Tirzepatide, commercially known as Mounjaro, is a once-weekly subcutaneous injectable medication that acts as a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Tirzepatide was initially developed to improve glycemic control in patients with type 2 diabetes mellitus. However, its substantial weight-reducing effects have led to increasing interest in its use for obesity management. In addition to its metabolic effects, growing attention has been directed toward its potential effects on the urinary and reproductive systems. Current evidence suggests potential benefits for kidney function and reductions in urinary albumin excretion. Conversely, dehydration resulting from gastrointestinal adverse effects may lead to acute kidney injury in some cases. To date, there is no clear evidence of clinically significant direct adverse effects on the lower urinary tract. Furthermore, weight loss and improved metabolic status may improve obesity-associated testosterone deficiency and erectile function in men. Nevertheless, evidence regarding fertility and other reproductive functions remains limited. This review aims to examine the current evidence concerning the effects of tirzepatide on body weight, kidney function, the urinary tract, and sexual and reproductive health. 1. Introduction Obesity is a chronic metabolic disease associated with an increased risk of type 2 diabetes mellitus, hypertension, cardiovascular disease, chronic kidney disease, testosterone deficiency, erectile dysfunction, fertility disorders, and certain lower urinary tract disorders. Therefore, substantial weight loss may provide health benefits beyond a reduction in body mass index (BMI). Tirzepatide is a long-acting dual agonist of GIP and GLP-1 receptors. Activation of these pathways increases glucose-dependent insulin secretion, suppresses glucagon secretion, improves insulin sensitivity, and reduces appetite and food intake, ultimately resulting in substantial body weight reduction. Its long half-life also allows administration by subcutaneous injection once weekly. 2. Mounjaro and Weight Loss The weight-reducing effect of tirzepatide is primarily associated with decreased appetite and caloric intake, in addition to improved metabolic regulation. Central effects on appetite-regulating centers are among the key mechanisms, while delayed gastric emptying contributes to this effect, particularly during the early stages of treatment. The SURMOUNT-1 trial demonstrated substantial reductions in body weight after 72 weeks of treatment. Mean weight loss was approximately 15.0% with a weekly dose of 5 mg, 19.5% with 10 mg, and 20.9% with 15 mg, compared with approximately 3.1% in the placebo group. These findings are particularly relevant to urology because obesity is associated with an increased risk of chronic kidney disease, erectile dysfunction, obesity-associated testosterone deficiency, urinary incontinence, and other urinary disorders. Figure 1. Simplified Metabolic Mechanism of Tirzepatide Tirzepatide activates GIP and GLP-1 receptors, increasing glucose-dependent insulin secretion, improving insulin sensitivity, suppressing glucagon secretion, and reducing appetite and food intake. These effects contribute to weight loss and improved metabolic status. 3. Effects of Tirzepatide on the Kidneys 3.1. Potential Renoprotective Effects The kidneys are among the most important components of the urinary system for which an increasing body of clinical evidence is available regarding the potential effects of tirzepatide. Renal analyses of the SURPASS trials suggest that tirzepatide may reduce urinary albumin excretion and potentially slow the decline in kidney function in some patients with type 2 diabetes mellitus.In the SURPASS-4 trial, tirzepatide treatment was associated with a lower incidence of a composite renal outcome, including a reduction of 40% or more in estimated glomerular filtration rate (eGFR), kidney failure, renal death, or the development of macroalbuminuria, compared with insulin glargine. A substantial component of this benefit was associated with a reduced incidence of new-onset macroalbuminuria. Pooled analyses of the SURPASS trials also demonstrated reductions in the urinary albumin-to-creatinine ratio (UACR), particularly among patients with pre-existing elevations in urinary albumin excretion. However, these findings should be interpreted cautiously, as further studies specifically designed to evaluate long-term renal outcomes are needed. 3.2. Dehydration and Acute Kidney Injury Despite its potential long-term renal benefits, tirzepatide may indirectly increase the risk of acute kidney complications in certain circumstances. Nausea, vomiting, and diarrhea are common adverse effects of treatment. When severe or persistent, these symptoms may cause fluid loss and dehydration. Dehydration can reduce circulating blood volume, impair renal perfusion, and increase the risk of acute kidney injury (AKI). Particular attention should therefore be given to patients with pre-existing kidney disease or severe gastrointestinal symptoms, especially when initiating treatment or increasing the dose. Importantly, acute deterioration in kidney function associated with tirzepatide may occur secondarily to dehydration and volume depletion rather than through direct nephrotoxicity. 