Refractory Pit1 plurihormonal tumours and thyrotroph adenomas.

Pit-1 tumours are derived from neoplastic cells of either somatotroph, lactotroph or thyrotroph cell lineages, but there are also distinct mixed tumours and plurihormonal tumours within this category as described within the 2022 edition of the WHO classification of pituitary tumours. Plurihormonal tumours and thyrotroph adenomas are transcriptionally similar and grouped together to discuss in this review, although it is clear an immature type of plurihormonal tumour exists which are more commonly associated with refractory disease. Management of residual or recurrent disease should follow that of other aggressive pituitary tumours, although a trial of somatostatin analogue therapy is certainly warranted before considering temozolomide therapy.

The molecular biology of thyrotroph pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs), which were formerly known as pituitary adenomas, are classified in 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. Since thyrotroph PitNETs are rare PitNETs, most previous studies about former thyroid stimulating hormone (TSH)-secreting pituitary adenoma have focused on a small number of cases. However, the diagnostic rate of thyrotroph PitNET has increased because of increased sensitivity of serum TSH measurement and widespread recognition that thyrotroph PitNETs are the cause of syndrome of inappropriate secretion of TSH (SITSH). Therefore, knowledge on the molecular mechanism of thyrotroph PitNET is gradually accumulating. Recently, comprehensive chromosomal, genetic, and epigenomic alterations in thyrotroph PitNET have been revealed with the availability of comprehensive gene and protein analyses, and the nature of thyrotroph PitNET is gradually being elucidated. However, further analysis is needed to determine whether the causes of these changes are directly responsible for the development of tumors.

Clinical and Therapeutic Characteristics of Pituitary TSH-Secreting Adenoma in Adolescent-Onset Patients: Six Case Studies and Literature Review.

Background: Thyrotropin-secreting adenoma (TSH-oma) is a very rare kind of functional pituitary adenoma, especially that which occurs in adolescents. However, its potential clinical and therapeutic characteristics are still unknown. Objectives: The study was aimed to summarize the clinical and therapeutic characteristics of patients with adolescent-onset TSH-oma. Methods: We retrospectively analyzed six (4.1%) adolescent-onset TSH-oma cases from 148 patients who were diagnosed with TSH-oma at our hospital between January 2012 and October 2020. A literature review was performed on the PubMed online database, and 14 adolescent-onset TSH-oma cases were retrieved. Then, the characteristics of clinical manifestations, treatment outcomes, and follow-ups were analyzed and compared to the adult TSH-oma patients. Results: Altogether, 20 adolescent-onset cases were included in this study having mean onset age of 13.4 ± 3.3 years. Males were found to be slightly predominant (M: F = 1.5:1) in our study. The median baseline levels of TSH, FT3, and FT4 in adolescent-onset cases were found to be 6.30 [interquartile range (IQR) 9.82] µIU/ml, 9.18 (IQR 11.61) pg/ml, and 3.22 (IQR 1.90) ng/dl, respectively, which were all significantly higher than the adult patients of our hospital. Also, the adolescent-onset cases showed more large tumor ratio (36.8% vs. 9.3%, p = 0.007) compared to the adult patients. Compared to the patients of all ages in the literature, the biochemical remission rate of SSAs (57.1%) and remission rate of TSS (38.9%) were found to be considerably lower in adolescent-onset patients, while the recurrence rate (44.4%) was found to be considerably higher. Conclusions: Adolescent-onset TSH-oma patients showed higher TSH and thyroid hormone levels, more large tumors, and worse treatment outcomes than adult cases. Hence, early diagnosis, multidisciplinary therapy, and close follow-up should be highlighted to improve the prognosis.

Response of thyrotropin-secreting pituitary tumors to preoperative lanreotide therapy. Report of two cases.

Case 1 was a 51-year-old man diagnosed with thyrotropin (TSH)-secreting pituitary tumor. The octreotide loading test showed suppression of TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. Three months after treatment initiation, tumor shrinkage was observed, and pituitary tumor resection was performed through transsphenoidal surgery. Case 2 was a 47-year-old woman in whom the octreotide loading test showed suppressed TSH secretion. Treatment with lanreotide preoperatively at 90 mg/month resulted in normalization of thyroid function. After six months of treatment, tumor reduction was observed, and transsphenoidal surgery was performed. In both cases, lanreotide administration before TSH-secreting pituitary tumor resection achieved normalization of thyroid function and tumor shrinkage. Treatment with lanreotide seems effective in patients who show TSH secretion suppression in the octreotide loading test.

