LOW TESTOSTERONE

• ACRONYMS AND DEFINITIONS

• BMD - Bone mineral density
• CVD - Cardiovascular disease
• DHT - Dihydrotestosterone
• EAU - European Association of Urology
• ED - Erectile dysfunction
• IPSS - International Prostate Symptom Score
• PSA - Prostate specific antigen
• RCT - Randomized controlled trial
• SERM - Selective estrogen receptor modulator
• SHBG - Sex-hormone binding globulin

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• TESTOSTERONE PHYSIOLOGY

• Overview
• Testosterone is the primary hormone involved in male sexual development and fertility. It also plays a vital role in muscle formation, body composition, bone health, and cognitive function.
• Lutenizing hormone from the pituitary stimulates the Leydig cells of the testes to produce 3 - 10 mg of testosterone a day. A small amount (5 - 8%) is converted to dihydrotestosterone (DHT), a more potent androgen, by the enzyme 5-alpha reductase. DHT is involved in prostate and external genitalia development, hair follicles (hair loss), and skin sebum production. An even smaller amount of testosterone (0.3 - 0.5%) is converted to estradiol by the enzyme aromatase. Estradiol plays an important role in bone health, cognitive function, and plasma lipid levels. Aromatase is present in fatty tissue, so obese men often overproduce estradiol.
• Follicle-stimulating hormone (FSH) stimulates testicular Sertoli cells, which support spermatogenesis [1,3]



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• SYMPTOMS OF LOW TESTOSTERONE

• Overview
• Symptoms of low testosterone depend on whether the deficiency occurs before or after puberty. Deficiency before puberty leads to developmental abnormalities, while deficiency after puberty has been associated with a broad array of symptoms.

• 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]

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• CAUSES OF LOW TESTOSTERONE

• Overview
  • Low testosterone occurs through two 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 consistent with primary hypogonadism include low testosterone and elevated FSH and LH
• Causes, risk factors, and symptoms of primary hypogonadism are presented in the tables below

References [1,2,3]

Primary hypogonadism
Cause	Risk factors/Symptoms/Other
Klinefelter's syndrome	1 in 600 births Small, firm testes or undescended testes Underdeveloped genitalia, infertility Reduced body hair, gynecomastia Tall stature, learning disabilities
Undescended testes or ectopic testes	Also called cryptorchidism 85% idiopathic
Testicular trauma	Blunt trauma Testicular torsion
Orchitis	Infections (ex. mumps)
Cancer treatment	Alkylating chemotherapeutic agents (ex. cyclophosphamide) Radiation
Varicocele	Possible cause
Defects of steroid biosynthesis	17,20 desmolase defect 17β-hydroxysteroid dehydrogenase defect
Y-chromosome defects	Microdeletions 46, XX male syndrome (1 in 10,000 - 20,000 births) 47,XYY syndrome (1 in 2,000 births)
Noonan syndrome	Cryptorchidism, short stature, short neck Deep philtrum, wide-spaced eyes, heart defects
LH receptor mutations	1 in 20,000 to 1 in 1,000,000 births Leydig cells do not develop

• Secondary hypogonadism
• Secondary hypogonadism occurs when the hypothalamus or pituitary fail to stimulate testosterone production. In studies, up to 85% of hypogonadism cases are secondary.
• Lab findings consistent with secondary hypogonadism include low testosterone with either low FSH/LH or inappropriately normal FSH/LH levels
• The etiology of secondary hypogonadism is unknown in 89% of cases, and most affected men carry a diagnosis of obesity, type two diabetes, or metabolic syndrome. Causes of secondary hypogonadism are presented in the table below. [28]

References [1,2,3,28,29]

Secondary hypogonadism
Cause	Comments
Unknown	Most common Often seen in obese men May be secondary to increased estradiol production in adipose tissue
Hyperprolactinemia	Prolactin-secreting pituitary adenomas Medications
Isolated hypogonadotropic hypogonadism (IHH)	GnRH deficiency
Kallmann syndrome	1 in 10,000 to 86,000 births GnRH deficiency and no sense of smell (anosmia) Cryptorchidism, cleft palate, hearing loss Bimanual synkinesis - movements of one hand are mirrored by the other hand
Hypopituitarism	Radiation therapy-induced Head trauma Infections (tuberculosis) Infiltrative diseases (hemochromatosis, sarcoidosis, histiocytosis) Vascular insufficiency (stroke) Congenital
Pituitary adenomas	Both hormone-secreting and inactive Visual field defects may be present (mass effect)
Prader-Willi syndrome	1 in 10,000 births Congenital disturbance of GnRH Chronic overeating, underdeveloped genitals Mild-to-moderate learning disabilities
Congenital adrenal hypoplasia with hypogonadotropic hypogonadism	1 in 12,500 births X-chromosome recessive disease
Pasqualini syndrome	Isolated LH deficiency
LH or FSH mutations	Mutations in the Beta subunit

