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 Dietary Approaches to Stop Hypertension, or DASH, diet was originally engineered to lower blood pressure, emphasizing fruits, vegetables, whole grains, low-fat dairy, and reduced sodium. But nutrition scientists have long suspected that the pattern could do more than protect the cardiovascular system. Its high fiber content, favorable fatty acid profile, and low glycemic load make it a plausible candidate for tackling the insulin resistance that sits at the metabolic heart of PCOS. The Iranian team took the hypothesis a step further by enriching the DASH framework with legumes, foods packed with plant protein, soluble fiber, and bioactive compounds that may independently improve glucose handling and lipid metabolism. The logic was simple: if the DASH diet is good, a legume-loaded variant might be better.

To test that idea, the researchers designed a rigorously structured randomized controlled trial. Fifty-four women with PCOS, aged 20 to 50 years, were enrolled in Yazd and randomly assigned to either the legume-based DASH diet or a control diet for 16 weeks. Crucially, both groups received calorie-restricted meal plans with an energy deficit of 500 to 700 kilocalories per day, meaning the comparison was not simply about eating less. The two diets differed in their overall dietary pattern and macronutrient composition, isolating the specific effect of the legume-enriched DASH approach. Of the randomized participants, 47 completed the full study, with 25 in the intervention arm and 22 in the control arm.

The methodological rigor of the trial deserves attention. The investigators analyzed their results using analysis of covariance, adjusting for baseline values of each outcome, changes in total energy intake, and physical activity levels, ensuring that observed differences were not merely artifacts of who started where or who moved more. All analyses followed the intention-to-treat principle, and multiple imputation was used to handle missing data, a statistical technique that fills gaps in a way that preserves the integrity of the randomization. The trial was registered prospectively in the Iranian Registry of Clinical Trials on June 12, 2023, and the study was conducted in accordance with the Declaration of Helsinki with ethics approval from the university’s research ethics committee.

The headline findings are striking in their specificity. Compared with the control diet, the legume-based DASH intervention produced statistically significant improvements in weight, with a partial eta-squared effect size of 0.11, and in waist circumference, with a partial eta-squared of 0.10, both at P values of 0.02. Hip circumference also improved significantly at P equals 0.03. These are not trivial effects; in the language of clinical research, partial eta-squared values in this range suggest moderate effects that could translate into meaningful clinical differences for patients. For women with PCOS, central adiposity is particularly consequential, because abdominal fat amplifies the insulin resistance that drives the syndrome’s hormonal chaos.

Perhaps the most patient-relevant result was the improvement in menstrual cycle duration, which reached statistical significance at P equals 0.02 with a partial eta-squared of 0.098. Irregular or absent ovulation is one of the most distressing features of PCOS, a leading cause of anovulatory infertility, and any dietary intervention that nudges cycles toward regularity carries real clinical weight. The lipid profile also responded favorably: high-density lipoprotein cholesterol, the protective HDL-C, improved significantly at P equals 0.04, and low-density lipoprotein cholesterol, the atherogenic LDL-C, showed one of the strongest effects in the trial at P equals 0.006 with a partial eta-squared of 0.14. Given that women with PCOS face elevated long-term cardiovascular risk, shifts in these lipid fractions could matter well beyond the 16-week study window.

Yet the trial is equally notable for what it did not find. The prespecified primary outcome, insulin resistance as measured by the homeostatic model assessment, or HOMA-IR, showed no significant adjusted between-group difference. Neither did fasting blood sugar, fasting insulin, the quantitative insulin sensitivity check index known as QUICKI, triglycerides, total cholesterol, or free testosterone. For an intervention explicitly designed to target the metabolic underpinnings of PCOS, the absence of glycemic improvement is a sobering result, and the failure to move free testosterone, the androgen most closely tied to symptoms like hirsutism and acne, will temper enthusiasm among clinicians hoping for a dietary fix for hyperandrogenism.

How should these null findings be interpreted? The authors are careful in their conclusion, stating that a legume-based DASH dietary pattern may improve anthropometric measures, menstrual cycle duration, and selected lipid parameters, particularly HDL-C and LDL-C, in women with PCOS and overweight or obesity, while acknowledging that the intervention did not significantly improve HOMA-IR or other glycemic indices and free testosterone over 16 weeks. Several possibilities merit consideration. Sixteen weeks may simply be too short a horizon for insulin sensitivity and androgen production to shift detectably, especially if the improvements in adiposity needed more time to cascade into hormonal change. The modest sample size of 47 completers also limits statistical power for outcomes with high inter-individual variability, and the calorie restriction in both arms may have blunted between-group differences by improving metabolic parameters across the board.

The study’s design also raises broader questions about how dietary interventions for PCOS should be evaluated. By matching both groups for calorie deficit, the trial isolated the effect of dietary pattern rather than energy restriction, which is scientifically elegant but clinically nuanced: in the real world, the legume-based DASH diet would be deployed alongside weight loss, and its benefits might compound. The significant effects on weight, waist circumference, and menstrual cycle duration, achieved against an active control that was itself calorie-restricted, suggest the dietary pattern contributes something beyond simple caloric arithmetic. Whether that contribution stems from the legumes themselves, the fiber density, the plant protein, the low glycemic load of the overall pattern, or an interaction among these factors cannot be disentangled from this trial alone.

