- What is testosterone replacement therapy
- What is the role of testosterone in men’s health?
- What causes low testosterone?
- What happens to testosterone levels with age?
- Does a naturally declining testosterone level cause the signs and symptoms of aging?
- How is low testosterone diagnosed?
- How is low testosterone treated?
- Can testosterone replacement therapy promote youth and vitality?
- Should I talk to my doctor about testosterone replacement therapy?
- Benefits of testosterone replacement therapy for men
- Testosterone replacement therapy contraindications
- Testosterone replacement therapy dosage
- Testosterone replacement therapy monitoring
- Testosterone replacement therapy risks
- What is the role of testosterone in men’s health?
What is testosterone replacement therapy
The indication of testosterone-replacement therapy treatment requires the presence of low testosterone level, and symptoms and signs of low testosterone or hypogonadism 1). Hypogonadism is seen in 19% of men in their 60s, 28% of men in their 70s, and 49% of men in their 80s 2). Low testosterone (hypogonadism) can be treated with the use of doctor-prescribed testosterone replacement therapy. Testosterone-replacement therapy treatment is safe and can be effective for men who are diagnosed with consistently abnormal low testosterone production and symptoms that are associated with this type of androgen (hormone) deficiency.
Testosterone is US Food and Drug Administration (FDA) approved as replacement therapy in men who have low testosterone levels and those with symptoms of hypogonadism 3). It is important to distinguish between primary (testicular) and secondary (pituitary-hypothalamic) hypogonadism. Symptoms highly suggestive of hypogonadism include decreased spontaneous erections, decreased nocturnal penile tumescence, decreased libido, decreased beard growth, and shrinking testicles. The normal range for early morning testosterone in a male is between 300 ng/dL to 1000 ng/dL 4).
Testosterone therapy is not FDA-approved to treat low libido in women.
While testosterone replacement therapy is the primary treatment option for men with low testosterone or hypogonadism, some conditions that cause hypogonadism are reversible without testosterone therapy. These should be addressed before testosterone therapy is contemplated. If testosterone therapy is needed, goal of treatment is to improve symptoms associated with testosterone deficiency and maintain sex characteristics. There are many different types of testosterone therapy. You should discuss the different options with your physician “your partner in care” to find out which therapy is right for you.
Hypogonadism is a common condition in the male population, with a higher prevalence in older men, obese men, and men with type 2 diabetes. If you are concerned about your testosterone levels It is important to talk to doctor about ways to manage.
Method of testosterone replacement therapy treatment depends on the cause of low testosterone, the patient’s preferences, cost, tolerance, and concern about fertility.
- Injections. Self or doctor administered in a muscle every 1–2 weeks; administered at a clinic every 10 weeks for longer-acting. Side effects: uncomfortable, fluctuating symptoms.
- Gels/Solutions. Applied to upper arm, shoulder, inner thigh, armpit. Side effects: may transfer to others via skin contact — must wait to absorb completely into skin.
- Patches. Adhere to skin every day to back, abdomen, upper arm, thigh; rotate locations to lessen skin reaction. Side effects: skin redness and rashes.
- Buccal Tablets. Sticky pill applied to gums twice a day, absorbs quickly into bloodstream through gums. Side effects: gum irritation.
- Pellets. Implanted under skin surgically every 3–6 months for consistent and long-term dosages. Side effects: pellet coming out through skin, site infection/ bleeding (rare), dose decreasing over time and hypogonadism symptoms possibly returning towards the end of dose period.
- Nasal Gel. Applied by pump into each nostril 3x a day. Side effects: nasal irritation or congestion.
Transdermal gels and intramuscular (IM) injections are the top 2 options 5).
Oral capsules and tablets of testosterone such as methyltestosterone should generally not be used to treat testosterone deficiency due to hepatic side effects and decreased efficacy when compared with other formulations 6). The buccal form should not be chewed or swallowed.
Transdermal formulations include testosterone gels, patches, solutions, and pellets. Testosterone gels are generally recommended due to patient preference, cost, convenience, and insurance coverage. The major advantage of gels is the maintenance of stable serum testosterone concentrations resulting in stable libido, energy, and mood. There are various formulations of testosterone gel. These gels should be applied to the shoulder, upper arms, or abdomen and should not be applied to the scrotum. A study showed the bioavailability of testosterone gel is 30% lower when applied to the abdomen as when compared with arms and shoulders 7).