• 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 with either low FSH/LH or inappropriately normal FSH/LH
• 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]

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• 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 had to be injected, but pharmaceutical developments have made it available in easy-to-apply gels and patches. These new, patent-protected dosage forms have incentivized 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 or no evidence to support many of the claims endorsed in advertising, and the long-term effects of testosterone therapy are mostly 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 a decline of 1 - 2% per year in men ≥ 30 years old, while others have found no effect. [4,5]
• A major confounder in these studies is the fact that men tend to gain weight with age, and weight gain is strongly associated with declining testosterone. To help control for this, a cross-sectional study compared testosterone levels across age groups 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. [PMID 22563890]
• 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 (e.g. diabetes, hypertension).

• Age-adjusted testosterone levels
• Normal testosterone values reported by laboratories typically range from 300 - 1200 ng/dl (10.4 - 40 nmol/l). These ranges are derived from a sample of healthy, nonobese men less than 40 years old. Given 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 this spectrum. [7,8]
• Testosterone levels from a random sample of men in the Boston, Massachusetts, area are shown in the table below. These ranges represent typical age-adjusted values.
• NOTE: The 95% CI (95% confidence interval) represents the middle 95th percentile, which is the range typically used by labs for normal values

• Ranges are based on log hormone concentrations since their distribution is skewed
• Reference [4]

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 controversial condition. Declining testosterone levels in most aging men are likely secondary to weight gain and its associated comorbidities, making low testosterone an indicator of poor health as opposed to a cause.

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• TESTOSTERONE LABS

• Overview
• Testosterone bound to protein is inactive, while unbound testosterone is active. Most testosterone circulates 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 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 (active).
• When measuring testosterone, the following values are often reported:
• 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 vary widely by lab. 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 upper limit was 850 ng/dl (range 726 - 1130). [PMID 26707506]
• The CDC offers laboratories a certification for measuring testosterone values in men. Some labs are CDC-certified, and many are not. Normal ranges for total testosterone in nonobese, young men (19 - 39 years) in the CDC-certified labs are 303 - 852 ng/dl. [30]
• Ranges are based on a sample of healthy, nonobese males less than 40 years old. See age-adjusted testosterone ranges for more.

• Proper measurement technique
• Blood testosterone levels follow a circadian rhythm, peaking in the morning before declining into the evening. Because of this, levels should be drawn in the morning. Some studies have also found a seasonal variation, with average levels being highest in January and lowest in May.
• Glucose and food intake can affect testosterone levels, so blood should be drawn after an overnight fast
• Levels that are mildly below the normal range should be confirmed with a repeat test, as studies have shown up to 30% of repeat values will be normal. Free testosterone and SHBG should also be checked. [2,32]
• FSH and LH levels may be appropriate to distinguish between primary and secondary hypogonadism

• Sex-hormone binding globulin (SHBG)
• Most testosterone circulates tightly bound to SHBG (≥ 50%)
• Changes in SHBG can affect the amount of free (active) testosterone
• SHBG and free testosterone should be checked in patients with borderline-low testosterone levels to see if alterations in SHBG have affected free levels
• 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]

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• 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

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• DIAGNOSIS

• Overview
• Once a man has been diagnosed with hypogonadism, further testing should be driven by history and physical exam findings. The majority of hypogonadism cases today are discovered through age-related hypogonadism screening. Further testing in these patients is likely to be of little value.
• Specific findings that should prompt further evaluation are listed in the table below

• Reference [1,2,3]

Finding	Considerations
Delayed or absent sexual development	Primary hypogonadism Consider genetic studies for Klinefelter's, etc.
Gynecomastia / galactorrhea	Consider hyperprolactinemia Check prolactin MRI to rule out prolactinoma Consider medications that raise prolactin (antipsychotics, metoclopramide, etc.)
Low impact fractures	Bone mineral density testing
Visual field defects	MRI to look for pituitary mass
Skin hyperpigmentation	Consider hemochromatosis Check iron level Diabetes and liver disease are commonly present
Centripetal obesity / moon facies / abdominal striae	Consider Cushing's syndrome

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• TESTOSTERONE AND ERECTILE DYSFUNCTION

• Testosterone levels and erectile dysfunction (ED)
• Testosterone plays an important role in erectile function. That being said, it appears that testosterone-related erectile dysfunction only occurs at very low levels.
• 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 only in the range of 0 - 230 ng/dl. The effect plateaued at 230 ng/dl, and no improvement was seen at higher levels. [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 (e.g. Viagra, Cialis) have also found no clear benefit of adding testosterone to these drugs [10,11,12]

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• TREATMENT OF LOW TESTOSTERONE

• Overview
• Patients with reversible hypogonadism (e.g. hyperprolactinemia) should have the underlying condition treated. Primary and secondary hypogonadism is treated with testosterone replacement therapy. Most testosterone replacement today is prescribed for age-related hypogonadism, which is a controversial practice.

