RESUMO
LIM homeobox 4 (LHX4) is a transcription factor crucial for anterior pituitary (AP) development. Patients with LHX4 mutation suffer from combined pituitary hormone deficiency (CPHD), short statures, reproductive and metabolic disorders and lethality in some cases. Lhx4-knockout (KO) mice fail to develop a normal AP and die shortly after birth. Here, we characterize a zebrafish lhx4-KO model to further investigate the importance of LHX4 in pituitary gland development and regulation. At the embryonic and larval stages, these fish express lower levels of tshb mRNA compared with their wildtype siblings. In adult lhx4-KO fish, the expressions of pituitary hormone-encoding transcripts, including growth hormone (gh), thyroid stimulating hormone (tshb), proopiomelanocortin (pomca) and follicle stimulating hormone (fshb), are reduced, the pomca promoter-driven expression in corticotrophs is dampened and luteinizing hormone (lhb)-producing gonadotrophs are severely depleted. In contrast to Lhx4-KO mice, Lhx4-deficient fish survive to adulthood, but with a reduced body size. Importantly, lhx4-KO males reach sexual maturity and are reproductively competent, whereas the females remain infertile with undeveloped ovaries. These phenotypes, which are reminiscent of those observed in CPHD patients, along with the advantages of the zebrafish for developmental genetics research, make this lhx4-KO fish an ideal vertebrate model to study the outcomes of LHX4 mutation.
Assuntos
Hipopituitarismo , Proteínas com Homeodomínio LIM , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Peixe-Zebra/genética , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Proteínas com Homeodomínio LIM/deficiência , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/deficiência , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Masculino , Feminino , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/deficiência , Técnicas de Inativação de Genes , Hipófise/metabolismo , Modelos Animais de Doenças , Animais Geneticamente ModificadosRESUMO
Objective: Individuals with hypopituitarism (HPs) have an increased risk of developing non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) due to growth hormone deficiency (GHD). We aimed to investigate the possible mechanisms underlying the relationship between GHD and NAFLD using proteomic and metabolomic insights. Methods: Serum metabolic alternations were assessed in male HPs using untargeted metabolomics. A rat model of HP was established through hypophysectomy, followed by recombinant human growth hormone (rhGH) intervention. The mechanisms underlying GHD-mediated NAFLD were elucidated through the application of label-free proteomics and phosphorylation proteomics. Results: Metabolomic analysis revealed that biomarkers of mitochondrial dysfunction and oxidative stress, such as alanine, lactate, and creatine, were significantly elevated in HPs compared to age-matched controls. In rats, hypophysectomy led to marked hepatic steatosis, lipid peroxidation, and reduced glutathione (GSH), which were subsequently modulated by rhGH replacement. Proteomic analysis identified cytochrome P450s, mitochondrial translation elongation, and PPARA activating genes as the major distinguishing pathways in hypophysectomized rats. The processes of fatty acid transport, synthesis, oxidation, and NADP metabolism were tightly described. An enhanced regulation of peroxisome ß-oxidation and ω-oxidation, together with a decreased NADPH regeneration, may exacerbate oxidative stress. Phosphoproteome data showed downregulation of JAK2-STAT5B and upregulation of mTOR signaling pathway. Conclusions: This study identified proteo-metabolomic signatures associated with the development of NAFLD in pituitary GHD. Evidence was found of oxidative stress imbalance resulting from abnormal fatty acid oxidation and NADPH regeneration, highlighting the role of GH deficiency in the development of NAFLD.
Assuntos
Hipopituitarismo , Metabolômica , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo , Proteômica , Animais , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Ratos , Hipopituitarismo/metabolismo , Hipopituitarismo/etiologia , Ratos Sprague-Dawley , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/metabolismo , HumanosRESUMO
PURPOSE: Disorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause. METHODS: Detailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings. RESULTS: By trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a gene region resulted in early embryonic lethality in homozygous mice. mRNA expression of ER-stress genes ATF4 and CHOP was increased in the children, suggesting defective protein transport. The pLI score of the gene, from gnomAD data, is 0.02. CONCLUSIONS: SEC31A might underlie a previously unrecognised clinical syndrome comprising gonadal dysgenesis, multiple pituitary hormone deficiencies, dysmorphic features and developmental delay. However, a variant that remains undetected, in a different gene, may alternatively be causal in this family.
