- ACRONYMS AND DEFINITIONS
- BMD - Bone mineral density
- DHT - Dihydrotestosterone
- EAU - European Association of Urology
- ED - Erectile dysfunction
- PSA - Prostate specific antigen
- RCT - Randomized controlled trial
- SERM - Selective estrogen receptor modulator
- SHBG - Sex-hormone binding globulin
- TESTOSTERONE PHYSIOLOGY
- Overview
- Testosterone is the primary hormone involved in male sexual development and fertility
- Testosterone also plays an important role in muscle formation, body composition, bone health, and cognitive function
- Testosterone is produced and secreted by the Sertoli cells of the testes. The testes produce 3 - 10 mg of testosterone a day.
- A small amount of testosterone (5 - 8%) is converted to dihydrotestosterone (DHT) by the enzyme 5-alpha reductase. DHT is a more potent androgen than testosterone. It is involved in prostate development, external genitalia development, hair follicles (hair loss), and skin sebum production.
- An even smaller amount of testosterone (0.3 - 0.5%) is converted to the hormone estradiol by the enzyme aromatase. Estradiol plays an important role in bone health, cognitive function (memory), and plasma lipid levels. Aromatase is present in fatty tissue, so obese men may overproduce estradiol. [1,3]
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- SYMPTOMS OF LOW TESTOSTERONE
- Overview
- Symptoms of low testosterone depend on whether testosterone deficiency develops before or after puberty
- Deficiency before puberty will lead to developmental abnormalities
- Deficiency after puberty can cause a number of symptoms, many of which are nonspecific and highly prevalent in men with normal testosterone levels
- Prepubertal symptoms of testosterone deficiency
- Delayed puberty
- Small testicular volume
- Cryptorchidism - undescended testes
- Hypopigmented scrotum
- No scrotal rugae
- Unclosed epiphyseal plates - continued linear growth into adulthood
- Gynecomastia
- Decreased body hair
- High-pitched voice
- Low hairline
- Decreased bone and muscle mass
- Small testicular volume [1,3]
- Postpubertal symptoms of testosterone deficiency
- Nonspecific symptoms
- Decreased energy
- Decreased vigor - more frequent at testosterone levels < 375 ng/dl
- Sleep disturbance
- Mild, unexplained anemia
- Diminished cognitive function
- Loss of muscle mass
- More specific symptoms
- Abnormal sperm production - decreased or absent sperm
- Diminished nocturnal erections - more frequent at testosterone levels < 317 ng/dl
- Gynecomastia
- Galactorrhea
- Decreased bone mass - height loss, low-impact fractures
- Decreased body hair - axillary and pubic; decreased shaving
- Shrinking testes
- Hot flushes
- Decreased libido - more frequent at testosterone levels < 230 ng/dl
- Erectile dysfunction - more frequent at testosterone levels < 245 ng/dl
- Symptoms consistent with age-related hypogonadism
- Hot flushes
- Decreased libido - more frequent at testosterone levels < 230 ng/dl
- Erectile dysfunction - more frequent at testosterone levels < 245 ng/dl
- Diminished nocturnal erections - more frequent at testosterone levels < 317 ng/dl
- Conditions that are most likely risk factors for low testosterone
- Obesity
- Insulin resistance and diabetes [1,2,3,30]
- CAUSES OF LOW TESTOSTERONE
- Overview
- Low testosterone occurs through two primary mechanisms:
- Primary hypogonadism - failure of the testes to produce adequate amounts of testosterone
- Secondary hypogonadism - failure of the hypothalamus or pituitary to stimulate testosterone production (See physiology above)
- Primary and secondary hypogonadism can also occur at the same time leading to combined hypogonadism
- Other conditions like androgen receptor defects can cause syndromes that mimic male hypogonadism. These conditions are rare and not discussed here.
- Primary hypogonadism
- Primary hypogonadism occurs when the testes fail to produce adequate amounts of testosterone
- Lab findings in primary hypogonadism will show low testosterone levels and elevated FSH and LH levels
- Causes, risk factors, and symptoms of primary hypogonadism are presented in the tables below
Primary hypogonadism | |
---|---|
Cause | Risk factors/Symptoms/Other |
Klinefelter's syndrome |
|
Undescended testes or ectopic testes |
|
Testicular trauma |
|
Orchitis |
|
Cancer treatment |
|
Varicocele |
|
Defects of steroid biosynthesis |
|
Y-chromosome defects |
|
Noonan syndrome |
|
LH receptor mutations |
|
- Secondary hypogonadism
- Secondary hypogonadism occurs when the hypothalamus or pituitary fail to stimulate testosterone production. In studies, up to 85% of hypogonadism has been found to be secondary.
