BACKGROUND:Children carrying germline RET mutations associated with multiple endocrine neoplasia type 2 (MEN2) are at high risk of developing medullary thyroid carcinoma (MTC). Prophylactic-intent thyroidectomy is recommended during childhood to prevent progression to advanced disease. Genotype-based recommendations combined with calcitonin measurements allow more individualized surgical timing. However, performing thyroidectomy at very young ages may expose children to long-term morbidity, particularly permanent hypoparathyroidism. METHODS:We conducted a retrospective national multicenter cohort study within the French Groupe d'Étude des Tumeurs Endocrines, including children younger than 15 years who underwent prophylactic-intent total thyroidectomy between 2010 and 2020 in the absence of clinically apparent structural disease. Data collected included RET genotype, age at surgery, preoperative calcitonin values interpreted relative to each laboratory's upper limit of normal, surgical procedures performed, histopathologic findings, postoperative complications, and clinical status at last follow-up. RESULTS:Sixty-four children (61 MEN2A, 3 MEN2B) underwent surgery at a median age of 4.6 years (interquartile range [IQR] = 3.2-8.3 years). Preoperative calcitonin was elevated in 44% of evaluable patients. Histopathology demonstrated C-cell hyperplasia in 52% and micro-MTC in 34%, while lymph node metastases were rare (3%). After a median follow-up of 6 years (IQR = 2.4-8.5 years), no patient had persistent structural disease. One patient had persistent moderate biochemical disease without structural evidence of MTC, although follow-up duration limits definitive long-term oncologic outcomes. Postoperative morbidity was notable: hypoparathyroidism occurred in 31% of patients and was permanent in 16%, predominantly among children operated before age 5 years. CONCLUSIONS:In this national contemporary cohort, prophylactic-intent thyroidectomy in pediatric MEN2 was associated with excellent short-term oncologic outcomes but also with a substantial rate of permanent hypoparathyroidism, particularly in very young children. These findings underscore the importance of multidisciplinary evaluation of both the timing and extent of surgery in expert centers.

Glucocorticoids are produced through activation of the hypothalamic-pituitary-adrenal (HPA) axis, initiated by the release of corticotropin-releasing factor (CRF) from the hypothalamus. CRF acts through two receptor subtypes, CRF1 and CRF2. However, the specific contributions of CRF1 and CRF2 receptors to age-related changes in brain glucocorticoid activity remain largely unexplored. In certain tissues, including the hippocampus, glucocorticoid signaling is further amplified by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which regenerates inactive glucocorticoid metabolites into their active form. Notably, prior research investigating the role of hippocampal 11β-HSD1 in aging has focused exclusively on male subjects. In this study, we used genetic mouse models lacking functional CRF1 or CRF2 receptors to investigate their respective roles in regulating hippocampal 11β-HSD1 activity and glucocorticoid levels across age and sex. Mice of both sexes at 6 and 18 months of age were analyzed. Hippocampal 11β-HSD1 activity was assessed by measuring the ratio of corticosterone to dehydrocorticosterone using mass spectrometry in tissue extracts from CRF1 and CRF2 wild-type (WT), heterozygous (HET), and knockout (KO) mice. Our results demonstrate that hippocampal 11β-HSD1 activity increases with age in female CRF1 WT and HET mice but not in CRF1 KO females. In contrast, aged males exhibit elevated 11β-HSD1 activity regardless of CRF1 genotype. In CRF1 males, the age-related increase in hippocampal 11β-HSD1 activity is associated with higher hippocampal corticosterone levels, whereas in CRF1 females, it corresponds with a decrease in hippocampal dehydrocorticosterone. CRF1 deficiency leads to reduced hippocampal levels of both corticosterone and dehydrocorticosterone in males and females at both ages. CRF1 deficiency is also associated with decreased plasma corticosterone levels in both male and female mice. Male, but not female, CRF2 mice show an age-dependent increase in hippocampal 11β-HSD1 activity, which is not altered by CRF2 deficiency. Moreover, CRF2 deficiency results in increased plasma corticosterone in female, but not in male, mice. Overall, our findings reveal that hippocampal 11β-HSD1 activity increases with age in both sexes. In females, this increase is dependent on the presence of functional CRF1 receptors. In contrast, males exhibit age-related increases in 11β-HSD1 activity independent of CRF1 function. These findings underscore the importance of considering sex as a biological variable when developing therapeutic strategies targeting 11β-HSD1 to mitigate age-related memory decline.

