Transfer of CVD-grown graphene for room temperature gas sensors.

An easy transfer procedure to obtain graphene-based gas sensing devices operating at room temperature (RT) is presented. Starting from chemical vapor deposition-grown graphene on copper foil, we obtained single layer graphene which could be transferred onto arbitrary substrates. In particular, we placed single layer graphene on top of a SiO2/Si substrate with pre-patterned Pt electrodes to realize a chemiresistor gas sensor able to operate at RT. The responses to ammonia (10, 20, 30 ppm) and nitrogen dioxide (1, 2, 3 ppm) are shown at different values of relative humidity, in dark and under 254 nm UV light. In order to check the sensor selectivity, gas response has also been tested towards hydrogen, ethanol, acetone and carbon oxide. Finally, a model based on linear dispersion relation characteristic of graphene, which take into account humidity and UV light effects, has been proposed.

Visible electroluminescence from a ZnO nanowires/p-GaN heterojunction light emitting diode.

In the current paper we apply catalyst assisted vapour phase growth technique to grow ZnO nanowires (ZnO nws) on p-GaN thin film obtaining EL emission in reverse bias regime. ZnO based LED represents a promising alternative to III-nitride LEDs, as in free devices: the potential is in near-UV emission and visible emission. For ZnO, the use of nanowires ensures good crystallinity of the ZnO, and improved light extraction from the interface when the nanowires are vertically aligned. We prepared ZnO nanowires in a tubular furnace on GaN templates and characterized the p-n ZnO nws/GaN heterojunction for LED applications. SEM microscopy was used to study the growth of nanowires and device preparation. Photoluminescence (PL) and Electroluminescence (EL) spectroscopies were used to characterize the heterojunction, showing that good quality of PL emission is observed from nanowires and visible emission from the junction can be obtained from the region near ZnO contact, starting from onset bias of 6V.

G protein oncogenes in pituitary tumors.

G proteins are involved in the transduction of external signals from cell surface receptors to intracellular effectors. Somatic mutations activating the a-subunit of G(s) (the stimulatory regulatory protein of adenylyl cyclase) by inhibiting its intrinsic GTPase activity have been first identified in human GH-secreting adenomas and subsequently found in thyroid tumors and in McCune-Albright syndrome. It has been therefore proposed that the gene encoding the GS a-subunit may be converted into an oncogene (gsp for GS protein) in cell types that proliferate in response to cAMP. Since several G proteins mediate signaling pathways that are effective in coupling external stimuli to cell proliferation, it appears most likely that in the near future other G protein oncogenes will be identified in human tumors.

Glycoprotein hormone alpha-subunit in pituitary adenomas.

Elevated serum glycoprotein hormone alpha-subunit (alpha-subunit) levels are seen in about one of six patients bearing pituitary adenomas. This finding has particular clinical significance in patients with nonfunctioning pituitary adenomas. Moreover, the measurement of alpha-subunit along with the calculation of the molar ratio between alpha-subunit and TSH, LH, or FSH is helpful in the diagnosis of glycoprotein hormone-secreting pituitary adenomas. Since serum alpha-subunit levels may vary greatly in several physiologic and pathologic conditions, care has to be taken to differentiate abnormal from normal states of alpha-subunit hypersecretion as well as to exclude causes of alpha-subunit overproduction only casually associated with the presence of pituitary tumors.

Excess of beta-subunit of thyrotropin (TSH) in patients with idiopathic central hypothyroidism due to the secretion of TSH with reduced biological activity.

