Pain intensity has been reported to fluctuate during the day in some experimental and clinical conditions, but the mechanisms underlying these fluctuations are unknown. Although the circadian timing system is known to regulate a wide range of physiological functions, its implication in pain regulation is largely unknown. Using highly controlled laboratory constant-routine conditions, we show that pain sensitivity is rhythmic over the 24 h and strongly controlled by the endogenous circadian timing system. We found that the circadian component of pain sensitivity can be modelled with a sinusoidal function, with a maximum in the middle of the night and a minimum in the afternoon. We also found a weak homeostatic control of pain sensitivity, with a linear increase over the 34 h of prolonged wakefulness, which slowly builds up with sleep pressure. Using mathematical modelling, we describe that the circadian system accounts for ∼80% of the full magnitude of pain sensitivity over the 24 h, and that sleep-related processes account for only ∼20%. Overall, our data reveal the neurobiological mechanisms involved in driving the rhythmicity of pain perception in humans. We show that pain sensitivity is controlled by two superimposed processes: a strong circadian component and a modest homeostatic sleep-related component. Our findings highlight the need to consider time of day in pain assessment, and indicate that personalized circadian medicine may be a promising approach to pain management.

Background: Iodine deficiency (ID) remains common in Europe, and may be especially detrimental during pregnancy. The aim of our study was to assess iodine status and thyroid function in healthy pregnant women in the Lyon metropolitan area. Methods: In a cross-sectional study, healthy pregnant women (n=228) with no history of thyroid disease were consecutively recruited from an obstetric clinic during all trimesters. Thyrotropin (TSH), free thyroxine (FT4), anti-thyroid peroxidase (anti-TPO) antibodies, thyroglobulin (Tg), and urinary iodine concentration (UIC) (n=100) were measured. Thyroid functions were compared with those in a control group of nonpregnant adults. Results: The median (range) UIC was 81 (8–832) μg/L, and 77% of pregnant women had a UIC <150 μg/L, indicating inadequate iodine intake. Overall, 11% of women had abnormal TSH or anti-TPO. The median FT4 (pmol/L) was 14.9, 12.6, and 11.5 in the first, second, and third trimesters, respectively. The median Tg in pregnant women was 16.2 μg/L, did not differ across trimesters, and was significantly higher than in the control group of nonpregnant adults (11.7 μg/L) (p=0.02). Controlling for maternal age and week of gestation, UIC was not a significant predictor of any of the thyroid function tests. Conclusions: Pregnant women in the Lyon area are iodine deficient and have increased serum Tg concentrations compared with nonpregnant controls, likely due to physiological thyroid hyperstimulation during gestation exacerbated by ID.

It is well known that thyroid dysfunction increases with age. This study is aimed to determine reference intervals, in males and females, suitable for thyroid disease exploration during adult life using routinely collected serum thyrotropin (TSH) data in a tertiary center from 2007 to 2018. Over 11 years, 295,775 TSH levels were measured in a single lab. Among the 156,025 TSH results available for analysis, 90,538 values were from female subjects, 82,019 were from patients aged >60 years and 26,825 were from patients aged >80 years. By using an indirect approach, we determined reference values of TSH adapted to age and sex, and we then evaluated the proportion of patients who would have been reclassified with these reference values. The median TSH ranged from 1.2–1.4 mUI/L during the study period. The upper limit of reference range of TSH increased with age; in females the median to 97.5th percentile values increased continuously from the age of 30 years to the oldest age group. Using new calculated reference values in patients with TSH above the conventional upper-limit reference value (4 mUI/L), the proportion of results reclassified as within the reference interval among patients aged >60 years ranged, according to age group, from 50.5% to 65.1% of females and from 33.0% to 37.7% of males. The use of TSH age-specific and sex-specific upper-limit reference values led to the reclassification of a great number of samples, notably among women. This suggests that age-specific TSH upper-limit reference intervals in daily practice should be used in order to avoid misclassification.

Background The benefit of exogenous melatonin is based on its bioavailability, which depends on the galenic form, the route of administration, the dosage, and the individual absorption and rate of hepatic metabolism. Objective The objective of this study is to investigate the bioavailability of melatonin after administration of an oral prolonged-release tablet (PR form) and an immediate-release sublingual spray (IR form). The main metabolite of melatonin, 6-sulfatoxymelatonin (6-SMT), was also measured, which has not been done in previous studies. Its determination is important as an index of the hepatic transformation of melatonin. Methods In this single-center, open-label, randomized, crossover study, 14 healthy male volunteers received one tablet of the PR form (1.9 mg melatonin) or two sprays of the IR form (1 mg melatonin) during two visits separated by a washout period. Blood samples were collected over 7 and 9 h for the IR and PR form, respectively, to determine the main pharmacokinetic parameters. Results The observed kinetics were consistent with those expected for immediate and prolonged-release forms. Pulverization of the spray resulted in an early, high plasma melatonin peak (C_max: 2332 ± 950 pg/mL; T_max: 23.3 ± 6.5 min), whereas tablet intake produced a lower peak (C_max: 1151 ± 565 pg/mL; T_max: 64.2 ± 44.2 min; p < 0.001 for comparison of C_max and T_max) followed by a plasma melatonin plateau and a more prolonged decay over time. Plasma melatonin/6-SMT AUC_0–540/420 ratio was 0.09 for the PR form and 0.16 for the IR form. Both galenic forms were well tolerated. Conclusions The results suggest that the galenic forms containing melatonin assessed in this study are suitable for the treatment of certain sleep disorders such as sleep onset delay and transient nocturnal awakenings for the IR form and insomnia for the PR form. Trial Registry Registration number: NCT04574141.