Normal thyrotrophs represent less than 5% of all anterior pituitary cells, which may explain why thyrotropinomas are so rare. In normal physiology, the set- point of the hypothalamic- pituitary- thyroid axis is maintained within a tight range, and reflects a balance between positive (e.g. hypothalamic thyrotropin- releasing hormone [TRH]) and negative (e.g. somatostatin [SA]; triiodothyronine [T3]) regulation (Figure 1). The critical role of thyroid hormone in constraining thyrotroph expansion/ growth is emphasized by the development of thyrotroph hyperplasia in patients who are chronically under- replaced or non- compliant with thyroxine re placement therapy.

Fig1. Schematic representation of the hypothalamic- pituitary- thyroid axis and major target organs. Key: α, thyroid hormone receptor α; β, thyroid hormone receptor β; ALB, albumin; SA, somatostatin; T3, triiodothyronine; T4, thyroxine; TBG, thyroxine- binding globulin; TR, thyroid receptor; TRH, thyrotropin- releasing hormone; TSH, thyrotropin; TTR, transthyretin.

The aetiopathogenesis of thyrotropinomas remains poorly under stood. While the majority arise within the sella, a small number of cases of TSH- secreting adenomas located within the nasopharynx have been reported. Although they have been observed in the context of multiple endocrine neoplasia type I and familial isolated pituitary adenoma (due to mutation in the aryl hydrocarbon receptor- interacting protein (AIP)), such cases are rare and the majority appear to arise sporadically. Data from analyses of all pituitary tumour subtypes (including a small number of TSH- secreting adenomas) point to clonal expansion from a single trans formed cell. Evidence for aberrant transcriptional regulation of thyrotrophs (with consequent TSH hypersecretion and unrestrained growth) has been sought but, to date, most studies have proved largely uninformative (including those examining proto- oncogenes (e.g. Gsp, ras) and tumour- suppressor genes (e.g. Rb or p53)). The pituitary- specific transcription factor Pit- 1 is overexpressed in some TSH- secreting pituitary adenomas, and might play a role in cell proliferation as well as promoting hormone cosecretion in this sub group of adenomas.

The hallmark of TSH- secreting pituitary adenomas is constitutive and autonomous secretion of TSH with failure of negative regulation by thyroid hormone. A somatic mutation of THRB (encoding TRβ), as well as aberrant expression of a TRβ4 isoform, have been proposed as potential mechanisms for the impaired regulation of TSH by triiodothyronine (T3). Thyrotropin- releasing hormone (TRH) receptors are present on most tumour cells. However, the attenuated/ absent response of TSH and α- subunit to exogenous TRH administration in the majority of patients with TSH- secreting pituitary adenomas suggests that the TRH receptor signalling pathway is impaired/ non- functional in these tumours. Most thyrotropinomas express somatostatin receptor (SSTR) subtypes 1, 2, 3, and 5, with SSTR2 the predominant isoform. Native somatostatin negatively regulates TSH secretion and has been implicated in cell cycle arrest. Depot somatostatin analogue therapy rapidly normalizes thyroid function in most patients with thyrotropinomas and can promote tumour shrinkage, suggesting that the primary molecular defect is unlikely to involve this pathway, although somatostatin analogue (SSA) resistant tumours are recognized.

Using an alternative approach, a recent study of whole- exome sequencing of a small number of thyrotropinomas similarly failed to identify a single common driver, suggesting that discrete primary events may underlie tumorigenesis in different patients.

Normal thyrotrophs share a common lineage with somatotrophs and lactotrophs, and are dependent on expression of Pit- 1. It is not surprising then that cosecretion of growth hormone (GH) and/ or prolactin (PRL) is observed in a significant proportion of cases (up to 30%) (Figure 2). Intriguingly, not all patients with bio chemical evidence of abnormal GH secretion manifest overt acromegaly. In addition, a subgroup of tumours demonstrates positive immunohistochemical staining for GH and/ or PRL, but do not exhibit clinical or biochemical acromegaly or hyperprolactinaemia. Similarly, so- called silent thyrotropinomas (clinically non- functioning pituitary adenomas, but with abundant positive TSH staining on immunohistochemistry) are well recognized. TSH- secreting macroadenomas are often accompanied by unbalanced hypersecretion of α- subunit, and double- immunostaining studies have suggested the existence of two different types of cells: one secreting α- subunit alone and another cosecreting α- subunit and β- TSH.

Fig2. Spectrum of histological appearances in thyrotropinomas. (a) pituitary adenoma demonstrating positive immunohistochemical staining for growth hormone (GH), TSH and (to a lesser extent) prolactin (PRL). (b) thyrotropinoma with significant fibrosis and calcification— note the hypodense areas within the right side of the sella (arrows) on MRI (which may be mistaken for vascular structures, but which are confirmed as foci of calcification on CT). For a colour version of this figure, please see colour plate section. Histology images provided courtesy of Dr Kieren Allinson, Department of Neuropathology, Addenbrooke’s Hospital, Cambridge.

TSH- secreting pituitary adenomas are almost always benign, with only a handful of malignant tumours (with metastases to brain, lung, liver, and/ or bone) reported to date. A subgroup of thyrotropinomas are more fibrotic than other pituitary tumours, which has been linked to local secretion of basic fibroblast growth factor by the adenoma cells. In this context, both microscopic and macroscopic calcification may be seen and can confound the interpretation of MR imaging, and make surgical resection more challenging (Figure 2).

Finally, not all TSH- secreting pituitary adenomas are associated with overt elevation of serum TSH levels— indeed it has been estimated that between 30% and 40% of cases have a TSH level which repeatedly falls within the reference range, but it is inappropriately normal for the ambient raised thyroid hormone levels. This may be explained, at least in part, by an increased bioactivity of neoplasm derived TSH.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الدينية يطلق الدورة التطويرية والفقهية الخامسة لملاكات العتبة العباسية المقدسة

قسم الشؤون الفكرية ينظّم ختمة قرآنية رمضانية لطلبة العلوم الدينية الأفارقة في النجف

شعبة الخطابة تقيم مجلسا للوعظ والإرشاد في الصحن الشريف تزامناً مع حلول شهر رمضان المبارك

قسم التطوير يختتم دورة إعداد المدربين لملاكات مديرية تربية كربلاء

المزيد

الآخبار الصحية

مفاجأة.. تحسين القدرة على التحمل لا يعتمد العضلات فقط

المرتفعات والأكسجين.. دراسة "مبشرة" لمرضى السكري

علماء يبتكرون "آلية" تتوقع موعد ظهور أعراض الزهايمر

ماذا يحدث لجسمك عند التوقف عن تناول الخضراوات والفواكه؟

المزيد

الآخبار التكنلوجية

رصد "القرش النائم" في أحد أقسى الأماكن على وجه الأرض

أسماك أعماق البحر تكشف نظاما بصريا يتجاوز "المألوف"

زوكربيرغ أمام القضاء في قضية إدمان المراهقين

"علي بابا" تكشف عن نموذج جديد للذكاء الاصطناعي

المزيد

مواضيع ذات صلة

Pituitary incidentaloma

Pathological evaluation of Pituitary carcinomas

Clinical Presentation and Diagnosis of Pituitary carcinomas

Cancer and The Environment

Cytogenetic Changes in Cancer

Telomerase as an Oncogene

Activation of Oncogenes by Chromosome Translocation or Fusions

Imaging of the Pituitary: Adenomas

T pit Family of tumours

Pit- 1 Family of tumours

Pituitary Adenomas

Molecular Mechanisms of Carcinogenesis