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To evaluate the prevalence of lymphocytic infiltrate in a large series of pituitary adenomas, we retrospectively studied tumor tissues from 1400 patients. Based on immunocytochemical data, tumors were classified as PRL (n=411), multihormonal (n=310), immunonegative (n=275), ACTH (n=166), GH (n=137), alpha subunit (n=44), FSH and/or LH, (n=42), and TSH (n=15) adenomas. The lymphocytic infiltrate was diagnosed on histological examination and investigated by immunostaining with anti LCA (human leucocyte common antigen), anti CD45RO (human T cell) and anti CD20 (human B cell) antibodies. Lymphocytic infiltrate was present in 40 adenomas (2.9%), 26 females and 14 males, aged 18 to 77 years (mean+/-SD, 37+/-14 years). The tumors were 19 PRL, 8 multihormonal, 4 GH, 4 alpha subunit, 3 ACTH, and 2 immunonegative adenomas. In PRL adenomas, the sex ratio (female/male) and the age were similar in patients with and without lymphocytic infiltrate (2.8 vs. 4.6 and 29+/-6 years vs. 32+/-11 years, respectively). The frequency of lymphocytic infiltrate was similar in PRL, GH, ACTH and multihormonal adenomas, but lymphocytic infiltrate was significantly more frequent in PRL adenoma than in immunonegative adenoma, and in alpha subunit adenoma than in immunonegative, ACTH and multihormonal adenomas. The lymphocytic cells were almost exclusively T cells. We conclude that lymphocytic infiltrates are rare in pituitary adenomas. Their frequency is not statistically different in major categories of secreting adenomas (PRL, GH, ACTH, multihormonal). Their pathophysiological significance remains to be established.

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We studied the boundary between adenoma and peritumoral anterior pituitary tissues in order to understand their mutual interactions during tumour progression. We selected 18 adenomas of different secretory type, grade and invasiveness in which fragments of peritumoral anterior pituitary were still attached to the adenoma. Immunohistochemistry was performed on serial sections with markers of the basement membranes (type IV collagen), the hormone-producing cells of the normal and neoplastic anterior pituitary, and the folliculo-stellate cells (S-100 protein). In passing from tumour to gland, localized areas of passive compression of the normal gland were seen in only 3 cases. In all the tumours, the boundary consisted partly or solely of a transitional zone characterized by the presence of enlarged cell-cords. Openings in the basement membrane of these enlarged cell-cords were seen in contact with the tumour tissue. Normal and neoplastic cells intermingled in the transitional zone. Normal residual cells could be seen in the central area of the tumour but no adenomatous cells were observed in the gland around the tumour. Folliculo-stellate cells were concentrated in the vicinity of the transition zone. These findings favour the existence of an active process of adenoma expansion within the normal parenchyma, without noticeable infiltration of tumour cells into surrounding gland.

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Our report is the first immunocytochemical study of the principal elements of the basement membrane (BM) and connective tissue in normal and adenomatous human anterior pituitaries. In normal tissues, both the parenchymatous BM limiting the endocrine cell cords and the endothelial BM around the capillaries were continuous and were stained with anti-laminin (LM), anti-type IV collagen (CIV) and anti-fibronectin (FN) antisera. Antiserum to type I collagen (CI) stained the connective tissue only. The same antigens were investigated in 23 human pituitary adenomas, 6 of them having been diagnosed as locally invasive by the radiologist and the neurosurgeon. In all cases a lack of cordal structure was observed and the parenchymatous BM was completely absent (9 cases) or fragmented (14 cases). No correlation could be established between the extent of parenchymatous BM alterations and the invasive behaviour of the tumour. In contrast, a continuous endothelial BM was observed around the blood vessels in all cases and its presence was confirmed in double immunofluorescence experiments using anti-von Willebrand factor and anti-LM or anti-CIV antisera. Anti-FN and CI also stained the wall of the vessels. The tumours showed arterial development, in addition to the capillaries found in normal tissue. The present results favour the hypothesis of a decreased synthesis of parenchymatous BM by human adenomatous pituitary cells in comparison with normal cells and show that these tumours are the site of an active arterial neovascularization.

