Molecular pathogenesis of pituitary tumours

2011 ◽  
pp. 112-121
Author(s):  
Ines Donangelo ◽  
Shlomo Melmed
Keyword(s):  
Growth Hormone ◽  
Pituitary Adenomas ◽  
Single Cells ◽  
Hormone Secretion ◽  
Cell Types ◽  
Pituitary Tumour ◽  
Thyroid Stimulating Hormone ◽  
Gene Products ◽  
Pituitary Tumours ◽  
Secretory Products

Pituitary adenomas are discovered in up to 25% of unselected autopsies, however, clinically apparent tumours are considerably less common. The pituitary gland is composed of differentiated cell types: somatotrophs, lactotrophs, corticotrophs, thyrotrophs, and gonadotrophs. Tumours may arise from any of these cell types and their secretory products depend on the cell of origin. The functional classification of pituitary tumorus is based on identification of cell gene products by immunostaining or mRNA detection, as well as measurement of circulating tumour and target organ hormone levels. Oversecretion of adrenocorticotropic hormone (ACTH) results in cortisol excess with Cushing’s disease. Growth hormone overproduction leads to acromegaly with typical acral overgrowth and metabolic abnormalities. Prolactin hypersecretion results in hypogonadism and galactorrhoea. Rarely, thyroid-stimulating hormone (TSH) hypersecretion leads to goitre and thyrotoxicosis, and gonadotropin excess results in gonadal dysfunction (1). Mixed tumours cosecreting growth hormone with prolactin, TSH, or ACTH may also arise from single cells. Clinically nonfunctional tumours are those that do not efficiently secrete their gene products, and most commonly they are derived from gonadotroph cells. Pituitary tumours are further defined radiographically as microadenomas (<1 cm in diameter) or macroadenomas (>1 cm in diameter). However, this classification does not reflect whether the pituitary tumour is amenable to total resection and limits assessment of invasive progression during serial imaging. Therefore, it is useful to apply the classification proposed by Hardy in 1973 and modified by Wilson in 1990 (Table 2.3.2.1), whereby pituitary tumours are classified into one of five grades and one of six stages, providing important preoperative information. Pituitary tumours cause morbidity by both abnormal hormone secretion as well as compression of regional structures. As a considerable proportion of patients do not achieve optimal therapeutic control of mass effects and/or hormone hypersecretion despite advances in therapeutic approaches, understanding pathogenesis and pituitary tumour growth patterns in individual patients will enable identification of subcellular treatment targets, ultimately decreasing tumour-related morbidity and mortality. Determinants of initiation and progression of pituitary adenomas are not fully understood. This chapter describes a spectrum of mechanisms implicated in pituitary tumorigenesis, including the role of pituitary plasticity, imbalances in cell cycle regulation, transcription factors, signalling pathways, and angiogenesis (Fig. 2.3.2.1). Molecular events related to tumorigenesis in human pituitary adenoma subtypes are summarized in Table 2.3.2.2. The causal role for selected genetic imbalances leading to development of pituitary tumours has been confirmed in several transgenic mouse models (Table 2.3.2.3).

scholarly journals HORMONE SECRETION BY CELLS DISSOCIATED FROM RAT ANTERIOR PITUITARIES

1973 ◽  
Vol 59 (2) ◽  
pp. 276-303 ◽  
Author(s):  
Colin R. Hopkins ◽  
Marilyn G. Farquhar
Keyword(s):  
Growth Hormone ◽  
Single Cells ◽  
Hormone Secretion ◽  
Cell System ◽  
Secretory Cells ◽  
Mechanical Dispersion ◽  
High K ◽  
Pituitary Secretion ◽  
Secretory Products ◽  
Stimulation Of

