Helena Filipsson Nyström

Fertility, sexuality and testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia.

Objective Fertility in males with congenital adrenal hyperplasia (CAH) is reported from normal to severely impaired. Therefore, we investigated fertility/fecundity, social/sexual situation, and pituitary–gonadal function in CAH males. Subjects and methods The patient cohort comprised 30 males, aged 19–67 years, with 21-hydroxylase deficiency. Their fertility was compared with age-matched national population data. For the evaluation of social/sexual factors and hormone status, age-matched controls were recruited (n=32). Subgroups of different ages (<30 years and older) and CYP21A2 genotypes (null (severe salt-wasting (SW)), I2splice (milder SW), and I172N (simple virilizing)) were also studied. Patients underwent testicular ultrasound examination (n=21) and semen analysis (n=14). Results Fertility was impaired in CAH males compared with national data (0.9±1.3 vs 1.8±0.5 children/father, P<0.001). There were no major differences in social and sexual factors between patients and controls apart from more fecundity problems, particularly in the I172N group. The patients had lower testosterone/estradiol (E2) ratio and inhibin B, and higher FSH. The semen samples were pathological in 43% (6/14) of patients and sperm concentration correlated with inhibin B and FSH. Testicular adrenal rest tumors (TARTs) were found in 86% (18/21). Functional testicular volume correlated positively with the testosterone/E2 ratio, sperm concentration, and inhibin B. Patients with pathological semen had increased fat mass and indications of increased cardiometabolic risk. Conclusions Fertility/fecundity was impaired in CAH males. The frequent occurrence of TARTs resulting in testicular insufficiency appears to be the major cause, but other factors such as elevated fat mass may contribute to a low semen quality.

The incidence rate of pituitary adenomas in western Sweden for the period 2001–2011

OBJECTIVE The number of studies on the incidence of pituitary adenomas (PAs) is limited. The aim of this study was to evaluate the standardised incidence rate (SIR) of PAs in western Sweden. DESIGN, SUBJECTS AND METHODS Data from adult patients diagnosed with PAs in 2001-2011, living in the Västra Götaland County, were collected from the Swedish Pituitary Registry (SPR). In addition, medical records on all patients diagnosed with PAs at the six hospitals in the region were reviewed. In total, 592 patients were included in the study.Age-SIR, given as rate/100 000 inhabitants (95% CI), was calculated using the WHO 2000 standard population as a reference. RESULTS The total SIR for PAs was 3.9/100 000 (3.6-4.3); 3.3/100 000 (2.9-3.7) for men and 4.7/100 000 (4.1-5.3) for women. In men, SIR increased with age, while in women SIR peaked at 25-34 years, mainly due to prolactinomas. Non-functioning PA (NFPA) was the most common PA (54%, 1.8/100 000 (1.6-2.0)) followed by prolactinomas (32%, 1.6/100 000 (1.3-1.9)), acromegaly (9%, 0.35/100 000 (0.25-0.45)), Cushings disease (4%, 0.18/100 000 (0.11-0.25)) and TSH-producing PA (0.7%, 0.03/100 000 (0.00-0.05)). The proportion of macroadenomas for NFPA was 82%, prolactinomas 37%, GH-producing PA 77%, ACTH-producing PA 28% and TSH-producing PA 100%. The lifetime risk for PAs was 0.27% (0.24-0.31) in men and 0.29% (0.26-0.33) in women. CONCLUSION This study provides a reliable estimate on the overall incidence of PAs and confirms an increased incidence of PAs compared with studies conducted in the pre-magnetic resonance imaging era. The lower proportion of prolactinomas compared with previous studies is probably explained by the different criteria used.

Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

OBJECTIVE Lifelong glucocorticoid therapy in patients with congenital adrenal hyperplasia (CAH) or the disease per se may result in increased cardiovascular risk. We therefore investigated cardiovascular and metabolic risk profiles in adult CAH males. SUBJECTS AND METHODS We compared CAH males (n = 30), 19-67 years old, with age- and sex-matched controls (n = 32). Subgroups of different ages (< 30 years or older) and CYP21A2 genotypes (null, I2splice, and I172N as the mildest mutation) were studied. Anthropometry, fat and lean mass measured by dual-energy X-ray absorptiometry, lipids, liver function tests, homocysteine, lipoprotein-(a), glucose and insulin during an oral glucose tolerance test (OGTT), urine albumin, adrenal hormones, and 24 h ambulatory blood pressure measurements were studied. RESULTS CAH males were shorter. Waist/hip ratio and fat mass were higher in older patients and the I172N group. Heart rate was faster in older patients, the I2splice, and I172N groups. Insulin levels were increased during OGTT in all patients and in the I172N group. γ-glutamyl transpeptidase was increased in older patients and in the I172N group. Testosterone was lower in older patients. Homocysteine was lower in younger patients, which may be cardioprotective. The cardiovascular risk seemed higher with hydrocortisone/cortisone acetate than prednisolone. Urinary epinephrine was lower in all groups of patients except in I172N. CONCLUSIONS Indications of increased risk were found in CAH males ≥ 30 years old and in the I172N group. In contrast, younger CAH males did not differ from age-matched controls. This is likely to reflect a better management in recent years.

Bone Mineral Density, Bone Markers, and Fractures in Adult Males with Congenital Adrenal Hyperplasia

OBJECTIVE The aim of this study was to determine bone mineral density (BMD), markers of bone metabolism, fractures, and steroids reflecting hormonal control in adult males with congenital adrenal hyperplasia (CAH). SUBJECTS, METHODS, AND DESIGN: We compared CAH males with 21-hydroxylase deficiency (n=30), 19-67 years old, with age- and sex-matched controls (n=32). Subgroups of CYP21A2 genotypes, age, glucocorticoid preparation, poor control vs overtreatment, and early vs late (>36 months) diagnosis were studied. BMD measured by dual energy X-ray absorptiometry and markers of bone metabolism and androgens/17-hydroxyprogesterone levels were investigated. RESULTS All, including older (>30 years), CAH patients had lower BMD in all measured sites compared with control subjects. The null group demonstrated lower BMD in more locations than the other groups. Osteoporosis/osteopenia was present in 81% of CAH patients compared with 32% in controls (≥30 years). Fracture frequency was similar, osteocalcin was lower, and fewer patients than controls had vitamin D insufficiency. IGF1 was elevated in the milder genotypes. In patients, total body BMD was positively correlated to weight, BMI, total lean body mass, and triglycerides, and negatively to prolactin. Patients on prednisolone had lower BMD and osteocalcin levels than those on hydrocortisone/cortisone acetate. Patients with poor control had higher femoral neck BMD. There were no differences in BMD between patients with an early vs late diagnosis. CONCLUSIONS CAH males have low BMD and bone formation markers. BMD should be monitored, adequate prophylaxis and treatment established, and glucocorticoid doses optimized to minimize the risk of future fractures.

Incidence rate and clinical features of hyperthyroidism in a long‐term iodine sufficient area of Sweden (Gothenburg) 2003–2005

To study hyperthyroidism in long‐term iodine sufficiency (IS), as iodine supply affects its occurrence.

Iodine status in the Nordic countries – past and present

Background Adequate iodine nutrition is dependent on ground water content, seafood, and, as many countries use iodized cow fodder, dairy products. In most countries, salt fortification programs are needed to assure adequate iodine intake. Objectives The objectives are threefold: 1) to describe the past and present iodine situation in the Nordic countries, 2) to identify important gaps of knowledge, and 3) to highlight differences among the Nordic countries’ iodine biomonitoring and fortification policies. Design Historical data are compared with the current situation. The Nordic countries’ strategies to achieve recommended intake and urine iodine levels and their respective success rates are evaluated. Results In the past, the iodine situation ranged from excellent in Iceland to widespread goiter and cretinism in large areas of Sweden. The situation was less severe in Norway and Finland. According to a 1960 World Health Organization (WHO) report, there were then no observations of iodine deficiency in Denmark. In Sweden and Finland, the fortification of table salt was introduced 50–75 years ago, and in Norway and Finland, the fortification of cow fodder starting in the 1950s helped improve the populations iodine status due to the high intake of milk. In Denmark, iodine has been added to household salt and salt in bread for the past 15 years. The Nordic countries differ with regard to regulations and degree of governmental involvement. There are indications that pregnant and lactating women, the two most vulnerable groups, are mildly deficient in iodine in several of the Nordic countries. Conclusion The Nordic countries employ different strategies to attain adequate iodine nutrition. The situation is not optimal and is in need of re-evaluation. Iodine researchers, Nordic national food administrations, and Nordic governmental institutions would benefit from collaboration to attain a broader approach and guarantee good iodine health for all.

