Transdifferentiation of somatotrophs to thyrotrophs in the pituitary of patients with protracted primary hypothyroidism

Vidal, Sergio; Horváth, Éva; Kovács, Kálmán; Cohen, Sandra; Lloyd, Ricardo V.; Scheithauer, Bernd W.

doi:10.1007/pl00008197

Cited by 97 publications

(53 citation statements)

References 55 publications

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“…In rats made hypothyroid by propylthiouracil administration, somatotrophs transform to stimulated thyrotrophs through bihormonal transitional cells, so-called thyrosomatotrophs that exhibit features common to both cell types (8). Presence of thyrosomatotrophs in human pituitary has been recently reported in cases of thyrotroph hyperplasia due to protracted primary hypothyroidism, supporting the notion that such cells contribute to the development of new thyrotrophs in the human gland as well (20). Previous experimental studies in rats with chemically induced hypothyroidism demonstrated that transdifferentiation of somatotrophs to thyrotrophs is reversible because thyrotrophs reverted to somatotrophs after discontinuation of propylthiouracil administration (8).…”

Section: Discussionmentioning

confidence: 69%

“…It is able to change its size and increase or reduce the number of specific cell populations to meet the actual requirements of the body. Previous studies have suggested that somatotrophs, the most abundant pituitary cell type, could play a key role in pituitary plasticity (20). In vitro studies have demonstrated that transdifferentiation of somatotrophs contributes to the preovulatory increase in the number of gonadotrophs (2).…”

Section: Discussionmentioning

confidence: 99%

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Reversible Transdifferentiation: Interconversion of Somatotrophs and Lactotrophs in Pituitary Hyperplasia

et al. 2001

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Previous studies conclusively demonstrated transformation of somatotrophs into bihormonal mammosomatotrophs in gestational lactotroph hyperplasia during pregnancy. Similar transdifferentiation of somatotrophs into thyrotrophs through bihormonal intermediate thryrosomatotrophs was documented during thyrotroph hyperplasia in both rodent and human pituitaries in hypothyroidism. The cessation of the stimulation resulted in reversal of the process in both conditions. The conversion of lactotrophs into somatotrophs was suggested but not documented previously in the human gland. The present study was undertaken to investigate cases of somatotroph hyperplasia by transmission electron microscopy, immunoelectron microscopy using double immunogold labeling for growth hormone and prolactin, as well as combined immunocytochemistry and in situ hybridization. Adenohypophysial tissue was removed from a 38-year-old man and a 29-year-old woman with longstanding acromegaly due to ectopic overproduction of growth hormone-releasing hormone (GRH) by bronchial carcinoid tumors. For comparison, two pituitary biopsies were studied: one from a 38-year old woman with idiopathic lactotroph hyperplasia and one from a 14-year-old boy with secondary lactotroph hyperplasia due to a suprasellar craniopharyngioma. In the patients with somatotroph hyperplasia, the prevailing cell type was the hyperplastic somatotroph joined by mammosomatotroph deriving from lactotrophs, whereas monohormonal lactotrophs were rare. The predominance of mammosomatotrophs and active lactotrophs was documented in the patient with idiopathic lactotroph hyperplasia, whereas the case of the patient with secondary lactotroph hyperplasia was characterized by monohormonal lactotrophs and somatotrophs, but mammosomatotrophs were rare. That finding in the pituitary of the boy suggests that participation of mammosomatotrophs in lactotroph hyperplasia is not unconditional. Our findings conclusively demonstrate conversion of lactotrophs into mammosomatotrophs during somatotroph hyperplasia, providing further evidence for the potential of reversible transdifferentiation between somatotrophs and lactotrophs in response to functional demand.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Reversible Transdifferentiation: Interconversion of Somatotrophs and Lactotrophs in Pituitary Hyperplasia

et al. 2001

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“…In humans, during pregnancy, lactotroph cells are recruited from GH-secreting cells, and the hyperplastic cell population may be bihormonal, secreting both hormones. Similarly, hypothyroid patients exhibit thy- rotroph hyperplasia with recruitment of GH-secreting cells, leading to bihormonal TSH-and GH-cell hyperplasia (33). It is unclear whether these bihormonal, hypertrophic cells arise as a consequence of transdifferentiation of already committed cells, or whether earlier more primitive stem cells undergo expansion.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms for pituitary tumorigenesis: the plastic pituitary

2003

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The anterior pituitary gland integrates the repertoire of hormonal signals controlling thyroid, adrenal, reproductive, and growth functions. The gland responds to complex central and peripheral signals by trophic hormone secretion and by undergoing reversible plastic changes in cell growth leading to hyperplasia, involution, or benign adenomas arising from functional pituitary cells. Discussed herein are the mechanisms underlying hereditary pituitary hypoplasia, reversible pituitary hyperplasia, excess hormone production, and tumor initiation and promotion associated with normal and abnormal pituitary differentiation in health and disease.

