were predictive of biochemical recurrence (BCR).228
As a further safety point of potential TTh in the real-life setting, recent data from a retrospective cohort study using data from the TriNetX database showed that hypogonadal men with a family history of PCa and treated with TTh did not significantly differ in terms of the risk of PCa diagnosis over 10 years versus comparable-age hypogonadal men who had not received TTh (HR 0.81, 95% CI 0.51–1.28). Similarly, no significant difference was found in the risk of receiving any active treatment for PCa between men who received TTh and those who did not (HR 0.55, 95% CI 0.29–1.03).229
Table 6 details the recommendations for several clinical scenarios for TTh. These apply only to men for whom TTh is indicated due to symptoms/signs and documented low tT values (Table 6).
Men without known PCa and normal PSA
There appears to be strong evidence that TTh does not increase the risk of PCa in this population.
Men without known PCa and elevated PSA or prostate nodule
Initiation of TTh should be deferred until further evaluation of the prostate abnormality with MRI and/or biopsy. If such evaluation fails to identify PCa, it is reasonable to then consider initiating TTh.
Men on active surveillance
Despite reassuring results to date, clinicians should only consider offering TTh to men on active surveillance if both the clinician and the patient understand the limitations of available data and are willing to accept the possible risks.
Men following RP
A consent form is recommended, noting that BCR is a risk following RP with or without TTh.
The 2018 AUA Guidelines on TD addressed the use of TTh following RP as follows: “Testosterone therapy can be considered in men who have undergone radical prostatectomy with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively.”8
The 2024 European Association of Urology Guidelines on Sexual and Reproductive Health made the following recommendation on the use of TTh following RP: “Fully counsel symptomatic hypogonadal men who have been surgically treated for localised prostate cancer (PCa) and who are currently without evidence of active disease considering testosterone therapy, emphasizing the lack of sufficient safety data on long-term follow-up.”16
Men following radiation therapy or brachytherapy
TTh may be reasonably offered to men after achieving a low post-treatment PSA value, usually at 3–6 months. A consent form is recommended.
Men with BCR or metastatic disease
TTh in these populations should only be offered under investigational conditions.
The EAU guidelines state that it is an absolute contraindication to use TTh in men with locally advanced or metastatic PCa.16
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Conclusions
This consensus paper comprehensively discusses relevant clinical aspects and the everyday real-life clinical work-up management strategies from the ICSM 2024 Panel on male hypogonadism. Following the criteria of a modified Delphi method, Panel experts strongly reiterate the need to consider serum tT in patients with symptoms and signs suggestive of male hypogonadism, without unnecessarily screening out male individuals who do not demonstrate significant clinical disorders. The need for a concomitant biochemical diagnosis of hypogonadism with reliable laboratory methods is confirmed, as well as an adequate discussion with patients to explain the usefulness of a TTh and the different available therapy modalities, thus including the risks and benefits of the different TTh types. In this context, the ICSM 2024 Panel confirms that while the benefits deriving from TTh in the field of QoL and sexual function are well established, for other specific conditions (eg, depressive disorders and bone health, cognitive and sleep disorders), the choice must not fall on TTh alone, but area-specific therapies must be the cornerstone of the treatment. For patients with a desire for parenthood, the use of TTh is contraindicated, but there are strategies for recovering spermatogenesis in previously T-replete men. Endogenous testosterone and TTh are not associated with a greater risk of PCa, but it is always necessary to thoroughly discuss any TTh in a patient with symptoms compatible with hypogonadism and previous PCa, before any treatment setting.
