Low Testosterone and Depression in Men: What Every Man Over 35 Should Know

By Kyle Roth, FNP-BC, APRN, MSN, MHA | Roth Family Medicine and Mental Health | Pocatello, Idaho

Depression in men is underdiagnosed, underreported, and undertreated. Men are less likely to recognize depressive symptoms, less likely to seek help, and more likely to present with atypical symptoms — irritability, anger, fatigue, and loss of drive — rather than the sadness and tearfulness more commonly associated with depression in women.

One of the most important and most commonly missed contributors to depression in men is low testosterone — a condition that affects an estimated 2–4 million American men and becomes increasingly prevalent with age.

Testosterone is not just a sex hormone. It is a neuroactive steroid with profound effects on brain function, mood regulation, motivation, and cognitive performance. Testosterone receptors are distributed throughout the brain, including in regions central to mood regulation: the prefrontal cortex, amygdala, hippocampus, and hypothalamus.

The relationship between testosterone and depression is well-established:

• Men with low testosterone have significantly higher rates of depression than men with normal testosterone levels
• Testosterone levels are inversely correlated with depression severity — lower testosterone predicts worse depression outcomes
• Testosterone replacement therapy (TRT) produces significant improvements in depression scores in hypogonadal men, with effect sizes comparable to antidepressants
• Men with treatment-resistant depression have higher rates of low testosterone than men who respond to antidepressants
• Testosterone deficiency impairs the efficacy of antidepressants — treating the testosterone deficiency can restore antidepressant response

Key Reference: Shores MM, et al. (2004). Low serum testosterone and mortality in male veterans. Archives of Internal Medicine, 164(14), 1524–1529.

The classic symptoms of low testosterone — reduced libido, erectile dysfunction, and reduced muscle mass — are well-known. But the mood and cognitive symptoms are equally important and often more distressing:

Mood symptoms:

• Persistent low mood, sadness, or emptiness
• Irritability, anger, or short fuse (often more prominent than sadness)
• Loss of motivation and drive — the "I don't care" feeling
• Reduced confidence and assertiveness
• Anxiety and increased stress sensitivity
• Emotional flatness — reduced capacity for joy or enthusiasm

Cognitive symptoms:

• Brain fog — difficulty concentrating, mental slowness
• Memory problems
• Reduced mental sharpness and clarity

Physical symptoms:

• Fatigue and low energy (often the most prominent complaint)
• Reduced libido
• Erectile dysfunction
• Reduced muscle mass and strength
• Increased body fat, particularly abdominal fat
• Reduced bone density
• Hot flashes or night sweats (less common but occur)
• Reduced body and facial hair

The key clinical pattern: A man who describes feeling "not himself" — less motivated, less confident, less engaged with life, more irritable, more tired — often has low testosterone as a contributing factor, even if he doesn't connect these symptoms to a hormonal cause.

Testosterone levels decline naturally with age — approximately 1–2% per year after age 30. But several factors accelerate this decline:

• Obesity: Adipose tissue converts testosterone to estrogen via aromatase. Abdominal obesity is particularly associated with low testosterone.
• Chronic stress: Elevated cortisol suppresses testosterone production through HPA-HPG axis interactions.
• Sleep deprivation: Testosterone is produced primarily during sleep, particularly during slow-wave sleep. Chronic sleep deprivation — including from obstructive sleep apnea — significantly reduces testosterone.
• Sedentary lifestyle: Physical inactivity is associated with lower testosterone.
• Alcohol: Chronic alcohol consumption suppresses testosterone production.
• Medications: Opioids, glucocorticoids, and certain other medications suppress testosterone.
• Chronic illness: Diabetes, metabolic syndrome, and inflammatory conditions are associated with low testosterone.
• Testicular injury or illness: Direct damage to the testes reduces testosterone production.

Diagnosis requires blood testing. The standard evaluation includes:

Total testosterone: The primary screening test. Normal range is approximately 300–1000 ng/dL, though optimal levels for mood and function are typically in the upper half of this range (500–900 ng/dL). Testing should be done in the morning (7–10 AM) when testosterone is at its daily peak.

Free testosterone: The biologically active fraction not bound to sex hormone-binding globulin (SHBG). Free testosterone is often more clinically relevant than total testosterone, particularly in men with elevated SHBG.

