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.
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.
The syndrome of growth hormone deficiency (GHD) in adulthood is characterized by adverse changes in body composition, reduced exercise capacity and quality of life, alterations in cardiovascular function as well as in lipid and carbohydrate metabolism. There is enough evidence to support long-term effects of recombinant human GH therapy on fracture risk, lipid metabolism parameters, body composition, and overall quality of life in adults with GHD, with low probability of side effects at currently suggested doses. Nevertheless, the endocrinologist's role in the careful selection of recombinant human GH therapy candidates, based on clinical characteristics, risk factors, degree of quality of life impairment, patient's ability and willingness to adhere to therapy, is of most importance in order to achieve the best efficacy and the greatest therapeutic safety.
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.
Methods to assess quality of life and recovery after endoscopic endonasal surgery (EES) for sellar lesions are limited and often biased by subjective patient-reported assessments. Objective in-situ assessments are lacking. Smartphone-based digital phenotyping has been increasingly studied across a variety of pathologies, utilizing built-in technologies to measure behavioral patterns pertaining to sleep, physical mobility, social interactions, and cognitive functioning, among others. We report our experience with smartphone-based digital phenotyping in two acromegalic patients treated with EES. Beiwe application was applied pre-operatively to passively collect global position system data in the pre- and postoperative period, including daily distance traveled, maximal distance traveled from home, number of separate places visited outside of home, and overall time spent at home. This study demonstrates the feasibility of DP for a small sample of acromegalic patients undergoing EES based on passively collected smartphone global position system data during the peri-operative period. This is part of a larger, ongoing study enrolling surgical patients as well as non-operative controls for comparison aimed at predicting postoperative outcomes with in-situ tool.
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.
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.
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.
Growth hormone deficiency (GHD) is one the most common and early endocrine complications in children and adolescent undergoing surgery for hypothalamic-pituitary neoplasm. Etiological factors include tumor mass effect, hypothalamic/pituitary damage caused by surgery and/or radiation therapy. The diagnosis and treatment of patients with brain tumors is extremely complex and requires close monitoring by a multidisciplinary expert team that must define the most appropriate treatment type and timing according to patient and tumor features, including GH replacement treatment (GH-rT), through the harmonization of the criteria used to define when the neoplastic disease is stable and when and how to start and stop GH-rT, in order to improve patient outcome and quality of life. Despite several proofs of safety, GH-rT remains a matter of debate.
Acromegaly is a chronic and progressive disorder caused by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess, responsible for the onset of multiple systemic complications. Targets of acromegaly treatment are the normalization of hormonal (GH/IGF-1) parameters, the removal/reduction/stabilization of the pituitary mass, the control of existing conditions, and the prevention of new ones, so to improve quality of life and normalize life expectancy. Patients often require a multimodal therapeutic approach, including surgery, medical therapy, and radiotherapy, that allows disease cure/control in the majority of the cases. However, some pituitary tumors are resistant to treatments and/or recur. Novelties in the field of medical treatment in acromegaly can be summarized as follows: (a) new protocols applied to existing medications; (b) new devices to administer old drugs; (c) new formulations, and (d) new drugs. In this review, we aim at summarizing the current protocols and drugs to treat acromegaly (standard of care), and presenting the new pharmacological options including those drugs that are still being tested and could be released in the market in the next few years.
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.
Transition is the time encompassing the achievement of full height and complete somatic development, representing a period of physical, psychological, and social changes. Considering the beginning of social adaptation, the research of independence, and the desire to manage health conditions, the acceptance of chronic care should be poor. Patients affected by growth hormone deficiency (GHD), characterized by heterogeneity in diagnosis, high comorbidity burden, need for daily injections, and lack of biological markers during follow-up, could have a high drop-out rate. Replacement treatment is meaningful because, even if GHD is not life-threatening, it could represent a risk for long-term metabolic, cardiovascular, bone, and psychosocial complications with, eventually, a reduction in quality of life. Moreover, the diagnosis is not always straightforward, since the studies on stimulation tests are limited, or molecules are lacking, cutoffs are often not validated in transition patients, and follow-up requires attention in specific cases (i.e., cancer survivors). The present review aims to describe the features of GHD during transition, focusing on etiologies, pitfalls in diagnosis, GH replacement therapy, and follow-up issues.
