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Axel Tjörnstrand and Helena Filipsson Nyström

Thyrotropin (TSH)-secreting adenomas (TSHomas) are the rarest form of pituitary adenomas, and most endocrinologists will see few cases in a lifetime, if any. In most cases, the diagnostic approach is complicated and cases may be referred after being presented as a syndrome of inappropriate TSH secretion or as a pituitary mass. This review aims to cover the past, present and possible future diagnostic approaches to TSHomas, including different clinical presentations, laboratory assessment and imaging advances. The differential diagnoses will be discussed, as well as possible coexisting disorders. By evaluating the existing reports and reviews describing this rare condition, this review aims to present a clinically practical suggestion on the diagnosic workup for TSHomas, Major advances and scientific breakthroughs in the imaging area in recent years, facilitating diagnosis of TSHomas, support the belief that future progress within the imaging field will play an important role in providing methods for a more efficient diagnosis of this rare condition.

Free access

Eric Mohlin, Helena Filipsson Nyström, and Mats Eliasson

Objective

To investigate the long-term prognosis of patients with Graves' disease (GD) after antithyroid drug (ATD) treatment and follow-up outside of highly specialised care.

Design and methods

Medical records of all patients diagnosed with first-time GD in 2000–2010 with at least 6 months ATD treatment at a central hospital and follow-up in primary health care in the county of Norrbotten in northern Sweden were retrospectively reviewed. Patients were followed for relapse until 31st December 2012. We included 219 patients (mean age 46 years, 82.5% women) with follow-up of maximum 10 years and 829 observed patient years. Data were analysed using Kaplan–Meier estimates and log-rank test.

Results

During the observation period, 43.5% of the patients had relapsed into active GD. The cumulative relapse rates were 22.6, 30.2, 36.9 and 41.5% after 6 months, 1, 3 and 5 years respectively. The presence of goitre (P=0.014) predicted relapse. Previous smoking was protective against relapse (P=0.003). The levels of free thyroxine or free tri-iodothyronine, age, gender, current smoking and ophthalmopathy did not predict relapse. Agranulocytosis was found in 1.7% (95% CI 0.7–4.0%).

Conclusion

A long-term remission of 56.5%, in an iodine-sufficient area where ATD is offered to most patients in the real world of central and district hospitals, is higher than in most studies. Relapse was most common during the first year, and prognosis was excellent after 4 years without relapse. The protective effect of previous smoking merits further research.

Free access

Helena Filipsson, Ernst Nyström, and Gudmundur Johannsson

Context

The diagnosis of central hypothyroidism (CH) is often difficult to establish as serum TSH levels may be low, normal, or slightly increased.

Objective

To explore the use of recombinant human TSH (rhTSH) in the diagnosis of CH.

Design

Randomized single-blind clinical trial.

Setting

Outpatient clinic of a tertiary care referral center.

Intervention

A single intramuscular injection of 0.1 and 0.9 mg rhTSH in random order with 1-week interval.

Participants

Eighteen adult patients with pituitary insufficiency and six healthy age-, sex-, and body mass index-matched controls. Six patients had untreated CH (newCH), six had treated CH (CH), and six patients were TSH sufficient (nonCH). Five weeks before TSH stimulation, levothyroxine was replaced with tri-iodothyronine (T3) for 4 weeks. One week before stimulation, treatment was withdrawn.

Main outcome measures

Thyroid hormones and thyroglobulin (Tg) before and 2, 3½, 7, 24, 48, and 72 h after each injection.

Results

In the newCH group, basal free thyroxine (FT4) levels were lower than in controls (P<0.05). After 0.9 mg rhTSH, the increases in FT4 and reverse T3 (rT3) were less marked in the newCH group than in controls (FT4±s.e.m. 9.2±0.5 to 19.7±1.2 vs 11.3±0.5 to 27.8.2±2.4 pmol/l, P<0.05). The CH group exhibited reduced basal and stimulated FT4 compared with the TSH-sufficient groups. Tg increased similarly among all study groups after rhTSH injection.

Conclusion

In this pilot study, patients with untreated CH had lower response to 0.9 mg rhTSH in FT4 and rT3 than controls. An rhTSH test may be useful in the diagnosis of CH, but further studies are required.

Free access

Henrik Falhammar, Helena Filipsson Nyström, Anna Wedell, and Marja Thorén

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.

Free access

Henrik Falhammar, Helena Filipsson Nyström, Anna Wedell, Kerstin Brismar, and Marja Thorén

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.