- Lab findings in secondary hypogonadism will show low testosterone levels with either low FSH/LH levels or inappropriately normal FSH/LH levels
- Among men with secondary hypogonadism, 89% of cases have an unknown etiology, and most affected men carry a diagnosis of obesity, type two diabetes, and/or metabolic syndrome. Causes of secondary hypogonadism are presented in the table below. [28]
Secondary hypogonadism | |
---|---|
Cause | Comments |
Unknown |
|
Hyperprolactinemia |
|
Isolated hypogonadotropic hypogonadism (IHH) |
|
Kallmann syndrome |
|
Hypopituitarism |
|
Pituitary adenomas |
|
Prader-Willi syndrome |
|
Congenital adrenal hypoplasia with hypogonadotropic hypogonadism |
|
Pasqualini syndrome |
|
LH or FSH mutations |
|
- Combined hypogonadism (primary and secondary)
- Combined hypogonadism is caused by deficiencies in both testosterone production and pituitary/hypothalamic stimulation
- Lab findings in combined hypogonadism will show low testosterone levels with either low FSH/LH levels or inappropriately normal FSH/LH levels
- Conditions associated with combined hypogonadism
- Alcoholism
- Age-related hypogonadism
- Cirrhosis
- Corticosteroid treatment
- DAX-1 mutation
- Hemochromatosis
- Sickle cell disease
- Thalassemia [1,2,3]
- Diseases associated with hypogonadism
- HIV - particularly in wasting syndrome
- End stage kidney disease
- COPD, moderate-to-severe
- Type 2 diabetes
- Obesity [1,2,3]
- AGE-RELATED HYPOGONADISM "LOW T"
- Overview
- Age-related hypogonadism, also referred to as "Andropause," "Male menopause," and "Low T," has become a highly commercialized condition
- Much of the current fervor surrounding age-related hypogonadism can be traced back to the development of convenient delivery systems for testosterone. In the past, testosterone typically had to be injected, but in recent years, testosterone has been made available in easy to apply gels and patches. These new, patent-protected dosage forms have provided incentives for drug companies to promote their products and "educate" physicians and the public about age-related hypogonadism, or "Low T."
- The hard push by drug manufacturers and some providers to promote age-related hypogonadism screening and treatment has been controversial
- There is limited to no evidence to support many of the claims endorsed in advertising, and the long-term effects of testosterone therapy are largely unknown. In addition, it's unclear if age-related hypogonadism is in fact a real pathological condition.
- Testosterone levels and age
- Longitudinal studies that have looked at whether testosterone levels naturally decline with age have been mixed
- Some studies have found that testosterone levels decline on average around 1 - 2% each year in men ≥ 30 years old
- Other studies have found no significant effect of aging on testosterone levels [4,5]
- A major factor confounding these studies is the fact that men tend to gain weight with age, and weight gain is strongly associated with declining testosterone levels. To help control for this effect, a recent cross-sectional study compared testosterone levels in men (n=325) who described themselves as being in "very good or excellent health." The study found no significant association between age and testosterone levels. [6]
- In summary, there is no conclusive evidence that testosterone levels naturally decline with age. Studies that have evaluated this association are largely confounded by age-related weight gain and its associated comorbidities (diabetes, hypertension, etc.).
- Age-adjusted testosterone levels
- Normal testosterone ranges reported by most laboratories are around 300 - 1200 ng/dl (10.4 - 40 nmol/l)
- These ranges were derived from a population of healthy, nonobese men who were < 40 years old [7,8]
- Given the fact that weight gain is strongly associated with declining testosterone levels, it's not surprising that a significant number of men ≥ 40 years will have testosterone levels on the lower end of the testosterone spectrum
- The table below shows testosterone values from a cohort of randomly sampled men in the Boston, Massachusetts area. The cohort was sampled at 3 different times.
- This table demonstrates that normal ranges for testosterone are much lower for a random sample of typical adult males
- NOTE: The 95% CI or "95% confidence interval" represents the middle 95th percentile which is the range of values that are typically used by labs for normal ranges
Average age of sample |
Average testosterone level ∼ 95% CI |
Average free testosterone level ∼ 95% CI |
---|---|---|
55 (N=1667) |
517 ng/dl (17.9 nmol/l) 167 - 867 ng/dl (5.8 - 30 nmol/L) |
11.5 ng/dl (0.4 nmol.l) 2.9 - 20.1 ng/dl (0.10 - 0.70 nmol/l) |
62 (N=947) |
459 ng/dl (15.9 nmol/l) 145 - 773 ng/dl (5.03 - 26.8 nmol/L) |
9.3 ng/dl (0.32 nmol/l) 3.3 - 15.3 ng/dl (0.11 - 0.53 nmol/l) |
68 (N=584) |
414 ng/dl (14.4 nmol/l) 94 - 734 ng/dl (3.3 - 25.5 nmol/L) |
7.1 ng/dl (0.25 nmol/l) 1.9 - 12.3 ng/dl (0.066 - 0.43 nmol/l) |
- Summary
- Age-related hypogonadism or "Low T" has become a highly marketed and somewhat manufactured condition
- Declining testosterone levels in aging men are likely secondary to weight gain and its associated comorbidities
- Reference ranges used in most laboratories do not represent ranges seen in typical populations of adult males
- Low testosterone is most likely an indicator of poor health as opposed to a cause
- TESTOSTERONE LABS
- Overview
- Most testosterone circulates in the blood bound to two proteins, sex-hormone binding globulin (> 50%) and albumin (30 - 40%). Testosterone bound to albumin is "weakly bound" meaning it can easily dissociate from albumin and become active. Testosterone bound to sex-hormone binding globulin (SHBG) is tightly bound and does not dissociate easily.
