Starting Testosterone Replacement Therapy in Men with Confirmed Hypogonadism
Recommended Initial Treatment
Transdermal testosterone gel 1.62% at 40.5 mg daily (2 pump actuations) applied to the shoulders and upper arms is the preferred first-line formulation for men with confirmed hypogonadism. 1, 2
This recommendation prioritizes stable day-to-day testosterone levels, lower risk of erythrocytosis compared to injectable formulations, and patient convenience, while acknowledging that treatment provides only modest improvements in sexual function and quality of life with minimal effects on physical function, energy, or cognition. 1
Diagnostic Confirmation Before Starting Treatment
Before initiating any testosterone therapy, you must confirm the diagnosis through:
- Two separate morning (8-10 AM) total testosterone measurements below 300 ng/dL, drawn on different days to account for assay variability 1, 2
- Presence of specific symptoms, particularly diminished libido and erectile dysfunction—these are the primary evidence-based indications for therapy 1
- Measurement of LH and FSH to distinguish primary (testicular) from secondary (hypothalamic-pituitary) hypogonadism, as this critically impacts treatment selection and fertility counseling 1
- Free testosterone by equilibrium dialysis in men with obesity or conditions affecting sex hormone-binding globulin 1
Critical pitfall to avoid: Do not start testosterone in men with normal testosterone levels (>300 ng/dL) even if symptomatic—this is explicitly contraindicated and provides no benefit. 1
Treatment Selection Algorithm
First-Line: Transdermal Testosterone Gel
Start with testosterone gel 1.62% at 40.5 mg daily applied to shoulders and upper arms because: 1, 2
- Provides more stable day-to-day testosterone levels compared to injections 1
- Lower risk of erythrocytosis than injectable formulations 1
- FDA-approved starting dose with clear titration protocol 2
Application instructions (critical for efficacy and safety):
- Apply to clean, dry, intact skin of shoulders and upper arms only—not abdomen, chest, genitals, or legs 2
- Cover application site with clothing once dry to prevent secondary exposure to women and children 2
- Wash hands immediately with soap and water after application 2
- Avoid swimming/showering for minimum 2 hours after application 2
Alternative: Intramuscular Testosterone Injections
Consider testosterone cypionate or enanthate 50-400 mg IM every 2-4 weeks if: 1, 2
- Cost is a primary concern (annual cost $156 vs $2,135 for transdermal) 1
- Patient preference favors less frequent administration 1
- Patient cannot reliably apply daily topical medication 1
Important caveat: Injectable testosterone has higher risk of erythrocytosis and causes fluctuating testosterone levels (peak at days 2-5, return to baseline by days 13-14), which may worsen mood variability. 1
Special Consideration: Fertility Preservation
If the patient desires fertility now or in the near future, testosterone therapy is absolutely contraindicated. 1
Instead, you must offer:
- Gonadotropin therapy (hCG plus FSH) for secondary hypogonadism to stimulate endogenous testosterone production while preserving spermatogenesis 1
- Clomiphene citrate 25-50 mg daily as an off-label alternative for secondary hypogonadism, which increases endogenous testosterone without suppressing sperm production 3
Exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis, causing azoospermia that may persist for months after discontinuation. 1
Dose Titration Protocol
Check testosterone levels at 14 days and 28 days after starting treatment, then adjust dose based on pre-dose morning total testosterone: 2
- If testosterone >750 ng/dL: Decrease by 20.25 mg (1 pump actuation) 2
- If testosterone 350-750 ng/dL: Continue current dose 2
- If testosterone <350 ng/dL: Increase by 20.25 mg (1 pump actuation) 2
Target mid-normal testosterone levels (500-600 ng/dL) to balance efficacy with safety. 1
For injectable testosterone, measure levels midway between injections (day 7 for every-2-week dosing). 1
Monitoring Requirements
Initial Phase (First Year)
- Testosterone levels at 2-3 months, then every 6-12 months once stable 1
- Hematocrit at baseline and periodically—withhold treatment if >54% and consider phlebotomy 1
- PSA at baseline and periodically in men >40 years—evaluate significant increases 1
- Prostate examination to assess for benign prostatic hyperplasia symptoms 1
Ongoing Monitoring
- Reassess symptoms at 12 months—if no improvement in sexual function, discontinue therapy as this is the primary evidence-based indication 4
- Continue monitoring hematocrit, PSA, and testosterone levels every 6-12 months 1
Absolute Contraindications
Do not start testosterone therapy in men with: 1, 5
- Active or treated breast or prostate cancer 1
- Men actively seeking fertility (use gonadotropins instead) 1
- Hematocrit >54% 1
- Untreated severe obstructive sleep apnea 5
- Uncontrolled heart failure 5
- Myocardial infarction or stroke within last 6 months 5
Setting Realistic Expectations
Counsel patients that testosterone therapy provides: 1
- Small improvements in sexual function and libido—the primary evidence-based benefit 1
- Little to no effect on physical functioning, energy, vitality, or cognition 1
- Modest improvements in metabolic parameters (fasting glucose, insulin resistance, triglycerides, HDL) 1
Common pitfall: Patients often expect dramatic improvements in energy and physical function, but evidence shows minimal benefit in these domains. Set appropriate expectations upfront to prevent disappointment and unnecessary continuation of therapy. 1
Alternative Approach for Secondary Hypogonadism
For men with secondary hypogonadism who wish to preserve fertility or prefer non-suppressive therapy, consider clomiphene citrate 25-50 mg daily (off-label use): 3
- Stimulates endogenous testosterone production without suppressing spermatogenesis 3
- Achieves similar improvements in sexual function as testosterone replacement 3
- Lower risk of polycythemia 3
- Not effective for primary hypogonadism—check LH/FSH first 3
If no response after 3 months, switch to testosterone replacement therapy. 3