Effects of somatostatin on somatotroph adenomas of the human pituitary: An in vitro functional and morphological study

The effects of somatostatin or the somatostatin analog SMS 201–995 were studied on 4 densely granulated somatotroph adenomas and 4 sparsely granulated somatotroph adenomas in vitro. Release of growth hormone (GH) into culture media during incubation with somatostatin or SMS 201 -995 were measured by radioimmunoassay, and light-microscopical and ultrastructural morphometric parameters were compared with those of cultured control somatotroph adenoma cells of the same tumor. In all tumors except for 1 densely granulated somatotroph adenoma, somatostatin or SMS 201–995 decreased GH release into culture media in 24- and 2-hour incubations. After 48-hour incubation with somatostatin or SMS 201–995, there was no change in cell size or secretory granule diameter. One densely granulated adenoma showed decreased cytoplasmic volume density (CVD) of Golgi apparatus and secretory granules, and a sparsely granulated adenoma had reduced CVD of endoplasmic reticulum. All the tumors that responded with decreased GH release exhibited increased CVD of lysosomes after incubation with somatostatin or SMS 201–995. These results indicate that both densely and sparsely granulated somatotroph adenomas respond to somatostatin inhibition and, furthermore, that inhibition of hormone release is associated with accumulation of lysosomes, suggesting lysosomal degradation of stored hormone. Hospital 20 Nov. (ISSSTE) Coyoacan y Felix Cuevas, Colonia del Valle and (Dept Patologia) y Hospital de Especialidades (C.M.N., IMSS) Cuauhtemoc y Dr. Marquez, Mexico City (IF).     

The TSH secretion in the human pituitary adenomas

TSH secretion by a pituitary tumor is very rare (2%) and it is often associated with another hormone: GH or PRL essentially. We present here nine tumors in which the TSH secretion was proved by immunocytochemistry (ICC) and by RIA in the tumor extracts, in the serum and in the culture medium. Four tumors secreted TSH only. Five tumors secreted TSH and GH predominantly. In 3 of them traces of other hormones (PRL and FSH) were also detected. The "pure" TSH adenomas were monomorphous with typical ultrastructural and immunocytochemical features. Plurihormonal TSH adenomas were bimorphous with different cells secreting GH and TSH or monomorphous with one type of cell which secreted TSH or GH or both TSH and GH. In a majority of the cases, the tumoral TSH secretion induced hyperthyroidism but in 2 patients with TSH adenoma there was euthyroidism and in another with TSH-GH adenoma there was no sign of acromegaly and GH serum levels were normal.     

Long-term treatment of acromegaly with the somatostatin analogue SMS 201-995 over 6 months

Summary This study examined the effects of the long-acting selective mini somatostatin analogue (SMS) 201-995 in two acromegalic patients who were treated for 3 and 6 months, respectively. During treatment the mean growth hormone levels (25.3 and 20.8 ng/ml vs 5.9 and 10.6 ng/ml) and somatomedin C levels (6.2 and 6.2 IU/ml vs 3.3 and 3.8 IU/ml) decreased and the patients reported an improvement in their symptoms. The main side effect was an increase in stool fat excretion which did exceed the normal range (<7 g/day) in one patient. Five acromegalics who received 2 × 50 µg SMS 201-995/day for 5 days showed a significant increase of stool fat excretion (1.7 vs 3.5 g/day;p<0.05). Fasting blood glucose levels, glucose tolerance, and glycosylated hemoglobin were not essentially effected. It is concluded that SMS 201-995 offers new possibilities in the treatment of acromegaly. The gastrointestinal and diabetogenic side effects of this substance, however, should be carefully monitored.Abbreviations GH growth hormone - HbA₁ glycosylated hemoglobin - OGTT oral glucose tolerance test - SMS selective mini somatostatin - TRH thyrotropin-releasing hormone - TSH thyroid-stimulating hormone     

Long-term treatment with SMS 201–995 in resistant acromegaly: Effectiveness of high doses and continuous subcutaneous infusion