A nasal testosterone gel is now approved in the United States. It should be given 3 times daily. Some patients may find this inconvenient. A testosterone patch should be applied to the back, abdomen, thigh or upper arm and should not be applied to the scrotum. A testosterone solution was discontinued by the FDA in 2017. Subcutaneous testosterone pellets are placed every 3 to 6 months into the subdermal fat of the buttocks, abdominal wall, or thigh but are not routinely recommended due to limited data on the serum testosterone concentrations during treatment.
Intramuscular injections of testosterone include testosterone enanthate and testosterone cypionate. These injections are generally recommended to be given at doses of 50 to 100 mg every week or 100 to 200 mg every 2 weeks 8). In 2014, the FDA approved an extra-long acting intramuscular injection form of testosterone called testosterone undecanoate, which is dosed at 750 mg followed by a second dose 4 weeks later and subsequent doses every 10 weeks 9). Testosterone undecanoate is not the first-line treatment of choice but generally used when patients do not have access to other forms of treatment.
What is the role of testosterone in men’s health?
Testosterone is a hormone produced primarily in the testicles. Testosterone is the most important sex hormone that men have. It is responsible for the typical male characteristics, such as facial, pubic, and body hair as well as muscle. Testosterone hormone also helps maintain sex drive, sperm production, and bone health. The brain and pituitary gland (a small gland at the base of the brain) control the production of testosterone by the testes.
Testosterone helps maintain men’s:
- Bone density
- Fat distribution
- Muscle strength and mass
- Facial and body hair
- Red blood cell production
- Sex drive
- Sperm production
What causes low testosterone?
Low testosterone can result from:
- Testicular injury (trauma, castration) or infection
- Radiation or chemotherapy treatment for cancer
- Some medications, such as opiate painkillers Hormone disorders (pituitary tumors or diseases, high levels of prolactin)
- Chronic diseases, such as liver and kidney disease, obesity, type 2 diabetes, and HIV/AIDS
- A genetic condition (Klinefelter syndrome, hemochromatosis, Kallmann syndrome, Prader-Willi syndrome, myatonic dystrophy)
- Anabolic Steroid use in the past
Low testosterone is common in older men. An accurate blood test needs to be done in the morning between 7am-10am.
What happens to testosterone levels with age?
Testosterone levels generally peak during adolescence and early adulthood. As you get older, your testosterone level gradually declines — typically about 1 percent a year after age 30 or 40. It is important to determine in older men if a low testosterone level is simply due to the decline of normal aging or if it is due to a disease (hypogonadism).
Hypogonadism is a disease in which the body is unable to produce normal amounts of testosterone due to a problem with the testicles or with the pituitary gland that controls the testicles. Testosterone replacement therapy can improve the signs and symptoms of low testosterone in these men. Doctors may prescribe testosterone as injections, pellets, patches or gels.
In the short term, low testosterone (also called hypogonadism) can cause:
- A drop in sex drive
- Poor erections
- Low sperm count
- Enlarged breasts
Over time, low testosterone may cause a man to lose body hair, muscle bulk, and strength and to gain body fat. Chronic (long-term) low testosterone may also cause weak bones (osteoporosis), mood changes, less energy, and smaller testes. Signs and symptoms (what you see and feel) vary from person to person.
Does a naturally declining testosterone level cause the signs and symptoms of aging?
Not necessarily. Men can experience many signs and symptoms as they age. Some may occur as a result of lower testosterone levels and can include:
- Changes in sexual function. This may include reduced sexual desire, fewer spontaneous erections — such as during sleep — and infertility.
- Changes in sleep patterns. Sometimes low testosterone causes insomnia or other sleep disturbances.
- Physical changes. Various physical changes are possible, including increased body fat, reduced muscle bulk and strength, and decreased bone density.
- Swollen or tender breasts (gynecomastia) and body hair loss are possible. You may have less energy than you used to.
- Emotional changes. Low testosterone may contribute to a decrease in motivation or self-confidence. You may feel sad or depressed, or have trouble concentrating or remembering things.
Some of these signs and symptoms can be caused by various underlying factors, including medication side effects, obstructive sleep apnea, thyroid problems, diabetes and depression. It’s also possible that these conditions may be the cause of low testosterone levels, and treatment of these problems may cause testosterone levels to rise. A blood test is the only way to diagnose a low testosterone level.
