Diagnosing and treating the elderly individual with hypopituitarism.

Hypopituitarism in the elderly is an underestimated condition mainly due to the non-specific presentation that can be attributed to the effects of aging and the presence of comorbidities. Diagnosis and treatment of hypopituitarism often represent a challenging task and this is even more significant in the elderly. Diagnosis can be insidious due to the physiological changes occurring with aging that complicate the interpretation of hormonal investigations, and the need to avoid some provocative tests that carry higher risks of side effects in this population. Treatment of hypopituitarism has generally the goal to replace the hormonal deficiencies to restore a physiological balance as close as possible to that of healthy individuals but in the elderly this must be balanced with the risks of over-replacement and worsening of comorbidities. Moreover, the benefit of some hormonal replacement therapies in the elderly, including sex hormones and growth hormone, remains controversial.

Treating Hypopituitarism in the Over 65s: Review of Clinical Studies.

The current increase of life expectancy is associated with the presence of endocrine diseases in the elderly. The management of hypopituitarism in this group of patients is a challenging task. A correct diagnosis, which represents an essential requisite for an appropriate medical treatment, can be difficult because of the physiological changes occurring in pituitary function with aging, which may lead to challenges in the interpretation of laboratory results. Furthermore, the treatment requires several careful considerations: the need to restore the hormonal physiology with replacement therapies must be balanced with the need to avoid the risks of the over-replacement, especially in the presence of concomitant cardiovascular and metabolic disease. Interactions with other drugs able to modify the absorption and/or the metabolism of hormonal replacement therapies should be considered, in particular for the treatment of hypoadrenalism and hypothyroidism. The most important challenges stem from the lack of specific studies focused on the management of hypopituitarism in older people.

Bone Metabolism Effects of Medical Therapy in Advanced Renal Cell Carcinoma.

The medical therapy of advanced renal cell carcinoma (RCC) is based on the use of targeted therapies, such as tyrosine kinase inhibitors (TKI) and immune-checkpoint inhibitors (ICI). These therapies are characterized by multiple endocrine adverse events, but the effect on the bone is still less known. Relatively few case reports or small case series have been specifically focused on TKI and ICI effects on bone metabolism. However, the importance to consider these possible side effects is easily intuitable because the bone is one of the most frequent metastatic sites of RCC. Among TKI used in RCC, sunitinib and sorafenib can cause hypophosphatemia with increased PTH levels and low-normal serum calcium levels. Considering ICI, nivolumab and ipilimumab, which can be used in association in a combination strategy, are associated with an increased risk of hypocalcemia, mediated by an autoimmune mechanism targeted on the calcium-sensing receptor. A fearsome complication, reported for TKI and rarely for ICI, is osteonecrosis of the jaw. Awareness of these possible side effects makes a clinical evaluation of RCC patients on anticancer therapy mandatory, especially if associated with antiresorptive therapy such as bisphosphonates and denosumab, which can further increase the risk of these complications.

Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases that may cause cortisol insufficiency together with other hormonal alterations. The most common form is 21-hydroxylase deficiency, in which the lack of pituitary negative feedback causes an increase in ACTH and adrenal androgens. Classical forms of CAHs can lead to severe adrenal failure and female virilization. To date, the appropriate management of pregnant CAH patients is still debated regarding appropriate maternal therapy modifications during pregnancy and the risks and benefits of prenatal treatment of the fetus. We conducted a literature search of relevant papers to collect current evidence and experiences on the topic. The most recent and significant articles were selected, and current international guidelines were consulted to update current recommendations and guide clinical practice. Given the lack of randomized clinical trials and other high-quality scientific evidence, the issue is still debated, and great heterogeneity exists in current practice in terms of risk/benefit evaluation and pharmacological choices for pregnancy and prenatal treatment. Glucocorticoid therapy is advised not only in classical CAH patients but also in non-classical, milder forms. The choice of which glucocorticoid to use, and the safety and benefits of dexamethasone therapy aimed at preventing genital virilization are still debated issues. Several advances, however, have been made, especially in terms of fertility and reproduction. This review aims to present the most recent scientific and real-world updates on pregnancy and prenatal management of CAH, with the presentation of various clinical scenarios and specific case-by-case recommendations.

Prevalence of CAH-X Syndrome in Italian Patients with Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency.