This article, presenting three clinical cases, discusses the analytical issues of testosterone measurement in blood (immunoassay and liquid chromatography and mass spectrometry). It also describes the different circulating testosterone fractions (total, free and bioavailable) and how to measure or calculate them.Beyond these analytical aspects, the article addresses the challenges encountered in establishing reference ranges and the specific difficulties related to different patient populations: men, women and children. Finally, in light of the evidence outlined in the article, we review the three cases.

Antimüllerian hormone (AMH), a protein secreted by granulosa cells, is a quantitative marker of the ovarian reserve. Due to its clinical value, the anti-müllerian hormone is a test highly prescribed by doctors, especially in the medically assisted procreation (MAP) department. The antral follicle count (AFC) and the result of the AMH test, are systematically evaluated during a fertility preservation consultation and also as part of the monitoring of ovarian function. Different methods for the measurement of AMH level exist, but none of them is currently available in our hormonology laboratory at Bordeaux University Hospital. The introduction of one of these technical assays in our laboratory could shorten the delay of reaching the result. According to our objectives, our study made it possible to observe the performance and analytical limits of the Biomerieux and Fujirebio technology, by comparing it with Roche technology, known as the reference, by analysing 50 AMH samples, on each of them and evaluating the results. In our study, despite a good agreement between the three assay methods, the importance of an international standard from a diagnostic point of view was once again noted. National medical commissions do strongly insist on the need of setting up an international standard in order to facilitate the development of reference values, decrease inter-laboratory variability and the cost due to repeated assays, as well as to improve patient safety by avoiding poor estimation of values.

The comorbidity of obesity, type 2 diabetes (T2D), and psychiatric disorders— particularly anxiety and depression—is well documented. However, it remains unclear whether T2D, independently of obesity, contributes to the development of emotional dysfunctions. Furthermore, alterations in the hypothalamic-pituitary-adrenal (HPA) stress axis are commonly associated with both T2D and depression, but the role of stress in emotional disorders linked to T2D has been poorly explored. This study aimed to investigate the impact of T2D, independent of obesity, on the neuroendocrine stress axis, as well as molecular, cellular, and behavioral indicators of emotional dysfunction. Using the non-obese Goto-Kakizaki (GK) rat model of T2D, we assessed the effects of diabetes on hormonal and neuronal stress responses, molecular and structural markers of stress in the brain, and anxiety- and depressive-like behaviors. We also evaluated the impact of adrenalectomy in GK rats to determine the contribution of glucocorticoids to their behavioral impairments. Our findings reveal that non-obese diabetes leads to heightened endocrine and brain responses to stress, along with upregulation of stress-related molecular markers and structural features indicative of chronic stress, particularly in the medial prefrontal cortex. Additionally, GK rats exhibited pronounced anxiety- and depressive-like behaviors. Importantly, lowering glucocorticoid levels in GK rats helped alleviate some of the metabolic and emotional disturbances. This study suggests that T2D, independent of obesity, induces stress-related brain and behavioral changes, partly mediated by glucocorticoids. Highlights ### Competing Interest Statement The authors have declared no competing interest. French National Research Agency, ANR-17-CE37-0020, MADAM, ANR-10-INBS-04

Among the tools necessary for the diagnosis of primary hyperaldosteronism, catheterization of the adrenal veins represents the major examination to determine the presence of lateralized aldosterone secretion. To ensure that the catheter is well positioned at the level of the adrenal veins, a cortisol dosage is carried out in parallel with the aldosterone dosage. At the Hormonology and Tumor Markers laboratory of the Bordeaux University Hospital, this cortisol assay is carried out on an Abbott Architect i2000, making it possible to extend the calibration range up to > 3,300 nmol/L. Beyond that, the supplier recommends carrying out a manual dilution using calibrator A in which the cortisol concentration is equal to 0 nmol/L. The downside is that this calibrator cannot be supplied alone. It is only available in a common box with the 5 other calibrators necessary to carry out the cortisol calibration range. To overcome this expensive strategy, we studied the use of another diluent: 0.9% NaCl. Samples from 11 CVS were diluted with 0.9% NaCl and a comparison of cortisol results was performed (n = 128). Passing-Bablok regression of cortisol concentrations did not show significant deviation from linearity. The interpretation of CVS selectivity was not impacted by the change of diluent nor the interpretation of secretion lateralization. This change of diluent therefore did not modify the appropriate medical decision: medicinal treatment in the case of the identification of a bilateral secretion or proposal for surgical intervention in the case of the identification of a lateralized secretion.