Assuntos
Disgenesia Gonadal , Hipopituitarismo , Animais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Camundongos , Disgenesia Gonadal/genética , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Camundongos Knockout , Linhagem , Hormônios Hipofisários/deficiência , Hormônios Hipofisários/genética , Proteínas de Transporte Vesicular/genéticaRESUMO
Pituitary hormone deficiency, hypopituitarism, is a dysfunction resulting from numerous etiologies, which can be complete or partial, and is therefore heterogeneous. This heterogeneity makes it difficult to interpret the results of scientific studies with these patients.Adequate treatment of etiologies and up-to-date hormone replacement have improved morbidity and mortality rates in patients with hypopituitarism. As GH replacement is not performed in a reasonable proportion of patients, especially in some countries, it is essential to understand the known consequences of GH replacement in each subgroup of patients with this heterogeneous dysfunction.In this review on hypopituitarism, we will address some particularities regarding insulin resistance, which is no longer common in these patients with hormone replacement therapy based on current guidelines, metabolic syndrome and its relationship with changes in BMI and body composition, and to vascular complications that need to be prevented taking into account the individual characteristics of each case to reduce mortality rates in these patients.
Assuntos
Hipopituitarismo , Resistência à Insulina , Síndrome Metabólica , Humanos , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/complicações , Terapia de Reposição Hormonal , Doenças Vasculares/etiologia , Doenças Vasculares/metabolismo , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/metabolismoRESUMO
Importance: Pituitary adenomas are neoplasms of the pituitary adenohypophyseal cell lineage and include functioning tumors, characterized by the secretion of pituitary hormones, and nonfunctioning tumors. Clinically evident pituitary adenomas occur in approximately 1 in 1100 persons. Observations: Pituitary adenomas are classified as either macroadenomas (≥10 mm) (48% of tumors) or microadenomas (<10 mm). Macroadenomas may cause mass effect, such as visual field defects, headache, and/or hypopituitarism, which occur in about 18% to 78%, 17% to 75%, and 34% to 89% of patients, respectively. Thirty percent of pituitary adenomas are nonfunctioning adenomas, which do not produce hormones. Functioning tumors are those that produce an excess of normally produced hormones and include prolactinomas, somatotropinomas, corticotropinomas, and thyrotropinomas, which produce prolactin, growth hormone, corticotropin, and thyrotropin, respectively. Approximately 53% of pituitary adenomas are prolactinomas, which can cause hypogonadism, infertility, and/or galactorrhea. Twelve percent are somatotropinomas, which cause acromegaly in adults and gigantism in children, and 4% are corticotropinomas, which secrete corticotropin autonomously, resulting in hypercortisolemia and Cushing disease. All patients with pituitary tumors require endocrine evaluation for hormone hypersecretion. Patients with macroadenomas additionally require evaluation for hypopituitarism, and patients with tumors compressing the optic chiasm should be referred to an ophthalmologist for formal visual field testing. For those requiring treatment, first-line therapy is usually transsphenoidal pituitary surgery, except for prolactinomas, for which medical therapy, either bromocriptine or cabergoline, is usually first line. Conclusions and Relevance: Clinically manifest pituitary adenomas affect approximately 1 in 1100 people and can be complicated by syndromes of hormone excess as well as visual field defects and hypopituitarism from mass effect in larger tumors. First-line therapy for prolactinomas consists of bromocriptine or cabergoline, and transsphenoidal pituitary surgery is first-line therapy for other pituitary adenomas requiring treatment.