21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), is associated with pathogenic variants in CYP21A2 gene. The clinical form of the disease ranges from classic or severe to non-classic (NC) or mild late onset. The CYP21A2 gene is located on the long arm of chromosome 6, within the RCCX region, one of the most complex loci in the human genome. The 3'untranslated sequence of CYP21A2 exon 10 overlap the last exon of TNXB gene (these genes lie on the opposite strands of DNA and have the opposite transcriptional direction) that encodes an extracellular matrix glycoprotein tenascin-X (TNX). A recombination event between TNXB and its pseudogene TNXA causes a 30 kb deletion producing a chimeric TNXA/TNXB gene (CAH-X chimera) where both CYP21A2 and TNXB genes are impaired. This genetic condition characterizes a subset of patients with 21OHD who display the hypermobility phenotype of Ehlers-Danlos syndrome (hEDS) (CAH-X Syndrome). The aim of this study was to assess the prevalence of CAH-X syndrome in an Italian cohort of patients with 21OHD. At this purpose, 196 probands were recruited. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were used to identify the CAH-X genotype. Twenty-one individuals showed the heterozygous continuous deletion involving the CYP21A2 and part of the TNXB gene. EDS-related clinical manifestations were identified in most patients carrying the CAH-X chimera. A CAH-X prevalence of 10.7% was estimated in our population.

Medullary Thyroid Cancer with Ectopic Cushing's Syndrome: A Case Report and Systematic Review of Detailed Cases from the Literature.

Background: Medullary thyroid cancer (MTC) is a neuroendocrine tumor arising from parafollicular C-cells of the thyroid gland that, in rare cases, can cause a paraneoplastic ectopic Cushing's syndrome (ECS). The development of Cushing's syndrome (CS) in MTC patients is generally associated with advanced disease and poor prognosis. Summary: We described a case of severe CS due to MTC in a young male. We performed a systematic review to identify cases of ECS due to MTC. We searched PubMed, Scopus, and Web of Science for publications between database inception and February 2022 and we collected the patient characteristics, disease presentation, employed treatment strategies, and disease outcomes. In addition to our patient, we identified 96 cases of ECS due to MTC reported in literature. Mean age at diagnosis was 44.4 years (range 10-84), and there was a male predominance (male:female [M:F] = 1.8:1). Most patients (51%) presented with metastatic disease at diagnosis and showed severe hypercortisolism. Seventeen patients developed distant metastasis and hypercortisolism during follow-up. Interestingly, in 48% of patients, the diagnosis of CS followed the diagnosis of MTC with a median time of 48 months but, among patients in whom the diagnosis was concomitant (38%), symptoms due to hypercortisolism were frequently the reason for seeking medical advice. Pathology results showed evidence of adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH) positive cells in 76% of patients in whom they were tested. The management of hypercortisolism was challenging in most patients with 48% requiring, eventually, definitive treatment with bilateral adrenalectomy (BLA). Recently, some limited evidence has emerged regarding tyrosine kinase inhibitors (TKIs) treatment for hypercortisolism in patients with ECS due to MTC. Despite limited information on survival, prognosis was generally poor and the main causes of death were either complications of CS or disease progression. Conclusions: Despite its rarity, MTC should be considered in the differential diagnosis of ECS. Management of hypercortisolism is a key factor to improve the patient's symptoms but it is often challenging and BLA is frequently required. Further studies are needed for investigating the role of TKIs in patients with MTC with ECS.

Genetic Basis of ACTH-Secreting Adenomas.

Cushing's disease represents 60-70% of all cases of Cushing's syndrome, presenting with a constellation of clinical features associated with sustained hypercortisolism. Molecular alterations in corticotrope cells lead to the formation of ACTH-secreting adenomas, with subsequent excessive production of endogenous glucocorticoids. In the last few years, many authors have contributed to analyzing the etiopathogenesis and pathophysiology of corticotrope adenomas, which still need to be fully clarified. New molecular modifications such as somatic mutations of USP8 and other genes have been identified, and several case series and case reports have been published, highlighting new molecular alterations that need to be explored. To investigate the current knowledge of the genetics of ACTH-secreting adenomas, we performed a bibliographic search of the recent scientific literature to identify all pertinent articles. This review presents the most recent updates on somatic and germline mutations underlying Cushing's disease. The prognostic implications of these mutations, in terms of clinical outcomes and therapeutic scenarios, are still debated. Further research is needed to define the clinical features associated with the different genotypes and potential pharmacological targets.

Grading Central Diabetes Insipidus Induced by Immune Checkpoint Inhibitors: A Challenging Task.

