Testosterone Supplementation

See Also

Androgen Replacement in Women

Precautions

Cardiovascular disease risk with Androgen Replacement is still unclear
Androgen Replacement is NOT recommended for asymptomatic men or those with normal range Serum Testosterone
Androgen Replacement is NOT recommended for Sexual Dysfunction empirically without measuring Testosterone Levels
Discontinue Testosterone Supplementation if no improvement after 3-6 months
Androgen Replacement may be abused as an Anabolic Aid in sports
1. Consider completing a Controlled Substance Contract

Indications
Men

Depression, Fatigue, Muscle wasting in HIV or AIDS
Symptomatic Testicular Failure AND low morning Serum Testosterone levels<300 ng/dl (two levels are recommended)
1. See Male Menopause
2. See Hypogonadism
3. FDA approved for low Testosterone due to underlying cause (e.g. pituitary disorder, testicular infection)
  1. Not FDA approved for normal Testosterone decline with routine aging
4. Symptoms
  1. Decreased libido
  2. Erectile Dysfunction (PDE5 Inhibitors are preferred as first-line)

Contraindications

Absolute Contraindications
1. Breast Cancer
2. Polycythemia Vera (Hematocrit >54%)
3. Prostate Cancer or suspicion for active Prostate Cancer (e.g. PSA > 4 mcg/L, Prostate Nodules)
4. Cardiovascular event (CVA or MI) in the last 6 months
Relative Contraindications
1. Normal Serum Testosterone
2. Hematocrit >48% (prior to starting Testosterone Replacement)
3. Fertility desired (Testosterone Replacement decreases spermatogenesis)
4. Untreated Obstructive Sleep Apnea
5. Uncontrolled Congestive Heart Failure

Efficacy

Positive
1. Increases bone density or decreases bone loss (Lumbar Spine, hip)
2. Increase Lean Body Mass and Muscle Strength
3. Decrease body fat
4. Increase serum Hematocrit
5. Increases sense of well-being, mood (variable effects)
6. Increases libido
Disproved
1. Does not improve cognition (with or without Dementia)
2. Does not improve Sexual Dysfunction when Testosterone Levels are normal or unmeasured
  1. Lee (2024) Cochrane Database of Systematic Reviews CD013071
    1. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013071.pub2/full

Adverse Effects
Cardiovascular (mixed results)

Cardiovascular Disease Risk
1. Increased mortality, CVA and MI may be associated with Testosterone Replacement
  1. Intramuscular Testosterone may be associated with higher Cardiovascular Risk than transdermal
  2. Vigen (2013) JAMA 310(17):1829-36 [PubMed]
2. One large VA study showed decreased cardiovascular mortality (but has not been replicated by other studies)
  1. Sharma (2015) Eur Heart J 36(4): 2706-15 [PubMed]
3. Transdermal Testosterone Gel (Androgel) does not appear to effect cardiovascular event risk
  1. However, there was an increased risk of Atrial Fibrillation (as well as Pulmonary Embolism and Acute Kidney Injury)
  2. Lincoff (2023) N Engl J Med 389(2):107-17 +PMID: 37326322 [PubMed]
4. Older studies suggested no increased cardiovascular disease risk
  1. Zmuda (1997) Am J Epidemiol 146:609-14 [PubMed]
Venous Thromboembolism
1. Increased risk with Testosterone Replacement
  1. http://www.safetyalertregistry.com/alerts/2558
2. Study shows increased risk for those with Thrombophilia
  1. Glueck (2019) J Clin Med 8(1): 11 [PubMed]
3. Study shows no increased risk with men without other risk factors
  1. Sharma (2016) Chest 150(3): 563-71 [PubMed]

Adverse Effects
General (decreased risk if Testosterone Level stable)

HDL Cholesterol declines
May exacerbate Sleep Apnea
Hepatotoxicity (especially oral preparations)
Virilization (Hirsutism, Alopecia, Acne)
Lethargy (low Serum Testosterone fluctuations)
Edema
Gynecomastia
Behavior and mood changes
1. Moodiness or irritability
2. Aggressive behavior
Increased Prostate Cancer growth (disproved)
1. Prostate Cancer risk is NOT increased
  1. Morales (2005) J Endocrinol Invest 28:122-7 [PubMed]
  2. Scultheiss (2004) Andrologia 36:355-65 [PubMed]
Erythropoesis stimulation related effects
1. Polycythemia, Thromboembolism and cerebral vascular accident risk

