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Anne Marie Hannon, Triona O'Shea, Claire Thompson, Mark J Hannon, Rosemary Dineen, Aftab Khalid Khattak, James Gibney, Domhnall O'Halloran, Steve Hunter, Chris J Thompson and Mark Sherlock

Pregnancy is rarely reported in acromegaly. Many patients are diagnosed in later life and younger patients may have subfertility due to hypopituitarism. We present a case series of 17 pregnancies in 12 women with acromegaly.

12 women with acromegaly who completed pregnancy were identified from centres involved in the Irish Pituitary Study. 11 women had pituitary macroadenomas, one woman had a microadenoma. Only 5/17 pregnancies had optimal biochemical control of acromegaly pre-conception, as defined by IGF-1 concentration in the age related reference level and plasma GH concentration of <2ug/L. In 6/17 pregnancies, dopamine agonist treatment was continued during pregnancy; all other acromegaly treatments were discontinued during pregnancy.

Effect of pregnancy on acromegaly; No patient developed new visual field abnormalities, or symptoms suggestive of tumour expansion during pregnancy. In 9/12 patients, plasma IGF-1 concentrations that were elevated pre-conception normalized during pregnancy. There was a reduction in plasma IGF-1 concentrations, though not into the normal range, in a further 2 pregnancies.

Effect of acromegaly on pregnancy; 15 healthy babies were born at term; one patient underwent emergency C-section at 32 weeks, for pre-eclampsia and one twin pregnancy had an elective caesarean section at 35 week’s gestation. Blood pressure remained within normal limits in the remainder of the pregnancies. Gestational diabetes did not develop in any pregnancy.

Our data suggests that pregnancy in women with acromegaly is generally safe, from a maternal and foetal perspective. Furthermore, biochemical control tends to improve despite the withdrawal of somatostatin analogue therapy during pregnancy.

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Adriana G Ioachimescu, Maria Fleseriu, Andrew R Hoffman, T Brooks Vaughan III and Laurence Katznelson

Background

Dopamine agonists (DAs) are the main treatment for patients with hyperprolactinemia and prolactinomas. Recently, an increasing number of reports emphasized DAs’ psychological side effects, either de novo or as exacerbations of prior psychiatric disease.

Methods

Review of prospective and retrospective studies (PubMed 1976, September 2018) evaluating the psychological profile of DA-treated patients with hyperprolactinemia and prolactinomas. Case series and case reports of psychiatric complications were also reviewed.

Results

Most studies were cross-sectional and had a control group of healthy volunteers or patients with nonfunctioning pituitary adenomas. There were few prospective studies, with/without control group, that included small numbers of patients. Compared with controls, patients with hyperprolactinemia generally had worse quality of life, anxiety, depression and certain personality traits. Patients receiving DAs had higher impulsivity scores than normoprolactinemic controls. Impulse control disorders (ICDs) were reported in both genders, with hypersexuality mostly in men. Multiple ICDs were sometimes reported in the same patient, usually reversible after DA discontinuation. In case reports, DA therapy was temporally associated with severe depression, manic episodes or psychosis, which improved after discontinuation and administration of psychiatric medications. Gender type of DA, dose and duration of therapy did not correlate with occurrence of psychiatric pathology.

Conclusion

Patients with hyperprolactinemia receiving DAs may develop changes in mood and behavior regardless of prior psychiatric history. Increased awareness for ICDs, depression, mania and other types of psychosis is needed by all physicians who prescribe DAs. Larger prospective controlled clinical studies are needed to delineate prevalence, risk stratification and management.

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Maurilio Deandrea, Francesca Garino, Mormile Alberto, Roberto Garberoglio, Ruth Rossetto, Nadia Bonelli, Stefano Spiezia, Massimo De Santis, Salvatore Monti, Maria Grazia Deiana, Toscano Vincenzo, Christian Cugini, Ghassan El Dalati and Paolo Piero Limone

Background

The purpose of this study was to confirm the generalisation of radiofrequency ablation (RFA) in the treatment of benign thyroid nodules (BTN) and to look for a correlation between final shrinkage and some ultrasound (US) findings in a large Italian population data set.

Methods

This prospective study included 337 patients with solid cold BTN from six Italian institutions. Nodule volume, US pattern, thyroid function, symptom/cosmetic scores and complications were evaluated before treatment and at 6 and 12 months. The primary outcome was to find a correlation between basal volume and US pattern of the nodules and final shrinkage. The secondary outcome was to confirm the efficacy and safety of RFA in a large data set.

Results

The median basal volume was 20.7 mL, and this significantly decreased after RFA at 6 months (7.3 mL (−63.5%), P < 0.001) and at 12 months (6 mL (−70%), P vs 6 months = 0.009). A significant correlation was found for US structure (a spongiform pattern showing a 76% reduction vs 67 and 66% of mix and solid patterns respectively, P < 0.01) as well as for vascularity (intense peripheral and intranodal patterns showing 71 vs 68 and 67% of weak peripheral and intranodal and peripheral patterns respectively, P < 0.03), but not for macrocalcifications. A slight inverse correlation was found between nodule basal volume and shrinkage (Spearman: −0.23). Mean symptoms/cosmetic scores were significantly reduced. No major complications were encountered.