Central diabetes insipidus (CDI) is a rare endocrine disease deriving from an insufficient production or secretion of anti-diuretic hormone. Recently, CDI has been reported as a rare side effect triggered by immune checkpoint inhibitors (ICI) in cancer patients. Despite its current rarity, CDI triggered by ICI is expected to affect an increasing number of patients because of the expanding use of these effective drugs in a growing number of solid and hematologic malignancies. An appropriate assessment of the severity of adverse events induced by anticancer agents is crucial in their management, including dosing adjustment and temporary withdrawal or discontinuation treatment. However, assessment of the severity of CDI induced by ICI may be challenging, as its main signs and symptoms (polyuria, dehydration, weight loss, and hypernatremia) can be incompletely graded. Indeed, the current grading system of toxicity induced by anticancer treatments does not include polyuria. Additionally, dehydration in patients affected by diabetes insipidus, including ICI-induced CDI, is different in certain aspects from that due to other conditions seen in cancer patients, such as vomiting and diarrhea. This prompted us to reflect on the need to grade polyuria, and how to grade it, and to consider a specific grading system for dehydration associated with CDI induced by ICI. Here we propose a new grading system for polyuria and dehydration, as critical symptoms of the CDI syndrome occurring in patients on ICI treatment, to obtain better management of both the adverse event and the triggering drugs.

The biochemical diagnosis of acromegaly: revising the role of measurement of IGF-I and GH after glucose load in 5 questions.

INTRODUCTION: Acromegaly is a rare disorder characterized by the excessive secretion of growth hormone (GH), mostly caused by pituitary adenomas. While in full-blown cases the diagnosis is easy to establish, milder cases are more challenging. Additionally, establishing whether full cure after surgery is reached may be difficult. AREAS COVERED: In this article, we will review the challenges posed by the variability in measurements of GH and its main effector insulin-like growth factor I (IGF-I) due to both biological changes, co-morbidities, and assays variability. EXPERT OPINION: Interpretation of GH and IGF-I assays is important in establishing an early diagnosis of acromegaly, in avoiding misdiagnosis, and in establishing if cure is achieved by surgery. Physicians should be familiar with the variables that affect measurements of these 2 hormones, and with the performance of the assays available in their practice.

Immune Checkpoint Inhibitor-Induced Central Diabetes Insipidus: Looking for the Needle in the Haystack or a Very Rare Side-Effect to Promptly Diagnose?

Immune checkpoint inhibitors have improved the survival in patients affected by an increasing number of malignancies, but they may also trigger various autoimmune side-effects, including endocrinopathies. Very rarely, immune checkpoint inhibitors have been reported to cause central diabetes insipidus. However, with their expanding use, the likelihood that oncologists will face this endocrine adverse event is expected to increase. By reviewing the limited literature on central diabetes insipidus induced by immune checkpoint inhibitors, some inconsistencies emerge in the diagnosis and the management of patients presenting with this toxicity, together with difficulties related to classifying its severity. Until now, specific guidelines on the management of central diabetes insipidus induced by immune checkpoint inhibitors are lacking. In clinical practice, endocrinological consultation may relieve medical oncologists from difficulties in treating this side-effect; oncologists, however, remain responsible for its early diagnose and the management of the causative drugs. To this aim, some practical suggestions are advised for the multidisciplinary management of cancer patients presenting with central diabetes insipidus induced by immune checkpoint inhibitors.

Immune Checkpoint Inhibitors as a Threat to the Hypothalamus-Pituitary Axis: A Completed Puzzle.

Immune checkpoint inhibitors (ICI) prolong the survival in an increasing number of patients affected by several malignancies, but at the cost of new toxicities related to their mechanisms of action, autoimmunity. Endocrine toxicity frequently occurs in patients on ICI, but endocrine dysfunctions differ based on the ICI-subclass, as follows: agents targeting the CTLA4-receptor often induce hypophysitis and rarely thyroid dysfunction, which is the opposite for agents targeting the PD-1/PD-L1 axis. Recently, few cases of central diabetes insipidus have been reported as an adverse event induced by both ICI-subclasses, either in the context of anterior hypophysitis or as selective damage to the posterior pituitary or in the context of hypothalamitis. These new occurrences demonstrate, for the first time, that ICI-induced autoimmunity may involve any tract of the hypothalamic-pituitary axis. However, the related pathogenic mechanisms remain to be fully elucidated. Similarly, the data explaining the endocrine system susceptibility to primary and ICI-induced autoimmunity are still scarce. Since ICI clinical indications are expected to expand in the near future, ICI-induced autoimmunity to the hypothalamic-pituitary axis presents as a unique in vivo model that could help to clarify the pathogenic mechanisms underlying both the dysfunction induced by ICI to the hypothalamus-pituitary axis and primary autoimmune diseases affecting the same axis.

Discovery, preclinical development, and clinical application of pralsetinib in the treatment of thyroid cancer.

