Ectopic growth hormone-releasing hormone (GHRH) syndrome in a case with multiple endocrine neoplasia type I

A 36-yr-old man with multiple endocrine neoplasia (MEN) type I had an ectopic growth hormone-releasing hormone (GHRH) syndrome due to a GHRH-secreting pancreatic tumor. The immunoreactive (IR)-GHRH concentration in his plasma ranged from 161 to 400 pg/ml (299 +/- 61 pg/ml, mean +/- SD; normal, 10.4 +/- 4.1 pg/ml), and a significant correlation was found between his plasma IR-GHRH and GH (r = 0.622, p less than 0.02). After removal of the pancreatic tumor, the high plasma GH concentration returned to nearly the normal range (42.2 +/- 31.3 to 9.6 +/- 3.8 ng/ml). These changes paralleled the normalization of his plasma IR-GHRH (16.1 +/- 3.8 pg/ml) and some of his symptoms related to acromegaly improved. However, plasma GH (7.7 +/- 1.3 ng/ml) and IGF-I (591 +/- 22 ng/ml) concentrations were high at 12 months after surgery, suggesting adenomatous changes in the pituitary somatotrophs. Before surgery, exogenous GHRH induced a marked increase in plasma GH, and somatostatin and its agonist (SMS201-995) completely suppressed GH secretion, but not IR-GHRH release. No pulsatile secretion of either IR-GHRH or GH was observed during sleep. An apparent increase in the plasma GH concentration was observed in response to administration of TRH, glucose, arginine or insulin, while plasma IR-GHRH did not show any fluctuation. However, these responses of plasma GH were reduced or no longer observed one month and one year after surgery. These results indicate that 1) a moderate increase in circulating GHRH due to ectopic secretion from a pancreatic tumor stimulated GH secretion resulting in acromegaly, and evoked GH responses to various provocative tests indistinguishable from those in patients with classical acromegaly, and 2) the ectopic secretion of GHRH may play an etiological role in the pituitary lesion of this patient with MEN type I.     

Role of vasoactive intestinal polypeptide (VIP) in regulating the pituitary function in man

Intramuscular injection of synthetic VIP (200 micrograms) resulted in a rapid increase in plasma prolactin (PRL) concentrations in normal women, which was accompanied by the 4- to 7-fold increase in plasma VIP levels. Mean (+/- SE) peak values of plasma PRL obtained 15 min after the injection of VIP were higher than those of saline control (28.1 +/- 6.7 ng/ml vs. 11.4 +/- 1.6 ng/ml, p less than 0.05). Plasma growth hormone (GH) and cortisol levels were not affected by VIP in normal subjects. VIP injection raised plasma PRL levels (greater than 120% of the basal value) in all of 5 patients with prolactinoma. In 3 of 8 acromegalic patients, plasma GH was increased (greater than 150% of the basal value) by VIP injection. In the in vitro experiments, VIP (10(-8), 10(-7) and 10(-6) M) stimulated PRL release in a dose-related manner from the superfused pituitary adenoma cells obtained from two patients with prolactinoma. VIP-induced GH release from the superfused pituitary adenoma cells was also shown in 5 out of 6 acromegalic patients. VIP concentrations in the CSF were increased in most patients with hyperprolactinemia and a few cases with acromegaly. These findings indicate that VIP may play a role in regulating PRL secretion in man and may affect GH secretion from pituitary adenoma in acromegaly.     

Ectopic corticotrophin-releasing-factor and growth hormone releasing factor secretion: diagnosis using human pituitary cell culture

Cell culture of human pituitary tissue has been used to diagnose a patient with Cushing's syndrome due to ectopic secretion of corticotrophin-releasing factor (CRF; case 1) and a case of acromegaly associated with ectopic secretion of a growth-hormone releasing factor (GRF; case 2). In both patients a pituitary tumour was not detected. Case 1 had a small cell carcinoma and symptoms of the ectopic ACTH syndrome, but in culture the carcinoma failed to secrete detectable ACTH. However, the culture medium used to maintain this carcinoma in vitro was found to contain a substance which stimulated ACTH secretion by human pituitary corticotrophs in cell culture. Radioimmunoassays and HPLC indicated that this substance had similar elution characteristics to human CRF and cross-reacted with antiserum to ovine CRF. Case 2 was found to have a lung tumour, the removal of which led to regression of her acromegalic symptoms. In culture, this tumour did not secrete GH, but did secrete a GRF. We conclude that the Cushing's syndrome and acromegaly, in cases 1 and 2, respectively, were due to ectopic secretion of CRF and GRF leading to hyperstimulation of the pituitary gland.     