BACKGROUND:The number of patients with type 2 diabetes (T2D) and type 1 diabetes (T1D) is on the rise, partly due to a global increase in new T1D cases among children. Beyond the well-documented microvascular and macrovascular complications, there is now substantial evidence indicating that diabetes also impacts the brain, leading to neuropsychological impairments. The risk of developing neuropsychiatric symptoms is notably higher in childhood due to the ongoing maturation of the brain, which makes it more susceptible to damage. Despite this awareness, the specific effects of diabetes on cognitive function remain poorly understood. SUMMARY:This review synthesizes literature on the impact of diabetes on cognition and its relationship with brain structural changes. It presents data and hypotheses to explain how T1D contributes to cognitive dysfunction, with a particular focus on children and adolescents. The emphasis on the pediatric population is intentional, as young diabetic patients typically have fewer comorbidities, reducing confounding factors and simplifying the investigation of cognitive alterations. KEY MESSAGE:We examine the roles of hypo- and hyperglycemia, as well as the emerging role of glucocorticoids in the development of neuropsychological disorders. When specific mechanisms related to T1D are available, they are highlighted; otherwise, data and hypotheses applicable to both T1D and T2D are discussed.

Objectif Il a été montré que le diabète de type 2 (DT2), lorsqu’il est classiquement étudié dans le contexte d’une obésité, peut entraîner une altération de l’axe corticotrope. Par contre, il n’est pas encore clairement démontré que le DT2 puisse, indépendamment de l’obésité, être à l’origine de l’atteinte de l’axe. Dans cette étude, nous évaluerons l’impact d’un DT2 sans obésité sur la réactivité de l’axe corticotrope ainsi que la contribution potentielle des glucocorticoïdes dans les désordres métaboliques de ce diabète. Matériel et méthodes La corticostérone a été dosée dans le plasma de rats Goto Kakizaki (GK), modèle génétique de DT2 non obèse issu de croisement de rats intolérants au glucose, et de rats Wistar contrôles au cours du cycle nycthéméral (début de phase inactive/active), d’un test de stress léger (open field) et dans différentes structures cérébrales. La glycémie et l’insulinémie basales et après stress ont ensuite été réalisés chez des rats GK contrôles et surrénalectomisés, supplémentés à faible dose en corticostérone. Résultats Les rats GK montrent une hyperréactivité de l’axe corticotrope ainsi que des niveaux élevés de corticostérone dans l’hypothalamus, le cortex préfrontal, l’amygdale et l’hippocampe. Après normalisation des concentrations de corticostérone par surrénalectomie, les rats GK présentent une amélioration des paramètres métaboliques après stress. Discussion Le DT2, indépendamment d’une obésité, est associé à une hyperréactivité de l’axe corticotrope ainsi qu’une élévation des glucocorticoïdes dans différentes structures cérébrales. Diminuer cette exposition aux glucocorticoïdes, améliore la gluco-sensibilité des rats diabétiques.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

According to animal studies, saffron and its main volatile compound safranal may reduce biological and behavioral signs of acute stress. However, little is known about its impact in humans. This study investigated the acute effect of a saffron extract and safranal on the biological and psychological stress responses in healthy men experiencing a laboratory stress procedure. In this double-blind, placebo-controlled, randomized, cross-over study, 19 volunteers aged 18–25 received a single dose of 30 mg saffron extract (Safr’InsideTM), 0.06 mg synthetic safranal, or a placebo on three visits separated by a 28-day washout. Thirteen minutes after administration, participants were exposed to the Maastricht acute stress test (MAST). Salivary cortisol and cortisone were collected from 15 min before the MAST (and pre-dose), 3 min before the MAST, and then 15, 30, 45, 60, and 75 min after the MAST, and stress and anxiety were measured using visual analogic scales. Compared to the placebo, stress and anxiety were significantly toned down after Safranal and Safr’InsideTM administration and coupled with a delay in the times to peak salivary cortisol and cortisone concentrations (p < 0.05). Safr’InsideTM and its volatile compound seem to improve psychological stress response in healthy men after exposure to a lab-based stressor and may modulate the biological stress response.

