Parenteral Testosterone–Induced Acute Psychosis in Klinefelter Syndrome

Anabolic-androgenic steroids, including testosterone, exert effects via androgen receptors and are prescribed for hypogonadism, osteoporosis, delayed puberty, and muscle-wasting conditions.¹ While somatic adverse effects are well recognized, psychiatric complications such as mood disturbances, mania, and psychosis remain underappreciated, particularly with therapeutic dosing.^2–4 These neuropsychiatric effects likely stem from dopaminergic modulation in limbic circuits and dysregulation of GABAergic and glutamatergic systems.^1,3 We report a rare case of acute psychosis following long-term parenteral testosterone replacement in a patient with undiagnosed Klinefelter syndrome.

Case Report

A 45-year-old married man from a lower-middle socioeconomic Hindu nuclear family presented to the emergency department with a 9-day history of overreligiosity, suspiciousness toward neighbors, odd and disorganized behavior, second-person auditory hallucinations (voices of God and somatic voices from body parts), persistently elevated mood, irritability, and reduced need for sleep. Neighbors alerted the family after noticing marked behavioral changes while the patient lived alone managing a farmhouse. There was no prior psychiatric or family history of mental illness.

History revealed primary infertility over 15 years despite regular marital life. Serum testosterone measured 12 years earlier during an infertility workup was low (52.86 ng/dL) but untreated. One year prior, severe generalized body aches led to osteoporosis diagnosis, prompting monthly intramuscular testosterone 250 mg (last dose 1 month before presentation) plus vitamin D supplementation. Karyotyping confirmed 47,XXY Klinefelter syndrome.

Mental status examination revealed adequate grooming but irritability with verbal aggression toward staff, labile affect, grandiose religious delusions (believing divine blessing with special powers), and paranoid ideas. The polymorphic and acute presentation was initially considered as acute polymorphic psychotic disorder, aligning with International Classification of Diseases, Eleventh Revision (ICD-11) code 6A23 acute and transient psychotic disorder (particularly with fluctuating polymorphic symptomatology). Differential diagnoses included a primary acute and transient psychotic disorder (ICD-11: 6A23) versus substance-induced psychotic disorder (ICD-11: 6C4E.6 psychotic disorder induced by other specified psychoactive substance, here, anabolic-androgenic steroid/testosterone).

Key baseline findings 1 year prior were as follows: serum testosterone 52.86 ng/dL (low), vitamin D deficient, and dual-energy x-ray absorptiometry T-scores: −3.2 (lumbar spine; osteoporosis) and −1.7 (femoral neck, osteopenia). At the current presentation, key findings included serum testosterone: 21 ng/dL (low) and hemoglobin A1c: 6.6% (prediabetes), with vitamin D and intact parathyroid hormone within normal limits.

Physical examination showed tall stature, smooth skin without acne, narrow shoulders, sparse/absent facial (Figure 1A) and axillary and abdominal hair (Figure 1B), sparse lightly pigmented pubic hair, normal penile length, bilateral small testes (<4 mL; 1 × 2 cm), and Tanner stage G1PH2—phenotypic features classic for Klinefelter syndrome.

Acute management included intramuscular haloperidol 5 mg and promethazine 25 mg twice daily with lorazepam for behavioral control. Endocrinology advised withholding testosterone and initiated annual intravenous zoledronate 5 mg for osteoporosis. Symptoms (irritability, grandiosity, and hallucinations) improved markedly within days; injectables were discontinued, and oral risperidone 2 mg (with trihexyphenidyl 2 mg) twice daily, sodium valproate 750 mg/day, and lorazepam were prescribed. The patient was discharged stable with outpatient follow-up.

Serial follow-up at 10 days, 1 month, and 2 months postdischarge demonstrated sustained clinical remission: Irritability resolved, sleep normalized, and hallucinations and delusions fully remitted. Risperidone was optimized to 4 mg/day; lorazepam was gradually tapered and discontinued. No relapse occurred. Testosterone enanthate (250 mg every 3 weeks) was cautiously reintroduced in consultation with endocrinology under close psychiatric monitoring, and the patient and caregivers were psychoeducated regarding relapse warning signs and adherence.

Discussion

The temporal association between 1 year of parenteral testosterone and psychosis onset, absent prior psychiatric illness, polymorphic presentation, low testosterone at presentation (trough level), and rapid resolution upon discontinuation strongly support substance-induced psychotic disorder (ICD-11: 6C4E.6) as the final diagnosis over a primary acute and transient psychotic disorder.^2–4 Injectable formulations cause supraphysiological peaks and troughs, potentially exacerbating dopaminergic dysregulation in vulnerable individuals.³ Klinefelter syndrome confers inherent psychiatric risk, including psychosis, possibly amplified by underlying hypogonadism and sudden androgen exposure.^5–7

This case highlights that even therapeutic parenteral testosterone can precipitate severe psychosis in susceptible patients, particularly those with Klinefelter syndrome. Clinicians must perform baseline psychiatric screening, monitor mental status vigilantly, and consider prompt discontinuation if symptoms emerge. The stable longitudinal course without relapse further supports the diagnosis of testosterone-associated substance-induced psychotic disorder and underscores the importance of careful risk-benefit assessment during rechallenge. Cautious reintroduction of testosterone under close psychiatric monitoring, as undertaken in this case, may be feasible when underlying hormonal deficiency mandates treatment.

Article Information

Published Online: July 30, 2026. https://doi.org/10.4088/PCC.26cr04203
© 2026 Physicians Postgraduate Press, Inc.
Prim Care Companion CNS Disord 2026;28(4):26cr04203
Submitted: February 2, 2026; accepted April 13, 2026.
To Cite: Anand A, Garg S. Parenteral testosterone–induced acute psychosis in Klinefelter syndrome. Prim Care Companion CNS Disord 2026;28(4):26cr04203.
Author Affiliations: Department of Psychiatry, Shri Guru Ram Rai Institute of Medical and Health Sciences, Uttarakhand, India (Anand, Garg).
Corresponding Author: Shobit Garg, MD, DPM, Department of Psychiatry, Shri Guru Ram Rai Institute of Medical and Health Sciences, Shri Guru Ram Rai University, Dehradun, Uttarakhand, 248001 India ([email protected]).
Financial Disclosure: None.
Funding/Support: None.
Patient Consent: Consent was received from the patient to publish the case report and photos, and information has been de-identified to protect patient anonymity.
ORCID: Shobit Garg: https://orcid.org/0000-0001-5913-9021