RESUMO
OBJECTIVE: Transsphenoidal surgery for lactotroph pituitary neuroendocrine tumor (PitNET) lowers serum prolactin concentrations, occasionally below the normal range. However, the clinical significance of postoperative hypoprolactinemia is still unclear. In this study, we retrospectively reviewed the female patients with lactotroph PitNET who were treated with transsphenoidal surgery to elucidate the influence of postoperative hypoprolactinemia on regular menstruation restoration and endocrinological remission. RESULTS: The serum prolactin levels in all thirty three participating females had decreased following surgery. Serum prolactin levels in seven patients had decreased below the lower limit of normal ranges (hypoproactinemia group) and in the remaining twenty six patients, it was within the normal range (non-hypoproractinemia group). In hypoprolactinemia group, regular menstruation was restored in all patients with only lactotroph axis deficiency. Nine patients from the non-hypoprolactinemia group experienced re-elevation of serum prolactin concentration (27%). No patient in hypoprolactinemia group experienced the relapse of hyperprolactinemia. These data suggest that early postoperative hypoprolactinemia after transsphenoidal surgery for lactotroph PitNET is not only a good predictive factor for endocrinological remission but also no unfavorable effects on regular menstruation restoration.
Assuntos
Menstruação , Neoplasias Hipofisárias , Prolactina , Humanos , Feminino , Neoplasias Hipofisárias/cirurgia , Prolactina/sangue , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Menstruação/fisiologia , Tumores Neuroendócrinos/cirurgia , Tumores Neuroendócrinos/sangue , Complicações Pós-Operatórias/etiologia , Lactotrofos , Hiperprolactinemia/sangue , Hiperprolactinemia/etiologia , Hiperprolactinemia/cirurgia , Hiperprolactinemia/fisiopatologia , Adulto JovemRESUMO
The pituitary is the central endocrine gland with effects on metabolic dysfunction-associated steatotic liver disease (MASLD). However, it is not clear whether the pituitary responds to free fatty acid (FFA) toxicity, thus dysregulating hepatic lipid metabolism. Here, we demonstrate that decreased prolactin (PRL) levels are involved in the association between FFA and MASLD based on a liver biospecimen-based cohort. Moreover, overloaded FFAs decrease serum PRL levels, thus promoting liver steatosis in mice with both dynamic diet intervention and stereotactic pituitary FFA injection. Mechanistic studies show that excessive FFA sensing in pituitary lactotrophs inhibits the synthesis and secretion of PRL in a cell-autonomous manner. Notably, inhibiting excessive lipid uptake using pituitary stereotaxic virus injection or a specific drug delivery system effectively ameliorates hepatic lipid accumulation by improving PRL levels. Targeted inhibition of pituitary FFA sensing may be a potential therapeutic target for liver steatosis.
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Ácidos Graxos não Esterificados , Fígado Gorduroso , Lactotrofos , Prolactina , Animais , Prolactina/metabolismo , Prolactina/sangue , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Camundongos , Lactotrofos/metabolismo , Lactotrofos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Humanos , Masculino , Metabolismo dos Lipídeos , Fígado/metabolismoRESUMO
The age-related alterations in pituitary function, including changes in prolactin (PRL) production contributes to the systemic susceptibility to age-related diseases. Our previous research has shown the involvement of Nrg1 in regulating the expression and secretion of PRL. However, the precise role of Nrg1 in mitigating the senescence of pituitary lactotrophs and the underlying mechanisms are yet to be comprehended. Here, data from the GEPIA database was used to evaluate the association between transient receptor potential cation channel subfamily M member 8 (TRPM8) and PRL in normal human pituitary tissues, followed by immunofluorescence verification using a human pituitary tissue microarray. TRPM8 levels showed a significant positive association with PRL expression in normal human pituitary tissues, and both TRPM8 and PRL levels declined during aging, suggesting that TRPM8 may regulate pituitary aging by affecting PRL production. It was also found that treatment with exogenous neuregulin 1 (Nrg1) markedly delayed the senescence of GH3 cells (rat lactotroph cell line) generated by D-galactose (D-gal). In addition, melatonin reduced the levels of senescence-related markers in senescent pituitary cells by promoting Nrg1 / ErbB4 signaling, stimulating PRL expression and secretion. Further investigation showed that Nrg1 attenuated senescence in pituitary cells by increasing TRPM8 expression. Downregulation of TRPM8 activation eliminated Nrg1-mediated amelioration of pituitary cell senescence. These findings demonstrate the critical function of Nrg1 / ErbB signaling in delaying pituitary lactotroph cell senescence and enhancing PRL production via promoting TRPM8 expression under the modulation of melatonin.