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Data from our group have shown that the human adenomatous and normal anterior pituitary may be the source of somatostatin (SRIH). SRIH-producing cells were identified in two somatotropic adenomas. Immunoreactive SRIH cells were present in both cases. In case 2, material was available for RNA studies, in situ hybridization and electron microscopy. The size of the transcript identified by Northern blot analysis was identical to that of hypothalamic SRIH mRNA. In situ hybridization showed that the SRIH gene was expressed in a cell subset superimposable to that identified by immunocytochemistry. Co-localization studies revealed that SRIH and growth hormone (GH) immunoreactivities were not present in the same cells. Ultrastructural immunogold labelling showed that SRIH cells had features distinct from those of the somatotropes. The results confirm that the somatotropic adenomas have the ability to synthesize SRIH, indicate that SRIH expression is restricted to a subset of adenoma cells different from GH-producing cells, and imply that SRIH cells are involved in paracrine regulation of neighbouring somatotropes.

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Four tumors consisting of pituitary adenomatous cells (AD) intricated with ganglion cells (GC) were studied. Each case was associated with a different clinical syndrome: acromegaly, amenorrhea-galactorrhea, Cushing's disease and isolated tumoral syndrome with no hormonal hypersecretion. (a) In the case with acromegaly, immunoreactive growth hormone (IR-GH) was present in 80% of AD. IR-vasoactive intestinal peptide (VIP) was found in 5%-10% of AD and in few GC. Rare GC and processes showed IR-GH-releasing hormone (GRH), -somatostatin (SRIH), -gonadotropin-releasing hormone and -adrenocorticotropin-releasing hormone. (b) In the case with amenorrhea-galactorrhea, IR-prolactin (PRL) was seen in 90% of AD. IR-PRL and -VIP were present in rare GC. (c) In the case with Cushing's disease, 60% of AD and very few GC contained IR-adrenocorticotropin (ACTH) and beta-lipotropin. Rare GC processes contained IR-SRIH. (d) In the case without pituitary hormone hypersecretion, PRL was localized in rare AD and GC. Pituitary hormone and neuropeptides were never colocalized in the same cells. No case displayed IR-neurophysins or -thyroliberin. Pituitary hormones were localized by ultrastructural immunogold labeling. These findings show that: (i) in three cases, pituitary hormones (PRL and ACTH), and, in one case, VIP could be localized in both adenomatous and ganglion cells; (ii) the pituitary hormone-containing cells in the tumors could be related to the hypersecretory syndromes; (iii) intratumoral IR-VIP and -GRH might be involved in GH and PRL hypersecretion in the cases with acromegaly and amenorrhea-galactorrhea.

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An immunocytochemical study was performed by the indirect peroxidase method on the pituitary tumour of 37 patients with clinical and biological signs of silent adenoma. Antisera were used against human PRL, human GH, ACTH1-24, human ACTH17-39, alpha-melanocyte stimulating hormone (alpha-MSH), human beta-endorphin, alpha-subunit of hCG (hCG-alpha), and beta-subunits of human LH (LH-beta), human FSH (FSH-beta) and human TSH (TSH-beta). Immunostaining in at least 5% of the tumour cell population, with one or more antisera, was present in 13 cases; hCG-alpha immunostaining was the one most frequently observed. Combined immunostaining was found in 7 cases. Exclusive immunostaining was present in 6 cases: 4 with hCG-alpha, 1 with ACTH1-24 and 1 with TSH-beta. It is concluded that a significant number of silent pituitary adenomas show a certain secretory pattern of pituitary hormones or subunits of glycoprotein hormones as revealed by the immunocytochemistry.

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Transsphenoidal pituitary surgery was performed in 64 patients with Cushing's disease in search of a corticotroph adenoma. In 4 patients, profuse local bleeding prevented completion of the exploration. Of the 60 patients who had an adequate exploration, 4 could not be followed after surgery. Short term assessment of the surgical outcome (3-6 months postoperatively) was performed on 60 patients, including the 4 who had incomplete pituitary exploration. Forty-two patients (70%) were judged as immediate successes [urinary cortisol excretion, less than 90 micrograms (less than 248 nmol)/day]; the mean urinary cortisol excretion and plasma ACTH level fell from 463 +/- 70 (+/- SE) to 26.7 +/- 3.6 micrograms/day (1277 +/- 193 to 74 +/- 10 nmol/day; n = 33) and from 111 +/- 33 to 36 +/- 14 pg/mL (24 +/- 7 to 8 +/- 3 pmol/L; n = 23) in patients who had both measurements pre- and postoperatively. Eighteen patients (30%) were judged as immediate failures; neither urinary cortisol excretion nor plasma ACTH levels changed significantly in patients who had both measurements pre- and postoperatively. The preoperative epidemiological, clinical, hormonal, and radiological characteristics of the 2 groups were similar. Histological examination of pituitary fragments removed in 58 of the 60 patients evaluated postoperatively revealed the presence of tumoral tissue in a higher percentage of patients in the immediate success group (72%) than in the immediate failure group (24%; P less than 0.01). The 42 patients in the immediate success group were followed from 6 months to 7 yr (median, 2 yr); 6 patients had recurrences from 2-3 yr after operation. Actuarial analysis indicates that the probability of a patient remaining well 6 yr after surgery is 72 +/- 20% (95% confidence limit). Most of the patients in the immediate success group had transient ACTH deficiency preceding a progressive return to normal pituitary-adrenal function.