Children with diabetes may display cognitive alterations although vascular disorders have not yet appeared. Variations in glucose levels together with relative insulin deficiency in treated type 1 diabetes have been reported to impact brain function indirectly through dysregulation of the hypothalamus–pituitary–adrenal axis. We have recently shown that enhancement of glucocorticoid levels in children with type 1 diabetes is dependent not only on glucocorticoid secretion but also on glucocorticoid tissue concentrations, which is linked to 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. Hypothalamus–pituitary–adrenal axis dysfunction and memory alteration were further dissected in a juvenile rat model of diabetes showing that excess 11β-HSD1 activity within the hippocampus is associated with hippocampal-dependent memory deficits. Here, to investigate the causal relationships between diabetes, 11β-HSD1 activity and hippocampus-dependent memory deficits, we evaluated the beneficial effect of 11β-HSD1 inhibition on hippocampal-related memory in juvenile diabetic rats. We also examined whether diabetes-associated enhancement of hippocampal 11β-HSD1 activity is due to an increase in brain glucose concentrations and/or a decrease in insulin signalling. Diabetes was induced in juvenile rats by daily i.p. injection of streptozotocin for 2 consecutive days. Inhibition of 11β-HSD1 was obtained by administrating the compound UE2316 twice daily by gavage for 3 weeks, after which hippocampal-dependent object location memory was assessed. Hippocampal 11β-HSD1 activity was estimated by the ratio of corticosterone/dehydrocorticosterone measured by LC/MS. Regulation of 11β-HSD1 activity in response to changes in glucose or insulin levels was determined ex vivo on acute brain hippocampal slices. The insulin regulation of 11β-HSD1 was further examined in vivo using virally mediated knockdown of insulin receptor expression specifically in the hippocampus. Our data show that inhibiting 11β-HSD1 activity prevents hippocampal-related memory deficits in diabetic juvenile rats. A significant increase (53.0±9.9

CONTEXT:Cortisol-lowering drugs may not restore a normal cortisol secretion in Cushing disease (CD).OBJECTIVE:This work aimed to assess the long-term cortisol exposure in medically treated CD patients using hair-cortisol (HF) and hair-cortisone (HE) measurement.METHODS:This multicenter prospective study included 3 groups of female patients: CushMed = 16 treated with a stable cortisol-lowering drug dosage and normal urinary free cortisol (UFC); CushSurg = 13 cured by pituitary surgery; CushBla = 15 receiving stable recommended doses of hydrocortisone following bilateral adrenalectomy. Patients were evaluated for 3 months with their usual treatments. Two late-night saliva and 24-hour urine samples were collected monthly in CushMed, and at study end in CushSurg and CushBla patients. A 3-cm hair sample was collected at study end from all patients. Main outcome measures included clinical score and centralized measurement of UFC, late-night salivary cortisol (LNSF), late-night salivary cortisone (LNSE), HE, HF.RESULTS:Despite having almost all UFCs normalized, CushMed patients exhibited increased HE as compared to CushSurg controls (P = .003). CushMed patients also had increased clinical score (P = .001), UFC (P = .03), LNSF, LNSE (P = .0001), and variability in the latter parameters (P = .004). CushBla patients had increased HF and HE, contrasting with LNSEs similar to CushSurg patients. Six of 15 CushMed patients exhibited increased HE concentrations and had increased antihypertensive drug dosage compared to CushMed patients with normal HE (P = .05).CONCLUSION:Despite normalized UFCs, a subset of medically treated CD patients displays an altered circadian rhythm of serum cortisol. A single HE measurement identifies chronic mild persistent hypercortisolism and could replace multiple saliva analyzes to monitor medical treatments in CD patients once UFC is normalized.

