Androgen Replacement


Article Author:
Omeed Sizar


Article Editor:
Jose Pico


Editors In Chief:
William Gossman


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
3/31/2019 9:17:45 PM

Indications

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.

Administration

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

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

Monitoring

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. Interprofessional monitoring of the patient will result in the best outcome. [Level V]

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]


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Androgen Replacement - Questions

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Which of the following formulations of testosterone is best for androgen replacement?



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What is not a side-effect of androgen use?



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Besides total testosterone level, what other blood tests are recommended prior to starting a male patient with hypogonadism on testosterone supplementation?



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For male patients receiving testosterone injections, which is the most reasonable monitoring plan to optimize hormone levels?



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A 60-year-old African American male with a history of hypertension and benign prostatic hyperplasia is diagnosed with primary hypogonadism. What is a contraindication to androgen replacement therapy?



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A 65-year-old male with a past medical history of coronary artery disease, hypertension, and diabetes mellitus type 2 presents to your clinic regarding possible testosterone replacement therapy. The patient has known primary hypogonadism. Five months ago he underwent percutaneous coronary intervention (PCI) for myocardial infarction. He complains of persistent fatigue, memory loss, and erectile dysfunction. Which hormone replacement strategy should be used in this patient?



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A 70-year-old male who started testosterone gel therapy 1 year ago presents for an annual visit. What labs should be ordered for routine monitoring at this time?



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Androgen Replacement - References

References

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     [PubMed]
Tan RS,Cook KR,Reilly WG, High estrogen in men after injectable testosterone therapy: the low T experience. American journal of men's health. 2015 May     [PubMed]
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     [PubMed]
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. The Journal of clinical endocrinology and metabolism. 2018 May 1     [PubMed]
Snyder PJ,Lawrence DA, Treatment of male hypogonadism with testosterone enanthate. The Journal of clinical endocrinology and metabolism. 1980 Dec     [PubMed]
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     [PubMed]
Golds G,Houdek D,Arnason T, Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health. International journal of endocrinology. 2017     [PubMed]
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. International journal of impotence research. 2007 Mar-Apr     [PubMed]
Hu X,Rui L,Zhu T,Xia H,Yang X,Wang X,Liu H,Lu Z,Jiang H, Low testosterone level in middle-aged male patients with coronary artery disease. European journal of internal medicine. 2011 Dec     [PubMed]
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 internal medicine. 2017 Apr 1     [PubMed]
Goodman N,Guay A,Dandona P,Dhindsa S,Faiman C,Cunningham GR, AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF TESTOSTERONE AND CARDIOVASCULAR RISK. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2015 Sep     [PubMed]
Hsu B,Cumming RG,Handelsman DJ, Testosterone, frailty and physical function in older men. Expert review of endocrinology & metabolism. 2018 May     [PubMed]
Harman SM,Metter EJ,Tobin JD,Pearson J,Blackman MR, Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. The Journal of clinical endocrinology and metabolism. 2001 Feb     [PubMed]
Vermeulen A,Kaufman JM, Diagnosis of hypogonadism in the aging male. The aging male : the official journal of the International Society for the Study of the Aging Male. 2002 Sep     [PubMed]
Carnegie C, Diagnosis of hypogonadism: clinical assessments and laboratory tests. Reviews in urology. 2004     [PubMed]
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. The Journal of clinical endocrinology and metabolism. 2011 Aug     [PubMed]

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