- Approximately 2% of testosterone is unbound, and it is considered the active form of testosterone
- When measuring testosterone, the following terms are often used:
- Total testosterone - total amount of testosterone in the blood (free + protein-bound)
- Free testosterone - amount of testosterone that is unbound (active form)
- Bioavailable testosterone - free testosterone + testosterone bound to albumin (testosterone bound to albumin is able to easily dissociate and become free). Also referred to as "Free and weakly bound" and "Free and albumin-bound testosterone")
- Normal ranges
- Normal ranges for testosterone values are presented in the table below
- Normal ranges tend to vary widely by labs. A survey of 120 labs in 47 U.S. states found that the average lower limit of normal for total testosterone was 231 ng/dl (range 160 - 300) and the average upper limit of normal was 850 ng/dl (range 726 - 1130). [PubMed abstract]
- Ranges are typically derived from a sample of healthy, nonobese males aged < 40 years
- The CDC offers laboratories a certification for measuring testosterone values in men. Some labs are CDC-certified and many are not. Normal ranges for testosterone in nonobese, young men (19 - 39 years) in the CDC-certified labs are 303 - 852 ng/dl. [30]
- See age-adjusted testosterone ranges above for typical ranges grouped by age
Total testosterone3 | Free testosterone (calculated)1 |
Free testosterone (equilibrium dialysis)2 |
Bioavailable2 |
---|---|---|---|
231 - 850 ng/dl (8 - 29.5 nmol/l) |
4.8 - 25 ng/dl | 52 - 280 pg/ml (1.5 - 3.2%) |
40 - 250 ng/dl (9 - 46% of total) |
- Proper measurement technique
- Blood testosterone levels follow a circadian rhythm with levels peaking in the morning and then declining into the evening. Because of this, levels should be drawn in the morning. Some studies have also found that levels have a seasonal variation with average levels being highest in January and lowest in May.
- Glucose and food intake can affect testosterone levels so levels should be drawn after an overnight fast
- Levels that are mildly below the normal range should be confirmed with a repeat level. Studies have shown that up to 30% of repeat values will be normal.
- Free testosterone and SHBG should also be checked when levels come back in the borderline-low range [2,32]
- FSH and LH levels may be appropriate to distinguish between primary and secondary hypogonadism
- Sex-hormone binding globulin (SHBG)
- Most circulating testosterone is tightly bound to SHBG (≥ 50%)
- Changes in SHBG can affect the amount of free (active) testosterone
- SHBG and free testosterone levels should be checked in patients with borderline-low testosterone levels to see if alterations in SHBG have affected levels of free testosterone
- Common conditions that can alter SHBG are listed below
- Conditions that may decrease SHBG levels
- Obesity
- Kidney disease (Nephrotic syndrome)
- Hypothyroidism
- Use of corticosteroids, progestins, and androgenic steroids
- Acromegaly (growth hormone tumors)
- Diabetes
- Conditions that may increase SHBG levels
- Aging
- Hyperthyroidism
- Use of estrogens
- Use of seizure medications
- HIV
- Liver cirrhosis
- Vegan diet [1,2,27]
- MEDICATIONS THAT MAY LOWER TESTOSTERONE
- Anabolic steroids
- Antipsychotics - may raise prolactin levels leading to hypogonadism
- Corticosteroids - daily doses of ≥ 15 mg
- Estrogens
- GnRH antagonists (e.g. degarelix)
- GnRH agonists (e.g. leuprorelin, triptorelin, goserelin)
- Ketoconazole - inhibits steroidogenesis
- Metoclopramide (Reglan®) - may raise prolactin levels leading to hypogonadism
- Opiate pain medication - suppress GnRH synthesis
- Progesterones
- Ramelteon (Rozerem®)
- Seizure and mood stabilizer medications
- DIAGNOSIS
- Overview
- The evaluation of patients with hypogonadism should be patient-specific and driven by history and physical exam findings
- The majority of testosterone testing today is done to screen for age-related hypogonadism. The cost-effectiveness and yield of further testing in these men is unknown.