alpha-Subunit and beta-subunit of TSH were measured in the sera of five patients with idiopathic central hypothyroidism due to the secretion of biologically inactive TSH, in seven normal controls matched for bone age and sex, and in five subjects with mild primary thyroid failure before and after TRH (200 micrograms, iv) stimulation. Basal serum alpha-subunit concentration in patients did not differ from that in normal controls (mean +/- SD, 0.40 +/- 0.20 vs. 0.38 +/- 0.28 ng/ml; P, NS), whereas TSH and TSH-beta were significantly higher in patients (TSH, 1.51 +/- 0.74 vs. 0.59 +/- 0.53 ng/ml, P less than 0.025; TSH-beta, 0.56 +/- 0.18 vs. 0.10 +/- 0.02 ng/ml, P less than 0.001). The concentration of TSH-beta was also significantly higher in patients with central hypothyroidism than in subjects with mild primary thyroid failure (0.56 +/- 0.18 vs. 0.24 +/- 0.08 ng/ml; P less than 0.01), although serum TSH levels did not differ in the two groups (1.51 +/- 0.74 vs. 2.16 +/- 0.52 ng/ml; P, NS). alpha-Subunit was significantly higher in primary hypothyroid subjects (1.50 +/- 0.87, P less than 0.05 compared with patients with central hypothyroidism). After TRH, alpha-subunit, TSH, and TSH-beta net increases (peak) were significantly higher in patients with central hypothyroidism than in normal controls (alpha-subunit: 0.95 +/- 0.5 vs. 0.47 +/- 0.19 ng/ml, P less than 0.05; TSH: 7.1 +/- 3.1 vs. 2.9 +/- 1.8 ng/ml, P less than 0.005; TSH-beta: 0.89 +/- 0.35 vs. 0.22 +/- 0.18 ng/ml, P less than 0.005), whereas they did not significantly differ from those recorded in hypothyroid controls. The beta/alpha ratio, which was 1.67 +/- 0.86 in patients and 0.35 +/- 0.18 in normal controls (P less than 0.005), slightly decreased after TRH to 1.24 +/- 0.78 in patients, but remained unchanged in normal controls (0.39 +/- 0.1). After TRH the alpha-subunit peak occurred at 20 min both in patients and in controls, whereas TSH and TSH-beta peaked at 60 min in patients and at 20 min in controls. One patient was given oral TRH (40 mg/day for 4 weeks). The beta/alpha ratio fell from 1.85 to 0.13. Interestingly, serum thyroid hormones, which did not increase after iv TRH and after the first doses of oral TRH, showed a definite increase. Sera from two patients were filtered on Sephadex G-100: in one of them TSH-beta eluted in the same position as labeled reference standard, whereas in the other one radioimmunoassayable TSH-beta eluted near the void volume. The above data indicate that in patients with idiopathic central hypothyroidism due to biologically inactive TSH there is an excess of circulating TSH-beta and suggest that TRH is implicated in the secretion of TSH of full biological potency.

Bromocriptine treatment of microprolactinomas: evidence of stable prolactin decrease after drug withdrawal.

Thirty-six women with PRL-secreting pituitary microadenomas [mean PRL, 114 +/- 12.5 (+/- SE) ng/ml] were treated with bromocriptine (BRC; 2.5-10 mg/day) for 12 months. During BRC treatment, serum PRL decreased in all patients. After termination of treatment, mean serum PRL levels, evaluated at 15, 30, and 45 days, were significantly decreased (-41.6%, -43.0%, and -40.2%, respectively) compared to pretreatment values. The patients were arbitrarily divided into 3 groups: 12 responders, in whom the PRL persistent posttreatment decrease was greater than 50%, 8 hyporesponders, in whom the PRL decrease was between 30% and 50%, and 16 nonresponders with absent or negligible PRL decrease. Four patients had normal PRL levels and clinical remission for 14-30 months after BRC withdrawal. In 18 women, BRC treatment was repeated for another 12 months. After termination of treatment, 11 patients were responders, 1 was a hyporesponder, and 6 were nonresponders. Four of these 18 patients still had normal PRL levels 8-28 months after drug discontinuation. The responses of PRL to TRH and domperidone were compared before and after termination of treatment at 30 and 45 days, respectively. Both mean peak values of PRL and absolute increases after TRH treatment were similar before and after BRC administration; however, a PRL response to TRH was present in 15% of 26 patients before treatment and in 42% after treatment. The mean peak values after domperidone were similar before and after BRC treatment, but the absolute increase over the basal value was much higher after BRC; PRL response to domperidone was present in 16% of 19 patients before BRC treatment and in 74% after BRC. These data suggest that BRC is effective in the treatment of some microprolactinomas; BRC effectiveness improves after prolonged periods of administration. The variations in PRL responses to TRH and domperidone suggest profound modification of PRL secretion after BRC treatment.