How is low testosterone diagnosed?
During a physical exam, your doctor will examine your body hair, breasts, penis, and the size and consistency of the testes and scrotum. Your doctor may check for loss of side (peripheral) vision, which could indicate a pituitary tumor, a rare cause of low testosterone.
Your doctor will also use blood tests to see if your total testosterone level is low. The normal range is generally 300 to 1,000 ng/dL, but this depends on the lab that conducts the test. To get a diagnosis of low testosterone, you may need more than one early morning (7–10 AM) blood test and, sometimes, tests of pituitary gland hormones.
If you have symptoms of low testosterone, your doctor may suggest that you talk with an endocrinologist. This expert in hormones can help find the cause. Be open with your doctor about your medical history, all prescription and nonprescription drugs you are now taking, sexual problems, and any major changes in your life.
Hypogonadism is diagnosed when the morning serum testosterone level is less than 300 ng/dL 10). However, clinical judgment is required when making the diagnosis of hypogonadism in a patient who has testosterone levels in the normal range but has persistent symptoms of testosterone deficiency 11). Of note, total testosterone less than 405.9 ng/dL is below the fifth percentile 12). In older men, one should aim for testosterone levels between 500 and 800 ng/dL while young adults should aim for testosterone levels between 600 and 900 ng/dL 13).
Initial laboratory testing should include 2 early mornings (8 AM to 10 AM) measurements of serum testosterone. If both measurements are low, then certain studies should be ordered to rule out secondary hypogonadism. Further testing includes FSH (follicle-stimulating hormone), LH (luteinizing hormone), prolactin, TSH (thyroid-stimulating hormone), complete blood count (CBC), and comprehensive metabolic panel. In cases of low normal testosterone with clinical symptoms, further testing to assess free or bioavailable testosterone should be done. These tests include sex hormone binding globulin (SHBG) and albumin to calculate the bioavailable testosterone which can be affected by obesity, type 2 diabetes, hypothyroidism, and liver disease.
Furthermore, semen analysis, pituitary MRI, testicular ultrasound and biopsy, and genetic studies can be ordered, if there is clinical suspicion of a secondary cause.
How is low testosterone treated?
Testosterone replacement therapy can improve sexual interest, erections, mood and energy, body hair growth, bone density, and muscle mass. There are several ways to replace testosterone:
- Gel or patches that you put on your skin
- Injections (shots)
- Tablets that stick to the gums
- Pellets inserted under the skin or pills (in some countries outside the United States)
The best method will depend on your preference and tolerance, and the cost.
There are potential risks with long-term use of testosterone. You should discuss with your physician how to monitor for prostate cancer and other risks to your prostate. Men with known or suspected prostate cancer, or with breast cancer, should not receive testosterone treatment.
Other possible risks of testosterone treatment include:
- A high red blood cell count
- Breast enlargement
- An increase in prostate size
- Sleep apnea—the occasional stopping of breathing during sleep (rarely)
- Fluid buildup (edema) in ankles, feet and legs (rarely)
Can testosterone replacement therapy promote youth and vitality?
Testosterone replacement therapy can help reverse the effects of hypogonadism, but it’s unclear whether testosterone replacement therapy would have any benefit for older men who are otherwise healthy.
Although some men believe that taking testosterone medications may help them feel younger and more vigorous as they age, few rigorous studies have examined testosterone therapy in men who have healthy testosterone levels. And some small studies have revealed mixed results. For example, in one study healthy men who took testosterone medications increased muscle mass but didn’t gain strength.
Should I talk to my doctor about testosterone replacement therapy?
If you wonder whether testosterone therapy might be right for you, talk with your doctor about the risks and benefits. Your doctor will likely measure your testosterone levels at least twice before discussing whether testosterone replacement therapy is an option for you.
A medical condition that leads to an unusual decline in testosterone may be a reason to take supplemental testosterone. However, treating normal aging with testosterone therapy is not currently advisable.
Your doctor will also likely suggest natural ways to boost testosterone, such as losing weight and increasing muscle mass through resistance exercise.
