Role of Regulatory Factors in Pituitary Tumour Formation

Abstract

The molecular basis of pituitary tumorigenesis remains controversial, but there are two major theories which have been subject to most investigation: hormonal (usually hypothalamic factors) and/or growth factor overstimulation, or a molecular defect within the pituitary itself. It has been shown, for example, that excessive regulatory hormone stimulation can lead to an increased number of cells in the pituitary in various physiological or pathological states such as pregnancy (lactotrophs), untreated primary hypothyroidism (thyrotrophs and lactotrophs),primary hypoadrenalism (corticotrophs) and ectopic GHRH-secreting tumours (somatotrophs). Animal models also provide data that in the presence of excessive hypothalamic hormone stimulation, adenoma formation can occur. However, evidence in favour of the monoclonal nature of pituitary tumours argues for an intrinsic molecular defect as the primary initiating event in tumour formation. We review the various hormonal factors and their receptors effecting the different types of pituitary cells, such as CRH, AVP and cortisol feedback on corticotrophs; GHRH, Galpha PKA, somatostatin and GH and IGF feedback on somatotrophs; GnRH, LH/FSH, activin and oestrogen feedback on gonadotrophs; dopamine, oestrogen and prolactin feedback on lactotrophs; and TRH, TSH and thyroid hormone feedback on thyrotrophs. The monoclonal origin of adenomas makes it unlikely that hypothalamic factors could initiate pituitary transformation, but they could still create an environment where there is a higher chance that a possible causative tumorigenic mutation may occur in one (or several) of the overstimulated pituitary cells, or enhance the proliferation of an already-mutated cell.

Hormonal Signaling and Pituitary Adenomas

“…Consistent with the view that this mutational change probably represents a late event associated with unusual malignant features, RAS mutations have been detected in metastases of pituitary carcinomas, but not in the primitive tumors [10]. Considering the possible loss of tumor suppressor genes in pituitary tumorigenesis, mutations of neither p53, retinoblastoma, nor cyclin-dependent kinase inhibitors p27 and p16 have been found in these neoplasia [1,2,3,4,5, 11, 12]. …”

“…The normal pituitary and pituitary tumors produce a wide number of growth factors and express their specific receptors [1,2,3,4,5, 42]. Transforming growth factor (TGF)-α, epidermal growth factor (EGF) and EGF receptors are all expressed in the pituitary.…”

“…Pituitary tumors may derive from excessive proliferation of each cell subtype and may present with specific endocrine syndromes (acromegaly, hyperprolactinemic syndrome, Cushing’s disease, TSH-induced hyperthyroidism, hypopituitarism) or mass symptoms or both. The genesis of pituitary tumors has been controversial for many years and the respective role and importance of intrinsic alterations of the pituicytes themselves, hypothalamic dysregulation and locally produced growth factors is still debated [1,2,3,4,5]. However, the demonstration by X-chromosomal inactivation analysis that the majority of pituitary adenomas derive from clonal expansion of a single initially transformed pituitary cell suggests that the general principles of tumorigenesis also apply to pituitary adenoma formation [6].…”

The premenstrual syndrome, premenstrual mastodynia, fibrocystic mastopathy and infertility have often common roots: effects of extracts of chasteberry (Vitex agnus castus) as a solution

“…A possible explanation for this phenomenon is a mutation of prolactin receptors which results in their hypersensitivity [37]. There is also some recently described evidence that such mutated prolactin receptors may be constitutively active [38]. Under these conditions a number of paracrine acting factors are locally secreted which stimulate further proliferation of surrounding cells [39].…”

CRH inhibits NF-κB signaling in human melanocytes

“…Nevertheless, the functional significance of CRH expression in peripheral tissues is still unresolved. CRH has been described to act as a growth factor [16,34], apoptosis regulator [3,7] and differentiation factor [8,9,22,46]. CRH also acts as pro-inflammatory factor, since it stimulates degranulation of mast cells and increases vascular permeability [38].…”