4. Effects of Tirzepatide on the Urinary Tract There is currently no convincing evidence that tirzepatide directly causes lower urinary tract disorders. Frequent urination, dysuria, urinary retention, prostatitis, and recurrent urinary tract infections are not characteristic or well-established adverse effects of the medication. Current evidence has also not demonstrated a consistent, clinically significant increase in the risk of urinary tract infections or urinary stones attributable to tirzepatide. It is important to distinguish tirzepatide from sodium-glucose cotransporter 2 (SGLT2) inhibitors. Tirzepatide does not lower blood glucose by increasing urinary glucose excretion; therefore, the mechanisms associated with certain urinary or genital infections linked to SGLT2 inhibitors should not automatically be attributed to tirzepatide. Nevertheless, urinary symptoms arising during treatment should undergo standard clinical evaluation rather than being automatically attributed to the medication. 5. Tirzepatide, Obesity, and Male Reproductive Health Obesity is strongly associated with a condition known as metabolic hypogonadism in men. Increased adipose tissue, insulin resistance, chronic inflammation, and increased conversion of testosterone to estrogen within adipose tissue may affect the hypothalamic-pituitary-gonadal axis. Consequently, substantial weight loss may improve hormonal and reproductive function, even in the absence of a direct pharmacological effect of tirzepatide on the testes. Small recent studies have suggested that tirzepatide treatment in men with obesity and metabolic testosterone deficiency may be associated with reductions in body weight, waist circumference, and fat mass, alongside increases in total, free, and bioavailable testosterone levels and improvements in erectile function measures. However, these findings remain preliminary and do not establish tirzepatide as a direct treatment for testosterone deficiency or erectile dysfunction. 6. Tirzepatide and Erectile Function Obesity, type 2 diabetes mellitus, insulin resistance, hypertension, and dyslipidemia are associated with erectile dysfunction through several mechanisms, including endothelial dysfunction, impaired nitric oxide signaling, vascular disease, neuropathy, chronic inflammation, and reduced testosterone levels.Therefore, tirzepatide may theoretically improve erectile function indirectly through weight loss, reductions in visceral fat, improved insulin sensitivity, reduced inflammation, and improvements in vascular health and hormonal balance. Reductions in body weight and fat mass, together with improved insulin sensitivity, reduced inflammation, better vascular health, and a more favorable testosterone-to-estrogen balance, may contribute to potential improvements in erectile function. Some emerging clinical evidence has reported encouraging findings in this area. However, current evidence does not establish a direct pharmacological effect of tirzepatide on the erectile process. Figure 2. Potential Relationship Between Tirzepatide and Male Sexual Health 7. Fertility and Spermatogenesis Scientific evidence regarding the direct effects of tirzepatide on spermatogenesis and human fertility remains insufficient. Theoretically, improvements in obesity and metabolic disorders may improve testosterone levels and certain indicators of sperm quality and reproductive capacity in some men. Nevertheless, tirzepatide should not currently be considered a treatment for male infertility. Evidence concerning its direct effects on prostate physiology, benign prostatic hyperplasia, prostate cancer, bladder function, and spermatogenesis is also insufficient to support definitive clinical conclusions. 8. Urinary and Reproductive Effects in Women Substantial weight loss and improvements in insulin resistance may indirectly improve reproductive function in some women, particularly when reproductive disorders are associated with obesity and metabolic dysfunction. However, direct evidence regarding the effects of tirzepatide on sexual and reproductive function in women remains limited. An important clinical consideration is its potential effect on oral hormonal contraceptives. Because tirzepatide delays gastric emptying, it may reduce the effectiveness of oral hormonal contraceptives. Accordingly, prescribing information recommends using a non-oral contraceptive method or adding a barrier method for four weeks after treatment initiation and for four weeks after each dose escalation. Tirzepatide is not recommended for weight management during pregnancy. Patients who become pregnant should consult their healthcare provider regarding treatment. 9. Potential Benefits and Risks for the Urinary and Reproductive Systems Current evidence suggests several potential benefits and risks associated with tirzepatide use. 9.1. Potential Benefits 1. Reduction in urinary albumin excretion Some studies have demonstrated reductions in the urinary albumin-to-creatinine ratio (UACR), particularly in patients with pre-existing elevated urinary albumin excretion. 