Benefits of testosterone replacement therapy for men
- Low testosterone comes with age — testosterone levels naturally decrease by 1% each year after age 30, though don’t severely deplete, even in advanced age
- Testosterone production may be disrupted by disorders of the testicles, pituitary gland, or brain
- Testosterone levels change from hour to hour — highest in the morning; lowest at night
- Testosterone levels can temporarily lower due to too much exercise, poor nutrition, severe illness, and with certain medications
- Normal testosterone levels should be between 300–1,000 ng/dL (nanograms per deciliter), depending on age and lab used
- Testosterone must be measured more than once for accurate assessment
Testosterone therapy is only recommended for hypogonadism patients. Boosting testosterone is NOT approved by the US Food and Drug Administration (FDA) to help improve your strength, athletic performance, physical appearance, or to treat or prevent problems associated with aging. Using testosterone for these purposes may be harmful to your health.
Male hypogonadism is a combination of low testosterone levels and the presence of any of these symptoms:
- Drop in sex drive (libido)
- Erectile dysfunction (ED — inability to get or keep an erection) and loss of spontaneous erections
- Lowered sperm count and infertility (inability to have children)
- Breast enlargement or tenderness
- Reduced energy
- Reduced muscle mass
- Shrinkage of testes
- Increased irritability, inability to concentrate, and depressed mood
- Hot flashes (when testosterone levels are very low)
You should NOT receive testosterone therapy if you have:
- Prostate or breast cancer (or suspected)
- Enlarged prostate causing difficulty with urination
- Elevated prostate specific antigen (PSA) levels
- High number of red blood cells
- Untreated sleep apnea (obstructed breathing during sleep)
- Planning to have children
- Heart attack or stroke within the last 6 months
- Blood clots
Testosterone replacement therapy contraindications
Contraindications to testosterone replacement therapy include 14):
- History of breast cancer
- Prostate cancer
- Uncontrolled heart failure
- Myocardial infarction or cerebrovascular accident within the past 6 months
- Untreated obstructive sleep apnea
- Hematocrit over 48%
- Men planning fertility
- A palpable undiagnosed prostate nodule
- An elevated PSA above 4 ng/mL
- An elevated PSA level above 3vng/mL in high-risk patients including African Americans and men with a first-degree relative with prostate cancer.
Testosterone replacement therapy dosage
Adult Male Dose for Hypogonadism
- Primary hypogonadism (congenital or acquired): Testicular failure due to conditions such as cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, Klinefelter Syndrome, chemotherapy, or toxic damage from alcohol or heavy metals. These men usually have low serum testosterone concentrations and gonadotropins (FSH, LH) above the normal range.
- Hypogonadotropic hypogonadism (congenital or acquired): Gonadotropin or luteinizing hormone-releasing hormone (LHRH) deficiency or pituitary-hypothalamic injury from tumors, trauma, or radiation. These men have low testosterone serum concentrations but have gonadotropins in the normal or low range.
- Testosterone Undecanoate: 750 mg (3 mL) IM injection followed by 750 mg (3 mL) injected after 4 weeks, then 750 mg (3 mL) every 10 weeks thereafter
- Testosterone Enanthate and Cypionate: 50 to 400 mg IM injection every 2 to 4 weeks
- 2 to 6 pellets (75 mg each) implanted subcutaneously every 3 to 6 months.
- The number of pellets to be implanted depends upon the minimal daily requirements of testosterone propionate administered parenterally. Thus, implant two 75 mg pellets for each 25 mg testosterone propionate required weekly.
- The chronological and skeletal ages must be taken into consideration, both in determining the initial dose and in adjusting the dose.
- This drug should be used only if the benefits outweigh the serious risks of pulmonary oil microembolism and anaphylaxis.
- Injections more frequently than every two weeks are not recommended.
- Adequate effect of the implants (pellets) continues for three to four months, sometimes as long as six months.
- Mucoadhesive Oral Patch: Apply a 30 mg patch to the gum region twice a day; morning and evening (about 12 hours apart).
- Transdermal Film: 2 to 6 mg applied to the back, abdomen, upper arm, or upper thigh once a day, preferably at night.
- Gel (in tubes, packets or spray): 5 g applied once a day, preferably in the morning. Consult the manufacturer product information for specific dosage and additional instructions of use.
- Transdermal Solution: Initial dose is 60 mg of testosterone (1 pump actuation of 30 mg of testosterone to each axilla), applied once a day, at the same time each morning. Consult the manufacturer product information for specific dosage and additional instructions of use.
Comments: Prior to initiating therapy with this drug, confirm the diagnosis of hypogonadism by ensuring that serum testosterone concentrations have been measured in the morning on at least two separate days, and that these serum testosterone concentrations are below the normal range.
