What are the treatment options for individuals with low bioavailable testosterone levels?

Treatment Options for Low Bioavailable Testosterone

For men with confirmed low bioavailable testosterone and symptoms of hypogonadism, testosterone replacement therapy is the primary treatment, with transdermal gel (50-100 mg daily) or intramuscular injections as first-line options, while men interested in preserving fertility should receive alternative hormonal therapies such as hCG, SERMs, or aromatase inhibitors instead of testosterone monotherapy. 1, 2

Diagnostic Confirmation Required Before Treatment

• Confirm both biochemical deficiency AND clinical symptoms before initiating any therapy, as diagnosis requires low testosterone levels on at least two separate morning measurements plus symptoms such as reduced libido, erectile dysfunction, fatigue, decreased muscle mass, or depressed mood 1, 3

• Free or bioavailable testosterone is a better index of gonadal status than total testosterone alone and should be measured when possible 3

• Repeat morning serum testosterone measurements on separate occasions to confirm low levels due to assay variability 3, 2

• Measure luteinizing hormone (LH) to distinguish primary hypogonadism (elevated LH) from secondary/hypogonadotropic hypogonadism (low or normal LH), as this determines treatment approach 1, 3, 2

Primary Treatment Options

Testosterone Replacement Therapy (TRT)

For men NOT concerned about fertility:

• Transdermal testosterone gel 1-1.62% is first-line: Apply 40.5-81 mg (50-100 mg of 1% gel) once daily to shoulders and upper arms, with dose titration based on serum levels at 14 and 28 days 2, 4, 5

• Intramuscular testosterone is an alternative: Traditional testosterone enanthate requires frequent injections with fluctuating levels, while newer testosterone undecanoate formulations allow injections every 3 months with more stable levels 4, 5

• Transdermal patches are available but associated with moderate to severe skin reactions in many users 4

• The American College of Physicians found moderate-certainty evidence that TRT produces small improvements in sexual function (SMD 0.35) and quality of life, with low-certainty evidence for small improvements in erectile function (SMD 0.27) 1

Alternative Hormonal Therapies (Fertility-Preserving)

For men interested in current or future fertility, testosterone monotherapy should NOT be prescribed as it suppresses spermatogenesis 1

Instead, use:

• Selective estrogen receptor modulators (SERMs) such as clomiphene citrate 1

• Human chorionic gonadotropin (hCG) alone or in combination 1

• Aromatase inhibitors (AIs) 1

• Combination therapy of the above agents 1

• For hypogonadotropic hypogonadism specifically, FSH analogues may improve sperm concentration, pregnancy rate, and live birth rate 1

Treatment by Etiology

Hypogonadotropic Hypogonadism (Secondary)

• Evaluate to determine the underlying etiology (pituitary adenoma, hypothalamic injury from tumors/trauma/radiation) 1, 2

• Check serum prolactin levels if LH is low or low-normal, as hyperprolactinemia requires specific treatment 1, 3

• Treatment with gonadotropins (hCG/FSH) is preferred if fertility is desired 1

Primary Hypogonadism

• Testosterone replacement is the mainstay, as the testes cannot respond to gonadotropin stimulation 2

• Causes include Klinefelter's syndrome, bilateral torsion, chemotherapy, orchitis, or orchiectomy 2

Monitoring and Dose Adjustment

• Titrate testosterone dose based on pre-dose morning serum testosterone concentration at approximately 14 and 28 days after starting treatment 2

• Target serum testosterone: 350-750 ng/dL (if >750 ng/dL decrease dose by 20.25 mg; if <350 ng/dL increase dose by 20.25 mg) 2

• Assess periodically thereafter for efficacy and adverse effects 3, 5

• Monitor for cardiovascular events, though low-certainty evidence shows small increase to no difference in adverse cardiovascular events 1

Adjunctive Non-Pharmacological Approaches

These should be implemented BEFORE or alongside TRT:

• Weight loss in men with obesity is imperative, as adequate nutrition and normal body mass index are independent factors affecting testosterone levels 3, 6

• Adequate sleep (specific duration and quality) 6

• Regular weight-bearing exercise 3, 6

• Smoking cessation 3

Nutraceuticals (Limited Evidence)

• Zinc supplementation in deficient men may have modest benefits 6

• Vitamin D supplementation (800 IU/day) specifically in cases of hypovitaminosis D 3, 6

• L-arginine, mucuna, and ashwagandha showed promising results in well-controlled trials of men with low testosterone 6

• Most other supplements (antioxidants, vitamins) have questionable clinical utility with inadequate data to recommend specific agents 1, 6

Critical Contraindications and Warnings

• Do NOT prescribe testosterone to men taking nitrates or those with severe hepatic impairment, hypotension, hereditary degenerative retinal disorders, recent stroke, or recent myocardial infarction 1

• Secondary exposure risk: Children must avoid contact with unwashed or unclothed application sites in men using testosterone gel, as virilization has been reported 2

• Age-related hypogonadism: Safety and efficacy of testosterone therapy in men with "late-onset hypogonadism" have not been definitively established, requiring cautious approach especially in older men with heart failure history 2, 5

Common Pitfalls to Avoid

• Treating based on symptoms alone without laboratory confirmation of low testosterone levels 3

• Failing to distinguish between primary and secondary hypogonadism, which require different management approaches 3

• Not considering other causes of similar symptoms (depression, sleep apnea, thyroid disorders) before attributing them to testosterone deficiency 3

• Prescribing testosterone to men desiring fertility without counseling about spermatogenesis suppression 1

• Using supplements with limited evidence as primary therapy rather than proven testosterone replacement 1, 6