http://repub.eur.nl/res/aut/30628/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/38062/ 2012-12-13T00:00:00Z This doctoral thesis describes in a large group of constitutional tall men and women the long-term effects of high-dose sex steroid treatment to reduce final height and the genetic determinants of tall stature. In part 1 we evaluated fertility and gonadal function in later life of two independent cohorts of tall women and one cohort of tall men who did or did not receive high-dose sex steroid treatment in adolescence. We found that estrogen treated women experienced more difficulties conceiving and more often received medical treatment for infertility compared with untreated women. Treated women had a decreased chance of achieving at least one live birth. We report a dose-response relationship between fertility in later life and the estrogen dose used, as women treated with 200 µg of EE significantly more often experienced fertility problems than women treated with 100 µg. Finally, we showed that treated women were at increased risk of being diagnosed with imminent ovarian failure. They exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed infertility. In men we found no long-term impact of this treatment on fatherhood or semen quality. Testosterone production, however, is reduced in androgen treated men. In part 2 we have shown in a candidate gene analysis that several common polymorphisms in the IGF-1, IGFBP-3 and HMGA2 genes are associated with extremely tall stature in a Dutch cohort. Next we have performed a genome-wide association study using extreme tall phenotype as trait. We discovered a new genome-wide significant SNP in the gene for RBM39, which is involved in sex steroid mediated transcription. http://repub.eur.nl/res/pub/34123/ 2011-12-01T00:00:00Z Context/objective: The growth hormone (GH)/insulin-like growth factor-1(IGF-1) axis is the key regulator of somatic growth in humans and its genes are plausible candidates to study the genetics of height variation. Here, we studied polymorphic variation in the GH/IGF-1 axis in the extremely tall Dutch. Methods: Case-control study of 166 tall cases with height >. 2 SDS and 206 controls with normally distributed height <. 2 SDS. Excluded were subjects with endocrine disorders or growth syndromes. We analyzed genomic DNA at 7 common polymorphisms in the GH-1, GH receptor (GHR), IGF-1 and IGFBP-3 genes. Results: The association of the GH-1 1663 SNP with tall stature approached statistical significance, with the T-allele more present in the tall (allele frequency (AF): 0.44 vs. 0.36; p = 0.084). Moreover, haplotype frequencies at this locus were significantly different between cases and controls, with the GGT haplotype most commonly seen in cases (p = 0.01). Allele frequencies of GHR polymorphisms were not different. For the IGF-1 CA-repeat we observed a higher frequency of homozygous 192-bp carriers among tall males compared to control males (AF: 0.62 vs. 0.55; p = 0.02). The IGFBP-3 -202 C-allele occurred more frequently in cases than in controls (AF: 0.58 vs. 0.50; p = 0.002). Within cases, those carrying one or two copies of the -202 C-allele were significantly taller than AA genotype carriers (AC, p = 0.028 and CC, p = 0.009). Serum IGFBP-3 levels were highest in AA genotype carriers, the -202 SNP explained 5.8% of the variation. Conclusion: Polymorphic variation in the GH-1, IGF-1 and IGFBP-3 genes is associated with extremely tall stature. In particular, the IGFBP-3 -202 SNP is associated not only with being very tall but also with height variation within the tall. http://repub.eur.nl/res/pub/34542/ 2011-11-01T00:00:00Z Background/Aims: Genetic variation in several candidate genes has been associated with short stature. Recently, a high-mobility group A2 (HMGA2) gene SNP has been robustly associated with height in the general population. Only few have attempted to study these genes in extremely tall stature. We therefore studied common genetic variation in candidate genes for height in extremely tall Dutch. Methods: We included 116 constitutionally tall cases with height >2 SD and 103 controls with normally distributed height <2 SD. We genotyped 10 common polymorphisms previously associated with height variation. Results: The HMGA2 gene SNP was significantly associated with tall stature. Using a logistic regression model, we calculated that carrying the HMGA2 (rs1042725) C allele significantly increased the odds of being tall (OR = 1.53, 95% CI 1.02-2.28; p = 0.03). In addition, controls with one or two copies of the C allele were significantly taller than controls carrying the TT genotype [TC: mean (SD) +0.61 (0.21) SDS; p = 0.004, and CC: +0.77 (0.25) SDS; p = 0.003]. Conclusion: Our study shows that a common polymorphism in the HMGA2 gene is not only associated with height variation in the general population but also plays an important role in one of the extremes of the height distribution. http://repub.eur.nl/res/pub/33478/ 2011-04-01T00:00:00Z Background/Objective: High-dose estrogen treatment to reduce final height of tall girls has been shown to interfere with fertility. Ovarian function has not been studied. We therefore evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence. Methods: This was a retrospective cohort study of 413 tall women aged 23-48 yr, of whom 239 women had been treated. A separate group of 126 fertile, normoovulatory volunteers aged 22-47 yr served as controls. Results: Fertility was assessed in 285 tall women (157 treated, 128 untreated) who had attempted to conceive. After adjustment for age, treated women were at increased risk of experiencing subfertility [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.38-3.81] and receiving infertility treatments (OR 3.44,95%CI 1.76-6.73). Moreover, fecunditywasnotably affected because treated women had significantly reduced odds of achieving at least one live birth (OR 0.26, 95% CI 0.13-0.52). Remarkably, duration of treatment was correlated with time to pregnancy (r = 0.23, P = 0.008). Ovarian function was assessed in 174 tall women (119 treated, 55 untreated). Thirty-nine women (23%) exhibited a hypergonadotropic profile. After adjusting for age category, treated women had significantly higher odds of being diagnosed with imminent ovarian failure (OR 2.83, 95% CI 1.04-7.68). Serum FSH levels in these women were significantly increased, whereas antral follicle counts and serum anti-Müllerian hormone levels were decreased. Conclusion: High-dose estrogen-treated tall women are at risk of subfertility in later life. Their fecundity is significantly reduced. Treated women exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility. Copyright http://repub.eur.nl/res/pub/27422/ 2010-12-01T00:00:00Z Background/Objective: Sex steroid treatment to reduce final height of tall boys has been available since the 1950s. In women, it has been shown to interfere with fertility. In men, no such data are available. We therefore evaluated fertility and gonadal function in tall men who did or did not receive high-dose androgen treatment in adolescence. Methods: We conducted a retrospective cohort study of 116 tall men, of whom 60 had been treated. Reproductive and gonadal function was assessed by standardized interview, semen analysis, endocrine parameters, ultrasound imaging, and fatherhood. Mean age at treatment commencement was 14.2 yr, and mean follow-up was 21.2 yr. Results: Sixty-six men (36 treated and 30 untreated) had attempted to achieve fatherhood. The probability of conceiving their first pregnancy within 1 yr was similar in treated and untreated men (26 vs. 24; Breslow P = 0.8). Eleven treated and 13 untreated men presented with a left-sided varicocele (P = 0.5). Testicular volume, sperm quality, and serum LH, FSH, and inhibin B levels were comparable between treated and untreated men. However, treated men had significantly reduced serum T levels, adjusted for known confounders [mean (sD) 13.3 (1.8) vs. 15.2 (1.9) nmol/liter; P = 0.005). In addition, testicular volume and serum inhibin B and FSH levels in treated men were significantly correlated with age at treatment commencement. Conclusion: At a mean follow-up of 21 yr after high-dose androgen treatment, we conclude that fatherhood and semen quality in tall treated men are not affected. Serum testosterone levels, however, are reduced in androgen-treated men. Future research is required to determine whether declining testosterone levels may become clinically relevant for these men as they age. Copyright http://repub.eur.nl/res/pub/24370/ 2009-06-01T00:00:00Z Context: IGF-I and IGFBP-3 play a central role in fetal and postnatal growth and levels are low in short SGA children. The -202 A/C and -185 C/T SNPs are located near elements involved in directing IGFBP3 promoter activity and expression. Changes in promoter CpG methylation status affect transcription factor binding and transcriptional activation of IGFBP3 in vitro. Objective: To assess the relationship between IGFBP3 promoter SNPs, IGFBP-3 levels, spontaneous growth and growth response to GH treatment in short prepubertal SGA children. To assess promoter methylation status in a subgroup of short SGA subjects and controls. Patients: 292 Short prepubertal SGA children, 39 short young SGA adults and 85 young adults with normal stature. Intervention: Short prepubertal SGA children received GH 1 mg/m2/day. Outcome measures: Fasting levels of IGF-I and IGFBP-3, baseline and delta height SDS. Results: At baseline, IGFBP-3 levels were highest in SGA children with -202 AA genotype and lower in children with 1 or 2 copies of the C-allele (P < 0.001). Children with C-202/C-185haplotype, compared to children with A-202/C-185haplotype, had lower IGFBP-3 levels (P = 0.003) and were shorter (P = 0.03). During GH treatment, children with C-202/C-185haplotype showed a significantly greater increase in IGFBP-3 SDS and in height SDS than children with A-202/C-185haplotype, resulting in similar IGFBP-3 levels and similar height SDS after 12 months of GH treatment. CpG methylation patterns showed a trend towards more methylation of CpGs involved in transcription factor binding in short young SGA adults compared to controls. Conclusion: Polymorphic variation in the IGFBP3 promoter region is correlated with IGFBP-3 levels, spontaneous growth and response to GH treatment in short SGA children.