Assuntos
Senescência Celular , Lactotrofos , Melatonina , Neuregulina-1 , Prolactina , Transdução de Sinais , Canais de Cátion TRPM , Prolactina/metabolismo , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPM/genética , Humanos , Senescência Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Lactotrofos/metabolismo , Lactotrofos/efeitos dos fármacos , Melatonina/farmacologia , Animais , Ratos , Neuregulina-1/metabolismo , Neuregulina-1/genética , Hipófise/metabolismo , Hipófise/efeitos dos fármacos , Envelhecimento/metabolismo , Receptor ErbB-4/metabolismo , Receptor ErbB-4/genética , Linhagem Celular , Masculino , FemininoRESUMO
INTRODUCTION: Lactotroph pituitary neuroendocrine tumors (PitNETs) are common pituitary tumors, but their underlying molecular mechanisms remain unclear. This study aimed to investigate the transcriptomic landscape of lactotroph PitNETs and identify potential molecular mechanisms and therapeutic targets through RNA sequencing and ingenuity pathway analysis (IPA). METHODS: Lactotroph PitNET tissues from five surgical cases without dopamine agonist treatment underwent RNA sequencing. Normal pituitary tissues from 3 patients served as controls. Differentially expressed genes (DEGs) were identified, and the functional pathways and gene networks were explored by IPA. RESULTS: Transcriptome analysis revealed that lactotroph PitNETs had gene expression patterns that were distinct from normal pituitary tissues. We identified 1,172 upregulated DEGs, including nine long intergenic noncoding RNAs (lincRNAs) belonging to the top 30 DEGs. IPA of the upregulated DEGs showed that the estrogen receptor signaling, oxidative phosphorylation signaling, and EIF signaling were activated. In gene network analysis, key upstream regulators, such as EGR1, PRKACA, PITX2, CREB1, and JUND, may play critical roles in lactotroph PitNETs. CONCLUSION: This study provides a comprehensive transcriptomic profile of lactotroph PitNETs and highlights the potential involvement of lincRNAs and specific signaling pathways in tumor pathogenesis. The identified upstream regulators may be potential therapeutic targets for future investigations.
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Perfilação da Expressão Gênica , Lactotrofos , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Análise de Sequência de RNA , Humanos , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/metabolismo , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/metabolismo , Lactotrofos/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Transcriptoma , Adulto , Redes Reguladoras de Genes , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
INTRODUCTION: This study sought to decipher the mechanism of transitions between life-history stages in a seasonally reproducing subtropical finch, Amandava amandava delineating the plasticity of the gonadotropes (LH cells), lactotropes (PRL cells), and thyrotropes (TSH cells) in the pituitary gland including the pars tuberalis, with regard to the in situ expression, morphological characteristics, and alteration in the plasma levels of hormones. METHODS: Immunohistochemistry of LH, PRL, TSH cells, morphometry and densitometry of expressed hormones (Image J software analysis), and ELISA for plasma hormonal levels were performed. RESULTS: LH, PRL, and TSH cells showed remarkable plasticity during the annual seasonal reproductive cycle. In the PT, all the 3 cell types were detected during the breeding phase, with additional detection of the TSH immunoreactivity during the pre-breeding and the PRL immunoreactivity during post-breeding phases. Pars distalis (PD) expressions and the plasma levels of the LH and TSH were at the peak during the breeding phase, but the PRL peak was during the post-breeding phase. In addition to PRL in the neurohypophysis and in the median eminence, hypothalamic PRL, and TSH were also elucidated. CONCLUSIONS: This study suggests activation of the gonadal axis by the PT TSH which might transduce seasonal cues, but not specifically photoperiod, in the birds of the tropics/subtropics. Post-breeding phase sustained high plasma TSH and peak plasma PRL might coordinate the transition to the non-breeding phase including the trigger of parental care as the later hormone assigned with. Hypothalamic TSH and PRL might influence events of seasonality through central modulation.
