Anti-Müllerian hormone concentration is associated with central adiposity and reproductive hormones in expectant fathers.

OBJECTIVE: The role of the anti-Müllerian hormone (AMH) as an indicator of physical and reproductive health in men is unclear. We assessed the relationships between AMH and follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and metabolic parameters, in a cohort of expectant fathers. DESIGN: ORIGINS Project prospective cohort study. SETTING: Community-dwelling men. PARTICIPANTS: Partners of pregnant women attending antenatal appointments. MAIN OUTCOME MEASURES: Serum AMH, FSH, LH, testosterone, and metabolic parameters. RESULTS: In 485 expectant fathers, median age 33 years, median AMH was 40 pmol/L (quartiles 29, 56). AMH was inversely correlated with FSH, age, and body mass index (BMI) (correlation coefficients: -.32, -.24, and -.17 respectively). The age association was nonlinear, with peak AMH between 20 and 30 years, a decline thereafter, and somewhat steady levels after 45 years. The inverse association of AMH with FSH was log-linear and independent of age and BMI (ß: -.07, SE: 0.01, p < .001). AMH was inversely correlated with waist circumference and directly associated with sex hormone-binding globulin. Testosterone was moderately correlated with AMH (correlation coefficient: .09, ß: .011, SE: 0.004, p = .014): this association was mediated by an inverse relationship with BMI (mediated proportion 0.49, p < .001). CONCLUSIONS: In reproductively active men, lower AMH is a biomarker for advancing age, and for poorer metabolic and reproductive health. The inverse association between AMH and FSH is independent of age and BMI, whereas the association of AMH and testosterone is mediated via BMI. The utility of AMH to predict reproductive and cardiometabolic outcomes in men warrants further investigation.

Self-collection: An appropriate alternative during the SARS-CoV-2 pandemic.

OBJECTIVES: To evaluate the reliability of self-collection for SARS-CoV-2 and other respiratory viruses because swab collections for SARS-CoV-2 put health workers at risk of infection and require use of personal protective equipment (PPE). METHODS: In a prospective study, patients from two states in Australia attending dedicated COVID-19 collection clinics were offered the option to first self-collect (SC) nasal and throat swabs (SCNT) prior to health worker collect (HC) using throat and nasal swabs (Site 1) or throat and nasopharyngeal swabs (Site 2). Samples were analysed for SARS-CoV-2 as well as common respiratory viruses. Concordance of results between methods was assessed using Cohen's kappa (κ) and Cycle threshold (Ct) values were recorded for all positive results as a surrogate measure for viral load. RESULTS: Of 236 patients sampled by HC and SC, 25 had SARS-CoV-2 (24 by HC and 25 by SC) and 63 had other respiratory viruses (56 by HC and 58 by SC). SC was highly concordant with HC (κ = 0.890) for all viruses including SARS-CoV-2 and more concordant than HC to positive results by any method (κ = 0.959 vs 0.933). Mean SARS-CoV-2 E-gene and N-gene, rhinovirus and parainfluenza Ct values did not differ between HC and SCNT. CONCLUSIONS: Self-collection of nasal and throat swabs offers a reliable alternative to health worker collection for the diagnosis of SARS-CoV-2 and other respiratory viruses and provides patients with easier access to testing, reduces exposure of the community and health workers to those being tested and reduces requirement for PPE.

Where in the world? Latitude, longitude and season contribute to the complex co-ordinates determining cortisol levels.

OBJECTIVE: Cortisol is a critical stress hormone with circadian rhythms synchronized by light. There are seasonal differences in expression of pro-inflammatory genes and in some diseases moderated by glucocorticoids. As light changes with season and with latitude and longitude, we assessed changes in population cortisol associated with these parameters. DESIGN: Retrospective data audit. PATIENTS: Populations across 4 states of Australia over 3 years. MEASUREMENTS: Serum cortisol levels, age, gender, time of collection, sunrise time, season and location were determined. RESULTS: In 4 geographically separate populations (n = 84 937), sunrise time and time of sample collection were the most important factors influencing median cortisol. Over 2 hours in the morning cortisol could decrease by up to 76 nmol/L, and for each hour that sunrise time advanced there was up to 6.9% increase in cortisol. A cyclic seasonal pattern of cortisol was confirmed each year in all populations with autumn/winter cortisol highest compared to spring/summer with differences of up to 44 nmol/L. There was less change in cortisol in latitudes closer to the equator but cortisol progressively increased from 25 to 30°S of the equator. In more southerly latitudes, seasonal cortisol variation also increased, and over the entire latitude range, there was up to 50 nmol/L change in cortisol. Longitude variation within a time zone had a minimal effect on median cortisol. CONCLUSIONS: Location, time of year and time of day are important influences on population cortisol levels. Elevated autumn/winter morning cortisol levels are likely due to sampling closer to the circadian peak due to later sunrise time. Understanding how the environment can influence cortisol levels may further our knowledge of physiology and disease.