A new procedure has been developed for dissociating anterior pituitary tissue and producing a viable suspension of single cells. The procedure involves incubation of small tissue blocks in 1 mg/ml trypsin (15 min), followed by incubation in 8 µg/ml neuraminidase and 1 mM EDTA (15 min), followed by mechanical dispersion. Cell yields are ∼55%, based on recovered DNA. By electron microscopy five types of secretory cells (somatotrophs, mammotrophs, thyrotrophs, gonadotrophs, and corticotrophs) plus endothelial and follicular cells can be identified and are morphologically well preserved up to 20 h after dissociation. Throughout this period, the cells incorporate linearly [3H]leucine into protein for up to 4 h at a rate 90% greater than hemipituitaries, and they synthesize, transport intracellularly, and release the two major pituitary secretory products, growth hormone and prolactin. Immediately after dissociation the cells' ability to respond to secretogogues (high K+ and dibutyryl cyclic AMP) is impaired, but after a 6–12-h culture period, the cells apparently recover and discharge 24% and 52%, respectively, of their content of prelabeled growth hormone over a 3-h period in response to these two secretogogues. This represents a stimulation of 109% and 470% over that released by cells incubated in control medium. The results demonstrate that function and morphologic integrity are preserved in this cell system. Therefore it is suitable for the study of various aspects of pituitary secretion and its control.

A critical reappraisal of MIB-1 labelling index significance in a large series of pituitary tumours: secreting versus non-secreting adenomas.

2002 ◽  
pp. 103-113 ◽  
Author(s):  
M L Jaffrain-Rea ◽  
D Di Stefano ◽  
G Minniti ◽  
V Esposito ◽  
A Bultrini ◽  
...  
Keyword(s):  
Operative Treatment ◽  
Hormone Secretion ◽  
Tumour Volume ◽  
Pituitary Tumour ◽  
Labelling Index ◽  
Pituitary Tumours ◽  
Life Threatening ◽  
The Mean ◽  
Monoclonal Antibody Mib 1 ◽  
Mib 1

Pituitary tumours are usually benign neoplasia, but may have a locally aggressive or malignant evolution. This study aimed to identify factors which mostly influence their proliferative activity, in order to clarify its value for clinical and research purposes. The proliferative index was determined in a prospective series of 132 pituitary tumours as the percentage of monoclonal antibody MIB-1-immunopositive cells and referred to as the MIB-1 labelling index (LI). Its distribution was analysed according to both univariate and multivariate models. A life-threatening pituitary tumour is presented separately. The mean LI was 1.24+/-1.59%, with significant differences between clinically secreting (CS) and clinically non-secreting (CNS) adenomas. In CS adenomas (n=65), LI was highly variable and markedly influenced by pre-operative pharmacological treatment (0.80+/-1.03 vs 2.06+/-2.39% in treated vs untreated cases, P=0.009); it decreased with patient's age (P=0.025, r=0.28) and increased with tumour volume and invasiveness. The influence of pre-operative treatment and macroscopic features on LI in this group was confirmed by multivariate analysis. In CNS adenomas (n=67), LI distribution was less variable than in CS adenomas (P<0.0001), it was age-independent and correlations with tumour volume, invasiveness or recurrence did not reach significance. In a rapidly growing parasellar tumour, the mean LI was 24% at first surgery and exceeded 50% at second surgery performed 4 months later. LI should be interpreted according to hormone secretion and pre-operative treatment. Unusually high LI values deserve particular attention.

Prolactinomas and hyperprolactinaemia (including macroprolactinaemia)

2011 ◽  
pp. 187-197 ◽  
Author(s):  
John S. Bevan
Keyword(s):  
Growth Hormone ◽  
Management Strategies ◽  
Pituitary Tumour ◽  
Thyroid Stimulating Hormone ◽  
Pressure Effects ◽  
Type I ◽  
Local Pressure ◽  
Thyrotrophin Releasing Hormone ◽  
Pituitary Tumorigenesis ◽  
Pituitary Prolactin

