vasoactive-intestinal-peptide and Acromegaly

Somatostatin is a peptide synthesized in many tissues that can act as a neurotransmitter, a systemic hormone, or a local hormone, and inhibits the secretion of hormones or other cell products. A long-acting synthetic analogue of somatostatin (SMS 201-995) has been developed which when administered subcutaneously has a biologic half-life of 90 to 120 minutes and can be administered 2 or 3 times per day. SMS 201-995 can lower plasma concentrations of growth hormone and somatomedin-C in patients with pituitary acromegaly, but no controlled trials to assess symptomatic response or change in tumor size have been done. In patients with pituitary thyrotropin-producing pituitary tumors, SMS 201-995 has been remarkably effective in producing biochemical and clinical responses and is the drug of first choice in this syndrome when tumor resection is not possible. In patients with the carcinoid syndrome, SMS 201-995 effectively reduces diarrhea, is the best available drug for treatment of carcinoid flush (effective in approximately 90% of cases), and is useful in treating carcinoid crisis. Eighty-five percent of patients with pancreatic islet cell tumors that produce vasoactive intestinal peptide will respond to SMS 201-995 with a reduction in diarrhea that often has been resistant to all other therapy. SMS 201-995 may also be useful in treating the symptoms in some patients with glucagonomas, growth hormone releasing hormone-producing tumors and insulinomas. Whether SMS 201-995 has a significant effect on gut neuroendocrine tumor growth remains uncertain. Certain nonmalignant diseases of the gut respond to somatostatin, including secretory diarrhea and fistulas of unknown cause. In general, SMS 201-995 has proved safe with few significant side effects, but whether the long-term use of the drug will result in an iatrogenic form of the somatostatinoma syndrome is uncertain.

Topics: Acromegaly; Adenoma, Islet Cell; Diarrhea; Gastrointestinal Diseases; Gastrointestinal Hemorrhage; Gastrointestinal Neoplasms; Growth Hormone; Humans; Intestinal Fistula; Malignant Carcinoid Syndrome; Octreotide; Pancreatic Neoplasms; Pancreatitis; Pituitary Neoplasms; Thyrotropin; Vasoactive Intestinal Peptide

Adult growth hormone deficient patients are known to exhibit reduced sweating and their ability to thermoregulate is diminished. Treatment of these patients with recombinant human growth hormone (r-hGH) is claimed to reverse these abnormalities. We have investigated this claim, as well as the mechanism underlying these altered sweating responses in GH-deficient patients as part of a placebo-controlled study on the effects of 6-12 months r-hGH therapy. Skin biopsies were obtained from these subjects and changes in morphology and innervation parameters for the eccrine sweat glands were examined. These included histochemistry for acetylcholinesterase (AChE) and immunohistochemistry for the neuropeptide vasoactive intestinal polypeptide (VIP) and for PGP9.5, a general neuronal marker. Sweat gland acinar size and periacinar innervation were measured by computerised image analysis. The patients underwent pilocarpine iontophoresis sweat rate tests and their serum insulin-like growth factor 1 (IGF-1) levels were assessed. Since active acromegaly involves excess GH secretion and hyperhidrosis, skin biopsies and sweat tests were also carried out on a group of these patients, as well as on control subjects. We have demonstrated a sweating defect in adult GH-deficiency which is accompanied by a reduction in AChE and VIP levels in the nerve supply to sweat glands. Following r-hGH therapy, an increase in AChE and VIP staining is seen in the sudomotor nerves accompanied by restoration of sweat rates and serum IGF-1 levels. Hence, normalization of sweat gland function includes recovery of sudomotor synapse constituents. A trophic effect of GH on sweat gland epithelium and/or on the associated nerves is proposed, supported by the observation that in acromegaly the size of sweat gland acini and the density of innervation to the sweat glands was greater than in controls.