INTRODUCTION: The use of targeted drug therapies has substantially increased in the treatment of RET-mutated thyroid and other solid cancers over the last decade. Multi-Kinase Inhibitors (MKI) have been approved by FDA, but limited efficacies and side effects make them uneasy to tolerate. Pralsetinib is an oral highly selective RET inhibitor drug that has been generated and clinically validated to have higher potency and less toxicity. AREAS COVERED: The present paper offers a brief summary of RET-related thyroid cancer genetics, an overview of the preclinical development of pralsetinib and reviews its clinical validation in the treatment of thyroid cancer. EXPERT OPINION: Pralsetinib is a new generation oral treatment that has been approved by the FDA for patients with RET-mutated thyroid cancer. Pralsetinib showed a safer toxicity profile compared to previously approved MKI, probably due to lower inhibition of other tyrosine kinases, especially VEGFR. The approval study ARROW trial showed that patients with RET-mutant medullary thyroid cancer had a better overall response rate to pralsetinib compared to standard-of-care treatments. Additional clinical trials or data enrichment of existing databases are desirable in order to verify and further describe the clinical benefit of pralsetinib in such patients to fully understand its pharmacological profile.

The ancient Greek poet Sappho and the first case report of the fight-or-flight response.

Sappho has always been regarded as one of the greatest lyric poets of ancient Greece. Her famous poem Fragment 31 V., also known as the "Ode to Jealousy", accurately describes the profound emotional reaction triggered by the sight of her beloved. The poet's precise description of each sign and symptom triggered by this arousal makes Sappho 31 V., to the best of our knowledge, the first analytical description of the acute stress response, the so-called "fight-or-flight" response, in human history. Here, Fragment 31 V. is re-read from a medical point of view, correlating the ancient Greek lyric text, the corresponding medical terms, and the underlying catecholamine mechanism of action.

Spectrum of DICER1 Germline Pathogenic Variants in Ovarian Sertoli-Leydig Cell Tumor.

Sertoli-Leydig Cell Tumors (SLCTs) are rare ovarian sex cord-stromal neoplasms, which predominantly affect adolescents and young female adults. The SLCTs clinical diagnosis and treatment remains challenging due to the rarity and the varied presentation. A large majority of SLCTs are unilateral, but also bilateral neoplasms have been reported, sometimes in the context of DICER1 syndrome. In fact, the most significant discovery regarding the molecular genetics basis of SLCTs was the finding of somatic and germline pathogenic variants in the DICER1 gene. The DICER1 protein is a key component of the micro-RNA processing pathway. Germline DICER1 pathogenic variants are typically inherited in an autosomal dominant pattern and are most often loss-of-function variants dispersed along the length of the gene. Contrarily, DICER1-related tumors harbor a characteristic missense "RNase IIIb hotspot" mutation occurring in trans, or, less frequently, loss of heterozygosity (LOH) event involving the wild-type allele. While DICER1 mutations have been identified in approximately 60% of SLCTs, especially in the moderately or poorly differentiated types, there are only a few case reports of ovarian SLCT with underlying germline DICER1 mutations. In this review, we focus on the molecular genetic features of SLCT, performing an extensive survey of all germline pathogenic variants modifying the whole sequence of the DICER1 gene. We point out that DICER1 genetic testing, coupled with an accurate variants classification and timely counseling, is of crucial importance in the clinical management of ovarian SLCT-affected patients.

Cushing's Syndrome Effects on the Thyroid.

The most known effects of endogenous Cushing's syndrome are the phenotypic changes and metabolic consequences. However, hypercortisolism can exert important effects on other endocrine axes. The hypothalamus-pituitary-thyroid axis activity can be impaired by the inappropriate cortisol secretion, which determinates the clinical and biochemical features of the "central hypothyroidism". These findings have been confirmed by several clinical studies, which also showed that the cure of hypercortisolism can determine the recovery of normal hypothalamus-pituitary-thyroid axis activity. During active Cushing's syndrome, the "immunological tolerance" guaranteed by the hypercortisolism can mask, in predisposed patients, the development of autoimmune thyroid diseases, which increases in prevalence after the resolution of hypercortisolism. However, the immunological mechanism is not the only factor that contributes to this phenomenon, which probably includes also deiodinase-impaired activity. Cushing's syndrome can also have an indirect impact on thyroid function, considering that some drugs used for the medical control of hypercortisolism are associated with alterations in the thyroid function test. These considerations suggest the utility to check the thyroid function in Cushing's syndrome patients, both during the active disease and after its remission.

Molecular Analysis of 21-Hydroxylase Deficiency Reveals Two Novel Severe Genotypes in Affected Newborns.