Prolactin promotes milk production in mammals. It was characterized as a hormone distinct from growth hormone, which also has lactogenic activity, as recently as 1971. In humans, the predominant prolactin species is a 23 kDa, 199 amino acid polypeptide synthesized and secreted by lactotroph cells in the anterior pituitary gland. Prolactin is produced also by other tissues including decidua, breast, T lymphocytes, and several regions of the brain, where its functions are largely unknown and its gene regulation different from that of the pituitary gene. Pituitary prolactin production is under tonic inhibitory control by hypothalamic dopamine, such that pituitary stalk interruption produces hyperprolactinaemia. The neuropeptides thyrotrophin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP) exert less important stimulatory effects on pituitary prolactin release (1). Following the discovery of prolactin as a separate hormone it became apparent that many apparently functionless ‘chromophobe’ pituitary adenomas were prolactinomas. Indeed, prolactinoma is the commonest type of functioning pituitary tumour diagnosed in humans. There is a marked female preponderance and prolactinoma is relatively rare in men. Several studies have revealed small prolactinomas in approximately 5% of autopsy pituitaries, most of which are undiagnosed during life. From a clinical standpoint, prolactinomas are divided arbitrarily into microprolactinomas (≤10 mm in diameter) and macroprolactinomas (>10 mm). This is a useful distinction which predicts tumour behaviour and indicates appropriate management strategies. Generally, microprolactinomas run a benign course. Some regress spontaneously, most stay unchanged over many years, and very few expand to cause local pressure effects. In contrast, macroprolactinomas may present with pressure symptoms, often increase in size if untreated and rarely disappear. Some clinicians find an intermediate category of meso-prolactinoma useful (10–20 mm in diameter), since this tumour group may have a more favourable treatment outcome than for larger macroprolactinomas. Prolactinomas are usually sporadic tumours. Molecular genetics has shown nearly all to be monoclonal, suggesting that an intrinsic pituitary defect is likely to be responsible for pituitary tumorigenesis (see Chapter 2.3.2). Occasionally, prolactinoma may be part of a multiple endocrine neoplasia syndrome type I, but this occurs too infrequently to justify screening in every patient with a prolactinoma. Mixed growth hormone and prolactin-secreting tumours are well recognized and give rise to acromegaly in association with hyperprolactinaemia. Most contain separate growth hormone and prolactin-secreting cells whereas a minority secrete growth hormone and prolactin from a single population of cells, the mammosomatotroph adenomas. Prolactin-secreting adenomas may produce other hormones such as thyroid-stimulating hormone (TSH) or adrenocorticotropic hormone (ACTH), but such tumours are uncommon. Malignant prolactinomas are also very rare. A few cases have been described which have proved resistant to aggressive treatment with surgery, radiotherapy, and dopamine agonists. In a small proportion, extracranial metastases in liver, lungs, bone, and lymph nodes have been documented. The alkylating agent temozolomide is effective against some aggressive prolactinomas (2).

scholarly journals Silent somatotroph tumour revisited from a study of 80 patients with and without acromegaly and a review of the literature

2017 ◽  
Vol 176 (2) ◽  
pp. 195-201 ◽  
Author(s):  
Laura Chinezu ◽  
Alexandre Vasiljevic ◽  
Jacqueline Trouillas ◽  
Marion Lapoirie ◽  
Emmanuel Jouanneau ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Transcription Factor ◽  
Somatostatin Receptors ◽  
Clinical Signs ◽  
Secretory Activity ◽  
Thyroid Stimulating Hormone ◽  
Lower Percentage ◽  
Review Of The Literature ◽  
Pituitary Tumours ◽  
Ki 67

