AIM-TEST: Microbiome-Targeted Nutrition for Functional Secondary Hypogonadism

Who can take part

• Male participants aged 30 to 65 years at the time of informed consent
• Ability to understand the study, provide written informed consent, and comply with study procedures, including repeated morning blood sampling, completion of validated Turkish patient-reported outcome measures, and collection of stool samples
• At least one persistent sexual symptom compatible with androgen deficiency for at least 3 months:
• reduced sexual desire or libido
• reduced spontaneous or morning erections; or
• erectile dysfunction
• Two fasting, post-sleep morning serum total testosterone measurements obtained on separate days 2 to 7 days apart, between 07:00 and 10:00, with both values at least 6.0 nmol/L and below 12.0 nmol/L
• Calculated free testosterone below 220 pmol/L, calculated from total testosterone, sex hormone-binding globulin, and albumin using the prespecified Vermeulen equation
• Serum luteinizing hormone and follicle-stimulating hormone concentrations that are low or inappropriately normal for the degree of testosterone deficiency, with no biochemical evidence of primary testicular failure
• No identified structural, congenital, infiltrative, or otherwise organic hypothalamic or pituitary disorder and no identified organic primary testicular disorder, based on the prespecified clinical and laboratory evaluation
• Body weight stable within 5% during the 12 weeks before randomization
• Any chronic medical condition and its associated medication regimen must be clinically stable for at least 12 weeks before randomization
• Agreement not to initiate testosterone therapy, fertility-directed hormonal therapy, anabolic-androgenic steroids, non-study testosterone-enhancing supplements, intensive structured weight-loss treatment, weight-loss medication, bariatric intervention, or non-study probiotic, prebiotic, synbiotic, or postbiotic products during the 12-week intervention period

Who cannot take part

• Known pituitary or hypothalamic tumour or other structural lesion; previous pituitary surgery or cranial radiotherapy; infiltrative pituitary disease; multiple pituitary hormone deficiency; or clinically significant traumatic brain injury affecting pituitary function
• Use within the previous 6 months of exogenous testosterone, anabolic-androgenic steroids, selective estrogen receptor modulators including clomiphene or enclomiphene, human chorionic gonadotropin, gonadotropins, aromatase inhibitors, dehydroepiandrosterone, or another androgen-active hormonal intervention
• Current use of a gonadotropin-releasing hormone agonist or antagonist, antiandrogen, chronic opioid therapy, systemic glucocorticoids above physiological replacement, ketoconazole at a dose expected to suppress steroidogenesis, or another medication known to materially suppress or alter the hypothalamic-pituitary-testicular axis
• Acute or subacute systemic illness, acute infection, or clinically significant inflammatory flare within 4 weeks before randomization
• Major surgery within 8 weeks before randomization
• Intentional or unintentional body-weight change greater than 5% during the 12 weeks before randomization, or planned initiation of an intensive weight-loss programme, weight-loss medication, or bariatric procedure during the intervention period
• Myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable cardiovascular disease within the previous 6 months; uncontrolled arrhythmia; decompensated heart failure; or another unstable cardiovascular condition
• Acute gastroenteritis or bowel preparation or colonoscopy within 4 weeks before randomization
• Systemic antibiotic use within 8 weeks before randomization
• Use within 4 weeks before randomization of a probiotic, prebiotic, synbiotic, postbiotic, microbiota-directed supplement, non-study testosterone-enhancing supplement, or a non-study product containing one or more active ingredients of the investigational formulation
• Participation in another interventional clinical study within 30 days before randomization or planned participation in another interventional study before completion of Week 24
• Elevated luteinizing hormone or follicle-stimulating hormone concentrations consistent with primary testicular failure
• Known Klinefelter syndrome, bilateral orchiectomy, clinically significant testicular trauma, testicular torsion with persistent dysfunction, bilateral cryptorchidism, gonadotoxic chemotherapy or radiotherapy, orchitis with testicular failure, or another established organic testicular disorder
• Known congenital hypogonadotropic hypogonadism or Kallmann syndrome
• Current fertility-directed hormonal therapy, current specialist evaluation for infertility that should not be delayed, or azoospermia or another fertility disorder requiring immediate standard care
• Estimated glomerular filtration rate below 45 mL/min/1.73 m², clinically significant hepatic impairment, or another clinically important unstable renal or hepatic condition
• Known prostate cancer or male breast cancer, a prostate-specific antigen result or prostate examination finding requiring standard-care evaluation before participation, or an unresolved clinical suspicion of prostate malignancy
• Active malignancy other than adequately treated non-melanoma skin cancer, unless participation is approved by the relevant treating specialist and the investigator and does not interfere with cancer management
• Active inflammatory bowel disease, untreated coeliac disease, clinically significant malabsorption, major gastrointestinal resection, or another gastrointestinal disorder expected to materially affect study-product tolerance, absorption, or microbiome interpretation
• Known allergy, hypersensitivity, or clinically important intolerance to any component of the active intervention or placebo
• A clinically important product-medication interaction or medical condition that cannot be safely managed based on the finalized study-product safety and interaction assessment
• Current substance-use disorder or uncontrolled major psychiatric illness likely to impair informed consent, study adherence, safety, or interpretation of patient-reported outcomes
• Initiation or clinically important dose change within the previous 12 weeks of a medication likely to materially affect sexual function, body weight, glucose metabolism, or testosterone concentrations. Stable background therapy may be permitted when prospectively approved by the investigator and maintained unchanged through Week 12
• Poorly controlled diabetes mellitus, defined as glycated hemoglobin greater than 9.0%, recurrent severe hypoglycaemia, or another clinically unstable metabolic disorder
• Any other condition, laboratory abnormality, or circumstance that, in the investigator's judgment, would create an unacceptable risk, prevent reliable completion of study procedures, or make participation clinically inappropriate
• Either qualifying total testosterone measurement below 6.0 nmol/L, or clinical or biochemical severity for which delaying standard diagnostic evaluation or established clinical management would be inappropriate
• Persistent hyperprolactinaemia requiring investigation or management; unexplained headache or visual-field symptoms; or another clinical indication for pituitary magnetic resonance imaging that has not been adequately evaluated before randomization
• Clinically important abnormality of prolactin, thyroid-stimulating hormone, free thyroxine, ferritin, transferrin saturation, or another screening test suggesting an untreated reversible or organic cause of hypogonadism
• Untreated or inadequately treated moderate-to-severe obstructive sleep apnoea
• Rotating or night-shift work, severe sleep disruption, or another circumstance that prevents standardized fasting post-sleep testosterone sampling
• Hematocrit greater than 50% at screening