Discordant effects of endogenous and exogenous somatostatin on growth hormone-releasing hormone secretion from perifused mouse hypothalami

The role of somatostatin (SRIF) on growth hormone-releasing hormone (GRH) secretion has been controversial because of discordant findings that may be model dependent. We have examined possible explanations for these findings by altering endogenous and exogenous SRIF tone in a mouse hypothalamic perifusion system, Four mediobasal hypothalamic fragments were perifused in a single chamber for 6 h. After a 2-hour equilibration period, test substances were introduced and maintained throughout the perifusion. After an additional 2 h, fragments were submaximally stimulated with 30 mM K+. Depletion of tissue SRIF by 10(-3) M cysteamine increased K+-stimulated GRH release 2-fold without altering basal GRH secretion. Removal of endogenous SRIF tone by anti-SRIF serum also augmented the GRH response to K+. Perifusion of SRIF at concentrations ranging from 10(-12) to 10(-8) M significantly increased the GRH response to K+ in a dose-dependent manner, A significant increase was also observed during the perifusion of 10(-9) M octreotide, Simultaneous perifusion with anti-SRIF serum and 10(-9) M octreotide (to which the antibody does not bind) resulted in a response of GRH to K+ that was similar to that observed with anti-SRIF serum alone. Combined perifusion with cysteamine and 10(-9) M SRIF also resulted in a GRH response to K+ that did not differ from the response observed during cysteamine alone, The enhancement of GRH secretion by reduction of endogenous SRIF tone or tissue content implies an inhibitory role of endogenous SRIF on GRH secretion, The seemingly paradoxical increase in GRH responses induced by exogenous SRIF and octreotide may be explained by an inhibitory effect on a yet unidentified interneuron which exerts a suppressive action on GRH secretion, The latter possibility could also explain the previously reported elevation of plasma GH after central administration of SRIF

Isolated familial somatotropinomas: Establishment of linkage to chromosome 11q13.1-11q13.3 and evidence for a potential second locus at chromosome 2p16-12

The majority of somatotropinomas are sporadic, although a small number occur with a familial aggregation, either as a component of an endocrine neoplasia complex that includes multiple endocrine neoplasia type 1 (MEN-1) and Carney complex (CNC) or as isolated familial somatotropinomas (IFS). IFS is defined as the occurrence of at least two cases of acromegaly or gigantism in a family that does not exhibit MEN-1 or CNC. This rare disease is associated with loss of heterozygosity (LOH) on chromosome 11q13, the locus of the MEN-1 gene, although the MEN-1 sequence and expression appear normal. These data suggest the presence of another tumor suppressor gene located at 11q13 that is important in the control of somatotrope proliferation. To establish linkage of IFS to 11q13 and to define the candidate interval of the IFS gene, we performed haplotype and allelotype analyses on two families with IFS. Collectively, allelic retention in one tumor and a recombinant haplotype in an affected individual mapped the tumor suppressor gene involved in the pathogenesis of IFS to a region of 8.6 cM between polymorphic microsatellite markers D11S1335 and INT-2 located at chromosome 11q13.1-13.3. Maximum two-point LOD scores for five markers within this region were 3.0 or more at θ = 0.0. As somatotropinomas are the predominant pituitary tumor subtype associated with CNC and arise before 30 yr of age, which is strikingly similar to the age at diagnosis for IFS, we explored the possibility that the putative CNC genes might also contribute to the pathogenesis of IFS. Although the genetic defect responsible for the complex is unknown, CNC has been mapped by linkage analysis to chromosomes 2p15-16 and 17q23-24 in different kindreds. Two-point LOD scores less than -2.0 were obtained using marker D17S949 from chromosome 17q23-24, excluding linkage. However, LOD scores of 2.5 were obtained for markers within 2p 16-12; therefore, linkage of IFS to chromosome 2p cannot be excluded. This report establishes linkage of the tumor suppressor gene involved in the pathogenesis of IFS to chromosome 11q13.1-13.3 and identifies a potential second locus at chromosome 2p16-12