Testosterone is the archetypal male hormone, or androgen, and is critical for men’s overall health.

Testosterone production in men occurs mainly in specialized cells in the testes called Leydig cells and is regulated by a signaling network known as the hypothalamic-pituitary-testicular axis: gonadotropin-releasing hormone (GnRH) from the brain’s hypothalamus triggers the pituitary gland to secrete luteinizing hormone (LH) into circulation; LH then stimulates Leydig cells to release testosterone. Because of a negative feedback loop, LH secretion increases when testosterone levels drop.¹ High LH levels in men with low testosterone levels indicate a testicular cause of hypogonadism, or primary hypogonadism. Secondary hypogonadism is due to abnormal signaling from the hypothalamus or pituitary gland and is marked by low testosterone without a rise in LH levels.¹

Normal levels of testosterone are necessary for proper male sexual development and function, and hypogonadism, or testosterone deficiency, is an important cause of sexual dysfunction and infertility.² Other symptoms of hypogonadism include low energy, depressed mood, decreased attention and memory, decreased muscle mass and strength, and increased body fat. Low testosterone levels have also been associated with a range of biomarkers of age-related diseases,³ as well as health problems such as anemia, osteoporosis, and increased risks of cardiovascular and metabolic diseases.^2,4 In addition, low testosterone levels in older men have been associated with lower quality of life and increased mortality.^5,6

The prevalence of low testosterone (hypogonadism) in men in the United States varies substantially depending on diagnostic criteria, age, and whether biochemical thresholds alone or symptomatic criteria are applied. The generally agreed-upon estimates are^7-13:

• Biochemical hypogonadism (low testosterone by laboratory threshold alone): 20–40% of adult men, increasing with age.
• Symptomatic androgen deficiency (low testosterone plus clinical symptoms): About 5.6% of men aged 30–79 years, rising to 18.4% in men age 70 and older.

Inflammaging—a term describing age-related changes in immune function resulting in increased chronic, low-grade inflammation throughout the body—appears to be a major contributing factor in late-onset hypogonadism.¹⁴ Type 2 diabetes also increases the risk of hypogonadism.²

Lifestyle strategies to address metabolic disturbances such as obesity and insulin resistance are important ways to improve testosterone status in older men. Healthy eating, exercise, and sleep habits are foundational components in hormone balance optimization. In addition, targeted evidence-based supplements may support the maintenance of balanced testosterone and other hormone levels.

Testosterone replacement therapy (TRT) is an option for some men with low testosterone levels. It has been shown to improve sexual function, bone density, body composition, and depressive symptoms in older men with low testosterone levels. This has led medical organizations, including the European Academy of Andrology and the Endocrine Society, to recommend TRT in men with chronically low testosterone levels plus related symptoms or conditions and without contraindications (untreated prostate cancer, severe uncontrolled heart failure, severe lower urinary tract symptoms, or high hematocrit).^6,15 Since these guidelines were published, even more compelling evidence has emerged showing the safety and potential benefits from TRT in older men with low testosterone levels.

Although much discussion on social media and on various websites about men’s health focuses on testosterone replacement therapy (TRT), it is important to understand that the ideal approach is individualized and encompasses far more than simply visiting a “T clinic” for a testosterone injection once a week. Before a man considers TRT, it is essential to ensure his background diet and lifestyle are conducive to optimal endogenous hormone production and rule out health conditions that would preclude TRT. For instance, a man who is chronically stressed, sleeps poorly, and has low testosterone should first focus on improving his sleep and mitigating the effects of stress before thinking about TRT.

Life Extension generally advocates for a phased and comprehensive approach to hormone optimization in men. Aging men who begin to experience symptoms consistent with declining testosterone should generally approach their journey back to peak performance as follows:

Phase 1: Rule Out Serious Medical Conditions

Partner with a qualified and knowledgeable healthcare provider to ensure there are no overt medical conditions contributing to symptoms. This is especially pertinent if symptoms have emerged rapidly and/or are associated with other unusual health concerns. For example, undiagnosed sleep apnea is a common, but underappreciated, potential contributor to low testosterone.^16-18

Phase 2: Optimize Lifestyle Factors

Optimize lifestyle factors that may be associated with low testosterone levels and contribute to symptoms. These include exercise habits,^19,20 weight management,^21,22 sleep quality and quantity,^23,24 stress management, social connections, and emotional and mental stimulation.

Note that evidence for the direct and specific associations between these lifestyle factors and testosterone levels has often not been robustly demonstrated in studies for factors other than weight loss (in overweight/obese men) and to a lesser degree sleep quality. Nevertheless, Life Extension suggests that many men would stand to benefit from optimizing all of these factors as symptoms arising from suboptimal status in these areas may resemble those of low testosterone levels.

Also, be aware that several medications can lower testosterone levels (see further discussion in the section of this Protocol titled “Factors That Affect Men’s Testosterone Levels”).

Phase 3: Optimize Nutrition and Leverage Targeted Supplementation

Meta-analyses and large-scale observational studies consistently demonstrate that specific dietary patterns are associated with lower testosterone levels in men. Low-fat diets show the strongest evidence, with a meta-analysis of intervention studies showing significant reductions in total testosterone, free testosterone, and dihydrotestosterone (DHT, a strong androgen and metabolite of testosterone), particularly pronounced in men following low-fat vegetarian diets (approx. 26% reduction).^25,26 Pro-inflammatory dietary patterns characterized by high intake of refined carbohydrates, processed meats, and fried foods are associated with higher odds of testosterone deficiency in U.S. population-based studies.^27,28 Conversely, adherence to high-quality dietary patterns, such as the Healthy Eating Index (HEI-2020) and diets rich in antioxidants, appear protective against testosterone decline.²⁹ Although these associations are statistically significant and biologically plausible, most evidence derives from cross-sectional analyses, and observed decreases are often clinically modest (mean differences of about 57 ng/dL), underscoring the need for large-scale randomized controlled trials to establish definitive causality. Nevertheless, focusing on minimally processed foods is a reasonable strategy for men concerned with hormonal health.

Targeted evidence-based supplementation is also a key aspect of this phase. For instance, studies show that pomegranate and cocoa bean extracts, Eurycoma longifolia (Tongkat ali), fenugreek, ashwagandha, vitamin D, zinc, and other nutrients can help support men’s hormonal health.

Supplementation with dehydroepiandrosterone (DHEA) may be appropriate at this stage as well. DHEA is a hormone but also serves as a precursor to androgens and estrogens. Its levels decline with age. Evidence from interventional human trials suggests DHEA's effect on testosterone in men is variable and dependent on age and context. In middle-aged men, 50 mg DHEA daily was found to increase free testosterone and prevent its decline following high-intensity exercise, though total testosterone was unchanged.³⁰ Conversely, in young men undergoing resistance training, 150 mg DHEA daily for eight weeks did not increase free or total testosterone levels.³¹ Similarly, a long-term, 2-year study in elderly men found that DHEA supplementation did not result in an increase in testosterone levels.³² A meta-analysis that included 31 trials with male subjects found that DHEA supplementation led to an increase of about 21 ng/dL on average.³³

Ample correlational evidence suggests low DHEA-Sulfate (DHEA-S) levels are associated with a variety of health concerns, and some clinical trials have indicated DHEA supplementation may improve some aspects of men’s health. Refer to the section of this Protocol entitled “DHEA & Men’s Health” for an overview of the evidence related to DHEA supplementation in men.

Phase 4: Testosterone Replacement Therapy

Testosterone replacement therapy (TRT) should only be considered after addressing phases one through three above. The approach to TRT itself is a phased process and can be nuanced. Note: the information in this section is generally based on current (as of early 2026) clinical guidelines on the management of low testosterone from the Endocrine Society and American Urological Association unless otherwise specified.^34-36

Phase 4a: The most important first step is to partner with a physician who has ample experience helping men optimize their hormones. This means that the physician takes the time to thoroughly assess symptoms and relevant lab tests and discusses the risks and benefits of TRT in the context of the patient’s health goals and priorities. Testosterone replacement therapy is not risk-free, and an individualized approach is critical. Inappropriate use of testosterone or related steroids can have long-term and possibly irreversible side effects. On the other hand, diligently administered TRT at physiologically appropriate levels is safe for most men and can provide substantial benefits.

Phase 4b: Lab testing. Assessing the levels of hormones and other factors via lab testing is essential in planning TRT. Total and free testosterone levels, luteinizing hormone (LH) as well as prostate-specific antigen (PSA) should be assessed. Other tests that may be performed initially include levels of follicle-stimulating hormone (FSH), prolactin, DHT, DHEA-S (a weak androgen and precursor for other steroid hormones), estradiol (E2, the most active estrogen), hemoglobin, hematocrit, albumin, and sex hormone-binding globulin (SHBG, a steroid hormone-carrying protein). In general, men whose total testosterone levels are around 300–400 ng/dL or lower and who have corresponding symptoms may be candidates for TRT or other hormone optimization therapies. Sometimes, a man whose testosterone levels are slightly above this range, but who has symptoms consistent with low testosterone, may benefit as well, but an experienced clinician will need to provide guidance to men in this situation.

Phase 4c: Initiating TRT. Once a thorough evaluation has been completed, therapeutic options can be discussed. In particular, patients concerned about fertility may want to try other hormonal approaches, such as human chorionic gonadotropin (hCG) or enclomiphene citrate, before resorting to TRT. The initiation of TRT should be undertaken with care and precision. The goal is to restore testosterone levels to a physiologically normal range while minimizing potential side effects and monitoring the body's response to treatment. Importantly, there is no universal “best” approach to TRT: what works best for one person may not work well for another.

4c.1: Choosing the Right Form of Testosterone. Testosterone can be administered in various forms, including intramuscular or subcutaneous injections, transdermal patches, gels, subcutaneous pellets, and oral formulations. Each form has its advantages and disadvantages:

• Intramuscular injections: Commonly administered every 3–14 days, intramuscular injections provide a reliable method for increasing testosterone levels—but may cause fluctuations in hormone levels since levels rise after the injection but start to fall before the next injection. Administering lower-dose injections twice a week, rather than higher doses every two weeks, may be preferable to maintain more consistent testosterone levels.
• Subcutaneous injections: Injections under the skin (subcutaneous) as opposed to into the muscle tissue may be a bit easier to self-administer and may therefore be preferred by some men.^38-42
• Transdermal patches and gels: Transdermal patches and gels offer steady hormone levels and are easy to apply. Skin irritation can be a drawback for sensitive individuals, though most men tolerate them well. Another drawback is potential hormone transfer to others (eg, children, spouse) through skin-to-skin contact. A formulation for underarm application is also available and can reduce unwanted transfer.
• Subcutaneous pellets: Inserted under the skin and replaced every three to six months, pellets provide long-term testosterone delivery but require minor surgical procedures. Also, once the pellet is inserted, it is impossible to adjust the dosage if needed.
• Oral formulations: Historically, oral formulations of testosterone were less commonly used due to potential liver toxicity. However, oral bioidentical testosterone (testosterone undecanoate, Jatenzo) was approved by the Food and Drug Administration (FDA) in 2019. Since then, a meta-analysis of clinical trials found oral testosterone was not linked to a higher risk of adverse side effects or serious adverse effects than placebo.⁴³ Some preliminary evidence suggests oral preparations may cause a bit less FSH suppression compared with long-acting injectables. However, LH suppression appears to be comparable. Moreover, oral preparations appear to lead to more FSH and LH suppression than nasal formulations. More research is needed to clarify the long-term effects of oral T preparations on the HPG axis and fertility.^44,45
• Nasal spray: Natesto is a testosterone gel for nasal use. Nasal testosterone has a short duration of action and appears to have the advantage of preserving fertility in men of reproductive age with low testosterone levels; however, its effectiveness in aging men has not been well studied.⁴⁶

The choice of delivery method should be made in consultation with an experienced physician, considering the patient's lifestyle, preferences, and any potential contraindications.

4c.2: Initial dosage and titration. Starting doses are typically conservative, aiming to avoid overly high levels of testosterone that could lead to side effects. For example, common starting doses might be:

• Intramuscular injections: 75–125 mg of testosterone enanthate or cypionate per week
• Transdermal gel or cream: 20–100 mg applied daily
• Subcutaneous pellets: 600–1,200 mg every three to six months

Following the initiation of therapy, follow-up testing is crucial to ensure testosterone levels are within the desired range. Dosage adjustments may be necessary based on these results and the patient's clinical response.

4c.3: Monitoring and managing side effects. Testosterone replacement therapy can have adverse side effects, but these mainly occur when levels are increased above normal values. Potential side effects include:

• Erythrocytosis: Increased number of red blood cells, which can increase the risk of clotting. Hematocrit levels should be checked regularly.
• Gynecomastia: Enlargement of breast tissue due to the conversion of excess testosterone to estrogen. Estradiol levels can be monitored to detect the potential for this effect. Notably, gynecomastia does not usually occur in men who restore their testosterone levels to physiologic levels (within the normal reference range of lab values) but may arise when levels exceed the normal range (supraphysiological levels).
• Prostate health: Regular PSA testing and digital rectal exams are recommended to monitor for signs of prostate issues.
• Lipid profiles: Lipid profiles should be monitored periodically as part of ongoing assessment of overall cardiovascular health. Interestingly, testosterone therapy may decrease high-density lipoprotein (HDL) levels but appears to enhance or not alter its protective cholesterol transport capacity. Thus, considered in conjunction with evidence showing TRT does not increase cardiovascular risk,⁴⁹ the impact of TRT on HDL levels is unlikely to be of significant concern for most men.^50-53

4c.4: Regular follow-up and adjustments. Men on TRT should have regular follow-up appointments with their healthcare provider to assess the efficacy of treatment and make any necessary adjustments (refer to the “Timing” subsection under “Lab testing” later in this Protocol for further details). Follow-up typically includes:

• Lab tests: To monitor levels of testosterone and other steroid hormones, hematocrit, PSA, and lipid profiles.
  • Life Extension generally suggests targeting the top one-third of the normal reference range for total testosterone. The specific numerical values corresponding with this range will vary from lab to lab due to variations in testing methods.
    • If your reference range is stratified by age, we suggest targeting the top one-third of the range for a man in his twenties.
• Symptom assessment: Symptoms and overall well-being should be monitored regularly for changes over time to ensure that TRT is having the desired effects.