- The table below lists some specific findings and their possible causes
Finding | Considerations |
---|---|
Delayed or absent sexual development |
|
Gynecomastia / galactorrhea |
|
Low impact fractures |
|
Visual field defects |
|
Skin hyperpigmentation |
|
Centripetal obesity / moon facies / abdominal striae |
|
- TESTOSTERONE AND ERECTILE DYSFUNCTION
- Testosterone levels and erectile dysfunction (ED) symptoms
- Testosterone plays an important role in maintaining erectile function. That being said, it appears that testosterone-related erectile dysfunction only occurs at very low levels of testosterone.
- A European study that included over 2800 men measured the correlation between testosterone levels and self-reported sexual function. The study found that sexual function improved with increasing testosterone levels only at the very low end of testosterone levels (0 - 230 ng/dl). The effect plateaued at 230 ng/dl, and no improvement in sexual function was seen for increasing testosterone levels above this value [PMID 21849522]
- Testosterone replacement and ED symptoms
- A number of small studies have evaluated the effect of testosterone replacement on ED symptoms. Results from these studies have been inconsistent across a wide range of patient populations (see sexual function studies below).
- In studies that only included patients with low testosterone levels, testosterone replacement had no clear effect on ED symptoms
- Studies that evaluated the addition of testosterone therapy to phosphodiesterase inhibitors have also found no clear benefit of adding testosterone to these therapies [10,11,12]
- Summary
- Men with very low testosterone levels (< 230 ng/dl) may see improvement in ED symptoms with testosterone replacement, although this has not been proven conclusively in clinical trials
- There is no evidence that testosterone replacement improves ED symptoms in men with levels ≥ 230 ng/dl
- TREATMENT OF LOW TESTOSTERONE
- Overview
- Patients with reversible causes of hypogonadism (ex. hyperprolactinemia) should have their conditions treated
- Patients with primary or secondary hypogonadism should be treated with testosterone replacement therapy
- The treatment of age-related hypogonadism is controversial (see age-related hypogonadism above). Patients who are overweight should be encouraged to lose weight because this will likely raise their testosterone levels naturally.
- Professional recommendations
- In 2020, the American College of Physicians recommended that therapy for age-related low testosterone be offered to men who have sexual dysfunction, but it should not be used to improve energy, vitality, physical function, or cognition. They recommended injectable products over other products because they are considerably cheaper. [31]
- Testosterone products
- Testosterone replacement products now come in a variety of forms
- See testosterone replacement therapies for a review of prescription testosterone products
- TREATMENT | Non-testosterone therapies
- Overview
- Low testosterone is typically treated with exogenous testosterone replacement therapy
- There are several other classes of medications that can raise testosterone levels by stimulating endogenous production
- Because these drugs rely on gonadal testosterone production, they are only effective in treating secondary hypogonadism (85% of hypogonadism cases)
- Estradiol and testosterone production
- A small percentage of testosterone (0.3 - 0.5%) is converted into estradiol by the enzyme aromatase. Estradiol suppresses GnRH, FSH, and LH release in the hypothalamus and/or pituitary. This in turn decreases testosterone production in the testis (see HPT axis above).
- Adipose tissue has a high level of aromatase, and obese men often have high estradiol levels
- Drugs that inhibit estradiol have been shown to increase testosterone levels, particularly in obese individuals
- The drugs most commonly used to treat secondary hypogonadism are aromatase inhibitors (e.g. letrozole, anastrozole) and clomiphene
- Current hypogonadism guidelines do not address the use of these medications [28,29]
- Clomiphene
- Clomiphene is a SERM that blocks estrogen receptors in the hypothalamus, and possibly, the pituitary. By blocking the negative effects of estradiol, clomiphene causes testosterone levels to rise.
- Studies
- In one study (N=125), clomiphene 25 mg once daily for 12 weeks raised average testosterone levels from a baseline value of 309 ng/dl to 642 ng/dl [PMID 22951175]
- In another smaller study (N=26), clomiphene 25 mg once daily for 12 weeks raised testosterone levels an average of 571 ng/dl in hypogonadal infertile males (baseline testosterone level < 350 ng/dl) [PMID 26176805]
- Aromatase inhibitors
- Aromatase inhibitors (e.g. letrozole, anastrozole) are a class of drugs that directly inhibit the aromatase enzyme. Blocking aromatase lowers estradiol levels and increases testosterone production.
