The clinical syndrome at the heart of the debate is defined by the coexistence of characteristic symptoms with persistently low serum testosterone concentrations. That dual requirement matters, because testosterone levels alone tell an incomplete story. The condition exerts wide-ranging effects across the male body, influencing sexual function, metabolic health, bone integrity, mood, haematopoiesis and overall quality of life. The authors classify hypogonadism into three broad categories: primary hypogonadism, arising from testicular failure; secondary hypogonadism, driven by dysfunction of the hypothalamic–pituitary axis; and functional hypogonadism, a form commonly associated with ageing, obesity and chronic systemic disease. The functional category has attracted growing attention because it blurs the line between endocrine disease and the physiological consequences of modern lifestyles, and because it may be partially reversible when the underlying drivers are addressed.

The mechanistic interplay between adiposity and testosterone is particularly striking. Adipose tissue expresses aromatase, the enzyme that converts androgens into oestrogens, so expanding fat mass both consumes testosterone and suppresses the hypothalamic–pituitary–gonadal axis through feedback and inflammatory adipocytokine signalling. This hypogonadal–obesity–adipocytokine hypothesis, illustrated in the review, describes a self-reinforcing cycle: low testosterone promotes visceral fat accumulation and insulin resistance, which in turn further suppress testosterone production. Recent work cited in the review has documented altered expression of aromatase and oestrogen receptors in adipose tissue from men with obesity and type 2 diabetes, providing a molecular substrate for the clinical observations. Breaking this cycle, whether through weight loss, pharmacotherapy or testosterone replacement itself, is therefore a central therapeutic goal.

Diagnosis remains the discipline’s most contested territory, and the review is emphatic about rigour. Confirmation requires both clinical features and biochemical evidence, typically obtained through morning serum testosterone measurements, because testosterone follows a diurnal rhythm that flattens with age and is blunted by poor sleep and illness. When values fall into a borderline zone, or when symptoms and total testosterone concentrations appear discordant, measurement of sex hormone-binding globulin and calculated free testosterone can provide additional clarity, since a substantial fraction of circulating testosterone is bound and biologically inactive. The authors highlight recent joint position statements from the Society for Endocrinology and the Association for Clinical Biochemistry and Laboratory Medicine aimed at standardizing biochemical confirmation, an attempt to reduce the diagnostic variability that has plagued the field. Symptom questionnaires such as the Aging Males’ Symptoms scale and the quantitative ADAM instrument can support, but never replace, laboratory confirmation.

Once the diagnosis is secure, the evidence for treatment is substantial. Meta-analyses of randomized trials report consistent improvements in sexual desire and erectile function, with testosterone therapy also enhancing the response to phosphodiesterase 5 inhibitors in men who previously failed to respond. The large TRAVERSE trial programme has added high-quality data on mood, showing improvement in depressive syndromes among hypogonadal men, while earlier trials demonstrated benefits in energy and health-related quality of life. Haematological effects are equally well documented: testosterone stimulates erythropoiesis, and randomized studies have shown that replacement therapy corrects anaemia in hypogonadal men, a finding with potential relevance for older men whose fatigue and functional decline are partly attributable to low red cell mass.

Metabolic and skeletal outcomes form a second pillar of benefit. Trials in men with type 2 diabetes and metabolic syndrome, including the TIMES2 study and the T4DM trial, indicate that testosterone replacement improves insulin resistance, glycaemic control and body composition, reducing fat mass while increasing lean mass. Registry data suggest that long-term therapy can even be associated with remission of type 2 diabetes in some hypogonadal men. On bone, testosterone is aromatized to oestradiol in skeletal tissue, and both sex steroids contribute to bone maintenance. Randomized trials have shown increases in bone mineral density and improvements in volumetric bone strength, and a 2024 analysis in the New England Journal of Medicine reported that testosterone treatment reduced fracture risk in men with hypogonadism, converting a long-standing surrogate outcome into a hard clinical endpoint.