Conclusions

This multicentre study validated the efficacy and safety of RFA for treating BTN and showed a clear correlation between final shrinkage and some common US findings.

Open access

Guodong Xu, Dingyun You, Liping Wong, Donghui Duan, Fanqian Kong, Xiaohong Zhang, Jinshun Zhao, Wenhua Xing, Li Li and Liyuan Han

Objective: Previous studies have shown sex-specific differences in all-cause and CHD mortality in type 2 diabetes. We performed a systematic review and meta-analysis to provide a global picture of the estimated influence of type 2 diabetes on the risk of all-cause and CHD mortality in women versus men.

Methods: We systematically searched PubMed, Embase, and Web of Science for studies published from their starting dates to 7 Aug 2018. The sex-specific hazard ratios (HRs) and their pooled ratio (women vs. men) of all-cause and CHD mortality associated with type 2 diabetes were obtained through an inverse-variance weighted random-effects meta-analysis. Subgroup analyses were used to explore potential sources of heterogeneity.

Results: The 35 analyzed prospective cohort studies included 2,314,292 individuals, among whom 254,038 all-cause deaths occurred. The pooled women vs. men ratio of the HRs for all-cause and CHD mortality were 1.17 (95% CI 1.12-1.23, I2=81.6%) and 1.97 (95% CI 1.49-2.61, I2=86.4%), respectively. The pooled estimate of the HR for all-cause mortality was approximately 1.30 in articles in which the duration of follow-up longer than 10 years, and 1.10 in articles in which the duration of follow-up less than 10 years. The pooled HRs for all-cause mortality in patients with type 2 diabetes was 2.33 (95% CI 2.02-2.69) in women and 1.91 (95% CI 1.72-2.12) in men, compared with their healthy counterparts.

Conclusions: The effect of diabetes on all-cause and CHD mortality is approximately 17% and 97% greater, respectively, for women than for men.

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Karin van der Tuin, Marina Ventayol, Willem Corver, Midia Khalifa, Dina Ruano, E P Corssmit, Frederik J Hes, Thera P Links, Jan Smit, Theo S. Plantinga, E Kapiteijn, Ton Van Wezel and Hans Morreau

OBJECTIVE: Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine-refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas.

DESIGN: Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell-, and 14 anaplastic thyroid carcinoma).

METHODS: Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants.

RESULTS: Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET [PTC1], PRKAR1A/RET [PTC2] and ETV6/NTRK3 (n=2), and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35).

CONCLUSION: Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants, and can be effectively identified in formalin-fixed tissue. These gene fusionsmight provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

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Yijie Xu, Haibin Li, Anxin Wang, Zhaoping Su, Guang Yang, Yanxia Luo, Lixin Tao, Shuohua Chen, Shouling Wu, Youxin Wang and Xiuhua Guo

Objective

This study aimed to determine if the metabolically healthy obese (MHO) is associated with an increased risk of myocardial infarction (MI) in Chinese population.

Design

The Kailuan study is a community-based prospective cohort study.

Methods

BMI and metabolic syndrome (MetS) were assessed in 91 866 participants without a history of MI or stroke. Participants were categorised into six mutually exclusive groups according to the BMI-MetS status: normal weight (BMI:  ≤ 18.5to < 24.0 kg/m2) without MetS (MH-NW), normal weight with MetS (MUH-NW), overweight (BMI:  ≤ 24.0to < 28.0 kg/m2) without MetS (MH-OW), overweight with MetS (MUH-OW), obese (BMI ≥ 28.0 kg/m2) without MetS (MHO) and obese with MetS (MUO). The hazard ratio (HR) with 95% CI was calculated for the incidence of MI using a multivariable Cox model.

Results

A total of 6745 (7.34%) individuals were classified as MHO. During a median 8-year follow-up, 1167 (1.27%) participants developed MI. The MHO group had an increased risk of MI (HR: 1.76, 95% CI: 1.37–2.25) in comparison with the MH-NW group after adjusting for potential confounding variables. After a similar adjustment, the risk of MI was significantly elevated in the MUH-NW (HR: 1.62, 95% CI: 1.28–2.05), MUH-OW (HR: 1.98, 95% CI: 1.67–2.35) and MUO group (HR: 2.06, 95% CI: 1.70–2.49).

Conclusions

MHO subjects showed a substantially higher risk of MI in comparison with MH-NW subjects. That said, even without measurable metabolic abnormalities, obesity was associated with a higher risk of MI.

