What is the recommended management for hypogonadism (low testosterone levels)?

Management of Low Testosterone Levels

Confirm the diagnosis with two separate morning testosterone measurements below 300-350 ng/dL combined with clinical symptoms of hypogonadism before initiating any treatment. 1, 2, 3, 4

Diagnostic Confirmation

Obtain two morning (8-10 AM) total testosterone measurements on separate days to account for natural variations and diurnal fluctuations. 5, 2, 3 A threshold below 300 ng/dL is generally accepted as diagnostic. 3, 4

Measure free testosterone or calculate the free testosterone index (total testosterone/SHBG ratio) when total testosterone is borderline (230-350 ng/dL) or in obese patients where SHBG may be altered. 2 Free testosterone provides a better index of gonadal status than total testosterone alone. 2

Measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to distinguish between primary hypogonadism (elevated LH/FSH indicating testicular failure) and secondary hypogonadism (low/normal LH/FSH indicating hypothalamic-pituitary dysfunction). 5, 2, 3

Check serum prolactin levels in all patients with low testosterone combined with low or normal LH, as hyperprolactinemia can suppress gonadotropin secretion. 5, 2

Consider pituitary MRI if testosterone is low with inappropriately low/normal LH to exclude pituitary adenoma or structural lesions. 5

Identify Reversible Causes Before Treatment

Evaluate and address obesity as a primary intervention. Weight loss through low-calorie diets can substantially improve testosterone levels in obese men with secondary hypogonadism. 5, 6 Obesity causes pseudo-hypogonadism through reduced SHBG rather than true pathological hypogonadism. 6

Screen for and optimize management of:

• Type 2 diabetes mellitus 1, 5
• Obstructive sleep apnea 5, 6
• Chronic opioid use 5
• Chronic corticosteroid use 5
• Depression 6

Implement lifestyle modifications first in obese patients with secondary hypogonadism, as diet and exercise interventions are more effective than testosterone treatment for reversing obesity-related testosterone reductions. 5, 6

Testosterone Replacement Therapy Indications

Initiate testosterone replacement only when BOTH criteria are met:

1. Confirmed low testosterone on two separate morning measurements
2. Clinical symptoms/signs of hypogonadism 1, 3, 4

Approved indications for testosterone replacement include: 3

• Primary hypogonadism (Klinefelter's syndrome, bilateral torsion, orchitis, vanishing testis syndrome, orchiectomy, chemotherapy-induced testicular failure)
• Secondary hypogonadism (pituitary/hypothalamic tumors, trauma, radiation, LHRH deficiency)

Do NOT initiate testosterone for age-related low testosterone to improve energy, vitality, physical function, or cognition, as evidence shows insufficient benefit. 1 The FDA specifically requires labeling that testosterone products are approved only for hypogonadism due to known organic causes. 1

Testosterone Formulation Selection

Choose from FDA-approved formulations based on patient preference, cost, and contraindications: 3, 7, 8

Topical gel (1.62%): Apply 40.5 mg (2 pump actuations) once daily to shoulders and upper arms in the morning. 3 Dose range: 20.25-81 mg daily. 3 Patients must cover application sites with clothing after drying and avoid swimming/showering for minimum 2 hours. 3

Intramuscular injections: Testosterone enanthate or cypionate provide effective delivery but cause fluctuating serum levels. 7 Newer testosterone undecanoate formulations require injections only every 3 months with more stable levels. 7

Other options: Transdermal patches (higher skin reaction rates), buccal preparations, subdermal pellets, and nasal formulations are available. 8

Target Testosterone Levels and Monitoring

Target mid-normal range testosterone levels during treatment (approximately 400-700 ng/dL). 5

Measure pre-dose morning testosterone at 14 days and 28 days after starting therapy or dose adjustment. 3

Adjust dosing based on serum levels: 3

• If >750 ng/dL: Decrease dose by 20.25 mg
• If 350-750 ng/dL: Continue current dose
• If <350 ng/dL: Increase dose by 20.25 mg

Monitor hemoglobin/hematocrit as testosterone increases red blood cell production and can cause erythrocytosis requiring dose reduction or phlebotomy. 1, 5, 9

Monitor PSA in men over 40 years to screen for prostate abnormalities. 5

Measure estradiol if gynecomastia or breast symptoms develop, as testosterone aromatizes to estradiol. 5

Absolute Contraindications

Do NOT prescribe testosterone in patients with: 9

• Prostate cancer
• Breast cancer
• Uncontrolled congestive heart failure
• Severe lower urinary tract symptoms
• Erythrocytosis (elevated hematocrit)

Avoid in men desiring fertility, as exogenous testosterone suppresses spermatogenesis through negative feedback on the HPG axis. 8

Fertility-Preserving Alternatives

For patients with secondary hypogonadism who desire fertility preservation, use gonadotropin therapy (hCG with or without FSH) instead of testosterone replacement. 5, 8

Selective estrogen receptor modulators (SERMs) like clomiphene can increase endogenous testosterone production while maintaining fertility in men with low/normal LH. 5, 8

Aromatase inhibitors represent another option to raise endogenous testosterone without suppressing spermatogenesis. 8

Critical Safety Warning

Counsel patients using topical testosterone about secondary exposure risk to children and women. 3 Virilization has been reported in children secondarily exposed to testosterone gel. 3 Patients must wash hands thoroughly after application, cover application sites with clothing, and ensure children avoid contact with unwashed/unclothed application sites. 3