- Studies
- In one study (N=12), letrozole 2.5 mg once weekly for 6 weeks raised average testosterone levels from a baseline value of 170 ng/dl to 565 ng/dl [PMID 18426834]
- In another study (N=26), anastrozole 1 mg once daily for 12 weeks raised testosterone levels an average of 408 ng/dl in hypogonadal infertile males (baseline testosterone level < 350 ng/dl) [PMID 26176805]
- CONTRAINDICATIONS TO TESTOSTERONE THERAPY
- Prostate cancer 1,2
- Breast cancer 1,2
- PSA > 4 ng/ml 1,2
- PSA > 3 ng/ml in men at high-risk for prostate cancer (African-Americans or men with first-degree relatives with prostate cancer) 2
- Nodule or induration on prostate examination (unless biopsy is negative) 2
- Severe sleep apnea 1,2
- Poorly controlled heart failure 2
- Men desiring fertility 1,2
- Hematocrit > 48% 1,2
- Severe BPH symptoms 1,2
- 1 EAU recommendation
- 2 Endocrine Society recommendation
- MONITORING TESTOSTERONE THERAPY
Recommendations for monitoring therapy |
---|
EAU recommendations
|
Endocrine Society recommendations
|
- BENEFITS OF TESTOSTERONE THERAPY
- Overview
- For patients with pathological primary or secondary hypogonadism, testosterone replacement is vital for normal development and function
- The majority of testosterone prescriptions are for age-related hypogonadism
- Testosterone therapy advertisements insinuate a wide range of benefits from testosterone therapy. These assertions are largely unproven in clinical trials.
- Trials evaluating testosterone therapy are plagued by a number of issues including small sample size, short study length, use of different testosterone preparations, heterogeneous outcome measures, heterogeneous sample populations, and mixed results. These issues make it difficult to draw conclusions about the benefits, if any, of testosterone therapy.
- In general, the strongest evidence for an effect of testosterone therapy is a modest improvement in libido and bone density. Evidence for any other purported benefit is weak and inconclusive.
- Erectile dysfunction (ED)
- The effect of testosterone replacement on erectile dysfunction is reviewed here - testosterone and ED
- Libido
- The effects of testosterone on libido have been inconsistent, but overall, testosterone appears to have a modest effect on libido in men with low testosterone levels.
- Several meta-analyses of randomized placebo-controlled trials have found that testosterone significantly improves libido in men with testosterone levels below 345 ng/dl. [11,13,14]
- Bone health
- A meta-analysis of randomized placebo-controlled trials found that intramuscular testosterone therapy improved lumbar bone mineral density (average +8%), but it did not have a significant effect on femoral neck BMD. Transdermal testosterone did not have a significant effect at either site. [PMID 16720668]
- A small randomized controlled trial that looked at the effects of testosterone gel on BMD found that one year of testosterone therapy improved BMD when compared to placebo (see bone studies below)
- No randomized controlled trials have analyzed the effect of testosterone on fracture risk
- Body composition and muscle strength
- Testosterone appears to have a small effect on body composition causing a slight decrease in body fat coupled with a slight increase in fat-free mass. A meta-analysis of randomized controlled trials found that on average, body fat decreased by 3.5 pounds with testosterone therapy when compared to placebo or control. There was no significant difference in change in body weight between testosterone and placebo or control. [PMID 16117815]
- Trials evaluating muscle strength outcomes with testosterone have been mixed. In general, there is no conclusive evidence testosterone therapy improves muscle strength. [2,16,17]
- See physical function and vitality studies below
- Insulin resistance and diabetes
- Low testosterone levels are associated with insulin resistance and diabetes. This association is likely secondary to the strong inverse relationship between weight gain and testosterone levels.
- Studies that have looked at the effects of testosterone on insulin sensitivity and glucose measures have been mixed. Testosterone therapy appears to improve some measures of insulin sensitivity, but it has no meaningful effect on long-term glucose control (hemoglobin A1C values). [1,18,20]
- Cholesterol
- Testosterone therapy has a mixed effect on cholesterol. In studies, HDL and total cholesterol tend to decline while LDL remains unchanged. [16,17]
- Cognition (concentration, memory, etc.)
- A randomized controlled trial that looked at the effects of testosterone on memory impairment in older men found no effect (see cognitive studies below)
- Results from other studies evaluating the effects of testosterone on cognition have been mixed [2,17]
- In general, there is no good evidence testosterone improves cognition of any kind
- Depression
- A meta-analysis of randomized placebo-controlled trials found that testosterone therapy improved depressive symptoms when compared to placebo. The studies were small, and the meta-analysis only encompassed 355 patients. [19,20]
- RISKS OF TESTOSTERONE THERAPY
- Overview
- No large, long-term, randomized controlled trials have evaluated the risks of testosterone therapy. Available evidence is mostly from observational studies and meta-analyses of short-term studies. This makes it difficult to establish firm, causal links between testosterone therapy and its potential risks.
- A review of the available information is presented below
- Cardiovascular disease
- One of the main concerns with testosterone therapy is the potential for therapy to increase the risk of cardiovascular disease
- In 2015, the FDA issued a drug safety warning about the potential increase in risk for heart attacks and strokes with testosterone products (FDA testosterone warning). The warning is based on data from observational studies and meta-analyses.