Topics: Acetylcholinesterase; Acromegaly; Adult; Antigens, Differentiation; Biopsy; Female; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; In Vitro Techniques; Insulin-Like Growth Factor I; Iontophoresis; Male; Middle Aged; Muscarinic Agonists; Pilocarpine; Sweat Glands; Sweating; Sympathetic Nervous System; Thyroxine; Triiodothyronine; Tyrosine 3-Monooxygenase; Ubiquitin Thiolesterase; Vasoactive Intestinal Peptide

We examined whether the cholinergic mechanism is involved in the paradoxical GH responses to vasoactive intestinal peptide (VIP) and peptide histidine methionine (PHM) in acromegaly. 28 patients with active acromegaly underwent i.v. bolus injections of thyrotropin-releasing hormone (TRH, 500 micrograms), GH-releasing hormone (GHRH, 100 micrograms), VIP (100 micrograms), and PHM (100 micrograms) with or without a prior atropine treatment (1 mg, i.m., 30 min before). Blood samples were collected before and at intervals up to 120 min after the injection, and plasma GH levels were measured. In response to TRH, GHRH, VIP and PHM, 23 (82%), 24 (86%), 13 (46%) and 7 (25%) patients, respectively, responded with a significant GH increase (> 50% and 6 micrograms/l above the basal level). The effect of atropine pretreatment was examined in only these responders to the respective peptides. When the GH responses were estimated by the area under the response curve, the atropine pretreatment was able to significantly suppress the GH response to GHRH, but not to TRH, VIP, or PHM. Although the lack of cholinergic involvement in the TRH-induced GH release in acromegaly is confirmatory to previous reports, the same results with the VIP- and PHM-induced GH release are novel. The present study may suggest that in acromegaly the physiological GH response is mediated by the cholinergic mechanism, but the paradoxical ones are not.

Topics: Acetylcholine; Acromegaly; Adult; Atropine; Basal Metabolism; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Middle Aged; Peptide PHI; Prolactin; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

We examined whether peptide histidine methionine (PHM) induces a paradoxical rise in plasma GH in patients with acromegaly. PHM (100 micrograms) was given as an iv bolus to eight patients with active acromegaly, and plasma GH levels were measured before and at intervals up to 120 min after the injection. For comparison, the effects of TRH (500 micrograms) and vasoactive intestinal peptide (VIP, 100 micrograms), peptides known to paradoxically stimulate GH secretion in acromegalics, were assessed in all of the patients. A paradoxical rise (greater than 50% above the basal) in plasma GH was observed in five patients after both TRH and VIP administrations, although TRH responders were not always VIP responders, nor did VIP responders always respond to TRH. In two patients, the GH response to PHM fulfilled the criteria of a paradoxical increase. Both of these patients were also TRH and VIP responders. These results suggest that PHM may be another hypothalamic hormone capable of paradoxically stimulating GH secretion in at least some acromegalics, although PHM appears to be a less potent stimulator of GH release than TRH and VIP. The pathophysiological significance of this phenomenon is yet to be determined.

Topics: Acromegaly; Adult; Female; Growth Hormone; Humans; Injections, Intravenous; Male; Middle Aged; Peptide PHI; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

The case of a 33-year-old-woman with Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome and acromegaly due to ectopic growth hormone-releasing hormone (GHRH) secretion by a thymic carcinoid tumour is reported. Immunohistochemistry revealed positive immunoreactivity for GHRH, vasoactive intestinal polypeptide, somatostatin and alpha-subunit in the tumour cells. A previously undescribed new germ line mutation of the MEN1 protein gene was revealed.

Topics: Acromegaly; Adult; Antineoplastic Agents; Carcinoid Tumor; Fatal Outcome; Female; Germ-Line Mutation; Growth Hormone-Releasing Hormone; Humans; Immunohistochemistry; Multiple Endocrine Neoplasia Type 1; Neoplasm Proteins; Peptides, Cyclic; Somatostatin; Thymus Neoplasms; Vasoactive Intestinal Peptide

Six GH adenomas and three prolactinomas were investigated by light- and electron-microscopic morphological and immunocytochemical methods and the effect of vasoactive intestinal polypeptide (VIP) on growth hormone (GH) and prolactin (PRL) secretion was tested in vitro. The tumour cells of the acromegalic patients revealed both GH and PRL immunoreactivity while prolactinomas showed only PRL activity. All the adenomas stained immunocytochemically also for VIP. By electron microscopy, the tumours included two densely and two sparsely granulated GH, two mixed GH/PRL, and three sparsely granulated PRL adenomas. The dissociated cells were explanted, and cultured in vitro. The cultures in micro test plates were treated with VIP at different concentrations between 10(-5)-10(-12) M. GH and PRL contents in the culture media were measured by radioimmunoassay. GH release was significantly stimulated by VIP in a dose-dependent manner over the whole concentration range, while VIP was effective on the PRL release only at 10(-6)-10(-7) M concentration. The cells of a mixed adenoma were grown in Petri dishes and used for ultrastructural and immunocytochemical studies. The cytoplasmic structure of the cells treated with VIP corresponded to that of active hormone-secreting cells with large ergastoplasmic fields and Golgi zones containing secretory granules. Massive exocytotic events were encountered mainly in the GH-type cells. GH and PRL double immunocytochemistry showed the predominance of GH cells, many of them containing low amounts of PRL as well. Cells predominantly containing PRL were spread among them, they also might contain GH as well. Some of the cells contained only a single immunoreactive hormone. The intensity of gold labelling of the secretory granules appeared higher in the VIP-treated cells than in the untreated control ones which showed a cytoplasmic structure characteristic of glandular cells with low secretory activity. As all the adenoma cells both contained and reacted to VIP, our results are in agreement with an autocrine or paracrine effect of this peptide. The fine structure of the cells in the cultures treated with VIP supply an additional argument to the assumption that VIP may serve as a growth factor for these cell types.

Topics: Acromegaly; Adenoma; Adult; Cytoplasm; Cytoplasmic Granules; Exocytosis; Female; Human Growth Hormone; Humans; Immunohistochemistry; Male; Microscopy, Electron; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

GH-secreting pituitary adenomas causing acromegaly can be classified into at least two types, i.e. the lactotroph-like adenoma and somatotroph-like adenoma. From a functional point of view, the lactotroph-like adenoma is characterized by positive GH responses to TRH and bromocriptine (Br) with a GH increase or decrease, respectively, whereas the somatotroph-like adenoma is characterized by a high GH response to GHRH and a low GH response to TRH and Br. In this study, we examined whether the loading of vasoactive intestinal peptide (VIP) and GnRH, another hypothalamic hormone capable of stimulating GH secretion in acromegaly, have a pathophysiological significance as TRH, GHRH, and Br tests. In 52 patients with active acromegaly, we performed iv bolus injections of TRH (500 micrograms), GHRH (100 micrograms), VIP (100 micrograms), and GnRH (100 micrograms), and a peroral administration of Br (2.5 mg), in order to compare the GH responses to these loads. There was a significant correlation that the higher was the GH response after TRH the greater was the GH decrease after Br. Although statistically insignificant, there was a trend (0.05 < p < 0.1) that the higher was the GH response after GHRH the smaller was the GH decrease after Br. In addition, as novel findings, we observed that the GH responses to GHRH, VIP, and GnRH were in significant positive correlations to each other, and that the higher were the GH responses after VIP and GnRH the smaller was the GH decrease after Br. In agreement with this, we also found that a simultaneous GH responsivity to VIP and/or GnRH in TRH-responsive acromegalics significantly enhanced the GH response to GHRH and lowered the Br responsiveness compared to the data of pure TRH-responders. From these results, we hypothesize that the positive GH responsiveness to VIP and GnRH, like that to GHRH, may be a feature of the somatotroph-like pituitary adenoma causing acromegaly. The present results appear to be of some help in understanding the basis of the great variabilities in the GH responses to various dynamic testings in acromegaly.

