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.

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.

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.

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.

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.

Variation of female prolactin levels with menopausal status and phase of menstrual cycle.

BACKGROUND: Prolactin is not commonly recognised as a hormone that changes significantly within the menstrual cycle or after menopause. The aim of this study was to determine the degree of variability of prolactin in these physiological states. METHOD: Prolactin levels obtained from 6540 subjects between January 2006 and November 2008 were divided into five groups: men, postmenopausal women and premenopausal women in follicular/non-cycling, ovulatory and luteal phases. The median and 97.5th centile was determined for each group. The 97.5th centile was used to define the upper limit of prolactin. RESULTS: The prolactin median and upper limits were not significantly different in men and postmenopausal women. They were significantly higher in premenopausal women compared to men and postmenopausal women. Within premenopausal women, the prolactin median and upper limits were significantly higher in ovulatory phase compared to follicular/non-cycling and luteal phases and in luteal phase compared to follicular/non-cycling phase. CONCLUSIONS: Prolactin levels varied significantly throughout the menstrual cycle, and the utility and accuracy of prolactin testing may be improved by applying specific reference intervals for each phase of the menstrual cycle. Alternatively, a single reference interval could be used if prolactin is only measured in the follicular phase, well before midcycle. Prolactin levels in postmenopausal women and men were not significantly different, and a common prolactin reference interval may be appropriate. Further studies to confirm formal reference ranges for these groups may be clinically helpful.

Assessment of thyroid function during pregnancy: first-trimester (weeks 9-13) reference intervals derived from Western Australian women.

OBJECTIVE: To establish first-trimester-specific reference intervals for thyroid function tests in pregnant Australian women. DESIGN, SETTING AND PARTICIPANTS: Serum samples were collected from 2159 pregnant women (9-13 weeks' gestation) attending a private pathology practice for first-trimester screening during October and November 2006. Levels of serum thyrotropin (TSH), free thyroxine (fT4), free triiodothyronine (fT3), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were measured by chemiluminescent immunoassay (Abbott ARCHITECT analyser). MAIN OUTCOME MEASURES: Reference intervals based on 2.5th and 97.5th percentiles for TSH, fT4 and fT3, after exclusion of 338 women with positive TPOAb or TgAb tests; comparison with reference intervals for non-pregnant women (TSH, 0.40-4.0 mU/L; fT4, 9-19 pmol/L; fT3, 3.0-5.5 pmol/L). RESULTS: Derived reference intervals for thyroid function tests during the first trimester of pregnancy were: TSH, 0.02-2.15 mU/L; fT4, 10.4-17.8 pmol/L; and fT3, 3.3-5.7 pmol/L. If the non-pregnant TSH reference range was applied to the study participants, 344 women (16.0%) whose serum TSH concentration was within the first-trimester-specific reference range would be misclassified as having subclinical hyperthyroidism, and 98 women (4.5%) with a TSH concentration above the first-trimester-specific upper reference limit would not be identified. CONCLUSIONS: The reference interval for TSH during the first trimester of pregnancy differs substantially from that for non-pregnant women, and applying the general laboratory reference range to pregnant women results in misclassification of thyroid status for 20.5% of women. Australian pathology laboratories should adopt pregnancy-specific reference intervals for thyroid function tests.

Use of the combined first-trimester screen result and low PAPP-A to predict risk of adverse fetal outcomes.

OBJECTIVES: To investigate associations between combined first-trimester screen result, pregnancy associated plasma protein-A (PAPP-A) level and adverse fetal outcomes in women. METHODS: Pregnancy outcomes for 10,273 women participating in a community based first-trimester screening (FTS) programme in Western Australia were ascertained by record linkage to birth and birth defect databases. A first-trimester risk cut-off of > or = 1 in 300 defined screen positive women. RESULTS: Screen positive pregnancies were more likely to have Down syndrome and birth defects (chromosomal or nonchromosomal) than screen negative pregnancies. When birth defects were excluded, screen positive pregnancies were at increased risk of pregnancy loss, low birth weight and preterm birth. Pregnancies with low PAPP-A (< or =0.3 multiples of the median (MoM)) had higher risk of chromosomal abnormality, birth defect, preterm birth, low birth weight, or pregnancy loss, compared to those with PAPP-A > 0.3 MoM. In pregnancies without birth defects, low PAPP-A was a stronger predictor of preterm birth, low birth weight or pregnancy loss than a screen positive result. CONCLUSIONS: Women with positive screen or low PAPP-A were at increased risk for some adverse fetal outcomes. The sensitivity of these parameters was insufficient to support primary screening, but increased surveillance during pregnancy may be appropriate.

Community-based screening for Down's Syndrome in the first trimester using ultrasound and maternal serum biochemistry.

Two years of community-based first trimester screening (FTS) were audited. All women with singleton pregnancy in a defined health region who completed FTS (ultrasound and biochemistry) were included (n= 10,436) and outcomes obtained for 98.4%. All scans were performed or supervised by experienced sonologists with Fetal Medicine Foundation (FMF) accreditation. FMF software generated all risk assessments based on nuchal translucency (NT), maternal serum-free beta human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein A (PAPP-A). The detection rate for Trisomy 21 was 90.6% with a screen-positive rate of 3.9%. These findings indicate that where FTS is accessible within routine antenatal care, a detection rate of 90% and low screen-positive rate can be achieved using the FMF programme.