Summary Seventeen patients (8 women and 9 men) resistant to all other forms of therapy were treated with the somatostatin analogue SMS 201-995 (octreotide, Sandostatin^®). The duration of treatment ranged from 1 to 5 years. Mean GH levels of only 4 patients were suppressed under 5 g/L during an 8 h serum profile with the standard dose of 0.1 mg 2 or 3 times daily. This standard dose suppressed mean GH levels in 10 other patients more than 50% of baseline, but for optimal effect higher doses up to 1.5 mg, 4 daily injections or continuous subcutaneous infusion (CSI) were needed. Octreotide had no influence on GH secretion in 3 patients. Suppression of mean GH levels under 5 g/L was achieved in 10 patients. Normalization of insulin-like growth factor I (IGF-I) occured in only 5 patients. Altogether, therapy with SMS 201-995 reduced GH levels from 23.8±32.2 g/L (mean±SD) to 6.7±5.0 g/L by 71.8% and IGF-I levels from 7.9±3.1 U/ml to 3.2±1.6 U/ml by 59.5%.We conclude that 1) treatment with SMS 201-995 in patients resistant to other forms of therapy may be less successful than previously reported for heterogenous groups of patients; 2) the dose regimen must be adapted to the individual patient for optimal effect and most of our patients needed higher doses than 300 g daily; 3) 4 or maybe more daily injections or CSI seem to be most effective; and 4) in a minority of patients SMS has no influence on GH-secretion.Abbreviations CSI continuous subcutaneous infusion - CT computerized tomography - GH growth hormone - IGF-I insulin-like growth factor I=Somatomedin-C - IRMA immunoradiometric assay - MRI magnetic resonance imaging - PRL prolactin - RIA radioimmunoassay - SD standard deviation - SMS octreotide=Sandostatin^® - TSH thyreoidea stimulating hormone - T4 thyroxine This work was supported by the Deutsche Forschungsgemeinschaft (Mue 585/3-3). Parts of this work were presented on the 34. Symposium Deutsche Gesellschaft für Endokrinologie Hannover, March 1990 (Acta Endocrinologica Suppl. 1 Vol. 122 (1990), 14)     

Response of thyrotropin-secreting pituitary adenomas to a long-acting somatostatin analogue

Thyrotropin-secreting pituitary adenomas are aggressive, invasive tumors that respond poorly to available surgical and medical treatments. Inappropriate release of thyrotropin by these tumors can result in hyperthyroidism. We treated five patients who had thyrotropin-secreting pituitary adenomas with the long-acting somatostatin analogue SMS 201-995, which was administered by subcutaneous injection in doses of 50 to 100 micrograms every 8 to 12 hours. Serum levels of thyrotropin were dramatically reduced by treatment in four of the five patients, and levels of another tumor marker, the alpha-subunit of thyrotropin, were reduced in all five. In two patients with hyperthyroidism due to production of excess thyrotropin by the tumor, treatment with the somatostatin analogue resulted in a sustained euthyroid state. One patient who was treated for more than 16 months had a persistent reduction in serum levels of thyrotropin and iodothyronines. We conclude that SMS 201-995 is an effective means of controlling hypersecretion of thyrotropin and the associated hyperthyroidism due to thyrotropin-secreting pituitary tumors.     

An Atypical Acidophil Cell Line Tumor Showing Focal Differentiation Toward Both Growth Hormone and Prolactin Cells

We report a case of giant pituitary adenoma in a child. Computerized tomography (CT) scan revealed a suprasellar extension tumor mass with hydrocephalus. There was no clinical evidence of acromegaly, gigantism, and other hormonal symptoms. Endocrinologic studies showed within normal value of serum growth hormone (GH: 4.2 ng/mL) and slightly increased levels of prolactin (PRL: 78 ng/mL) and other pituitary hormone values were within normal range. On suppression test by bromocryptin, both GH and PRL levels were reduced. Histopathological findings revealed that the tumor consisted of predominantly chromophobic and partly eosinophilic adenoma cells. Immunohistochemical staining detected GH and PRL in a small number of distinctly different adenoma cells, respectively. Nonradioactivein situ hybridization (ISH) also showed GH and PRL mRNA expression in identical immunopositive cells. Electron microscopy (EM) demonstrated adenoma cells with moderate or small numbers of two types of dense granules and without fibrous body which are characteristic of sparsely granulated GH-cell adenomas. The adenoma does not fit into any classification but may be an atypical acidophil cell line tumor showing focal differentiation toward both GH and PRL cells.     