Circulating thyrotropin bioactivity in sporadic central hypothyroidism.

The etiopathogenesis of sporadic central hypothyroidism (CH) involves pituitary and hypothalamic lesions. Pituitary CH (pCH) implies a diminished number of functioning thyrotropes, accounting for the quantitative impairment of TSH secretion. Hypothalamic CH (hCH) is characterized by normal or even increased TSH concentrations and qualitative abnormalities of TSH secretion, including a decreased bioactivity of circulating TSH. However, controversy still exists about the actual occurrence of bioinactive TSH among CH patients, and no data are available in pCH. Therefore, we studied 41 CH patients with different hypothalamic-pituitary disorders. Immunoreactive TSH (TSH-I) ranged from 0.08-11.1 mU/L (normal, 0.24-4.0), free T4 (FT4) ranged from 0.6-8.8 pmol/L (normal, 9-18), and FT3 ranged from 1.2-5.4 pmol/L (normal, 4-8). A blunted TSH response to TRH (<4 mU/L), indicating prevalent pCH, was found in 56% of the patients, and a net TSH-I increment > or =4 mU/L, indicating prevalent hCH, was found in the remaining 44%. Net TSH-I increments showed significant correlation with basal FT4 (P < 0.02), indicating the relevance of pituitary TSH reserve in the pathogenesis of CH. Circulating TSH was immunoconcentrated and tested in bioassay and in ricin affinity chromatography. The ratio between biological (B) and immunological (I) activities of circulating TSH was reduced (n = 25; TSH B/I, 0.38+/-0.19) compared to the values recorded in normal subjects (n = 26; TSH B/I, 1.53+/-0.54; P < 0.001) and primary hypothyroid patients (n = 24; TSH B/I, 0.74+/-0.31; P < 0.001), but no difference between pCH (n = 9; 0.36+/-0.16) and hCH (n = 16; 0.39+/-0.20) was seen. TSH B/I values in CH patients showed a limited overlap with normal values (20%) and a highly significant correlation with the FT3 response to endogenous TRH-stimulated TSH (P < 0.005). The elevated sialylation degree of TSH molecules may explain part of these findings. In conclusion, the secretion of TSH molecules with reduced bioactivity is a common alteration in the patients with hypothalamic-pituitary lesions, contributing along with the impairment of pituitary TSH reserve to the pathogenesis of CH.

Immunodetection of chorionic gonadotropin and its subunits in human nonfunctioning pituitary adenomas.

Human nonfunctioning pituitary adenomas (NFPA) may produce CG in addition to the classical glycoprotein hormones (LH, FSH, and TSH). The aim of the present study was to localize LH beta, FSH beta, TSH beta, alpha-subunit (alpha SU), CG, and its beta-subunit (beta SU) in NFPA using a highly specific immunohistochemical technique. Nine NFPA, obtained at surgery, were processed for both electron microscopy and immunohistochemistry. Three tumors resulted oncocytomas, and six were null cell. Using an immunofluorescence technique, all tumors were positive for at least one glycoprotein; in particular, seven adenomas were markedly positive for CG beta, whereas only two were positive for the intact CG. No association among LH beta, FSH beta, and CG beta positivity could be demonstrated in the different adenomas. In the seven tumors positive for both CG beta and alpha SU, double fluorescence labeling demonstrated that six cases localized CG beta and alpha SU in different cells, but only one tumor showed the two subunits colocalized in the same cells. These data confirm that pituitary tumors synthesize both alpha SU and beta SU of glycoprotein hormones; in particular, the present study indicates that the majority of NFPA is able to synthesize CG, particularly its beta SU. Moreover, the localization of CG beta and alpha SU in different tumoral cells might account for the preferential expression of beta SU and alpha SU instead of the intact hormonal molecules in NFPA.

Hypothalamic peptides modulate cytosolic free Ca2+ levels and adenylyl cyclase activity in human nonfunctioning pituitary adenomas.