• Professional recommendations
• In 2020, the American College of Physicians recommended that therapy for age-related low testosterone be offered to men with sexual dysfunction. It should not be used to improve energy, vitality, physical function, or cognition. Injectable products are preferred over other products because they are considerably cheaper. [31]

• Testosterone products
• See testosterone replacement therapies

• Estradiol and testosterone
• A small percentage of testosterone (0.3 - 0.5%) is converted into estradiol by the enzyme aromatase. Estradiol suppresses FSH and LH release from the pituitary, and this, in turn, decreases testosterone production in the testis (see HPT axis). High levels of aromatase are found in adipose tissue, which means overweight men often have high estradiol levels. Drugs that inhibit estradiol have been shown to increase testosterone levels, particularly in obese individuals.
• Clomiphene and the aromatase inhibitors letrozole and anastrozole inhibit estradiol and have been used to treat hypogonadism in obese men. Small studies have found them to be effective, but current guidelines do not address their use. [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) directly inhibit the aromatase enzyme, which lowers estradiol 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]

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• 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

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• MONITORING TESTOSTERONE THERAPY

• Reference [3,30]

Recommendations for monitoring therapy
EAU recommendations Therapy response - assess at 3, 6, and 12 months after initiating therapy and annually thereafter Testosterone level - there is insufficient data to recommend an ideal range. Therapy should restore levels to mid-normal range. Testosterone levels should be checked according to product guidelines. (see testosterone replacement therapies for product-specific recommendations) Hematocrit - obtain baseline level. Monitor at 3, 6, and 12 months after initiating therapy and annually thereafter. Decrease or discontinue therapy if elevated. PSA - obtain baseline PSA and rectal exam. Recheck PSA at 3, 6, and 12 months after initiating therapy and annually thereafter. Bone Mineral Density (BMD) - in men with abnormal BMD, recheck BMD at 6 months and 1 year after starting therapy, and annually thereafter Cardiovascular disease - men with baseline cardiovascular disease should be assessed by a cardiologist before starting therapy and monitored thereafter [3]
Endocrine Society recommendations Therapy response - assess at 3 to 12 months after initiating therapy and annually thereafter Testosterone level - recheck at 3 to 6 months after initiating therapy. Therapy should restore levels to mid-normal range. Therapy-specific recommendations: Testosterone enanthate or cypionate injections - measure serum testosterone concentrations midway between injections. If midinterval testosterone is > 600 ng/dL (24.5 nmol/L) or < 350 ng/dL (14.1 nmol/L), adjust dose or frequency. Transdermal gels - assess testosterone concentrations 2 - 8 hours following the gel application, after the patient has been on treatment for at least 1 week Transdermal patches - assess testosterone concentrations 3 - 12 hours after application Buccal tablet - assess testosterone concentrations immediately before or after application of fresh system Pellets - measure testosterone concentrations at the end of the dosing interval Testosterone undecanoate (Aveed) - measure serum testosterone levels at the end of the dosing interval just prior to the next injection See testosterone replacement therapies for more Hematocrit - obtain baseline level. Recheck at 3 to 6 months after initiating therapy and annually thereafter. If hematocrit is > 54%, stop therapy until decreases to safe level, evaluate patient for hypoxia and sleep apnea, reinitiate therapy at a reduced dose. Bone Mineral Density (BMD) - in men with abnormal BMD, recheck BMD after 1 to 2 years of testosterone therapy PSA - in men 55 - 69 years of age and for men 40 - 69 years of age who are at increased risk for prostate cancer (African Americans or men with first-degree relatives with prostate cancer), perform digital rectal examination and check PSA level before initiating treatment. Check PSA and perform digital rectal examination 3 - 12 months after initiating testosterone treatment, and then in accordance with guidelines for prostate cancer screening depending on the age and race of the patient. Obtain urology consult for the following: An increase in serum or plasma PSA concentration greater than 1.4 ng/ml within 12 months of initiating treatment PSA > 4 ng/ml Detection of a prostatic abnormality on digital rectal examination Worsening of lower urinary tract symptoms [30]

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• 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. Advertisements for this use insinuate a wide range of benefits, which are largely unproven. Testosterone trials are plagued by a number of issues, including small sample size, short length, use of different preparations, heterogeneous populations and outcome measures, and mixed results. Evidence of a benefit is strongest for a modest improvement in libido and bone density, while proof of other effects is weak and inconclusive.

