GHRP-2 and Triple Stimulus Drive Cortisol Surges Modulated by DHT and Visceral Fat
Background
Glucocorticoid secretion is tightly regulated by the hypothalamic-pituitary axis, yet how the sex-steroid milieu modulates cortisol output in humans remains poorly defined. Animal data implicate androgens and estrogens as controllers of HPA-axis activity, but translating those findings to clinical populations has been hampered by a lack of controlled human studies with defined hormonal conditions. Abdominal visceral fat (AVF) independently perturbs cortisol dynamics, and the relative contributions of androgenic metabolites such as 5α-dihydrotestosterone (DHT) versus aromatized estrogen are unresolved. Understanding which secretagogue types interact with the sex-steroid environment is essential for interpreting cortisol responses in clinical and performance contexts.
Study Design
42 healthy men underwent a double-blind, placebo-controlled, prospectively randomized crossover. Four sex-steroid milieus were imposed: double placebo, placebo + testosterone, testosterone + dutasteride (dual 5α-reductase blockade), or testosterone + anastrozole (aromatase blockade). On separate fasted mornings, each participant received i.v. injections of saline, GHRH, GHRP-2, somatostatin (SS), and a triple stimulus (GHRP-2/GHRH/L-arginine). Serum cortisol was sampled at 10-min intervals for 5 h; primary endpoints were peak cortisol concentrations, pulsatile cortisol secretion, and correlations with age and computerized tomography-estimated AVF.
Results
Baseline (saline-infused) cortisol did not differ across sex-steroid milieus (overall mean 364 ± 14 nmol/L). Stimulated peak cortisol was strongly determined by secretagogue type (P < 0.001): triple stimulus produced the highest peak (868 ± 27 nmol/L), followed by GHRP-2 (616 ± 42 nmol/L); saline, SS, and GHRH yielded a pooled grand mean of 420 ± 21 nmol/L and were statistically indistinguishable. After GHRP-2 injection, pulsatile cortisol secretion increased with age (R² = 0.16, P = 0.012). After the triple stimulus, pulsatile secretion correlated inversely with serum DHT concentrations (R² = 0.53, P = 0.026) and directly with CT-estimated AVF (R² = 0.11, P = 0.038).
Triple stimulus peak cortisol (868 ± 27 nmol/L) was more than double the grand mean of non-stimulating conditions (420 ± 21 nmol/L), and DHT explained 53% of variance in triple-stimulus pulsatile secretion.
Key Findings
- Triple stimulus peak cortisol: 868 ± 27 nmol/L vs. GHRP-2 at 616 ± 42 nmol/L (P < 0.001).
- Saline, SS, and GHRH produced statistically equivalent cortisol (grand mean 420 ± 21 nmol/L).
- DHT inversely predicted triple-stimulus pulsatile cortisol: R² = 0.53, P = 0.026.
- Abdominal visceral fat directly correlated with triple-stimulus pulsatile cortisol: R² = 0.11, P = 0.038.
- GHRP-2-stimulated pulsatile cortisol rose with age: R² = 0.16, P = 0.012.
Why It Matters
Clinicians and users employing GHRP-2 in hormonal contexts must account for background androgen status: higher DHT strongly attenuates stimulated cortisol pulsatility, meaning men on 5α-reductase inhibitors (e.g., finasteride/dutasteride for hair loss or BPH) may experience amplified cortisol responses to the same peptide dose. Greater abdominal visceral fat independently magnifies triple-stimulus cortisol output, so body-composition context modulates HPA reactivity regardless of gonadal hormone profile. Age additionally sensitizes the cortisol axis to GHRP-2, complicating dose extrapolation across age groups. Translation to a clinical protocol is not yet possible — ACTH dynamics and native ghrelin action in defined steroid milieus remain uncharacterized per the authors' own stated next steps.