Assuntos
Tentilhões , Gonadotrofos , Hormônio Luteinizante , Prolactina , Reprodução , Estações do Ano , Tireotropina , Animais , Reprodução/fisiologia , Hormônio Luteinizante/sangue , Hormônio Luteinizante/metabolismo , Gonadotrofos/metabolismo , Gonadotrofos/fisiologia , Prolactina/sangue , Prolactina/metabolismo , Tentilhões/fisiologia , Tireotropina/sangue , Tireotropina/metabolismo , Lactotrofos/metabolismo , Lactotrofos/fisiologia , Masculino , Adeno-Hipófise/metabolismo , Feminino , Tireotrofos/metabolismo , Tireotrofos/fisiologiaRESUMO
OBJECTIVE: A somatic mutational hotspot in the SF3B1 gene was reported in lactotroph tumours. The aim of our study was to examine the prevalence of driver SF3B1 variants in a multicentre independent cohort of patients with lactotroph tumours and correlate with clinical data. DESIGN AND METHODS: This was a retrospective, multicentre study involving 282 patients with lactotroph tumours (including 6 metastatic lactotroph tumours) from 8 European centres. We screened SF3B1 exon 14 hotspot for somatic variants using Sanger sequencing and correlated with clinicopathological data. RESULTS: We detected SF3B1 variants in seven patients with lactotroph tumours: c.1874G > A (p.Arg625His) (n = 4, 3 of which metastatic) and a previously undescribed in pituitary tumours variant c.1873C > T (p.Arg625Cys) (n = 3 aggressive pituitary tumours). In two metastatic lactotroph tumours with tissue available, the variant was detected in both primary tumour and metastasis. The overall prevalence of likely pathogenic SF3B1 variants in lactotroph tumours was 2.5%, but when we considered only metastatic cases, it reached the 50%. SF3B1 variants correlated with significantly larger tumour size; higher Ki67 proliferation index; multiple treatments, including radiotherapy and chemotherapy; increased disease-specific death; and shorter postoperative survival. CONCLUSIONS: SF3B1 variants are uncommon in lactotroph tumours but may be frequent in metastatic lactotroph tumours. When present, they associate with aggressive tumour behaviour and worse clinical outcome.
Assuntos
Lactotrofos , Neoplasias Hipofisárias , Humanos , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/genética , Prevalência , Estudos Retrospectivos , Fatores de Transcrição , Fatores de Processamento de RNA/genética , FosfoproteínasRESUMO
In humans and mice, loss-of-function mutations in growth hormone-releasing hormone receptor (GHRHR) cause isolated GH deficiency. The mutant GHRHR mouse model, GhrhrLit/Lit (LIT), exhibits loss of serum GH, but also fewer somatotropes. However, how loss of GHRH signaling affects expansion of stem and progenitor cells giving rise to GH-producing cells is unknown. LIT mice and wild-type littermates were examined for differences in proliferation and gene expression of pituitary lineage markers by quantitative reverse transcription polymerase chain reaction and immunohistochemistry at postnatal day 5 (p5) and 5 weeks. At p5, the LIT mouse shows a global decrease in pituitary proliferation measured by proliferation marker Ki67 and phospho-histone H3. This proliferative defect is seen in a pituitary cell expressing POU1F1 with or without GH. SOX9-positive progenitors show no changes in proliferation in p5 LIT mice. Additionally, the other POU1F1 lineage cells are not decreased in number; rather, we observe an increase in lactotrope cell population as well as messenger RNA for Tshb and Prl. In the 5-week LIT pituitary, the proliferative deficit in POU1F1-expressing cells observed neonatally persists, while the number and proliferative proportion of SOX9 cells do not appear changed. Treatment of cultured pituitary explants with GHRH promotes proliferation of POU1F1-expressing cells, but not GH-positive cells, in a mitogen-activated protein kinase-dependent manner. These findings indicate that hypothalamic GHRH targets proliferation of a POU1F1-positive cell, targeted to the somatotrope lineage, to fine tune their numbers.
