What are the physiological and clinical consequences of daytime administration of somatropin (recombinant human growth hormone) compared with nighttime dosing?

Daytime Administration of Somatropin: Physiological and Clinical Consequences

Administering somatropin during the day disrupts the physiological circadian pattern of growth hormone secretion and results in suboptimal metabolic effects compared to evening administration. 1

Physiological Rationale for Evening Dosing

Growth hormone exhibits a strong circadian rhythm in humans, with the major secretory pulse occurring shortly after sleep onset during slow-wave sleep. 2 This natural pattern is critical because:

• In normal adults, approximately 70% of GH pulses during sleep coincide with slow-wave sleep stages III and IV, and the amount of GH secreted correlates directly with the concurrent amount of slow-wave sleep 2
• Growth hormone naturally peaks during nighttime hours in diurnal humans, as demonstrated in recent circadian physiology research 3
• The sleep-onset GH pulse often represents the major secretory output in adults, making timing of replacement therapy particularly important 2

Direct Evidence: Morning vs. Evening Administration

A controlled study in GH-deficient patients directly compared morning (0800h) versus evening (2000h) subcutaneous somatropin injections and found clinically significant differences: 1

Pharmacokinetic Differences

• Evening injections produced 81% greater GH bioavailability (AUC 83.3 vs. 46.0 μg·L/12h, P<0.01) compared to morning injections 1
• The higher bioavailability after evening dosing likely results from increased skin and subcutaneous temperatures when patients are in bed 1
• The 2000-0800h AUC after evening injection matched the corresponding AUC in healthy reference subjects 1

Metabolic Consequences of Morning Dosing

Morning administration produces several unfavorable metabolic effects: 1

• Daytime insulin levels were significantly elevated after morning injections (P<0.05), suggesting increased insulin resistance during waking hours 1
• Nighttime lipid intermediates remained below normal after morning injection (P<0.05), indicating disrupted lipid metabolism 1
• Blood alanine levels tended to be elevated after morning GH injection (P=0.08), suggesting altered amino acid metabolism 1
• The normal inverse relationship between circadian lipid intermediates and blood alanine/lactate concentrations disappeared after morning injections, indicating disruption of coordinated metabolic regulation 1

IGF-1 Patterns

• Mean 24-hour IGF-1 levels were similar between morning (179.5 μg/L) and evening (189.8 μg/L) dosing 1
• However, morning dosing produced a circadian variation in IGF-1 suggesting steady-state had not been reached, whereas evening dosing produced stable levels 1
• Both dosing schedules resulted in IGF-1 levels below the reference value (248.4 μg/L) 1

Current Clinical Guidelines

Standard clinical practice recommends evening administration to mimic physiological circadian rhythm: 4

• The Endocrine Society recommends daily subcutaneous injections typically administered at night to mimic the physiological circadian rhythm of endogenous GH secretion 4
• This recommendation applies to standard daily formulations used across all approved indications 4

Clinical Implications

The metabolic effects of subcutaneous GH injections are clearly influenced by the time of administration, and the closest similarity to normal hormone and metabolite patterns is achieved by evening injection. 1

Practical Considerations

• Injection sites must be rotated daily regardless of timing to prevent lipoatrophy 4
• IGF-1 monitoring should occur at least twice yearly to guide dosing 4
• Clinical consultations every 3-6 months should assess growth parameters and metabolic function 4

Common Pitfall to Avoid

Do not administer somatropin in the morning simply for patient convenience—the metabolic disadvantages include reduced bioavailability, elevated daytime insulin levels, disrupted lipid metabolism, and loss of normal metabolic coordination between substrates. 1 While patients may prefer morning dosing for lifestyle reasons, the physiological evidence strongly supports evening administration for optimal therapeutic outcomes.