Targeted nutrient supplements are reasonable, evidence-based additions to a comprehensive program designed to support sex hormone production and metabolism. Generally, these nutrients are supported by published clinical evidence showing that they beneficially affect testosterone levels or levels of other steroid hormones. Such nutrients are described below.

Note that we do not include here discussion of nutritional support for health concerns that often arise in the context of men’s hormonal health. Men should consult other relevant Life Extension Protocols for information regarding:

• Prostate enlargement (benign prostate hyperplasia, BPH)
• Hair loss
• Erectile dysfunction
• Acne
• Male infertility

Eurycoma longifolia (Tongkat ali)

Reported dosage: 100–400 mg daily

Eurycoma longifolia is an Asian shrub that has multiple common names including longjack and Tongkat ali. Eurycoma has a wide array of therapeutic uses, such as to enhance sexual function, fertility, muscle growth, and bone health in men.⁵⁴ In a clinical trial involving 76 men with late-onset hypogonadism, 200 mg of Eurycoma extract per day improved testosterone levels and scores on the Aging Males’ Symptoms scale: after one month, testosterone levels had normalized in 90.8% of participants and symptoms had normalized in 71.7%.⁵⁵ Another trial that included 25 male and female participants aged 57–72 years found 400 mg of Eurycoma extract daily for five weeks increased total and free testosterone levels as well as hand muscle strength in both men and women.⁵⁶

A meta-analysis of five randomized controlled trials found Eurycoma increased testosterone levels in healthy men and those with hypogonadism.⁵⁴ In a randomized placebo-controlled trial in 105 men aged 50–70 years with total testosterone levels below 300 ng/dL, those given 100 and 200 mg per day of Eurycomaextract had increased total testosterone levels and improved scores on the Aging Males’ Symptoms scale and Fatigue Severity Scale after 12 weeks compared with placebo. Average total testosterone levels increased from 187.3 to 203.8 ng/dL in the 100 mg group and from 200.5 to 225.0 ng/dL in the 200 mg group. In addition, Eurycoma-treated men had increased free testosterone and DHEA levels, decreased cortisol levels, and increased muscle strength, but these changes were not significantly different from those seen in the placebo group.⁵⁷ In another randomized placebo-controlled trial in 45 middle-aged men with testosterone deficiency, 200 mg of Eurycoma per day for six months increased total testosterone levels, improved erectile function, and enhanced muscle strength—and these effects were stronger in men who simultaneously engaged in strength and fitness training.⁵⁸ A controlled trial in 63 adults with moderate stress levels found four weeks of treatment with 200 mg of Eurycoma extract daily improved self-rated tension, anger, and confusion; reduced salivary levels of the stress hormone cortisol; and increased salivary testosterone.⁵⁹

Fenugreek

Reported dosage: 400–600 mg daily

Fenugreek (Trigonella foenum-graecum) seeds are rich in steroidal compounds and are used to treat metabolic problems including obesity and type 2 diabetes.⁶⁰ Most, though not all, clinical trials have shown fenugreek can increase testosterone levels a small amount and have positive effects on body composition and athletic performance.^60-62

In a randomized placebo-controlled trial in 120 men between 43 and 70 years of age with symptoms of testosterone deficiency, 600 mg of fenugreek seed extract per day for 12 weeks increased testosterone levels, improved sexual function, and relieved other symptoms of hypogonadism.⁶³ Another placebo-controlled trial involving 88 men over 40 years of age with symptoms of low testosterone found 200 mg of fenugreek twice daily for eight weeks improved scores on the Aging Males’ Symptoms scale and increased total testosterone (from 430 to 490 ng/dL) and free testosterone levels (7.7 to 8.8 pg/mL), whereas these levels dropped with placebo. In addition, fenugreek improved cholesterol and triglyceride levels, erectile function, and perceived stress.⁶⁴ A randomized controlled trial in 60 healthy young men found treatment with fenugreek extract at 300 mg twice daily raised free testosterone levels but had only a small and statistically non-significant effect on total testosterone levels after eight weeks compared with placebo.⁶⁵

An uncontrolled trial that included 100 men aged 35 to 60 years found 500 mg of fenugreek extract per day for 12 weeks increased free and total testosterone levels, and improved mood, mental alertness, cardiovascular risk, libido, and sexual function. A similar trial involving 50 male volunteers aged 35 to 65 years found 500 mg of fenugreek extract per day for 12 weeks increased free testosterone levels from 8.17 to 11.97 pg/mL; although total testosterone levels also rose (from 405 to 436 ng/dL), this change was not statistically significant. Improvements were also noted in mental alertness and mood, cardiovascular health, and libido.⁶⁶

Ashwagandha

Reported dosage: Standardized extract, 60–600 mg daily

Ashwagandha is an herb that helps the body adapt to stress and as such is described as an adaptogen. Emerging research suggests ashwagandha may also increase testosterone levels in men.⁶² This may be related to ashwagandha’s ability to reduce levels of the stress hormone cortisol, since elevated cortisol levels tend to correlate with lower testosterone concentrations.^67,68

A randomized, placebo-controlled, crossover trial enrolled 50 overweight or obese men aged 40 to 70 years who reported mild-to-moderate fatigue or reduced vitality. They received 60 mg per day of a standardized ashwagandha extract with 35% withanolides (Shoden) and placebo, each for eight weeks, in random order. Compared with placebo, salivary testosterone levels increased 14.7% and salivary DHEA-S levels increased 18% during treatment with ashwagandha.⁶⁹ A randomized controlled trial in 60 healthy adults examined the effect of supplementing with 240 mg per day of the same ashwagandha extract for 60 days: ashwagandha reduced cortisol and DHEA-S levels in both men and women but did not significantly alter testosterone levels compared with placebo.⁷⁰

Ashwagandha may also improve muscular and sexual function. In an eight-week, randomized, controlled trial, 57 male subjects aged 18 to 50 years engaged in regular resistance training and received 300 mg of another standardized ashwagandha extract with 5% withanolides (KSM-66) or placebo twice daily. Ashwagandha increased strength (assessed by bench press performance), body fat loss, and arm and chest muscle size compared with placebo. It also reduced exercise-induced muscle damage more than placebo. In addition, testosterone levels increased more in the ashwagandha group than the placebo group (96.2 vs. 18.0 ng/dL).⁷¹ In an eight-week, randomized, controlled trial including 50 adult men with low libido, 300 mg of the same ashwagandha extract twice daily improved sexual function and increased testosterone levels compared with placebo.⁷²

Pomegranate & Cocoa Bean Extracts

Reported Dosage: 200–400 mg daily

Pomegranate (Punica granatum) is a fruit with high concentrations of free radical-scavenging polyphenols. Ellagitannins are the most abundant pomegranate polyphenols and may contribute to pomegranate’s anti-inflammatory, oxidative stress-reducing, antidiabetic, and cardioprotective effects.⁷³ Preclinical studies indicate the ellagitannin metabolite, urolithin B, is a strong inhibitor of aromatase, and may thereby inhibit the conversion of testosterone into estrogen.^74,75 A pilot observational study in 60 volunteers (22 males and 38 females) indicated pomegranate juice, at 500 mL per day for two weeks, may increase salivary testosterone levels in men and women.⁷⁶

Cocoa beans from the cacao tree (Theobroma cacao) are also rich in antioxidant polyphenols. Preclinical studies have indicated polyphenols from cocoa beans can increase the production of testosterone and nitric oxide.^77,78 Nitric oxide may promote healthy testosterone production by supporting the hypothalamic-pituitary-testicular axis and increasing secretion of LH.⁷⁹

Several clinical trials have indicated a proprietary combination of pomegranate rind and cacao seed extracts called Tesnor may increase testosterone levels in men. In a randomized, double-blind, placebo-controlled trial involving 120 healthy young men aged 21 to 35, 400 mg of Tesnor increased free and total testosterone levels, as well as LH levels, whereas 200 mg of the supplement per day increased only free testosterone levels, after 56 days.⁸⁰ A similar trial in 120 men aged 36 to 55 years found, after 56 days, both doses increased free and total testosterone levels, improved scores on an the Aging Males' Symptoms scale, and increased general, psychological, and sexual well-being compared with placebo.⁸¹

A randomized, double-blind, placebo-controlled study evaluated the effects of Tesnor on sexual function in aging males aged 40 to 70 years with mild-to-moderate erectile dysfunction and low libido and whose total testosterone levels were at least 300 ng/dL.⁸² The study found 400 mg of the supplement daily for 84 days significantly improved self-reported sexual function and erection hardness scores compared with placebo. The supplement group also experienced improvements in hand-grip strength, six-minute walk distance, sleep quality, and fatigue. However, testosterone levels were not measured at the end of the trial.⁸²

Zinc

Reported dosage: 30–50 mg daily

Zinc is involved in almost every aspect of male reproductive function, including testosterone metabolism.⁸³ It acts as an antioxidant and protects the testes from various toxins; and deficiency has been correlated with low testosterone levels in observational research.^84-86

In an uncontrolled clinical trial in nine elderly men with marginal zinc deficiency, 30 mg of elemental zinc (as zinc gluconate) daily increased average total testosterone levels from 239 to 410 ng/dL after three months and 461 ng/dL after six months.⁸⁷ Another uncontrolled trial by the same research group found 15 mg of zinc (as zinc acetate) three times daily for one year increased testosterone levels in men with hypogonadism related to sickle cell anemia.⁸⁸ In an uncontrolled trial in 100 hemodialysis patients, 58 mg of zinc (as zinc sulfate) daily for six weeks increased testosterone levels from 447 to 848 ng/dL, but also increased LH levels.⁸⁹

A placebo-controlled trial included 20 hypogonadal men who were on hemodialysis for kidney failure and had low-normal zinc levels; average testosterone levels increased from a baseline of 280 to 520 ng/dL in those given 50 mg of elemental zinc (as zinc acetate) per day for six months, but not in those given placebo. Furthermore, zinc suppressed LH levels and improved sexual function.⁹⁰ However, studies in healthy young men and young men with infertility but without known zinc deficiency have found zinc supplementation did not increase testosterone levels.^91,92

Shilajit

Reported dosage: 200–500 mg daily

Shilajit, a complex natural material found mainly in the rocks of the Himalayas, is thought to be made by the slow decomposition of plants. It contains a somewhat variable array of nutrients including minerals, amino acids and proteins, fatty acids, and flavonoids that has never been fully described and has been used as a food and medicine in India and Nepal for centuries.⁹³ In one uncontrolled trial, 28 men with infertility were treated with 100 mg of shilajit twice daily for 90 days; at the end of the trial, testosterone levels increased by 23.5%.⁹⁴ A randomized placebo-controlled trial by the same researchers involving 75 men aged 45 to 55 years found 250 mg of shilajit twice daily for 90 days increased levels of total testosterone (484 to 583 ng/dL), free testosterone (15.36 to 18.30 pg/mL), and DHEA-S (145.09 to 190.57 mcg/dL), whereas these levels decreased or were unchanged with placebo.⁹⁵

Vitamin D

Reported dosage: 1,500–3,332 IU (38–83 mcg) daily

Vitamin D is needed for reproductive health, and some studies have reported a link between vitamin D deficiency and hypogonadism in men.^96-98 A meta-analysis of 18 studies with a combined total of 9,892 participants found low vitamin D levels were associated with a small but statistically significant decrease in total testosterone levels, and the relationship was strongest in men with frailty.⁹⁹

Findings from clinical trials investigating the effects of vitamin D supplementation on testosterone levels have been mixed and inconclusive.^98,100,101 In an uncontrolled trial in 102 middle-aged men with vitamin D deficiency, treatment with 600,000 IU (15,000 mcg) of oral vitamin D every one to two months (depending on vitamin D levels achieved) for 12 months resulted in an increase in the average total testosterone level from 359 to 461 ng/dL; in addition, participants had improved erectile function and decreased estradiol levels, hemoglobin A1c (HbA1c, a marker of long-term blood glucose control), and body-mass index (BMI, a measure used to screen for overweight and obesity) at the end of the trial.¹⁰² A placebo-controlled trial that included 54 overweight men with vitamin D deficiency participating in a weight loss program found 3,332 IU (83.3 mcg) of vitamin D daily for one year increased total testosterone (from 10.7 to 13.4 nmol/L [309 to 386 ng/dL]), bioavailable testosterone (from 5.21 to 6.25 nmol/L [150 to 180 ng/dL]), and free testosterone levels (from 0.222 to 0.267 nmol/L [6.4 to 7.7 ng/dL]), whereas placebo led to no significant changes in testosterone levels.¹⁰³

Vitamin D might have a role in a comprehensive approach to hypogonadism in older men. A randomized placebo-controlled trial in 148 men aged 70 years and older with low testosterone levels compared TRT plus a strength-training exercise and supplement program with TRT alone, exercise and supplements alone, and neither. TRT consisted of testosterone undecanoate injections (1,000 mg) at 0, 4, and 16 weeks; the supplements were 1,520 IU (83.3 mcg) vitamin D, 800 mg calcium, and 34 grams of protein (via a food bar and a drink). After 20 weeks, the TRT plus exercise and supplements group had greater improvements in tests of muscle strength and endurance, quality of life, tiredness, leg fat, and heart rate variability (a marker of cardiac resilience), whereas in the TRT alone group, only leg, hip, and buttock fat improved.¹⁰⁴

More research is needed to better understand the potential role of vitamin D therapy in late-onset hypogonadism.