Background Silent somatotroph tumours are growth hormone (GH) immunoreactive (IR) pituitary tumours without clinical and biological signs of acromegaly. Their better characterisation is required to improve the diagnosis. Materials and methods Twenty-one silent somatotroph tumours were compared to 59 somatotroph tumours with acromegaly. Tumours in each group were classified into GH and plurihormonal (GH/prolactin (PRL)/±thyroid-stimulating hormone (TSH)) and into densely granulated (DG) and sparsely granulated (SG) types. The two groups were then compared with regards to proliferation (Ki-67, p53 indexes and mitotic count), differentiation (expression of somatostatin receptors SSTR2A–SSTR5 and transcription factor Pit-1) and secretory activity (% of GH- and PRL-IR cells). Results The silent somatotroph tumours represented 2% of all tested pituitary tumours combined. They were more frequent in women than in men (P = 0.002), more frequently plurihormonal and SG (P < 0.01), with a lower percentage of GH-IR cells (P < 0.0001) compared to those with acromegaly. They all expressed SSTR2A, SSTR5 and Pit-1. The plurihormonal (GH/PRL/±TSH) tumours were mostly observed in women (sex ratio: 3/1) and in patients who were generally younger than those with acromegaly (P < 0.001). They were larger (P < 0.001) with a higher Ki-67 index (P = 0.007). Conclusions The silent somatotroph tumours are not uncommon. Their pathological diagnosis requires the immunodetection of GH and Pit-1. They are more frequently plurihormonal and more proliferative than those with acromegaly. A low secretory activity of these tumours might explain the normal plasma values for GH and insulin-like growth factor 1 (IGF1) and the absence of clinical signs of acromegaly.

Incidentally found small pituitary adenomas may have no effect on fertility

1988 ◽  
Vol 117 (3) ◽  
pp. 361-364 ◽  
Author(s):  
M. W. Abd El-Hamid ◽  
G. F. Joplin ◽  
P. D. Lewis
Keyword(s):  
Growth Hormone ◽  
Histological Examination ◽  
Pituitary Adenomas ◽  
Clinical Case ◽  
Pituitary Tumours ◽  
Fertility Effect ◽  
Pituitary Glands ◽  
Female Subjects

Abstract. Histological examination of the pituitary glands from 486 unselected autopsies revealed 97 clinically unsuspected adenomas in 78 glands (16%). Prolactinomas numbered 48; no hormone was found in 30, LH in 8, ACTH in 7, growth hormone (GH) and prolactin in 3, and GH alone in 1. Eleven of 194 female subjects and 37 out of 292 males had one or more prolactinoma. Clinical case notes, available for 57 of 78 subjects with adenomas, were reviewed to obtain data on fertility. Of the 25 women with case notes, 6 of the 11 with prolactinomas and 11 of the 14 with adenomas of other types had conceived. For the 32 males, 10 of the 23 with prolactinomas and 5 of the 9 with other types had procreated. These findings show that pituitary tumours not identified in life may have no major anti-fertility effect, and suggest that treatment of small intrasellar lesions discovered clinically by chance may not be necessary.

Invasive mixed growth hormone/prolactin secreting pituitary tumour: complete shrinking by octreotide and bromocriptine, and lack of tumour growth relapse 20 months after octreotide withdrawal

1992 ◽  
Vol 126 (2) ◽  
pp. 179-183 ◽  
Author(s):  
Jean-Louis Sadoul ◽  
Antoine Thyss ◽  
Pierre Freychet
Keyword(s):  
Growth Hormone ◽  
Tumour Growth ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Clinical Signs ◽  
Treatment Protocol ◽  
Pituitary Tumour ◽  
Prolactin Secretion ◽  
Close Monitoring ◽  
Complete Control