- A small number of recent studies with varying designs have looked at the effects of testosterone replacement therapy on cardiovascular disease risk (see cardiovascular disease studies below). These studies have had mixed results. A randomized controlled trial that was designed to evaluate the effect of testosterone on muscle strength was stopped early when the testosterone therapy group had a higher incidence of cardiovascular-related events (see TOM trial below)
- Two meta-analyses of placebo-controlled, randomized trials looked at the risk of cardiovascular events with testosterone. One found a significant increased risk, and the other did not. The meta-analyses are limited by the fact that most of the included trials were < 1 year in length. [PMID 25139126, PMID 23597181]
- In conclusion, there is some evidence that testosterone therapy increases the risk of cardiovascular events. A large, long-term, randomized controlled trial is needed to establish causality.
- Prostate cancer
- Testosterone stimulates prostate growth and development
- Studies have not found an association between endogenous (natural) levels of testosterone and prostate cancer risk
- There are no large, long-term, randomized controlled trials that have evaluated the risk of prostate cancer with testosterone therapy
- A meta-analysis of randomized controlled trials compared the rates of prostate events (defined as prostate biopsies, prostate cancers, increase in International Prostate Symptom Score (IPSS) > 4, prostate-specific antigen (PSA) > 4 ng/ml or PSA increment ≥ 1.5 ng/ml during treatment, and acute urinary retention) between men on testosterone therapy and placebo. Men on testosterone therapy had a significantly higher risk of prostate events than men on placebo (OR 1.78, 95%CI [1.07 - 2.95]). For each individual prostate event, there was no significant difference between the two groups, although these comparisons are likely underpowered. The meta-analysis only encompassed 643 testosterone-treated men, and only 2 of the 19 studies included in the analysis lasted longer than a year. [23]
- In conclusion, the effect of testosterone therapy on prostate cancer risk is unknown. A large, long-term, randomized controlled trial is needed to evaluate the risk.
- Prostate Specific Antigen (PSA) changes
- PSA is a protein produced by cells of the prostate gland
- PSA levels are elevated in men with prostate cancer, but they can also be elevated in men with benign conditions of the prostate including prostatic hypertrophy and prostatitis
- Testosterone stimulates the prostate gland, and testosterone therapy may raise PSA levels. Current guidelines from the Endocrine Society and EAU recommend monitoring PSA levels in men undergoing testosterone replacement therapy (see monitoring therapy).
- A meta-analysis of randomized controlled trials lasting 3 - 12 months found that PSA levels rose an average of 0.154 ng/ml (95%CI [0.069 - 0.238]) in patients treated with testosterone when compared to control. Subgroup analysis showed that patients treated with transdermal testosterone did not have a significant increase in PSA (95%CI [-0.021 - 0.190], p=0.116) where patients treated with intramuscular testosterone did (95%CI [0.117 - 0.425], p=0.001). The study found no significant difference between the groups for incidence of elevated PSA levels. [24]
- Testosterone therapy appears to cause a slight increase in PSA levels, although available data is from short-term studies only. Current Endocrine Society guidelines (see monitoring therapy) recommend using PSA velocity and change in PSA as triggers for urological evaluation. While this may be prudent, there are no studies that validate this approach. [2]
- Erythrocytosis and thromboembolism
- Erythrocytosis is an increase in the production of red blood cells
- Testosterone stimulates erythrocytosis by increasing erythropoietin production and stimulating bone marrow [1]
- A meta-analysis of randomized and nonrandomized studies found that hemoglobin levels increased an average of 0.80 mg/dl (95%CI [0.45 - 1.14 mg/dl]) and hematocrit levels an average of 3.18% (95%CI [1.35 - 5%]) in men treated with testosterone when compared to placebo or no treatment [PMID 20525906]
- Elevated red blood cell levels may theoretically increase the risk of vascular thromboembolism. Two observational studies found an increased risk of venous thromboembolism among men who were using testosterone therapy. [PMID 27903495, PMID 31710339] Another observational study that looked at the risk of thrombosis based on hematocrit levels in the general population had mixed findings. [PMID 31309714]
- Summary
- Testosterone therapy raises hematocrit levels in a significant number of patients. Current Endocrine Society and EAU guidelines recommend hematocrit monitoring in patients on testosterone replacement (see monitoring therapy). If hematocrit levels rise above 54%, therapy should be stopped and restarted at a lower dose once the hematocrit normalizes. [2,3]
- It's unclear if testosterone and/or an elevated hematocrit increases the risk of thrombosis
- TESTOSTERONE STUDIES
Physical function and vitality studies
- Design: Randomized, placebo-controlled trials (N=790, length = 1 year) in men ≥ 65 years old and testosterone < 275 ng/dl
- Treatment: Testosterone gel 1% vs Placebo gel for 1 year. Dose was adjusted to keep testosterone within normal range.