Rationalizing Thyroid Function Testing: Which TSH Cutoffs Are Optimal for Testing Free T4?

Context: Thyroid function testing often uses thyrotropin (TSH) measurement first, followed by reflex testing for free thyroxine (T4) if TSH is outside the reference range. The utility of different TSH cutoffs for reflex testing is unknown. Objective: To examine different TSH cutoffs for reflex free T4 testing. Design, Setting, and Patients: We analyzed concurrent TSH and free T4 results from 120,403 individuals from a single laboratory in Western Australia (clinical cohort) and 4568 Busselton Health Study participants (community cohort). Results: In the clinical cohort, restricting free T4 measurement to individuals with TSH <0.3 or >5.0 mU/L resulted in a 22% reduction in free T4 testing compared with a TSH reference range of 0.4 to 4.0 mU/L; using TSH cutoffs of 0.2 and 6.0 mU/L resulted in a 34% reduction in free T4 testing. In the community cohort, the corresponding effect was less: 3.3% and 4.8% reduction in free T4 testing. In the clinical cohort, using TSH cutoffs of 0.2 and 6.0 mU/L, elevated free T4 would go undetected in 4.2% of individuals with TSH levels of 0.2 to 0.4 mU/L. In most, free T4 was marginally elevated and unlikely to indicate clinically relevant hyperthyroidism. Low free T4 would go undetected in 2.5% of individuals with TSH levels of 4 to 6 mU/L; in 94%, free T4 was marginally reduced and unlikely to indicate clinically relevant hypothyroidism. Conclusions: Setting TSH cutoffs at 0.1 to 0.2 mU/L less than and 1 to 2 mU/L greater than the reference range for reflex testing of free T4 would reduce the need for free T4 testing, with minimal effect on case finding.

A time-adjusted cortisol cut-off can reduce referral rate for Synacthen stimulation test whilst maintaining diagnostic performance.

OBJECTIVE: Cortisol cut-offs can predict requirement for Synacthen stimulation tests (SST). We assessed the performance of a standard cortisol cut-off (375 nmol/L) across the morning and compared this with a time-adjusted cut-off. DESIGN: Retrospective audit PATIENTS: Community reference set (n=12 550) and SST patients (n=757). MEASUREMENTS: In the reference population, time-specific cortisol medians were calculated and used to convert cortisol to time-adjusted Multiples of the Median (MoM). In 757 SST patients, the predictive performance of a standard cortisol cut-off (375 nmol/L) and its time-adjusted MoM equivalent were compared. RESULTS: Median cortisol decreased by ~30 nmol/L per hour between 0700 and 1200h. In the reference population, proportions below the 375 nmol/L cut-off increased throughout the morning (range 35%-64%), whereas using the time-adjusted MoM cut-off proportions were consistent (range 46%-50%), with a 17% maximal difference in referral rates between the two cut-offs after 1100h. A similar pattern was noted in the SST cohort. When a cortisol MoM cut-off was used to predict SST success, the excess proportion of patients tested and misclassification rates were lower and more consistent than when the standard cut-off was used. A median cortisol of 375 nmol/L equated to 444 and 313 nmol/L before 0800 and after 1100 h, respectively. CONCLUSION: The use of a standard cortisol cut-off results in 17% more patients being referred for SST later in the morning. A time-adjusted cortisol cut-off provides consistent and lower referral rates, whilst maintaining similar or better performance than a standard single cut-off in predicting outcome of SST.

Longitudinal changes in maternal serum concentrations of antimüllerian hormone in individual women during conception cycles and early pregnancy.