Assuntos
Adenoma , Neoplasias Hipofisárias , Adulto , Criança , Feminino , Humanos , Gravidez , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/metabolismo , Adenoma/terapia , Hormônio Adrenocorticotrópico/biossíntese , Bromocriptina/uso terapêutico , Cabergolina/uso terapêutico , Hormônio do Crescimento Humano/biossíntese , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Hipopituitarismo/terapia , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/terapia , Prolactinoma/diagnóstico , Prolactinoma/etiologia , Prolactinoma/metabolismo , Prolactinoma/terapiaRESUMO
Introduction: The pituitary gland, regulating various hormones, is central in the endocrine system. As spontaneous recovery from hypopituitarism is rare, and exogenous-hormone substitution is clumsy, pituitary replacement via regenerative medicine, using pluripotent stem cells, is desirable. We have developed a differentiation method that in mice yields pituitary organoids (POs) derived from human embryonic stem cells (hESC). Efficacy of these POs, transplanted subcutaneously into hypopituitary mice, in reversing hypopituitarism was studied. Methods: hESC-derived POs were transplanted into inguinal subcutaneous white adipose tissue (ISWAT) and beneath dorsal skin, a relatively avascular region (AR), of hypophysectomized severe combined immunodeficient (SCID) mice. Pituitary function was evaluated thereafter for ¾ 6mo, assaying basal plasma ACTH and ACTH response to corticotropin-releasing hormone (CRH) stimulation. Histopathologic examination of organoids 150d after transplantation assessed engraftment. Some mice received an inhibitor of vascular endothelial growth factor (VEGF) to permit assessment of how angiogenesis contributed to subcutaneous engraftment. Results: During follow-up, both basal and CRH-stimulated plasma ACTH levels were significantly higher in the ISWAT group (p < 0.001 - 0.05 and 0.001 - 0.005, respectively) than in a sham-operated group. ACTH secretion also was higher in the ISWAT group than in the AR group. Histopathologic study found ACTH-producing human pituitary-cell clusters in both groups of allografts, which had acquired a microvasculature. POs qPCR showed expression of angiogenetic factors. Plasma ACTH levels decreased with VEGF-inhibitor administration. Conclusions: Subcutaneous transplantation of hESC-derived POs into hypopituitary SCID mice efficaciously renders recipients ACTH-sufficient.
Assuntos
Células-Tronco Embrionárias Humanas , Hipopituitarismo , Doenças da Hipófise , Humanos , Camundongos , Animais , Células-Tronco Embrionárias Humanas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Camundongos SCID , Hipófise/metabolismo , Doenças da Hipófise/metabolismo , Hipopituitarismo/metabolismoRESUMO
OBJECTIVE: To describe the treatment and long-term outcomes of patients with acromegaly from all healthcare regions in Sweden. DESIGN AND METHODS: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991 to 2011. The latest clinical follow-up date was December 2012, while mortality data were collected for 28.5 years until June 2019. RESULTS: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy, and 39% medical treatment. At the 5- and 10-year follow-ups, insulin-like growth factor 1 levels were within the reference range in 69 and 78% of patients, respectively. In linear regression, the proportion of patients with biochemical control including adjuvant therapy at 10 years follow-up increased over time by 1.23% per year. The standardized mortality ratio (SMR) (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed between 1991 and 2000, SMR: 1.06 (0.85-1.33) nor between 2001 and2011, SMR: 0.87 (0.61-1.24). In contrast, non-controlled patients at the latest follow-up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively. CONCLUSIONS: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.