The effects of hypothalamic peptides (TRH, GnRH, arginine vasopressin, vasoactive intestinal peptide, GHRH, CRH, and SRIH) on cytosolic free calcium concentrations ([Ca2+]i) and adenylyl cyclase (AC) activity were evaluated in 12 nonfunctioning pituitary adenomas. TRH, GnRH, and arginine vasopressin induced a marked [Ca2+]i rise in 10/12, 4/12, and 2/5 tumors, respectively. The transients induced by these peptides were due to both Ca2+ mobilization from the intracellular stores and Ca2+ influx from the extracellular medium. AC activity was evaluated in 10 adenomas; 1 microM vasoactive intestinal peptide induced a 2- to 6-fold stimulation of the enzyme activity in all tumors, while neither GHRH nor CRH were effective. Moreover, in 5/10 tumors 1 microM SRIH reduced both AC activity and [Ca2+]i, while in 2/10 the peptide caused a significant rise in [Ca2+]i despite the AC inhibition and in 3/10 SRIH did not modify either AC activity or [Ca2+]i. This study indicates that in nonfunctioning pituitary adenomas a wide spectrum of hypothalamic peptides modulate [Ca2+]i and AC activity. Moreover, the presence of biologically active receptors may offer a possible target for therapeutic intervention.

Diagnostic value of the acid-labile subunit in acromegaly: evaluation in comparison with insulin-like growth factor (IGF) I, and IGF-binding protein-1, -2, and -3.

In normal subjects the main form of circulating insulin-like growth factor (IGF) is the 150-kDa complex. This complex is formed by the IGF peptide, the acid-stable IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS). Experimental and clinical data have demonstrated that ALS is primarily under the control of GH and plays a critical role in maintaining constant levels of circulating IGF-I. In this study we evaluated ALS, IGF-I, and IGFBP-1, -2, and -3 in 45 acromegalic patients in basal conditions and, in 37 of these, twice after surgical therapy compared with 100 age- and sex-matched control subjects to estimate their value as parameter of GH secretory state. The results demonstrated that in acromegaly before treatment all parameters (ALS, 523 +/- 26; IGF-I, 129 +/- 6; IGFBP-1, 0.7 +/- 0.1; IGFBP-3, 234 +/- 21; nmol/L; mean +/- SEM) but IGFBP-2 were significantly different (P<0.0001) from those in healthy subjects (ALS, 281 +/- 4; IGF-I, 22 +/- 1; IGFBP-1, 1.6 +/- 0.1; IGFBP-3, 91 +/- 3). IGF-I was more sensitive (100%) than ALS (89%), and both were more predictive of disease status than IGFBP-3, in that 27% of the patients had IGFBP-3 levels within the normal range. Considering the ALS/IGFBP-3 molar ratio, almost 55% of ALS circulated in a free form in active acromegaly. Before treatment, the IGF-I/IGFBPs (-1 + -2 + -3) molar ratio, which can be regarded as free, biologically active, IGF-I, was greatly increased (0.77 +/- 0.06; P<0.0001) compared with that in control subjects (0.23 +/- 0.01). After surgery, all 10 patients with controlled disease showed normalization of ALS (100% sensitivity), whereas 9 of them had normal IGFBP-3; reevaluation after varying lengths of time showed all these parameters within the normal range. In the 27 patients with active disease, IGF-I and ALS were more predictive of disease status (91% and 83% negative predictive values, respectively) than IGFBP-3 (53%). The basal ALS concentration correlated only with IGFBP-3 (r = 0.70; P<0.001). In postsurgery samples (first control) a statistically significant (P<0.001) correlation was found between mean GH values as well as minimum GH after oral glucose tolerance test and ALS (r = 0.72 and 0.83, respectively), IGF-I (r = 0.69 and 0.77), IGFBP-3 (r = 0.50 and 0.72), and IGFBP-2 (r = -0.36 and -0.63). Similarly, IGF-I, IGFBP-3, and ALS were positively correlated among themselves and negatively correlated with IGFBP-2 (P<0.001). In conclusion, in the diagnosis of acromegaly, the measurement of total IGF-I appears to be the most sensitive parameter among the subunits of the 150K complex, and IGFBP-3 the least sensitive. For ALS, this subunit is quite sensitive and appears to be a useful parameter in reassessment after surgical treatment.

Contractile properties and fiber type distribution of quadriceps muscles in adults with childhood-onset growth hormone deficiency.