Effect of growth hormone-releasing factor on plasma growth hormone, prolactin and somatomedin C in hypopituitary and short normal children

We studied the effect of a single intravenous bolus of 0.5 microgram/kg of growth hormone-releasing factor (GRF) on plasma GH, prolactin (PRL) and somatomedin C (SMC) in 12 short normal children and 24 patients with severe GH deficiency (GHD), i.e. GH less than 5 ng/ml after insulin and glucagon tolerance tests. GRF elicited an increase in plasma GH in both short normal and GHD children. The mean GH peak was lower in the GHD than in the short normal children (8.2 +/- 2.5 vs. 39.2 +/- 5.1 ng/ml, p less than 0.001). In the GHD patients (but not in the short normals) there was a negative correlation between bone age and peak GH after GRF (r = -0.58, p less than 0.005); GH peaks within the normal range were seen in 5 out of 8 GHD children with a bone age less than 5 years. In the short normal children, GRF had no effect on plasma PRL, which decreased continuously between 8.30 and 11 a.m. (from 206 +/- 22 to 86 +/- 10 microU/ml, p less than 0.005), a reflection of its circadian rhythm. In the majority of the GHD patients, PRL levels were higher than in the short normal children but had the same circadian rhythm, except that a slight increase in PRL was observed 15 min after GRF; this increase in PRL was seen both in children with isolated GHD and in those with multiple hormone deficiencies; it did occur in some GHD patients who had no GH response to GRF. Serum SMC did not change 24 h after GRF in the short normal children. We conclude that: (1) in short normal children: (a) the mean GH response to a single intravenous bolus of 0.5 microgram/kg of GRF is similar to that reported in young adults and (b) GRF has no effect on PRL secretion; (2) in GHD patients: (a) normal GH responses to GRF are seen in patients with a bone age less than 5 years and establish the integrity of the somatotrophs in those cases; (b) the GH responsiveness to GRF decreases with age, which probably reflects the duration of endogenous GRF deficiency, and (c) although the PRL response to GRF is heterogeneous, it does in some patients provide additional evidence of responsive pituitary tissue.     

Comparative in vivo and in vitro studies on abnormal GH secretion in patients with acromegaly

Eight patients with active acromegaly due to GH-producing pituitary adenoma were studied. GH secretory dynamics in vitro was evaluated by adding GRF, CRF, or a somatostatin analog, SMS 201-995 to the perifusate of dispersed cells from tumors. A comparison was made between the data obtained in preoperative tests for GH secretion and those obtained in experiments in vitro. Before operation, the GRF test (100 micrograms, iv) resulted in no GH response in three of six patients examined. The CRF test (100 micrograms, iv) resulted in a paradoxical GH increase in two of the same six patients. In vitro studies performed on adenoma cells revealed that exposure to GRF (100 ng/ml) elicited an increase in GH in seven of eight patients examined. Exposure to CRF (100 ng/ml) caused an enhanced GH secretion in four of the same eight patients. There were cases in which GH response to these hypothalamic hormones was observed in vitro but not in vivo, whereas there was only one case in which CRF caused an increase in GH in vivo but not in vitro. Thus, GH secretory dynamics was not always the same in vivo and in vitro. The discrepancy could be ascribed to the different secretory status of hypothalamic hormone (e.g., GRF or somatostatin) in vivo in each acromegalic patient.     

Effect of opiates on growth hormone secretion in acromegaly.