Hyperthyroidism caused by a TSH producing pituitary adenoma

Elevated levels of free triiodothyronine (fT3) of 8.8 ng/dl (normal range 2.0 to 4.2) and free thyroxin (fT4) of 3.5 pg/ml (0.8 to 1.7) were found in the course of an examination of a 53-year old patient due to a planned hysterectomy. As thyrotropin (TSH) also was elevated with 5.8 mU/l (0.4 to 4.5), these findings corresponded to an inappropriate secretion of TSH (IST). Additional examinations revealed a blunted rise of TSH secretion after i.v. injection of 200 micrograms thyrotropin releasing hormone (TRH) as well as lacking suppression of TSH secretion after oral doses of 75 micrograms T3 during one week. alpha-TSH levels with 3.7 micrograms/l were elevated in comparison to a matched normal sample just as the molar ratio alpha-TSH/TSH with 6.95 and sex hormone-binding globulin (SHBG) with 175 nmol/l and showed an absence of inhibition in the T3 suppression test. These results were suggestive of neoplastic inappropriate secretion of TSH (nIST) due to a TSH-secreting pituitary adenoma. In concordance, the magnetic resonance imaging (MRI) showed a 1 cm tumor in the sella. The adenoma could also be visualized by 111In-octreotide and 123I-epidepride scintigraphies of the pituitary gland. After transsphenoidal resection, histological examination of the tumor resulted in the finding of a TSH-secreting adenoma. Postoperative TSH levels were not detectable, indicating the complete removal of the adenoma. Levels of fT3 and fT4 were slightly below normal with 1.9 pg/ml and 0.7 ng/dl, respectively. A control scintigraphy with 111In-octreotide following an equivocal MRI showed no uptake in the pituitary.     

垂体生长激素分泌瘤细胞有关生长抑素调节的受体和受体后过程的某些变化

为了解生长抑素（ＳＲＩＦ）在人垂体生长激素（ＧＨ）分泌瘤发病中的作用，在２５例肢端肥大症患者体外地养的垂体瘤细胞观察了ＳＲＩＦ激动剂（ＳＭＳ），抑制性鸟苷酸调节蛋白（Ｇｉ）拮抗剂百日咳毒素（ＰＴ）和钙离子载体Ａ２３１８７对ＧＨ分泌的影响．以及ＳＭＳ对细胞内ｃＡＭＰ水平的抑制作用。发现：ＳＭＳ可以使８４．０％（２１／１２５例）的ＧＨ瘤细胞ＧＨ分泌量明显抑制，揭示ＳＲＩＦ受体及受体后过程的功能基本正常；在３１．６％（６／１９例）患者的ＧＨ瘤细胞ＰＴ不能阻断ＳＭＳ对ＧＨ分泌的抑制作用，提示这些瘤细胞膜上Ｇｉ的功能异常；在３５．０％（７／２０例）用者的ＧＨ瘤细胞Ａ２３１８７未能拮抗ＳＭＳ对ＧＨ分泌的抑制作用，说明ＳＲＩＦ对Ｃａ￣（２＋）通道功能的调节有异常。在部分瘤细胞ＳＭＳ对ＧＨ分泌和细胞内ｃＡＭＰ的作用不一致。上述结果表明ＳＲＩＦ对垂体ＧＨ瘤细胞ＧＨ分泌的抑制作用由第二信使介导，但部分瘤细胞存在着受体后Ｇｉ和／或Ｃａ￣（２＋）通道功能的缺陷。     

