Frontiers of hormone research最新文献

Acromegaly is a rare disorder characterized by chronic hypersecretion of growth hormone (GH) and, consequently, of its mediator, insulin-like growth factor 1 (IGF-1), due in >95% of the cases to a GH-secreting pituitary adenoma (PA)/Pituitary Neuroendocrine Tumor (PitNET). PAs/PitNETs are extremely heterogeneous for clinical, biochemical, radiological, intra-operative, and histological features and, differently from other histologically benign lesions, can cause significant morbidity because of locally aggressive behavior, resistance/recurrence after treatment, and, although very rarely, metastasization. PAs/PitNETs' classification and nomenclature have consistently changed in the course of time, reflecting knowledges about their complex biology, with the aim of stratifying patient risk and, therefore, uniform therapeutic strategies. According to the last WHO Classification, based on pituitary transcription factors (i.e., Pit-1, TPIT, and SF-1), GH-secreting PAs/PitNETs pertain to the Pit-1-lineage. Several subtypes can be distinguished, i.e., somatotroph (sparsely and densely granulated), mixed (mammosomatotroph, mixed somatotroph-lactotroph, and acidophilic stem cell), and plurihormonal (mature and immature Pit-1 lineage), based on hormone staining at immunohistochemistry and granulation, with distinct clinical and radiological features. Unfortunately, this classification does not fully reflect the spectrum of tumor phenotypes, does not consider the presence of drug-target receptors (i.e., somatostatin), nor molecular features that, on the contrary, have been increasingly demonstrated to influence biological behavior. Therefore, efforts of pituitary expert of the various disciplines are still necessary to reach a more comprehensive and detailed PitNET stratification to improve patient care through precision medicine.

Pituitary acrogigantism is a very rare disease that is caused by chronic growth hormone (GH) axis excess that begins during childhood and adolescence. As such, it represents one of the most severe manifestations of acromegaly. In most cases, acrogigantism is caused by a pituitary adenoma, but hyperplasia can also accompany the adenoma or rarely occur alone. Individual cases of pituitary acrogigantism due to peripheral neuroendocrine tumor-derived GH-secreting hormone excess that stimulates pituitary GH hypersecretion have been reported. About half of patients with pituitary acrogigantism carry an identifiable germline genetic alteration (pathogenic variants, copy number variations, alterations of topologically associated domains (TADs), mosaicism), making it one of the most genetically-determined endocrine tumors. Among the genetic causes, pathogenic variants in the AIP gene (30%), the TADopathy X-linked acrogigantism (10%), and McCune-Albright syndrome (5%) are the most frequent causes. Molecular alterations induced by these genetic and genomic changes lead to large aggressive somatotropinomas that occur at an early age, secrete abundant amounts of GH, and produce treatment-resistant increases in insulin-like growth factor 1. X-linked acrogigantism occurs in the first year of life and is usually present by the age of 36 months, whereas, McCune-Albright syndrome-related GH excess usually presents before 5 years of age. AIP-related pituitary acrogigantism has a median age at diagnosis of about 16 years of age. Patients with pituitary acrogigantism have a heavy burden of disease and a complex treatment journey; the need to control final height makes it imperative to provide a diagnosis and effective hormonal control as rapidly as possible. Multimodal therapy is often required, and this can be complicated by the need for medical therapies that are not labeled for use in the pediatric population.

Introduction: Endoscopic endonasal approach (EEA) plays a central role in the treatment of GH-secreting pituitary adenomas (PAs)/pituitary neuroendocrine tumors (PitNETs), allowing to treat not only micro- or regular macro- PAs/PitNEts, but also more complex cases, otherwise requiring a transcranial or other open approaches.

Materials and methods: All consecutive cases of GH-secreting PAs/PitNETs treated by EEA from May 1998 to June 2023 at our Institution were included. Patients clinical, bio-chemical, and neuroradiological features were considered, as well the surgical approach adopted for each case and its related complications. Surgical and endocrinological was determined at 3 months follow-up.

Results: Our series is composed of 356 patients (57.6% females, mean age: 47 ± 12.7 years old): 118 (33.1%) micro-, 180 (50.6%) regular macro- and 58 (16.3%) irregular/invasive PAs/PitNEts. Radical removal was achieved in 296 (83.1%) patients and biochemical control in 270 (75.8%) at 3 months follow-up. Better surgical results and higher hypersecretion remission rate were demonstrated for micro- and regular endo-/endosuprasellar PAs/PitNETs than for irregular ones (respectively p < 0.001 and p < 0.001). Higher complication and endocrinological function permanent worsening rates were observed in the group of tumors with a supradiaphragmatic extension.

Conclusions: Our study confirmed the efficacy and safety of EEA in the short-term follow-up in patients with GH-secreting PAs/PitNETs. This approach has demonstrated to be highly versatile, allowing to tailor the surgery to each specific case, with the aim of obtaining the radical removal and consequently the biochemical remission with minimal complications, patients discomfort, or endocrinological sequelae in a large number of cases.

Growth hormone deficiency can be congenital or acquired. While acquired cases are related to organic causes that affect the hypothalamic-pituitary axis, structural abnormalities may or may not be detected in congenital cases. Hence, brain magnetic resonance imaging (MRI) is paramount in this context since it reflects diverse pathological processes with prognostic importance. This article will discuss the neuroradiologist's perspective on pediatric growth hormone deficiency assessment. The most common hypothalamic-pituitary findings will be explored, based on a brief overview of the pituitary development as well as on a review of the normal pituitary gland MRI appearance and the technical requirements for adequate imaging of the sellar and supra-sellar regions.