Pediatric Male Dose for Delayed Puberty
Use: To stimulate puberty in selected males with clearly delayed puberty
- Testosterone Enanthate: 50 to 200 mg every 2 to 4 weeks for 4 to 6 months
- 2 pellets (each pellet contain 75 mg of testosterone) implanted subcutaneously every 3 to 6 months
- Duration of therapy: 4 to 6 months
- The chronological and skeletal ages should be taken into consideration when determining the initial dose and when adjusting the dose.
- An X-ray of the hand and wrist to determine bone age should be obtained every six months to assess the effect of treatment on the epiphyseal centers.
- Report frequent or persistent erections.
- Androgen therapy should be used very cautiously in children and only by specialists who are aware of the adverse effects on bone maturation.
Renal Dose Adjustments
- Testosterone Cypionate IM injection: Contraindicated in renal disease
Liver Dose Adjustments
- Testosterone Cypionate IM injection: Contraindicated in liver disease
- The doses of this drug should be adjusted according to the patient’s response and the appearance of adverse reactions.
Testosterone replacement therapy monitoring
Lab tests needed before starting androgen replacement include hemoglobin, hematocrit (red blood cell count), liver function tests, lipid panel, digital rectal exam, PSA level, 2-morning testosterone levels, and consider a DEXA scan.
Monitoring should be done as follows 15):
- One month after treatment: morning testosterone level
- Three to 6 months after treatment during 1 year: morning testosterone level, liver function tests, lipid profile, PSA, digital rectal exam, estradiol, hemoglobin, and hematocrit, blood pressure
- Annually after 1 year: morning testosterone level, liver function tests, lipid profile, digital rectal exam, PSA, estradiol, Hgb, and hematocrit (red blood cell count), blood pressure
Referral to urology is recommended if there is an increase in PSA level greater than 1.4 ng/mL within any 12-month period. If hematocrit rises above 54%, then stop therapy as soon as possible 16). It is important to look out for signs of sleep apnea on annual follow-up visits. DEXA scans need to be repeated 1 to 2 years after initiating therapy in hypogonadal men with osteoporosis 17). Hyperestrogenism can be a side effect of replacement therapy because testosterone can be aromatized to estrogen 18). Aromatase inhibitors may need to be prescribed. Therefore, estradiol levels in men need to be assessed to rule out hyperestrogenism. Physicians need to regularly monitor patients receiving testosterone therapy and should discontinue therapy in those who fail to follow up.
Testosterone replacement therapy risks
Testosterone replacement therapy has various risks. For example, testosterone therapy may:
- Elevate red blood cell count (erythrocytosis), thereby increasing the risk of blood clots or venous thromboembolism 19)
- Cause acne or other skin reactions
- Contribute to sleep apnea — a potentially serious sleep disorder in which breathing repeatedly stops and starts
- Stimulate noncancerous growth of the prostate (benign prostatic hyperplasia) and growth of existing prostate cancer
- Enlarge breasts
- Limit sperm production or cause testicle shrinkage
- Increase the risk of a blood clot forming in a deep vein (deep vein thrombosis), which could break loose, travel through your bloodstream and lodge in your lungs, blocking blood flow (pulmonary embolism)
In addition, testosterone therapy may impact your risk of heart disease. Research has had conflicting results, so the exact risk isn’t clear yet. Most notable are the TOM (Testosterone in Older Men) trial and the TEAAM (Testosterone’s Effects on Atherosclerosis Progression in Aging Men) trials. Low testosterone levels have been associated with increased risk of coronary artery disease 20). Published in JAMA 2017, a study 21) found that testosterone replacement was associated with a lower risk of cardiovascular outcomes. In 2015, the FDA concluded a possible increased cardiovascular risk associated with testosterone use requiring labeling change to inform the public. The FDA requires that you are made aware that the possibility of cardiovascular events may exist during treatment.
The American Association of Clinical Endocrinologists 22) issued a guideline in response to the 2015 FDA labeling requirement on cardiovascular risk and stated that there is no compelling evidence that testosterone therapy increases cardiovascular risk. On the other hand, testosterone deficiency has been associated with falls, sarcopenia, frailty, osteopenia, and osteoporosis 23).
Serum PSA levels can increase in response to testosterone treatment, so it is important to rule out prostate cancer before starting therapy as it can worsen the disease process. Patients on replacement therapy need to be reevaluated for prostate cancer at 3 months and 1 year after beginning treatment 24).