For the millions of women living with PCOS worldwide, the practical message is cautiously encouraging. A legume-enriched DASH diet, rich in beans, lentils, chickpeas, vegetables, fruits, and whole grains, appears to be a safe and beneficial pattern that improves body composition, cholesterol fractions, and menstrual regularity, even if it does not yet demonstrate the power to reverse insulin resistance or lower free testosterone within four months. Future trials with larger samples, longer durations, and perhaps direct comparisons of legume-enriched versus standard DASH patterns will be needed to pin down the active ingredients. In the meantime, this trial adds a valuable, rigorously controlled data point to the growing evidence that what women with PCOS eat, not just how much, shapes their metabolic and reproductive health.

Subject of Research: Effects of a legume-based DASH diet on metabolic and hormonal outcomes in women with polycystic ovary syndrome

Article Title: Effects of legume-based DASH diet on anthropometric factors, glucose/lipid profiles and free testosterone level in women with polycystic ovary syndrome (PCOS): a randomized clinical trial

Article References: Bolukyazdi, M., Ghadiri-Anari, A., Fallahzadeh, H., & Nadjarzadeh, A. (2026). Effects of legume-based DASH diet on anthropometric factors, glucose/lipid profiles and free testosterone level in women with polycystic ovary syndrome (PCOS): a randomized clinical trial. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02291-8

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02291-8

Keywords: PCOS, DASH diet, legumes, insulin resistance, free testosterone, lipid profile, menstrual cycle, randomized controlled trial, women's health, nutrition, obesity, endocrinology

The findings arrive at a moment when the scientific community is increasingly aware that polycystic ovary syndrome, or PCOS, is not a single disease but a spectrum of overlapping phenotypes. Affecting an estimated five to ten percent of women of reproductive age, the syndrome is defined by the 2003 Rotterdam ESHRE/ASRM criteria, which require two of three features: oligo-ovulation or anovulation, clinical or biochemical hyperandrogenism, and polycystic ovarian morphology on ultrasound. That broad definition captures women whose experiences of the disorder can differ dramatically. Some struggle primarily with irregular cycles and fertility; others are marked by the visible stigmata of androgen excess, including coarse terminal hair growth on the face and body, a condition known as hirsutism, along with acne and androgenic alopecia. Understanding which biological signals distinguish these phenotypes has become a central goal of reproductive endocrinology.

The rationale for studying PSA in this context rests on a surprising body of evidence accumulated over nearly three decades. Although PSA, encoded by the KLK3 gene, is produced abundantly by prostatic epithelial cells, immunoreactive PSA has also been detected in female tissues, including the breast, the salivary glands, and the endometrium, and measurable amounts circulate in the blood of healthy women at concentrations far below those seen in men. Crucially, early work by Melegos, Diamandis and colleagues in 1997 demonstrated that female serum PSA rises in conditions of androgen excess, and subsequent studies showed that antiandrogen drugs lower PSA levels in hirsute women, providing pharmacological evidence that the protein functions as a downstream readout of androgen action in female tissues. In other words, PSA in women is not a prostate marker at all; it is a marker of what androgens are actually doing to target tissues.

This biological logic made PSA an attractive candidate for the Turkish research team, led by Seyma Donmez Sahip and Batuhan Turgay of the University of Health Sciences at Ankara Bilkent City Hospital, with Turgay also affiliated with Ankara University’s Reproductive Health center. Their hypothesis was straightforward: if PSA reflects androgen activity, and if hirsute women with PCOS experience more intense androgenic stimulation of hair follicles and sebaceous glands than their non-hirsute counterparts, then hirsute patients should display higher serum concentrations of both total and free PSA. To test this, the investigators enrolled ninety women diagnosed with PCOS by Rotterdam criteria between May 2022 and January 2023, stratifying them into hirsute and non-hirsute groups using the modified Ferriman-Gallwey score, the standard clinical instrument for visually grading terminal hair growth across nine androgen-sensitive body areas.

The methodology reflects careful attention to the confounders that plague hormonal research. Venous blood samples were drawn on cycle days two or three, when baseline reproductive hormones are most reliably interpreted, and the panel included total and free PSA alongside total and free testosterone, DHEA-S, luteinizing hormone, and metabolic parameters. Insulin resistance was quantified using the homeostatic model assessment, HOMA-IR, a calculation derived from fasting glucose and insulin that estimates how hard the pancreas must work to maintain normal blood sugar. This detail matters because insulin resistance is not merely a metabolic side effect of PCOS; it is widely regarded as a central driver of the syndrome, amplifying ovarian and adrenal androgen production while suppressing hepatic synthesis of sex hormone-binding globulin, the carrier protein that keeps circulating testosterone biologically inert.