Open access

Henrik Falhammar, Helena Filipsson Nyström, Urban Ekström, Seth Granberg, Anna Wedell, and Marja Thorén

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.

Free access

Axel Tjörnstrand, Kerstin Gunnarsson, Max Evert, Erik Holmberg, Oskar Ragnarsson, Thord Rosén, and Helena Filipsson Nyström

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)), Cushing's 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.

Free access

Oskar Ragnarsson, Anders F Mattsson, John P Monson, Helena Filipsson Nyström, Ann-Charlotte Åkerblad, Maria Kołtowska-Häggström, and Gudmundur Johannsson

Objective

Quality of life (QoL) is impaired in hypopituitary patients and patients with primary adrenal insufficiency. The aim of this study was to analyse the impact of glucocorticoid (GC) replacement on QoL. The main hypothesis was that ACTH-insufficient patients experience a dose-dependent deterioration in QoL.

Design, patients and methods

This was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Data from 2737 adult GH-deficient (GHD) hypopituitary patients were eligible for analysis. Thirty-six per cent were ACTH sufficient and 64% ACTH insufficient receiving a mean±s.d. hydrocortisone equivalent (HCeq) dose of 22.3±8.7 mg (median 20.0). QoL at baseline and 1 year after commencement of GH replacement was assessed by the QoL-assessment of GHD in adults.

Results

At baseline, no significant difference in QoL was observed between ACTH-sufficient and -insufficient patients. Increasing HCeq dose was associated with worse QoL. Patients on HCeq ≤10 mg had the best and patients receiving ≥25 mg demonstrated the poorest QoL. At 1 year of GH replacement, the improvement in QoL did not differ between ACTH-sufficient and -insufficient patients, and no association was observed between HCeq dose and QoL improvement.

Conclusion

Adult hypopituitary patients with untreated GHD receiving GC replacement have similar QoL as ACTH-sufficient patients. Among ACTH-insufficient patients, there is a dose-dependent association between increasing dose and impaired QoL. This association may be explained by supraphysiological GC exposure although it remains plausible that clinicians may have increased GC doses in order to address otherwise unexplained QoL deficits.

Free access

Camilla A M Glad, Edna J L Barbosa, Helena Filipsson Nyström, Lena M S Carlsson, Staffan Nilsson, Anna G Nilsson, Per-Arne Svensson, and Gudmundur Johannsson

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.

Free access

Mirna Abraham-Nordling, Kristina Byström, Ove Törring, Mikael Lantz, Gertrud Berg, Jan Calissendorff, Helena Filipsson Nyström, Svante Jansson, Gun Jörneskog, F Anders Karlsson, Ernst Nyström, Hans Ohrling, Thomas Örn, Bengt Hallengren, and Göran Wallin

Introduction

The incidence of hyperthyroidism has been reported in various countries to be 23–93/100 000 inhabitants per year. This extended study has evaluated the incidence for ∼40% of the Swedish population of 9 million inhabitants. Sweden is considered to be iodine sufficient country.

Methods

All patients including children, who were newly diagnosed with overt hyperthyroidism in the years 2003–2005, were prospectively registered in a multicenter study. The inclusion criteria are as follows: clinical symptoms and/or signs of hyperthyroidism with plasma TSH concentration below 0.2 mIE/l and increased plasma levels of free/total triiodothyronine and/or free/total thyroxine. Patients with relapse of hyperthyroidism or thyroiditis were not included. The diagnosis of Graves' disease (GD), toxic multinodular goiter (TMNG) and solitary toxic adenoma (STA), smoking, initial treatment, occurrence of thyroid-associated eye symptoms/signs, and demographic data were registered.

Results

A total of 2916 patients were diagnosed with de novo hyperthyroidism showing the total incidence of 27.6/100 000 inhabitants per year. The incidence of GD was 21.0/100 000 and toxic nodular goiter (TNG=STA+TMNG) occurred in 692 patients, corresponding to an annual incidence of 6.5/100 000. The incidence was higher in women compared with men (4.2:1). Seventy-five percent of the patients were diagnosed with GD, in whom thyroid-associated eye symptoms/signs occurred during diagnosis in every fifth patient. Geographical differences were observed.

Conclusion

The incidence of hyperthyroidism in Sweden is in a lower range compared with international reports. Seventy-five percent of patients with hyperthyroidism had GD and 20% of them had thyroid-associated eye symptoms/signs during diagnosis. The observed geographical differences require further studies.