Assuntos
Lactotrofos , Doenças da Hipófise , Humanos , Animais , Camundongos , Animais Recém-Nascidos , Hipófise , Proliferação de Células/genéticaRESUMO
Serum prolactin increases from birth to adulthood in rats, being higher in females from birth. The maturation of hypothalamic/gonadal prolactin-releasing and -inhibiting factors does not explain some sex differences observed. During the first weeks of life, prolactin secretion increases, even when lactotrophs are isolated in vitro, in the absence of those controls, suggesting the participation of intra-pituitary factors in this control. The present work aimed to study the involvement of pituitary activins in the regulation of prolactin secretion during post-natal development. Sex differences were also highlighted. Female and male Sprague-Dawley rats at 11, 23 and 45postnatal days were used. Pituitary expression of activin subunits and activin receptors was maximum in p11 female pituitaries, being even higher than that observed in males. Those expressions decrease with age in females, and then the gender differences disappear at p23. Inhbb expression strongly increases at p45 in males, being the predominant subunit in this sex in adulthood. Activin inhibition of prolactin is mediated by the inhibition of Pit-1 expression. This action involves not only the canonical pSMAD pathway but also the phosphorylation of p38MAPK. At p11, almost all lactotrophs express p-p38MAPK in females, and its expression decreases with age with a concomitant increase in Pit-1. Our findings suggest that the inhibitory regulation of pituitary activins on prolactin secretion is sex specific; this regulation is more relevant in females during the first week of life and decreases with age; this intra-pituitary regulation is involved in the sex differences observed in serum prolactin levels during postnatal development.
Assuntos
Lactotrofos , Prolactina , Feminino , Ratos , Masculino , Animais , Prolactina/metabolismo , Ativinas/metabolismo , Ratos Sprague-Dawley , Hipófise/metabolismo , Lactotrofos/metabolismo , Fatores de Transcrição/metabolismoAssuntos
Lactotrofos , Tumores Neuroendócrinos , Doenças da Hipófise , Neoplasias Hipofisárias , Sarcoma , Humanos , Lactotrofos/patologia , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/patologia , Neoplasias Hipofisárias/terapia , Neoplasias Hipofisárias/patologia , Hipófise/patologia , Sarcoma/patologiaRESUMO
Interest in epigenetics has gained substantial momentum as a result of their identified role in the regulation of tumor progression as well as their ability to pharmacologically target genes. Pituitary neuroendocrine tumors (PitNETs) tend to be inactivated via epigenetic modification, and although emerging evidence has suggested a role for epigenetic factors in PitNET tumorigenesis, the degree to which these factors may be targeted by new therapeutic strategies still remains poorly understood. The objective of the present study was to examine the participation of the EZH2/H3K27me3 axis in the proliferation of lactotroph tumor cells. We demonstrated that the levels of EZH2 and H3K27me3 were increased in murine experimental prolactin (PRL) tumors with respect to a control pituitary, in contrast with the low p21 mRNA levels encountered, with an H3K27me3 enrichment being observed in its promoter region in a GH3 tumor cell. Furthermore, specific EZH2/H3K27me3 axis inhibition blocked the proliferation of primary tumor cell culture and GH3 cells, thereby making it an attractive therapeutic target for PRL PitNETs.