When the two phenotypic groups were compared directly, the results partially confirmed expectations. Hirsute women had significantly higher body mass index, with a p-value of 0.044, higher acne prevalence at p equal to 0.032, and higher free testosterone at p equal to 0.014, painting a coherent picture of a phenotype in which androgenic and metabolic disturbances cluster together. Interestingly, menstrual disturbance ran in the opposite direction: amenorrhea and oligomenorrhea were more frequent among non-hirsute women, a reminder that the severity of ovulatory dysfunction and the intensity of cutaneous androgen effects do not march in lockstep. Ovarian morphology and alopecia showed no significant differences between the groups, and, contrary to the primary hypothesis, neither total nor free PSA concentrations differed significantly between hirsute and non-hirsute patients, with all such comparisons yielding p-values above 0.05.

But the story changed when the researchers abandoned group comparisons in favor of correlation analysis across the whole cohort. Using Spearman rank correlation, a non-parametric method appropriate for biological variables that do not follow normal distributions, the team uncovered strikingly strong positive associations. PSA correlated with the Ferriman-Gallwey hirsutism score at a rank correlation coefficient of 0.896, with total testosterone at 0.779, with HOMA-IR at 0.838, with DHEA-S at 0.807, and with luteinizing hormone at 0.804, all with p-values below 0.001. In clinical research, correlation coefficients of this magnitude are rare; values approaching 0.9 indicate that two variables rise and fall together almost in lockstep across the study population. The implication is that PSA behaves as a continuous integrator of androgenic and metabolic load, even if the binary split into hirsute and non-hirsute categories is too coarse to reveal differences in group means.

This distinction between categorical and continuous analysis carries real methodological weight. Phenotypic classification by Ferriman-Gallwey score necessarily dichotomizes a graded biological variable, and thresholds for hirsutism vary by ethnicity and remain imperfectly standardized. A molecule whose expression is driven by tissue-level androgen action may respond smoothly to the full range of androgen exposure, so that averaging PSA values across a threshold-defined group obscures the very dose-response relationship that correlation analysis exposes. The strong PSA-HOMA-IR correlation adds a further layer, suggesting that PSA may capture the intertwined androgen-insulin axis that many investigators consider the engine of PCOS pathophysiology, in which hyperinsulinemia potentiates luteinizing hormone-driven ovarian theca cell androgen synthesis and reduces binding-protein-mediated sequestration of free testosterone.

The new findings also sit within a contested literature. Prior studies of PSA in PCOS have produced mixed results: some reported elevated PSA in affected women compared with controls, a 2019 systematic review and meta-analysis in Hormone and Metabolic Research found overall differences supporting PSA as a potential androgen-excess marker, and work in adolescent girls explored its diagnostic value, while other investigations failed to replicate clear group-level differences. The Ankara study’s design differs from much of this literature in that it compared PSA across PCOS phenotypes rather than between PCOS and healthy controls, asking a subtler question about within-syndrome heterogeneity. The answer, that PSA does not separate hirsute from non-hirsute patients but correlates powerfully with hirsutism severity, androgen concentrations, and insulin resistance, suggests that PSA’s utility may lie not as a diagnostic classifier but as a quantitative index of androgenic-metabolic activity.

For patients and clinicians, the practical implications remain preliminary. PSA is not proposed as a replacement for testosterone measurement or for careful clinical assessment of hirsutism, acne, and cycle regularity, and the study’s authors emphasize that their results underscore the heterogeneity of PCOS and the need for comprehensive phenotypic evaluation rather than a single biomarker shortcut. Yet the research adds to a growing recognition that molecules once considered sexually dimorphic in absolute terms may carry meaningful physiological information in both sexes, and that the androgen signaling pathway, so central to PCOS, leaves measurable fingerprints throughout the body. If future longitudinal studies confirm that serum PSA tracks with long-term metabolic risk in women with PCOS, a cheap and widely available immunoassay, already deployed in laboratories worldwide, could find an unexpected second career in women’s health, transforming a prostate cancer biomarker into a lens on the hormonal and metabolic complexity of one of medicine’s most heterogeneous syndromes.

Subject of Research: Serum prostate-specific antigen as a marker of androgenic and metabolic activity in hirsute and non-hirsute phenotypes of polycystic ovary syndrome

Article Title: Serum Prostate-Specific Antigen Concentrations in Polycystic Ovary Syndrome: A Comparative Analysis of Hirsute and Non-Hirsute Phenotypes

Article References: Sahıp, S. D., Eyol, M. M., Ersoy, E., Erden Deveci, E., Bahadır, I. B., & Turgay, B. (2026). Serum Prostate-Specific Antigen Concentrations in Polycystic Ovary Syndrome: A Comparative Analysis of Hirsute and Non-Hirsute Phenotypes. Reproductive Sciences. https://doi.org/10.1007/s43032-026-02187-4

Image Credits: AI Generated

DOI: 10.1007/s43032-026-02187-4

Keywords: polycystic ovary syndrome, prostate-specific antigen, hirsutism, hyperandrogenism, PCOS phenotypes, insulin resistance, free testosterone, biomarkers, reproductive endocrinology, Ferriman-Gallwey score, HOMA-IR, Rotterdam criteria