Adults with GH deficiency (GHD) report weakness and fatigability. The origin of such symptoms is still debated. This work aimed to clarify whether weakness and fatigability depend on impairment of skeletal muscle contractile capacity. Five males with childhood-onset GHD (age +/- SE, 29.6 +/- 1.9) and 13 age- and sex-matched controls were enrolled in the study. Quadriceps muscle cross-sectional area (CSA), strength, twitch characteristics, and fatigue index of voluntary and electrically evoked contractions were determined in vivo in all subjects. Fiber type distribution and CSA of identified types of skeletal fibers were determined on needle biopsy samples of the vastus lateralis muscle of all subjects. Fiber type distribution was assessed on the basis of myosin heavy chain (MHC) isoform composition determined by electrophoresis on polyacrylamide gels. Fiber CSA was determined on cross-cryosections of fiber bundles immunostained by monoclonal antibodies against MHC isoforms. Absolute values of strength and fiber CSA of quadriceps were significantly lower in patients affected by GHD than in controls. However, once strength and fiber CSA were normalized for quadriceps CSA and subject height, respectively, differences disappeared. No difference was found between GHD patients and controls for quadriceps muscle twitch characteristics, fatigue index, and fiber type distribution. The results reported here suggest that weakness and fatigability in childhood-onset GHD do not have a skeletal muscle origin.

Criteria of cure and follow-up of central hyperthyroidism due to thyrotropin-secreting pituitary adenomas.

The recorded number of patients with central hyperthyroidism due to TSH-secreting pituitary adenoma doubled in the last few years after the introduction of ultrasensitive TSH assays in the assessment of thyroid function; however, information about the results and the criteria for cure after pituitary surgery is scanty. Seventeen patients with a TSH-secreting adenoma, diagnosed on the basis of detectable TSH levels in the face of high free thyroid hormone concentrations and pituitary lesion at neuroimaging, underwent pituitary surgery. Hypersecretion of other pituitary hormones was diagnosed in 5 of 17 patients. Four patients were initially misdiagnosed and treated with thyroid surgery or radioiodine therapy. The majority (86%) of hyperthyroid patients normalized thyroid hormone concentrations and regained euthyroidism, although pituitary imaging, alpha-subunit, and alpha-subunit/TSH molar ratio normalized in only 47%, 54%, and 58% of patients, respectively. Moreover, TSH secretion was normally suppressed by T3 in 40% of the patients. Interestingly, the finding of undetectable TSH levels 7 days after surgery was highly predictive of successful outcome. During long term follow-up, there was one relapse of hyperthyroidism. Early diagnosis of TSH-secreting adenomas permits a high rate of remission of hyperthyroidism after surgery. However, normalization of thyroid function alone does not necessarily reflect complete removal of the tumor, and more comprehensive criteria of cure based on pituitary imaging, hormone measurement, and suppression of TSH during T3 administration should be used. Lastly, all patients need an accurate long term follow-up to monitor the possible recurrence of the adenoma.

Lack of desensitization of adenomatous somatotrophs to growth-hormone releasing hormone in acromegaly.

The study was undertaken to investigate whether GHRH causes desensitization in GH-secreting adenomas in analogy to the normal situation. For this purpose, GH secretion after repeated GHRH administration to acromegalic patients in vivo and cultured adenomatous somatotrophs in vitro was studied. Six acromegalic patients and 6 normal subjects received 3 consecutive 50 micrograms GHRH rapid iv injections at 2-h intervals. Blood samples were drawn at 0, 15, 30, 60, and 120 min after each dose. The acromegalic patients had variable responses to the first injection and in each patient the second and third injections elicited serum GH responses that were quite similar to those after the first one. The GH increment, evaluated as net incremental area under the curve (mean +/- SE; nanograms per ml/120 min) was 2660 +/- 1501 after the first injection, 2176 +/- 1378 after the second injection, and 1978 +/- 1191 after the third injection; P = NS. On the contrary, in normal subjects a marked elevation of GH was observed only after the first injection (net incremental area under the curve, mean +/- SE after the first injection: 710 +/- 154; after the second injection: 6 +/- 39 and after the third injection: 108 +/- 28, P less than 0.01 vs. the first dose). The effect of in vitro GHRH pretreatment on the subsequent response to GHRH was evaluated in monlayer cultures from 12 GH-secreting adenomas. At 10(-8) M, GHRH significantly stimulated GH release from 8 adenomas. The GHRH pretreatment that was effective in inducing desensitization in cultured rat anterior pituitary cells, i.e. preexposure of the cultured cells to 10(-8) M GHRH for 4 h at 37 C, did not abolish the GH response to the subsequent challenge with GHRH (mean percent stimulation: 150 +/- 14% in untreated cells vs. 153 +/- 30% in pretreated cells; P = NS). Only in one adenoma, did GHRH-promoted desensitization occur. No modification was found in GHRH unresponsive adenomas. In the adenomas, not only the efficacy but also the potency of GHRH on GH release after GHRH pretreatment was of the same order of magnitude as in untreated cells. No desensitization to GHRH action occurred when the pretreatment time was prolonged up to 8 h and the GHRH concentration in the preincubation medium was increased to 10(-7) M.(ABSTRACT TRUNCATED AT 400 WORDS)

