Can Testosterone Affect The Brain? From Hormone Treatment To Psychosis

Can a testosterone injection affect the mind? A rare case shows how hormones can affect the brain. After about a year of hormone replacement therapy, a man with no history of mental illness experienced intense hallucinations and delusions. The rapid improvement after treatment was discontinued led doctors to suspect a testosterone-related reaction.

Testosterone is an important hormone for several functions in the male body, including the maintenance of muscles, bones, sperm production, and sexual characteristics. When levels of this hormone are too low, doctors may recommend replacement therapy. Although this treatment is considered safe when used correctly, there are lesser-known effects that can involve the brain and behavior.

Significant mood swings, irritability, agitation, and, in rare situations, psychotic symptoms have been described. One case report drew attention to this possibility by describing a 45-year-old man who, after approximately a year of receiving testosterone injections, experienced a radical change in behavior and began hearing voices that he said came from God and even from different parts of his own body.

The man had a significant history that was only understood during the investigation. He had been married for many years but had never been able to have children. About 12 years before the psychiatric episode, tests performed for infertility had already shown a very low concentration of testosterone. At the time, however, the problem was not treated.

A year before his hospitalization, he began experiencing severe, generalized pain and was diagnosed with osteoporosis, a disease in which bones become more fragile and more prone to fractures. Since low testosterone can contribute to bone loss, he began receiving a monthly injection of 250 milligrams of testosterone, in addition to vitamin D.

Later, doctors discovered an explanation for several of these problems: he had Klinefelter syndrome, a genetic condition in which a man is born with an extra X chromosome, usually presenting a chromosomal combination called 47,XXY. This condition can cause very low testosterone production, infertility, small testicles, and a higher risk of certain health problems.

After approximately one year of testosterone treatment, the man began to exhibit changes that were very different from his usual behavior. In just nine days, he developed an exaggerated religiosity, became extremely suspicious of his neighbors, displayed disorganized behavior, and slept much less without seeming to feel sleep-deprived. He also became irritable and verbally aggressive.

The most striking aspect, however, was the voices. He reported hearing voices that seemed to speak directly to him and believed he heard the voice of God. Furthermore, he described voices that seemed to come from specific parts of his own body. These experiences are called auditory hallucinations: the person perceives a voice or sound as real, even though there is no external source producing that sound.

He also developed beliefs that he had received a kind of divine blessing that gave him special powers and began to distrust other people. Neighbors noticed that his behavior had changed so much that they alerted his family, who sought medical attention.

Doctors needed to investigate several possibilities. Psychosis is a condition in which a person may partially lose the ability to distinguish their perceptions and beliefs from reality. It can involve hearing or seeing things that other people don't perceive, developing false and very rigid beliefs, and exhibiting disorganized behavior.

In this man's case, however, there was an important clue: he had never had a psychiatric illness before, nor did he have a family history of mental disorders. Furthermore, the symptoms appeared after a prolonged period of testosterone treatment. Doctors also re-confirmed Klinefelter syndrome and found consistent physical signs, such as tall stature, sparse body hair, and very small testicles.

Interestingly, even after receiving testosterone, his blood concentration was again very low when he arrived at the hospital, probably because the last injection had been given about a month earlier. This doesn't mean the testosterone had no effect. Injections can produce large variations in hormone concentration over time, with periods of increase and decrease.

Testosterone doesn't only act on muscles, bones, and reproductive organs. The brain also has receptors capable of responding to this hormone. When testosterone reaches the brain, it can influence chemical systems involved in mood, motivation, behavior, and perception of reality.

One of these is the dopamine system, a brain chemical important for motivation and reward, but which also participates in the processes involved in psychosis when its activity becomes dysregulated. Testosterone can also influence other systems responsible for balancing neuronal activity.

Researchers believe that, in some vulnerable individuals, relatively rapid changes in androgen levels may contribute to a dysregulation of these circuits. In the case of injections, there is another important characteristic: unlike some forms of replacement that maintain more stable levels, an intramuscular injection can produce a significant increase in the hormone followed by a drop over the weeks. These fluctuations can be significant in particularly susceptible individuals.

The medical team decided to temporarily discontinue the testosterone injections and treated the psychiatric symptoms with antipsychotic medications and other drugs to control agitation and stabilize behavior. The change was rapid. Within a few days, the irritability, grandiose ideas, and hallucinations began to disappear.

In follow-ups conducted ten days, one month, and two months later, the man remained stable: he returned to sleeping normally and stopped hearing voices and exhibiting delusional beliefs. There were no new crises during this period. Since testosterone was still necessary to treat the hormonal deficiency and bone health, the doctors subsequently decided to reintroduce it with much more caution, increasing the interval between applications and maintaining close psychiatric monitoring.

The patient and his family were also instructed to recognize warning signs, such as abrupt changes in behavior, reduced need for sleep, intense irritability, or the return of the voices.

The authors considered that the sequence of events strongly points to a psychosis related to testosterone treatment, but it is important not to turn a single case into a general rule. The study does not demonstrate that testosterone causes psychosis in all people who undergo hormone replacement therapy.

The man also presented with Klinefelter syndrome, a condition that may be associated with a higher risk of psychiatric problems, which may have contributed to his vulnerability. Furthermore, the study does not allow us to know exactly what mechanism triggered the symptoms.

What makes the case particularly interesting is the combination of factors: there was no prior history of mental illness, the symptoms appeared after the start of hormone replacement therapy, there was significant improvement after its discontinuation, and no new crisis occurred during follow-up.

The main message is not that men who need testosterone should avoid treatment, but that significant changes in behavior or perception of reality during hormone therapy need to be taken seriously. For people with risk factors, joint monitoring by endocrinology and psychiatry can be especially important.

READ MORE:

Parenteral Testosterone–Induced Acute Psychosis in Klinefelter Syndrome

Abhijeet Anand and Shobit Garg

Prim Care Companion CNS Disord 2026;28 (4):26cr04203

https://doi.org/10.4088/PCC.26cr04203

Abstract: 

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