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.

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.

Lenvatinib treatment for thyroid cancer in COVID era: safety in a patient with lung metastases and SARS-CoV-2 infection.

During the coronavirus disease 2019 (COVID-19) pandemic, clinicians are required to manage patient care for pre-existing conditions. Currently, there are no clear indications regarding the management of lenvatinib-treated patients for radioiodine-refractory thyroid cancer and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 74-year-old male patient was treated with lenvatinib since March 2019, with disease recurrence in the thyroid bed and bilateral multiple lung metastases. The patient partially responded to treatment, with reduction in lung metastases. In September 2019, the patient tested positive for SARS-CoV-2 and isolated at home. Initially asymptomatic, the patient developed mild symptoms. Lenvatinib treatment continued with daily monitoring of vital signs. After telemedicine consultation of patient's clinical condition, severity of symptoms was low. He tested negative for SARS-CoV-2 21 days after testing positive. The patient received the full course of lenvatinib treatment. This is the first reported case of a lenvatinib-treated patient who developed COVID-19 and could continue treatment. Despite concerns over COVID-19, clinicians should not overlook treatment of pre-existing diseases or discontinue treatment, particularly for cancer. Clinicians should evaluate a patient's history and clinical presentation, monitoring the patient to reduce the development of complications in high-risk settings, avoiding treatment discontinuation.

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.

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.

Walter E. Dandy: his contributions to pituitary surgery in the context of the overall Johns Hopkins Hospital experience.

BACKGROUND: Walter E. Dandy (1886-1946) was an outstanding neurosurgeon who spent his entire career at the Johns Hopkins Hospital. After graduating from medical school in 1910, he completed a research fellowship in the Hunterian laboratory with Harvey Cushing and then joined the Department of Surgery as resident, rising to the rank professor in 1931. Dandy made several contributions that helped building the neurosurgical specialty, most famously the introduction of pneumo-ventriculography to image brain lesions for which he received a Nobel prize nomination. He also performed many pituitary surgeries, although his role in this area is less known and overshadowed by that of Cushing's. PURPOSE: This retrospective cohort study was designed to unveil Dandy's pituitary work and place it in the context of the overall pituitary surgeries performed at the Johns Hopkins Hospital. METHODS: Pituitary surgery data were obtained by screening the paper and electronic surgical pathology records of the Department of Pathology, as well as the general operating room log books of the Johns Hopkins Hospital housed in the Chesney Medical Archives. RESULTS: A total of 3211 pituitary surgeries associated with a pathological specimen were performed between February 1902 and July 2017 in 2847 patients. Most of the surgeries (2875 of 3211 89%) were done by 21 neurosurgeons. Dandy ranks 4th as number of surgeries, with 287 pituitary operations in 35 years of activity. He averaged 8 pituitary surgeries per year, a rate that positions him 6th among all Hopkins neurosurgeons. With the exception of his first operation done in July 1912 while Cushing was still at Hopkins, Dandy approached the pituitary gland transcranially, rather than transphenoidally. The majority of Dandy's pituitary patients had a pathological diagnosis of pituitary adenomas, followed by craniopharyngiomas and sellar cysts. In the decades Dandy operated, pituitary surgeries represented 0.56% of the total Johns Hopkins surgeries, a percentage significantly greater (p < 0.001) than the 0.1% observed in modern days. Dandy's pituitary clinical work was matched by important experimental studies done in the early stages of his career. CONCLUSIONS: This study highlights the role of Dandy as an important contributor to advance our understanding of pathophysiology and treatment of pituitary diseases.

Autoimmunity in Type 2 Diabetes: When the Only Effective Therapy Becomes Immunosuppressive.

BACKGROUND: Type B insulin resistance syndrome is a rare form of diabetes due to the presence of anti-insulin receptor antibodies [1, 2], which causes glycemic decompensation and antidiabetic therapy failure and instead responds to immunosuppressive therapy. CASE REPORT: A 67-year-old patient was admitted to the hospital due to autoimmune hemolytic anemia and glycemic decompensation. We first prescribed subcutaneous basal-bolus insulin and then intravenous insulin without improvement in blood sugar levels (between 300 and 500 mg/dL). Considering the non-response to therapy and the autoimmune diathesis of the patient (hemolytic anemia and mixed connective tissue disease), we suspected an autoimmune etiopathogenesis of glycemic decompensation; we excluded type 1 diabetes mellitus (specific antibodies were negative), and we considered the anti-insulin-antibodies-(-assayed and negative) and anti-insulin receptor antibodies (not assayed due to the lack of a center specialized in this assay in the area). Therefore, we decided to start Rituximab. After 2 weeks from the infusion, the patient improved glycemic compensation, reducing insulin requirement. Further, 2 months after the first infusion, the patient stopped insulin, returning to oral therapy with Metformin. To date, the patient has completed 3 cycles of Rituximab with the benefit of glycemic control (HbA1c 6.7%). CONCLUSION: The brilliant response to Rituximab supports the hypothesis of an autoimmune pathogenesis. The anti-insulin receptor antibodies (in the type B insulin resistance syndrome) affect mostly middle-aged adults, especially women, in the context of other autoimmune diseases. Hence, it is necessary to consider the diagnosis of this rare disease in order to perform timely and effective treatment.

Reconsidering the role of depression and common psychiatric disorders as partners in the type 2 diabetes epidemic.

