H. Doorenbos, W. D. Reitsma, P. Terpstra and J. W. E. Visser
N Benhadi, E Fliers, T J Visser, J B Reitsma and W M Wiersinga
To determine the log-linear relationship between TSH and free thyroxine in healthy subjects, and the variation in baseline TSH/free thyroxine (FT4) combination in each individual.
Subjects and methods
Twenty-one healthy volunteers (nine males and 12 females; mean age 60 years, range 51–74) were randomized to receive at 2300 h with 2-week intervals a single dose of placebo, 125 μg T4 and 250 μg T4 (arm 1, n=10), or placebo, 25 μg triiodothyronine (T3) and 50 μg T3 (arm 2, n=11). Blood samples were taken in the morning (0800–1100 h) before and following the administration of the drug for the assessment of TSH, FT4 and T3.
Intra- and inter-individual variation and the individuality index of the four baseline serum samples were respectively 21.6%, 41.9% and 0.52 for TSH; 9.9%, 16.5% and 0.60 for FT4; and 9.3%, 16.0% and 0.58 for T3. Substantial differences existed in the location of individual working points within the reference range. T4 administration increased FT4 (but not T3) and decreased TSH, resulting in a log-linear relationship (log TSH=1.50–0.059×FT4, P<0.05) for the whole group. T3 administration increased T3 and decreased TSH (but not FT4), resulting in a log-linear relationship (log TSH=0.790–0.245×T3, P<0.001) for the whole group. Log-linear relationships were not always significant when assessed for each subject separately.
Individuality indices of TSH, FT4 and T3 are all ≤0.6, thereby limiting the usefulness of the population-based reference values. Accurate assessment of individual setpoints of the HPT axis was not possible with the applied single doses of T4 or T3, and will require either prolonged administration or higher single doses of thyroid hormone.
H. K. A. Visser, H. J. Degenhart, E. Desmit and W. S. Cost
Using isotope dilution methods the secretion rates of cortisol, aldosterone, deoxycorticosterone, corticosterone and 18-hydroxycorticosterone were determined in two brothers (76/12 and 108/12 years old) with dwarfism, chronic hypokalaemia alkalosis, tendency to hyponatraemia and normal blood pressure. Both patients showed a decreased response of the blood pressure to infused angiotensin.
The urinary excretion of cortisol, cortisone, corticosterone, 11-dehydrocorticosterone and their tetrahydrometabolites as well as of aldosterone was determined. In general, results were in agreement with those of the secretion rate studies.
The results suggest a relatively small mineralocorticoid excess (mainly corticosterone) to high plasma-renin concentrations. The differences in both the plasma-renin concentrations and the steroid secretory rates during low and high sodium intake indicate that the renin-angiotensin-mineralocorticoid system is still under regular control, although the normal regulatory process is severely disturbed.
The primary defect in these patients is probably not a relative insensitivity of the arterial walls to the pressor effect of angiotensin as suggested by Bartter et al. (1962), but rather a renal tubular defect in the re-absorption of sodium.
Liset E M Elstgeest, Elisa J de Koning, Ingeborg A Brouwer, Natasja M van Schoor, Brenda W J H Penninx and Marjolein Visser
Previous prospective studies on the association between vitamin D status and depression used a single 25-hydroxyvitamin D (25(OH)D) measurement. We investigated the association between change in serum 25(OH)D and parallel change in depressive symptoms over time in Dutch older adults.
A population-based, prospective study in two cohorts of older men and women from the Longitudinal Aging Study Amsterdam.
Serum 25(OH)D concentrations were determined at two time points: in 1995/1996 and 13 years later in the older cohort (aged 65–88y, n = 173) and in 2002/2003 and 6 years later in the younger cohort (55–65 years, n = 450). At these time points, depressive symptoms were measured with the Center for Epidemiologic Studies Depression scale (CES-D). Associations were tested by multiple linear regression analyses.
During follow-up, serum 25(OH)D concentrations increased in 32.4% of the older cohort and in 69.8% of the younger cohort. In the older cohort, change in 25(OH)D was not associated with change in CES-D score. In the younger cohort, no associations were observed in participants with higher baseline 25(OH)D concentrations (>58.6 nmol/L), but in those with lower baseline 25(OH)D concentrations, an increase in 25(OH)D was associated with a decrease in CES-D score (adjusted B per 10 nmol/L 25(OH)D increase: −0.62 (95% CI: −1.17, −0.07)).
Our study suggests that over 6 years, an increase in serum 25(OH)D is associated with a small decrease in depressive symptoms in young older adults with lower baseline 25(OH)D. Well-designed intervention trials are required to determine causality.
G F Kerkhof, R W J Leunissen, R H Willemsen, F H de Jong, J A Visser, J S E Laven and A C S Hokken-Koelega
Preterm birth has been associated with reduced reproduction rates, and controversies remain regarding the effect of being born small for gestational age (SGA) on ovarian function. Recent findings in young men showed no effect of preterm and SGA birth on testis function. We hypothesised that follicle pool size in young adult women is also not affected by preterm and SGA birth.