Topics: Acromegaly; Adult; Aged; Bromocriptine; Dose-Response Relationship, Drug; Female; Gonadotropin-Releasing Hormone; Growth Hormone; Humans; Male; Middle Aged; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

There is an almost general agreement on the clinical significance of TRH and bromocriptine (Br) tests in acromegaly. That is that positive GH responses to these tests (with an increase or a decrease, respectively) are known to be very frequently associated with the presence of PRL-containing somatotroph adenomas of the pituitary. In this context, however, very little is known about the clinical significance of paradoxical GH responses to vasoactive intestinal peptide (VIP) and LHRH in acromegaly. We therefore examined, as the principal objective of this study, whether a relationship exists among the GH (in some cases also PRL) responses to TRH, VIP, LHRH and Br in acromegaly. Another aim of this study was to examine whether a sexual difference exists in GH and PRL secretion in acromegaly. We examined a total of 24 patients comprising 8 men and 16 women. In agreement with previous reports, TRH-responders tended to have a higher level of basal PRL than TRH-nonresponders. In contrast, VIP-responders and LHRH-responders tended to have a lower PRL level than their respective counterparts. Although Br responsiveness was unexpectedly similar between TRH-responders and nonresponders, it was revealed that pure TRH-responders who were not responsive to VIP or LHRH were more sensitive to Br and more hyperprolactinemic than the remaining TRH-responders. This suggests that the simultaneous GH responsivity to VIP and/or LHRH in TRH-responders may be a factor which lowers their Br responsiveness and basal PRL levels. With respect to a sexual difference in GH and PRL secretion, it was revealed that female acromegalics had higher levels of basal GH and PRL than male patients. In addition, it was found that female acromegalics had supernormal levels of basal PRL, but a subnormal PRL responsiveness to TRH. As the major implication of this study, we hypothesize that the positive GH response to TRH associated with a high sensitivity to Br may, as already suggested, be characteristic of PRL-containing somatotroph adenomas, whereas the GH responsivity to VIP, and possibly also to LHRH, co-existing with no or low sensitivity to Br may be a feature of pure somatotroph adenomas. Although this study is devoid of immunohistochemical evidence to support this hypothesis, we suggest that the present in vivo data may be of some help in understanding the basis of the great variabilities in the GH responses to various dynamic testings in acromegaly.

Topics: Acromegaly; Adult; Bromocriptine; Female; Gonadotropin-Releasing Hormone; Growth Hormone; Humans; Male; Middle Aged; Prolactin; Sex Characteristics; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

We examined whether the GH-releasing effect of peptide histidine methionine (PHM) in acromegaly may be mediated by activation of pituitary receptors for vasoactive intestinal peptide (VIP), which is structurally similar to but more powerful than PHM in stimulating GH secretion in acromegaly. VIP (50 or 100 micrograms) or PHM (50, 100, or 200 micrograms) was given as an i.v. bolus to 11 patients with active acromegaly, and plasma GH levels were measured before and at intervals up to 120 min after the injection. A paradoxical GH response (> 50% and > 6 micrograms/l above the basal) to 50 or 100 micrograms of VIP was observed in 4 (36%) or 5 (45%) patients, respectively. 2 (18%) patients showed paradoxical GH responses to both 50 and 100 micrograms of PHM, and, interestingly, as many as 5 (45%) patients showed positive GH responses to 200 micrograms of PHM. 3 of these 5 responders to 200 micrograms of PHM were also responders to both doses of VIP. To add to, one of the responders to 100 micrograms of VIP did not show a positive GH response to even 200 micrograms of PHM. These results may suggest that in at least some acromegalics the PHM stimulation of GH secretion is mediated by activation of pituitary VIP receptors by PHM and/or by PHM binding to its specific receptors which may have appeared concomitantly with VIP receptors. However, the occasional heterogeneity of the VIP- and PHM-induced GH responses may suggest that on some somatotroph adenomas either VIP or PHM receptors may appear independently.