Surgical Outcome and Treatment of Thyrotropin-Secreting Pituitary Tumors in a Tertiary Referral Center.

OBJECTIVE: Thyrotropin (TSH)-secreting pituitary tumors are rare and typically present with hyperthyroidism. Here we report the diagnosis, treatment, and surgical outcomes in a series of patients with TSH-secreting pituitary tumors in a tertiary referral center. METHODS: Descriptive retrospective study that included all patients with TSH-secreting pituitary tumors who underwent transsphenoidal surgery in the endocrinology and nutrition unit of the Virgen del Rocío University Hospital (Seville, Spain) between 2004 and 2016. RESULTS: The mean age at diagnosis was 42.8 ± 17 years. The mean time from onset of symptoms to diagnosis was 13 ± 10 months. Four patients displayed symptoms indicating hyperthyroidism (1 suffered from tachycardia); 3 patients showed symptoms because of mass effect (visual impairment and headache) and 3 patients were diagnosed based on incidental findings after routine blood tests (high free thyroxine levels). Eight patients had macroadenomas, and 2 patients had microadenomas. Five patients underwent conventional pituitary surgery, and 5 patients underwent expanded endoscopic transsphenoidal surgery. Six patients achieved cure after surgery. The other patients received radiotherapy and/or treatment with somatostatin analogs. Analysis of somatostatin receptor (SSTR) expression by immunohistochemistry could be performed in 6 tumors. CONCLUSIONS: Our results confirm the clinical and hormonal heterogeneity caused by TSH-secreting pituitary adenomas. Surgery is considered the first choice of treatment for these tumors. We observed surgical cure rates similar to those reported in recent published series. SSTR2 and SSTR3 are highly expressed in TSH-secreting pituitary adenomas. Our results suggest that somatostatin analog treatment may be also helpful in the treatment of TSH-secreting pituitary adenomas.

Nonfunctioning Pituitary Adenoma Recurrence and Its Relationship with Sex, Size, and Hormonal Immunohistochemical Profile.

BACKGROUND: Tumor recurrence or incomplete resection in nonfunctioning pituitary adenomas (NFPAs) is relatively common. However, predictive factors of tumor recurrence in NFPAs are not well established. We evaluated possible factors related to tumor recurrence in a large cohort of NFPAs at a single pituitary neurosurgery center. METHODS: A retrospective analysis was conducted of 410 medical records of patients with NFPAs treated by transsphenoidal surgery between 2000 and 2014. RESULTS: Among the participants, 210 were female (51.0%). A total of 14.1% had giant adenomas. Null-cell pituitary adenomas (n = 239; 58.9%) were the most frequent, followed by silent gonadotroph adenomas (n = 112; 27.3%). Null-cell adenomas were more frequent in women (P = 0.008) and silent gonadotroph adenomas were more frequent in men (P = 0.004). Recurrence was not related to sex or age. Tumor recurrence occurred more often among silent corticotropic adenomas and giant adenomas (hazard ratio 2.45; P < 0.0001 and hazard ratio 2.35; P = 0.001, respectively). Silent thyrotrophic adenoma presented a comparable frequency of recurrence of silent corticotropic adenomas, despite having borderline significance (P = 0.07). CONCLUSIONS: NFPA tumors have a high heterogeneous hormonal profile and may have prognostic importance. Silent corticotropic adenomas and giant adenomas present a high rate of recurrence.

MicroRNAs in pituitary tumors.