Morphine at doses of 5 mg and 10 mg does not stimulate growth hormone (GH) secretion in normal subjects, and its effect on GH secretion in acromegaly is not widely documented. We investigated the effect of 15 mg intravenous morphine on growth hormone in patients with active acromegaly compared to normal subjects (7 acromegalics and 5 controls). Their mean (+/- SEM) age was 30.5 +/- 7.6 years and 29.5 +/- 0.5 years, respectively. Basal and peak response of growth hormone after morphine was measured with simultaneous assay of cortisol to exclude the effect of stress. Mean (+/- SEM) basal growth hormone was 103.16 +/- 28.04 ng/ml in acromegalics compared to 4.51 +/- 1.43 ng/ml in controls. Morphine caused an elevation of growth hormone in both acromegalics and normal subjects (p < 0.05). However, the Delta (peak minus basal) response of growth hormone was comparable between the two groups. A concurrent fall in cortisol was noted after morphine in both the groups, excluding the effect of stress on growth hormone. We conclude that higher doses (15 mg) of morphine are required to stimulate GH secretion in normal subjects, and that opioids exert a positive modulating effect on growth hormone secretion in patients with active acromegaly suggesting partial autonomy of the pituitary tumor.     

Pituitary surgery for the management of acromegaly

Active acromegaly is almost always the result of a benign growth hormone (GH)-secreting adenoma of the pituitary gland. Because the same pituitary stem cell can produce both GH and prolactin (PRL), many acromegalic patients also have hyperprolactinemia. The advantages of surgical excision of pituitary adenomas associated with acromegaly include: (1) prompt decrease in GH; (2) reliable and immediate relief of the mass effect from the tumor (decompression of the optic nerves and chiasm), and (3) the opportunity to obtain tumor tissue for characterization and investigative study. Currently, more than 97% of operations for removal of pituitary tumors associated with acromegaly are done using the transsphenoidal approach rather than craniotomy. Technical advances to make the surgery safer continue to evolve, and include endoscopic approaches, computer-guided image-based intraoperative visualization, and intraoperative magnetic resonance imaging. Criteria for satisfactory remission of acromegaly after surgery are the same as those used for medical management. They include normal insulin-like growth factor (IGF)-I and suppression of GH to undetectable levels (<1.0 ng/ml) during an oral glucose tolerance test (OGTT). Data from a recent series of 86 patients operated upon for acromegaly at the University of Virginia and followed for more than 1 year have been reviewed. In patients receiving surgery as the initial procedure, 67% had a normal IGF-I, and 52% suppressed to <1.0 ng/ml in an OGTT. There was one true recurrence of disease diagnosed 81 months after surgery. Results are best in patients with noninvasive microadenomas. Gamma knife radiosurgery has been a valuable adjunct in those patients who fail to achieve postoperative remission. Pathological evaluation of the tumors revealed that 16% expressed GH only, 25% stained for GH and glycoprotein hormones (follicle stimulating hormone, thyroid hormone, thyroid stimulating hormone, alpha-subunit), 21% for GH and PRL, and 33% for GH, PRL and glycoprotein hormones. There was one acidophil stem cell tumor and 10% had the mammosomatotroph subtype. This contemporary series was free of mortality or serious complications. One patient had a transient cerebrospinal fluid leak and 3 developed transient SIADH with hyponatremia. Surgical treatment remains an important aspect of the combined management of patients with acromegaly.     

Effect of a single administration of somatostatin analogue (SMS 201-995) on GH, TSH and insulin secretion in patients with acromegaly

The effect of a long-acting somatostatin analogue SMS 201-995 on GH secretion was investigated. Eleven acromegalic patients received a single dose of 50 micrograms SMS 201-995 administered subcutaneously, and plasma GH, IGF-I, GRF, TSH, IRI and blood glucose were determined at regular intervals. Nine of 11 patients had elevated basal plasma GH levels above 5 ng/ml. In all patients, plasma GH levels fell immediately from 39.5 +/- 17.3 ng/ml (mean +/- SEM) to 4.3 +/- 1.6 ng/ml (P less than 0.05) with a maximal inhibition of 82.9 +/- 3.3% of the basal levels and the suppression persisted for about 6 h of the observation period. IGF-I and GRF levels were not apparently altered. TSH and IRI levels also rapidly fell. Blood glucose levels fell slightly by 0.5 h. Ten of 11 patients had pain at injection sites. Except for this, no side effects were observed. Our results show that the new somatostatin analogue SMS 201-995 may inhibit GH hypersecretion in acromegalic patients for significant periods, suggesting that this agent can be a useful clinical tool for the treatment of acromegaly.     