Safety has been the field’s defining controversy. The historical fear that testosterone fuels prostate cancer stemmed from the observation, dating to Huggins and Hodges in 1941, that androgen deprivation shrinks metastatic disease. The modern saturation model proposes instead that androgen-dependent growth plateaus at low concentrations, so raising testosterone from deficient to normal levels has limited proliferative effect. Contemporary data reviewed by the authors, including meta-analyses of prostate cancer incidence in treated men and studies of therapy in prostate cancer survivors after definitive local treatment, do not demonstrate increased oncological risk when monitoring is appropriate. Cardiovascular safety has followed a similar arc from alarm to reassurance: early observational studies suggesting excess myocardial infarction were followed by the TRAVERSE trial, published in 2023, which found that testosterone replacement did not increase major adverse cardiovascular events in middle-aged and older men, and by subsequent European expert panel position statements concluding that appropriately monitored therapy is cardiovascularly safe.

Not all risks can be dismissed, however, and the review is candid about the caveats. Testosterone therapy suppresses spermatogenesis through inhibition of gonadotropin secretion, making it inappropriate for men who wish to preserve fertility; alternatives such as selective oestrogen receptor modulators, aromatase inhibitors, human chorionic gonadotropin and, in trials of male obesity-related hypogonadism, the aromatase inhibitor leflutrozole can raise testosterone while maintaining or restoring sperm production. Erythrocytosis remains the most common laboratory adverse effect requiring dose adjustment, and testosterone therapy can worsen obstructive sleep apnoea, which should be assessed and treated before and during treatment. The authors also flag a practical laboratory pitfall: contamination of the venipuncture site with topical testosterone gel can produce falsely elevated readings, a reminder that even the diagnostic pathway demands attention to detail.

The therapeutic arsenal has expanded considerably. Transdermal gels and solutions remain the most widely used formulations, offering physiological absorption but requiring daily application and posing a theoretical risk of transfer to partners and children. Newer oral testosterone undecanoate formulations, absorbed via the lymphatic system when taken with food, avoid the hepatotoxicity that doomed earlier oral preparations and have shown efficacy across body mass index ranges in phase III trials. Long-acting intramuscular testosterone undecanoate injections provide stable levels for ten to fourteen weeks, while subcutaneous enanthate auto-injectors and subdermal pellets serve patients who prefer less frequent administration. Intranasal gel offers rapid achievement of steady-state levels and, notably, has been shown in trials to preserve semen parameters better than other routes, an option for younger men with fertility concerns. Patient preference, adherence data and pharmacokinetic profiles all inform the choice, and the review stresses that individualized selection, careful counselling and structured monitoring of testosterone levels, haematocrit and prostate-specific antigen are essential to optimize outcomes.

The broader significance of this update lies in its recalibration of a polarized debate. The evidence now supports a middle path: testosterone deficiency is a real and treatable syndrome with demonstrable benefits across sexual, metabolic, skeletal, haematological and psychological domains, but it is neither a panacea for ageing nor a condition to be diagnosed from a single afternoon blood test. Regulatory bodies, including the European Medicines Agency and the US Food and Drug Administration, have moved toward positions consistent with the trial evidence, though the FDA continues to require labelling about possible cardiovascular risk in age-related use. For the millions of men worldwide whose symptoms, metabolic disease and bone fragility intersect with low testosterone, the message from this authoritative synthesis is measured but clear: with rigorous diagnosis, appropriate patient selection and disciplined monitoring, testosterone replacement therapy has earned its place in modern endocrine practice.