Dihydroergocriptine in management of microprolactinomas.

The effects of dihydroergocriptine (DHECP), a dihydrogenated ergot alkaloid with dopaminergic agonistic and alpha-adrenergic antagonistic properties, were studied in 22 women with PRL-secreting microprolactinomas and compared with those recorded in 36 previously studied patients treated with bromocriptine (BRC). After acute administration of 5 mg DHECP, orally, serum PRL decreased by 61 +/- 18% (+/- SD); only 1 patient was unresponsive. The nadir was reached at 300 min. Long term treatment with increasing DHECP doses caused a progressive PRL fall from 125 +/- 142 (+/- SD) to 81 +/- 159 micrograms/L after 1 week of a 3 mg twice daily regimen, to 64 +/- 88 micrograms/L after 1 week of 5 mg twice daily, 46 +/- 57 micrograms/L after 1 week of 10 mg twice daily, and 28 +/- 34 to 33 +/- 45 micrograms/L throughout 9 months of treatment with 10 mg DHECP 3 times daily. Seventy-seven percent of patients had normal serum PRL levels during chronic treatment. All women, including those with supranormal serum PRL levels, resumed regular menses, and 16 had ovulatory cycles; 1 woman became pregnant. Galactorrhea disappeared in all. During treatment the PRL response to TRH, initially absent in all patients, became positive in 10. In 7 patients, after DHECP treatment for 9 months, high definition computed tomographic scan no longer showed the focal lesions initially seen. After drug withdrawal, serum PRL increased again in all except 1 patient. Two patients had regular menses for 6 months, and 3 still had no adenoma imaged by high definition computed tomography. In BRC-treated patients the serum PRL changes and clinical results were very similar to those in the DHECP-treated patients, except for the persistence of normal serum PRL levels in 4 patients after drug withdrawal. On the other hand, side-effects were negligible during DHECP treatment, but remarkable during BRC. Systolic and diastolic blood pressures decreased by only 5.4 and 3.0 mm Hg, respectively, after acute 5 mg DHECP administration, but decreased by 12.8 and 14 mm Hg after acute 2.5 mg BRC administration. Orthostatic hypotension and peripheral vasomotor phenomena occurred in the long term DHECP treated patients except one, but they occurred in 9 and 3 of those treated with BRC, respectively. Gastric discomfort or mild nausea occurred in 12 DHECP-treated patients, while mild or severe nausea or vomiting were observed in 18, 11, and 2 of those taking BRC, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical, biochemical, and morphological correlates in patients bearing growth hormone-secreting pituitary tumors with or without constitutively active adenylyl cyclase.