- Primary outcomes: 1. Sexual function 2. 6-minute walking distance 3. Functional Assessment of Chronic Illness Therapy-Fatigue scale
- Results:
- Primary outcomes: Testosterone was significantly better for sexual function (p<0.001) but not for 6-min walk test (p=0.20) or functional assessment (p=0.30)
- Findings: In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment.
- Design: Randomized, placebo-controlled trial (N=209, length = 6 months) in men ≥ 65 years old with mobility limitations and testosterone level of 100 - 350 ng/dl
- Treatment: Testosterone gel 1% vs Placebo gel for 6 months. Dose was adjusted to keep testosterone > 500 ng/dl.
- Primary outcome: Change from baseline in maximal voluntary muscle strength in a leg-press exercise
- Results: The trial was stopped early due to higher rate of adverse cardiovascular events in the testosterone group
- Findings: In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy.
Sexual function
- Design: Randomized, placebo-controlled trials (N=790, length = 1 year) in men ≥ 65 years old and testosterone < 275 ng/dl
- Treatment: Testosterone gel 1% vs Placebo gel for 1 year. Dose was adjusted to keep testosterone within normal range.
- Primary outcomes: 1. Sexual function 2. 6-minute walking distance 3. Functional Assessment of Chronic Illness Therapy-Fatigue scale
- Results:
- Primary outcomes: Testosterone was significantly better for sexual function (p<0.001) but not for 6-min walk test (p=0.20) or functional assessment (p=0.30)
- Findings: In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment.
- Design: Randomized, placebo-controlled trial (N=76, length = 16 week) in men with ejaculatory dysfunction and testosterone < 300 ng/dl
- Treatment: Testosterone solution 60 mg once daily vs Placebo for 16 weeks. Doses were adjusted to keep testosterone in the normal range.
- Primary outcome: The primary outcome was a change in the score of the three-item Male Sexual Health Questionnaire-Ejaculatory Dysfunction-Short Form (MSHQ-EjD-SF)
- Results:
- Primary outcomes: Testosterone +3.1, Placebo +2.5 (p=0.596)
- Findings: Testosterone replacement was not associated with significant improvement in ejaculatory dysfunction in androgen deficient men.
- Design: Randomized, placebo-controlled trial (N=88, length = 40 weeks) in men with type 2 diabetes, ED, and testosterone < 346 ng/dl
- Treatment: Testosterone undecanoate 1000 mg IM at 0,6, and 18 weeks vs Placebo injection
- Primary outcome: Constitutional symptoms using the aging male symptoms (AMS) score, sexual desire (question 17 AMS score), and erectile function (International Index of Erectile Function-5)
- Results:
- Primary outcomes: Mean difference in change in AMS score was -0.9 (p=0.67)
- Findings: In this trial, testosterone treatment did not substantially improve constitutional or sexual symptoms in obese, aging men with type 2 diabetes with mild to moderate symptoms and modest reduction in testosterone levels typical for the vast majority of such men.
Cardiovascular disease
- Design: Randomized, placebo-controlled trial (N=138, length = 12 months) in men ≥ 65 years old with testosterone level < 275 ng/dl
- Treatment: Testosterone gel vs Placebo. Dose was adjusted to maintain testosterone in the normal range.
- Primary outcome: Noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography
- Results:
- Primary outcomes: Testosterone was associated with a greater increase (estimated diff 41 mm3, p=0.003)
- Findings: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding.
- Design: Randomized, placebo-controlled trial (N=308, length = 3 years) in men ≥ 60 years with testosterone of 100 - 400 ng/dl
- Treatment: Testosterone gel 75 mg daily vs Placebo gel. Dose was adjusted to maintain testosterone in a range of 500 - 900 ng/dl.
- Primary outcome: Coprimary outcomes included common carotid artery intima-media thickness and coronary artery calcium
- Results:
- Primary outcomes (carotid thickness): Testosterone - 0.012 mm/yr, Placebo - 0.010 mm/yr (p=0.89)
- Primary outcomes (coronary calcium): Testosterone - 31.4 units/yr, Placebo - 41.4 units/yr (p=0.54)
- Findings: Among older men with low or low-normal testosterone levels, testosterone administration for 3 years vs placebo did not result in a significant difference in the rates of change in either common carotid artery intima-media thickness or coronary artery calcium nor did it improve overall sexual function or health-related quality of life. Because this trial was only powered to evaluate atherosclerosis progression, these findings should not be interpreted as establishing cardiovascular safety of testosterone use in older men.
- Design: Retrospective cohort study (N=8709, length = 3 years) in men with testosterone < 300 ng/dl who underwent coronary angiography in the Veterans Affairs system between 2005 and 2011
- Exposure: Testosterone therapy vs No testosterone
- Primary outcome: Primary outcome was a composite of all-cause mortality, MI, and ischemic stroke
- Findings: Among a cohort of men in the VA health care system who underwent coronary angiography and had a low serum testosterone level, the use of testosterone therapy was associated with increased risk of adverse outcomes. These findings may inform the discussion about the potential risks of testosterone therapy.