OBJECTIVE: To study antimüllerian hormone (AMH) from gestation week 0-7. DESIGN: Longitudinal study of 85 pregnant women with AMH and reproductive hormones sampled during conception cycle and early pregnancy until week 7. SETTING: Fertility clinic. PATIENT(S): Of 85 pregnant women, 69 had a singleton pregnancy, 1 a twin pregnancy, and 15 had a nonviable pregnancy (3 chemical pregnancies, 11 miscarriages, and 1 blighted ovum). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relationship between AMH and gestation week, woman's age, body mass index (BMI), FSH dose, treatment modality, reproductive hormones, viability of pregnancies, and fetal gender. RESULT(S): During the conception cycle, 86.1% of women had their maximum AMH at or before ovulation. The AMH level did not remain constant in viable pregnancies, but moved significantly away from baseline pregnancy level. In natural pregnancies the overall trend was for decreasing AMH level. In treatment pregnancies AMH level either consistently increased or decreased from gestation week 4 (time of first positive hCG) through to week 7. In contrast, the AMH level in nonviable pregnancies showed sporadic changes, both increasing and decreasing in the same individual from gestation weeks 4-7. The AMH level was negatively correlated with patient's age (r = -0.507) and P level (r = -0.220), but no other associations were observed with BMI, FSH dose, treatment modality, or fetal gender. CONCLUSION(S): The AMH level peaked at or before ovulation in most women, trended down with natural pregnancies, and consistently increased or decreased in women with a viable pregnancy after therapy. Nonviable pregnancies showed erratic AMH patterns. Factors responsible for these different responses in pregnancy remain to be identified.

Quantifying the intraindividual variation of antimüllerian hormone in the ovarian cycle.

OBJECTIVE: To quantify intraindividual variability of antimüllerian hormone (AMH) as analytical and biological coefficients of variation and assess the effects of variation on clinical classification. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Thirty-eight women referred by general practitioners. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Total intraindividual variability (CVW), analytical (CVA) and biological variability (CVI) for each woman and for AMH ranges: low (<5 pmol/L), reduced (5-10), moderate (>10-30) and high (>30 pmol/L), with calculation of proportion of women crossing clinical cutoffs and expected variability around each cutoff. RESULT(S): Cycling women (n = 38) contributed 238 blood samples (average 6 samples each). The average total intraindividual AMH variability was 20% (range: 2.1% to 73%). Biological variation was 19% (range: 0 to 71%) and at least twice the analytical variation of 6.9% (range: 4.5% to 16%). Reclassification rates were highest in women with low (33%) or reduced AMH (67%) levels. Expected variations around the 5, 10, and 30 pmol/L cutoffs were 3-7, 7-13, and 20-40 pmol/L, respectively. In a woman with mean AMH in the 10-30 pmol/L range, the span of results that could occur was 7-40 pmol/L. CONCLUSION(S): Total variation in AMH was 20%, and the majority of this was biological. Changes in AMH resulted in reclassification in 29% of women and occurred most frequently in those with low and reduced AMH. In cycling women, the variability in AMH should be considered by clinicians, especially if a result is close to a clinical cutoff.

The log TSH-free T4 relationship in a community-based cohort is nonlinear and is influenced by age, smoking and thyroid peroxidase antibody status.

BACKGROUND: The TSH-T4 relationship was thought to be inverse log-linear, but recent cross-sectional studies of selected populations report a complex, nonlinear relationship. The TSH-T4 relationship has not been evaluated in an unselected, community-based cohort, and there are limited data regarding clinical factors which affect it. OBJECTIVE: To analyse the TSH-free T4 relationship in a community-based cohort. DESIGN, PARTICIPANTS AND METHODS: In a cross-sectional, retrospective study, we analysed serum TSH and free T4 concentrations from 4427 participants (55% female) in the 1994 Busselton Health Study who were not taking thyroxine. Simple linear, segmented-linear and nonlinear regression models of log10 TSH on free T4 were compared for goodness of fit. RESULTS: All 5 log TSH-free T4 models tested (separate lines, segmented conterminal line, quartic, error function, double-sigmoid curve) fitted significantly better than a simple linear model (each P < 0·01 by Vuong test). Ranking by Akaike information criterion indicated that the segmented conterminal line and double-sigmoid models provided best fit, followed by the error function, quartic and separate lines models. From multiple regression analysis, age tertile, current smoking and TPOAb status each significantly influenced the TSH-free T4 relationship, whereas BMI category and diabetes did not. A sex difference in the TSH-free T4 relationship was apparent only in the lower part of the free T4 reference range. CONCLUSION: In a community-based setting, the relationship between log TSH and free T4 is complex, nonlinear and influenced by age, smoking and TPOAb status.

Reconciling the Log-Linear and Non-Log-Linear Nature of the TSH-Free T4 Relationship: Intra-Individual Analysis of a Large Population.