Morphologically unclassified GH-producing adenoma showing galactorrhea without acromegaly

A 24-year-old woman with a large pituitary adenoma had amenorrhea and galactorrhea, but no physical stigmata of acromegaly despite slightly elevated serum growth hormone (GH) and normal serum prolactin (PRL) levels. Subtotal removal of the tumor cured galactorrhea and resulted in normalization of serum GH concentration. The question is raised whether amenorrhea and galactorrhea were related to excessive GH production in this patient. Absence of acromegaly might have been due to the short duration of the disease. The tumor was a chromophobic, periodic acid-Schiff-negative adenoma. Immunocytochemistry and in situ hybridization revealed focal GH immunoreactivity and diffuse, weak signal for GH messenger RNA. By electron microscopy, the tumor showed no features of GH or PRL-producing adenomas. Two different cell types could be distinguished: the majority were similar to null cells, whereas a small number of cells resembled somatotrophs and lactotrophs, possessing many secretory granules and exhibiting exocytosis. On the basis of its ultrastructure, this tumor can be classified as an atypical acidophil cell line adenoma in which adenomatous null cells transformed to the differentiated cells capable of producing GH.     

Effects of Medical Therapy on Pituitary Tumors

Previously surgery and irradiation were the only available procedures to treat patients with pituitary tumors. During the last few decades, novel drugs such as dopamine agonists and long-acting somatostatin analogs were developed and, an alternative medical therapy emerged. This paper summarizes the effect of medical therapy on the morphologic features of pituitary tumors and illustrates the ultrastructural alterations on electron micrographs. Currently drugs can be used in the management of pituitary tumors secreting GH, PRL, and/or TSH in excess. No medical therapy is available so far for ACTH-, FSH-, LH-, or alpha-subunit-secreting tumors as well as non-hormone-secreting pituitary tumors. Dopamine agonists are effective in the management of PRL-secreting tumors; they cause marked reversible tumor shrinkage in the substantial majority of patients. Long-acting somatostatin analogs are useful in the management of GH- and TSH-secreting pituitary tumors; they lead to mild to moderate tumor shrinkage in approximately 50% of cases. In patients treated with these drugs reduction of elevated blood hormone levels and amelioration of clinical symptoms ensue. It should be emphasized that no permanent cure is obtained. Blood hormone levels increase and the clinical symptoms reappear after discontinuation of treatment. Recently GH receptor blockers (pegvisomant) were introduced in the treatment of GH-producing pituitary adenomas. To the authors' knowledge the effect of these durgs on the morphology of pituitary tumors has not been revealed so far.     

Effects of medical therapy on pituitary tumors

Previously surgery and irradiation were the only available procedures to treat patients with pituitary tumors. During the last few decades, novel drugs such as dopamine agonists and long-acting somatostatin analogs were developed and, an alternative medical therapy emerged. This paper summarizes the effect of medical therapy on the morphologic features of pituitary tumors and illustrates the ultrastructural alterations on electron micrographs. Currently drugs can be used in the management of pituitary tumors secreting GH, PRL, and/or TSH in excess. No medical therapy is available so far for ACTH-, FSH-, LH-, or alpha-subunit-secreting tumors as well as non-hormone-secreting pituitary tumors. Dopamine agonists are effective in the management of PRL-secreting tumors; they cause marked reversible tumor shrinkage in the substantial majority of patients. Long-acting somatostatin analogs are useful in the management of GH- and TSH-secreting pituitary tumors; they lead to mild to moderate tumor shrinkage in approximately 50% of cases. In patients treated with these drugs reduction of elevated blood hormone levels and amelioration of clinical symptoms ensue. It should be emphasized that no permanent cure is obtained. Blood hormone levels increase and the clinical symptoms reappear after discontinuation of treatment. Recently GH receptor blockers (pegvisomant) were introduced in the treatment of GH-producing pituitary adenomas. To the authors' knowledge the effect of these drugs on the morphology of pituitary tumors has not been revealed so far.     