Octreotide and bromocriptine were used to treat an acromegalic patient harbouring an invasive pituitary tumour secreting growth hormone and prolactin. Octreotide (100 μg, subcutaneously, three times daily) and bromocriptine (15 mg orally, daily) rapidly improved clinical signs and symptoms, including diabetes that initially required insulin. Complete control of growth hormone and prolactin secretion was obtained and maintained by this treatment protocol for 12 months without affecting the other pituitary functions. A major tumour shrinkage was apparent by magnetic resonance imaging after six months, and was considered to be complete after 12 months of treatment. Octreotide was then discontinued without any relapse in either growth hormone secretion or tumour growth over a 20-month period following withdrawal. Attempts were made to discontinue bromocriptine, but a maintenance therapy (2.5 mg daily) was required to control rebounds of prolactin hypersecretion. Two months after octreotide withdrawal, acute pancreatitis secondary to cholelithiasis required surgery; this complication was attributed to octreotide (pre-treatment ultrasonography was normal). These findings suggest that combination therapy with octreotide and bromocriptine may be considered in pituitary macroadenomas secreting growth hormone and prolactin. They also emphasize the need for a close monitoring of cholelithiasis, not only during octreotide therapy but also after the drug's withdrawal.

Acromegaly

2011 ◽  
pp. 197-209 ◽  
Author(s):  
John A. H. Wass ◽  
Peter J. Trainer ◽  
Márta Korbonits
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Anterior Pituitary ◽  
Pituitary Tumour ◽  
Insulin Like Growth Factor ◽  
Pituitary Tumours ◽  
Epiphyseal Fusion ◽  
Hands And Feet

Acromegaly is the condition most often associated with an anterior pituitary tumour, which results from growth hormone and insulin-like growth factor 1 (IGF-1) excess. It causes most characteristically enlargement of the hands and feet (Greek: akron, extremities; megas, great). Gigantism, which is the juvenile counterpart of acromegaly, is also caused by a pituitary tumour secreting growth hormone, but it causes excessive growth before epiphyseal fusion. It occurs less frequently than acromegaly because pituitary tumours in children are much less common than in adults.

Melanin-concentrating hormone stimulates human growth hormone secretion: a novel effect of MCH on the hypothalamic-pituitary axis

2006 ◽  
Vol 290 (5) ◽  
pp. E982-E988 ◽  
Author(s):  
Gabriella Segal-Lieberman ◽  
Hadara Rubinfeld ◽  
Moran Glick ◽  
Noga Kronfeld-Schor ◽  
Ilan Shimon
Keyword(s):  
Growth Hormone ◽  
Energy Homeostasis ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Pituitary Hormones ◽  
Thyroid Stimulating Hormone ◽  
Pituitary Cells ◽  
Human Pituitary ◽  
Gh Secretion ◽  
Melanin Concentrating Hormone

Melanin-concentrating hormone (MCH), a 19-amino acid orexigenic (appetite-stimulating) hypothalamic peptide, is an important regulator of energy homeostasis. It is cleaved from its precursor prepro-MCH (ppMCH) along with several other neuropeptides whose roles are not fully defined. Because pituitary hormones such as growth hormone (GH), ACTH, and thyroid-stimulating hormone affect body weight and composition, appetite, insulin sensitivity, and lipoprotein metabolism, we investigated whether MCH exerts direct effects on the human pituitary to regulate energy balance using dispersed human fetal pituitaries (21–22 wk gestation) and cultured GH-secreting adenomas. We found that MCH receptor-1 (MCH-R1), but not MCH receptor-2, is expressed in both normal (fetal and adult) human pituitary tissues and in GH cell adenomas. MCH (10 nM) stimulated GH release from human fetal pituitary cultures by up to 62% during a 4-h incubation ( P < 0.05). Interestingly, neuropeptide EI (10 nM), which is also cleaved from ppMCH, increased human GH secretion by up to 124% in fetal pituitaries. A milder, albeit significant, induction of GH secretion by MCH (20%) was seen in cultured GH-secreting pituitary adenomas. A comparable stimulation of GH secretion was seen when cultured mouse pituitary cells were treated with MCH. Treatment of cultured GH adenoma cells with MCH (100 nM) induced extracellular signal-regulated kinases 1 and 2 phosphorylation, suggesting activation of MCH-R1. In aggregate, these data suggest that MCH may regulate pituitary GH secretion and imply a potential cross-talk mechanism between appetite-regulating neuropeptides and pituitary hormones.

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