The term 'fugitive acromegaly' was introduced by the neurosurgeons Bailey and Cushing in 1928 to describe subjects manifesting signs and symptoms of somatotroph hyperfunction with pituitary insufficiency. Currently, it identifies patients with subtle acromegalic dysmorphisms and inconsistent hormonal profile, possibly presenting only with hyperprolactinemia and related clinical symptoms. Patients have rapidly growing, locally invasive, relapsing pituitary macrotumors that can be classified as either acidophil stem cell tumors (ASCTs) or sparsely granulated somatotroph tumors (SGSTs), both of PIT1-lineage. ASCTs also express estrogen receptor (ER)α, show predominant prolactin (PRL) release, and less abundantly, growth hormone (GH). In contrast, SGSTs have moderately increased GH and IGF1 levels, but rarely PRL increase. ASCTs often present resistance to dopamine agonists, and long-acting somatostatin analogs are used. In contrast, SGSTs are often resistant to somatostatin analogues and instead are treated with the GH receptor antagonist pegvisomant. Differential diagnosis includes mammosomatotroph, mixed GH-/PRL-secreting, immature PIT1-lineage, and densely granulated somatotroph tumors. Studies in ER-sensitive rat tumoral mammosomatotroph cells (GH3, GH4C1) suggest that overexpression of chaperones in immature PIT1-/ER-expressing progenitors induces posttranscriptional conformational changes to tumor suppressors of the ERα and aryl hydrocarbon receptor pathways, like AIP, leading to the development of aggressive pituitary tumors like those causing fugitive acromegaly.

Acromegaly and gigantism are rare diseases, usually caused by a growth hormone-secreting pituitary adenoma, recently renamed GH-secreting pituitary neuroendocrine tumor (GH-PitNET). The transsphenoidal approach is the mainstay of treatment, although a non-negligible number of patients require a multimodal approach with neo-adjuvant or adjuvant medical and radiation therapy. Understanding the clinical complexity of acromegaly and gigantism is essential to improve treatment safety and success. A multidisciplinary skilled team is required to provide adequate pre-operative evaluation and management of the comorbidities associated with GH-PitNETs. Specific intraoperative surgical and anesthesiologic challenges (i.e., mucosal and bone hypertrophy, reduced intracarotid distance, and tumor invasiveness) to ensure maximal and safe resection. The same is for postoperative management to provide precise tumor histological characterization to be used in association with clinical-radiological and biochemical data to tailor patient management in terms of acromegaly control and treatment/prevention of comorbidities. This paper critically revises the indications and limitations of endoscopic transsphenoidal surgery for GH-PitNETs, discusses the frequently complex preoperative evaluation of patients with acromegaly, and analyzes the challenging aspects of the disease, underling the importance of a multidisciplinary framework, which should include a dedicated team of surgeons (neuro- and ENT-), endocrinologists, radiologists, pathologists, and anesthesiologists.

The past century witnessed the evolution of growth hormone (GH) treatment from pituitary-derived GH, available for treatment of selected cases of GH deficiency (GHD), to recombinant human GH (rhGH), currently approved for several clinical disorders besides GHD. Treatment with rhGH has a proven efficacy in improving short stature in patients affected by GHD, alongside beneficial effects on metabolic and bone health. Long-term safety of rhGH treatment has been intensively investigated, providing reassuring results, especially in patients treated for isolated GHD. The use of rhGH in supraphysiological doses in conditions other than GHD and the intrinsic risk factors associated with certain clinical conditions prompt the need to prolong surveillance studies on rhGH safety. Finally, long-acting rhGH formulations are being introduced into the market, with the goal of increasing adherence and reducing treatment burden for patients on rhGH treatment. In this review, we will discuss indications, efficacy, and safety profile of treatment with rhGH in pediatric patients affected by GHD. We will also briefly discuss the newer formulation of rhGH.

Somatostatin and its analogs have been for years a mainstay treatment for a variety of hypersecretory conditions and neoplasms of the endocrine system. This chapter summarizes their pharmacological properties, their indication in the context of acromegaly, and the best way to handle this class of drugs for the treatment of the patient with acromegaly.

The replacement therapy of growth hormone (GH) in adults suffering from GH deficiency (GHD) still presents several challenges and uncertainties for the clinical endocrinologist. The decision to initiate treatment for GHD in adults necessitates a careful and personalized evaluation of potential benefits and risks. Although improvements in body composition, bone health, cardiovascular risk factors, and quality of life have been observed, evidence supporting a reduction in cardiovascular events and mortality is still inadequate, and treatment expenses remain high. To optimize treatment outcomes while minimizing side effects, it is recommended to initiate GH replacement therapy with low doses, aiming for a proper clinical response and insulin-like growth factor-I levels within the age-appropriate reference range. Despite being generally safe, certain aspects of GH replacement therapy require continuous long-term monitoring, including the potential risks of glucose intolerance, recurrence of pituitary/hypothalamic tumors, and cancer.

Acromegaly is a chronic systemic disease, with a long clinical history, requiring a holistic approach to fully understand patient issues: the longer the time of disease activity, the greater will be the severity and number of complications. The duration of active disease is the major determinant of the onset and progression of complications. The variables that contribute to determine a decline in the quality of life of these patients are numerous and include disease duration, heterogeneity of complications, social context, and treatments. Complications are frequently found at the time of diagnosis that, unfortunately, is burdened by a significant delay since the appearance of the first symptoms in the majority of the cases. Normalization of insulin-like growth factor 1 and growth hormone levels, on the contrary, will lead to improvement, sometimes disappearance, of some complications, and the mortality of these patients will be equal to that of the general population. Therefore, improving clinician ability to early diagnose and treat acromegaly is of fundamental importance to improve patient quality and duration of life, as well as to optimize the utilization of Health System resources.