Provocation of a paradoxical growth hormone response to corticotropin-releasing hormone by pretreatment with metoclopramide in patients with acromegaly and normal subjects

Two of 7 patients with acromegaly and one of 7 normal subjects exhibited a paradoxical rise in growth hormone (GH) to human corticotropin-releasing hormone (CRH) when pretreated with metoclopramide, although CRH alone did not induce an increase in GH. In one of these two patients with acromegaly, the GH increase to metoclopramide alone also reached the criteria of a paradoxical response. These two acromegalic patients showed a GH increase to metoclopramide pretreatment before and up to two months after surgery. In another acromegalic patient, whose GH level remained high 5 months after surgery, metoclopramide induced an increase in GH level, while in a patient who had an above-normal GH level 18 months after surgery, the resumption of physiological GH secretion after surgery was evidenced by a postoperative absence of a GH response to metoclopramide. It is suggested from these results that the GH response to metoclopramide and the metoclopramide-provoked GH response to CRH in patients with acromegaly result from the secretion of GH from nonadenomatous cells of the pituitary.     

Acromegaly induced by growth hormone replacement therapy

Recombinant human growth hormone (GH) has been shown to be efficacious and safe in the treatment of various growth disorders and GH deficiency. We here report a 61-year-old man with idiopathic hypopituitarism in whom clinically active acromegaly developed. Complete GH deficiency had been diagnosed earlier by arginine stimulation testing, and therapy with recombinant human GH (maintenance dose 2 IU/day) was implemented at the age of 54 years. At presentation, the patient's insulin-like growth factor 1 (IGF-1; 439 ng/ml) and insulin-like growth factor binding protein 3 (4.3 mg/l) levels were highly elevated. Endogenous GH production and pituitary adenoma were excluded. Retrospectively, IGF-1 levels up to 621 ng/ml had been documented (but not appreciated) in the preceding 7 years. Upon GH dose reduction, the IGF-1 serum levels returned to normal, and the patient's clinical status stabilized. No GH receptor polymorphisms were identified in the patient's genomic DNA. This observation demonstrates that the indiscriminate use of recombinant GH bears the risk of active acromegaly, emphasizing the need for long-term patient monitoring programs as integral part of GH therapy.     

Effects of corticotropin releasing factor and growth hormone releasing factor on pituitary hormone secretion in patients with congenital thyrotropin deficiency. Abnormal response of growth hormone to corticotropin releasing factor

Blood concentrations of anterior pituitary hormones, ACTH, GH, TSH, PRL, LH, and FSH were determined in corticotropin releasing factor (CRF) test (synthetic ovine CRF 1.0 microgram per kg body weight) and growth hormone releasing factor (GRF) test (synthetic human pancreatic GRF-44 100 micrograms) in 2 female sibling patients with congenital isolated TSH deficiency, in their mother, in 2 patients with congenital primary hypothyroidism and in 8 normal controls. The patients with isolated TSH deficiency showed normally increased plasma ACTH and serum GH after CRF and GRF, respectively, and also showed an abnormal GH response to CRF. The serum GH showed a rapid increase to maximum levels (12.9 ng/ml) within 30 to 60 min followed by decrease. The possibility of secretion of abnormal GH could be excluded by the fact that on serum dilution, GH value gave a linear plot passing through zero. In addition, serum PRL, LH and FSH levels after CRF administration in case 1 and PRL after GRF in case 2 were also slightly increased but these responses were marginal. The mother of the patients, patients with congenital primary hypothyroidism, and normal healthy controls showed normal responses of pituitary hormones throughout the experiment. Data from the present study and a previous report show that abnormal GH response to the hypothalamic hormones (CRF, TRH and LHRH) may be observed in patients with congenital isolated TSH deficiency.     

Acromegaly with 'normal' serum growth hormone levels. Clinical features, diagnosis and results of transsphenoidal microsurgery.