Somatic mutations in the alpha-chain (alpha s) of the stimulatory regulatory protein of adenylyl cyclase (Gs) causing constitutive activation of the enzyme have been identified in a subset of human GH-secreting pituitary adenomas. This study reports on the differences between acromegalic patients bearing tumors without (group 1; n = 51) or with (group 2; n = 29) this alteration. No difference in age, sex, clinical features, duration of the disease, or cure rate was observed between the two groups. By contrast, group 2 patients had higher basal GH levels than group 1. Moreover, a significant difference in sellar morphology was found; group 2 patients more frequently showed sellas of normal size (grade I) than group 1. Hypersecretory activity of group 2 tumors was also apparent at electron microscopy; contrary to those of group 1, cells of group 2 tumors were densely granulated and showed prominent rough endoplasmic reticulum and Golgi complex. With respect to group 1, group 2 patients were less responsive to GH-releasing hormone, while they were more sensitive to somatostatin- and dopamine-induced GH inhibition. These results suggest that patients with constitutively active adenylyl cyclase have hyperactive tumors; the sensitivity of these tumors to inhibitory agents (somatostatin and dopamine), possibly counteracting the expression of activating mutations, might explain the low rate of tumor growth.

Growth hormone and prolactin secretion in acromegaly: correlations between hormonal dynamics and immunocytochemical findings.

A morphological study was carried out on pituitary adenomas removed from 13 normoprolactinemic and 9 hyperprolactinemic acromegalic patients whose hormonal dynamics had been carefully investigated. Double immunocytochemical labeling with the protein-A-gold electron microscopic technique was used to detect the presence of GH and PRL in the adenomas. Two morphological patterns were found; 11 adenomas contained cells positive only for GH, and 11 contained a variable proportion (from 10-98%) of cells positive for PRL. The great majority of cells positive for PRL also were positive for GH and so were actually mammosomatotrophic cells. Among the normoprolactinemic patients, no cells containing PRL were found in the tumors from 8 patients, and 10-26% of the cells of the tumors of the other 5 patients contained PRL. Two thirds of the hyperprolactinemic patients had tumors containing mammosomatotrophs (18-80%) with or without the concomitant presence of mammotrophs (0-18%). A positive correlation was found between the serum PRL levels and the percentage of mammosomatotrophs. No significant differences in GH secretory responses to TRH, dopamine, GHRH, and SRIH were found between patients having tumors with or without cells positive for PRL. We conclude that 1) the frequency of mammosomatotrophs in adenomas from acromegalic patients is higher than that previously estimated using different immunocytochemical methods; and 2) serum GH responses to TRH and dopamine are not strictly related to the presence of mammosomatotrophs and/or mammotrophs within the tumor.

Effect of sulpiride-induced hyperprolactinemia on serum testosterone response to HCG in normal men.

In six normal volunteers hyperprolactinemia was induced by sulpiride (150 mg/day) for 10 days. Both before and during sulpiride hCG was injected; the higher testosterone response to hCG, when PRL levels were enhanced, suggests a possible stimulatory role of PRL on Leydig cells.

Glycoprotein hormone alpha-subunit response to growth hormone (GH)-releasing hormone in patients with active acromegaly. Evidence for alpha-subunit and GH coexistence in the same tumoral cell.

Basal serum concentrations of glycoprotein hormone alpha-subunit and its response to GH-releasing hormone (GHRH) were studied in 22 acromegalic patients and in normal subjects. Four out of 22 patients had a basal alpha-subunit concentration (1.2-3.5 ng/ml) clearly above the upper limit of the normal range. GHRH injection (1 microgram/kg body weight, bolus dose iv) produced a clear alpha-subunit response [mean % increase: 120 +/- 37 (SD)] in the 4 patients with elevated basal alpha-subunit levels. No increase in serum glycoprotein hormones (TSH, LH, and FSH) occurred. Selective adenomectomy in 2 patients resulted in normalization of both serum GH and alpha-subunit levels, as well as disappearance of the abnormal alpha-subunit response to GHRH. In in vitro studies, only these 2 adenomas secreted alpha-subunit in large amounts (534 and 388 ng/mg protein . 30 min) and was it further stimulated by GHRH (% increase: 83 and 126). Morphological studies done with protein A-gold particle immunotechnique demonstrated that in these adenomas the great majority of the cells contained secretory granules positive for both GH and alpha-subunit. We conclude that: 1) alpha-subunit hypersecretion is present in some acromegalic patients (about 20%), 2) GHRH stimulates alpha-subunit release both in vivo and in vitro only in patients with elevated basal alpha-subunit levels, and 3) in these patients alpha-subunit derives from a common adenomatous cell secreting both alpha-subunit and GH molecules.