Is weekly testosterone replacement therapy (TRT) more effective than biweekly dosing?

Weekly Testosterone Dosing is Superior to Biweekly Administration

For testosterone replacement therapy, weekly injections are strongly preferred over biweekly dosing because they maintain more stable, physiologic testosterone levels throughout the dosing interval, avoiding the problematic supraphysiologic peaks and subtherapeutic troughs that occur with longer intervals.

The Pharmacokinetic Problem with Biweekly Dosing

Standard intramuscular testosterone esters (enanthate, cypionate) administered every 2-3 weeks create non-physiologic fluctuations that compromise treatment efficacy and safety 1:

• Peak testosterone levels occur 2-5 days post-injection and frequently exceed the upper limit of normal with standard biweekly dosing 2
• Testosterone levels return to baseline by 10-14 days, meaning patients spend at least 50% of the time outside the therapeutic range 2, 3
• These fluctuations result in patients experiencing symptom recurrence before the next injection is due 3

Evidence Supporting Weekly Administration

Weekly subcutaneous testosterone cypionate maintains stable therapeutic levels throughout the entire dosing interval 4:

• Mean total testosterone remained 627 ± 206 ng/dL across all time points between weekly injections, with free testosterone at 146 ± 51 pg/mL 4
• All measurements stayed well within the normal physiologic range with no supraphysiologic peaks 4
• The subcutaneous route is relatively painless and allows for easy self-administration using insulin syringes 4, 5

A pilot study of weekly subcutaneous testosterone enanthate demonstrated 100% of patients achieved both peak and trough levels within normal range, with mean trough of 14.48 nmol/L and peak of 21.65 nmol/L 5.

Clinical Algorithm for Dosing Frequency Selection

Start with weekly dosing as the default approach 2:

1. Initiate weekly subcutaneous testosterone cypionate or enanthate at 50-100 mg per week 4, 5
2. Measure testosterone levels at 1-2 months to assess adequacy and adjust dosing 2
3. Target mid-normal range testosterone (450-600 ng/dL) to optimize symptom relief while minimizing adverse effects 6, 2
4. For patients requiring intramuscular administration, maintain weekly frequency rather than extending to biweekly 1

Safety Advantages of Weekly Dosing

The more stable testosterone levels achieved with weekly administration reduce specific adverse effects:

• Erythrocytosis occurs in 43.8% with standard intramuscular injections versus only 15.4% with more frequent dosing regimens, attributed to supraphysiologic testosterone peaks 2
• Estradiol levels remain more physiologic with weekly dosing, as biweekly injections often generate supraphysiological estradiol 3
• Monitor hematocrit at each visit; if >52%, consider dose reduction or temporary discontinuation 2

Alternative Formulations for Stable Levels

If weekly injections are not feasible, consider formulations designed for physiologic stability 1, 2:

• Transdermal testosterone gels maintain stable levels throughout the day with dosing flexibility from 20.25-120 mg/day 2
• Testosterone undecanoate injections provide therapeutic levels for 12 weeks with normal DHT and estradiol, though optimal intervals after individual titration average 12 weeks (range 10.4-12.7 weeks) 3, 7
• Transdermal preparations are preferred by 71% of patients after trial due to convenience and ease of use 1

Monitoring Protocol for Injectable Testosterone

For patients on weekly injections 1, 2:

• Measure testosterone midway between injections (3-4 days after injection) targeting 500-600 ng/dL 1
• Check levels at 2-3 months after initiation or dose changes 1
• Once stable, monitor every 6-12 months 1
• Monitor hematocrit more closely than lipids, as polycythemia represents the most common adverse effect 6

Critical Caveats

• Do not use 17-alpha-alkylated androgens (methyltestosterone) due to liver toxicity and unfavorable lipid effects 6
• Testosterone therapy should not be commenced for 3-6 months in patients with recent cardiovascular events 6
• The annual cost difference is substantial: transdermal formulations cost $2,135 versus $156 for intramuscular preparations, though weekly dosing may increase injection costs 1