Maca

Reported dosage: 1,500–5,000 mg daily

Maca (Lepidium meyenii) is a plant that grows at high altitudes in Peru and has a history of use as an aphrodisiac and fertility aid. In a randomized placebo-controlled trial in 80 older men with normal hormone levels but symptoms of hypogonadism, 1,666 mg of maca powder three times daily for 12 weeks improved subjective measures of symptoms of male aging, androgen deficiency, prostate symptoms, and sexual function without changing total or free testosterone levels.¹⁰⁵ Other clinical trials have also shown 1,500–3,000 mg of maca per day did not increase testosterone or estradiol levels in healthy men.^106-108 In fact, one placebo-controlled clinical trial found maca lowered levels of free testosterone in male subjects with infertility,¹⁰⁹ and a small observational study involving 50 men living in the Peruvian highlands found maca users had lower testosterone-to-estradiol ratios than non-users.¹¹⁰

Trimethylglycine

Reported dosage: 2,500–5,000 mg daily

Trimethylglycine (TMG), also known as betaine, is a compound that acts as a methyl donor in a number of biological methylation reactions, including metabolism of homocysteine—an amino acid linked to cardiovascular and neurological diseases—into methionine.¹¹¹

In a randomized, controlled, crossover trial, 43 healthy male athletes, aged 18 to 45 years, received 2.5 or 5 grams per day of TMG and placebo, each for three weeks, in random order. Trimethylglycine, at either dose, increased average total testosterone levels from 477 to 506 ng/dL, whereas placebo had no significant effect on testosterone levels.¹¹² Other clinical trials have shown 2–2.5 grams per day of TMG may increase testosterone levels and/or improve physical performance in young athletes under 18 years old.^113-115 Whether or not TMG can benefit older men with declining testosterone levels is unknown at this time.

Dehydroepiandrosterone (DHEA) is an androgen produced mainly in the adrenal cortex, with smaller amounts produced in the testes, ovaries (in women), and brain.¹³⁰ It serves as a precursor to synthesize other androgens (androstenedione, testosterone, and dihydrotestosterone [DHT]) and estrogens (estradiol and estrone) in the adrenal glands and other tissues. It also exerts direct effects on cellular function through its interactions with androgen receptors.¹³¹

Most of the DHEA in circulation is in its more stable sulfated form, DHEA-S, which is quickly converted back to DHEA in the tissues. Levels of DHEA and DHEA-S decline with aging such that, by the age of 80 years, they have fallen by 80– 90% relative to peak values.¹³¹ Although “optimal" levels of DHEA-S throughout the lifespan have not been clearly established, Life Extension recommends most aging men strive to maintain DHEA-S levels of 350–500 mcg/dL. This range corresponds with levels seen in healthy young adults, as well as with levels noted in clinical trials showing benefits from DHEA therapy.^132-135 In general, the reported dosage used in the clinical studies described through this discussion range from 25–450 mg daily.

DHEA & Testosterone Levels

A meta-analysis of 42 randomized controlled trials found that DHEA administration slightly increased testosterone levels in men (by about 21 ng/dL), though the effect was smaller in older men. In addition, the effect of DHEA on testosterone status was more pronounced when doses higher than 50 mg per day were used and treatment lasted longer than 12 weeks.³³ Another meta-analysis that included 25 randomized controlled trials with a total of 1,353 older male participants found DHEA supplementation increased blood levels of testosterone and estradiol.¹³⁶ In an uncontrolled trial in aging men with clinical symptoms consistent with low testosterone levels, 25 mg of DHEA daily for one year increased blood levels of total and free testosterone, other androgens (DHEA, DHEA-S, androstenedione, and DHT), estradiol, and a variety of other hormones.¹³⁷

A pooled analysis of findings from four clinical trials found estradiol levels increased by an average of 4.8 pg/mL in men who received 50 or 75 mg of DHEA per day for 12 months compared with placebo.¹³⁸ Normal estradiol levels in men are roughly 10–50 pg/mL, though exact reference ranges vary between labs; for instance, LabCorp’s reference range for estradiol in adult men is 8–35 pg/mL and Quest’s is 29 pg/mL or less using the more-sensitive LC/MS methodology.^139-141

DHEA & Associations with Health Concerns

DHEA status has been associated with various health conditions in aging men and supplementation may have benefits that extend beyond its ability to increase testosterone levels. Below are the main health conditions for which DHEA may have positive effects in men.

Cardiovascular Health

In a systematic review of 25 observational studies, 18 of which were included in a meta-analysis, lower DHEA-S levels were correlated with increased risk of adverse cardiovascular outcomes, as well as death for any reason, in both men and women with cardiovascular disease.¹⁴² A study involving 313 men aged 50 to 75 years found higher DHEA-S levels were associated with lower risk of high blood pressure (averaging 152 mcg/dL in those without hypertension vs. 126 mcg/dL in those with hypertension), although they were also linked to higher levels of total and low-density lipoprotein cholesterol (LDL-C).¹⁴³ Another study found DHEA-S levels were lower in 49 Japanese men with heart failure compared with 32 control subjects, averaging 79.0 mcg/dL in heart failure patients and 131.8 mcg/dL in those without heart failure; moreover, in those with heart failure, decreasing DHEA-S levels were correlated with increasing heart failure severity.¹⁴⁴ Observational studies also suggest higher DHEA-S levels may protect against atrial fibrillation.¹⁴⁵ One study that followed 1,180 participants, including 547 men, for an average of 12.3 years found men with the highest DHEA-S levels (175–850 mcg/dL) were 58% less likely to develop atrial fibrillation than those with the lowest levels (0.4–64 mcg/dL).¹⁴⁶

Clinical trials assessing the effects of DHEA supplementation on cardiovascular health are sparse. In a randomized placebo-controlled trial in 42 men and 50 women aged 65 to 75 years, 50 mg of DHEA per day for 12 months improved a measure of arterial stiffness. In the treated group, average DHEA-S levels increased from 59 to 333 mcg/dL, but average levels in the placebo group dropped non-significantly from 56 to 46 mcg/dL.¹³² A randomized placebo-controlled trial in 24 men with high cholesterol levels found 25 mg of DHEA daily for 12 weeks improved blood vessel function, lowered blood glucose levels, and reduced levels of a marker of thrombosis (blood clot) risk. In this trial, the average DHEA-S level rose more than four-fold (from 117.4 to 488.7 mcg/dL) in the DHEA group, but was stable (from 111.3 to 115.8 mcg/dL) in the placebo group.¹⁴⁷ In a placebo-controlled crossover trial in men with coronary artery disease, 150 mg of DHEA per day for 40 days increased DHEA-S by 4.5-fold, increased estrogen (but not testosterone) levels, and lowered fibrinogen levels, but did not affect other measures of thrombosis risk.¹⁴⁸ On the other hand, a meta-analysis of randomized controlled trials found DHEA supplementation had no effect on triglyceride, total cholesterol, LDL-cholesterol, or HDL-cholesterol levels in men.¹⁴⁹

Metabolic Health

A large study that used data from 5,189 middle-aged and older adults (2,171 men and 3,018 women) collected over a median of 10.9 years indicated lower DHEA-S and DHEA levels were associated with an increased risk of developing type 2 diabetes in both men and women; after adjusting for cardiometabolic risk factors, the relationship between diabetes risk and levels of DHEA, but not DHEA-S, persisted.¹⁵⁰ Other observational studies have reported declining DHEA-S levels were associated with increased risk of type 2 diabetes in men.^151,152 In a study that included 1,021 men with type 2 diabetes, higher DHEA levels were correlated with improved lipid profiles.¹⁵³ In a study that examined hormone levels in 304 young and middle-aged men, lower DHEA, but not DHEA-S, levels were associated with obesity and metabolic syndrome.¹⁵⁴ Another study in 85 men aged 60 to 70 years found lower DHEA-S levels were associated with obesity and insulin resistance.¹⁵⁵ On the other hand, a study in 314 men aged 65 years and older found higher DHEA-S levels were unrelated to body-mass index (BMI).¹⁵⁶

A meta-analysis of findings from 14 randomized controlled trials found treatment with DHEA, in doses up to 50 mg daily for less than 12 weeks, reduced blood glucose levels in participants aged 60 years and older but had no significant effect on insulin levels or measures of insulin resistance.¹⁵⁷ In a randomized controlled trial in 125 subjects (57 men and 68 women) aged 65 to 75 years, 50 mg of DHEA per day for one year resulted in improved glucose control in a subgroup of 77 participants whose glucose tolerance was impaired at the beginning of the trial. In addition, levels of triglycerides and inflammatory cytokines decreased in the DHEA group. DHEA-S levels increased in treated men from 68 to 371 mcg/dL.¹³³ In a randomized placebo-controlled trial with 56 elderly participants (28 men and 28 women), 50 mg of DHEA per day for six months decreased insulin levels and improved insulin sensitivity.¹⁵⁸

In a crossover trial in 30 men between 41 and 60 years of age with DHEA-S levels below 200 mcg/dL, 40 days of treatment with 150 mg of DHEA per day resulted in a 4.5-fold increase in DHEA-S levels and improved a range of cardiometabolic markers compared with placebo.¹⁵⁹ On the other hand, a secondary analysis using data from a placebo-controlled trial that included 61 elderly men with DHEA levels averaging around 63 mcg/dL found 50 mg of DHEA per day for one year did not affect measures of glucose control, despite an approximately five-fold increase in DHEA-S levels.¹⁶⁰

Non-alcoholic fatty liver disease (NAFLD), now generally referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is a chronic condition that is closely linked to metabolic disturbance and cardiovascular disease. Observational studies involving NAFLD patients have found patients with advanced disease marked by severe fibrosis had substantially lower average DHEA-S levels compared with patients with simple fatty liver. The relationship between low DHEA status and advanced NAFLD was seen in both women and men.^161,162 On the other hand, an observational study with 158 Japanese men found DHEA-S levels were higher in those with NAFLD than those without the condition. In addition, among men with NAFLD, levels were higher in those with high alanine aminotransferase (ALT) levels, a marker of liver inflammation. The severity of liver disease in participants in this study was not evaluated with biopsies, as it was in other studies. The study authors suggested the observed increase in DHEA-S levels may have reflected a compensatory mechanism by the adrenal glands to protect against liver damage. They also proposed lower levels seen in studies that identified individuals with more severe liver disease may have been related to a reduced ability of the liver to sulfate DHEA.¹⁶³ More research into the potential association of DHEA-S levels with NAFLD is warranted.

Cognitive Health

Observational studies indicate higher DHEA status is associated with cognitive health. A systematic review of 25 studies found correlations between higher DHEA-S levels and better overall cognitive function in both men and women.¹⁶⁴ Furthermore, a meta-analysis of 31 studies found Alzheimer disease patients had lower DHEA-S levels than individuals without Alzheimer disease.¹⁶⁵

One large observational study involving 5,061 adults over the age of 50 years found higher DHEA-S levels were correlated with better overall cognitive function in men, but were not related to rate of cognitive decline during six years of monitoring.¹⁶⁶ Another study that followed 410 men and 345 women, aged 65 years and older, for three years found those with the lowest baseline DHEA-S levels (< 45.3 mcg/dL) had faster decline in cognitive function than those with the highest levels (>146.2 mcg/dL), and the relationship was stronger in men than women.¹⁶⁷ In a study that included 56 men and 64 women aged 51 years and older, male participants with higher DHEA-S levels performed better on tests of executive function and memory.¹⁶⁸ In a test that used genetic markers to assess hormone levels, higher DHEA-S and other androgen levels correlated with a lower risk of Alzheimer disease in men, though not in women.¹⁶⁹ On the other hand, several observational studies have not found a link between DHEA status and cognitive function or decline in men.^170-172

So far, clinical evidence suggests DHEA supplementation does not improve cognitive function in men. A review of six randomized controlled trials in healthy older participants found no benefit from DHEA supplementation, at doses of 50 mg per day for two weeks to 12 months, on cognitive function in either men or women.¹⁷³ In addition, a randomized placebo-controlled trial in 58 male and female Alzheimer disease patients found 50 mg of DHEA twice daily for six months did not improve cognition or reduce disease severity.¹⁷⁴

Stress, Mood, & Mental Health

DHEA and DHEA-S appear to be involved in emotional processing and behavior. Some evidence suggests higher DHEA and DHEA-S levels suppress brain signals during exposure to negative stimuli, representing a possible protective mechanism against negative responses including depression.¹⁷⁵

In a meta-analysis of findings from 10 observational studies, individuals with depression were found to have lower DHEA-S levels.¹⁷⁶ One study that included 38 men and 79 women found, in those with severe depression, DHEA-S levels were significantly lower than in those with very mild, mild, or moderate depression (76 mcg/dL vs. 101–120 mcg/dL).¹⁷⁷ Another study that followed 1,418 older men and 1,665 older women for four years found lower DHEA-S levels were associated with more baseline depressive symptoms and a higher likelihood of developing depression in both men and women.¹⁷⁸ Other small studies have indicated lower DHEA status may be associated with lower likelihood of a positive response to medication and higher risk of recurrent episodes in patients with depression.^179,180

DHEA supplementation may be helpful for treating depression. A systematic review and meta-analysis of findings from 15 randomized controlled trials with a combined total of 853 male and female participants found DHEA therapy had beneficial effects on depressive symptoms compared with placebo, although a firm conclusion could not be drawn due to the low quality of the evidence.¹⁸¹ In a placebo-controlled crossover trial, 46 participants including 23 men with mid-life-onset depression received DHEA and placebo for six weeks each in random order. The daily dose of DHEA was 90 mg for three weeks and 450 mg for three weeks. DHEA therapy increased average DHEA-S levels from 162.7 to 864.8 mcg/dL in men and was more effective than placebo at improving depression and sexual function scores in both sexes.¹⁸² Smaller placebo-controlled trials involving both male and female depression patients have also found DHEA therapy decreased depression.^183,184 In a trial involving 133 human immunodeficiency virus (HIV)-positive patients (110 men and 23 women) with persistent depressive symptoms, DHEA therapy, at doses ranging from 100 to 400 mg per day for eight weeks, reduced depressive symptoms in both male and female participants; in fact, almost twice as many participants improved with DHEA therapy than with placebo.¹⁸⁵

Some men without depression benefit psychologically from DHEA therapy. In a placebo-controlled crossover trial that included 13 men and 17 women aged 40 to 70 years, 50 mg of DHEA per day for six months led to a dramatic increase in perception of physical and psychological well-being.¹⁸⁶ A randomized placebo-controlled trial in men with heroin addiction found 34 of 49 participants (69%) in the group receiving 100 mg of DHEA per day for one year had significant improvement in withdrawal symptoms, as well as depression and anxiety scores.¹⁸⁷ In a placebo-controlled trial in 26 women and 18 men with hypopituitarism receiving growth hormone replacement therapy, six months of treatment with 50 mg per day of DHEA increased male participants’ DHEA-S levels from 7.0 to 205.2 mcg/dL and improved their self-esteem and depression symptoms.¹⁸⁸ On the other hand, in a placebo-controlled trial in 225 healthy older subjects (110 men and 115 women), DHEA therapy, at 50 mg daily for one year, had no effect on well-being, sexual function, or cognitive function in either men or women, despite increasing DHEA-S levels two- to four-fold.¹⁸⁹