Assuntos
Acromegalia/terapia , Adenoma/terapia , Antineoplásicos Hormonais/uso terapêutico , Adenoma Hipofisário Secretor de Hormônio do Crescimento/terapia , Procedimentos Neurocirúrgicos , Somatostatina/análogos & derivados , Transtornos da Visão/fisiopatologia , Acromegalia/metabolismo , Adenoma/complicações , Adenoma/metabolismo , Adenoma/patologia , Adulto , Idoso , Causas de Morte , Quimioterapia Adjuvante , Feminino , Adenoma Hipofisário Secretor de Hormônio do Crescimento/complicações , Adenoma Hipofisário Secretor de Hormônio do Crescimento/metabolismo , Adenoma Hipofisário Secretor de Hormônio do Crescimento/patologia , Humanos , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Mortalidade , Modelos de Riscos Proporcionais , Radiocirurgia , Radioterapia , Radioterapia Adjuvante , Sistema de Registros , Suécia , Carga Tumoral , Transtornos da Visão/etiologia , Campos VisuaisRESUMO
Variants in transcription factor GLI2 have been associated with hypopituitarism and structural brain abnormalities, occasionally including holoprosencephaly (HPE). Substantial phenotypic variability and nonpenetrance have been described, posing difficulties in the counseling of affected families. We present three individuals with novel likely pathogenic GLI2 variants, two with truncating and one with a de novo missense variant p.(Ser548Leu), and review the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low-risk variants. Four Zn-finger variants: p.(Arg479Gly), p.(Arg516Pro), p.(Gly518Lys), and p.(Tyr575His) were classified as likely pathogenic, and three other variants as possibly pathogenic: p.(Pro253Ser), p.(Ala593Val), and p.(Pro1243Leu). We analyze the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants and evidence a morbidity spectrum that includes hypopituitarism (58%), HPE (6%) or other brain structure abnormalities (15%), orofacial clefting (17%) and dysmorphic facial features (35%). We establish that truncating and Zn-finger variants in GLI2 are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the GLI2-related phenotypic variability. The most prevalent phenotypic feature is post-axial polydactyly (65%) which is also the mildest phenotypic expression of the condition, reported in many parents of individuals with systemic findings. Our approach clarifies clinical risks and the important messages to discuss in counseling for a pathogenic GLI2 variant.
Assuntos
Holoprosencefalia , Hipopituitarismo , Holoprosencefalia/genética , Humanos , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Mutação , Proteínas Nucleares/genética , Fenótipo , Zinco , Proteína Gli2 com Dedos de Zinco/genéticaRESUMO
Aging and age-related diseases represent hot topics of current research. Progressive damage in morphology and function of cells and tissue characterizes the normal process of aging that is influenced by both genetic and environmental factors. The ability of each individual to adapt to these stressors defines the type of aging and the onset of age-related diseases (i.e., metabolic syndrome, inflammatory disorders, cancer, and neurodegenerative diseases). The endocrine system plays a critical role in this process because of its complex relationships with brain, immune system, and skeletal muscle; thus, alterations in hormonal networks occur during aging to maintain homeostasis, with consequent under- or overactivity of specific hypothalamic-pituitary-peripheral hormone axes. On the other hand, the increase in life expectancy has led to increasing incidence of age-related diseases, including endocrine disorders, which may prompt assessment of endocrine function in aging individuals. In this context, there is growing awareness that natural changes of endocrine physiology and physiopathology occurring with increasing age may necessitate age-driven diagnostic cutoffs requiring validation in the elderly. This review aims to analyze the available literature on the hormone response to the most important dynamic tests currently used in the clinical practice for the screening of anterior pituitary-related diseases to underline pitfalls in interpretation during aging.
Assuntos
Envelhecimento/metabolismo , Hipopituitarismo/diagnóstico , Hipopituitarismo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Animais , Testes de Química Clínica , HumanosRESUMO
Growth hormone (GH) deficiency is a common pituitary hormone deficiency in childhood cancer survivors (CCS). The identification, diagnosis, and treatment of those individuals at risk are important in order to minimize associated morbidities that can be ameliorated by treatment with recombinant human GH therapy. However, GH and insulin-like growth factor-I have been implicated in tumorigenesis, so there has been concern over the use of GH therapy in patients with a history of malignancy. Reassuringly, GH therapy has not been shown to increase risk of tumor recurrence. These patients have an increased risk for development of meningiomas, but this may be related to their history of cranial irradiation rather than to GH therapy. In this review, we detail the CCS who are at risk for GHD and the existing evidence on the safety profile of GH therapy in this patient population.