Subject of Research: Diagnosis, clinical benefits and safety of testosterone replacement therapy in male hypogonadism

Article Title: Update on testosterone deficiency and therapeutic options for testosterone replacement therapy

Article References: Thompson, T., Mubarak, M., Jones, T. H., Pearce, I., & Modgil, V. (2026). Update on testosterone deficiency and therapeutic options for testosterone replacement therapy. Nature Reviews Urology. https://doi.org/10.1038/s41585-026-01190-3

Image Credits: AI Generated

DOI: 10.1038/s41585-026-01190-3

Keywords: testosterone deficiency, male hypogonadism, testosterone replacement therapy, hypothalamic-pituitary-gonadal axis, obesity, type 2 diabetes, bone mineral density, cardiovascular safety, prostate cancer, TRAVERSE trial, free testosterone, hypogonadism diagnosis

The study, led by Gianni Binotto of the University of Padova and Carmen Fava of the University of Turin, together with colleagues from major Italian haematology centres in Milan, Turin, Bari, Pavia and Bologna, focused on six adult patients with Philadelphia chromosome–positive chronic myeloid leukaemia in chronic phase. This form of leukaemia is defined by a characteristic genetic swap between chromosomes 9 and 22, which creates the BCR-ABL1 fusion gene encoding a constitutively active tyrosine kinase. It is this rogue enzyme that tyrosine kinase inhibitors are designed to block, and the Philadelphia chromosome serves as the molecular fingerprint of the disease. All six patients in the series had already been exposed to at least two prior tyrosine kinase inhibitors and had either become resistant to them or suffered intolerable side effects, placing them among the most challenging cases that clinicians encounter in routine practice.

What set these patients apart was not only their treatment history but their overall health profile. The cohort carried a substantial burden of comorbidities, predominantly cardiovascular in nature. Hypertension, peripheral arterial disease, ischaemic heart disease and metabolic disorders featured prominently among their conditions. This detail matters because several first- and second-generation tyrosine kinase inhibitors, notably nilotinib and ponatinib, have been associated with arterial occlusive events, including heart attacks, strokes and peripheral vascular complications. For patients whose blood cancer is under control but whose arteries are compromised, the choice of therapy becomes a delicate balancing act between suppressing the leukaemia and protecting the cardiovascular system. Asciminib, with its distinctive mechanism of action, has been proposed as a particularly attractive option for exactly this population.

The reason lies in the drug’s unusual binding mode. Whereas earlier tyrosine kinase inhibitors target the ATP-binding site of the ABL1 kinase, asciminib selectively targets the myristoyl pocket, a regulatory region of the protein that is otherwise not exploited by any other approved drug in the class. This allosteric mechanism gives asciminib high specificity for its target and is thought to underpin its potentially improved safety profile. Because the myristoyl pocket is a distinct structural feature of ABL1, the drug can remain active against certain mutations that confer resistance to ATP-site competitors. Among these is the notorious T315I mutation, often described as the most formidable resistance mutation in chronic myeloid leukaemia, which has historically limited treatment options dramatically. Asciminib’s efficacy has been demonstrated in both clinical trials and real-world settings, including heavily pretreated patients and those carrying the T315I mutation, making it a valuable addition to the therapeutic arsenal.

In the Italian case series, asciminib was administered for a median duration of 16.5 months, providing a meaningful window in which to observe both efficacy and tolerability. The results were strikingly consistent. All six patients achieved or maintained clinically meaningful molecular responses, including major molecular responses and deep molecular responses. These endpoints are measured by tracking the level of BCR-ABL1 transcript in the blood using sensitive polymerase chain reaction assays, and deeper responses correlate with better long-term outcomes and, in some cases, the possibility of treatment-free remission. For patients who had already cycled through multiple therapies without success, the ability of asciminib to induce or sustain such responses represents a significant clinical benefit.

Equally important was the drug’s tolerability. Treatment was well tolerated across the cohort, with no discontinuations due to adverse events. No arterial occlusive events were observed, and no significant cardiovascular worsening occurred during the observation period. This is a notable finding given the cardiovascular vulnerability of the patients involved. Even more remarkably, no haematologic toxicity was recorded, even in a patient with underlying bone marrow hypoplasia, a condition in which the bone marrow’s capacity to produce blood cells is already diminished. Myelosuppression is a common concern with many anticancer therapies, and the absence of this toxicity in a compromised patient suggests that asciminib’s high target specificity translates into a genuinely gentler profile at the level of normal blood-forming tissue.

