AndroGel Mental Health and Mood Impact: What the Evidence Actually Shows

Does testosterone gel improve mood?

A 2019 systematic review and meta-analysis by Walther and colleagues pooled 27 placebo-controlled randomized trials covering 1,890 men and found a significant reduction in depressive symptoms with testosterone treatment compared with placebo (Hedges g 0.21, 95% CI 0.10 to 0.32) [1]. Response, defined as a score reduction of 50% or more, was more likely with testosterone (odds ratio 2.30, 95% CI 1.30 to 4.06), and dropout rates did not differ significantly from placebo (odds ratio 0.79, 95% CI 0.61 to 1.01) [1].

A Hedges g of 0.21 is a small effect by the usual convention. It is a standardized difference, used because the pooled trials measured depression on different rating scales [1].

An earlier meta-analysis of 16 trials with 944 men also found a significant positive effect of testosterone on mood, with two subgroups worth knowing. The effect was statistically significant in hypogonadal men but not in eugonadal men, and it was significant in trials with a mean age under 60 but not in trials with a mean age over 60 [7].

The T-Trials: 790 older men, one year of gel

The Testosterone Trials assigned 790 men aged 65 or older with a serum testosterone below 275 ng/dL and symptoms suggesting low testosterone to testosterone gel or placebo gel for one year, with the dose adjusted to bring levels into the mid-normal range for men aged 19 to 40 [2].

Sexual function responded most clearly: sexual activity measured by the Psychosexual Daily Questionnaire increased significantly (P<0.001), as did sexual desire and erectile function [2]. On vitality, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale, testosterone had no significant benefit [2].

The mood finding is easy to overstate. The investigators reported that men who received testosterone had slightly better mood and lower severity of depressive symptoms than men on placebo [2]. Mood was not a primary outcome; the trials centered on sexual function, physical function and vitality [2].

High doses, mania and aggression

The strongest controlled evidence on testosterone and mood at high exposure comes from a study of supraphysiologic dosing, not replacement. Pope and colleagues gave 56 men aged 20 to 50 either testosterone cypionate at doses rising to 600 mg a week or placebo for 6 weeks each, in a crossover design [5]. Testosterone significantly increased manic scores on the Young Mania Rating Scale (P=0.002), manic scores on daily diaries (P=0.003), liking of the drug effect (P=0.008) and aggressive responses on a computerized provocation test (P=0.03) [5].

The reaction varied widely between individuals. Of 50 men who reached the 600 mg weekly dose, 42 (84%) had minimal psychiatric effects (maximum mania score below 10), 6 (12%) became mildly hypomanic (score 10 to 19) and 2 (4%) became markedly hypomanic (score 20 or higher) [5]. Responders and non-responders did not differ significantly on baseline demographic, psychological, laboratory or physiological measures [5].

The testosterone gel 1% label warns that testosterone has been subject to abuse, typically at doses above those recommended and in combination with other anabolic androgenic steroids, and that such abuse can lead to serious cardiovascular and psychiatric adverse reactions [4].

What a testosterone gel 1% label lists

The figures below come from the testosterone gel 1% prescribing information.

In a 180-day phase 3 trial of testosterone gel 1%, adverse events the investigators judged at least possibly related to treatment included depression in 1% of men on 50 mg, 0% on 75 mg and 1% on 100 mg; emotional lability in 0%, 3% and 3%; nervousness in 0%, 3% and 1%; and decreased libido in 0%, 3% and 1% [4]. Less common reactions, reported in fewer than 1% of patients, included amnesia, anxiety and hostility [4]. Six patients (4%) stopped the trial because of adverse events, and those events included depression, sadness and memory loss [4].

The label also warns that sleep apnea may occur in patients with risk factors [4].

The testosterone gel 1% label's boxed warning is about transfer, not mood: virilization has been reported in children secondarily exposed to testosterone gel, and the listed signs include aggressive behavior, along with genital enlargement, pubic hair, increased erections and libido, and advanced bone age [4]. In most reported cases these signs regressed once exposure was removed; in a few, enlarged genitalia did not fully return to age-appropriate size and bone age stayed modestly advanced [4].

Memory and cognition

The T-Trials included a cognitive function study that randomized 788 men, 394 to testosterone and 394 to placebo [3]. Within that group, 493 men met criteria for age-associated memory impairment (mean age 72.3 years, mean baseline testosterone 234 ng/dL) [3]. The primary outcome was delayed paragraph recall, scored from 0 to 50 and measured at 6 and 12 months, and there was no significant change from baseline in the testosterone group [3]. Secondary measures were visual memory (Benton Visual Retention Test), executive function (Trail-Making Test B minus A) and spatial ability (Card Rotation Test) [3].

Smaller, shorter studies have pointed the other way. In one randomized, double-blind trial, 25 healthy men aged 50 to 80 received weekly intramuscular testosterone enanthate 100 mg or saline for 6 weeks, and the testosterone group showed significant improvements in spatial memory, spatial ability and verbal memory compared with baseline and placebo, although not on every measure [8]. Total testosterone rose about 130% at week 3 and estradiol rose about 77%, so the authors noted it was unclear whether the changes came from testosterone, estradiol or both [8].

Observational data link low testosterone to Alzheimer's disease risk, but they cannot show that treatment lowers it. A meta-analysis of 7 prospective cohort studies with 5,251 elderly men and 240 Alzheimer's cases found low plasma testosterone associated with a higher risk (relative risk 1.48, 95% CI 1.12 to 1.96) [9].

Do you need confirmed low testosterone first?

FDA states that testosterone products are approved only for men who lack or have low testosterone in conjunction with an associated medical condition, such as testicular failure from genetic problems or chemotherapy, or hypothalamic or pituitary disorders, and that none are approved for low testosterone without such a condition [6]. The testosterone gel 1% label carries a limitation of use stating that safety and efficacy in age-related hypogonadism have not been established, and FDA requested in June 2026 that this limitation be removed, along with revisions to prostate cancer and benign prostatic hyperplasia safety information [6][4].

The testosterone gel 1% label instructs that hypogonadism be confirmed with morning serum testosterone measured on at least two separate days, both below the normal range [4]. The Endocrine Society guideline makes the same point: diagnose hypogonadism only in men with symptoms and signs consistent with testosterone deficiency plus unequivocally and consistently low serum testosterone, measured fasting in the morning and confirmed on repeat testing [10]. Trial entry cutoffs are not diagnostic thresholds: the T-Trials required a level below 275 ng/dL and TRAVERSE required two fasting levels below 300 ng/dL [2][11].

The American Urological Association guideline emphasizes accurate assessment of total testosterone, symptoms and signs, and proper monitoring while on treatment [12].