SHBG (sex hormone-binding globulin): Elevated SHBG reduces free testosterone availability. Common in older men, men with hyperthyroidism, and men with liver disease.

LH and FSH: Luteinizing hormone and follicle-stimulating hormone help distinguish primary hypogonadism (testicular failure) from secondary hypogonadism (pituitary/hypothalamic dysfunction).

Estradiol: Elevated estradiol (from aromatization of testosterone) can cause symptoms similar to low testosterone and is important to assess before and during TRT.

Prolactin: Elevated prolactin suppresses testosterone and can indicate a pituitary adenoma.

Complete metabolic panel, CBC, thyroid panel: To assess for contributing conditions.

TRT is the primary treatment for symptomatic hypogonadism. Available formulations include:

Topical gels/creams: Applied daily to the skin. Convenient, produces stable levels, but carries risk of transfer to partners and children.

Injections (testosterone cypionate or enanthate): Administered weekly or biweekly. Cost-effective, highly effective, but produces peaks and troughs that some men find uncomfortable.

Pellets: Implanted subcutaneously every 3–6 months. Produces stable, consistent levels. Increasingly popular for its convenience.

Nasal gel (Natesto): Applied intranasally three times daily. Preserves fertility better than other formulations.

Oral testosterone (Jatenzo, Tlando): Newer oral formulations that bypass first-pass hepatic metabolism.

For men with borderline-low testosterone and identifiable contributing factors, addressing root causes can meaningfully improve testosterone levels:

• Weight loss (particularly reduction of abdominal fat)
• Resistance exercise (the most potent natural testosterone stimulator)
• Sleep optimization and treatment of sleep apnea
• Stress reduction
• Alcohol reduction
• Optimizing vitamin D and zinc status

For younger men who wish to preserve fertility, clomiphene citrate (an estrogen receptor modulator) stimulates the pituitary to increase LH production, which in turn stimulates testicular testosterone production. This approach preserves fertility while raising testosterone levels.

For men with low testosterone and depression, TRT often produces significant mood improvements — but the timeline and magnitude vary:

• Energy and motivation typically improve within 3–6 weeks
• Mood and emotional wellbeing improve over 3–6 months
• Libido typically improves within 3–6 weeks
• Cognitive function improves over 3–6 months
• Body composition changes (muscle gain, fat loss) occur over 6–12 months

For men with both low testosterone and depression, the combination of TRT and antidepressant therapy is often more effective than either alone. TRT can restore antidepressant response in men who have not responded to antidepressants alone.

TRT requires ongoing monitoring:

• Testosterone levels: Checked 4–6 weeks after initiation and periodically thereafter to ensure therapeutic range
• Hematocrit: TRT increases red blood cell production; elevated hematocrit increases clotting risk
• PSA (prostate-specific antigen): Monitored in men over 40 to screen for prostate cancer
• Estradiol: Monitored to detect excessive aromatization
• Lipid panel: TRT can affect lipid levels

TRT is contraindicated in men with active prostate cancer, breast cancer, or severe untreated sleep apnea.

Will TRT affect my fertility? Exogenous testosterone suppresses sperm production by reducing LH and FSH. Men who wish to preserve fertility should discuss alternatives (clomiphene, hCG) with their provider before starting TRT.

Is TRT safe long-term? When properly monitored, TRT is safe for most men. The cardiovascular risks of TRT have been extensively studied; current evidence suggests that TRT in hypogonadal men does not increase cardiovascular risk and may reduce it by improving metabolic parameters.

How do I know if my depression is testosterone-related? Key indicators: male, over 35, prominent fatigue and loss of motivation alongside mood symptoms, reduced libido, history of weight gain or metabolic syndrome, poor response to antidepressants. A simple morning testosterone test can answer the question.

1. Shores MM, et al. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2004;164(14):1524–1529.
2. Zarrouf FA, et al. Testosterone and depression: systematic review and meta-analysis. J Psychiatr Pract. 2009;15(4):289–305.
3. Bhasin S, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715–1744.

Medical Disclaimer: This content is for educational purposes only and does not constitute medical advice.

Kyle Roth, FNP-BC, APRN, MSN, MHA | Roth Family Medicine and Mental Health | Pocatello, Idaho | 208-904-4705 | www.rothfamilymed.com