• Erectile dysfunction (ED)
• The effect of testosterone replacement on erectile dysfunction is reviewed here - testosterone and ED

• Libido
• In trials, the effects of testosterone on libido have been inconsistent, but overall, it appears to have a modest benefit. Several meta-analyses of randomized placebo-controlled trials have found that testosterone significantly improves libido in men with 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 BMD (average +8%), but it did not significantly affect 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 and a slight increase in fat-free mass. A meta-analysis of randomized controlled trials found that body fat decreased an average of 6.2% with testosterone therapy when compared to placebo or control. There was no significant effect on body weight. [PMID 16117815]
• Trials evaluating muscle strength outcomes have been mixed. See physical function and vitality studies below. [2,16,17]

• Insulin resistance and diabetes
• Low testosterone levels are associated with insulin resistance and diabetes; this 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. [1,18,20]

• Cholesterol
• Testosterone therapy has mixed effects on cholesterol. In studies, HDL and total cholesterol declined while LDL remains unchanged. [16,17]

• Cognition (concentration, memory, etc.)
• A randomized controlled trial (N=493) that looked at the effects of testosterone on memory impairment in older men found no effect (see cognitive studies below). Results from other studies have been mixed. [2,17]

• Depression
• A small meta-analysis of randomized placebo-controlled trials that encompassed 355 patients found that testosterone therapy improved depressive symptoms when compared to placebo [PMID 21386088]

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• RISKS OF TESTOSTERONE THERAPY

• Overview
• No large randomized controlled trial has evaluated the long-term risks of testosterone therapy. Available evidence is from observational studies and meta-analyses of small trials. Because of this, a definitive link between testosterone and adverse outcomes cannot be established. A review of the available information is presented below

• Cardiovascular disease (CVD)
• One of the main concerns of testosterone therapy is that it will increase CVD risk. In 2015, the FDA issued a drug safety warning about a possible link between testosterone therapies and heart attacks and strokes. [FDA testosterone warning] The warning was based on data from observational studies and meta-analyses.
• Recent studies that have looked at the effects of testosterone on CVD have been mixed (see cardiovascular disease studies below). A randomized controlled trial designed to evaluate testosterone's effect on muscle strength was stopped early when the testosterone group had a higher incidence of cardiovascular-related events (see TOM trial below).
• Two meta-analyses that looked at the effects of testosterone on CVD came to differing conclusions, with one finding a link and the other none. The meta-analyses were limited because most of the trials were less than a 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, and this raises the concern that testosterone therapies could increase the risk of prostate cancer. No long-term trial has evaluated this issue, but studies have not found an association between endogenous levels of testosterone and prostate cancer risk.
• A meta-analysis of randomized controlled trials compared the rate of prostate events (defined as prostate biopsies, prostate cancers, increase in IPSS > 4, PSA > 4 ng/ml or PSA increment ≥ 1.5 ng/ml during treatment, and acute urinary retention) between testosterone therapy and placebo. Testosterone-treated men had a significantly higher risk of prostate events than placebo-treated men (OR 1.78, 95%CI [1.07 - 2.95]). For each individual event, there was no significant difference between the two groups, although these comparisons were likely underpowered. The study only encompassed 643 testosterone-treated men, and just 2 of the 19 studies lasted longer than a year. [PMID 16339333]
• Until better data is available, the effect of testosterone therapy on prostate cancer risk will remain unknown

• Prostate Specific Antigen (PSA) changes
• PSA is a protein produced by the prostate gland (see prostate specific antigen), and high serum levels are a marker for prostate cancer. Levels can also be elevated in benign conditions, including prostatic hypertrophy and prostatitis.
• Testosterone therapy can raise PSA levels, and treatment guidelines recommend PSA monitoring during 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 compared to control. Subgroup analysis showed that transdermal testosterone did not cause a significant increase in PSA (95%CI [-0.021 - 0.190], p=0.116), where intramuscular testosterone did (95%CI [0.117 - 0.425], p=0.001). [PMID 25621688]
• Testosterone therapy causes a slight increase in PSA levels; the long-term significance of this is unknown. Current Endocrine Society guidelines 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, an increase in red blood cell production, is stimulated by testosterone. A meta-analysis found that hemoglobin and hematocrit levels rose an average of 0.80 mg/dl (95%CI [0.45 - 1.14 mg/dl]) and 3.18% (95%CI [1.35 - 5%]), respectively, in men treated with testosterone. [PMID 20525906]
• Elevated red blood cell levels can theoretically increase the risk of venous thromboembolism (VTE). Two observational studies found an increased risk of VTE in men using testosterone. [PMID 27903495, PMID 31710339] A third study that looked at the association of hematocrit levels with thrombosis in the general population found that higher levels increased the risk of cardiac thrombosis but had no effect on VTE. [PMID 31309714]
• Testosterone therapy can raise hematocrit levels, theoretically increasing the risk of VTE. Levels should be monitored during therapy, and testosterone should be held or stopped if they rise above 54% (see monitoring therapy). [2,3]

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• TESTOSTERONE STUDIES

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• 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)