Free access

C Peters, A S P van Trotsenburg and N Schoenmakers

Congenital hypothyroidism (CH) may be primary, due to a defect affecting the thyroid gland itself, or central, due to impaired thyroid-stimulating hormone (TSH)-mediated stimulation of the thyroid gland as a result of hypothalamic or pituitary pathology. Primary CH is the most common neonatal endocrine disorder, traditionally subdivided into thyroid dysgenesis (TD), referring to a spectrum of thyroid developmental abnormalities, and dyshormonogenesis, where a defective molecular pathway for thyroid hormonogenesis results in failure of hormone production by a structurally intact gland. Delayed treatment of neonatal hypothyroidism may result in profound neurodevelopmental delay; therefore, CH is screened for in developed countries to facilitate prompt diagnosis. Central congenital hypothyroidism (CCH) is a rarer entity which may occur in isolation, or (more frequently) in association with additional pituitary hormone deficits. CCH is most commonly defined biochemically by failure of appropriate TSH elevation despite subnormal thyroid hormone levels and will therefore evade diagnosis in primary, TSH-based CH-screening programmes. This review will discuss recent genetic aetiological advances in CH and summarize epidemiological data and clinical diagnostic challenges, focussing on primary CH and isolated CCH.

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Gunn-Helen Moen, Marissa LeBlanc, Christine Sommer, Rashmi B Prasad, Tove Lekva, Kjersti R Normann, Elisabeth Qvigstad, Leif Groop, Kåre I Birkeland, David M Evans and Kathrine F Frøslie

Objective

Hyperglycaemia during pregnancy increases the risk of adverse health outcomes in mother and child, but the genetic aetiology is scarcely studied. Our aims were to (1) assess the overlapping genetic aetiology between the pregnant and non-pregnant population and (2) assess the importance of genome-wide polygenic contributions to glucose traits during pregnancy, by exploring whether genetic risk scores (GRSs) for fasting glucose (FG), 2-h glucose (2hG), type 2 diabetes (T2D) and BMI in non-pregnant individuals were associated with glucose measures in pregnant women.

Methods

We genotyped 529 Norwegian pregnant women and constructed GRS from known genome-wide significant variants and SNPs weakly associated (p > 5 × 10−8) with FG, 2hG, BMI and T2D from external genome-wide association studies (GWAS) and examined the association between these scores and glucose measures at gestational weeks 14–16 and 30–32. We also performed GWAS of FG, 2hG and shape information from the glucose curve during an oral glucose tolerance test (OGTT).

Results

GRSFG explained similar variance during pregnancy as in the non-pregnant population (~5%). GRSBMI and GRST2D explained up to 1.3% of the variation in the glucose traits in pregnancy. If we included variants more weakly associated with these traits, GRS2hG and GRST2D explained up to 2.4% of the variation in the glucose traits in pregnancy, highlighting the importance of polygenic contributions.

Conclusions

Our results suggest overlap in the genetic aetiology of FG in pregnant and non-pregnant individuals. This was less apparent with 2hG, suggesting potential differences in postprandial glucose metabolism inside and outside of pregnancy.

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Rafael A Carvalho, Betsaida Urtremari, Alexander A L Jorge, Lucas S Santana, Elisangela P S Quedas, Tomoko Sekiya, Viviane C Longuini, Fabio L M Montenegro, Antonio M Lerario, Sergio P A Toledo, Stephen J Marx, Rodrigo A Toledo and Delmar M Lourenço Jr

Background

Loss-of-function germline MEN1 gene mutations account for 75–95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated.

Objective

To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile.

Methods and patients

A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS.

Results

Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected.

Conclusions

Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.

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I A Franzini, F M Yamamoto, F Bolfi, S R Antonini and V S Nunes-Nogueira

Objective

We assessed the effectiveness of puberty blockade with a gonadotropin-releasing hormone (GnRH) analog in increasing adult height (AH) in girls with puberty onset between 7 and 10 years of age.

Methods

We performed a systematic review and included controlled studies in which girls with early puberty (EP) were assigned to the GnRH analog or no treatment groups. The primary outcome analyzed was AH. Search strategies were applied to the MEDLINE, EMBASE, LILACS and CENTRAL databases.

Results

We identified 1514 references, and six studies fulfilled our eligibility criteria. Two studies were randomized and four were not randomized. At the baseline of each trial, height, chronological age, bone age, predicted AH (PAH) and target height (TH) were equal between the groups. All studies used intramuscular triptorelin every 28 days in the intervention groups. The mean duration of the therapy was 2 years. Meta-analysis of AH among the six studies (comprising 332 girls) showed no significant difference between the groups (mean difference = 0.50 cm, 95% confidence interval = −0.72 to 1.73 cm, I 2 = 0%). In a sub-group analysis based on PAH (<155 cm and <TH; <TH, but >155 cm and equal to TH), there was no difference in average AH between the groups. The quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation approach was low.

Conclusion

We found no evidence from controlled experimental and observational studies that compared with no treatment, the use of GnRH analogs improved AH in girls with EP.