Les patients diabétiques de type 1 présentent des déficits mnésiques modestes, mais bien caractérisés, avec notamment une altération hippocampique en lien avec une augmentation de la biodisponibilité des glucocorticoïdes, et ce, dès l’enfance, alors que les troubles vasculaires ne sont pas encore installés. Cette étude évalue, dans un modèle de raton diabétique, l’effet bénéfique de l’inhibition de l’activité de la 11β-hydroxystéroïde-deshydrogénase de type 1 (11βHSD1), enzyme capable de réguler leur biodisponibilité, sur les performances mnésiques ainsi que le rôle respectif de l’hyperglycémie et du défaut de sécrétion insulinique dans la dérégulation de l’activité de cette enzyme. Les performances mnésiques de ratons diabétiques, traités pendant 3 semaines par un inhibiteur spécifique de l’activité 11βHSD1, ont été étudiées par un test de localisation d’objet. Puis, le rôle respectif de l’insuline et du glucose a été examiné grâce à un modèle : i) de souris knock-down pour le récepteur de l’insuline au niveau hippocampique ; et ii) de tranches hippocampiques maintenues ex-vivo dans des bains de concentrations différentes de glucose et d’insuline. L’inhibiteur reverse les effets délétères du diabète sur la mémoire hippocampique. L’insuline ne montre pas d’effet modulateur de l’activité de la 11βHSD1 alors qu’une concentration élevée de glucose s’accompagne d’une augmentation de l’activité 11βHSD1. Si plusieurs mécanismes sont décrits pour expliquer le rôle du glucose dans la survenue des troubles mnésiques chez les diabétiques, cette étude souligne son importance au regard de l’exposition accrue aux glucocorticoïdes de l’hippocampe et propose la 11βHSD1 comme cible thérapeutique potentielle.

BACKGROUND:Primary aldosteronism is responsible for a major cardiovascular risk that can be avoided by specific treatment. A better characterization of the hypertensive population with primary aldosteronism would not only improve the overall diagnosis but also allows a better selection of patients requiring adrenal vein sampling (AVS).METHODS:Creation of a prospective single-center Bordeaux ABORDAGE study of hypertensive patients with primary aldosteronism who underwent AVS. Primary aldosteronism was diagnosed according to the recommendations of the SFE/SFHTA. Peripheral and central blood pressure measurements were performed with mercury sphygmomanometer, SphygmoCor applanation tonometer and ambulatory blood pressure measurement. An adrenal computed tomography and an unstimulated AVS were performed in each patient.RESULTS:One hundred and eighty-eight patients were included in our study. They were mostly men (61.7%), with a mean age of 48.7 ± 10.5 years, BMI of 29.7 ± 5 kg/ m2 and duration of hypertension of 101.5 ± 84 months. AVS was selective in 82.3% of patients and lateralization was concordant with CT in only 35.4% of patients. Lateralized secretion was significantly associated with a marked biological primary aldosteronism and hypertension. In multivariate analysis, no variable specifically differentiated patients with aldosterone lateralization.CONCLUSION:The ABORDAGE population description is consistent with the data found in the literature. These characteristics are ultimately those expected in essential hypertension population, which therefore, could explain part of the underdiagnosis of primary aldosteronism. Only AVS is able to predict the lateralization of secretion with a post adrenalectomy recovery of about 90% in case of lateralization. The generalization of AVS would, therefore, increase the proportion of patients with primary aldosteronism cured.

An 18-year-old woman was referred by her GP to the endocrinology department of the University Hospital of Bordeaux on suspicion of premature ovarian failure because of a disorder of the menstrual cycle and pathological results of biological exploration of the gonadotropic axis. Repeatedly-found elevated concentrations of FSH contrasted with a normal concentration of LH leading to a hypothesis of ovarian failure. However, different investigations favoured an analytical interference. The presence of heterophilic antibodies or anti-mouse antibodies (HAMA) was unlikely but, finally, a complex combining FSH and autoantibody (called macro-FSH) was evidenced.

ObjectiveDisturbances in the activity of the hypothalamus-pituitary-adrenal axis could lead to functional alterations in the brain of diabetes patients. In a later perspective of investigating the link between the activity of the hypothalamus-pituitary-adrenal axis and the developing brain in children with diabetes, we assessed here nocturnal cortisol metabolism in prepubertal children with type 1 diabetes mellitus (T1DM).MethodsPrepubertal patients (aged 6–12 years) diagnosed with T1DM at least 1 year previously were recruited, along with matched controls. Nocturnal urine samples were collected, with saliva samples taken at awakening and 30 minutes after awakening. All samples were collected at home over 5 consecutive days with no detectable nocturnal hypoglycaemia. The State-Trait Anxiety Inventory (trait scale only) and Child Depression Inventory were also completed. Glucocorticoid metabolites in the urine, salivary cortisol (sF) and cortisone (sE) were measured by liquid chromatography–tandem mass spectrometry. Metabolic data were analysed by logistic regression, adjusting for sex, age, BMI and trait anxiety score.ResultsUrine glucocorticoid metabolites were significantly lower in T1DM patients compared to controls. 11β-hydroxysteroid dehydrogenase type 1 activity was significantly higher, while 11β-hydroxysteroid dehydrogenase type 2, 5(α+β)-reductase and 5α-reductase levels were all lower, in T1DM patients compared to controls. There was a significant group difference in delta sE level but not in delta sF level between the time of awakening and 30 minutes thereafter.ConclusionsOur findings suggest that altered nocturnal cortisol metabolism and morning HPA axis hyperactivity in children with T1DM leads to greater cortisol bioavailability and lower cortisol production as a compensatory effect. This altered nocturnal glucocorticoid metabolism when cortisol production is physiologically reduced and this HPA axis hyperactivity question their impact on brain functioning.

Objective Hair cortisol (HF) and cortisone (HE) measurements reflect tissular exposure to cortisol over months and are increased in overt Cushing’s syndrome (CS). No data is available in mild CS. We compared the diagnostic performance of HF and HE between patients with overt or mild CS. Design Single centre retrospective study. Methods HF&HE were measured by LC-MS/MS in 48 consecutive adult females with Cushing’s disease (CD), ectopic ACTH syndrome, secreting adenomas and carcinomas, and adrenal incidentalomas. All had impaired dexamethasone suppression tests. Overt CS (n = 25) was diagnosed in front of specific symptoms, a mean UFC (>1.5 ULN) and increased midnight serum cortisol or salivary cortisol. Mild CS (n = 23) was diagnosed in patients lacking specific symptoms and displaying at least one additional biological abnormality including mildly increased UFC (≤1.5 ULN), increased midnight serum cortisol or salivary cortisol and suppressed plasma ACTH in patients with adrenal tumours. In this study, 84 healthy subjects and obese patients served as controls. Results HF and HE showed roughly similar performance in overt CS (92 and 100% sensitivity, 91 and 99% specificity, respectively). HF and HE were lower in mild CS but higher than in controls (P < 0.01). HE was correlated with midnight serum cortisol (P < 0.02) and volume of adrenal incidentalomas (P < 0.04) but not with UFC. HF and HE had 59% and 68% sensitivity, and 79 and 94% specificity, respectively, for the diagnosis of mild CS. Contrary to UFC, both HF and HE were in the range of overt CS in 11/23 patients with mild CS. Patients with mild CS and increased HE required more antihypertensive treatments and showed worser lipid profiles than patients with normal HE. Conclusions HF and HE measurement performed better in overt than in mild CS but is a useful adjunct to diagnose mild CS and to identify adrenocortical incidentalomas responsible for excessive cortisol exposure.

Anxiety, stress, and low mood are closely related and may contribute to depressive symptoms. Among non-pharmacological solutions to improve subclinical mood symptoms and resilience to stress, natural products such as saffron—identified as promising following preliminary beneficial effects in major depressive disorder—represent a relevant strategy. This study aimed to assess the efficacy of 8 weeks' supplementation with 30 mg standardized saffron extract on emotional well-being in healthy adults with subclinical feelings of low mood and anxiety and/or stress and evaluate the acute effect of saffron in response to a lab-based psychosocial stressor. The study adopted a double-blind, randomized, parallel groups design in which 56 healthy male and female individuals (18–54 years) received either a saffron extract or a placebo for 8 weeks. Chronic effects of saffron on subjective anxiety, stress, and depressive feelings were assessed using a questionnaire battery [including Profile of Mood State-2, (POMS)] and acute effects in response to a lab-based psychosocial stressor were measured through psychological and physiological parameters. Urinary crocetin levels were quantified. Participants who received the saffron extract reported reduced depression scores and improved social relationships at the end of the study. Urinary crocetin levels increased significantly with saffron supplementation and were correlated with change in depression scores. The typical stress-induced decrease in heart rate variability (HRV) during exposure to the stressor was attenuated following acute saffron intake. Saffron extract appears to improve subclinical depressive symptoms in healthy individuals and may contribute to increased resilience against the development of stress-related psychiatric disorders. Clinical trials number: NCT03639831.