Among 216 consecutive patients with growth hormone secreting pituitary adenomas who underwent primary neurosurgical treatment at the University of Erlangen-Nürnberg, 8 cases of acromegaly with 'normal' basal growth hormone levels (less than or equal to 5 ng/ml) were seen. They all had the typical clinical features of acromegaly, exhibited an abnormal growth hormone secretion following an oral glucose load, and had markedly elevated somatomedin C levels. The GRH- and TRH/GnRH-tests were not found helpful in establishing the diagnosis. Neuroradiology could demonstrate a pituitary adenoma in all of the patients. Following transsphenoidal microsurgical resection of the tumours, growth hormone secretion during oral glucose tolerance testing was normalised in 7 of the 8 patients. Immunohistology and explant culture studies documented growth hormone secreting pituitary adenomas in all cases. The authors conclude that even the finding of repetitive 'normal' (less than or equal to 5 ng/ml) serum GH levels does not exclude active acromegaly and when the clinical diagnosis of acromegaly is suspected, dynamic endocrine testing may reveal abnormal secretion patterns of GH in these cases. Transsphenoidal microsurgical resection of a pituitary adenoma offers a good chance of clinical and endocrinological remission in these cases.     

Plasma levels of total and active ghrelin in acromegaly and growth hormone deficiency

Ghrelin is an endogenous growth hormone (GH) secretagogue recently isolated from the stomach. Although it possesses a strong GH releasing activity in vitro and in vivo, its physiological significance in endogenous GH secretion remains unclear. The aim of this study was to characterize plasma ghrelin levels in acromegaly and growth hormone deficiency (GHD). We investigated plasma total and active ghrelin in 21 patients with acromegaly, 9 patients with GHD and 24 age-, sex- and BMI-matched controls. In all subjects, we further assessed the concentrations of leptin, soluble leptin receptor, insulin, IGF-I, free IGF-I and IGFBP-1, 2, 3 and 6. Patients with acromegaly and GHD as well as control subjects showed similar levels of total ghrelin (controls 2.004+/-0.18 ng/ml, acromegalics 1.755+/-0.16 ng/ml, p=0.31, GHD patients 1.704+/-0.17 ng/ml, p=0.35) and active ghrelin (controls 0.057+/-0.01 ng/ml, acromegalics 0.047+/-0.01 ng/ml, p=0.29, GHD patients 0.062+/-0.01 ng/ml, p=0.73). In acromegalic patients plasma total ghrelin values correlated negatively with IGF-I (p<0.05), in GHD patients active ghrelin correlated with IGF-I positively (p<0.05). In the control group, total ghrelin correlated positively with IGFBP-2 (p<0.05) and negatively with active ghrelin (p=0.05), BMI (p<0.05), WHR (p<0.05), insulin (p=0.01) and IGF-I (p=0.05). Plasma active ghrelin correlated positively with IGFBP-3 (p=0.005) but negatively with total ghrelin and free IGF-I (p=0.01). In conclusion, all groups of the tested subjects showed similar plasma levels of total and active ghrelin. In acromegaly and growth hormone deficiency plasma ghrelin does not seem to be significantly affected by changes in GH secretion.     

The effects of testosterone and estrogen on the pituitary growth hormone response to growth hormone-releasing factor

The effects of testosterone and estrogen on the pituitary growth hormone response to hypothalamic growth hormone-releasing factor (GRF) were evaluated in vivo using male and female rats and in vitro using a pituitary cell monolayer culture system. In vivo the increase in plasma growth hormone (GH) concentration in response to a 500 ng/kg dose of GRF was similar in gonadectomized male and female rats. Pretreatment of intact and gonadectomized male rats with testosterone caused significant enhancement of the pituitary GH response to GRF, whereas pretreatment of gonadectomized female rats with 17 beta-estradiol did not alter the response. The GH response to GRF was not different between prepubertal (i.e., 30-day-old) male and female rats. However, following puberty (i.e., by 60 days of age), the response in male rats was significantly greater than that observed in female rats. The in vitro preincubation of anterior pituitary cells with either testosterone or 17 beta-estradiol did not cause any shift in the dose-response curve between GRF and GH. These results demonstrated that androgens play an active role in modulating the pituitary response to GRF in vivo.     

