title: Unequal autonegative feedback by GH models the sexual dimorphism in GH secretory dynamics.
abstract: Growth hormone (GH) secretion, controlled principally by a GH-releasing hormone (GHRH) and GH release-inhibiting hormone [somatostatin (SRIF)] displays vivid sexual dimorphism in many species. We hypothesized that relatively small differences within a dynamic core GH network driven by regulatory interactions among GH, GHRH, and SRIF explain the gender contrast. To investigate this notion, we implemented a minimal biomathematical model based on two coupled oscillators: time-delayed reciprocal interactions between GH and GHRH, which endow high-frequency (40-60 min) GH oscillations, and time-lagged bidirectional GH-SRIF interactions, which mediate low-frequency (occurring every 3.3 h) GH volleys. We show that this basic formulation, sufficient to explain GH dynamics in the male rat [Farhy LS, Straume M, Johnson ML, Kovatchev BP, and Veldhuis JD. Am J Physiol Regulatory Integrative Comp Physiol 281: R38-R51, 2001], emulates the female pattern of GH release, if autofeedback of GH on SRIF is relaxed. Relief of GH-stimulated SRIF release damps the slower volleylike oscillator, allowing emergence of the underlying high-frequency oscillations that are sustained by the GH-GHRH interactions. Concurrently, increasing variability of basal somatostatin outflow introduces quantifiable, sex-specific disorderliness of the release process typical of female GH dynamics. Accordingly, modulation of GH autofeedback on SRIF within the interactive GH-GHRH-SRIF ensemble and heightened basal SRIF variability are sufficient to transform the well-ordered, 3.3-h-interval, multiphasic, volleylike male GH pattern into a femalelike profile with irregular pulses of higher frequency.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Virginia Health System, Charlottesville, Virginia 22908, USA. leon@virginia.edu
authors.forename: Leon S
authors.initials: LS
authors.lastname: Farhy
authors.forename: Martin
authors.initials: M
authors.lastname: Straume
authors.forename: Michael L
authors.initials: ML
authors.lastname: Johnson
authors.forename: Boris
authors.initials: B
authors.lastname: Kovatchev
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D003198:Computer Simulation; D004334:Drug Administration Schedule; D019277:Entropy; D005246:Feedback; D005260:Female; D005544:Forecasting; D013006:Growth Hormone / Q000378:metabolism / Q000502:physiology*; D013007:Growth Hormone-Releasing Hormone / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007267:Injections; D008297:Male; D008954:Models, Biological; D051381:Rats; D012727:Sex Characteristics; D013004:Somatostatin / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000906:Antibodies; D013004:Somatostatin; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone