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Androgen Replacement

Editor: Jose Pico Updated: 3/22/2022 8:25:23 AM

Hypogonadism occurs in 19% of men in their 60s, 28% of men in their 70s, and 49% of men in their 80s.[1]

  • Testosterone is FDA-approved as replacement therapy in men who have low testosterone levels and those with symptoms of hypogonadism.
  • Testosterone is also FDA-approved for use in congenital or acquired hypogonadotropic hypogonadism (when there is a pituitary-hypothalamic injury, LHRH deficiency, or gonadotropin deficiency) resulting from tumors, trauma, or radiation.

It is essential 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. In males, the normal range for early morning testosterone is between 300 ng/dL to 1000 ng/dL.[2]

Hypogonadism is diagnosed when the morning serum testosterone level is less than 300 ng/dL. However, clinical judgment is required when diagnosing hypogonadism in a patient with testosterone levels in the normal range but persistent testosterone deficiency symptoms.[3] Of note, total testosterone less than 405.9 ng/dL is below the fifth percentile.[4] In senior men, one should aim for testosterone levels between 500 and 800, while young adults should aim for testosterone levels between 600 and 900.

Initial laboratory testing should include two early mornings (8 AM to 10 AM) serum testosterone measurements. In addition, certain studies should be ordered to rule out secondary hypogonadism if both measurements are low. Further testing includes FSH (follicle-stimulating hormone), LH (luteinizing hormone), prolactin, TSH (thyroid-stimulating hormone), complete blood count (CBC), and comprehensive metabolic panel (CMP). In cases of low normal testosterone with clinical symptoms, further testing to assess free or bioavailable testosterone is necessary. 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 are options if there is clinical suspicion of a secondary cause. Testosterone therapy is not FDA-approved to treat low libido in women.

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Testosterone has many biologic effects as it can act as three hormones. Testosterone can act directly on the androgen receptor or operate in tissues via conversion to dihydrotestosterone (DHT) by the enzyme 5-alpha reductase. Finally, testosterone can act as an estrogen following conversion by aromatase to estradiol. In many tissues, the activity of testosterone depends on its reduction to DHT, which binds to cytosol receptor proteins. When transported to the nucleus, this steroid-receptor complex initiates transcription events and cellular changes related to androgen action. These three actions are crucial to understanding the therapeutic indications and adverse effects of androgen replacement therapy.[5]


Testosterone cypionate injected IM is absorbed slowly, and hence it can be given every two to four-week intervals. The majority of (98%) of testosterone in plasma is bound to globulin. The distribution between free and bound forms is dependent on the amount of this testosterone-estradiol binding globulin in the plasma. The half-life is directly proportional to the free testosterone concentration in plasma. The half-life of IM testosterone cypionate is approximately eight days. A majority (90 percent) of testosterone is excreted in the urine as glucuronic or sulfuric acid conjugates of testosterone, and it is converted into an inactive form by the liver.[6]

There are many formulations for testosterone. Transdermal gels and intramuscular (IM) injections are the top two options. It is essential to note the difference and side effects when choosing patient candidates for testosterone therapy. There are many ways to administer testosterone, including oral, buccal, transdermal (gel, patch, solution, pellet), and IM injection.

  • Oral Capsule of testosterone undecanoate:158 mg, 198 mg, 237 mg
  • Nasal Gel: 5.5 mg/actuation (7.32 g)
  • Transdermal Gel: 25 mg/2.5 g (1%) in 2.5 g, 50 mg/5 g (1%) in 5 g, 20.25 mg/1.25 g (1.62%) in 1.25 g; 40.5 mg/2.5 g (1.62%) in 2.5 g, 50 mg/5 g (1%) (5 g), Pump: 12.5 mg/actuation (1%) in 75 g, 20.25 mg/actuation (1.62%) in 75 g
  • Transdermal Patch 24 Hours 2 mg/24 hr in each patch (pack of 60 patches); 4 mg/24 hr in each patch (pack of 30 patches)
  • Transdermal Solution: 30 mg/actuation (90 mL)
  • Implant: 75 mg pellet
  • Intramuscular
    • Testosterone cypionate: Depo 100 mg/mL (10 mL); 200 mg/mL (1 mL, 10 mL)
    • Testosterone enanthate: 200 mg/mL (5 mL)
    • Testosterone undecanoate 750 mg/3 mL (3 mL)
  • Subcutaneous injection 50 mg/0.5 mL (0.5 mL); 75 mg/0.5 mL (0.5 mL); 100 mg/0.5 mL (0.5 mL) in auto-injector

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 compared with other formulations. The buccal form should not be chewed or swallowed.

Transdermal formulations include testosterone gels, patches, solutions, and pellets. Testosterone gels are generally the recommended formulation due to patient preference, cost, convenience, and insurance coverage. The chief advantage of gels is maintaining 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 not to the scrotum. A study showed the bioavailability of testosterone gel is 30% lower when applied to the abdomen than when compared with arms and shoulders.[7] A nasal testosterone gel now has approval in the United States. It should be applied three times daily. Some patients may find this inconvenient. The patient should apply the testosterone patch to the back, abdomen, thigh, or upper arm and not to the scrotum. 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. The FDA discontinued a testosterone solution in 2017.