Muscular Health

DHEA can be converted to testosterone in skeletal muscles, potentially increasing muscle growth and strength.¹⁹⁰ Decreasing levels of DHEA and DHEA-S may be a contributing factor in sarcopenia (age-related muscle wasting), as well as frailty (muscle weakness, slowness, weight loss, exhaustion, and low physical activity).^191,192

In a study that involved 1,214 participants (690 women and 524 men) aged 35 to 86 years, those whose DHEA-S levels were lower than expected for their age were more likely to have conditions that lead to frailty, including chronic illness, persistent pain and pain sensitivity, and reduced muscle strength and physical function.¹⁹³ In a study that included 1,886 community-dwelling individuals between 60 and 91 years old, those with the lowest DHEA-S levels within their gender group had a 50% higher chance of being frail than those with the highest levels.¹⁹² A study involving 591 elderly men and 307 elderly women living in community or assisted living facilities found higher DHEA-S levels were correlated with lower likelihood of frailty in both male and female participants, and the correlation was stronger in those with low BMI.¹⁹⁴ Another study that followed 416 men, aged 65 years and older, for four years found lower baseline DHEA-S levels were associated with increased risk of developing frailty.¹⁹⁵ However, one study in 1,839 older subjects (874 men and 965 women) found lower DHEA-S levels were not associated with frailty risk.¹⁹⁶

The effect of DHEA supplementation on muscle health in men remains uncertain. A systematic review of eight randomized controlled trials with a total of 661 elderly participants found DHEA therapy may have improved some aspects of muscle strength but did not consistently improve physical function.¹⁹⁷ Conversely, in a placebo-controlled trial that included 87 elderly men with low DHEA-S levels, 75 mg per day of DHEA, with or without a low-dose testosterone patch, did not enhance physical fitness, muscle strength, or physical performance after two years, despite raising average DHEA-S levels from below 100 mcg/dL to greater than 300 mcg/dL.¹⁹⁸

Body Weight & Composition

Higher DHEA-S levels have been associated with lower percentage of body fat in elderly men.¹⁹⁹ Some clinical evidence has indicated DHEA supplementation may improve body composition in aging men. A controlled trial in 16 men and 20 women, aged 72 to 75 years, with low DHEA-S levels found 50 mg of DHEA daily for six months resulted in decreased fat mass and increased lean body mass.²⁰⁰ The same research group conducted a randomized placebo-controlled trial in 56 elderly participants (28 women and 28 men) with age-related declines in DHEA-S levels. After six months of treatment with 50 mg of DHEA per day, DHEA-S levels in men increased from 74.6 to 357.8 mcg/dL, and abdominal and subcutaneous fat were reduced.¹⁵⁸ Although no differences in thigh muscle strength and volume were seen at six months, adding a weightlifting intervention to treatment or placebo during a four-month follow-up trial resulted in greater increases in muscle strength and volume in the DHEA group than the placebo group, suggesting DHEA may enhance the muscular response to weight training.²⁰¹ A placebo-controlled crossover trial with 19 participants, aged 50 to 65 years, found 100 mg of DHEA per day for six months restored youthful DHEA-S levels in all participants and decreased fat mass in men, but not women.²⁰²

Not all trials have shown DHEA therapy can improve body composition in older men. For example, a secondary analysis of findings from a randomized placebo-controlled trial in which 119 elderly individuals (58 women and 61 men) with DHEA-S levels averaging around 48–63 mcg/dL found treatment with 50 mg of DHEA per day for one year raised DHEA-S levels to 324–420 mcg/dL, but did not lead to changes in body composition or affect abdominal fat mass in either men or women.^160,203 In a randomized placebo-controlled trial that included 225 healthy 55- to 85-year-old adults (115 women and 110 men), 50 mg of DHEA per day for one year increased DHEA-S levels two- to four-fold, bringing them to normal young-adult levels, but did not alter body composition in either sex.²⁰⁴ In addition, in a placebo-controlled crossover trial in 22 men between 50 and 69 years of age with DHEA-S levels below 150 mcg/dL, 50 mg of DHEA per day for four months did not improve body composition.²⁰⁵

Sexual Health

Lower DHEA-S levels in men have been correlated with erectile dysfunction in some,^206-208 but not all,^209,210 observational studies. In an uncontrolled clinical trial in men with erectile dysfunction, 50 mg of DHEA per day for six months improved erectile function in 27 men with high blood pressure and 28 men with no known underlying condition, but not in 24 men with type 2 diabetes or six men with neurological disorders.²¹¹ This same dose of DHEA was also more effective than placebo for improving erectile function without increasing testosterone levels in a six-month controlled trial that included 40 men with erectile dysfunction of unknown origin.²¹² However, in a placebo-controlled trial in 79 men with sexual dysfunction and low DHEA-S (< 129 mcg/dL) and/or testosterone levels, 50 mg of DHEA twice daily for 16 weeks did not improve sexual interest or erectile function.²¹³

Bone & Joint Health

A large study examined DHEA-S levels in 2,568 men between 69 and 81 years of age and found those with levels below the median of 60 mcg/dL were 22% more likely to experience any fracture and 33% more likely to experience a major osteoporotic fracture compared with those whose levels were higher than 60 mcg/dL.²¹⁴ In a study of 1,089 Korean men, those with the lowest DHEA-S levels were 2.59 times more likely to have low bone mineral density than those with the highest levels.²¹⁵ Another study that included 154 Korean men and women found declining DHEA-S levels were correlated with decreasing bone density in the hip (but not the spine), regardless of gender, over four years.²¹⁶ Despite this evidence suggesting a relationship between lower DHEA status and poor bone health, multiple clinical trials have found DHEA supplementation does not increase bone density in men.^138,217

Low DHEA status has been correlated with joint disorders in men. In an observational study of 2,050 individuals over 65 years old, lower DHEA-S levels were associated with osteoarthritis of the hand, hip, and knee in both men and women.²¹⁸ However, in a study that followed 2,494 men for 10.7 years, DHEA-S levels, which averaged 114–125 mcg/dL, were not correlated with the need for knee or hip replacement surgery.²¹⁹ Other data suggests DHEA-S levels may also be lower in patients with rheumatoid arthritis and polymyalgia rheumatica.^220,221

Mortality

Higher DHEA status has been linked to lower mortality in men in multiple observational studies. A meta-analysis that pooled data from six studies with a total of 6,744 elderly participants found a 49% increase in cardiovascular disease-related mortality in those with lower, compared with higher, DHEA-S levels. When the findings were analyzed by gender, lower DHEA-S levels were associated with a 67% increase in cardiovascular mortality and 41% increase in all-cause mortality in men, but was not linked to mortality in women.²²² A meta-analysis of 18 observational studies in subjects with known cardiovascular disease found lower DHEA-S levels were correlated with increased risk of cardiovascular and all-cause mortality in both men and women.¹⁴²

In a study that included data from 940 adults who were followed for 27 years, higher DHEA-S levels (≥ 200 vs. ≤ 129 mcg/dL) were the strongest predictor of longevity in men, but were unrelated to longevity in women.²²³ Another study that followed 2,644 men in their seventies for 4.5 years found the overall death rate was 54% higher and cardiovascular death rate was 61% higher in men whose DHEA-S levels were 98 mcg/dL or lower, versus those with levels greater than 98 mcg/dL.²²⁴ A study that monitored 4,255 male veterans of the Vietnam war for 15 years found higher DHEA-S levels and lower cortisol-to-DHEA-S ratios were associated with lower all-cause mortality.²²⁵ Interestingly, a study in 950 individuals aged 65 years and older found a steep rate of decline or extreme variability in DHEA-S levels were each associated with increased mortality risk in men, but low baseline levels were not associated with mortality in either sex, during up to 17 years of monitoring. The combination of steep decline plus extreme variability was even more predictive of mortality: the risk of death was 14.1% in those with both patterns and 4.8% in those with neither.²²⁶

When used appropriately in men who are good candidates, testosterone replacement therapy (TRT) can offer substantial benefits and quality of life enhancements. Whereas many older men are good candidates for TRT, there are a few situations that warrant some caution. In general, the following factors should be considered to determine whether TRT is appropriate for an individual^34-36:

Factors that generally preclude TRT: Men with active high-grade prostate cancer or breast cancer should generally not receive TRT. Men with low-grade prostate cancer may still be eligible for TRT but should discuss this in detail with a knowledgeable and qualified healthcare provider. Because TRT reduces sperm cell production and reduces male fertility, men planning to have children within six to 12 months are likely not good candidates for TRT, although concurrent use of human chorionic gonadotropin (hCG), or possibly gonadotropin-releasing hormone (GnRH), may combat this side effect. Testosterone replacement therapy should be cautiously considered in men with severe urinary symptoms or high hematocrit levels.

It is widely recommended that men with uncontrolled heart failure or those who have had recent major cardiovascular events should also avoid TRT due to potential risks; however, this guidance remains controversial as some clinical evidence suggests TRT has benefits in men with heart failure of any severity.^227,228 Furthermore, its safety in men with and without cardiovascular disease has been consistently demonstrated. A large body of evidence including three large randomized controlled trials, multiple smaller randomized controlled trials, and 19 meta-analyses have shown TRT was not associated with increased risk of major adverse cardiovascular events, leading the Androgen Society to issue a position paper stating TRT is conclusively not associated with increased risk of stroke, heart attack, or cardiovascular death.^49,52

Symptoms & lab testing: Testosterone replacement therapy is appropriate for men who exhibit symptoms of low testosterone (eg, reduced libido, fatigue, reduced muscle mass, depression) and have low total testosterone levels (generally below 300–400 ng/dL), ideally on at least two separate morning measurements. Physicians experienced in prescribing testosterone may elect to prescribe TRT outside these guidelines, but this should be addressed on a case-by-case basis. Dietary and lifestyle changes and supplements described in this overview may help men with symptoms but whose testosterone levels are within the normal range. If these strategies do not improve symptoms, a discussion with their healthcare provider about whether to proceed with TRT is then warranted.

Certain medical considerations: Testosterone replacement therapy may be appropriate for men with specific medical conditions that are associated with low testosterone levels, such as obesity, mild unexplained anemia, bone density loss, diabetes, exposure to chemotherapy or testicular radiation, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), chronic narcotic use, infertility, pituitary dysfunction, and chronic corticosteroid use. These conditions warrant testosterone testing and possible treatment even in the absence of typical hypogonadal symptoms. Sleep apnea has been associated with low testosterone levels. Screening for sleep apnea is a good idea before TRT initiation, as TRT may at least transiently worsen sleep apnea.

A growing body of evidence indicates that, when used appropriately in men whose baseline testosterone levels are initially low, testosterone replacement therapy (TRT) does not increase risks of prostate cancer, cardiovascular disease, blood clot-related adverse outcomes, or all-cause mortality. Moreover, TRT appears safe in men with high cardiovascular risk, those with mild-to-moderate benign prostatic hyperplasia (BPH), and those who have been successfully treated for prostate cancer.^229-236

Nevertheless, men with low testosterone levels should undergo an evaluation of their prostate, cardiovascular, and overall health prior to considering TRT. Ongoing therapy should be accompanied by regular monitoring of hormone levels and markers of prostate and cardiovascular risk.^46,237 Hematocrit should also be monitored since TRT has been associated with increased red blood cell numbers, especially when administered as intramuscular injections and in higher doses.^46,237

The American Urological Association has indicated testosterone therapy should not be initiated in men with the following conditions⁴⁶:

• High hematocrit
• Locally advanced or metastatic prostate cancer
• History of a cardiovascular event (eg, heart attack or stroke) within the past three months
• Those of reproductive age and currently trying to conceive

Other guidelines suggest men with breast cancer, severe lower urinary tract symptoms (ie, due to severe BPH), and severe untreated obstructive sleep apnea should avoid testosterone therapy due to the possibility of worsening these conditions.⁴⁶ Notably, TRT-induced worsening of sleep apnea appears to be short-lived.

Before initiating TRT, men should undergo lab testing. This includes total and free testosterone, and may include luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, dihydrotestosterone (DHT), dehydroepiandrosterone-sulfate (DHEA-S), and estradiol, as well as ancillary biomarkers such as hemoglobin, hematocrit, and sex hormone-binding globulin (SHBG).^2,34,35,254 It is also a good time to check markers of cardiovascular, metabolic, and overall health status.

Assessment of Testosterone Status

Total, free, and bioavailable testosterone levels are important indicators of testosterone status. Only about 2% of testosterone in the bloodstream is not bound to proteins and is therefore described as “free testosterone.” The remainder is bound to three carrier proteins: about 50% bound to albumin, 44% to SHBG, and 4% to corticosteroid binding protein (CBG).²⁵⁵ SHBG binds testosterone with approximately 100,000 times more strength than albumin and is a major regulator of testosterone availability. Total testosterone is a measure of bound and unbound testosterone, whereas free testosterone reflects only the unbound active portion. Bioavailable testosterone is a less commonly reported parameter that includes both free and albumin-bound testosterone.²⁵⁵

Hypogonadism is readily diagnosed when total testosterone levels are low, but measuring free testosterone levels can help more clearly identify men with low testosterone activity who might benefit from treatment.²⁵⁵ Sex hormone-binding globulin production is affected by common conditions such as aging, obesity, liver disease, and thyroid disease, as well as by certain medications.²⁵⁶ This leads to changes in testosterone bioavailability that are not necessarily reflected in total testosterone levels. For example, in aging men without obesity, free testosterone levels drop more quickly than total testosterone levels due in part to increased SHBG production.¹ Importantly, low free testosterone levels have been found to correlate more closely with symptoms of androgen deficiency than low total testosterone levels.²⁵⁵ Based on such evidence, the Endocrine Society recommends testing both total and free testosterone levels when assessing male hormone status.³⁴

Timing

Testosterone levels fluctuate during the course of the day. Levels generally reach their maximum in the morning and decline after a meal. Therefore, men undergoing testosterone testing should have their blood drawn first thing in the morning after fasting overnight.²⁵⁷ Ideally, if testosterone levels are low on an initial blood test, results should be confirmed with a second blood test on a separate occasion²; however, many physicians will start a 3–6 month trial of TRT in symptomatic men with a single blood test showing low testosterone levels and whose overall health status makes them a good candidate for TRT.

