Somatostatin (SRIH) is a physiological inhibitor of growth hormone (GH) secretion, but its role in the regulation of adrenocorticotropic hormone (ACTH), prolactin (PRL) and thyroid-stimulating hormone (TSH) release is unclear. SRIH (1 pM to 1 µM) did not affect basal and corticotropin-releasing hormone (CRH)-stimulated ACTH release by normal rat pituitary cells cultured in medium with 10% fetal calf serum (FCS). In cells deprived of serum for 48 h, or preincubated with the glucocorticoid-receptor-blocking agent, RU 38486, CRH-stimulated ACTH release was significantly suppressed by 1 pM to 0.10 nM SRIH. Preincubation with 5 nM dexamethasone completely abolished this inhibitory effect of SRIH on ACTH release. PRL release by pituitary cells cultured in phenol red-free culture medium with 10% estrogen-stripped FCS showed a very low sensitivity to SRIH. Increasing concentrations of 10 and 50 pM and 1 nM estradiol made PRL release by these cells significantly less sensitive to 50 nM dopamine, whereas the sensitivity to SRIH increased to a similar extent. In all instances dopamine and SRIH together exerted additive inhibitory effects, the extent of which remained similar under all conditions. After a 2-hour incubation, thyrotropin-releasing hormone-stimulated TSH secretion was significantly suppressed by 100 nM and 1 µM SRIH only in cells cultured in medium with 10% hypothyroid serum, and not in cells cultured in medium with 10% FCS. Such a difference in the sensitivity of thyrotrophs to SRIH disappeared during longer incubation. Conclusions: (1) ACTH release by normal corticotrophs is only sensitive to SRIH in the absence of the physiological peripheral feedback regulation by glucocorticoids. (2) PRL release by normal lactotrophs is sensitive to SRIH in the presence of physiological concentrations of estradiol. As the estradiol concentration increases, the dopamine sensitivity of PRL release decreases to the same extent as SRIH sensitivity increases, while the additive inhibitory effect of the combination of dopamine and SRIH remains the same. (3) TSH release by normal thyrotrophs is more sensitive to SRIH if the cells have been cultured in hypothyroid serum. (4) The reaction of corticotrophs, lactotrophs and thyrotrophs to SRIH seems to be determined by the concentration of the respective ‘peripheral’ physiological feedback hormones.
Both insulin-like growth factor I (IGF-I) and somatostatin (SRIH) have been shown to directly inhibit GH release and the total GH content of cultured pituitary cells. In the present study we evaluated the interrelationship between the effects of a recombinant human IGF-I analog ([Thr59]IGF-I) and SRIH on GH release by cultured normal rat pituitary cells together with the effects of glucocorticoids. In all experiments anterior pituitary cells were preincubated for 24 h without or with IGF-I, SRIH, and/or dexamethasone. Thereafter, 24-h incubations without or with IGF-I, dexamethasone, SRIH, and GHRH were performed. Both IGF-I and SRIH inhibited basal and GHRH-stimulated GH release in a dose-dependent manner; the maximal inhibitory concentrations were 5 nM IGF-I and 10 nM SRIH. These concentrations inhibited basal and GHRH-stimulated GH release by 23% and 40% (IGF-I) and 80% and 85% (SRIH), respectively. The combination of IGF-I and low concentrations of SRIH exerted an additive inhibitory effect on GHRH-stimulated GH release; IGF-I (1 nM) and SRIH (10 pM) together inhibited GH release by 50%, while the maximal inhibitory concentrations of 5 nM IGF-I and 10 nM SRIH virtually completely inhibited GH release (by 93%). Preincubation with 5 and 100 nM dexamethasone attenuated the sensitivity of somatotrophs to SRIH and completely abolished the inhibitory effects of IGF-I. This effect of dexamethasone could be reversed by coincubation with the glucocorticoid receptor antagonist RU 38486. High concentrations of 5-10 nM of the recombinant human IGF-I analog stimulated PRL cell content (5 and 10 nM) and release (10 nM), while a purified IGF-I preparation extracted from human blood exerted a parallel inhibitory effect on GH and PRL release. We conclude that 1) IGF-I and SRIH exert an additive direct inhibitory effect on basal and GHRH-stimulated GH secretion by normal cultured pituitary cells; 2) glucocorticoids directly attenuate the sensitivity of somatotrophs to SRIH, but completely prevent the inhibitory effects of IGF-I on GH secretion; and 3) in contrast to a purified IGF-I preparation extracted from human blood (which inhibits GH and PRL release) high concentrations of the recombinant IGF-I preparation (which inhibit GH release) stimulate PRL production.
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