Growth Hormone (GH) Secretion in Patients with an Inactivating Defect of the GH-Releasing Hormone (GHRH) Receptor Is Pulsatile: Evidence for a Role for Non-GHRH Inputs into the Generation of GH Pulses

Abstract

GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10-20 pulses in each 24-h cycle. The exact roles in pulse generation played by somatostatin, GHRH, and the recently isolated GH-releasing peptide, Ghrelin, are not fully elucidated. To investigate the GHRH-mediated GH secretion in human, we investigated pulsatile, entropic, and 24-h rhythmic GH secretion in two young adults (male, 24 yr; female, 23 yr) from a Moroccan family with a novel inactivating defect of the GHRH receptor gene. Data were compared with values in age- and gender-matched controls. Plasma GH concentration were measured by a sensitive immunofluorometric assay, with a detection limit of 0.01 mU/L. All plasma GH concentrations in the female patient were measurable; in the male patient 30 of 145 samples were at or below the detection limit. GH secretion was pulsatile, with 21 and 23 secretory episodes/24 h in the male and female patients, respectively. The fraction of basal to total GH secretion was raised in both patients by 0.18 and 0.15, respectively. The total 24-h GH production rate was greatly diminished; in the male patient it was 6.9 mU/L (normal values for his age, 26--63 mU/L), and in the female patient it was 4.2 mU/L (normal values for her age, 96--390 mU/L). The nyctohemeral plasma GH rhythm was preserved (P < 0.001), with normal acrophases (0430 and 0218 h in the male and female, respectively). Approximate entropy was greatly elevated in both subjects (0.82 in the male and 1.17 in the female; upper normal values for age and gender, 0.24 and 0.59, respectively). Intravenous injection of 50 microg GHRH failed to increase the plasma GH concentration in both patients, but 100 microg GH-releasing peptide-2 elicited a definite increase (male patient, 0.13 to 1.74 mU/L; female patient, 0.29 to 0.87 mU/L). Both patients had a partial empty sella on magnetic resonance imaging scanning. In summary, the present studies in two patients with a profound loss of function mutation of the GHRH receptor favor the view that in the human the timing of GH pulses is primarily supervised by intermittent somatostatin withdrawal, and the amplitude of GH pulses is driven by GHRH. In addition, we infer that effectual GHRH input controls the GH cell mass and the orderliness of the secretory process.

Growth Hormone-Releasing Hormone Receptor Mutations in Familial Growth Hormone Deficiency

“…A small but significant GH response to GH secretagogues, compounds that are thought to stimulate GH secretion independently from the GHRHR, has been reported by others and us. 31,37 However, the response is very mild (possibly as a result of severe somatotroph hypoplasia) and is still consistent with the IGHD diagnosis.…”

Distribution and morphology of the juxtapositions between growth hormone-releasing hormone-(ghrh)-immunoreactive neuronal elements

“…Passive immunization with somatostatin antiserum does not alter pulsatile GH release, but immunization with antibodies raised against both somatostatin and GHRH abolishes GH bursts [8]. In contrast to these findings, patients with an inactivating defect of the GHRH receptor gene maintain the regular frequency of the GH release with a diminished total 24-h GH production rate, suggesting that GH pulses are under the control of intermittent somatostatin withdrawal while the amplitude of GH pulses is driven by GHRH [9]. The fundamental role of somatostatin in the GH pulse generation has been supported by previous data describing that most of the descending phases of somatostatin pulses are associated with the initiation of GH pulses in goats [5].…”

“…Preceding studies revealed that patients with inactivating defect of the GHRH receptor gene still maintain the regular frequency of the GH release with a diminished total 24-h GH production rate [9]. Although these data seem to indicate that somatostatin, instead of GHRH, is responsible for the pulsatile release of GH, more studies are required due to the heterogenity and limited number of the patient pool used.…”

Pubertal alterations in growth and body composition: IX. Altered spontaneous secretion and metabolic clearance of growth hormone in overweight youth

“…Evidence that somatostatin primarily modulates GH pulse timing in humans includes a rebound-like pulse of GH that occurs during short-term somatostatin withdrawal [40] and a reduction in the frequency and area of GH peaks but conserved GH pulsatility during intravenous somatostatin infusion [41]. The separate functions of GHRH and somatostatin for controlling GH pulse amplitude and frequency are uniquely demonstrated in young adults with a recessive point mutation that results in truncated and inactive GHRH receptors [42]. Compared with healthy adults, these individuals have extremely low serum GH concentrations because of very small GH burst amplitudes, but the GH secretory burst frequency is 2-to 3-fold greater than age-and sex-matched control subjects [42].…”

“…The separate functions of GHRH and somatostatin for controlling GH pulse amplitude and frequency are uniquely demonstrated in young adults with a recessive point mutation that results in truncated and inactive GHRH receptors [42]. Compared with healthy adults, these individuals have extremely low serum GH concentrations because of very small GH burst amplitudes, but the GH secretory burst frequency is 2-to 3-fold greater than age-and sex-matched control subjects [42].…”