Predicting therapeutic response and degree of pituitary tumour shrinkage during treatment of acromegaly with octreotide LAR

BACKGROUND/AIMS: The efficacy of transsphenoidal surgery in the treatment of patients with acromegaly is largely dependent on tumour size. A reduction in pituitary tumour volume by medical therapy might therefore improve subsequent surgical cure rates. This study prospectively determined the effects of the depot somatostatin analogue octreotide LAR on pituitary tumour size, GH and IGF-I levels and clinical symptoms in a cohort of previously untreated patients with acromegaly. METHODS: Six patients newly diagnosed with acromegaly (mean age 53 years; range 42-76 years) received intramuscular octreotide LAR every 28 days for 6 months. The initial dose of LAR was 20 mg, but increased to 30 mg after the initial 3 injections if mean GH levels were >5 mU/l. Prior to commencing LAR therapy, each patient received 3 injections of subcutaneous octreotide (50, 100 and 200 mug) in a randomized order on separate days, and the serum GH response was measured. Pituitary tumour volume was calculated from MRI or computed tomography scans at baseline, then 3 and 6 months after initiation of treatment, and assessed by a 'blinded' radiologist in random order. At baseline, 4 patients had a macroadenoma and 2 patients had a microadenoma. For the latter, the whole gland volume was measured. RESULTS: Serum GH levels decreased from 29.6 +/- 19.2 mU/l (mean +/- SD) at baseline to 12.1 +/- 10.5 mU/l at 3 months and 10.4 +/- 9.3 mU/l at 6 months. Three patients achieved a mean serum GH level of <5 mU/l. In these patients, the serum GH had declined to <5 mU/l in response to a single 100 mug subcutaneous octreotide injection. Serum IGF-I levels decreased by a mean of 45 +/- 7.4%. Tumour volume decreased in all patients: mean baseline volume 2,175 mm(3) (range 660-6,998) decreasing to 1,567 mm(3) (range 360-4,522) at 3 months (p < 0.05) and 1,293 mm(3) (range 280-4,104) at 6 months (p < 0.002). The mean percentage decrease in size was 29% (range -54 to +4%) at 3 months (p < 0.02) and 47% (range 21-97%) at 6 months (p < 0.002). There was no statistically significant correlation between GH response and tumour shrinkage. CONCLUSIONS: A single test dose of subcutaneous octreotide may be useful in predicting the subsequent efficacy of octreotide LAR. Octreotide LAR results in significant shrinkage of pituitary tumours of newly diagnosed patients with acromegaly. Whether its administration to such patients for 6-12 months can improve the efficacy of subsequent transsphenoidal surgery will require further study.     

Growth hormone-releasing factor (GRF) stimulation test in the diagnosis of pituitary adenomas

The studies aimed at evaluation of pituitary reserve of growth hormone following stimulation with GRF have been carried out in a group of 33 patients (11 women and 22 men, of age between 25 and 62 years) with pituitary tumors. The studied material included cases with pituitary adenoma characterized by excessive secretion of growth hormone (somatotropinoma), prolactin (prolactinoma) or alpha subunits of glycoprotein hormones (alphoma), and those with hormonally inactive adenoma. The GRF stimulation tests were carried out in hospitalized patients after overnight fast between 8.00 and 10.00 a.m. Blood samples for hormonal determinations were taken before the test, and after 15, 30, 60, 90 and 120 minutes following intravenous administration of 100 micrograms of GRF 1-29. Besides growth hormone, also the blood serum concentrations of other pituitary hormones were determined in the patients studied, both in the basal state and during the dynamic tests. In patients with acromegaly the results of the determinations of growth hormone following stimulation with GRF showed considerable individual variability. In 5 cases there was an increase in blood serum growth hormone concentration. No response to GRF was noted in the remaining 8 cases. In adenoma cases of prolactinoma type, growth hormone concentration began to rise already at the 15-th minute of the test in most cases. In three cases of prolactinoma associated with acromegaly no response to GRF was observed. The cases of alphoma-type adenoma were usually characterized by the secretion of pituitary hormones other than growth hormone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acromegaly in a patient with normal pituitary gland and somatotropic adenoma located in the sphenoid sinus