Effects of Medical Therapy on Pituitary Tumors

Previously surgery and irradiation were the only available procedures to treat patients with pituitary tumors. During the last few decades, novel drugs such as dopamine agonists and long-acting somatostatin analogs were developed and, an alternative medical therapy emerged. This paper summarizes the effect of medical therapy on the morphologic features of pituitary tumors and illustrates the ultrastructural alterations on electron micrographs. Currently drugs can be used in the management of pituitary tumors secreting GH, PRL, and/or TSH in excess. No medical therapy is available so far for ACTH-, FSH-, LH-, or alpha-subunit-secreting tumors as well as non-hormone-secreting pituitary tumors. Dopamine agonists are effective in the management of PRL-secreting tumors; they cause marked reversible tumor shrinkage in the substantial majority of patients. Long-acting somatostatin analogs are useful in the management of GH- and TSH-secreting pituitary tumors; they lead to mild to moderate tumor shrinkage in approximately 50% of cases. In patients treated with these drugs reduction of elevated blood hormone levels and amelioration of clinical symptoms ensue. It should be emphasized that no permanent cure is obtained. Blood hormone levels increase and the clinical symptoms reappear after discontinuation of treatment. Recently GH receptor blockers (pegvisomant) were introduced in the treatment of GH-producing pituitary adenomas. To the authors' knowledge the effect of these durgs on the morphology of pituitary tumors has not been revealed so far.     

Effects of growth hormone treatment on thyroid function in pediatric patients with Prader–Willi syndrome

It is unclear whether hypothyroidism is present in patients with Prader–Willi syndrome (PWS). This study aimed to clarify the state of the hypothalamic–pituitary–thyroid axis and the effects of growth hormone (GH) treatment on thyroid function in pediatric patients with PWS. We retrospectively evaluated thyroid function in 51 patients with PWS before GH treatment using a thyroid‐releasing hormone (TRH) stimulation test (29 males and 22 females; median age, 22 months). We also evaluated the effect of GH therapy on thyroid function by comparing serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels at baseline, 1 year, and 2 years after GH therapy. TSH, fT4, and fT3 levels were 2.28 μU/ml (interquartile range [IQR]; 1.19–3.61), 1.18 ng/dl (IQR; 1.02–1.24), and 4.02 pg/dl (IQR; 3.54–4.40) at baseline, respectively. In 49 of 51 patients, the TSH response to TRH administration showed a physiologically normal pattern; in two patients (4.0%), the pattern suggested hypothalamic hypothyroidism (delayed and prolonged TSH peak after TRH administration). TSH, fT4, and fT3 levels did not change significantly during 1 or 2 years after GH treatment. The TSH response to TRH showed a normal pattern in most patients, and thyroid function did not change significantly during the 2 years after initiating GH treatment.     

Immunocytochemical hormonal features of pituitary adenomas of aging Wistar male rats

Pituitary adenomas were the most common grossly visible naturally occurring neoplasms found in over 27% of rats surviving beyond 17 months of age. Twenty-three pituitary adenomas, fixed in buffered neutral formalin and embedded in paraffin, were tested for the presence of prolactin (PRL), growth hormone (GH) and thyroid stimulating hormone (TSH) using the unlabeled peroxidase-antiperoxidase method. The adenoma cells in 6 (26%) of the 23 tumors stained with two or three of the tested hormones, but clear evidence that individual neoplastic cells contained more than one hormone was not found. These findings suggest that in aging male Wistar rats the spontaneous pituitary adenomas may originate from undifferentiated cells, PRL-, GH- and TSH-cells in a diminishing order of frequency.     