Assuntos
Neoplasias Encefálicas , Sobreviventes de Câncer , Hormônio do Crescimento Humano/deficiência , Adulto , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/terapia , Sobreviventes de Câncer/estatística & dados numéricos , Criança , Irradiação Craniana/efeitos adversos , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/metabolismo , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/epidemiologia , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Fatores de RiscoRESUMO
Growth hormone (GH) deficiency (GHD) in children is defined as impaired production of GH by the pituitary gland that results in growth failure. This disease might be congenital or acquired, and occurs in isolation or in the setting of multiple pituitary hormone deficiency. Isolated GHD has an estimated prevalence of 1 patient per 4000-10,000 live births and can be due to multiple causes, some of which are yet to be determined. Establishing the correct diagnosis remains key in children with short stature, as initiating treatment with recombinant human GH can help them attain their genetically determined adult height. During the past two decades, our understanding of the benefits of continuing GH therapy throughout the transition period from childhood to adulthood has increased. Improvements in transitional care will help alleviate the consequent physical and psychological problems that can arise from adult GHD, although the consequences of a lack of hormone replacement are less severe in adults than in children. In this Review, we discuss the differential diagnosis in children with GHD, including details of clinical presentation, neuroimaging and genetic testing. Furthermore, we highlight advances and issues in the management of GHD, including details of transitional care.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hipopituitarismo/diagnóstico , Hipopituitarismo/terapia , Estatura/genética , Criança , Diagnóstico Diferencial , Humanos , Hipopituitarismo/metabolismo , Hipófise/metabolismo , Transição para Assistência do AdultoRESUMO
Pituitary hormone deficiency occurs in â¼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.
Assuntos
Ensaios de Triagem em Larga Escala/métodos , Hipopituitarismo/patologia , Mutação , Hormônios Hipofisários/deficiência , Splicing de RNA/genética , Fator de Transcrição Pit-1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Masculino , LinhagemRESUMO
Pituitary hormone axes modulate glucose metabolism and exert direct or indirect effects on insulin secretion and function. Cortisol and growth hormone are potent insulin-antagonistic hormones. Therefore impaired glucose tolerance, elevated fasting glucose concentrations and diabetes mellitus are frequent in Cushing's disease and acromegaly. Also prolactinomas, growth hormone (GH) deficiency, hypogonadism and hypothyroidism might be associated with impaired glucose homeostasis but usually to a lesser extent. Therefore glucose metabolism needs to be closely monitored and treated in patients with pituitary adenomas. Correction of the pituitary dysfunction is frequently followed by improvement of glucose homeostasis.
Assuntos
Intolerância à Glucose/metabolismo , Hipopituitarismo/metabolismo , Insulina/metabolismo , Hormônios Hipofisários/metabolismo , Glicemia , HumanosRESUMO
OBJECTIVE: Growth hormone (GH) replacement alters the peripheral interconversion of thyroxine (T4) and triiodothyronine (T3). However, little is known about the clinical impact of these alterations. We aimed to compare changes observed in the serum T3:T4 ratio with known biological markers of thyroid hormone action derived from different peripheral tissues. DESIGN: We prospectively studied twenty GH deficient men before and after GH replacement in a tertiary referral endocrine center. Serum biochemical measurements included insulin like growth factor-1 (IGF-1), thyroid hormones (free & total T3, free & total T4 and reverse T3) and TSH. Changes in thyroid hormone concentration were compared to alterations in hepatic and bone biomarkers of thyroid hormone action. RESULTS: GH replacement provoked a decline in serum free T4 concentration (-1.09 ± 1.99 pmol/L; p = 0.02) and an increase in free T3 (+0.34 ± 0.15 pmol/L; p = 0.03); therefore, the free T3:free T4 ratio increased from 0.40 ± 0.02 to 0.47 ± 0.02 (p = 0.002). Sex hormone binding globulin (SHBG) level was unchanged. However, a decline in serum ferritin (-26.6 ± 8.5 ng/mL; p = 0.005) correlated with a fall in freeT4. Alterations in lipid profile, including a rise in large HDL sub-fractions and Lp (a) (+2.1 ± 21.1 nmol/L; p = 0.002) did not correlate with thyroid hormone levels. Significant increases were recorded in serum bone turnover markers - procollagen type 1 amino-terminal propeptide +57.4%; p = 0.0009, osteocalcin +48.6%; p = 0.0007; c-terminal telopeptides of type 1 collagen +73.7%; p = 0.002. Changes in bone formation markers occurred in parallel with fluctuations in thyroid hormone. CONCLUSION: GH-induced alterations in the thyroid axis are associated with complex, tissue specific effects on thyroid hormone action. Modulation of bone turnover markers suggests that GH may improve the biological action of thyroid hormone on bone.