BACKGROUND AND OBJECTIVE: Congenital adrenal hyperplasia involves a series of autosomal recessive disorders where adrenal steroidogenesis is affected. We present a detailed molecular investigation of 13 newborns affected from the severe form of congenital adrenal hyperplasia related to 21-hydroxylase deficiency. METHODS: All patients were diagnosed with classical congenital adrenal hyperplasia in the neonatal period due to adrenal crisis and/or ambiguous genitalia presentation. None of the infants was identified through a congenital adrenal hyperplasia newborn screening program. A molecular analysis of the CYP21A2 gene and a familiar segregation analysis were performed. RESULTS: Adrenal crisis was the most severe manifestation in the male salt-wasting newborns while all female patients presented with atypical genitalia. Newborns were correctly genotyped and no genotype-phenotype divergences were found. Two novel severe genotypes, not previously reported, were identified. The novel CYP21A2 frameshift mutations (c.793delG and c.297dupG) were added to the other 45 variants recently reported in the literature, leading to a total count of 279 pathogenic variants affecting the gene. CONCLUSIONS: We have successfully genotyped 13 infants diagnosed with classical congenital adrenal hyperplasia after birth. Our molecular approach led to the identification of two novel frameshift CYP21A2 pathogenic variants related to the salt-wasting form of congenital adrenal hyperplasia.

Cortisol circadian rhythm and jet-lag syndrome: evaluation of salivary cortisol rhythm in a group of eastward travelers.

PURPOSE: The activity of the hypothalamus-pituitary-adrenal axis plays a crucial role as an endogenous stress-reactive system. Lifestyle and work often interfere with the endogenous circadian rhythms and can modify the physiological patterns of stress-hormones secretion, including cortisol. We evaluated the cortisol circadian rhythm in the "jet-lag syndrome" that is the most known condition associated with the desynchronization of the circadian rhythm. METHODS: To assess the modifications of cortisol secretion after a long-haul flight, we compared baseline and post-travel salivary cortisol rhythm in a group of 28 healthy eastward travelers (from the U.S.A. or Canada to Italy). The salivary samples were collected about 1 week before the departure at 11 p.m. on day 0 and at 8 a.m., 12 a.m. (midday) and 11 p.m. on day 1 (R0). The same samples were obtained after the landing, the day they flew back home (R1). RESULTS: Statistical analysis showed a significant difference between R0 and R1 for each sample considered (p < 0.005). In particular, the post-travel salivary cortisol levels detected at 11 p.m. both on day 0 and on day 1, were significantly higher than at baseline. Post-travel morning salivary cortisol levels were lower compared with basal rhythm and increased during the morning, reaching the acrophase at 12 a.m. CONCLUSIONS: In eastward travelers, crossing more than five time zones, the cortisol circadian rhythm after the return to the East "remained behind," being synchronized with the West time. This impaired cortisol secretion can contribute to the pathogenesis of the jet-lag syndrome.

Medical Approaches in Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) represents one of the most aggressive endocrine tumors. In spite of a correct therapeutic strategy based on a multidisciplinary approach between endocrinologist, surgeon and oncologist, the prognosis is often poor. Surgery is the mainstay treatment in ACC. Mitotane, a dichloro-diphenyl-trichloro-ethane derivate, represents the main medical treatment of ACC in consideration of its adrenocytolitic activity and it is mainly employed as adjuvant treatment after complete surgical resection and for the treatment of advanced ACC. However, the use of mitotane as adjuvant therapy is still controversial, also in consideration of the retrospective nature of several studies. The recurrence of disease is frequent, especially in advanced disease at the diagnosis. Therefore, in these contexts, conventional chemotherapy must be considered in association with mitotane, being the combination etoposide, doxorubicin and cisplatin (EDP) the standard of care in this setting. A more modern therapeutic approach, based on the need of a salvage therapy for advanced ACC that progresses through first-line EDP, is focused on molecular-targeted therapies. However, robust clinical trials are necessary to assess the real efficacy of these treatments.

A novel MEN1 pathogenic variant in an Italian patient with multiple endocrine neoplasia type 1.

The multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome characterized by the predisposition to developing multiple endocrine and non-endocrine tumors, typically characterized by the association between parathyroid gland hyperplasia or tumors, gastroenteropancreatic tumors and pituitary adenomas. The MEN1 gene is located on the long arm of chromosome 11 (11q13) and it encodes for the protein "menin". We here reported the case of a MEN1-patient, affected by primary hyperparathyroidism, insulinoma, pituitary non-hyperfunctioning adenoma and bilateral adrenal masses, carrying a novel heterozygous pathogenic variant (c.1252_1254delGACinsAT), located in exon 9 of MEN1 gene.