GHRP-2 and GHRH Drive of Pulsatile GH Secretion Controlled by Age, Estrogen, and Visceral Fat in Women
Background
Growth hormone (GH) secretion declines markedly across the female lifespan, but the relative contributions of menopause-related estrogen loss, aging per se, and abdominal visceral fat accumulation to this decline remain poorly resolved. Standard clinical assessments of the GH axis rarely disentangle these three covariates simultaneously, making cross-study comparisons unreliable. Two major peptidyl secretagogues — GHRH (acting via the GHRH-receptor) and GHRP-2 (acting primarily via the GHSR) — stimulate GH through distinct hypothalamic and pituitary mechanisms, yet whether their relative potency is modulated differently by age, estradiol (E₂), and visceral adiposity in women had not been established.
Study Design
Healthy premenopausal (PRE, n = 20) and postmenopausal (POST, n = 22) women underwent a low- vs. high-E₂ clamp protocol to achieve age-independent hypo- and euestrogenemia. Under each estrogen condition, participants received a continuous intravenous infusion of either GHRH or GHRP-2. Pulsatile GH secretion was the primary endpoint. Abdominal visceral fat was quantified by computerized tomography (CT). Statistical analysis employed analysis of covariance (ANCOVA) and stepwise forward-selection multivariate regression to partition variance in GH responses among age, E₂ status, secretagogue type, and CT-derived visceral fat.
Results
All four covariates — age (P < 0.001), E₂ status (P = 0.006), secretagogue type (P < 0.001), and an age × peptide interaction (P = 0.014) — independently controlled pulsatile GH secretion. POST women had significantly lower GH responses to both GHRH (P = 0.028) and GHRP-2 (P < 0.001) than PRE women, independent of E₂ status, confirming an age effect beyond estrogen withdrawal. Independently of age, GHRP-2 was more stimulatory than GHRH under both low E₂ (P = 0.011) and high E₂ (P < 0.001) conditions, indicating a consistent secretagogue-type advantage for GHSR-mediated drive.
Stepwise multivariate analysis showed CT-estimated abdominal visceral fat explained 22% of variability in GHRH action (P = 0.002), while age and E₂ together explained 60% of variability in GHRP-2 drive (P < 0.001).
The divergence in variance partitioning between GHRH and GHRP-2 responses suggests that the two secretagogue pathways are regulated by distinct physiological covariates: GHRH-receptor sensitivity tracks more closely with visceral adiposity, whereas GHSR-mediated drive is predominantly shaped by hormonal and aging factors.
Key Findings
- Age independently lowered GH responses to both GHRH (P = 0.028) and GHRP-2 (P < 0.001) in POST vs. PRE women.
- GHRP-2 was more stimulatory than GHRH under low E₂ (P = 0.011) and high E₂ (P < 0.001), regardless of age.
- Visceral fat explained 22% of variance in GHRH-stimulated GH secretion (P = 0.002).
- Age and E₂ together explained 60% of variance in GHRP-2-driven GH secretion (P < 0.001).
- Age × peptide interaction (P = 0.014) confirmed that aging differentially modulates the two secretagogue pathways.
Why It Matters
Clinicians and researchers testing GH-axis function must control for age, estrogen status, and visceral fat simultaneously — failing to account for any single factor can produce spurious group differences in secretagogue-stimulated GH output. For those considering GHRP-2 in a clinical or investigational context, the data indicate that its superior stimulatory potency over GHRH persists across estrogen states, but the magnitude of response is heavily dependent on menopausal status and biological age rather than adiposity alone. Protocol designers using peptide-secretagogue challenges as GH-axis biomarkers in aging or body-composition studies should pre-stratify participants by menopausal status and obtain CT-based visceral fat measurements to avoid confounding. The finding that visceral fat predominantly explains GHRH — not GHRP-2 — variance also has practical implications: weight-loss interventions may improve GHRH-mediated GH drive more than GHRP-2-mediated drive in postmenopausal women.