Assuntos
Lactotrofos , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Humanos , Camundongos , Animais , Histonas/metabolismo , Lactotrofos/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Linhagem Celular Tumoral , Epigênese Genética , Proliferação de Células/genética , Neoplasias Hipofisárias/genética , Tumores Neuroendócrinos/genéticaRESUMO
Regulated exocytosis consists of the fusion between vesicles and the plasma membranes, leading to the formation of a narrow fusion pore through which secretions exit the vesicle lumen into the extracellular space. An increase in the cytosolic concentration of free Ca2+ ([Ca2+]i) is considered the stimulus of this process. However, whether this mechanism can be preserved in a simplified system of membrane lawns with docked secretory vesicles, devoid of cellular components, is poorly understood. Here, we studied peptide discharge from individual secretory vesicles docked at the plasma membrane, prepared from primary endocrine pituitary cells (the lactotrophs), releasing hormone prolactin. To label secretory vesicles, we transfected lactotrophs to express the fluorescent atrial natriuretic peptide (ANP.emd), previously shown to be expressed in and released from prolactin-containing vesicles. We used stimulating solutions containing different [Ca2+] to evoke vesicle peptide discharge, which appeared similar in membrane lawns and in intact stimulated lactotrophs. All vesicles examined discharged peptides in a subquantal manner, either exhibiting a unitary or sequential time course. In the membrane lawns, the unitary vesicle peptide discharge was predominant and slightly slower than that recorded in intact cells, but with a shorter delay with respect to the stimulation onset. This study revealed directly that Ca2+ triggers peptide discharge from docked single vesicles in the membrane lawns with a half-maximal response of â¼8 µM [Ca2+], consistent with previous whole-cell patch-clamp studies in endocrine cells where the rapid component of exocytosis, interpreted to represent docked vesicles, was fully activated at <10 µM [Ca2+]. Interestingly, the sequential subquantal peptide vesicle discharge indicates that fluctuations between constricted and dilated fusion pore states are preserved in membrane lawns and that fusion pore regulation appears to be an autonomously controlled process.
Assuntos
Lactotrofos , Ratos , Animais , Lactotrofos/metabolismo , Cálcio/metabolismo , Prolactina/metabolismo , Ratos Wistar , Fusão de Membrana/fisiologia , Peptídeos/metabolismo , Vesículas Secretórias/metabolismo , Exocitose/fisiologiaRESUMO
CONTEXT: Pituitary tumors are the third most common brain tumor and yet there is no standardization of the surveillance schedule and assessment modalities after transsphenoidal surgery. EVIDENCE ACQUISITION: OVID, EMBASE and the Cochrane Library databases were systematically screened from database inception to March 5, 2020. Inclusion and exclusion criteria were designed to capture studies examining detection of pituitary adenoma recurrence in patients 18 years of age and older following surgical resection with curative intent. EVIDENCE SYNTHESIS: A total of 7936 abstracts were screened, with 812 articles reviewed in full text and 77 meeting inclusion criteria for data extraction. A pooled analysis demonstrated recurrence rates at 1 year, 5 years and 10 years for non-functioning pituitary adenomas (NFPA; N = 3533 participants) were 1%, 17%, and 33%, for prolactin-secreting adenomas (PSPA; N = 1295) were 6%, 21%, and 28%, and for growth-hormone pituitary adenomas (GHPA; N = 1257) were 3%, 8% and 13%, respectively. Rates of recurrence prior to 1 year were 0% for NFPA, 1-2% for PSPA and 0% for GHPA. The mean time to disease recurrence for NFPA, PSPA and GHPA were 4.25, 2.52 and 4.18 years, respectively. CONCLUSIONS: This comprehensive review of the literature quantified the recurrence rates for commonly observed pituitary adenomas after transsphenoidal surgical resection with curative intent. Our findings suggest that surveillance within 1 year may be of low yield. Further clinical trials and cohort studies investigating cost-effectiveness of surveillance schedules and impact on quality of life of patients under surveillance will provide further insight to optimize follow-up.