The American Urological Association recommends checking blood testosterone levels two to four weeks after initiating or making a change in TRT. It also recommends monitoring testosterone levels every 6–12 months during ongoing TRT.²⁵⁸ The British Society for Sexual Medicine guideline recommends testing at 3, 6, and 12 months, followed by annual testing.²⁵⁹ Generally, for ongoing monitoring of testosterone levels during TRT, men should have their blood drawn at their “trough” level; that is, the blood draw should be done in the morning on the day their next injection is scheduled. The blood draw should be before the TRT dosage for that day. This allows for monitoring of the lowest on-treatment testosterone level.^258,259

Since acute illness such as a cold or the flu can affect testosterone levels, men should not get tested while they are sick.²⁵⁷ Similarly, some medications, such as corticosteroids or opioids, can affect testosterone levels²; thus, men using medications short-term to treat an acute illness should wait until after they have finished their short-term medications to have their testosterone levels checked.

Lab Factors

Another important consideration is that testosterone tests differ from one another in various ways. The methods by which the tests are run, and their corresponding normal ranges, can vary from lab to lab and even within the same lab if that lab offers different kinds of testosterone tests. In particular, free testosterone testing often differs between labs. Therefore, men should be sure the testosterone testing they are doing is performed by a reputable lab and follow-up testosterone testing is done by the same lab using the same methodology to ensure the results of their tests are comparable.

Immunoassays for total testosterone offer some advantages over LC-MS/MS. They are less expensive, correlate well with LC-MS/MS in most men, and have faster turnaround times for results. However, LC-MS/MS is recommended for assessing low total testosterone levels, such as in women and hypogonadal men.²⁶⁰

Free testosterone levels are usually estimated using a calculation based on reliable total testosterone, SHBG, and albumin measurements. Although equilibrium dialysis is the gold standard, it is expensive and not widely available (though more labs are now adopting this method and costs are coming down). Immunoassay methods provide a direct measure of free testosterone, but are less accurate than equilibrium dialysis.^{2,34,35,254,257} Note that results for free testosterone obtained via equilibrium dialysis are generally much higher than those obtained through calculation based on total testosterone measured via LC-MS/MS. For example, LabCorp performs free testosterone assessment by direct analog enzyme immunoassay (EIA), which is substantially less expensive and has faster turnaround times than equilibrium dialysis; and is still reasonably accurate in most circumstances. Quest Diagnostics, on the other hand, offers a competitively priced equilibrium dialysis-based free testosterone assay.

Reliability also depends on factors beyond methodology, such as proper sample handling, laboratory expertise, and quality control measures, highlighting the importance of using a reputable lab for accurate assessment of hormone levels and all other lab testing.

Optimal Hormone Levels

Optimal target testosterone levels during TRT have also not been rigorously defined, but “mid-normal,” “upper half,” or “upper-mid range” of the established normal reference ranges for testosterone are typical treatment goals.^259,261,262 For example, the American Urological Association suggests a target on-treatment total testosterone level of 450–600 ng/dL. Notably, robust randomized trials of testosterone therapy (eg, TRAVERSE and the Testosterone Trials) treated men to a “mid-normal” range.^52,263 In The Testosterone Trials, the researchers modified the dosage of TRT as needed to keep participants’ total testosterone levels between 500 and 900 ng/dL.²⁶³ Ultimately, symptoms are crucial in guiding TRT dosage—the optimal levels listed here are not requirements for optimal benefits of TRT.

Because some symptoms of male hormone imbalance may be caused by disproportionate estradiol levels relative to testosterone levels, Life Extension suggests that most men strive to maintain a total testosterone-to-estradiol ratio of about 23 to 40.

Estrogen in Aging Men

Estrogen is present in lower amounts in men than in reproductive-aged women, but estradiol, the most active form of estrogen, still plays a vital role in male hormone balance. For example, an observational study that followed 954 healthy men for a median of 25.2 years found lower baseline estradiol levels were associated with higher risk of cardiovascular disease-related death: men with the lowest estradiol levels had a nearly 12-fold increase in risk of cardiovascular death, and the correlation was strongest in non-Hispanic White men.²⁶⁴ Another observational study in 793 older men found those with the highest estradiol levels (> 34.3 pg/mL) had one-third the risk of hip fracture compared to those with low estradiol levels (≤ 18.1 pg/mL) during 16–18 years of monitoring. The highest risk of hip fracture was seen in men with low levels of both estradiol and testosterone.²⁶⁵

Lower testosterone-to-estradiol ratios have been linked to higher risks of metabolic syndrome and its components in men.^266,267 In an observational study that analyzed data from 1,612 men, the average testosterone-to-estradiol ratio was 22.6, and men with higher ratios were found to have fewer epigenetic markers of biological aging and mortality risk.¹⁶⁹ A study that included 356 male patients with coronary artery disease calculated a median (middle) testosterone-to-estradiol ratio of 15.8, and found lower testosterone-to-estradiol ratios were associated with higher levels of thromboxane B2 (a marker of blood clot risk) and lower levels of nitric oxide (a marker of vascular health); in addition, during a median follow-up of 23.7 months, those with lower testosterone-to-estradiol ratios had a higher risk of all-cause mortality.²⁶⁸

Testosterone for testosterone replacement therapy (TRT) is available as intramuscular or subcutaneous injections; transdermal (topical) gels, creams, solutions, and patches; oral capsules, subdermal implants, and nasal formulations.⁴⁶ Importantly, there is no “one-size-fits-all” approach to TRT. Individuals vary, and hormone replacement requires careful attention to changing signs and symptoms as well as periodic laboratory testing. The choice to initiate TRT and the mode of therapy should be made in consultation with a qualified and experienced healthcare provider, and based on an individuals’ hormone levels and signs and symptoms.²⁷⁸

How is Testosterone Replacement Therapy Administered?

Injections

The historical method for administering testosterone is by intramuscular injection. Injections may be needed every one to three weeks. Once- to twice-weekly injections may be preferable to stabilize adequate levels. Testosterone enanthate (Delatestryl, Xyosted), testosterone cypionate (Depo-Testosterone), and testosterone undecanoate (Aveed) are examples of injectable forms of testosterone and are typically used at dosages of 75–100 mg weekly or 150–200 mg every two weeks.²⁷⁸ Testosterone injections rapidly restore normal hormone levels, as well as increase bone mineral density and lean body mass, decrease body weight and waist circumference, lower some cardiovascular risk markers, improve urinary and erectile function, and raise self-reported quality of life.^46,278

Some side effects have been attributed to testosterone injection therapy. These include pain at the injection site, increased levels of prostate-specific antigen (PSA), and high hemoglobin and red blood cell numbers.²⁷⁸ These effects are most often seen with higher dosages of testosterone.

Transdermal Approaches

Transdermal testosterone therapy allows for more consistent testosterone levels to be sustained. AndroGel and Axiron are examples of alcohol-based bioidentical testosterone gels, typically used in doses of 50–100 mg (5–10 grams of 1% testosterone gel) applied once daily.²⁷⁸ Cream-based formulations are available as compounded products, but no cream-based formulation is FDA approved for use in TRT as of mid-2026.⁴⁶ The location of application depends on the product; for example, AndroGel is applied to the upper arms and shoulders, whereas Axiron is applied to the armpit.²⁷⁹ With Axiron, the recommended initial dose is one pump (30 mg) applied to each armpit once daily at the same time each morning; previous use of underarm deodorants or antiperspirant does not alter efficacy, nor are there any grooming requirements such as shaving. Alternatively, a patch known as Androderm that provides either 2 or 4 mg of testosterone, or a combination of both for 6 mg, may be used nightly.⁴⁶ It is difficult to compare doses between gels and patches since gels are only absorbed at a rate of 9–14%; and although the testosterone in Androderm is absorbed at a rate of about 20%, it is labeled in accordance with the absorbable amount rather than the amount actually present in the patch (ie, the 2 mg patch is manufactured with 9.7 mg and the 4 mg patch with 19.5 mg of testosterone).^280,281

Transdermal testosterone has been shown to normalize hormone levels over a period of a few days.²⁸⁰ It can also improve bone density, increase lean body mass, and decrease fat mass, but its effects on body composition are less substantial than with injections. On the other hand, the effects of transdermal testosterone on mood and sexual function appear to be at least as robust as with injection.²⁷⁸

Adverse side effects associated with transdermal use of testosterone include skin irritation, which is more common with patches than with gels. Transdermal testosterone can also cause a rise in PSA levels that depends on the dose being used. Importantly, residual testosterone gel on the skin or clothing of the person using transdermal testosterone can be transferred by direct contact with others, and has been reported to cause problems such as precocious puberty (ie, abnormally early onset of puberty) in children.²⁷⁸ The use of an armpit-administered formulation may reduce the risk of testosterone transfer.

Oral Preparations

Until recently, oral testosterone therapy was hampered by low bioavailability due to extensive transformation in the liver after absorption through the gastrointestinal tract, as well as potential liver toxicity.⁴⁶ Testosterone undecanoate is a testosterone ester that has demonstrated sufficient oral bioavailability to normalize low androgen levels without damaging liver cells or adversely affecting liver function.^282,283 The first oral testosterone undecanoate capsule (Jatenzo) was approved for use in 2019, and two others (Tlando and Kyzatrex) were approved in 2022.²⁸⁴ Because its absorption is still inconsistent and half-life is short, testosterone undecanoate is generally taken in divided doses with food.^46,278 Jatenzo is ideally taken with fatty food but Tlando and Kyzatrex are formulated with lipids and do not require dietary fat for optimal absorption.²⁸⁴ In addition to restoring normal hormone levels, oral testosterone has been found to improve bone mineral density and body composition similarly to transdermal testosterone and has positive effects on sexual function, mood, cognition, and quality of life.²⁷⁸

Oral testosterone has been reported to cause dose-related adverse side effects such as digestive upset, increased hematocrit, worsening of high blood pressure, and decreased HDL-cholesterol levels. However, several clinical trials lasting as long as one year have found oral testosterone undecanoate, at doses of 160–240 mg per day, did not increase PSA levels or prostate volume in older men being treated for symptoms of hypogonadism.^285-289 Even men treated with oral testosterone undecanoate for two years were recently reported to have no significant PSA level elevation.²⁸²

Subdermal Implants

Testosterone pellets (Testopel) are implanted under the skin in a fatty area (eg, near the hip) and can provide consistent long-term therapy in men with testosterone deficiency. Typical dosages are 600–900 mg (8–12 pellets of 75 mg each) implanted subcutaneously every three to six months, with the dose individualized based on clinical response and serum testosterone levels.²⁹⁰ Note, however, that while these dosages are described as typical in recent expert reviews, the FDA-approved labeled indication for Testopel is 150–450 mg (2–6 pellets) every three to six months. For men switching from injections to pellets, the labeled suggested conversion is to implant two 75 mg pellets for each 25 mg of weekly injected testosterone. For example, a man injecting 100 mg of testosterone cypionate weekly would use eight pellets.²⁹¹

Testosterone pellets have been shown to normalize testosterone levels and improve mood and sexual function. Subdermal testosterone pellets have the advantages of requiring infrequent clinic visits and having no risk of testosterone transfer; however, implantation is a minimally invasive procedure. Furthermore, side effects can occur at the implant site, such as extrusion (breaking through the skin surface) and, in rare cases, infection, bleeding, and scarring. Testosterone pellets have also been associated with increased hematocrit and red blood cell numbers, though this is usually due to high doses.⁴⁶ Subdermally implanted testosterone pellets are less commonly used to treat age-related low testosterone levels as it is difficult to adjust the dosage or remove the pellets should an adverse reaction occur.

Nasal Formulations

Testosterone can be efficiently absorbed across mucous membranes, such as with Natesto, which is administered intranasally.

Natesto is a testosterone gel for nasal use that was approved in 2014 for use in men with low testosterone levels. Nasal testosterone is applied at a dose of 11 mg three times daily and quickly achieves target testosterone levels. One study examining the effects of nasal testosterone found improved bone mineral density, body composition, mood, and sexual function 90 days after the beginning of therapy. Because of its short duration of action, nasal testosterone appears to have the advantage of only mildly suppressing the hypothalamic-pituitary-testicular axis. This means it does not inhibit sperm production and therefore preserves fertility in men of reproductive age with low testosterone levels; however, its effectiveness in aging men has not been well-studied.⁴⁶

In the early 2000s, a series of seven, coordinated, placebo-controlled, clinical trials was undertaken to determine the effects of testosterone replacement therapy (TRT) in older men with hypogonadism. Known as the Testosterone Trials, they included 788 men aged 65 years and older with baseline total testosterone levels below 275 ng/dL. Participants were treated for one year with a topical testosterone gel at doses adjusted to achieve mid-normal levels for young men. Testosterone replacement therapy was found to have the following effects³²¹:

• Improved all aspects of sexual function
• Improved walking distance by a small amount
• Slightly improved mood and depressive symptoms, but not vitality
• Corrected mild-to-moderate anemia
• Increased bone mineral density
• Did not increase adverse cardiovascular or prostate events

Although TRT appeared to increase coronary artery plaque, a re-analysis of the data later suggested this finding may have been attributable to a significantly higher abdominal fat mass (measured as wait-to-hip ratio) in the treatment group compared with the control group, and was likely not an effect of TRT.³²²

Since then, numerous clinical trials have added to the body of evidence demonstrating TRT’s cardiovascular, prostatic, and overall safety and its potential multi-faceted benefits in older men with low testosterone levels. One particularly important randomized controlled trial, known as the TRAVERSE trial, involved 5,246 men in the United States between 45 and 80 years of age with total testosterone levels below 300 ng/dL, symptoms of testosterone deficiency, and existing or high risk of heart disease. They received transdermal testosterone gel at a dose adjusted to achieve total testosterone levels of 350–750 ng/dL or placebo for an average of 27.1 months. The primary finding from the trial was that TRT did not increase risk of major adverse cardiovascular events (heart attack, stroke, or cardiovascular disease-related death).⁵²

Based on the findings from this study and the large body of prior evidence, a position paper was issued by the Androgen Society stating the cardiovascular safety of TRT has been conclusively established.⁴⁹ Furthermore, in February 2025, the FDA recommended removing a warning related to increased adverse cardiovascular event risk from labels on all testosterone products.³²³

A number of secondary outcomes from the TRAVERSE trial have since been examined, showing positive effects from TRT:

• Reduced blood pressure, with a greater effect in those with higher baseline blood pressure³²⁴; but note that postmarketing studies for several testosterone drug products have shown modest blood pressure increases, so blood pressure should be monitored 6–12 weeks after initiating TRT³²⁵
• Corrected and prevented anemia in men with and without baseline anemia, respectively³²⁶
• Increased libido and sexual activity and reduced other symptoms of hypogonadism, but did not relieve erectile dysfunction³²⁷
• Led to small improvements in mood and energy levels in those with and without significant depressive symptoms, but not those with persistent depressive disorder³²⁸
• Increased prostate-specific antigen (PSA) levels but did not affect risk of prostate cancer or events related to other prostate problems²⁴⁰

Contrary to findings from some other trials, data from the TRAVERSE trial indicated TRT did not prevent progression to type 2 diabetes in those with pre-diabetes or improve blood glucose control in those with existing type 2 diabetes³²⁹ and did not reduce fracture risk.³³⁰

The TRAVERSE trial had several important limitations, including the use of doses targeting low-normal testosterone levels, a high participant dropout rate, and a relatively short follow-up period.³³¹

The remainder of this section aims to flesh out some of the other research that contributes to our current understanding of the benefits and risks associated with TRT. It is important to bear in mind that the use of testosterone at doses that raise testosterone levels into the upper-normal range or in men without overt testosterone deficiency remains largely unstudied.