Since the presence of microRNAs was first observed in normal pituitary, the majority of scientific publications addressing their role and the function of microRNAs in the pituitary have been based on pituitary tumor studies. In this review, we briefly describe the involvement of microRNAs in the synthesis of pituitary hormones and we present a comprehensive inventory of microRNA suppressors and inducers of pituitary tumors. Finally, we summarize the functional role of microRNAs in tumorigenesis, progression and aggressiveness of pituitary tumors, mechanisms contributing to the regulation (transcription factors, genomic modifications or epigenetic) or modulation (pharmacological treatment) of microRNAs in these tumors, and the interest of thoroughly studying the expression of miRNAs in body fluids.

SOX2 regulates the hypothalamic-pituitary axis at multiple levels.

Sex-determining region Y (SRY) box 2 (SOX2) haploinsufficiency causes a form of hypopituitarism in humans that is characterized by gonadotrophin deficiency known as hypogonadotrophic hypogonadism. Here, we conditionally deleted Sox2 in mice to investigate the pathogenesis of hypogonadotrophic hypogonadism. First, we found that absence of SOX2 in the developing Rathke pouch of conditional embryos led to severe anterior lobe hypoplasia with drastically reduced expression of the pituitary-specific transcription factor POU class 1 homeobox 1 (POU1F1) as well as severe disruption of somatotroph and thyrotroph differentiation. In contrast, corticotrophs, rostral-tip POU1F1-independent thyrotrophs, and, interestingly, lactotrophs and gonadotrophs were less affected. Second, we identified a requirement for SOX2 in normal proliferation of periluminal progenitors; in its absence, insufficient precursors were available to produce all cell lineages of the anterior pituitary. Differentiated cells derived from precursors exiting cell cycle at early stages, including corticotrophs, rostral-tip thyrotrophs, and gonadotrophs, were generated, while hormone-producing cells originating from late-born precursors, such as somatotrophs and POU1F1-dependent thyrotrophs, were severely reduced. Finally, we found that 2 previously characterized patients with SOX2 haploinsufficiency and associated hypogonadotrophic hypogonadism had a measurable response to gonadotropin-releasing hormone (GnRH) stimulation, suggesting that it is not the absence of gonadotroph differentiation, but rather the deficient hypothalamic stimulation of gonadotrophs, that underlies typical hypogonadotrophic hypogonadism.

Transdifferentiation of pituitary thyrotrophs to lactothyrotrophs in primary hypothyroidism: case report.

Primary hypothyroidism causes adenohypophysial hyperplasia via stimulation by hypothalamic thyrotropin-releasing hormone (TRH). The effect was long thought to simply result in thyroid-stimulating hormone (TSH) and prolactin (PRL) cell hyperplasia, an increase in TSH and PRL blood levels with resultant pituitary enlargement, often mimicking adenoma. Recently, it was shown that transformation of growth hormone (GH) cells into TSH cells takes place in both clinical and experimental primary hypothyroidism. Such shifts from one cell to another with a concomitant change in hormone production are termed "transdifferentiation" and involve the gradual acquisition of morphologic features of thyrotrophs ("somatothyrotrophs"). We recently encountered a unique case of pituitary hyperplasia in a 40-year-old female with primary hypothyroidism wherein increased TSH production was by way of PRL cell recruitment. The resultant "lactothyrotrophs" maintained TSH cell morphology (cellular elongation and prominence of PAS-positive lysosomes) but expressed immunoreactivity for both hormones. No co-expression of GH was noted nor was thyroidectomy cells seen. This form of transdifferentiation has not previously been described.

In vivo and in vitro response to octreotide LAR in a TSH-secreting adenoma: characterization of somatostatin receptor expression and role of subtype 5.

Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of pituitary adenomas. Medical therapy with somatostatin analogues (SSAs) effectively reduces TSH secretion in approximately 80% of patients and induces shrinkage in about 45% of tumors. According with previous data, resistance to SSA treatment might be due to heterogeneity in somatostatin receptors (SSTRs) expression. We report the case of TSHoma in a 41-year-old man treated with octreotide LAR that caused a dramatic decrease of TSH and thyroid hormones and tumor shrinkage already after 3 months of pre-surgical therapy. In search of potential molecular determinants of octreotide effectiveness, we measured, in primary cultures from this tumor, SSTR and dopamine D2 receptor (D2R) expression, and octreotide and/or cabergoline effects on TSH secretion and cell proliferation. SSTR5 and D2R expression was higher than SSTR2. Octreotide significantly inhibited TSH secretion more effectively than cabergoline (P<0.001), whereas the combined treatment was comparable with cabergoline alone. Similarly, octreotide resulted more effective than cabergoline on cell proliferation, while the combination did not show any additive or synergistic effects. In conclusion, the significant antisecretive and antiproliferative effect of octreotide in this patient might be related to the high expression of SSTR5, in the presence of SSTR2. After reviewing the literature, indeed, in line with previous observations, we hypothesize that SSTR5/SSTR2 ratio in TSHomas may represent a useful marker in predicting the outcome of therapy with SSAs. The role of D2R should be further explored considering that the presence of D2R can influence SSTRs functionality.