Assuntos
Adenoma , Lactotrofos , Neoplasias Hipofisárias , Somatotrofos , Humanos , Adolescente , Adulto , Neoplasias Hipofisárias/cirurgia , Neoplasias Hipofisárias/patologia , Lactotrofos/patologia , Somatotrofos/patologia , Qualidade de Vida , Recidiva Local de Neoplasia/epidemiologia , Adenoma/cirurgia , Adenoma/patologia , Estudos RetrospectivosRESUMO
Granulomatous hypophysitis is a rare and poorly understood condition. Although certain cases are treated as primary pituitary autoimmune disorders, rare cases may be associated with pituitary neuroendocrine tumours (PitNETs) and systemic inflammatory diseases. Here, we report a case of a 47-year-old man that underwent endoscopic trans-sphenoidal excision of a pituitary mass diagnosed as PitNET. On histologic evaluation, the neoplasm showed an admixture of granulomas with extensive inflammatory infiltrate and lactotroph PitNET/adenoma. Careful anamnestic examination revealed a diagnosis of Crohn's disease 20 years prior. Although rarely done, both PitNET and Crohn's disease may be associated with granulomatous hypophysitis, and our patient had both conditions. During the 6-year follow-up, PitNETs and hypophysitis did not recur, while Crohn's disease was only partially controlled by medical therapy. To our knowledge, this is the first description of association of granulomatous hypophysitis, PitNET and Crohn's disease.
Assuntos
Doença de Crohn , Hipofisite , Lactotrofos , Neoplasias Hipofisárias , Prolactinoma , Masculino , Humanos , Pessoa de Meia-Idade , Doença de Crohn/complicações , Recidiva Local de Neoplasia/complicações , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico , Hipofisite/complicações , Hipofisite/diagnóstico , Prolactinoma/complicaçõesRESUMO
Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by the lactotroph cells of the pituitary. There are two main isoforms of PRL: 23-kDa PRL (named full-length PRL) and vasoinhibins (including 5.6-18 kDa fragments). Both act as circulating hormones and cytokines to stimulate or inhibit vascular formation at different stages and neovascularization, including endothelial cell proliferation and migration, protease production, and apoptosis. However, their effects on vascular function and cardiovascular diseases are different or even contrary. In addition to the structure, secretion regulation, and signal transduction of PRL/vasoinhibins, this review focuses on the pathological mechanism and clinical significance of PRL/vasoinhibins in cardiovascular diseases.
Assuntos
Doenças Cardiovasculares , Prolactina , Humanos , Lactotrofos , Hipófise/fisiologia , Prolactina/química , Prolactina/fisiologia , Isoformas de ProteínasRESUMO
Objective: A 22-year-old man complaining erectile dysfunction underwent transsphenoidal surgery for a 2.7 cm sellar mass with total resection and was confirmed at pathology to have a lactotroph pituitary neuroendocrine tumor (PiNET). Postoperatively, the patient's PRL remained at high level and therefore accepted high-dose dopamine receptor agonist (DA) therapy. After over 3 months of bromocriptine (BRC) (15mg/day) and over 3 years of cabergoline (CAB) (3mg/week) therapy, the patient's prolactin (PRL) never achieved long-term normalization. He was diagnosed with DA-resistant lactotroph PitNET. Method: In this study, the patient was given hydroxychloroquine (HCQ) (200 mg/d) and CAB (3 mg/w) in combination for four months. His PRL level was tested by blood test every month. Results: Taking the combination therapy of HCQ and CAB, the patient's uncontrolled PRL level was normalized within one month and was maintained at the normal level thereafter. Pituitary magnetic resonance imaging (MRI) images with enhancement showed no recurrence. The patient also regained normal sexual function. Discussion: This is the first report on the combination of HCQ with CAB for the effective treatment of DA-resistant lactotroph pituitary neuroendocrine tumor in a patient, which might provide a novel treatment strategy for clinical management.