Cardiovascular Health

Testosterone has long been believed to contribute to the higher heart disease risk in men compared with women, but current evidence puts this assumption into question and suggests estrogen’s well-established cardioprotective effects may have a more important role in this disparity between genders.³³² In fact, although not all studies agree, multiple observational studies have linked low testosterone levels with increased risk of cardiovascular disease and mortality in older men.^332-334 A meta-analysis of 37 observational studies that followed 43,000 men for an average of 6.4 years found low testosterone levels were associated with increased risk of cardiovascular disease, as well as cardiovascular and overall mortality.³³⁵ One large observational study examined data from 83,010 male veterans with low testosterone levels and found risks of heart attack, stroke, and all-cause mortality were significantly reduced in those who reached normal testosterone levels with TRT compared with those who did not achieve normal testosterone levels with TRT and those who did not receive TRT.³³⁶

Two meta-analyses that included findings from 26 and 30 randomized controlled trials involving a total of 10,941 and 11,502 participants, respectively, found TRT in men with hypogonadism did not increase the risks of adverse cardiovascular outcomes, including death due to cardiovascular disease or any cause, heart attack, stroke, congestive heart failure, atrial fibrillation, pulmonary embolism, or venous thrombosis.^229,231 Another meta-analysis included data from 10 large controlled trials with a combined total of 179,631 men with hypogonadism. This analysis found TRT reduced mortality without increasing the risk of adverse cardiovascular events compared with no treatment or placebo.²³³ The TRAVERSE trial, described above, provided additional evidence for TRT’s safety in men with hypogonadism and existing or high risk of cardiovascular disease.⁵² Furthermore, a meta-analysis of seven randomized controlled trials in hypogonadal men with existing heart failure found TRT was safe in this population.²²⁷

A study in 1,287 men with an average age of 76 years found higher testosterone levels were correlated with less coronary artery calcium, a marker of atherosclerosis.³³⁷ On the other hand, in a randomized placebo-controlled trial in 306 older men with low or low-normal testosterone levels (total testosterone levels of 100–400 ng/dL and free testosterone levels < 50 pg/mL), three years of TRT using a 1% testosterone gel dosed to achieve a target total testosterone level of 500–900 ng/dL had no effect on carotid artery plaque progression.³³⁸

Due to the overwhelming evidence indicating TRT’s safety and potential benefits on cardiovascular health, in early 2025, the FDA rescinded its requirement that manufacturers of prescription testosterone products include a warning on their labels regarding increased risk of heart attack and stroke.³²³

Prostate Health

The conversion of testosterone to dihydrotestosterone (DHT, a more potent androgen) within the prostate gland is essential for its proper growth and function. Excess androgenic stimulation has long been assumed to play a role in benign prostatic hyperplasia (BPH, noncancerous growth of the prostate) and prostate cancer. This assumption, combined with the effectiveness of antiandrogen therapies in treating prostatic conditions, led to theoretical concerns regarding the safety of TRT, especially in men with existing prostate disease.²³⁰ However, saturation of androgen receptors in prostate tissue occurs at extremely low testosterone levels, above which there is no further stimulation of prostate cell proliferation.²³⁸ Such extremely low testosterone levels can be achieved with medical androgen-deprivation therapy (also known as medical castration), but in general do not occur naturally in men.³³⁹

Prostate specific antigen is a non-specific marker of prostate activity and levels are frequently elevated in BPH and prostate cancer. A meta-analysis of observational evidence found higher testosterone levels were linked to higher PSA levels in a subset of men without BPH. The analysis also found a relationship between TRT and increased PSA levels was only seen in men treated with intramuscular (but not oral or transdermal) TRT.³⁴⁰ Nevertheless, numerous observational and clinical trials have been unable to find an association between TRT and prostate problems. One meta-analysis of findings from 21 randomized placebo-controlled trials involving 3,461 patients with late-onset hypogonadism found both short-term (less than one year) and long-term (one year or longer) TRT improved erectile function without affecting prostate volume, urinary flow and bladder voiding, or PSA levels.³⁴¹ In fact, observational studies have found lower testosterone levels to be associated with increased risk of BPH, and have not demonstrated a correlation between higher testosterone levels and increased prostate cancer risk or progression.²³⁰ For example, in a secondary analysis of data from 5,204 participants in the TRAVERSE trial, TRT did not increase prostate cancer risk during an average follow-up period of 33 months.²⁴⁰ In an 18-year observational study involving 78,615 men, no correlation was seen between TRT use and prostate cancer or prostate cancer-related mortality.²⁴⁵ Interestingly, a large observational study with 231,408 participants found TRT use had no relationship with overall prostate cancer risk, but was linked to a 50% lower risk of aggressive prostate tumors and a 35% higher risk of low-risk prostate tumors.³⁴² Another intriguing observational study followed 38,340 participants for more than five years and found risk of prostate cancer decreased over time in TRT users: whereas short-term TRT users had the same prostate cancer risk as non-users, long-term users were 40% less likely to develop prostate cancer.³⁴³

Glucose & Lipid Metabolism

The relationship between testosterone and metabolic disturbance is well established, and TRT has demonstrated metabolic benefits that augment those of diet and lifestyle interventions in men with low testosterone levels and metabolic disease.³⁴⁴ A meta-analysis of findings from 12 randomized controlled trials and one observational study involving a combined total of 1,596 participants found TRT improved blood glucose regulation, reduced total and LDL-cholesterol levels, lowered triglyceride levels, and increased HDL-cholesterol levels in men with hypogonadism and type 2 diabetes.³⁴⁵ Another meta-analysis that used data from 16 randomized placebo-controlled trials with a total of 1,373 participants found TRT improved metabolic parameters in older men with late-onset hypogonadism and metabolic disturbance. Specifically, TRT improved hemoglobin A1c (HbA1c), HOMA-IR (a measure of insulin resistance), waist circumference, and levels of leptin, insulin, and total cholesterol, although HDL-cholesterol levels decreased with TRT.³⁴⁶ In a meta-analysis that included 18 randomized controlled trials involving a total of 1,415 testosterone-deficient men with metabolic syndrome or type 2 diabetes, TRT was again found to improve HbA1c and HOMA-IR, waist circumference, and triglyceride and LDL-cholesterol levels.³⁴⁷

One large, randomized, placebo-controlled trial included 1,007 subjects, aged 50 to 74 years, with total testosterone levels below 404 ng/dL, a waist circumference of at least 95 cm (indicating abdominal obesity), and either type 2 diabetes or pre-diabetes. Their metabolic disease was treated with a lifestyle-based intervention plus either intramuscular injections of 1,000 mg testosterone undecanoate or placebo at the beginning of the trial, after six weeks, and every three months thereafter for two years. At the end of the trial, performance on the oral glucose tolerance test improved in the TRT plus lifestyle changes group resulting in a reduced proportion of type 2 diabetes cases compared with the placebo group, but there were no other differences in markers of metabolic health. Remarkably, testosterone therapy plus lifestyle changes reduced type 2 diabetes prevalence from 21% in the placebo group to 12% in the TRT plus lifestyle group.³⁴⁸ In a long observational study, 229 men with low testosterone levels (< 346 ng/dL) and prediabetes (HbA1c of 5.7– 6.4%) received TRT, whereas 87 matched controls did not, for up to eight years. Hemoglobin A1c values improved in the TRT group, with 90% achieving normal values; but 40.2% progressed to type 2 diabetes in the control group. In addition, men who received TRT had greater improvement in other metabolic markers, including body weight, waist circumference, lipid profile, and fasting blood glucose levels, as well as sexual function.³⁴⁹ Another study followed 356 men with symptomatic hypogonadism (total testosterone levels < 350 ng/dL) and type 2 diabetes for 11 years. All the participants received standard diabetes care, but only half also received TRT as 1,000 mg testosterone undecanoate injections every 12 weeks. At the end of the study, 90% of TRT-treated participants had achieved the target HbA1c of 7% and 34.3% no longer had diabetes, whereas non–TRT-treated participants had no significant changes in diabetes status or HbA1c.³⁵⁰

Body Composition & Physical Function

Testosterone stimulates the breakdown of body fat, suppresses new fat cell genesis, and promotes protein synthesis and growth of new muscle cells.^5,351 It also reduces insulin resistance and blood glucose dysregulation—metabolic contributors to fat accumulation.^272,352 TRT has been found to increase lean body mass in randomized controlled trials involving men with low testosterone levels related to aging, type 2 diabetes, obesity, liver disease, opioid use, human immunodeficiency virus (HIV) infection, and spinal cord injury.^351,353,354 A meta-analysis of findings from eight randomized placebo-controlled trials in men over 60 years of age with total testosterone levels of 500 ng/dL or lower found TRT, in various doses and forms of administration, increased lean body mass and decreased fat mass.³⁵⁵

Clinical trials in men with obesity have shown TRT can reduce fat mass, waist circumference, body weight, and body mass index (BMI).⁵ Furthermore, TRT preserves muscle mass during weight loss among men with obesity and hypogonadism. One randomized placebo-controlled trial included 83 men over 65 years of age with hypogonadism (total testosterone < 300 ng/dL), obesity, and frailty participating in a six-month diet and exercise program for weight loss. Those who also received testosterone gel, at a dose of at least 40.5 mg of testosterone per day (adjusted to maintain levels within the normal range for men aged 19 to 40 years), had better muscle and bone mineral density preservation and improved aerobic capacity compared with those who received placebo, despite no differences in weight loss or muscle strength gain.³⁵⁶

Another randomized placebo-controlled trial included 100 men, aged 47 to 60 years, with obesity and hypogonadism (total testosterone < 346 ng/dL). The participants engaged in a 10-week weight-loss intervention using a very-low-calorie diet, followed by 46 weeks on a low-calorie diet. In addition, they received 1,000 mg of testosterone undecanoate or placebo by intramuscular injection at the beginning of the trial, after six weeks, and every 10 weeks thereafter for the entire 56 weeks. Whereas the groups had similar weight loss, those who received TRT lost body fat but not muscle mass, yet those given placebo lost both muscle and fat.³⁵⁷ Secondary analyses showed TRT also improved symptoms of testosterone deficiency,³⁵⁸ reduced leptin levels,³⁵⁹ and lowered levels of markers of bone loss³⁶⁰; however, 82 weeks after stopping TRT, body composition improvements were lost.³⁶¹

Some evidence indicates TRT may improve physical function in those with age-related mobility limitations.³⁵¹ In a randomized placebo-controlled trial in 99 men over 65 years of age with limited mobility whose total testosterone levels were below 350 ng/dL and/or free testosterone levels were below 50 pg/mL, six months of treatment with a topical testosterone gel providing 100 mg of testosterone per day increased muscle strength and improved physical function.³⁶² A systematic review and meta-analysis of randomized controlled trials investigating the effects of TRT on muscle health concluded TRT increased muscle mass and strength as well as physical performance.³⁶³

Several factors influence the effects of TRT on body composition. A meta-analysis that included 48 randomized controlled trials found intramuscular testosterone increased lean body mass by 5.7% and increased strength by 10–13%, whereas transdermal testosterone gel led to an average increase in lean body mass of only 1.7% and increase in muscle strength of 2–5%.³⁶⁴ Men with lower baseline total testosterone levels appear to benefit more from TRT with regard to body composition changes.³⁶⁵ Estradiol levels can also influence body composition: in a study in 105 men with baseline total testosterone levels below 300 ng/dL, those with intermediate estradiol levels had the best baseline body composition. In addition, those with the lowest estradiol levels had the greatest reductions in total and abdominal fat percentages after six months of treatment with testosterone cypionate at an initial dose of 200 mg intramuscularly every two weeks, then adjusted for a target total testosterone level of 500–800 ng/dL, and subsequently to 300–600 ng/dL.³⁶⁶ Importantly, physical exercise enhances the benefits of TRT on muscle mass and is necessary for maintaining muscle strength and aerobic fitness.³⁶⁷

Inflammation & Oxidative Stress

Some of testosterone’s positive health effects may be related to its ability to reduce inflammation and oxidative stress. An observational study in 10,041 men found lower testosterone levels were associated with higher levels of inflammatory markers related to cardiovascular disease, including high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha.³⁶⁸ Furthermore, a systematic review of correlational studies reported a consistent relationship between lower testosterone levels and higher levels of inflammatory markers, especially CRP, in older men.³⁶⁹