Assuntos
Remodelação Óssea , Terapia de Reposição Hormonal/métodos , Hormônio do Crescimento Humano/uso terapêutico , Hipopituitarismo/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Globulina de Ligação a Hormônio Sexual/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Adenoma/complicações , Adenoma/metabolismo , Adulto , Idoso , Osso e Ossos/metabolismo , Colágeno Tipo I/metabolismo , Ferritinas/metabolismo , Hormônio do Crescimento Humano/deficiência , Humanos , Hipopituitarismo/metabolismo , Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/metabolismo , Lipoproteína(a)/metabolismo , Lipoproteínas HDL/metabolismo , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Osteocalcina/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptídeos/metabolismo , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/metabolismo , Pró-Colágeno/metabolismo , Estudos Prospectivos , Tiroxina/uso terapêutico , Adulto JovemRESUMO
Fungal infections involving the pituitary gland are rare and can be life threatening. A 75-year-old man with hypertension and diabetes mellitus presented with headache and hyponatraemia. Imaging study showed right upper lung mass, and mass resection showed aspergilloma without tissue invasion on histology. The patient developed visual impairment a few weeks later, and MRI of the brain revealed bilateral sphenoid sinusitis and pituitary invasion. The trans-sphenoidal biopsy confirmed invasive Aspergillus infection. His sphenoidal sinuses were endoscopically debrided, and he was treated with oral voriconazole. Pituitary aspergillosis should be considered in the differential diagnosis in patients with lung aspergilloma with headache and sinusitis. Prompt biopsy and antifungal treatment are important due to the high mortality rate of the infection.
Assuntos
Síndrome de Secreção Inadequada de HAD/diagnóstico , Neuroaspergilose/diagnóstico , Doenças da Hipófise/diagnóstico , Aspergilose Pulmonar/diagnóstico por imagem , Idoso , Antifúngicos/uso terapêutico , Complicações do Diabetes , Diabetes Mellitus , Endoscopia , Cefaleia/etiologia , Hemoptise/etiologia , Humanos , Hipertensão , Hiponatremia/etiologia , Hipopituitarismo/diagnóstico , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Síndrome de Secreção Inadequada de HAD/etiologia , Síndrome de Secreção Inadequada de HAD/metabolismo , Imageamento por Ressonância Magnética , Masculino , Neuroaspergilose/complicações , Neuroaspergilose/tratamento farmacológico , Neuroaspergilose/metabolismo , Doenças da Hipófise/complicações , Doenças da Hipófise/tratamento farmacológico , Doenças da Hipófise/metabolismo , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/cirurgia , Insuficiência Renal Crônica , Sinusite Esfenoidal/complicações , Sinusite Esfenoidal/diagnóstico , Sinusite Esfenoidal/terapia , Cirurgia Torácica Vídeoassistida , Voriconazol/uso terapêuticoRESUMO
BACKGROUND: Giant pituitary adenoma (≥4 cm) is a rare tumor whose clinical features and prognosis are not well known. AIM: To evaluate the clinical characteristics and therapeutic outcomes of giant non-functioning PA (gNFPA). PATIENTS AND METHODS: A retrospective multicenter study of gNFPA patients diagnosed in a 12-year period was performed. In each patient, clinical data and therapeutic outcomes were registered. RESULTS: Forty patients (24 men, age 54.2 ± 16.2 years) were studied. The maximum tumor diameter [median (interquartile range)] was 4.6 cm (4.1-5.1). Women had larger tumors [4.8 cm (4.2-5.4) vs. 4.5 cm (4.0-4.9); p=0.048]. Hypopituitarism [partial (n=22, 55%) or complete (n=9, 22.5%)] at diagnosis was present in 77.5% of the patients. Visual field defects were found in 90.9%. The most used surgical technique was endoscopic endonasal transsphenoidal (EET) surgery (n=31, 77.5%). Radiotherapy was used in 11 (27.5%) patients (median dose 50.4 Gy, range 50-54). Thirty-seven patients were followed for 36 months (10-67 months). Although more than half of these patients showed tumor persistence (n=25, 67.6%), tumor size was significantly reduced [0.8 cm (0-2.5); p<0.001]. At last visit, 12 patients (32.4%) showed absence of tumor on MRI. Hypopituitarism rate was similar (75.0%), although with significant changes (p<0.001) in the distribution of the type of hypopituitarism. The absence of tumor at the last visit was positively associated with positive immunohistochemical staining for FSH (p=0.01) and LH (p=0.006) and negatively with female sex (p=0.011), cavernous sinus invasion (p=0.005) and the presence of Knosp grade 4 (p=0.013). CONCLUSION: gNFPAs are more frequent in men but tumors are larger in women. Surgical treatment is followed by a complete tumor resection rate of approximately 30%. Positive immunostaining for gonadotropins is associated with tumor absence at last revision, while female sex and invasion of the cavernous sinuses with tumor persistence.
Assuntos
Adenoma , Hipopituitarismo , Avaliação de Resultados em Cuidados de Saúde , Neoplasias Hipofisárias/cirurgia , Transtornos da Visão , Campos Visuais/fisiologia , Adenoma/complicações , Adenoma/patologia , Adenoma/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Hipopituitarismo/cirurgia , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/patologia , Estudos Retrospectivos , Transtornos da Visão/etiologia , Transtornos da Visão/fisiopatologia , Transtornos da Visão/terapiaRESUMO
Several different proteins regulate, directly or indirectly, the production of growth hormones from the pituitary gland, thereby complex genetics is involved. Defects in these genes are related to the deficiency of growth hormones solely, or deficiency of other hormones, secreted from the pituitary gland including growth hormones. These studies can aid clinicians to trace the pattern of the disease between the families, start early treatment and predict possible future consequences. This paper highlights some of the most common and novel genetic anomalies concerning growth hormones, which are responsible for various genetic defects in isolated growth and combined pituitary hormone deficiency disease.
Assuntos
Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética , Pediatria/métodos , Doenças da Hipófise/genética , Doenças da Hipófise/metabolismo , Nanismo Hipofisário/diagnóstico , Nanismo Hipofisário/genética , Nanismo Hipofisário/metabolismo , Humanos , Hipopituitarismo/diagnóstico , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Doenças da Hipófise/diagnósticoRESUMO
Hypopituitarism is defined as one or more partial or complete pituitary hormone deficiencies, which are related to the anterior and/or posterior gland and can have an onset in childhood or adulthood. The most common aetiology is a sellar or suprasellar lesion, often an adenoma, which causes hypopituitarism due to tumour mass effects, or the effects of surgery and/or radiation therapy. However, other clinical conditions, such as traumatic brain injury, and autoimmune and inflammatory diseases, can result in hypopituitarism, and there are also genetic causes of hypopituitarism. Furthermore, the use of immune checkpoint inhibitors to treat cancer is increasing the risk of hypopituitarism, with a pattern of hormone defects that is different from the classic patterns and depends on mechanisms that are specific for each drug. Moreover, autoantibody production against the pituitary and hypothalamus has been demonstrated in studies investigating the development or worsening of some cases of hypopituitarism. Finally, evidence suggests that posterior pituitary damage can affect oxytocin secretion. The aim of this Review is to summarize current knowledge on non-classic and emerging causes of hypopituitarism, so as to help clinicians improve early identification, avoid life-threatening events and improve the clinical care and quality of life of patients at risk of hypopituitarism.