Labs
Monitoring while on Testosterone

See Androgen Replacement in Women for monitoring women
Baseline Labs
1. See Male Hypogonadism
2. Morning Serum Testosterone level
  1. Confirm low Testosterone (<300 ng/dl) on 2 different morning Serum Testosterone levels
  2. Consider Free Testosterone and Sex Hormone Binding Globulin (SHBG)
3. Prostate Specific Antigen (PSA)
  1. Obtain Prostate Specific Antigen (PSA) in age >=40 years old
  2. Avoid starting Testosterone replacment if PSA abnormal (e.g. >4 ng/ml)
4. Digital Rectal Exam and Prostate examination
5. Complete Blood Count (or Hematocrit)
  1. Baseline Hematocrit >48% is a contraindication for starting Testosterone Replacement
6. Liver Function Tests (if using oral Testosterone, which is not recommended)
Monitoring for non-injectable preparations
1. History and exam
  1. Follow-up at 3-6 months after initiation of therapy, and then annually if stable
2. Total Serum Testosterone
  1. Obtain 3-6 months after starting therapy, then annually if stable
  2. Goal total Serum Testosterone level to mid-normal range 400 to 700 ng/dl AND Improved symptoms
3. Complete Blood Count
  1. Obtain 3-6 months after starting therapy, then annually if stable
  2. Stop Androgen Replacement if Hematocrit >54%
4. Prostate Specific Antigen (PSA) and Digital Rectal Exam (DRE)
  1. Indicated if older than age 40 years and baseline PSA >0.6 ng/ml
  2. Obtain PSA, DRE baseline and 3-6 months after initiation of therapy
    1. Refer to urology if >1.4 ng/ml increase within 12 months or Prostate nodularity
5. Bone Mineral Density
  1. Indicated in men with Osteoporosis or low mechanism Fracture
  2. Obtain at 1-2 years after initiation of therapy
6. Liver Function Tests
  1. If using oral Testosterone (which, again, is not recommended)
Monitoring for Establishing Injection Dose
1. Serum Testosterone at one week post injection
  1. Level above normal: decrease subsequent doses
2. Serum Testosterone at two weeks post injection
  1. Level below normal: increase injection frequency

Dosing
Testosterone Injection (Intramuscular)

Transdermal delivery is preferred over intramuscular
1. Cardiovascular Risks may be higher with injectable
Medications: Every 2 weeks
1. Testosterone cypionate (Depo-Testosterone)
  1. Start 50 to 100 mg every 2 weeks (may increase up to 200 to a maximum of 400 mg)
2. Testosterone enanthate (Delatestryl)
  1. Start 50 to 100 mg every 2 weeks (may increase up to 200 to a maximum of 400 mg)
3. Testosterone Propionate
  1. Start 10 to 25 mg every 3 weeks
Medications: Every 10 weeks
1. Testosterone undecanoate (Aveed) injectable
2. Dose: 3-mL (750 mg) Intramuscular Injection
  1. Give once at starting protocol THEN
  2. Give again in 4 weeks THEN
  3. Give every 10 weeks
3. Adverse effects
  1. Pulmonary-Oil Microembolism (POME) and Anaphylaxis
4. Precautions
  1. Carries black box warning (regarding POME, Anaphylaxis) and certification for prescribers

Dosing
Testosterone Transdermal (preferred, physiologic)

Background
1. Serum Testosterone peaks 2 hours post-patch application
2. Risk of skin-to-skin transmission of Testosterone
Testosterone Patch (Testoderm)
1. Dose: One 4 or 6 mg patch
2. Apply to shaved Scrotum every 24 hours
3. Much less irritating than Androderm
Transdermal Testosterone Solution (Axiron)
1. Dose: 60 mg daily (30 to 120 mg daily)
2. Apply to axillary area (similar to deodorant)
3. Risk for transfer to others
Androderm ($98 per month)
1. Typical dose: 4 mg patch daily
  1. Manufacturer changed dose in 2011
  2. Androderm 2 mg patch (instead of 2.5 mg)
  3. Androderm 4 mg patch (instead of 5 mg)
2. May cause rash (8% of patients)
3. Apply to skin every 24 hours
  1. Abdomen
  2. Thigh
  3. Between Shoulder blades
Transdermal Gels
1. Dosing: Equivalent to 50-100 mg daily
2. Formulations
  1. Testim 1%
  2. Fortesta
  3. Androgel (Testosterone 1% gel) four pumps (5 grams) topically daily
    1. May cause local skin reaction
    2. Apply to upper arms, Shoulders and Abdomen
    3. Avoid bathing for 5 hours after application
  4. Androgel (Testosterone 1.62% gel) two pumps topically daily
    1. Newer preparation released in 2011
    2. Equivalent to 4 pumps of the 1%
    3. Apply to upper arms, Shoulders, but NOT to Abdomen (due to less absorption)
    4. Avoid bathing for 2 hours after application

Dosing
Other forms

Testosterone buccal (Striant) 30 mg to gums twice daily
1. May cause oral irritation
2. New option less studied than other forms
Testosterone implanted pellets (Testopel)
1. Dose: 150 to 450 mg (up to 600 to 900 mg) implanted SQ every 3-6 months
2. Used for Delayed Puberty in males
Testosterone intranasal gel (Natesto)
1. Dose: One actuation (33 mg) in each nostril three times daily
Oral Testosterone (not recommended)
1. Listed for completeness
2. Not recommended due to hepatotoxicity and less effect
3. Agents
  1. Methyltestosterone (Android)
  2. Fluoxymesterone (Halotestin)

References