Iodine deficiency in a study population of pregnant women in Sweden

Iodine deficiency in utero may impair neurological development of the fetus. In Sweden, iodine nutrition is considered to be adequate in the general population. The aim of this study was to evaluate iodine nutrition during pregnancy in Sweden.

SNPs within the GH-signaling pathway are associated with the early IGF1 response to GH replacement therapy in GHD adults

OBJECTIVE GH-deficient (GHD) adults have reduced serum concentrations of IGF1. GH replacement therapy increases serum IGF1 concentrations, but the interindividual variation in treatment response is large and likely influenced by genetic factors. This study was designed to test the hypothesis that single-nucleotide polymorphisms (SNPs) in genes within the GH signaling pathway influence the serum IGF1 response to GH replacement. DESIGN AND METHODS A total of 313 consecutive GHD adults (58.1% men; mean age 49.7 years) were studied before and after 1 week, 6 months, and 1 year of GH treatment. GH dose was individually titrated to normalize serum IGF1 levels. Six SNPs in the GH receptor (GHR) and the GH signaling pathway (JAK2, STAT5B, SOCS2, and PIK3CB) genes were selected for genotyping. The GHR exon 3-deleted/full-length (d3/fl) polymorphism was analyzed using tagSNP rs6873545. RESULTS After 1 week of GH replacement, homozygotes of the fl-GHR showed a better IGF1 response to GH than carriers of the d3-GHR (P=0.016). Conversely, homozygotes of the minor allele of PIK3CB SNP rs361072 responded better than carriers of the major allele (P=0.025). Compared with baseline, both SNPs were associated with the IGF1 response at 6 months (P=0.041 and P=0.047 respectively), and SNP rs6873545 was further associated with the IGF1 response at 1 year (P=0.041). CONCLUSIONS Our results indicate that common genetic variants in the GH signaling pathway may be of functional relevance to the response to GH replacement in GHD adults.

Genotypes associated with lipid metabolism contribute to differences in serum lipid profile of GH-deficient adults before and after GH replacement therapy

OBJECTIVE GH deficiency (GHD) in adults is associated with an altered serum lipid profile that responds to GH replacement therapy (GHRT). This study evaluated the influence of polymorphisms in genes related to lipid metabolism on serum lipid profile before and after 1 year of GHRT in adults. DESIGN AND METHODS In 318 GHD patients, total cholesterol (TC) serum concentrations, LDL-C, HDL-C, and triglycerides (TG) were assessed. Using a candidate gene approach, 20 single nucleotide polymorphisms (SNPs) were genotyped. GH dose was individually titrated to obtain normal serum IGF1 concentrations. RESULTS At baseline, the minor alleles of cholesteryl ester transfer protein (CETP) gene SNPs rs708272 and rs1800775 were associated with higher serum TC and apolipoprotein E (APOE) gene SNP rs7412 with lower TC concentrations; CETP SNPs rs708272, rs1800775, and rs3764261 and apolipoprotein B (APOB) gene SNP rs693 with higher serum HDL-C; APOE SNP rs7412, peroxisome proliferator-activated receptor gamma (PPARG) gene SNP rs10865710 with lower LDL-C, and CETP SNP rs1800775 with higher LDL-C; and APOE/C1/C4/C2 cluster SNP rs35136575 with lower serum TG. After treatment, APOB SNP rs676210 GG genotype was associated with larger reductions in TC and LDL-C and PPARG SNP rs10865710 CC genotype with greater TC reduction. All associations remained significant when adjusted for age, sex, and BMI. CONCLUSIONS In GHD adults, multiple SNPs in genes related to lipid metabolism contributed to individual differences in baseline serum lipid profile. The GH treatment response in TC and LDL-C was influenced by polymorphisms in the APOB and PPARG genes.

Voice problems due to virilization in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder in which the lack of 21‐hydroxylase results in cortisol and aldosterone insufficiency and an overproduction of adrenal androgens. High levels of androgens in women may cause virilization of the larynx and a masculine voice. The purpose of the present study was to investigate subjective voice problems due to virilization in women with CAH.