LOW TESTOSTERONE

• ACRONYMS AND DEFINITIONS

• ACP - American College of Physicians
• AUA - American Urological Association
• BMD - Bone mineral density
• CVD - Cardiovascular disease
• DHT - Dihydrotestosterone
• EAU - European Association of Urology
• ED - Erectile dysfunction
• IPSS - International Prostate Symptom Score
• LH - Lutenizing hormone
• 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.

• AUA 2018 recommendations
• The AUA states that a testosterone value < 300 ng/dl should be considered low [33]

• 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

• Reference [33]

AUA 2018 Recommendations for Diagnosing Testosterone Deficiency
Step 1 - Whom to test Check a total testosterone level (proper measurement) in men with any of the following: Signs and symptoms of low testosterone - see symptoms Unexplained anemia Bone density loss Diabetes Exposure to chemotherapy Direct or scatter radiation therapy to the testes HIV History of chronic narcotic use Infertility Pituitary disorders Chronic corticosteroid use If level is less than 300 ng/dl, proceed to Step 2
Step 2 - Further testing Repeat the total testosterone level (proper measurement) and also order an LH and hematocrit For patients with findings consistent with less common etiologies, consider other testing below Hematocrit < 50%, high-normal or elevated LH, and total testosterone < 300 ng/dl Testosterone deficiency confirmed. Order a PSA in men ≥ 40 years old. Hematocrit > 50%, and total testosterone < 300 ng/dl Evaluate for polycythemia (e.g. polycythemia vera, sleep apnea, smoking) before starting therapy LH low or low-normal and total testosterone < 300 ng/dl Order prolactin level and proceed to Step 3
Step 3 - Prolactin results If prolactin is elevated, order pituitary MRI and refer to endocrinology If prolactin is normal, testosterone deficiency is confirmed. Order a PSA in men ≥ 40 years old.

• Reference [1,2,3]

Findings that may indicate a need for other testing
Finding	Considerations
Delayed or absent sexual development	Primary hypogonadism LH and FSH are usually very high Consider karyotyping to look for Klinefelter's (47,XXY) and other abnormalities
Gynecomastia / galactorrhea	Consider hyperprolactinemia Check prolactin and estradiol levels 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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• 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.

• AUA 2018 treatment recommendations
• Whom to treat
• Men with a total testosterone level < 300 ng/dl combined with symptoms and/or signs of low testosterone are candidates for treatment
• Therapy recommendations
• Lifestyle modification, including weight loss and physical activity, can raise testosterone levels and should be recommended in all appropriate patients
• FDA-approved commercial products are preferred over compounded products
• Testosterone-deficient patients with low or low-normal LH levels are also candidates for selective estrogen receptor modulator use (e.g. clomiphene) as a treatment for testosterone deficiency, particularly those wishing to preserve their fertility
• Therapy should not be started within 3 - 6 months of a cardiovascular event
• Clinicians may use aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators, or a combination thereof in men with testosterone deficiency desiring to maintain fertility
• Men with prostate cancer
• Previously-treated or in-situ prostate cancer on active surveillance - provider and patient must weigh potential benefits and unknown risks of testosterone therapy. There are limited data on men on active surveillance who are candidates for testosterone therapy. Available literature indicate that patients with and without high-grade prostatic intraepithelial neoplasias who were on testosterone therapy did not experience significant increases in PSA or subsequent cancer diagnosis compared to men not receiving testosterone.
• Locally advanced or metastatic disease - should only receive testosterone in a research setting
• Post-radical prostatectomy - if the patient has favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes) and an undetectable PSA, testosterone therapy can be considered. Limited data have demonstrated no significant increases in prostate cancer recurrence in men treated with testosterone compared to controls, although an increase in PSA among men in high-risk groups receiving testosterone has been shown, highlighting the need for appropriate patient selection.
• Radiation therapy - available studies evaluating the safety of testosterone therapy in men treated with radiation therapy have suggested that after radiation therapy, patients (with or without a history of androgen deprivation therapy) do not experience recurrence or progression of prostate cancer and experienced either a steady decline in PSA values to < 0.1 ng/mL or had nonsignificant changes in PSA. [33]

• ACP 2020 treatment 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, and the AUA guidelines list them as an option in men with low or low-normal LH levels and those who desire to maintain fertility. [28,29,33]

• 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
AUA 2018 recommendations Target total testosterone range - 450 to 600 ng/dl Therapy response - assess response at 3 - 6 months. If symptoms have not improved, discontinue testosterone. Testosterone levels - intervals for checking levels during initiation depend on the product (see below). After a proper dose has been determined, levels can be checked every 6 - 12 months. Topical gels, patches, and intranasal formulations - check 2 to 4 weeks after starting. Therapy should be applied on the day of testing. Short-acting intramuscular or subcutaneous testosterone (testosterone cypionate or enanthate) - check no earlier than 3 - 4 cycles Long-acting intramuscular testosterone (testosterone undecanoate) - check halfway between the first two 10-week injections Long-acting subcutaneous pellets - The first testosterone measurement should be obtained two to four weeks after initial implant to determine if the number of inserted pellets needs to be increased or decreased to achieve the appropriate therapeutic level. Patients should then be tested after 10 - 12 weeks to determine when the next administration should occur. Anastrozole, clomiphene citrate, or hCG - test no earlier than 4 weeks after starting See testosterone replacement therapies for more Hematocrit - check before therapy and do not start testosterone unless hematocrit is < 50%. Measure every 6 - 12 months during therapy. If levels rise above 54% and the patient's testosterone level is high or high-normal, reduce the testosterone dose. If the patient's testosterone level is normal or low-normal, consider phlebotomy. PSA - check before therapy in men ≥ 40 years and those with a history of prostate cancer. During therapy, check PSA in accordance with recommended screening (see AUA screening recommendations). For men with a history of prostate cancer, check according to cancer therapy guidelines or more frequently, if desired. LH - in men receiving SERM therapy (e.g. clomiphene), measure 4 weeks after initiating therapy, and if loss of response occurs [33]
Endocrine Society 2018 recommendations Target total testosterone range - therapy should restore levels to the mid-normal range Therapy response - assess at 3 to 12 months after initiating therapy and annually thereafter Testosterone level - check level 3 to 6 months after initiating therapy. Therapy-specific recommendations for timing blood draws are provided below. 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 (see prostate cancer screening recommendations). 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]
EAU 2014 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]

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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
• 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]

• 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
• Testosterone stimulates red blood cell production (erythropoiesis). Hemoglobin and hematocrit levels typically rise during the first six months of therapy before plateauing. Studies have shown that the degree of erythropoiesis varies by testosterone product, with the following increases in average hemoglobin being seen:
• Short-acting IM testosterone - 1.6 mg/dl
• Long-acting IM testosterone - 1.4 mg/dl
• Transdermal testosterone - 0.9 mg/dl
• Topical patches - 0.7 mg/dl [33]
• 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, possible 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]

• Infertility
• Exogenous testosterone suppresses sperm production by inhibiting pituitary FSH release through negative feedback. After therapy cessation, it can take months for sperm counts to return to normal. In a review encompassing 30 studies and 1549 men, recovery to 20 million sperm/ml (a level indicative of fertility) occurred in 67% of men within 6 months of cessation, 90% within 12 months, and 100% within 2 years. [33,34]

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• TESTOSTERONE STUDIES

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• BIBLIOGRAPHY

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