The authors are careful to frame these observations appropriately. With only six patients, the series cannot deliver the statistical power of a randomised trial, and the findings are presented as a summary of the drug’s clinical data alongside real-world experience rather than as definitive evidence. Nevertheless, the study argues that real-world data of this kind play an essential role in supporting treatment decisions, because patients seen in everyday practice are often older, more comorbid and more heavily pretreated than those enrolled in pivotal clinical trials. Regulatory trials typically exclude individuals with uncontrolled hypertension, prior arterial events or reduced bone marrow reserve, precisely the characteristics that defined this Italian cohort. Demonstrating that asciminib can be used safely and effectively in such patients fills an important evidence gap that trial data alone cannot address.

The broader context of chronic myeloid leukaemia treatment makes these findings resonate. Since the introduction of imatinib at the turn of the millennium, survival in chronic myeloid leukaemia has risen to near-normal life expectancy for many patients, turning a fatal disease into a chronic condition managed with daily oral therapy. But this success has created its own challenges: patients now live for decades with their disease and their medication, so long-term tolerability, cardiovascular safety and quality of life have become central concerns. Second-generation inhibitors improved response rates but introduced new toxicity profiles, and resistance mutations continue to emerge. Drugs that combine deep molecular activity with a favourable cardiovascular and haematologic safety profile address the most pressing unmet needs in the field, particularly for the growing population of long-term survivors with age-related comorbidities.

Asciminib’s allosteric mechanism also represents a conceptual milestone in targeted cancer therapy. Rather than competing with ATP at the active site, the drug locks the kinase into its inactive conformation by engaging a pocket used naturally by the protein’s own regulatory lipid, myristate. This approach, sometimes described as a STAMP inhibitor, an acronym for specifically targeting the ABL myristoyl pocket, illustrates how structural biology can be exploited to design molecules with exquisite selectivity. The Italian case series adds a practical, bedside-level dimension to this molecular story, showing that the elegance of the mechanism is reflected in clinical outcomes for patients who have few alternatives left.

For clinicians managing chronic myeloid leukaemia, the message from this small study is one of cautious encouragement. In a real-world cohort of heavily pretreated patients with substantial comorbidity burden, asciminib demonstrated sustained efficacy and a favourable safety profile, with cardiovascular tolerability standing out as a particular strength. The authors conclude that these findings reinforce the potential role of asciminib for patients with resistance or intolerance to multiple tyrosine kinase inhibitors, as well as for those at high cardiovascular risk. As more real-world data accumulate across centres and countries, the picture of who benefits most from this allosteric inhibitor will continue to sharpen, helping physicians tailor therapy to the individual patient rather than to the average trial participant. For the six Italian patients documented here, and for the many others like them worldwide, that individualisation may make all the difference between merely surviving with leukaemia and truly living well with it.

Subject of Research: Real-world efficacy and safety of the allosteric BCR-ABL1 inhibitor asciminib in heavily pretreated chronic myeloid leukaemia patients

Article Title: Real-world Italian experience with asciminib in chronic myeloid leukaemia–chronic phase: case series and drug profile overview

Article References: Binotto, G., Cattaneo, D., Di Biase, F., Ditonno, P., Elena, C., Restuccia, R., & Fava, C. (2026). Real-world Italian experience with asciminib in chronic myeloid leukaemia–chronic phase: case series and drug profile overview. Annals of Hematology. https://doi.org/10.1007/s00277-026-07284-7

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07284-7

Keywords: asciminib, chronic myeloid leukaemia, tyrosine kinase inhibitors, BCR-ABL1, myristoyl pocket, cardiovascular safety, molecular response, T315I mutation, real-world evidence, haematology, drug resistance, Annals of Hematology