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In patients with TSH-secreting pituitary adenomas associated with hyperthyroidism, TSH secretion usually does not respond to exogenous TRH stimulation. To determine the basis for this unresponsiveness, we studied TRH binding to the membranes of two such TSH-secreting pituitary adenomas. The patients, a 28-yr-old man and a 60-yr-old woman, had clinical and biochemical hyperthyroidism with increased serum TSH levels (15.7 and 14 mU/L, respectively; normal range, 1.1-7.2) and alpha-subunit to TSH molar ratios greater than 1 (2.4 and 1.7, respectively). Neither patients had an increase in serum TSH in response to TRH (200 micrograms, iv). Immunocytochemistry of the two adenomas, removed by transsphenoidal surgery showed a pure population of thyrotropic cells. Binding studies were performed by incubation of tumor cell membrane suspensions with increasing amounts of [3H]TRH. Two PRL-secreting adenomas and one normal human pituitary were used as controls. The characteristics of the TRH-binding sites from the control tissues were similar to those previously reported (Kd, 56, 30, and 49 nM; maximum binding, 187, 46, and 94 fmol/mg protein, respectively). In contrast, no specific TRH binding was found in the two TSH-secreting adenomas. We conclude that the unresponsiveness of TSH after TRH administration is related to the absence of specific TRH-binding sites in these thyrotropic tumors.

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The S-100 protein was localized by immunocytochemistry in 70 pituitary tumors including 30 prolactin, 16 growth hormone, two corticotropin and 22 non-functioning adenomas. Positive immunostaining was observed in only one case (prolactin adenoma). It is concluded that in functioning and non-functioning pituitary tumors there is no particular involvement of S-100 protein-containing cells, at least under the conditions of this study.

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SRIH and GH secretions by GH-secreting adenomatous human pituitary cells were analyzed in vitro in a perifusion system. Of the 13 adenomas studied, 7 secreted SRIH, in variable amounts (50 to 700 pg/ml/2 min., corresponding to 600 10,700 pg for the total experiment. SRIH secretion increased during the perifusion, the highest levels being observed at the end of the perifusion. GH secretion also varied from one adenoma to the other (6 to 500 ng/ml). In most cases, the secretion profiles were negatively correlated, GH secretion decreasing while SRIH secretion was increasing. In the presence of 10(-7) M TRH, GH secretion increased while that of SRIH decreased. The hypothesis of a paracrine and/or an autocrine role for SRIH as well as its possible in situ synthesis are discussed.

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A mitochondrial preparation from duck adrenal gland was used, under aerobic conditions, to show that the oxygen requirement for the last step of aldosterone biosynthesis (transformation of 18-hydroxycorticosterone into aldosterone) is at the cytochrome P-450 level only. Vitamin C and tetramethyl-p-phenylene-diamine (TMPD) were used to increase oxygen consumption at the cytochrome a3 level, thereby decreasing its availability to cytochrome P-450. The vitamin C plus TMPD system acts as an 'oxygen trap'. Results show that despite reducing equivalents provided by L-malate, vitamin C plus TMPD strongly inhibits aldosterone biosynthesis from 18-hydroxycorticosterone (89%). Moreover, we used KCN in order to block oxygen consumption, even in the presence of vitamin C plus TMPD. Under these conditions, the inhibition of aldosterone biosynthesis from 18-hydroxycorticosterone is reduced by 51%. The reversal of this inhibition by KCN was evident but only partial. According to polarographic and electron microscopy studies, the reversal of inhibition can only be explained by an increased availability of oxygen at the cytochrome P-450 level. Experiments performed under aerobic conditions, without a nitrogen atmosphere, show that oxygen is required in the transformation of 18-hydroxycorticosterone into aldosterone, at the cytochrome P-450 level. This suggests that a classical hydroxylating mechanism is involved.