Common psychiatric disorders (CPDs) and depression contribute significantly to the global epidemic of type 2 diabetes (T2D). We postulated a possible pathophysiological mechanism that through Bridge-Symptoms present in depression and CPDs, promotes the establishment of emotional eating, activation of the reward system, onset of overweight and obesity and, ultimately the increased risk of developing T2D. The plausibility of the proposed pathophysiological mechanism is supported by the mechanism of action of drugs such as naltrexone-bupropion currently approved for the treatment of both obesity/overweight with T2D and as separate active pharmaceutical ingredients in drug addiction, but also from initial evidence that is emerging regarding glucagon-like peptide 1 receptor agonists that appear to be effective in the treatment of drug addiction. We hope that our hypothesis may be useful in interpreting the higher prevalence of CPDs and depression in patients with T2D compared with the general population and may help refine the integrated psychiatric-diabetic therapy approach to improve the treatment and or remission of T2D.

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.

Evaluation of the prevalence of the most common psychiatric disorders in patients with type 2 diabetes mellitus using the patient health questionnaire: results of the cross-sectional "DIA2PSI" study.

AIMS: Common Psychiatric Disorders (CPDs) are associated with the development of overweight and obesity, the strongest risk factors for the onset and maintenance of Type 2 Diabetes mellitus (T2D). To the best of our knowledge, this is the first study to assess the prevalence of CPDs in patients with T2D in Italy. METHODS: This is a monocentric cross-sectional study; n = 184 T2D patients were screened for CPDs using the Patient Health Questionnaire (PHQ). Primary outcome was to evaluate the prevalence of CPDs. To assess association between CPDs and risk factors, we have utilized univariable logistic regression models. RESULTS: 64.1% were men, median age was 67 (59-64) and median BMI 27 (25-30) kg/m2. The 42.9% tested positive for one or more mental disorders, 25.6% for depression. Patients with higher BMI (p = 0.04) had an increased likelihood of testing positive to the PHQ. Patients who had implemented lifestyle changes (p < 0.01) and were aware that mental health is linked to body health (p = 0.07) had a reduction in the likelihood of testing positive. CONCLUSIONS: Prevalence of CPDs in T2D patients is higher than in the general population. Since CPDs favor the onset and subsistence of T2D, integrated diabetic-psychiatric therapy is required for improvement or remission of T2D in patients with comorbid CPDs.

[Thyroxine replacement therapy in patients with thyroid cancer and thyroid hormone resistance syndrome]. / Terapia sostitutiva tiroxinica in pazienti affetti da carcinoma tiroideo e sindrome di resistenza agli ormoni tiroidei.

Resistance to thyroid hormone (RTH) is a genetic syndrome defined by an impaired sensitivity to thyroid hormones. It is characterized by discrepancies between the blood levels of thyroid hormones (FT3, FT4) and TSH, and by the coexistence of hypothyroidism and hyperthyroidism symptoms. Here we describe the case of a patient affected with thyroid cancer and RTH in whom it was difficult to obtain a good control of TSH after total thyroidectomy despite high doses of thyroxine replacement therapy. This represents a unique model to improve the understanding of the alterations in the feedback mechanism in patients with RTH and to optimize the replacement therapy in patients with concomitant thyroid cancer who need adequate TSH control.

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.

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.

Parathyroid Carcinoma All-In-One, a Rare Life-Threatening Case With Multiple Systemic Manifestations: Case Report and Review of the Literature.

Parathyroid carcinoma (PC) is an extremely rare disease. Although it may occasionally occur in genetic syndromes, it is more often sporadic. It is usually associated with a consistent secretion of PTH, causing severe hypercalcemia and potentially all clinical conditions due to primary hyperparathyroidism. Management of PC can be challenging: some clinical, biochemical, and radiological features may be useful, but the final diagnosis of malignancy strictly relies on histological criteria. To date, radical surgery is the first-choice treatment and is the only effective therapy to control hypercalcemia and other clinical manifestations. On the other hand, chemo- or radiotherapy, local treatments, or novel drugs should be reserved for selected cases. We report an exceptionally unusual case of life-threatening PC, associated with several systemic manifestations: moderate pancreatitis, portal thrombosis, kidney stones, brown tumors, osteoporosis, hungry bone syndrome (HBS), chondrocalcinosis, neuropathy, and depression. The clinical case also represents an opportunity to provide a review of the recent literature, associated with a complete evaluation of the main diagnostic and therapeutic approaches.

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.

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.

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.

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.

Subclinical thyroid diseases and isolated hypothyroxinemia during pregnancy.

Thyroid diseases in pregnancy are common. While data on management of overt diseases are clear, there is no consensus regarding subclinical thyroid disease. Many studies have tried to clarify the impact of subclinical thyroid disease on pregnancy outcomes without reaching universal conclusions. As several studies are present in literature, but no univocal indication is present to manage each condition, the present review tries to summarize the recent indications for such disease. The most updated guidelines are 2017 American thyroid association for thyroid disease during pregnancy, which at present represent the most accurate and reliable guide. Subclinical hyperthyroidism during pregnancy has not been associated with adverse outcomes and only needs follow up. Subclinical hypothyroidism is associated with adverse obstetric and offspring outcomes. At present thyroxine treatment is recommended in selected cases, as beneficial effects are not clear for all these patients. Data regarding the association between isolated hypothyroxinemia and adverse maternofetal outcome are controversial but treatment is not indicated. Autoimmune thyroid disease represents the main thyroid risk factor for adverse pregnancy outcomes. If patients have normal TSH values, treatment is not indicated. A possible thyroxine treatment can be evaluated on a case-by-case basis in euthyroid patients with history of abortion/infertility. In the last years, risks of subclinical thyroid dysfunction on the outcome of gestation and new-born have been scaled back. Further prospective studies are necessary to better understand thyroid dysfunction in pregnancy to perfectly target treatment in appropriate settings.

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.