There is no firm scientific evidence that long-term testosterone replacement is associated with either prostate cancer or cardiovascular events. Prostate cells are stimulated by testosterone, so be extra vigilant about cancer screenings. African American men over age 45 — especially those with family history of cancer — are already at risk for prostate cancer.
References [ + ]
|1.||↵||Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther Clin Risk Manag. 2009;5(3):427–448. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701485/|
|2.||↵||Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR., Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J. Clin. Endocrinol. Metab. 2001 Feb;86(2):724-31|
|3, 5, 6, 10, 13.||↵||Sizar O, Pico J. Androgen Replacement. [Updated 2018 Dec 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534853|
|4.||↵||Vermeulen A, Kaufman JM. Diagnosis of hypogonadism in the aging male. Aging Male. 2002 Sep;5(3):170-6.|
|7.||↵||Miller J, Britto M, Fitzpatrick S, McWhirter C, Testino SA, Brennan JJ, Zumbrunnen TL. Pharmacokinetics and relative bioavailability of absorbed testosterone after administration of a 1.62% testosterone gel to different application sites in men with hypogonadism. Endocr Pract. 2011 Jul-Aug;17(4):574-83|
|8.||↵||Snyder PJ, Lawrence DA. Treatment of male hypogonadism with testosterone enanthate. J. Clin. Endocrinol. Metab. 1980 Dec;51(6):1335-9.|
|9.||↵||Schubert M, Minnemann T, Hübler D, Rouskova D, Christoph A, Oettel M, Ernst M, Mellinger U, Krone W, Jockenhövel F. Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism. J. Clin. Endocrinol. Metab. 2004 Nov;89(11):5429-34.|
|11.||↵||Carnegie C. Diagnosis of hypogonadism: clinical assessments and laboratory tests. Rev Urol. 2004;6 Suppl 6:S3-8.|
|12.||↵||Bhasin S, Pencina M, Jasuja GK, Travison TG, Coviello A, Orwoll E, Wang PY, Nielson C, Wu F, Tajar A, Labrie F, Vesper H, Zhang A, Ulloor J, Singh R, D’Agostino R, Vasan RS. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J. Clin. Endocrinol. Metab. 2011 Aug;96(8):2430-9.|
|14, 15, 16.||↵||Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2018 May 01;103(5):1715-1744|
|17.||↵||Golds G, Houdek D, Arnason T. Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health. Int J Endocrinol. 2017;2017:4602129|
|18.||↵||Tan RS, Cook KR, Reilly WG. High estrogen in men after injectable testosterone therapy: the low T experience. Am J Mens Health. 2015 May;9(3):229-34|
|19.||↵||Ponce OJ, Spencer-Bonilla G, Alvarez-Villalobos N, Serrano V, Singh-Ospina N, Rodriguez-Gutierrez R, Salcido-Montenegro A, Benkhadra R, Prokop LJ, Bhasin S, Brito JP. The efficacy and adverse events of testosterone replacement therapy in hypogonadal men: A systematic review and meta-analysis of randomized, placebo-controlled trials. J. Clin. Endocrinol. Metab. 2018 Mar 17|
|20.||↵||Rosano GM, Sheiban I, Massaro R, Pagnotta P, Marazzi G, Vitale C, Mercuro G, Volterrani M, Aversa A, Fini M. Low testosterone levels are associated with coronary artery disease in male patients with angina. Int. J. Impot. Res. 2007 Mar-Apr;19(2):176-82|
|21.||↵||Cheetham TC, An J, Jacobsen SJ, Niu F, Sidney S, Quesenberry CP, VanDenEeden SK. Association of Testosterone Replacement With Cardiovascular Outcomes Among Men With Androgen Deficiency. JAMA Intern Med. 2017 Apr 01;177(4):491-499.|
|22.||↵||Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, Cunningham GR., AACE Reproductive Endocrinology Scientific Committee. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF TESTOSTERONE AND CARDIOVASCULAR RISK. Endocr Pract. 2015 Sep;21(9):1066-73.|
|23.||↵||Hsu B, Cumming RG, Handelsman DJ. Testosterone, frailty and physical function in older men. Expert Rev Endocrinol Metab. 2018 May;13(3):159-165.|
|24.||↵||Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 2018 May 01;103(5):1715-1744.|