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Among 190 human pituitary adenomas investigated, 140 contained arterial blood vessels (nearly 75 percent). In 160 adenomas (PRL-, GH-secreting or nonfunctioning tumors) arterial vessels were present in 80 to 90 percent of the cases, whereas in 30 corticotropic adenomas (Cushing's disease), 5 only contained arterial vessels. According to data of the literature and to our own findings, such vessels should originate from the anterior pituitary itself or from the surrounding structures (trabecular, interlobar, capsular arteries). This arterial blood supply could appear even at the microadenoma stage and increase as the tumor growths. Consequently, the blood from portal origin will be diluted or excluded, so that tumor cells would escape from hypothalamic control.

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Specific receptors for TRH were characterized on cellular membranes of 6 out of 13 somatotrophic adenomas obtained from acromegalic patients. These receptors had the same dissociation constant (Kd: 62 +/- 10 nM) as those found in human PRL-secreting adenomas, but their maximal number of binding sites (Bmax: 76 +/- 24 fmol/mg of protein) was six fold smaller. A good correlation was found between the presence of TRH receptors and the in vitro TRH-induced stimulation of GH secretion. The increase in GH release varied from 25 to 200%. It was thus concluded that these receptors are functional. However, why only some of the human somatotrophic adenomas possess TRH receptors and respond to TRH in vitro needs further investigations.

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Basal plasma prolactin (Prl) level, tumour size and [3H]thyroliberin (TRH) binding to tumour membranes were studied in 18 patients bearing Prl-secreting adenomas. Big tumours (grade III) were associated with high plasma Prl levels (median value: 1929 (range: 207-3570) ng/ml) and possessed numerous membrane TRH receptors (median value: 508 (range: 0-1200) fmol/mg of protein). By contrast, smaller tumours (grade II and I) were associated with lower plasma Prl levels (median values: 1085 (range: 40-1890) and 295 (range: 98-788) ng/ml, respectively) and possessed fewer membrane TRH receptors (median values 122 (range: 11-328) and 13 (range: 0-52) fmol/mg of protein, respectively). A direct positive correlation was demonstrated between the plasma Prl level and the number of [3H]TRH binding sites (rho: 0.729 P less than 0.001). That the higher number of TRH receptors is associated with the largest tumours may be of importance in hyperprolactinaemia and should be taken in account when speculating on the pathogenesis of human Prl-secreting adenomas.

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The interaction between somatostatin (SRIF) and thyrotropin-releasing hormone (TRH) on growth hormone (GH) release has been studied on dispersed somatotrophic tumor cells obtained from 7 acromegalic patients. TRH increased GH secretion in 4 cases and SRIF decreased GH secretion in 5 cases. When TRH and SRIF were concomitantly perifused, SRIF, when active by itself, prevented and reversed the TRH-induced stimulation of GH release, while TRH never antagonized the inhibitory effect of SRIF. We conclude that, in these adenomatous cells, the physiological inhibitory factor (SRIF) overcomes the nonphysiological stimulatory factor (TRH) in the control of GH secretion.

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All 347 patients surgically treated for a prolactinoma from January 1, 1976 to December 31, 1982, in the neurosurgical ward of Foch Hospital, were retrospectively studied. The frequency of postoperative normalisation of plasma prolactin (PRL) depends on prolactinoma size, preoperative PRL level, duration of first clinical symptom, previous oestroprogestative contraception, and adenoma necrosis. Postoperative PRL values were normalized in 75% of small prolactinomas (grade 0, 1 or 2) with preoperative PRL values less than 200 ng/ml, and clinical duration less than 5 years (n = 102). There was no operative death and minor morbidity (2.7%). Among the 96 patients with postoperative PRL normalisation, operated between 1976 and 1979, 70 were followed up for an average time of 4.4 +/- 0.2 years. 17% of patients had hyperprolactinemia recurrence with a delay of 1.5 +/- 0.4 years. Postoperative PRL levels near the upper normal limit, and weak PRL response to TRH tests were found to be unfavourable prognostic factors for hyperprolactinemia recurrence. Pregnancy did not increase the risk of recurrence, but could reflect genuine long-lasting remission. Selective adenomectomy remains an interesting treatment for prolactinoma, particularly if the adenoma is small, recent and with PRL moderately increased. The frequency of postoperative PRL normalisation after surgery is less than with bromocriptine, but surgery is the only treatment able to achieve a definitive cure with a low iatrogenic risk.

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