CONTEXT: The TSH-T4 relationship was thought to be inverse log-linear, but recent cross-sectional studies report a complex, nonlinear relationship; large, intra-individual studies are lacking. OBJECTIVE: Our objective was to analyze the TSH-free T4 relationship within individuals. METHODS: We analyzed data from 13 379 patients, each with six or more TSH/free T4 measurements and at least a 5-fold difference between individual median TSH and minimum or maximum TSH. Linear and nonlinear regression models of log TSH on free T4 were fitted to data from individuals and goodness of fit compared by likelihood ratio testing. RESULTS: Comparing all models, the linear model achieved best fit in 31% of individuals, followed by quartic (27%), cubic (15%), null (12%), and quadratic (11%) models. After eliminating least favored models (with individuals reassigned to best fitting, available models), the linear model fit best in 42% of participants, quartic in 43%, and null model in 15%. As the number of observations per individual increased, so did the proportion of individuals in whom the linear model achieved best fit, to 66% in those with more than 20 observations. When linear models were applied to all individuals and averaged according to individual median free T4 values, variations in slope and intercept indicated a nonlinear log TSH-free T4 relationship across the population. CONCLUSIONS: The log TSH-free T4 relationship appears linear in some individuals and nonlinear in others, but is predominantly linear in those with the largest number of observations. A log-linear relationship within individuals can be reconciled with a non-log-linear relationship in a population.

Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes.

Genetic factors contribute strongly to sex hormone levels, yet knowledge of the regulatory mechanisms remains incomplete. Genome-wide association studies (GWAS) have identified only a small number of loci associated with sex hormone levels, with several reproductive hormones yet to be assessed. The aim of the study was to identify novel genetic variants contributing to the regulation of sex hormones. We performed GWAS using genotypes imputed from the 1000 Genomes reference panel. The study used genotype and phenotype data from a UK twin register. We included 2913 individuals (up to 294 males) from the Twins UK study, excluding individuals receiving hormone treatment. Phenotypes were standardised for age, sex, BMI, stage of menstrual cycle and menopausal status. We tested 7,879,351 autosomal SNPs for association with levels of dehydroepiandrosterone sulphate (DHEAS), oestradiol, free androgen index (FAI), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, progesterone, sex hormone-binding globulin and testosterone. Eight independent genetic variants reached genome-wide significance (P<5 × 10(-8)), with minor allele frequencies of 1.3-23.9%. Novel signals included variants for progesterone (P=7.68 × 10(-12)), oestradiol (P=1.63 × 10(-8)) and FAI (P=1.50 × 10(-8)). A genetic variant near the FSHB gene was identified which influenced both FSH (P=1.74 × 10(-8)) and LH (P=3.94 × 10(-9)) levels. A separate locus on chromosome 7 was associated with both DHEAS (P=1.82 × 10(-14)) and progesterone (P=6.09 × 10(-14)). This study highlights loci that are relevant to reproductive function and suggests overlap in the genetic basis of hormone regulation.

Chronic kidney disease in the Top End of the Northern Territory of Australia, 2002-2011: a retrospective cohort study using existing laboratory data.

BACKGROUND: The Northern Territory of Australia has a very high incidence of treated end-stage kidney disease (ESKD), largely confined to Indigenous Australians living in remote, under-resourced areas. Surveillance of chronic kidney disease (CKD) is still in its infancy in Australia. We estimate the prevalence and rate of progression of measured CKD across a region using inexpensive readily available laboratory information. METHODS: Using a retrospective de-identified extraction of all records with a serum creatinine or urinary albumin-to-creatinine ratio from the single largest ambulatory pathology provider to the Top End of the Northern Territory of Australia between 1st February 2002 and 31st December 2011, the yearly total and age-specific prevalence of measured microalbuminuria, overt albuminuria and estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), and the prevalence of progressive CKD, were calculated. RESULTS: There was a steady increase in the proportion tested across all health districts in the region, more prominent in non-urban districts. In 2009, the regional adult prevalence of measured microalbuminuria and overt albuminuria was as high as 8.1 %, overt albuminuria alone up to 3.0 % and eGFR < 60 up to 2.3 %. Rates of progressive disease were extremely high, particularly for those with albuminuria (53.1-100 % for those with urinary albumin-creatinine ratio > 300 mg/mmol). CONCLUSIONS: The rates of testing, particularly in districts of high measured prevalence of markers of CKD, are encouraging. However, extremely high rates of progressive CKD are troubling. Further describing the outcomes of CKD in this population would require analysis of linked datasets.