Assuntos
Lactotrofos , Tumores Neuroendócrinos , Neoplasias Hipofisárias , Prolactinoma , Adulto , Cabergolina/uso terapêutico , Ergolinas/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Lactotrofos/patologia , Masculino , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/cirurgia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/cirurgia , Prolactina , Prolactinoma/complicações , Prolactinoma/tratamento farmacológico , Prolactinoma/patologia , Adulto JovemRESUMO
This case report concerns a 31-year-old male with an aggressive pituitary tumor who presented initially with bitemporal hemianopsia and slightly elevated prolactin. On magnetic resonance imaging of the brain, there was a sellar mass with parasellar invasion to the lateral aspects of the internal carotid arteries, compressing the optic chiasm. On histopathological analysis, the diagnosis was made of a densely granulated lactotroph pituitary tumor with a Ki67 proliferation rate of 15%, a mitotic count of 6/10 high-power fields, and p53 positivity. Based on these features, the tumor was classified as a grade 2b tumor according to the Trouillas classification, and a more aggressive behavior of the tumor could be expected. In order to anticipate a future need for alternative drug treatments, the following analyses were undertaken: MGMT methylation (present) as well as the expression of estrogen receptor (negative), programmed-death ligand 1 (60 - 70% positive tumor cells), vascular endothelial growth factor-A and somatostatin receptor 2 (both positive). There was regrowth of residual tumor tissue, and the treatment consisted thus far of repeat surgery, cabergoline, pasireotide, and radiotherapy. Chemotherapy with temozolomide could not yet be initiated due to a concurrent infertility treatment. This case is unique because the tumor displays atypical characteristics, both in terms of morphology and behavior. It also illustrates how pathologists can play an important role in determining the diagnosis, prognosis, and possibilities for targeted therapy.
Assuntos
Lactotrofos , Neoplasias Hipofisárias , Adulto , Cabergolina/uso terapêutico , Humanos , Antígeno Ki-67 , Lactotrofos/patologia , Masculino , Neoplasias Hipofisárias/patologia , Prolactina/uso terapêutico , Receptores de Estrogênio/uso terapêutico , Proteína Supressora de Tumor p53/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/uso terapêuticoRESUMO
Among pituitary adenomas, prolactinomas are the most frequently diagnosed (about 50%). Dopamine agonists are generally effective in the treatment of prolactinomas. However, a subset of about 25% of patients does not respond to these agents. The management of drug-resistant prolactinomas remains a challenge for endocrinologists and new inhibitory treatments are needed. Pituitary activins inhibit lactotroph function. Its expression and action were found reduced in animal models of lactotroph hyperplasia (female mice overexpressing the B subunit of the human chorionic gonadotrophin and female mice knockout for dopamine receptor type 2). In these models, an oophorectomy avoids prolactinoma development. Hormonal replacement with oestradiol and/or progesterone is not enough to reach the tumor size observed in transgenic females. We postulated that the loss of gonadal inhibins after an oophorectomy contributes to prevent hyperplasia development. Here, we demonstrated that an oophorectomy at 2 months age recovers the following in adulthood: (i) pituitary activin expression, (ii) activin receptor expression specifically in lactotroph population, (iii) activin biological activity in lactotrophs with a concomitant reduction of Pit-1 expression. To summarize, when an oophorectomy is performed, inhibins are lost and the inhibitory action of pituitary activins on lactotroph population is recovered, helping to prevent lactotroph hyperplasia development. These results emphasize the importance of the inhibitory action of activins on lactotroph function, positioning activins as a good therapeutic target for the treatment of resistant prolactinomas.