Monomorphous Plurihormonal Pituitary Adenoma of Pit-1 Lineage in a Giant Adolescent with Central Hyperthyroidism

Thyrotropin (TSH)-secreting pituitary adenomas are exceedingly rare at the pediatric age and no cases of co-secretion with other pituitary hormones in these tumors have been described in this age range. We present a case of a monomorphous plurihormonal pituitary adenoma that co-secreted TSH and GH in a pediatric patient. A 13-year-old male presented with increasing height velocity (17.75 cm/year, 9.55SD), weight loss, and visual impairment. Initial biochemical evaluations revealed secondary hyperthyroidism. A giant pituitary tumor compressing the surrounding structures was detected by magnetic resonance, and a transsphenoidal surgery was initially performed. Pathological examinations revealed an atypical, monomorphous plurihormonal Pit-1 lineage tumor with mixed features of silent subtype 3 adenoma and acidophil stem cell adenoma. In the postoperative period, secondary hyperthyroidism recurred with high levels of both GH and IGF1. In addition, due to tumor re-growth, a multimodality treatment plan was undertaken including surgery, somatostatin analogs, and radiotherapy. We report the first pediatric case of a plurihormonal TSH- and GH-secreting pituitary adenoma, further expanding the clinical manifestations of pediatric pituitary tumors. Comprehensive pathological evaluation and close follow-up surveillance are crucial to the prompt delivery of the best therapeutic options in the context of this particularly aggressive pituitary tumor.     

Palliative therapy of an ectopic cushing's syndrome due to a metastatic carcinoid tumor

Summary The case of a 39-year-old patient with ectopic Cushing's syndrome due to a metastatic carcinoid tumor is presented. Palliative therapy consisting of 800 mg ketokonazole and 0.3 mg SMS 201-995/die resulted in clinical remission and correction of hypokaelmia and hypercortisoluria. Combined therapy was clearly superior to monotherapy with ketokonazole or SMS 201-995, respectively. Side effects were not observed, the tumor masses remained unchanged throughout the observation period of now 19 months.Abbreviations ACTH adrenocorticotropic hormone - opDDD 1,1 dichloro-2(o-chlorophenyl)-2-(p-chlorophenyl)-ethane - 5-HIAA 5-hydroxyindolaceticacid - VIP vasoactive intestinal pepide - CRH corticotropin releasing hormone     

A Plurihormonal TSH-Secreting Pituitary Microadenoma: Report of a Case with an Atypical Clinical Presentation and Transient Response to Bromocriptine Therapy

Inappropriate secretion of thyrotropin (TSH) is a rare cause of hyperthyroidism, and it is caused by either a TSH-producing pituitary adenoma (usually a macroadenoma) or to selective pituitary resistance to thyroid hormone. The case of a 31-yr-old male who presented with clinical features of thyrotoxicosis, including episodes of thyrotoxic paralysis, and a thyroid profile characterized by free hyperthyroxinemia and hypertriiodothyronemia with a nonsuppressed, inadequately normal TSH is reported. Dynamic testing showed both, lack of TSH stimulation by thyroid-releasing hormone (TRH), and lack of suppression by T3, consistent with autonomous TSH secretion. Pituitary MRI revealed a microadenoma. Seventy five percent of the patient’s serum TSH immunoreactivity eluted as α-subunit in Sephadex G-100 chromatography. A diagnosis of TSH-secreting microadenoma was established, and the patient was treated successfully with bromocriptine, which resulted in both clinical and biochemical resolution of his hyperthyroidism. Two months later, he became hyperthyroid again during bromocriptine therapy. Octreotide was started with adequate control of his symptoms and normalization of his free T4 level. He eventually underwent transsphenoidal surgery with successful resection of a chromophobic microadenoma which immunostained for TSH, growth hormone (GH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). One month postoperatively he is clinically and biochemically euthyroid on no medications.     

Treatment of prolactinomas and growth hormone-producing adenomas with an injectable bromocriptine retard preparation and a somatostatin analogue delivered by an implantable pump

Among 14 patients with prolactinomas a single injection of 50 mg bromocriptine in a retard preparation resulted in a decrease of the initially elevated serum prolactin levels (to 4-62% of the initial value) in 12 cases and in a tumor shrinkage in 9 patients. In 3 out of 4 acromegalics injection and/or infusion of the somatostatin analogue SMS 201-995 (in 2 patients with an implanted Infusaid pump) led to a normalization of growth hormone and somatomedin-C levels.