Most of the observational and clinical evidence indicates TRT reduces inflammatory marker levels, but some studies have found no effect.³⁶⁹ One observational study that followed 778 men with hypogonadism for up to 11 years found hs-CRP, as well as markers of liver inflammation (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), decreased in those treated with TRT, but increased in those not treated with TRT.³⁷⁰

In a randomized controlled trial in 38 men aged 60 to 78 years with bioavailable (free plus albumin-bound) testosterone levels below the young healthy male reference range of ≥ 211 ng/dL and abdominal obesity (waist circumference ≥ 99 cm), 50 or 100 mg of testosterone per day via transdermal gel for 24 weeks reduced urine levels of markers of oxidative stress compared with placebo. Furthermore, the decrease in oxidative stress was proportional to the amount of body fat lost.³⁷¹ A similar trial in 39 men with type 2 diabetes and bioavailable testosterone levels lower than 211 ng/dL found transdermal gel providing 50 or 100 mg of testosterone daily decreased levels of hepcidin, a protein regulator of iron transport and marker of cardiovascular inflammation, more than placebo.³⁷² A randomized, placebo-controlled, crossover trial involving 27 men with hypogonadism (total testosterone < 127 ng/dL and bioavailable testosterone < 69 ng/dL) found treatment with three 100 mg intramuscular testosterone injections two weeks apart reduced levels of the inflammatory cytokines TNF-alpha and IL-1beta, and increased levels of the anti-inflammatory cytokine IL-10.³⁷³ In 50 metabolic syndrome patients with late-onset hypogonadism, 1,000 mg of testosterone undecanoate as an intramuscular injection every 12 weeks for one year reduced hs-CRP levels and improved markers of metabolic health (waist circumference, abdominal fat mass, and insulin resistance) better than a placebo gel.³⁷⁴

Bone Health

Testosterone acts on bone directly and indirectly, stimulating growth and, through its conversion to estrogen, inhibiting bone breakdown.³⁷⁵ Some, but not all, observational evidence suggests age-related declining testosterone levels are associated with decreased bone mineral density and increased fracture risk.^5,375 In one recent study that included 408 men over 60 years of age, osteoporosis was more prevalent in those with total testosterone levels lower than 300 ng/dL.³⁷⁶ Even in young and middle-aged men, higher testosterone levels were linked to higher bone density in one study with 3,875 participants.³⁷⁷

Over the past two decades, a number of clinical trials have investigated the effect of TRT on bone density in men, and most have shown benefits, especially in men with low baseline testosterone levels and osteopenia or osteoporosis.³⁷⁵ For example, in a secondary analysis of the TRAVERSE trial, testosterone therapy was associated with a 42% reduction in major osteoporotic fractures, though no significant difference was observed in overall fracture incidence. Testosterone treatment also led to statistically significant increases in bone mineral density at the lumbar spine (+2.1%) and total hip (+1.1%) compared with placebo, along with favorable changes in bone turnover markers including decreased C-terminal telopeptide of type I collagen (CTX) and increased procollagen type 1 N-terminal propeptide (P1NP).³⁷⁸ Additionally, in a randomized placebo-controlled trial involving 55 men with obesity, type 2 diabetes, and symptomatic hypogonadism, treatment with intramuscular injections of testosterone undecanoate (1,000 mg at the beginning of the trial, six weeks later, and every 10 weeks thereafter) improved lumbar spine, but not hip, bone mineral density and decreased levels of markers of bone turnover after two years.³⁷⁹ However, a meta-analysis of 52 randomized controlled trials with a total of 1,081 participants found TRT did not significantly improve bone mineral density or reduce risk of falling or fracture.³⁸⁰

Importantly, the effect of TRT on bone health may be more rapidly and accurately reflected in tests that measure bone metabolism. In an uncontrolled trial, 50 men with total testosterone levels at or below 300 ng/dL were treated with 40 mg per day of oral testosterone undecanoate for one year. Although an increase in bone density was not statistically significant in this time frame, markers of bone metabolism improved significantly.³⁸¹

Mood, Cognitive, & Sexual Function

Men with hypogonadism often describe a range of interrelated functional symptoms that substantially reduce quality of life, such as³⁸²:

• Reduced sexual desire and activity
• Low energy
• Poor sleep
• Weakness
• Weight gain
• Cognitive dysfunction
• Reduced well-being

Randomized controlled trials have consistently shown TRT can improve sexual function, including sexual desire, erection, and orgasm, in men with hypogonadism, though the benefit is small.^383,384 For example, a secondary analysis of data from 5,204 men participating in the TRAVERSE trial found TRT improved mood, sexual activity, sexual desire, and hypogonadal symptoms as soon as six months after starting treatment, though it did not improve erectile function.³²⁷

Findings regarding TRT’s effect on mood and cognition have been inconsistent. In a randomized placebo-controlled trial, 83 men over 65 years of age with hypogonadism (total testosterone < 300 ng/dL), obesity, and frailty participated in a six-month diet and exercise program for weight loss. About half of them were also treated with a testosterone gel, providing 40.5 mg of testosterone per day or more as needed to maintain levels within the normal range for men aged 19 to 40 years. At the end of the trial, those who received TRT had better scores on tests of attention, memory, and global cognition.³⁸⁵ A meta-analysis of findings from 27 randomized placebo-controlled trials involving 1,890 subjects found TRT reduced depressive symptoms, particularly when used in higher doses (> 500 mg per week) and in men with less symptom variability before starting treatment.³⁸⁶ However, a meta-analysis that included findings from 17 randomized controlled trials with a total of 1,438 participants was unable to find a consistent benefit from TRT on depressive symptoms or any cognitive domain.³⁸⁷ In addition, a review of 21 relevant clinical trials found TRT did not improve cognitive function, even in elderly men with hypogonadism, regardless of their baseline cognitive function.³⁸⁸ In the Testosterone Trials–Cognitive Function Trial, testosterone treatment in older men with low testosterone did not significantly improve cognitive function compared with placebo across multiple domains including verbal memory, visual memory, and executive function over 12 months.³⁸⁹

Aging

Aging is one of the most important factors determining testosterone levels in men. After about the age of 35 years, gonadotropin-releasing hormone (GnRH) production begins to gradually decline and Leydig cells become less responsive to stimulation by luteinizing hormone (LH). The combined result is reduced testosterone production without elevation of LH levels.¹ In fact, testosterone levels drop by about 1–2% per year in aging men.³³² At the same time, sex hormone-binding globulin (SHBG) levels typically increase, further reducing the bioavailable portion of testosterone in aging men.¹ At about 65–70 years of age, testosterone activity is frequently low enough to trigger an observable increase in LH secretion over time. In some cases, LH levels become frankly elevated.^1,390 On the other hand, age-related changes in hypothalamic-pituitary-testicular axis function may be small or absent in healthy older men.¹

It is important to note that aging is also associated with decreased hormone metabolism, which may help compensate for reduced testosterone production. In addition, other tissues in the body may become more sensitive to testosterone stimulation. These changes in testosterone metabolism and activity may have important impacts on the effects of TRT.¹

Diet & Nutrition

An industrialized, overly processed diet that is nutrient-poor and calorie-dense contributes to high rates of metabolic problems such as obesity and type 2 diabetes. These conditions are associated with chronic inflammation, high oxidative stress, and insulin resistance, leading to suppressed testosterone production and poor sexual health.^352,391 Conversely, a nutrient-dense diet can support healthy hormone balance throughout life. Low levels of key nutrients such as vitamin B12,³⁹² vitamin C,³⁹³ magnesium,^143,394 zinc,⁸⁶ and vitamin D⁹⁸ have been associated with low testosterone levels in some men. Polyphenols, found especially in fruits and vegetables, support healthy function of the hypothalamic-pituitary-testicular axis by reducing oxidative stress and may help prevent age-related hypogonadism.^395,396 Therefore, ensuring adequate intake of a wide array of nutrients is necessary for optimal testosterone status.

Weight loss, regardless of how it is achieved, has a substantial positive effect on testosterone levels and should be used as first-line treatment—ahead of TRT—for men with obesity-induced low testosterone levels.^397,398 Dietary changes that lead to weight loss increase total testosterone, free testosterone, and SHBG levels and decrease estradiol levels in men with obesity-related hypogonadism.^399,400 Bariatric surgery, which results in greater weight loss than diet alone, has a more potent testosterone-elevating effect than diet.³⁹⁹ One meta-analysis that included data from 28 studies with 1,022 participants found bariatric surgery increased free testosterone levels by an average of 216 ng/dL; in addition, free testosterone and SHBG were increased and estradiol levels were decreased following weight loss surgery.⁴⁰¹

Various types of restricted diets, especially if they do not induce weight loss, can negatively affect testosterone levels in men. For example, an observational study that included 3,128 men found, after correcting for BMI and age, adherence to a low-fat diet was linked to lower testosterone levels than eating an unrestricted diet.⁴⁰² Intermittent fasting, also known as time-restricted eating, has also been associated with reductions in total and free testosterone levels in multiple randomized controlled trials.⁴⁰³

A meta-analysis of findings from 27 trials with 307 male participants found a high-protein version of a ketogenic diet, which severely limits carbohydrate intake, caused a substantial decrease in total testosterone levels.⁴⁰⁴ A ketogenic diet was found to raise SHBG and reduced free testosterone levels after just three weeks in a small crossover study that included five men with obesity.⁴⁰⁵ A controlled trial in 10 male subjects found a single dose of a ketone supplement (beta-hydroxybutyrate), which induced ketosis without weight loss, led to a rapid increase in SHBG release compared with placebo. In addition, total testosterone levels decreased following the ketone supplement; but this effect was not statistically significant.⁴⁰⁵ Conversely, a ketogenic diet that triggers weight loss has been found to improve both metabolic health and total testosterone levels in obese men with hypogonadism.^397,406

Plant-based diets do not appear to meaningfully influence testosterone status. A study that used data from 191 male participants in the National Health and Nutrition Examination Survey (NHANES) found scores on a plant-based eating index were not correlated with total testosterone levels.⁴⁰⁷ A six-week clinical trial in eight male endurance athletes found that eating a vegetarian diet that included dairy products and eggs for six weeks slightly lowered total testosterone levels—but free testosterone, SHBG, and other hormone levels were unchanged.⁴⁰⁸ Observational studies have found men who ate a vegan diet had higher total testosterone and SHBG, but had similar or slightly lower free testosterone levels compared with men who ate an omnivorous diet.^409,410

A common misconception about phytoestrogens, such as isoflavones found in soybeans, has led some men to believe that eating soy foods may lower their testosterone levels. In fact, a meta-analysis of findings from 41 studies found soy food consumption and isoflavone intake had no effect on levels of total testosterone, free testosterone, estradiol, estrone (another type of estrogen), or SHBG in men.⁴¹¹

Exercise

Physical activity may enhance testosterone production by inducing weight loss and improving metabolic health.⁴¹² In a large meta-analysis that included data from 21,074 participants in nine studies, those with a higher physical activity level (more than 75 minutes per week) had higher total testosterone levels than those who were less physically active.³⁹⁰ Clinical trials have shown moderate-to-intense physical activity, especially endurance and strength-training exercise, can briefly increase testosterone levels, but the effect may be blunted by obesity and older age.^413,414 A meta-analysis of eight trials involving 202 men with hypogonadism found exercise interventions that promoted weight loss improved testosterone levels, and the effect was stronger in older men.⁴¹² However, a meta-analysis of 11 randomized controlled trials involving 421 participants found exercise interventions with a median of 12 weeks’ duration were not sufficient for increasing resting testosterone levels in healthy but insufficiently active men.⁴¹⁵

Sleep

Sleep plays an important role in regulation of sex hormones, including testosterone. Sleep loss has been associated with suppression of the hypothalamic-pituitary-testicular axis, resulting in reduced testosterone synthesis. Furthermore, lack of sleep increases afternoon and evening stress signaling, increasing cortisol production, which contributes to suppression of testicular function as well as metabolic disturbance.^416,417 However, not all studies have found a relationship between sleep loss and testosterone levels.⁴¹⁸ Findings from one observational study suggested the effect is small: the study analyzed data from 2,295 male participants in the NHANES and found each hour less of sleep was correlated with a 5.85 ng/dL decrease in total testosterone.⁴¹⁹ Other evidence suggests sleep timing may be a mediating factor: a clinical trial in 15 healthy young men found sleep loss in the second half of the night reduced testosterone levels, but sleep loss in the first part of the night did not.⁴²⁰ In addition, an observational study in 298 men found those with an evening chronotype (those who naturally prefer nighttime activity, a late bedtime, and a late rising time) had higher free testosterone but not total testosterone levels.⁴²¹

Obstructive sleep apnea, a common sleep breathing disorder that causes sleep fragmentation, has been linked to reduced testosterone levels, and both conditions are strongly related to obesity and metabolic disease.^16,422 One meta-analysis that included 18 studies with a total of 1,823 male participants found neither mild nor moderate sleep apnea was correlated with testosterone levels. However, a significant correlation between severe sleep apnea and low testosterone levels was detected and persisted even when the effects of age and BMI were taken into account.⁴²³ Unfortunately, sleep apnea treatment with continuous positive airway pressure has not been consistently shown to raise testosterone levels.^424,425 It is important to note that TRT can temporarily worsen sleep apnea, an effect that appears to resolve within a few months.⁴²⁶

Stress

Stress signaling helps regulate reproductive function in part by influencing sex hormone production, but the exact nature of the relationship between stress and testosterone levels is not fully understood. A systematic review encompassing 21 clinical studies in 881 healthy individuals found experimental psychosocial stress typically resulted in an immediate and temporary rise in testosterone production, although findings were somewhat mixed.⁴²⁷ On the other hand, preclinical research has indicated chronic stress can reduce LH and testosterone levels through complex stress signaling networks.^427,428 Also, male shift workers have lower testosterone levels than daytime workers, which suggests stress associated with this type of work schedule and related sleep pattern disruption may play a role.^429,430 Although testosterone levels were not significantly different in men with combat-related post-traumatic stress disorder (PTSD, a chronic stress-related ailment) than in healthy controls,⁴³¹ they were higher in those with PTSD that was not complicated by major depression or alcoholism.⁴³²