Topics: Acromegaly; Adult; Dose-Response Relationship, Drug; Female; Growth Hormone; Humans; Male; Middle Aged; Peptide PHI; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Vasoactive Intestinal Peptide

We re-examined whether CRH stimulates GH secretion in acromegaly. Human CRH (100 micrograms) was given as an iv bolus to 15 patients with active acromegaly, and plasma GH levels were measured before and at intervals up to 120 min after the injection. For comparison, we assessed in all the patients the effects of TRH (500 micrograms), GnRH (100 micrograms), vasoactive intestinal peptide (100 micrograms) and peptide histidine methionine (100 micrograms), which are known paradoxically to stimulate GH secretion in acromegaly. A paradoxical GH response (greater than 50% above the basal) to TRH, GnRH, vasoactive intestinal peptide and peptide histidine methionine was observed in 12 (80%), 4 (27%), 5 (33%) and 2 (13%) patients, respectively. All the patients were responsive to at least one of these 4 peptides. However, none of the patients showed a positive GH response to hCRH. These results do not support a GH-releasing activity of CRH in acromegaly. Even if CRH has such an effect, it does not appear as potent as TRH, GnRH, vasoactive intestinal peptide and peptide histidine methionine. However, the possibility cannot be excluded that our negative data might have been due to the use of hCRH vs ovine CRH in earlier studies.

Topics: Acromegaly; Adult; Aged; Corticotropin-Releasing Hormone; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Injections; Male; Methionine; Middle Aged; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

Long-acting somatostatin analogues such as SMS 201-995 (Sandoz) are being evaluated in a wide range of clinical indications, including gut neuroendocrine tumours and acrogemaly. Long-term continuous SMS 201-995 treatment has achieved useful symptomatic improvement in diarrhoea in 4 patients with metastatic VIPomas who had relapsed following previous treatment. Clinical improvement has outlasted suppression of VIP secretion (suggesting an additional direct antisecretory action of SMS 201-995) and has occurred despite expansion of hepatic metastases. In 6 patients with tumours secreting gastrin and/or glucagon, secretion of these peptides was acutely inhibited by SMS 201-995. However, endocrine and clinical responses to chronic treatment have been less consistent. SMS 201-995 is active orally at doses of 4-8 mg and when given thrice-daily to 6 patients with active acromegaly, suppressed mean 24-h growth hormone levels by 51-88%. Despite significantly reduced plasma insulin concentrations, glucose tolerance did not deteriorate. SMS 201-995 was also effective in suppressing thyroid-stimulating hormone (TSH) and thyroid hormone secretion in a patient with mild thyrotoxicosis due to non-tumoural inappropriate TSH hypersecretion. In all cases SMS 201-995 treatment has been well tolerated and has few side-effects.

Topics: Acromegaly; Adenoma; Adult; Aged; Diarrhea; Female; Gastrointestinal Neoplasms; Glucagonoma; Growth Hormone; Humans; Hyperthyroidism; Liver Neoplasms; Male; Middle Aged; Neoplasms, Glandular and Epithelial; Octreotide; Pancreatic Neoplasms; Pituitary Neoplasms; Somatostatin; Streptozocin; Thyrotropin; Vasoactive Intestinal Peptide; Vipoma; Zollinger-Ellison Syndrome

In an attempt to characterize GH and PRL secretion in acromegaly, the effects of various stimuli on GH and PRL release by cultured pituitary adenoma cells derived from acromegalic patients were studied. In addition, the PRL responses of somatotroph adenoma cells were compared to those of prolactinoma cells. GH-releasing hormone-(1-44) (GHRH) consistently stimulated GH secretion in all 14 somatotroph adenomas studied in a dose-dependent manner. The sensitivity as well as the magnitude of the GH responses to GHRH were highly variable in individual tissues. Somatotroph adenomas that did not respond to dopamine were more sensitive and had greater GH responses to GHRH. In 8 of 9 somatotroph adenomas that concomitantly secreted PRL, the addition of GHRH likewise increased PRL release. Omission of extracellular Ca2+ blocked the stimulatory effect of GHRH on GH and PRL secretion. When cells were coincubated with 0.1 nM somatostatin, GH and PRL secretion induced by 10 nM GHRH were completely blocked in most adenomas. Similarly, coincubation of dopamine resulted in inhibition of GHRH-induced hormone secretion in some adenomas. Addition of TRH to the incubation medium, on the other hand, significantly stimulated GH secretion in 8 of 14 adenomas, while TRH stimulated PRL release in all of the adenomas. Vasoactive intestinal peptide (VIP) and corticotropin-releasing hormone (CRH) produced an increase in GH and PRL secretion in other adenomas. In prolactinoma cells, somatostatin and dopamine unequivocally suppressed PRL secretion; however, other stimuli including GHRH, VIP, and CRF were ineffective. TRH induced a significant increase in PRL secretion in only one prolactinoma. These results suggest that responsiveness to GHRH and somatostatin is preserved in somatotroph adenomas; the responsiveness to GHRH is inversely correlated to that to dopamine; and PRL cells associated with somatotroph adenomas possess characteristics similar to those of GH cells. Further, the GH stimulatory actions of TRH and VIP are different.

