TESTOSTERONE

• ACRONYMS AND DEFINITIONS

• DHT - Dihydrotestosterone
• EAU - European Association of Urology
• ED - Erectile dysfunction
• PSA - Prostate specific antigen
• SERM - Selective estrogen receptor modulator

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• 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 hair line
• 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 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
  • 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

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 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]

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 levels with either low FSH/LH levels or inappropriately normal FSH/LH levels
• Combined hypogonadism is seen in some disease states

References [1,2,3]

Combined hypogonadism
Alcoholism
Age-related hypogonadism
Cirrhosis
Corticosteroid treatment
DAX-1 mutation
Hemochromatosis
Sickle cell disease
Thalassemia

• DISEASE STATES ASSOCIATED WITH HYPOGONADISM
• In certain diseases, hypogonadism is highly prevalent

References [1,2,3]

Diseases associated with hypogonadism
HIV - particularly in wasting syndrome
End stage kidney disease
COPD, moderate-to-severe
Type 2 diabetes
Obesity

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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 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 only 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 conclusion, 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

• 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)

• StraightHealthcare analysis:
• 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

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• MEASURING TESTOSTERONE LEVELS

• 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

• - To convert ng/dl to nmol/l, multiply ng/dl by 0.0347
• ¹CPL labs, ²LabCorp®, ³PMID 26707506

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)

• CHECKING TESTOSTERONE LEVELS
• Blood testosterone levels follow a circadian rhythm with levels peaking in the morning and then declining into the evening
• Testosterone levels should be drawn in the morning
• Glucose and food intake also affect testosterone levels so the 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]
• 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 presented in the table below

• References [1,2,27]

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

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• MEDICATIONS THAT MAY CAUSE LOW TESTOSTERONE

Medications that may cause low 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
Seizure and mood stabilizer medications

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• DIAGNOSTIC WORKUP

• 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

• 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) 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 [9]


• 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.
• 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]

• StraightHealthcare analysis:
• 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

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• 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.


• Testosterone products
• See testosterone replacement therapies for a review of prescription testosterone products

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• CONTRAINDICATIONS TO TESTOSTERONE THERAPY

• Contraindications to testosterone therapy include the following:
• Prostate cancer¹^,²
• Breast cancer¹^,²
• PSA > 4 ng/ml¹^,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 apnea¹^,²
• Poorly controlled heart failure²
• Men desiring fertility¹^,²
• Hematocrit > 48%¹^,²
• Severe BPH symptoms¹^,²


• ¹ EAU recommendation
• ² Endocrine Society recommendation

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• MONITORING TESTOSTERONE THERAPY

• Overview
• The EAU and Endocrine Society give slightly different recommendations for monitoring testosterone therapy
• Recommendations for checking testosterone levels and adjusting therapy vary by product (see testosterone replacement therapies for product-specific recommendations)


• 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
  • Bucal 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
• 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 conclusion 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 discussed 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. [15]
• 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. [16]
• 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]


• 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.)
• Results from studies evaluating the effects of testosterone on cognition have been mixed. In general, there is no good evidence testosterone improves cognition of any kind. [2,17]


• 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]

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• 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/Thromboembolism
• Erythrocytosis is an increase in the production of red blood cells
• Testosterone stimulates erythrocytosis by increasing erythropoietin production and stimulating bone marrow [1]
• Elevated red blood cell levels may theoretically increase the risk of vascular thromboembolism. An observational study published in 2016 found a small increase in risk of venous thromboembolism among men who recently started testosterone therapy. [PubMed abstract]
• 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 [26]
• 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]

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• 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 [PubMed abstract]
• 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) [PubMed abstract]


• 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 [PubMed abstract]
• 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) [PubMed abstract]

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• TESTOSTERONE STUDIES

• Physical function and vitality

• Effects of Testosterone Treatment in Older Men - NEJM (2016) [PMID 26886521]
• DESIGN: Randomized, placebo-controlled trials (N=790, length=1 year)
• PRIMARY OUTCOMES: 1. Sexual function 2. 6-minute walking distance 3. Functional Assessment of Chronic Illness Therapy-Fatigue scale
• 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.


• Adverse events associated with testosterone administration - The TOM trial - NEJM (2010) [PMID 20592293]
• DESIGN: Randomized, placebo-controlled trial (N=209, length=6 months)
• PRIMARY OUTCOME: Change from baseline in maximal voluntary muscle strength in a leg-press exercise
• 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

• Effects of Testosterone Treatment in Older Men - NEJM (2016) [PMID 26886521]
• DESIGN: Randomized, placebo-controlled trials (N=790, length=1 year)
• PRIMARY OUTCOMES: 1. Sexual function 2. 6-minute walking distance 3. Functional Assessment of Chronic Illness Therapy-Fatigue scale
• 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.


• Testosterone Replacement in Androgen-Deficient Men With Ejaculatory Dysfunction: A Randomized Controlled Trial - J Clin Endocrinol Metab (2015) [PMID 26158605]
• DESIGN: Randomized, placebo-controlled trial (N=76, length=16 week)
• 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)
• FINDINGS: Seventy-six participants were randomized; 66 completed the study. Baseline demographic and clinical characteristics were comparable between the treatment arms. T replacement improved the MSHQ-EjD-SF score (mean score change, +3.1); however, this effect was not statistically different from placebo (mean score change, +2.5; P = .596). No differences were seen in any of the secondary outcomes or frequency of adverse events.


• Effect of testosterone treatment on constitutional and sexual symptoms in men with type 2 diabetes in a randomized, placebo-controlled clinical trial - J Clin Endocrinol Metab (2014) [PMID 24978674]
• DESIGN: Randomized, placebo-controlled trial (N=88, length=40 weeks)
• 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)
• FINDINGS: In this trial, T treatment did not substantially improve constitutional or sexual symptoms in obese, aging men with T2D with mild to moderate symptoms and modest reduction in T levels typical for the vast majority of such men.



• Cardiovascular disease risk

• Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone - JAMA (2017) [PMID 28241355]
• DESIGN: Randomized, placebo-controlled trial (N=138, length=12 months)
• PRIMARY OUTCOME: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography
• 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.


• Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. - JAMA (2015) [PMID 26262795]
• DESIGN: Randomized, placebo-controlled trial (N=308, length=3 years)
• PRIMARY OUTCOME: Coprimary outcomes included common carotid artery intima-media thickness and coronary artery calcium
• 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.


• Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels - JAMA (2013) [PubMed abstract]
• DESIGN: Retrospective cohort study (N=8709, length=3 years)
• EXPOSURE: Testosterone therapy vs no therapy
• 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

• Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment - JAMA (2017) [PMID 28241356]
• DESIGN: Subgroup analysis of a randomized, placebo-controlled trial (N=493, length=1 year)
• PRIMARY OUTCOME: Mean change from baseline to 6 months and 12 months for delayed paragraph recall
• 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 studies

• Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial - JAMA Intern Med (2017) [PMID 28241231]
• DESIGN: Randomized, placebo-controlled trial (N=211, length=1 year)
• PRIMARY OUTCOME: Spine and hip volumetric BMD as determined by quantitative computed tomography at baseline and 12 months. Bone strength estimated by finite element analysis of quantitative computed tomography data.
• 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

• Serum Testosterone (T) Level Variability in T Gel-Treated Older Hypogonadal Men: Treatment Monitoring Implications - J Clin Endocrinol Metab (2015) [PMID 26120790]
• DESIGN: Randomized, placebo-controlled trial (N=47, length=24 hours)
• 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
• 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.

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• BIBLIOGRAPHY

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