Assuntos
Lactotrofos , Neoplasias Hipofisárias , Prolactinoma , Ativinas/metabolismo , Adulto , Animais , Feminino , Humanos , Hiperplasia , Inibinas/metabolismo , Inibinas/uso terapêutico , Lactotrofos/metabolismo , Lactotrofos/patologia , Camundongos , Ovariectomia , Neoplasias Hipofisárias/metabolismo , Prolactina/metabolismo , Prolactinoma/metabolismo , Prolactinoma/prevenção & controleRESUMO
Prolactin (PRL), a hormone involved in lactation, is mainly produced and secreted by the lactotrophs of the anterior pituitary (AP) gland. We previously reported a method to generate functional adrenocorticotropic hormone-producing cells by differentiating the AP and hypothalamus simultaneously from human induced pluripotent stem cells (iPSCs). However, PRL-producing cells in the induced AP have not been investigated. Here, we confirmed the presence of PRL-producing cells and evaluated their endocrine functions. We differentiated pituitary cells from human iPSCs using serum-free floating culture of embryoid-like aggregates with quick reaggregation (SFEB-q) method and evaluated the appearance and function of PRL-producing cells. Secretion of PRL from the differentiated aggregates was confirmed, which increased with further culture. Fluorescence immunostaining and immunoelectron microscopy revealed PRL-producing cells and PRL-positive secretory granules, respectively. PRL secretion was promoted by various prolactin secretagogues such as thyrotropin-releasing hormone, vasoactive intestinal peptide, and prolactin-releasing peptide, and inhibited by bromocriptine. Moreover, the presence of tyrosine hydroxylase-positive dopaminergic nerves in the hypothalamic tissue area around the center of the aggregates connecting to PRL-producing cells indicated the possibility of recapitulating PRL regulatory mechanisms through the hypothalamus. In conclusion, we generated pituitary lactotrophs from human iPSCs; these displayed similar secretory responsiveness as human pituitary cells in vivo. In the future, this is expected to be used as a model of human PRL-producing cells for various studies, such as drug discovery, prediction of side effects, and elucidation of tumorigenic mechanisms using disease-specific iPSCs. Furthermore, it may help to develop regenerative medicine for the pituitary gland.
Assuntos
Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/fisiologia , Lactotrofos/fisiologia , Adeno-Hipófise/citologia , Prolactina/biossíntese , Técnicas de Cultura de Células , Linhagem Celular , Proliferação de Células , Células Cultivadas , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Lactotrofos/efeitos dos fármacos , Hormônio Liberador de Prolactina/farmacologia , Hormônio Liberador de Tireotropina/farmacologia , Peptídeo Intestinal Vasoativo/farmacologiaRESUMO
BACKGROUND: Dopaminergic agonists (DA) are the first-line treatment in lactotroph pituitary tumor but treatment usually needs to be life-long. After surgical transsphenoid resection, remission rates range from 60 to 90%, with low morbidity. OBJECTIVE: The objective was to evaluate outcome of surgical treatment of selected non-invasive prolactinoma, and to identify factors associated with long-term remission. METHOD: Early postoperative (3 months) and last follow-up data for non-invasive lactotroph tumors operated on in intention-to-cure in our center between 2008 and 2017 were retrospectively reviewed: prolactin (PRL) level, DA treatment, pituitary function, and MRI data. Remission was defined as PRL plasma level below the upper limit of normal without DA treatment. RESULTS: Fifty-three of the 60 patients (32 of the 33 microadenomas) were in remission at 3 months and 46 (28/33 microadenomas) at last follow-up 22.7 months (range, 1.1-126.5 months) after surgery. Five-year recurrence-free survival was 77.5% [65.8-91.2]. Male gender, larger tumor size at diagnosis and before surgery, and higher plasma PRL level at diagnosis were all significantly associated with lower remission rates on univariate analysis. Transient diabetes insipidus and hyponatremia occurred in 2 and 5 patients respectively. One case of isolated thyrotroph insufficiency was observed. During follow-up, 13 women became pregnant (12 spontaneously). CONCLUSION: This cohort confirmed the high remission rate of lactotroph tumors after surgery in a selected population, with limited morbidity, and conserved pituitary function in almost all cases.