Medications

Environmental Toxins

Men’s fertility and testosterone levels have been notably declining for the past two decades. Whereas changes in dietary patterns and rising rates of obesity and metabolic disease are likely to be contributing factors, increasing exposure to environmental toxins, especially endocrine disruptors, has also been implicated.⁴⁴⁸

Endocrine disruptors are chemicals that interfere with androgen production or action.^449,450 A number of endocrine disruptors that have been linked to lower testosterone levels are widely distributed in the environment, such as:

• Perfluoroalkyl and polyfluoroalkyl substances (PFAS). Perfluoroalkyl and polyfluoroalkyl substances are a group of compounds with an array of uses, including in flame retardants, textile coatings, furniture finishes, non-stick cooking surfaces, and food packaging. Certain PFAS are well known for their ability to persist in the environment and accumulate in humans and other animals. These compounds are sometimes termed “forever chemicals.” Their wide use and persistence has led to their detectability in soils, drinking water, indoor dust, and seafood.^451,452 Laboratory research suggests PFAS have endocrine disrupting effects, including suppressing androgen receptor activity.^451,453,454 In addition, meta-analyses have linked higher blood and semen concentrations of certain PFAS to lower total and free testosterone levels.^455,456
• Bisphenol-A and other bisphenols. Bisphenols such as bisphenol-A (BPA), as well as bisphenol-S (BPS) and bisphenol-F (BPF)—bisphenols commonly used in “BPA-free” materials), have been shown to reduce testosterone levels in laboratory research⁴⁵⁷ and higher bisphenol levels have been correlated with lower testosterone levels in observational studies.^450,458 These compounds are found in polycarbonate plastics and epoxy resins used in an array of plastic or plasticized products, including food and beverage packaging, medical supplies, and dental sealants and fillers. ^450,459 Bisphenols are ingested via foods contaminated through processing and packaging and by contact with bisphenol-laden consumer products.⁴⁵⁹
• Phthalates. Phthalates are plasticizers used in a multitude of consumer products such as adhesives, detergents, cosmetics, construction materials, fabrics and textiles, electronics, food packaging, children’s toys, and even some drugs and supplements. Phthalates are so widely used they are now commonly found in ground water and packaged—and even unpackaged (albeit to a lesser degree than packaged)—foods.^459,460 Higher exposure to phthalates has been linked to lower testosterone production.⁴⁶¹
• Pesticides. Organophosphate pesticides, such as glyphosate-based herbicides (eg, Roundup), are widely deployed in modern agriculture and are found in the soil and water in regions where they are used. Animal studies generally indicate glyphosate-based herbicides can interfere with testosterone secretion and suggest even low-level exposure can reduce testosterone levels.^462,463 A study in 2,130 U.S. adults found higher urinary glyphosate concentrations were associated with lower bioavailable testosterone fractions.⁴⁶⁴

Air pollution is another possible contributor to reduced testosterone levels. Air pollutants may exert their testosterone-lowering effect by triggering oxidative stress and inflammation, as well as interfering with normal testicular cell function.⁴⁶⁵ Exposure to high ambient levels of heavy metals such as cadmium and lead also increases oxidative stress in the testes, leading to impaired testosterone production.^449,460

Emerging evidence suggests exposure to some of these pollutants at levels considered safe can negatively impact health. Furthermore, the potential additive or synergistic effects of exposures to multiple endocrine disruptors and other pollutants are largely unknown.^466,467

Negative effects of endocrine disruptors may be mitigated by increasing antioxidant intake.^468-470 In addition, the following actions may help reduce exposure to endocrine disruptors^471,472:

• Choose clothing, cosmetics, toys, cookware, food containers, and other products made from natural materials whenever possible
• Avoid consumer products labeled non-stick or stain-resistant
• Minimize processed and packaged foods
• Keep foods that are packaged in plastic or cans (which often have plastic coatings inside) cool
• Avoid heating food in plastic and drinking hot beverages from plastic cups
• Minimize use of scented cleaning, personal care, and beauty products, as well as scented air fresheners and candles
• Use a vacuum with HEPA filtration and dust often with a wet cloth or mop
• Avoid using pesticides and herbicides around your home

Recreational Drugs & Alcohol

Men who use anabolic steroids (usually testosterone) for a prolonged time to enhance physical performance experience low testosterone levels after stopping drug use, a withdrawal effect that has been shown to persist for months to years and may even be irreversible in some cases.⁴⁷³

Alcohol and some recreational drugs have also been associated with decreased testosterone levels. Healthy men who are long-term regular alcohol users, regardless of their consumption level, have been found to have lower total and free testosterone and higher estradiol levels compared with alcohol non-users.⁴⁷⁴ Although total testosterone and estradiol levels were found to be higher in men with alcohol use disorder compared with non-drinkers, their levels of SHBG were also higher, reducing their bioavailable hormone levels.⁴⁷⁵ Interestingly, higher testosterone levels have also been linked to increased risk of chronic alcohol use and alcohol use disorder in young and middle-aged men, showing the complexity of this relationship.⁴⁷⁶ Whereas some studies have found lower testosterone levels in male infertility patients who used cannabis,^477,478 meta-analyses have not been able to show cannabis use was significantly correlated with testosterone levels.^479,480 Men with cocaine addiction have a higher risk of hypogonadism,⁴⁸¹ and animal research suggests methamphetamine use may damage the testes and reduce testosterone levels.⁴⁸²

Cardiovascular Disease

Testosterone has a blood pressure-lowering effect and promotes metabolic health, and declining levels have been associated with cardiovascular problems including hypertension, coronary artery disease, cerebrovascular disease, chronic heart failure, and atrial fibrillation.^259,483

Metabolic Dysfunction, Inflammation, & Oxidative Stress

Adult-onset hypogonadism without a known primary cause, or functional hypogonadism, is common in men with metabolic conditions such as obesity, type 2 diabetes, and metabolic syndrome.³⁵² Up to 75% of men with severe obesity have functional hypogonadism.⁴³⁵ Weight gain lowers testosterone levels and increases sexual dysfunction risk, whereas weight loss has the opposite effect.⁴⁸⁴

Low testosterone contributes to increased abdominal fat, creating a cycle where more fat lowers testosterone further, increasing fat accumulation. Type 2 diabetes and insulin resistance also disrupt the hypothalamic-pituitary-testicular axis, whereas low testosterone increases type 2 diabetes risk.^352,435

Several mechanisms link metabolic disease with functional hypogonadism. Obesity and related conditions suppress luteinizing hormone (LH) secretion, possibly due to high levels of leptin, leptin and insulin resistance, and neuroinflammation. This reduced LH stimulation lowers testosterone production.^272,352,435 Furthermore, obesity-induced oxidative stress, mitochondrial dysfunction, and leptin overactivity may directly impair Leydig cell function.^352,435,485

Metabolic disease also reduces sex hormone-binding globulin (SHBG) production due to liver dysfunction and increased inflammatory cytokines. This can temporarily raise testosterone availability, increasing its conversion to estradiol, which suppresses the hypothalamus more than testosterone.^269,435 However, many men with obesity-related hypogonadism have low estradiol levels, worsening blood glucose regulation and fat accumulation. This highlights the roles of inflammation, oxidative stress, and leptin and insulin resistance in disrupting the hypothalamic-pituitary-testicular axis in men with metabolic disease.^272,352,485

Chronic Kidney Disease (CKD)

Chronic kidney disease (CKD) is closely linked to metabolic disorders and cardiovascular disease and has been correlated with reduced testosterone synthesis and secretion.⁴⁹³ Furthermore, low testosterone levels in CKD patients have been linked to increased disease progression and mortality.⁴⁹⁴

Liver Disease

Advanced liver disease disrupts hormone balance. Not only does the liver produce hormone transport proteins such as albumin and SHBG, it is also responsible for most hormone metabolism.⁴⁹⁵ Low testosterone levels in patients with cirrhosis may contribute to frailty and mortality.⁴⁹⁶

Viral Infections

Viral illnesses such as human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) have been linked to testosterone deficiency. Men living with HIV have been found to be more likely to develop hypogonadism at an earlier age compared with men without HIV.^435,497 In the context of certain respiratory infections, the relationship appears to be bi-directional: infection appears to cause an inflammatory response that reduces testosterone production—an effect that may persist for months or longer—whereas having low testosterone levels prior to infection has been correlated with increased severity of infection.^498,499

Cognitive & Mood Problems

Low testosterone levels are associated with low energy and motivation levels, as well as depressed mood and decreased memory and attention.⁴ Age-related testosterone deficiency has also been found to be correlated with increased risk of major depression, cognitive impairment, and dementia.^388,500,501 Furthermore, depression and its medical treatment may contribute to hypogonadism.⁵⁰¹

Sexual Dysfunction

Sexual dysfunction (eg, reduced libido, infrequent sexual activity, and erectile function) is common in men with low testosterone. Testosterone replacement therapy in men with unequivocal hypogonadism consistently improves libido, but its effectiveness for erectile dysfunction is less reliable and may not be significant if erectile dysfunction is the primary symptom. The likelihood of benefit from testosterone therapy increases as baseline testosterone levels decrease, particularly when levels are below 200 ng/dL.⁵⁰²

Autoimmune Diseases

Testosterone has important effects on immune function. Several observational studies have linked hypogonadism in men to increased risk of autoimmune diseases such as rheumatoid arthritis, lupus, and multiple sclerosis.^503,504

Osteoporosis

Hypogonadism is a well-established cause of osteoporosis. Testosterone is needed for its direct anabolic (growth-promoting) effects on bones. It also supports bone health through its conversion to estradiol. Furthermore, testosterone deficiency is associated with decreased vitamin D activation in the kidney, which can lead to bone demineralization.⁴

Sarcopenia & Frailty

Testosterone has a critical anabolic effect on protein metabolism and maintenance of muscle mass. Decreasing testosterone levels are accompanied by muscle loss. In older men, hypogonadism can cause sarcopenia—age-related loss of muscle mass and strength—which contributes to frailty.⁵⁰⁵

Anemia

Testosterone stimulates production of red blood cells in the bone, and low testosterone levels, especially when induced by medications, causes anemia.^4,506

Why Do Men Need Balanced Hormone Levels?

Testosterone is the dominant male hormone (androgen) and is critical for men’s overall health. Testosterone levels normally decline with aging.⁵⁰⁷ Low testosterone levels are associated with multiple health problems, including sexual dysfunction, decreased muscle mass and strength, bone loss, and increased risks of cardiovascular and metabolic diseases.⁵ In addition, low testosterone levels in older men have been associated with depressive symptoms, cognitive dysfunction, lower quality of life, and increased mortality.^5,6

Testosterone replacement therapy (TRT) has been shown to improve sexual function, bone density, body composition, and depressive symptoms in older men with low levels. This has led the Endocrine Society and the American Urological Association to recommend TRT in men with chronically low testosterone levels and related symptoms or conditions.^6,508 In addition, TRT has demonstrated a high degree of safety and a wide range of older men may benefit from its potential protective effects on chronic disease and mortality risks.^6,15

What Can Contribute to Low Testosterone Levels?

• Disease of the testes (primary hypogonadism)¹
• Any condition or circumstance affecting the pituitary and/or hypothalamus (secondary hypogonadism),¹ including:
• Increasing age¹
• Obesity³⁵²
• Type 2 diabetes³⁵²
• Liver and kidney diseases^494,495
• Inflammation and oxidative stress^14,485
• Viral infections such as human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and COVID-19^497,498
• Certain medications and recreational drugs^259,509

Why is it Important to Get Hormone Levels Tested?

Testosterone levels are affected by luteinizing hormone (LH, a pituitary hormone that regulates testicular production of testosterone) and sex hormone-binding globulin (SHBG, a protein that binds testosterone, rendering it inactive), as well as levels and activity of dehydroepiandrosterone (DHEA, a hormone precursor to testosterone and estrogen) and aromatase (an enzyme that converts testosterone to estrogen).

Comprehensive hormone testing can provide an accurate overview of your hormone balance and help guide TRT. This includes testing levels of free and total testosterone, estradiol (the most active estrogen), LH, DHEA-sulfate, as well as SHBG and albumin. Because hormone levels will vary between and within men, it is important to repeat tests periodically to identify trends over time.

Testosterone replacement therapy should be embarked upon with the guidance of a qualified healthcare professional experienced in men’s hormone restoration and balance. The decision to start TRT should be based on symptoms, lab values, and consideration of health conditions.

Does Testosterone Replacement Therapy Increase the Risk of Prostate Cancer?

No. Observational data has shown TRT was not associated with an increased risk of prostate cancer incidence or mortality.^230,245,246 The use of testosterone by men who have or have had prostate cancer remains controversial; however, current research indicates TRT is a safe option for prostate cancer patients who have symptomatic testosterone deficiency and have completed successful treatment or are under active surveillance for low-risk disease.^250,252 More clinical trials are needed to guide treatment decisions in hypogonadal patients with intermediate- or high-risk prostate cancer.²⁵³ All men should discuss the risks and benefits of testosterone restoration with a qualified healthcare provider before initiating testosterone treatment, including with respect to prostate health.

What Nutrients Boost Testosterone Levels?

Aside from hormone replacement therapy and diet and lifestyle changes that promote metabolic health, there are nutrients that have been shown to support healthy testosterone levels and male hormone balance. These include:

• Eurycoma. A meta-analysis of randomized controlled trials found extracts from the Asian plant Eurycoma longifolia can increase testosterone levels in healthy men and those with hypogonadism.⁵⁴
• Fenugreek. Clinical trials have shown fenugreek can increase testosterone levels a small amount and have positive effects on body composition and athletic performance.⁶¹
• Ashwagandha. Ashwagandha has been reported to increase testosterone, possibly through its stress-reducing effects.⁶⁸
• Pomegranate and cacao seed. Several clinical trials have shown a blend of pomegranate and cacao seed extracts can promote testosterone production.⁸¹
• Zinc. Healthy zinc status is necessary for normal production of testosterone, and supplementation has been reported to increase testosterone levels in men at risk of zinc deficiency.⁸⁶
• DHEA. As a precursor to testosterone, adequate dehydroepiandrosterone (DHEA) levels are required for healthy testosterone and estrogen production. DHEA levels tend to decline with age, and supplementation may support hormone balance in aging men.^33,136