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 two weeks.[8] In 2014, the FDA approved an extra-long-acting intramuscular injection form of testosterone called testosterone undecanoate, which gets dosed at 750 mg followed by a second dose four weeks later and subsequent doses every ten weeks.[9] Testosterone undecanoate is not the first-line treatment of choice but is generally used when patients do not have access to other forms of treatment.

Due to its many formulations, it is important to watch out for different adverse effects at each visit. Buccal tablets can irritate gums and oral mucosa. Testosterone gels can get transferred to a woman or child who comes in contact with the gel. So, patients are advised to cover the application site with clothing and wash the skin before having skin-to-skin contact to avoid transmission. Testosterone patches can cause skin reactions, and injectables can cause mood, energy, and libido fluctuations. 

In 2015, the FDA concluded a possible increased cardiovascular risk associated with testosterone use requiring labeling change to inform the public. Testosterone use has been associated with erythrocytosis related to hematocrit, thereby increasing the risk of venous thromboembolism.[10] Serum PSA levels can increase in response to testosterone treatment, so it is essential to rule out prostate cancer before starting therapy as it can worsen the disease process. Patients on replacement therapy require reevaluation for prostate cancer at three months and one year after beginning treatment.[11] There have been no significant effects of testosterone on lower urinary tract symptoms and BPH.[10] Physicians need to specifically address the risks and benefits of testosterone therapy before initiating treatment.

Contraindications to androgen replacement therapy include[11]:

  • History of breast cancer
  • Prostate cancer
  • Uncontrolled heart failure
  • Myocardial infarction or cerebrovascular accident within the past six months
  • Untreated obstructive sleep apnea
  • Hematocrit over 48%
  • Men planning fertility
  • A palpable undiagnosed prostate nodule
  • An elevated PSA above 4 ng/mL
  • An increased PSA level above 3 ng/mL in high-risk patients, including African Americans and men with a first-degree relative with prostate cancer

Lab tests needed before starting androgen replacement include Hemoglobin (Hgb), Hematocrit (Hct), Liver Functional Tests (LFTs), lipid panels, DRE, PSA level, two-morning testosterone levels, and consider a DEXA scan. Monitoring should be done as follows[11]:

  • One month after treatment: morning testosterone level
  • Three to six months after treatment during one year: morning testosterone level, LFTs, lipid profile, PSA, DRE, estradiol, Hgb, and Hct, blood pressure
  • Annually after one year: morning testosterone level, LFTs, lipid profile, DRE, PSA, estradiol, Hgb, and Hct, blood pressure

Referral to urology is recommended if there is an increase in PSA level greater than 1.4 ng/mL within any 12 months. If hematocrit rises above 54%, stop therapy as soon as possible.[11] 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.[12] Hyperestrogenism can be a side effect of replacement therapy because testosterone undergoes aromatization to estrogen.[13] Aromatase inhibitors may be necessary. Therefore, estradiol levels in men need to be assessed to rule out hyperestrogenism. Physicians need to monitor patients receiving testosterone therapy regularly, and they should discontinue treatment in those who fail to follow up.


There are no reports of acute overdosage with testosterone. Call the local poison control center for up-to-date guidance at 1-800-222-1222.

Enhancing Healthcare Team Outcomes

Physicians, pharmacists, and nurses, operating as an interprofessional team need to be aware of the risks, benefits, and contraindications for testosterone replacement therapy. There are conflicting trials on the cardiovascular risks of testosterone therapy, most notable the TOM (Testosterone in Older Men) trial and the TEAAM (Testosterone's Effects on Atherosclerosis Progression in Aging Men) trials. Low testosterone levels have correlated with an increased risk of coronary artery disease.[14][15] Published in JAMA 2017, a study found that testosterone replacement was associated with a lower risk of cardiovascular outcomes.[16] The American Association of Clinical Endocrinologists (AACE) issued a guideline in response to the 2015 FDA labeling requirement on cardiovascular risk. It stated that there is no compelling evidence that testosterone therapy increases cardiovascular risk.[17] On the other hand, testosterone deficiency correlates with falls, sarcopenia, frailty, osteopenia, and osteoporosis.[18] 

Clinicians need to prescribe androgen replacement therapy by using risk-benefit assessment of individual patient's clinical needs and risk of adverse reactions. Pharmacists should verify dosing, check for potential interactions, and provide thorough counseling for administration, which will vary depending on the formulation. Nurses can also counsel patients on dosing and administration and assess treatment effectiveness. Both pharmacists and nurses need to inform the prescriber of any concerns they may encounter, so an open communication channel between team members is vital. Interprofessional monitoring of the patient will result in the best outcomes with the fewest adverse events. [Level 5]



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Level 3 (low-level) evidence


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. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2011 Jul-Aug:17(4):574-83. doi: 10.4158/EP10192.OR. Epub     [PubMed PMID: 21454244]


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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. The Journal of clinical endocrinology and metabolism. 2004 Nov:89(11):5429-34     [PubMed PMID: 15531493]


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. The Journal of clinical endocrinology and metabolism. 2018 Mar 17:():. doi: 10.1210/jc.2018-00404. Epub 2018 Mar 17     [PubMed PMID: 29562341]

Level 1 (high-level) evidence


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Level 1 (high-level) evidence


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