Assuntos
Hipofisite Autoimune/complicações , Lesões Encefálicas Traumáticas/complicações , Síndrome da Sela Vazia/complicações , Hipopituitarismo/etiologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Apoplexia Hipofisária/complicações , Hemorragia Subaracnóidea/complicações , Adenoma/complicações , Hormônio Adrenocorticotrópico/deficiência , Hormônio Adrenocorticotrópico/genética , Nanismo Hipofisário/genética , Doenças do Sistema Endócrino/genética , Doenças Genéticas Inatas/genética , Humanos , Hipoglicemia/genética , Hipogonadismo/genética , Hipofisite/complicações , Hipopituitarismo/induzido quimicamente , Hipopituitarismo/genética , Hipopituitarismo/metabolismo , Hipotireoidismo/genética , Ocitocina/metabolismo , Neoplasias Hipofisárias/complicaçõesRESUMO
Cranial radiotherapy induces endocrine disorders and reproductive abnormalities, particularly in long-term female cancer survivors, and this might in part be caused by injury to the pituitary gland, but the underlying mechanisms are unknown. The aim of this study was to investigate the influence of cranial irradiation on the pituitary gland and related endocrine function. Female Wistar rat pups on postnatal day 11 were subjected to a single dose of 6 Gy whole-head irradiation, and hormone levels and organ structure in the reproductive system were examined at 20 weeks after irradiation. We found that brain irradiation reduced cell proliferation and induced persistent inflammation in the pituitary gland. The whole transcriptome analysis of the pituitary gland revealed that apoptosis and inflammation-related pathways were up-regulated after irradiation. In addition, irradiation led to significantly decreased levels of the pituitary hormones, growth hormone, adrenocorticotropic hormone, thyroid-stimulating hormone and the reproductive hormones testosterone and progesterone. To conclude, brain radiation induces reduction of pituitary and reproduction-related hormone secretion, this may due to reduced cell proliferation and increased pituitary inflammation after irradiation. Our results thus provide additional insight into the molecular mechanisms underlying complications after head irradiation and contribute to the discovery of preventive and therapeutic strategies related to brain injury following irradiation.
Assuntos
Irradiação Craniana , Hipopituitarismo/etiologia , Hipopituitarismo/metabolismo , Hipófise/metabolismo , Hipófise/efeitos da radiação , Hormônios Hipofisários/biossíntese , Hormônio Adrenocorticotrópico/biossíntese , Animais , Biomarcadores , Proliferação de Células/efeitos da radiação , Biologia Computacional/métodos , Irradiação Craniana/efeitos adversos , Modelos Animais de Doenças , Ciclo Estral/efeitos da radiação , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos da radiação , Hipopituitarismo/patologia , Imuno-Histoquímica , Hipófise/patologia , Hormônios Hipofisários/deficiência , Lesões por Radiação/complicações , Ratos , Transdução de Sinais/efeitos da radiação , Transcriptoma , Proteína Supressora de Tumor p53/metabolismoRESUMO
OBJECTIVES: Variants in fibroblast growth factor receptor-1 (FGFR1) may either cause isolated hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS). Although the relationship of genes classically involved in IHH with combined pituitary hormone deficiency (CPHD) is well established, variants in FGFR1 have been presented as a rare cause of this phenotype recently. CASE PRESENTATION: Herein, we report an adopted 16-year-old male presented with delayed puberty and micropenis. He had undergone surgery for bilateral undescended testes in childhood. He was normosmic, and the pituitary imaging was normal. However, hypogonadotropic hypogonadism and growth hormone deficiency were detected, associated with a heterozygous nonsense variant (c.1864 C>T, p.R622X) in FGFR1. CONCLUSIONS: FGFR1 variants are among the causes of IHH and KS, which are inherited in an autosomal dominant manner and can be associated with midline defects. It should also be kept in mind that CPHD may be associated with FGFR1 variants in a subject with normal olfactory function.