2. Potential improvement in kidney outcomes Tirzepatide may help limit the deterioration of kidney function in some patients with type 2 diabetes mellitus. However, further studies are required to confirm its long-term renal benefits. 3. Potential improvement in erectile function Weight loss and improved metabolic status may indirectly improve erectile function in some men with obesity. 4. Potential improvement in testosterone levels Preliminary evidence suggests that testosterone levels may improve in men with obesity and testosterone deficiency associated with metabolic dysfunction. 9.2. Potential Risks 1. Acute kidney injury Severe or persistent vomiting and diarrhea may cause fluid loss and dehydration, impair renal perfusion, and increase the risk of acute kidney injury. 2. Urinary tract effects There is currently no convincing evidence of a clinically significant increase in urinary tract infections or urinary stones attributable to tirzepatide. 3. Effects on fertility Evidence regarding the direct effects of tirzepatide on spermatogenesis and male fertility remains limited. Its direct effects on female reproductive function have also not been established. 4. Interaction with oral contraceptivesDelayed gastric emptying may affect the effectiveness of oral hormonal contraceptives. Patients should follow prescribing recommendations regarding additional contraceptive protection when initiating treatment or increasing the dose. 5. Pregnancy Tirzepatide is not recommended for weight management during pregnancy. Medical advice should be sought if pregnancy occurs during treatment. Overall, assessing the potential benefits and risks of tirzepatide requires consideration of the patient’s clinical status, kidney function, and treatment-related adverse effects. Several urinary and reproductive effects remain insufficiently characterized and require further investigation. 10. Important Clinical Considerations for Urologists From a urological and reproductive medicine perspective, tirzepatide may be particularly relevant to patients with obesity accompanied by diabetes, kidney disease, or sexual dysfunction. Kidney function should be assessed using serum creatinine and estimated glomerular filtration rate (eGFR), particularly in patients with chronic kidney disease or those experiencing severe vomiting or diarrhea during treatment. The urinary albumin-to-creatinine ratio (UACR) may also be used to assess albuminuria in patients with diabetes or suspected diabetic kidney disease. In men with obesity and erectile dysfunction, other contributing factors should be evaluated, including blood pressure, blood glucose, lipid levels, and morning testosterone concentrations. Weight loss alone should not be relied upon as the sole treatment for erectile dysfunction. Patients should also be advised to maintain adequate fluid intake and seek medical evaluation if persistent vomiting or diarrhea is accompanied by reduced urine output, dizziness, or low blood pressure. Figure 3. Potential Urinary and Reproductive Effects of Tirzepatide Weight loss and improved metabolic status may contribute to reduced urinary albumin excretion, potential renal benefits, and improvements in testosterone levels and erectile function in some patients. Conversely, severe gastrointestinal adverse effects may cause fluid loss and dehydration, impair renal perfusion, and increase the risk of acute kidney injury. 11. Conclusion Tirzepatide represents an important development in the pharmacological management of obesity and type 2 diabetes mellitus. Clinical trials have demonstrated the potential for body weight reductions exceeding 20% in some patients receiving the higher therapeutic doses. Regarding the urinary and reproductive systems, current evidence suggests potentially beneficial or neutral effects across most studied domains, while emphasizing the need for caution regarding indirect complications associated with dehydration. The available evidence primarily concerns reductions in urinary albumin excretion and the possibility of renoprotective effects. Conversely, severe gastrointestinal adverse effects may lead to dehydration and volume depletion, potentially resulting in secondary acute kidney injury. Emerging evidence also suggests that substantial weight loss and associated metabolic improvements may contribute to improvements in obesity-associated testosterone deficiency and erectile function in men. However, tirzepatide should not currently be used as a direct treatment for erectile dysfunction, testosterone deficiency, infertility, or lower urinary tract disorders. Further prospective studies specifically designed to evaluate its effects on kidney function, the urinary tract, the prostate, erectile function, sex hormones, and fertility are needed to establish its clinical effects more precisely. Figure 4. Clinical Summary Tirzepatide contributes to weight loss, improved glycemic control, and better metabolic health, which may be associated with potential renal and sexual health benefits. Conversely, severe nausea, vomiting, or diarrhea may cause dehydration and reduced renal perfusion, increasing the risk of acute kidney injury. Al Mustaqbal University The First University in Iraq