Brief report: Does PTH increase with age, independent of 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium?

CONTEXT: Circulating PTH concentrations increase with age. It is uncertain whether an age-related PTH increase occurs independent of changes in circulating 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium. OBJECTIVE: The purpose of this article was to analyze the relationship between PTH and age, controlling for 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium. METHODS: This was a retrospective, cross-sectional study analyzing the relationship between PTH and age in 2 independent datasets (laboratory 1, n = 17 275 and laboratory 2, n = 4878). We further analyzed subgroups after excluding participants with estimated glomerular filtration rate of <60 mL/min/1.73 m(2) or 25-hydroxyvitamin D of <50 nmol/L (for subgroups, n = 12 051 for laboratory 1 and 3473 for laboratory 2). RESULTS: After adjustment for sex, ionized calcium, 25-hydroxyvitamin D, phosphate, and estimated glomerular filtration rate, each 10-year increase in age was associated with a 5.0% increase in PTH (95% confidence interval [CI], 4.4%-5.6%; P < .001) in laboratory 1 and a 4.2% increase in laboratory 2 (95% CI, 3.0%-5.4%; P < .001). In the subgroups, each 10-year increase in age was associated with a 6.1% increase in PTH (95% CI, 5.5%-6.8%; P < .001) in laboratory 1 and a 4.9% increase (95% CI 3.5%-6.2%; P < .001) in laboratory 2. CONCLUSION: PTH concentrations increase with age, independent of 25-hydroxyvitamin D, ionized calcium, phosphate, and renal function. Further research is required to explore the underlying mechanisms and clinical relevance and to determine whether the use of age-related PTH reference ranges improves diagnostic accuracy, particularly in elderly individuals.

Does the thyroid-stimulating hormone measured concurrently with first trimester biochemical screening tests predict adverse pregnancy outcomes occurring after 20 weeks gestation?

CONTEXT: Maternal hypothyroidism in early pregnancy is associated with adverse outcomes, but not consistently across studies. First trimester screening for chromosomal anomalies is routine in many centers and provides an opportunity to test thyroid function. OBJECTIVE: To determine if thyroid function tests performed with first trimester screening predicts adverse pregnancy outcomes. DESIGN, PARTICIPANTS AND SETTING: A cohort study of 2411 women in Western Australia with singleton pregnancies attending first trimester screening between 9 and 14 weeks gestation. OUTCOME MEASURES: We evaluated the association between TSH, free T4, free T3, thyroid antibodies, free beta human chorionic gonadotrophin (ß-hCG) and pregnancy associated plasma protein A (PAPP-A) with a composite of adverse pregnancy events as the primary outcome. Secondary outcomes included placenta previa, placental abruption, pre-eclampsia, pregnancy loss after 20 weeks gestation, threatened preterm labor, preterm birth, small size for gestational age, neonatal death, and birth defects. RESULTS: TSH exceeded the 97.5th percentile for the first trimester (2.15 mU/L) in 133 (5.5%) women, including 22 (1%) with TSH above the nonpregnant reference range (4 mU/L) and 5 (0.2%) above 10 mU/L. Adverse outcomes occurred in 327 women (15%). TSH and free T4 did not differ significantly between women with or without adverse pregnancy events. On the multivariate analysis, neither maternal TSH >2.15 mU/L nor TSH as a continuous variable predicted primary or secondary outcomes. CONCLUSION: Testing maternal TSH as part of first trimester screening does not predict adverse pregnancy outcomes. This may be because in the community setting, mainly mild abnormalities in thyroid function are detected.

Impact of routine reporting of estimated glomerular filtration rate using the CKD-EPI formula in a community population: A cross-sectional cohort study.