Cognitive function
- Design: Subgroup analysis of a randomized placebo-controlled trial (N=493, length = 1 year) in men ≥ 65 years old with testosterone < 275 ng/dl
- Treatment: Testosterone gel vs Placebo gel. Dose was adjusted to maintain testosterone in the normal range.
- Primary outcome: Mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with age-associated memory impairment
- Results:
- Primary outcomes: There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with age-associated memory impairment in the testosterone and placebo groups (adjusted estimated difference, -0.07, 95%CI [-0.92 to 0.79], p=0.88)
- Findings: Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions
Bone health
- Design: Randomized, placebo-controlled trial (N=211, length = 1 year) in men ≥ 65 years old with testosterone < 275 ng/dl
- Treatment: Testosterone gel vs Placebo gel. Dose was adjusted to maintain testosterone in the normal range.
- Primary outcome: Spine and hip volumetric BMD (vBMD) as determined by quantitative computed tomography at baseline and 12 months. Bone strength estimated by finite element analysis of quantitative computed tomography data.
- Results:
- Primary outcome (increase in spine vBMD): Testosterone - 7.5%, Placebo - 0.8% (p<0.001)
- Findings: Testosterone treatment for 1 year of older men with low testosterone significantly increased volumetric BMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk.
Testosterone measurements
- Design: Randomized placebo-controlled trial (N=47, length = 24 hours) in men ≥ 65 years old with testosterone < 275 ng/dl
- Treatment: Testosterone gel vs Placebo gel for 16 weeks. Dose was adjusted to maintain testosterone between 400 - 800 ng/dl.
- Primary outcome: Variability of serum testosterone 2 hours after the gel application on two outpatient visits and at multiple time points over 24 hours during the inpatient day was measured
- Results:
- Ambulatory 2-hour postapplication testosterone levels did not correlate significantly with either 2-hour postapplication serum testosterone or average 24-hour testosterone measured during the inpatient day
- Findings: Large within-individual variations in serum testosterone after testosterone gel application render ambulatory 2-hour post application testosterone level a poor indicator of average serum testosterone on another day. Our data point out the limitations of dose adjustments based on a single postapplication serum testosterone measurement.
- BIBLIOGRAPHY
- 1 - PMID - 24119423 Lancet review 2014
- 2 - PMID - 20525905 Endocrine Soc GL
- 3 - European Association of Urology Guidelines on Male Hypogonadism 2014
- 4 - PMID 17148559 - Longitudinal study in American men
- 5 - PMID 23775354 - Longitudinal study in Australian men
- 6 - PMID 22563890 - Cross sectional study in well men
- 7 - PMID 21697255 - Testosterone levels in healthy men
- 8 - LabCorp® website
- 9 - PMID 21849522 - Correlation between levels and symptoms
- 10 - PMID 20525905 - Endocrine Soc male hypogonadism GL 2010
- 11 - PMID 24978674 - Trial of T replacement in diabetics
- 12 - PMID 23165659 - Testosterone added to viagra
- 13 - PMID 17285782 - May clinic sex fxn MA
- 14 - PMID 16181230 - Clin End sex fxn MA
- 15 - PMID 16720668 - MA of BMD trials
- 16 - PMID 16117815 - MA of body composition and lipid trials
- 17 - PMID 18167405 - JAMA trial in older men
- 18 - PMID 17496236 - DM Care study
- 19 - PMID 19625884 - Depression MA
- 20 - PMID 21386088 - DM Care TIMES study
- 21 - PMID 25139126 - MA of CV risk - no effect
- 22 - PMID 23597181 - MA of CV risk - effect
- 23 - PMID 16339333 - MA of prostate events
- 24 - PMID 25621688 - MA of PSA trials
- 25 - PMID 10522982 - Transdermal vs IM test
- 26 - PMID 20525906 - MA of erythrocytosis
- 27 - PMID 2400756 - Vegan diet and SHBG
- 28 - PMID 28078215 - Off label therapies for testosterone replacement, Translational Andrology and Urology (2016)
- 29 - PMID 27337642 - Enclomiphene Citrate for the Treatment of Secondary Male Hypogonadism, Expert Opin Pharmacother (2016)
- 30 - PMID 29562364 - Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab (2018)
- 31 - PMID 31905405 - Testosterone Treatment in Adult Men With Age-Related Low Testosterone: A Clinical Guideline From the American College of Physicians, Ann Intern Med (2020)
- 32 - PMID 33350323 - Monthly Variations in Serum Testosterone Levels: Results from Testosterone Screening of 8,367 Middle-Aged Men, J Urol (2021)