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“…We propose that these cells represent intermediate forms of somatotroph-derived thyrotrophs with ultrastructural features and a bi-hormonal expression pattern distinct from that of "mature" thyroidectomy cells. The corresponding condition in humans is thyrotroph hyperplasia in primary hypothyroidism and bihormonal thyro-somatotroph cells have been demonstrated in pituitary specimens from such patients [23].…”

Section: Discussionmentioning

confidence: 98%

“…Examples of endocrine cell transdifferentiation include pituitary (GH to TSH [8,23], GH to PRL [24][25][26][27][28] and GH to gonadotroph cells [29]), thyroid C cells [30] and adrenal chromaffin cells [31,32]. The process of pituitary transdifferentiation [8] implies the existence of bi-hormonal cells as intermediates, it does not require cell division [24,26,27] and can be induced by stimulation of hormonal feedback systems [8,23,28] or by treatment with growth factors [24,27].…”

Section: Discussionmentioning

confidence: 99%

Somatotroph to thyrotroph cell transdifferentiation during experimental hypothyroidism ‐ a light and electron‐microscopy study

Radian

Coculescu

Morris

2003

J Cellular Molecular Medi

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Somatotroph and thyrotroph pituitary cells share a common precursor cell expressing the transcription factor Pit1 in ontogeny. Cells expressing both thyrotropin (TSH) and growth-hormone (GH) are found in adult rat pituitary and in human pituitary adenomas in acromegaly, and these tumors contain both thyrotropin-releasing hormone (TRH) and the TRH receptors (TRHR). It has been shown that stimulation of TSH expression in primary hypothyroidism promotes changes suggestive of somatotroph to thyrotroph cell transdifferentiation. We tested this hypothesis and the role of TRH in experimental primary hypothyroidism in rats. Adult female Long-Evans rats, 6 months old, were administered the antithyroid drug methimazole (0,1% w/v) in the drinking water for 42 days. Animals were sacrificed by perfusion fixation under anaesthesia at weekly intervals and pituitary tissue processed in acrylic resin for immunofluorescence and immuno-electronmicroscopy for TSH, GH and TRHR. In the hypothyroid rat pituitary immunofluorescent somatotrophs were greatly reduced in number and gradually replaced by thyrotrophs during methimazole administration. Colocalization of GH and TSH in the same cell was noted. Immunoelectronmicroscopy demonstrated the development of enlarged thyrotrophs with dilated rough endoplasmic reticulum containing an electron-dense material and intracisternal granules, both of which are immunoreactive for TSH ('thyroidectomy cells'). The somatotrophs showed reduced GH immunoreactivity and also the presence of TSH-type, small-size secretory granules. This suggests that the greatly increased number of TSH-cells in methimazole-induced-hypothyroidism is due, at least partially, to the transdifferentiation of somatotroph into thyrotroph cells. TRHR immunofluorescence was expressed in many somatotrophs in normal rat pituitary and unlike immunoreactive GH, its expression was enhanced during hypothyroidism. The number of TRHR-immunoreactive cells increased in parallel with the number of TSH-immunoreactive cells. This indicates a role for TRH stimulation in the transdifferentiation process. Taken together, these data suggest that, in addition to the cell mutation mechanism involving an early totipotential progenitor cell, transdifferentiation of existing somatotroph cells also plays a part in the pathogenesis of multihormonal GH-secreting adenomas.

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Transdifferentiation of somatotrophs to thyrotrophs in the pituitary of patients with protracted primary hypothyroidism

Cited by 97 publications

References 55 publications

Reversible Transdifferentiation: Interconversion of Somatotrophs and Lactotrophs in Pituitary Hyperplasia

Reversible Transdifferentiation: Interconversion of Somatotrophs and Lactotrophs in Pituitary Hyperplasia

Mechanisms for pituitary tumorigenesis: the plastic pituitary

Somatotroph to thyrotroph cell transdifferentiation during experimental hypothyroidism ‐ a light and electron‐microscopy study

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