Topics: Acromegaly; Adenoma; Adult; Cells, Cultured; Corticotropin-Releasing Hormone; Dopamine; Female; Growth Hormone; Growth Hormone-Releasing Hormone; Humans; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Radioimmunoassay; Somatostatin; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

Vasoactive intestinal polypeptide (VIP) was administered as an iv bolus of 1 micrograms/kg BW to 8 acromegalic patients and in doses of 0.5 and 1 microgram/kg BW to 15 normal volunteers. Both systolic and diastolic blood pressures decreased, and pulse rate increased transiently after VIP injection. VIP stimulated PRL release from the anterior pituitary in normal subjects. Plasma PRL responses to VIP in women were dose dependent and larger than those in men. On the other hand, plasma GH levels rose markedly after VIP injection in all 6 patients with untreated acromegaly. In 2 patients studied after transsphenoidal microadenomectomy, there was no plasma GH response to VIP. In 2 other patients with inactive acromegaly as well as in normal subjects, VIP failed to affect plasma GH levels. In all 6 patients with active acromegaly, LRH (1-2 micrograms/kg BW, iv) did not increase plasma GH levels, but TRH (5-10 micrograms/kg BW, iv) caused significant increases in plasma GH, the magnitude of which was not similar to that of increases seen after VIP injection. Paradoxical GH responses to TRH were not observed in patients in the inactive phase after transsphenoidal surgery. These findings suggest that VIP stimulates GH release in vivo in acromegalic patients. A VIP test as well as a TRH test offer promise as simple and reliable techniques to evaluate the activity of acromegaly, particularly after transsphenoidal surgery.

Topics: Acromegaly; Adult; Blood Pressure; Female; Growth Hormone; Humans; Male; Middle Aged; Pituitary Hormones, Anterior; Prolactin; Pulse; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

The effects of vasoactive intestinal polypeptide (VIP), dopamine, and somatostatin (SRIF) on GH secretion were examined in vitro in perifused pituitary adenoma tissues obtained at surgery from seven patients with acromegaly. The perifusion of VIP at 5 x 10(-8) M resulted in a significant increase in effluent GH levels in five of the seven adenomas. A dose-related GH response was observed from 5 x 10(-9) to 5 x 10(-7) M VIP in two adenomas examined. SRIF at 5 x 10(-8) to 10(-7) M suppressed not only baseline secretion of GH but also inhibited GH rises elicited by VIP in six of the seven adenomas. Dopamine at 5 x 10(-7) to 5 x 10(-6) M decreased the baseline secretion of GH in six of the seven adenomas. In four of the six adenomas responsive to dopamine, dopamine suppressed VIP-induced GH release when perifused simultaneously. In the remaining two dopamine-sensitive adenomas in which VIP alone failed to affect GH release, the inhibition by dopamine of GH release was blocked by VIP perifused concomitantly with dopamine. Synthetic TRH or theophylline perifused at the end of the experiment stimulated GH release in all of the adenomas, indicating the viability of tumor cells throughout the study. These results suggest that VIP stimulates GH release by its direct action on pituitary adenoma cells of acromegalic patients and that VIP, SRIF, and dopamine interact at the pituitary level in modulating GH secretion from these adenomas.

Topics: Acromegaly; Adenoma; Adult; Dopamine; Female; Gastrointestinal Hormones; Growth Hormone; Humans; Male; Middle Aged; Pituitary Neoplasms; Somatostatin; Theophylline; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide