A 42-year-old man sits in a Melbourne endocrinology clinic, two printed lab results in his hand. His total testosterone has come back at 7.8 nmol/L, well below the local lab's 12.0 nmol/L lower limit. He is 38 kilograms above a healthy weight, his fasting glucose is creeping towards the type 2 diabetes line, and his partner has been asking when they will start trying for a second child. Two years ago his GP wrote him a script for testosterone replacement. He never filled it. This week, his endocrinologist suggested something different: a GLP-1 receptor agonist, alongside structured weight loss and a fertility-sparing plan. He wants to know if a diabetes and weight loss drug can really put his hormones, and his sperm, back in order. The most interesting new data, presented at ENDO 2026 in mid-June, suggests the answer may be yes.
The biology: why fat tissue turns down the testosterone dial
The link between excess adipose tissue and low testosterone is not a folk observation. Adiposity drives insulin resistance, increases peripheral aromatisation of testosterone to oestradiol, and suppresses the hypothalamic-pituitary-gonadal (HPG) axis at every level [5]. In a man carrying 20 kilograms of extra weight, the result is often a picture labelled "obesity-related hypogonadism" on the discharge summary: low or low-normal LH and FSH, low total testosterone, and a sperm count that has quietly drifted down. The orthodox clinical reflex has been to replace what is missing, with testosterone replacement therapy (TRT) via gel, injection, or implant, and to revisit the fertility conversation later [5][6].
That reflex, Pratibha Natesh, an endocrinologist at Warwick Medical School, argued at ENDO 2026, deserves a serious second look. Her systematic review, abstract MON-157, pulled every randomised controlled trial of GLP-1 receptor agonists in men aged 18 to 65 that reported testosterone or sperm endpoints, and only five trials survived inclusion after two independent reviewers screened each paper [1][2][3]. That is a strikingly thin evidence base for a question that affects a large share of men attending endocrinology and fertility clinics across Australia and the UK.
What the five trials actually show
Two trials drive the signal. The first, a 16-week prospective randomised open-label study of 30 obese men (mean age 46.5, mean BMI 41.2) with functional hypogonadism, randomised participants to liraglutide 3.0 mg daily or 50 mg transdermal testosterone gel, after lifestyle measures had failed [4]. Total testosterone rose in both arms, +5.9 ± 7.2 nmol/L on TRT versus +2.6 ± 3.5 nmol/L on liraglutide. Liraglutide, however, also lifted LH and FSH, signalled a recovering HPG axis, and produced a mean 7.9 kg of weight loss against 0.9 kg in the TRT arm. Metabolic syndrome resolved in two of fifteen liraglutide patients and in none of the testosterone patients.
The second trial randomised 25 men with type 2 diabetes and hypogonadism to semaglutide or TRT for 24 weeks [2][3]. TRT produced the larger testosterone increase, but sperm quality improved only in the semaglutide arm. Morphologically typical sperm rose from 2% to 4% in the GLP-1 group, while in the TRT arm sperm count and quality declined, a familiar signal of exogenous testosterone's suppressive effect on the gonadal axis. Twenty-four weeks is, in fact, roughly one full spermatogenic cycle, since human spermatogenesis spans approximately three months, so the morphology result reflects one pass through that cycle rather than a long-term trajectory [7].
Three additional trials in healthy, non-obese men found no effect of GLP-1s on testosterone, a pattern that Natesh and her co-authors interpret as a mechanistic clue [2][3]. The hormonal benefit, they argue, is unlikely to be a direct action of the drug on testicular tissue. It is more plausibly mediated by weight loss and improved insulin sensitivity, the same metabolic levers that drive obesity-related hypogonadism in the first place. Researchers have, however, identified GLP-1 receptors on Leydig cells, Sertoli cells, and sperm cells themselves, leaving open a more direct endocrine pathway that the trial data have not yet resolved [7].
The bigger signal from Mayo Clinic
The most eye-catching number, however, comes from outside the systematic review. At the American Urological Association annual meeting in Washington DC in May 2026, Andrés Guillén-Lozoya presented a Mayo Clinic analysis of more than 1,600 men prescribed GLP-1 or dual GLP-1/GIP agonists. After treatment, total testosterone rose by approximately 30% [2]. The cohort is retrospective, the comparator is not clearly defined, and the abstract has not yet been peer reviewed. Still, the order of magnitude is large enough to make any practising endocrinologist pause before reaching for the testosterone script.
The Nature News coverage of the ENDO 2026 data also captured the trial design limitations that the press release glossed over [1][2]. Both key trials randomised 25 to 30 men, far too few to support a change in clinical guidelines on their own. The Mayo Clinic analysis, while large, lacks the randomisation that would let a clinician cleanly attribute the testosterone rise to the drug rather than to the weight loss that came with it. Natesh herself is clear: "The evidence is still preliminary, and more robust trials are needed to confirm the association" [2].
Should endocrinologists try GLP-1s before TRT?
For an obese man with low testosterone and a clear desire to preserve or improve fertility, the new data already justifies a serious discussion. Natesh is explicit about the clinical direction: treat the underlying cause, excess weight and poor metabolic health, and the hormone axis often follows [1].
"This work supports a shift away from prescribing testosterone replacement in men with obesity and low testosterone and toward treating the underlying cause, excess weight and poor metabolic health, which can naturally restore hormone levels and preserve fertility."
Pratibha Natesh made the case in those terms in the Endocrine Society press release that accompanied the ENDO 2026 presentation, adding that "improving metabolic health can have positive effects far beyond weight alone" [1].
For an obese man with low testosterone who is not seeking fertility, the calculus is more nuanced. TRT reliably raises serum testosterone, often improves energy, libido, and lean mass, and is broadly safe in appropriately selected patients. A GLP-1 first approach trades a faster biochemical fix for a slower, metabolic one that appears to address the root cause, at the cost of gastrointestinal side effects, the price of the drug, and the unknown durability of the testosterone effect once treatment stops.
The honest answer for a clinician in 2026 is to ask a more specific question. Is the presenting problem a low number on a pathology report, or a metabolic disease that has knocked the axis sideways? If the latter, the ENDO 2026 data, combined with the Mayo Clinic signal, argues for a GLP-1 first conversation, ideally alongside an endocrinologist comfortable in both reproductive and metabolic medicine. For men whose hypogonadism is severe, symptomatic, and unlikely to resolve with weight loss alone, combination therapy or a carefully sequenced plan may be the right call.
Questions a patient might raise at the next appointment
This article is informational, not a substitute for individual clinical advice, and treatment decisions belong with a qualified clinician. With that caveat, three questions tend to clarify the path forward. First, what is the fertility plan over the next one to two years, and is the partner open to a deferred plan if metabolic treatment restores testosterone naturally? Second, what is the magnitude of the weight that needs to come off, and is a GLP-1 receptor agonist the safest, most sustainable way to lose it in this man's clinical context, taking into account the out-of-pocket cost that still applies in Australian and many UK practices? Third, if TRT is started, will it be sequenced with a fertility-sparing protocol, and at what point will a GLP-1 be layered in or substituted?
The field, Natesh cautioned, is still moving. Larger randomised trials are needed before any guideline body can formally endorse a GLP-1 first pathway for obesity-related hypogonadism, and the current evidence, as Nature News noted, remains preliminary [2]. The signal, however, is enough to make one prediction with confidence: the next decade of men's endocrinology will not be about which drug raises the number fastest on a lab slip, but about which approach restores the underlying physiology and protects the fertility that a generation of replacement scripts has quietly compromised.