AIM: Most laboratories are moving to report estimated glomerular filtration rates (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. However, data on the prevalence of chronic kidney disease (CKD) in the population and its economic impact have to date been modelled using data derived from the modification of diet in renal disease (MDRD) equation. Evaluating the impact of CKD-EPI on prevalence has important implications for referral patterns and health expenditure. METHODS: eGFR were calculated from 2 295313 creatinine results from 833334 patients using the MDRD and CKD-EPI formulae. The proportion of patients in each CKD stage was determined and annual rates of change of eGFR in patients assigned to a new CKD stage compared with their previous CKD stage calculated. The effects of age on eGFR were assessed. RESULTS: Reporting of eGFR using the CKD-EPI equation reduced the prevalence of CKD stages III-V from 9.2% to 7.6%. A total of 181126 patients were reclassified using CKD-EPI with 171298 changing to a better CKD stage. Reclassification rates were highest in CKD stages II and III. Patients reclassified from stage III to II tended to be younger or female. eGFR declines rapidly after the age of 60. CONCLUSIONS: Introduction of routine eGFR reporting using the CKD-EPI formula will reduce the population prevalence of CKD. CKD-EPI reporting better identifies patients at risk of further decline in renal function. Improvement in the classification should reduce unnecessary costs related to surveillance and referral. The impact of ageing on renal function should be appreciated.

The effects of season, daylight saving and time of sunrise on serum cortisol in a large population.

Cortisol is critical for maintenance of health and homeostasis and factors affecting cortisol levels are of clinical importance. There is conflicting information about the effects of season on morning cortisol and little information on the effects of sunlight on population cortisol assessment. The aim of this study was to assess whether changes in median serum cortisol occurred in a population in conjunction with changing seasons, daylight saving time (DST) or time of sunrise. We analysed serum cortisol results (n = 27,569) from a single large laboratory over a 13-year period. Subjects with confounding medications or medical conditions were excluded and data analysed in 15-minute intervals. We assessed the influence of traditional seasons, seasons determined by equinox/solstice, DST and time of sunrise on median cortisol. The median time of cortisol collection did not vary significantly between seasons. Using traditional seasons, median cortisol was lowest in summer (386 nmol/L) and spring (384 nmol/L) with higher cortisol in autumn (406 nmol/L) and winter (414 nmol/L). Median cortisol was lowest in the summer solstice quarter with significant comparative increases in the spring equinox quarter (3.1%), the autumn equinox quarter (4.5%) and the winter solstice quarter (8.6%). When cortisol was modelled against time, with adjustment for actual sunrise time on day of collection, for each hour delay in sunrise there was a 4.8% increase in median cortisol (95% CI: 3.9-5.7%). In modelling to explain the variation in cortisol over the morning, sunrise time was better than season in explaining seasonal effects. A subtle cyclic pattern in median cortisol also occurred throughout the months of the year. A 3-year trial of DST allowed comparison of cortisol in DST and non DST periods, when clock time differed by one hour. There was modest evidence of a difference in acrophase between DST and non DST cortisol (p = 0.038), with DST peak cortisol estimated to occur 58 minutes later than non-DST peak. In summary, we found that time of sunrise and time of cortisol collection were the most important factors influencing median cortisol. For each hour later that the sun rose there was an almost 5% increase in median cortisol. There was significant seasonal variability with lowest cortisol noted in summer coinciding with the earliest sunrise time. This is an important finding which is consistent with the understanding that light is the major zeitgeber in entrainment of the human circadian cortisol rhythm. Our data suggest this rhythm is resistant to the arbitrary changes in clock time with daylight saving.

The relationship between TSH and free T4 in a large population is complex and nonlinear and differs by age and sex.

CONTEXT: The relationship between TSH and T4 is thought to be inverse log-linear, but recent studies have challenged this. There are limited data regarding age and sex differences in the TSH-T4 relationship. OBJECTIVE: The purpose of this study was to evaluate the TSH-free T4 relationship in a large sample. METHODS: In a cross-sectional, retrospective study, we analyzed TSH and free T4 results from 152 261 subjects collected over 12 years by a single laboratory. For each free T4 value (in picomoles per liter), the median TSH was calculated and analyzed by sex and age (in 20-year bands). RESULTS: The relationship between log TSH and free T4 was nonlinear. Mathematical modeling confirmed that it was described by 2 sigmoid curves with inflexion points at free T4 concentrations of 7 and 21 pmol/L. For free T4 within the reference range (10-20 pmol/L), median TSH was higher in men than in women (P < .001) and increased across age bands with the highest values in those 80 years and older (P < .001). In contrast, in overt hypothyroidism (n = 4403), TSH was lower in older age groups than in those aged 20-39 years (P < .001). CONCLUSIONS: The TSH-free T4 relationship is not inverse log-linear but can be described by 2 overlapping negative sigmoid curves. At physiological free T4 concentrations, TSH is higher in men and in older people, whereas the TSH response to hypothyroidism is more robust in younger people. These results advance understanding of the TSH-free T4 relationship, which is central to thyroid pathophysiology and laboratory diagnosis of thyroid disease.