In recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central... Show moreIn recent years, variants in immunoglobulin superfamily member 1 (IGSF1) have been associated with congenital hypopituitarism. Initially, IGSF1 variants were only reported in patients with central hypothyroidism (CeH) and macroorchidism. Later on, IGSF1 variants were also reported in patients with additional endocrinopathies, sometimes without macroorchidism. We studied IGSF1 as a new candidate gene for patients with combined CeH and growth hormone deficiency (GHD). We screened 80 male and 14 female Dutch patients with combined CeH and GHD for variants in the extracellular region of IGSF1, and we report detailed biomedical and clinical data of index cases and relatives. We identified three variants in our patient cohort, of which two were novel variants of unknown significance (p.L570I and c.1765+37C>A). In conclusion, we screened 94 patients with CeH and GHD and found variants in IGSF1 of which p.L570I could be of functional relevance. We provide detailed phenotypic data of two boys with the p.C947R variant and their large family. The remarkable phenotype of some of the relatives sheds new light on the phenotypic spectrum of IGSF1 variants. Show less
Spoel, E. van der; Roelfsema, F.; Heemst, D. van 2021
Objective: To investigate the relationship between LH and testosterone (T), which characteristics associate with the strength of this relationship, and their interrelationships with GH, TSH,... Show moreObjective: To investigate the relationship between LH and testosterone (T), which characteristics associate with the strength of this relationship, and their interrelationships with GH, TSH, cortisol, and ACTH.Design: Hormones were measured in serum samples collected every 10 minutes during 24 hours from 20 healthy men, comprising 10 offspring of long-lived families and 10 control subjects, with a mean (SD) age of 65.6 (5.3) years. We performed cross-correlation analyses to assess the relative strength between 2 timeseries for all possible time shifts.Results: Mean (95% CI) maximal correlation was 0.21 (0.10-0.31) at lag time of 60 minutes between LH and total T concentrations. Results were comparable for calculated free, bioavailable, or secretion rates of T. Men with strong LH-T cross-correlations had, compared with men with no cross-correlation, lower fat mass (18.5 [14.9-19.7] vs. 22.3 [18.4-29.4] kg), waist circumference (93.6 [5.7] vs. 103.1 [12.0] cm), high-sensitivity C-reactive protein (0.7 [0.4-1.3] vs. 1.8 [0.8-12.3] mg/L), IL-6 (0.8 [0.6-1.0] vs. 1.2 [0.9-3.0] pg/mL), and 24-hour mean LH (4.3 [2.0] vs. 6.1 [1.5] U/L), and stronger LH-T feedforward synchrony (1.5 [0.3] vs. 1.9 [0.2]). Furthermore,T was positively cross-correlated withTSH (0.32 [0.21-0.43]), cortisol (0.26 [0.19-0.33]), and ACTH (0.26 [0.19-0.32]).Conclusions: LH is followed by T with a delay of 60 minutes in healthy older men. Men with a strong LH-T relationship had more favorable body composition, inflammatory markers, LH levels, and LH-T feedforward synchrony. We observed positive correlations between T and TSH, cortisol, and ACTH. Show less
Spoel, E. van der; Roelfsema, F.; Akintola, A.A.; Jansen, S.W.; Slagboom, P.E.; Westendorp, R.G.J.; ... ; Heemst, D. van 2020
Context: Hormones of the hypothalamic-pituitary-target gland axes are mostly investigated separately, whereas the interplay between hormones might be as important as each separate hormonal axis... Show moreContext: Hormones of the hypothalamic-pituitary-target gland axes are mostly investigated separately, whereas the interplay between hormones might be as important as each separate hormonal axis.Objective: Our aim is to determine the interrelationships between GH, TSH, ACTH, and cortisol in healthy older individuals.Design: We made use of 24-hour hormone serum concentrations assessed with intervals of 10 minutes from 38 healthy older individuals with a mean age (SD) of 65.1 (5.1) years from the Leiden Longevity Study. Cross-correlation analyses were performed to assess the relative strength between 2 24-hour hormone serum concentration series for all possible time shifts. Cross-approximate entropy was used to assess pattern synchronicity between 2 24-hour hormone serum concentration series.Results: Within an interlinked hormonal axis, ACTH and cortisol were positively correlated with a mean (95% confidence interval) correlation coefficient of 0.78 (0.74-0.81) with cortisol following ACTH concentrations with a delay of 10 minutes. Between different hormonal axes, we observed a negative correlation coefficient between cortisol and TSH of -0.30 (-0.36 to -0.25) with TSH following cortisol concentrations with a delay of 170 minutes. Furthermore, a positive mean (95% confidence interval) correlation coefficient of 0.29 (0.22-0.37) was found between TSH and GH concentrations without any delay. Moreover, cross-approximate entropy analyses showed that GH and cortisol exhibit synchronous serum concentration patterns.Conclusions: This study demonstrates that interrelations between hormones from interlinked as well as different hypothalamic-pituitary-target gland axes are observed in healthy older individuals. More research is needed to determine the biological meaning and clinical consequences of these observations. Show less