Tumores hipofisários secretores de TSH: relato de dois casos e revisão da literatura / TSH-secreting pituitary tumors: two case reports and literature review

INTRODUÇÃO: Tumores hipofisários secretores de hormônio estimulante da tireoide (TSH), tireotropinomas, são raros e correspondem a menos de 2 por cento de todos os adenomas da hipófise. Manifestam-se clinicamente com sintomas e sinais de tireotoxicose, eventualmente associados a sintomas compressivos, sobretudo visuais, devido ao efeito de massa do tumor. Esses tumores se caracterizam pela presença de níveis séricos elevados de hormônios tireoidianos e níveis séricos elevados, ou inapropriadamente normais, de TSH. Frequentemente, ao diagnóstico, há relato de tratamento prévio cirúrgico, medicamentoso e/ou ablativo, por hipótese de hipertireoidismo primário por doença de Graves. OBJETIVO: Relatar dois casos de tireotropinomas acompanhados na Unidade de Neuroendocrinologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP) e revisar a literatura visando ao manejo desta afecção. CONCLUSÃO: Na presença de hormônios tireoidianos elevados e níveis de TSH inapropriadamente normais ou elevados, a possibilidade de adenoma hipofisário produtor de TSH deve ser considerada com vistas à realização da terapia adequada.

INTRODUCTION: TSH-secreting pituitary adenomas are rare pituitary functioning tumors accounting for less than 2 percent of the pituitary adenomas. The clinical feature consists of thyrotoxicosis occasionally associated to tumoral symptoms due to mass effect. The biochemical feature consists of elevated thyroid hormones levels and normal or high TSH concentrations. This disease is often wrongly diagnosed as Grave's disease, and the ablative therapy is frequently conducted prior to the diagnosis. OBJECTIVE: To report two cases followed in the Neuroendocrine Unit of Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo and to review the literature aiming at the management of this affection. CONCLUSION: In the presence of elevated thyroid hormone levels associated with inappropriate normal or increased TSH levels, the possibility of a TSH-secreting pituitary adenoma should be considered for the proper medical treatment.

Analysis of hypertrophic thyrotrophs in pituitaries of athyroid Pax8-/- mice.

Thyroid hormone is important for pituitary development and maintenance. We previously reported that in the Pax8(-/-) mouse model of congenital hypothyroidism, lactotrophs are almost undetectable, whereas the thyrotrophs exhibit hyperplasia and hypertrophy. Because the latter might be caused by an overstimulation of thyrotrophs with TRH, we analyzed TRH-R1(-/-)Pax8(-/-) double-knockout mice, which miss a functional thyroid gland and the TRH transducing receptor-1 at pituitary target sites. Interestingly, in these double mutants, the hypertrophy and hyperplasia of the thyrotrophs still persist, suggesting that the phenotype is rather a direct consequence of the athyroidism of the animals. The increased expression of TSH in the Pax8(-/-) mice was paralleled by a strongly up-regulated expression of deiodinase type 2 (Dio2) in thyrotrophic cells. Moreover, coexpression of TSH and Dio2 could also be demonstrated in the pituitary of wild-type mice, underlining the important role of this enzyme in the negative feedback regulation of TSH by thyroid hormone. As another consequence of the athyroidism in the mutant mice, tyrosine hydroxylase mRNA expression was found to be also highly up-regulated in thyrotrophic cells of the pituitaries from Pax8(-/-) mice, whereas the transcript levels in the hypothalamus were not affected. Accordingly, tyrosine hydroxylase protein levels, enzyme activities, and ultimately dopamine concentrations were found to be strongly increased in the pituitaries of Pax8(-/-) mice compared with wild-type animals. These findings may explain in part the reduced number of lactotrophs found in the pituitary of athyroid Pax8(-/-) mice and suggest a novel paracrine regulatory mechanism of lactotroph activity.

Coexistence of corticotroph adenoma and thyrotroph hyperplasia in a dog.

Pituitary thyrotroph hyperplasia results from prolonged primary hypothyroidism in humans, mice and rats. In dogs with Cushing's disease, many cases have low serum thyroid hormones concentrations due to euthyroid sick syndrome. A 6-year-old castrated male Beagle diagnosed with Cushing's disease had a high serum thyroid stimulating hormone (TSH) concentration that was treated by hypophysectomy. On histological examination, the resected pituitary gland contained both a corticotroph adenoma and thyrotroph hyperplasia. The TSH-positive cell ratio in this case was greater than that of healthy Beagles. In the present case, the pituitary thyrotroph hyperplasia was probably caused by primary hypothyroidism. In conclusion, this Beagle is the first histological confirmation of the coexistence of a corticotroph adenoma and thyrotroph hyperplasia.

[TSH-secreting pituitary tumors: two case reports and literature review]. / Tumores hipofisários secretores de TSH: relato de dois casos e revisão da literatura.

INTRODUCTION: TSH-secreting pituitary adenomas are rare pituitary functioning tumors accounting for less than 2% of the pituitary adenomas. The clinical feature consists of thyrotoxicosis occasionally associated to tumoral symptoms due to mass effect. The biochemical feature consists of elevated thyroid hormones levels and normal or high TSH concentrations. This disease is often wrongly diagnosed as Grave's disease, and the ablative therapy is frequently conducted prior to the diagnosis. OBJECTIVE: To report two cases followed in the Neuroendocrine Unit of Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo and to review the literature aiming at the management of this affection. CONCLUSION: In the presence of elevated thyroid hormone levels associated with inappropriate normal or increased TSH levels, the possibility of a TSH-secreting pituitary adenoma should be considered for the proper medical treatment.

Thyrotropin secretion by thyrotropinomas is characterized by increased pulse frequency, delayed diurnal rhythm, enhanced basal secretion, spikiness, and disorderliness.

CONTEXT: Hormone secretion by somatotropinomas, corticotropinomas, and prolactinomas exhibits increased pulsatility and basal secretion, accompanied by greater disorderliness. OBJECTIVE: Our objective was to evaluate TSH secretion by thyrotropinomas with up-to-date analytical and mathematical tools. DESIGN: Twenty-four hour blood samplings at 10-min intervals in a clinical research laboratory in five patients with a thyrotropinoma and 10 healthy age- and gender-matched controls were performed. The obtained serum TSH profiles were analyzed with a new deconvolution method, approximate entropy, Cosinor analysis, and by quantification of spikiness. RESULTS: TSH burst frequency and basal secretion were increased in patients compared with controls. TSH secretion patterns in patients were more irregular than in controls, but the diurnal rhythm was preserved at a higher mean in all patients, although with a 2-h phase delay. CONCLUSION: TSH secretion by thyrotropinomas shares many characteristics with other pituitary hormone-secreting adenomas.

A case of atypical thyrotroph cell adenoma, which re-grew within 3 months after surgery and required multimodal treatment.

OBJECTIVE AND IMPORTANCE: Thyrotroph cell adenoma accounts for only 1% of all pituitary adenomas. This tumor is tough and firm because of significant interstitial fibrosis, and is difficult to remove. Atypical adenoma has an aggressive biological character, invades the surrounding structures, and grows rapidly. Atypical thyrotroph cell adenoma is extremely rare. CLINICAL PRESENTATION: A 32-year-old man presented with hyperthyroidism and bitemporal hemianopsia. Head magnetic resonance imaging revealed a large sellar tumor compressing the optic chiasma and invading the left cavernous sinus. INTERVENTION: Transsphenoidal surgery was performed and subtotal removal was achieved. Histological examination showed atypical thyrotroph cell adenoma. Gamma knife surgery was planned, but the tumor re-grew within 3 months, and reattached to the optic chiasma. Second transcranial surgery failed to remove residual tumor behind the pituitary stalk. Conventional irradiation followed by octreotide administration resulted in decreased tumor size and stable euthyroidism. The tumor has been controlled for 22 months since first surgery and diagnosis. CONCLUSION: Atypical thyrotroph cell adenoma has an aggressive biological character and grows rapidly. Multimodal treatment including medication and radiotherapy is required.

TSH-secreting adenomas: rare pituitary tumors with multifaceted clinical and biological features.

TSH-secreting pituitary adenomas (TSH-omas) are a rare cause of hyperthyroidism in clinical practice. As their diagnosis is often delayed, these tumors are mostly diagnosed as macroadenomas, preventing an effective and radical cure and leading to serious local and systemic comorbidities. In addition to neurosurgery, medical therapy with the effective and tolerable SS analogs is a fundamental tool for the treatment of TSHomas. We report 3 cases of TSH-macroadenomas which displayed different clinical presentations. All patients showed increased free-thyroid hormone levels with inappropriately normal (2 patients) or high (1 patient) TSH levels. Magnetic resonance imaging (MRI)/computed tomography (CT) evidenced a pituitary macroadenoma and octreoscan was positive in all patients. In the 2 patients who underwent neurosurgery, hormonal hypersecretion by the tumor normalized. Histology showed nuclear pleomorphism and fibrosis, whereas immunohistochemistry showed positivity for TSH and, in a lesser amount, for FSH. In one of these patient (case 1), however, the presence of a tumor remnant inside the left cavernous sinus prompted us, in accordance with the patient, to start therapy with octreotide- long-acting release. As the third patient had a cardiac comorbidity which contraindicated neurosurgery, he underwent satisfactory treatment with long-acting SS analogs alone which normalized thyroid hormone levels. In this case, previous treatment with amiodarone confused and delayed the correct diagnosis of TSH-oma. As a result of improved laboratory and morphological techniques, TSH-omas should currently be diagnosed in early stages, thus enabling most patients to be managed satisfactorily through a combined approach.

Somatostatin receptor subtypes mRNA in TSH-secreting pituitary adenomas: a case showing a dramatic reduction in tumor size during short octreotide treatment.

TSH-secreting adenoma is a rare pituitary adenoma, and the expression levels of the specific subtypes of somatostatin receptors (sstr) mRNAs have remained obscure. To determine the quantitative expression of the sstr1-5 mRNAs in TSH-secreting adenomas that may be related to the efficacy of treatment with a somatostatin analogue, expression of the sstr1-5 mRNAs was examined and compared in TSH-secreting adenomas and other pituitary adenomas. The pituitary adenomas were obtained at transsphenoidal surgery from 4 cases of TSH-secreting adenoma, including 1 patient showing a significant shrinkage of the tumor size after only 10 days of octreotide treatment, 2 patients without tumor size reduction and 1 patient without treatment, and 5 GH-secreting adenomas, 6 prolactinomas, 5 nonfunctioning adenomas, 4 ACTH-secreting adenomas and normal pituitaries at autopsy from 4 normal subjects. In comparison to the normal pituitary, sstr2A>sstr1>sstr5>sstr3 mRNAs were expressed in the TSH-secreting adenomas examined. No expression of sstr2B or sstr4 mRNA was observed. The expression level of sstr2 mRNA was significantly higher than those in normal pituitary, prolactinomas, ACTH-secreting and nonfunctioning pituitary adenomas. The patient with marked shrinkage of the tumor showed the highest expression of both sstr2 and sstr5 mRNAs among all the cases of pituitary adenoma. A TSH-secreting tumor without shrinkage showed a similar expression level of sstr2 mRNA. These findings demonstrated that TSH-secreting adenomas express sstr1, 2A, 3 and 5 mRNAs, predominantly sstr2A, and in addition to the expression of sstr2 mRNA, the expression level of sstr5 mRNA may be a factor affecting the tumor shrinkage by somatostatin analogues against TSH-secreting adenomas.