Ectopic acromegaly is a very rare clinical entity occurring in less than 1% of acromegalic patients. In most cases it is caused by GHRH or rarely GH-secreting neoplasms. Even rarer are ectopic pituitary adenomas located in the sphenoid sinus or nasopharynx that originate from pituitary remnants in the craniopharyngeal duct. This dissertation presents the difficulties in visualizing GH-secreting adenoma located in the sphenoid sinus. A 55-year-old man had somatic features of acromegaly for several years. MRI imaging revealed a slightly asymmetric pituitary gland (14 yen 4 mm) without focal lesions. Simultaneously, a spherical mass, 10 mm in diameter, corresponding with ectopic microadenoma was demonstrated on the upper wall of the sphenoid sinus. The serum GH level was 4.3 mg/l, IGF-1 = 615 mg/l, and a lack of GH suppression with oral glucose was proven. After preliminary treatment with a long-acting somatostatin analogue, transsphenoidal pituitary tumour removal was performed. Histopathological, electron microscopical and immunohistochemical analysis revealed densely granulated somatotropic pituitary adenoma: GH(+), PRL(-), ACTH(-), TSH(-), FSH(-), LH(-), MIB1 < 1%, SSTR3(+) and SSTR5(+). Post-surgical evaluation showed normal pituitary MRI scans, GH and IGF-1 levels 0.18 mug/l and 140 mg/l, respectively, as well as normal GH suppression with oral glucose. The careful analysis of possible pituitary embryonic malformations points out their significance for proper localization of extrapituitary adenomas.     

Growth hormone in normal female rat plasma appears on gel filtration as a large molecular weight form

Gel filtration of female rat plasma with normal growth hormone (GH) concentrations (less than 100 ng/m1) showed that nearly all the immuno-reactivity was centred on a peak with an apparent molecular weight in the region of 82,000. In contrast, pituitary GH was almost entirely monomeric. The majority of plasma prolactin (PRL) in the same samples had a molecular weight of 23,000 (i.e. monomeric), and was similar in profile to pituitary PRL. Samples from male rats showed some GH immunoreactivity at the 82,000 molecular weight position but more than 65% coeluted with monomeric PRL. In female plasma with GH concentration between 300 and 1,000 ng/ml, immuno-reactivity resolved into peaks at the void volume, the monomeric position, and a peak at 82,000 that decreased, as a percentage of the total, with increasing GH concentration. These results indicate the possible presence of a GH binding factor, with greater activity in female than male rat plasma.     

Effects of substance P and neurotensin on growth hormone and thyrotropin release in vivo and in vitro

Conscious ovariectomized (OVX) rats bearing a cannula implanted in the third ventricle were injected with 2 μl of 0.9% NaCl containing varying doses of substance P (SP) or neurotensin (NT) and plasma GH and TSH levels were measured by RIA in jugular blood samples drawn through an indwelling silastic catheter. Control injections of physiologic saline iv or into the third ventricle did not modify plasma hormone levels. Intraventricular injection of SP or NT at doses of either 0.5 or 2 μg elevated plasma GH concentrations within 5 min and they remained elevated for 60 min. Third ventricular injection of similar doses of SP or NT had no effect on plasma TSH. An intermediate dose of 1 μg of SP or NT given iv had no effect on plasma GH but NT elevated plasma TSH. Incubation of hemipituitaries from OVX rats with varying doses of SP or NT did not alter GH release into the medium but TSH release was enhanced with NT at doses of 100 or more ng/ml of medium. It is suggested that SP acts centrally to stimulate growth hormone-releasing factor (GRF) or to inhibit somatostatin release and thereby enhance GH release and that NT acts directly on the pituitary to stimulate TSH release.     

Hypothalamic growth hormone-releasing factor (GRF) participates in the negative feedback regulation of growth hormone secretion

Effects of growth hormone (GH) excess on immunoreactive hypothalamic GH-releasing factor (GRF) and somatostatin (SRIF) were studied in rats. Hypothalamic GRF content significantly reduced after 7-day daily treatment with 160 micrograms of rat GH or after inoculation of GH-secreting rat pituitary tumors, MtT-F4 for 9 or 13 days and GH3 for 3 months. Basal and 59 mM K+-evoked release of GRF from incubated hypothalami diminished, more than the content, by 43-51% in MtT-F4 tumor- or by 67-83% in GH3 tumor-bearing rats. In contrast, there was a small but significant increase in content or release of SRIF in rats harboring the GH3 or MtT-F4 tumor, respectively. These results indicate the existence of a negative feedback loop via hypothalamic GRF as well as SRIF in control of GH secretion.