In 279 young women of the PROGRAM/PREMS study, aged 18–24 years, the influence of gestational age, birth length and birth weight on serum levels of anti-Müllerian hormone (AMH) was analysed with multiple regression modelling. Additionally, AMH levels were analysed in preterm- versus term-born females and in three subgroups: females born SGA with either short stature or catch-up growth (SGA-CU), and females born term and appropriate for gestational age with normal stature (AGA controls).
Preterm and SGA birth did not affect AMH and other hormone levels. Older age at menarche and oral contraceptive pill use (OC-use) were related to lower AMH levels, and maternal smoking during gestation was related to higher AMH levels. After correction for maternal smoking, lower socioeconomic status (SES) was associated with lower AMH levels. In subgroup comparisons, SGA-CU women showed higher AMH levels than AGA controls, also after adjustment for several factors.
Preterm and SGA birth did not affect AMH levels. Factors associated with serum AMH levels were OC-use, age at menarche, maternal smoking during gestation and SES. We conclude that preterm- and/or SGA-born females are not likely to have a reduced follicle pool size.
S. L. S. Drop, I. M. E. Frohn-Mulder, H. K. A. Visser, W. G. Sippell, H. G. Dörr and M. Schöneshöfer
In two children with isolated congential hyperreninaemic hypoaldosteronism, as well as in their relatives, plasma levels of aldosterone (Aldo), corticosterone (B), deoxycorticosterone (DOC), 18-OH-B and 18-OH-DOC were measured before and after an iv bolus of 0.25 mg Synacthen® (Ciba). A corticosterone methyl oxidase deficiency type II was demonstrated in one child. Her normoreninaemic parents (no consanguinity) had plasma values consistent with heterozygosity. The results in the other child and one asymptomatic sib were compatible with a partial corticosterone methyl oxidase deficiency type I. His parents were consanguine but had normal Aldo levels. Overnight dexamethasone administration did not suppress any of the steroids measured except cortisol, suggesting synthesis of these steroids by the zona glomerulosa.
W van Dorp, K Blijdorp, J S E Laven, R Pieters, J A Visser, A J van der Lely, S J C M M Neggers and M M van den Heuvel-Eibrink
Obesity and gonadal dysfunction are known major side effects of treatment in adult childhood cancer survivors (CCS). In the general population, obesity has a negative influence on female fertility. We aimed to evaluate whether obesity and serum insulin are associated with decreased ovarian reserve markers in CCS.
Retrospective single-center cohort study.
Data of 191 female survivors of childhood cancer were analyzed. Median follow-up time was 18.8 (2.3–48.8) years. Outcome measures were serum anti-Müllerian hormone (AMH) and total follicle count (FC). Potential risk factors were: BMI; body composition measures, determined by dual-energy X-ray absorptiometry (total fat percentage, lean body mass, and visceral fat percentage); and fasting insulin.
Lower serum AMH was found in obese subjects (β (%) −49, P=0.007) and in subjects with fasting insulin in the highest tertile (β (%) −43, P=0.039). Total fat percentage tends to be associated with serum AMH (β (%) −2.1, P=0.06). Survivors in the highest tertile of insulin had significantly lower FC than survivors in the lowest tertile (β −6.3, P=0.013). BMI and other measures of body composition were not associated with FC. Correlation between serum AMH and antral follicle count (AFC) was ρ=0.32 (P=0.08).
Obesity and insulin resistance are associated with gonadal damage, as reflected by decreased AMH and reduced FC in adult survivors of childhood cancer. In contrast to its highly predictive value for AFC in the healthy female population, serum AMH does not seem to correlate as well with AFC in CCS.
S R Ali, J Bryce, M Cools, M Korbonits, J G Beun, D Taruscio, T Danne, M Dattani, O M Dekkers, A Linglart, I Netchine, A Nordenstrom, A Patocs, L Persani, N Reisch, A Smyth, Z Sumnik, W E Visser, O Hiort, A M Pereira, S F Ahmed and on behalf of Endo-ERN
To identify cross-border international registries for rare endocrine conditions that are led from Europe and to understand the extent of engagement with these registries within a network of reference centres (RCs) for rare endocrine conditions.
Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%.
Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RCs were aware of 11 (41%). Of 21 registries identified by the RC, RD-Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RCs, the awareness and participation rate in an international registry was highest for rare diabetes at 75 and 56% respectively. Of the 37 sex development RCs, the corresponding rates were highest for disorders of sex development at 70 and 52%. Of the 33 adrenal RCs, the rates were highest for adrenocortical tumours at 68 and 43%. Of the 43 pituitary RCs, the rates were highest for pituitary adenomas at 43 and 29%. Of the 31 genetic tumour RCs, the rates were highest for MEN1 at 26 and 9%. For the remaining conditions, awareness and participation in registries was less than 25%.
Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries.