Androgen Replacement

Article Author:
Omeed Sizar
Article Editor:
Jose Pico
12/19/2018 7:23:01 AM
PubMed Link:
Androgen Replacement


Hypogonadism is seen 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. 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.[2]

Hypogonadism is diagnosed when the morning serum testosterone level is less than 300 ng/dL. 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.[3] Of note, total testosterone less than 405.9ng/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 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 (CMP). 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.

Testosterone therapy is not FDA-approved to treat low libido in women.

Mechanism of Action

Testosterone has many biologic effects as it can act as three hormones. Testosterone can act directly on the androgen receptor or it can act in tissues via conversion to dihydrotestosterone (DHT) via the enzyme 5-alpha reductase. Finally, testosterone can act as an estrogen following conversion by aromatase to estradiol. These 3 actions are extremely important to understand the adverse effects of androgen replacement therapy.


There are many formulas of testosterone. Transdermal gels and intramuscular (IM) injections are the top 2 options. It is important 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 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. 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[5].

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.[6] 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.[7] Testosterone undecanoate is not the first-line treatment of choice but generally used when patients do not have access to other forms of treatment.

Adverse Effects

Due to many types of 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 be 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 fluctuations in mood, energy, and libido. 

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.[8] 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.[9] There have been no significant effects of testosterone on lower urinary tract symptoms and BPH.[8] Physicians need to specifically address the risks and benefits of testosterone therapy before initiating treatment.


Contraindications to androgen replacement therapy include[9]:

  • 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


Lab tests needed before starting androgen replacement include Hgb, Hct, LFTs, lipid panel, DRE, PSA level, 2-morning testosterone levels, and consider a DEXA scan.

Monitoring should be done as follows[9]:

  • One month after treatment: morning testosterone level
  • Three to 6 months after treatment during 1 year: morning testosterone level, LFTs, lipid profile, PSA, DRE, estradiol, Hgb, and Hct, blood pressure
  • Annually after 1 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-month period. If hematocrit rises above 54%, then stop therapy as soon as possible.[9] 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.[10] Hyperestrogenism can be a side effect of replacement therapy because testosterone can be aromatized to estrogen.[11] 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.

Enhancing Healthcare Team Outcomes

Physicians, pharmacists, and nurses 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 been associated with increased risk of coronary artery disease.[12][13] Published in JAMA 2017, a study found that testosterone replacement was associated with a lower risk of cardiovascular outcomes.[14] The American Association of Clinical Endocrinologists (AACE) 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.[15] On the other hand, testosterone deficiency has been associated with falls, sarcopenia, frailty, osteopenia, and osteoporosis.[16]