A fair shred of evidence supports the mutual relationship between the hypothalamus-pituitary testis axis and the growth hormone (GH) pathway. Nevertheless, the role of GH on male sexual function and fertility is controversial, due to conflicting data from literature. The present review summarizes the available andrological consequences of two pathological extremes, i.e., either GH excess or deficiency. GH excess drives different disorders of male sexual health. On one hand, it indirectly favors the onset of erectile dysfunction (40.2% of cases) mostly by its detrimental vascular and metabolic effects, while testosterone levels don't appear as a key factor. On the other hand, GH excess directly impairs fertility, leading to secondary hypogonadism. Of note, compared to controls, this condition adversely affects the main sperm parameters, i.e., sperm concentration (p = 0.00), progressive motility (p = 0.03), and normal morphology (p = 0.02). Although with limited evidence, GH deficiency also fosters erectile dysfunction, while its effect on fertility is still unclear. On the whole, the available literature shows that any GH disorder plays a negative role in both male general and sexual health. Nevertheless, the potential benefit of testosterone replacement therapy in this population has not yet been explored.
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.
Subjects: Neoplasms--drug therapy | Antineoplastic Agents--adverse effects | Endocrine Glands--drug effects | Endocrine System Diseases--chemically induced Metabolic Networks and Pathways--drug
Long-term cancer survivors are at high risk of developing cardiac complications from the treatments, both systemic agents and thoracic irradiation, received to cure the primary tumor. Modern advances, particularly in the field of radiotherapy, aim to reduce the risk of cardiovascular disease. Also, new diagnostic tools increasingly improve their efficacy in early detection of the preclinical treatment-induced cardiac damage. In this review, we summarize the mechanisms of radiotherapy- and chemotherapy-induced cardiac injury, the available clinical data, the strategies to mitigate cardiac exposure with modern radiotherapy and the current diagnostic tools for an early detection and prompt management of these complications in long-term cancer survivors.
Growth hormone deficiency (GHD) is common in childhood cancer survivors (CCS). Major risk factors for GHD include radiation therapy, both cranial and total body irradiation, and tumor location. Some newer anti-cancer therapies may impact growth and the GH-IGF-1 axis as well. While untreated childhood-onset GHD adversely impacts adult height in CCS, longstanding GHD can cause or exacerbate multiple metabolic and skeletal health problems. This chapter discusses considerations in the diagnosis and treatment of GHD in CCS and discusses long-term outcomes in survivors of childhood cancer who have GHD.
Diabetes mellitus (DM) is commonly found in cancer patients. The relationship between DM and cancer appears to be bidirectional: DM has been associated with an increased risk of developing several types of cancer while also cancer treatments, through the induction of metabolic derangements, can facilitate the onset of DM, or worsen glucose control. In particular, novel antineoplastic treatments such as immunotherapy and targeted therapies have been associated with both acute and long-term metabolic consequences. An adequate management of DM in cancer patients is pivotal, since DM can negatively affect the clinical outcomes of these subjects, being associated with worse survival. However, DM management in cancer patients may be challenging given the peculiarities of these conditions. Lower reliability of HbA1c, a thorough evaluation of the safety profile of antidiabetic drugs, and the need to adapt glycemic targets to patients' prognosis should be taken into consideration. Moreover, DM is commonly encountered also in the ever-growing population of cancer survivors, contributing to their increased cardiovascular risk. In conclusion, taking in consideration the lack of specific guidelines, the particular features of the condition, and the potential impact on prognosis, a multidisciplinary management of DM in cancer patients and survivors is warranted.
