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Mijin Kim, Bo Hyun Kim, Hyungi Lee, Hyewon Nam, Sojeong Park, Min Hee Jang, Jeong Mi Kim, Eun Heui Kim, Yun Kyung Jeon, Sang Soo Kim, and In Joo Kim

Objective

Little is known about the role of estrogen in thyroid cancer development. We aimed to evaluate the association between hysterectomy or bilateral salpingo-oophorectomy (BSO) and the risk of subsequent thyroid cancer.

Design

A nationwide cohort study

Methods

Data from the Korea National Health Insurance Service between 2002 and 2017 were used. A total of 78 961 and 592 330 women were included in the surgery group and no surgery group, respectively. The surgery group was categorized into two groups according to the extent of surgery: hysterectomy with ovarian conservation (hysterectomy-only) and BSO with or without hysterectomy (BSO).

Results

During 8 086 396.4 person-years of follow-up, 12 959 women developed thyroid cancer. Women in the hysterectomy-only (adjusted hazard ratio = 1.7, P < 0.001) and BSO (adjusted hazard ratio = 1.4, P < 0.001) groups had increased risk of thyroid cancer compared to those in the no surgery group. In premenopausal women, hysterectomy-only (adjusted hazard ratio = 1.7, P < 0.001) or BSO (adjusted hazard ratio = 1.4, P < 0.001) increased the risk of subsequent thyroid cancer, irrespective of hormone therapy, whereas, there was no significant association between hysterectomy-only (P = 0.204) or BSO (P = 0.857) and thyroid cancer development in postmenopausal women who had undergone hormone therapy.

Conclusions

Our findings do not support the hypotheses that sudden or early gradual decline in estrogen levels is a protective factor in the development of thyroid cancer, or that exogenous estrogen is a risk factor for thyroid cancer.

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I C M Pelsma, K M J A Claessen, P E Slagboom, D van Heemst, A M Pereira, H M Kroon, Y F M Ramos, M Kloppenburg, N R Biermasz, and I M Meulenbelt

Introduction

Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis.

Methods

Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (n = 337, mean age: 59.8 ± 7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (n = 456, mean age: 59.8 ± 6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGFBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed.

Results

Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR = 1.10 (1.04–1.17), P=0.002 vs females OR = 1.04 (1.01–1.07), P = 0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had a lower risk to develop hip OA (OR = 0.41 (0.18–0.90), P = 0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had a higher risk to develop knee OA (OR = 1.90 (1.20–2.99), P = 0.006).

Conclusion

Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process.

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Marissa Penna-Martinez, Gesine Meyer, Anette Bøe Wolff, Beate Skinningsrud, Corrado Betterle, Alberto Falorni, William Er Ollier, Dag Undlien, Eystein Sverre Husebye, Simon H S Pearce, Anna L Mitchell, and Klaus Badenhoop

OBJECTIVE

While vitamin D regulates immune cells, little is known about it in autoimmune Addison´s disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes.

DESIGN

Cross-sectional study

METHODS

A total of 1028 patients with AAD from Germany (n=239), Italy (n=328), Norway (n=378), UK (n=44) and Poland (n=39) and 679 controls from Germany (n=301) and Norway (n=378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1); 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP).

RESULTS

Vitamin D deficiency (25(OH)D3 10-20 ng/ml) was highly prevalent in AAD patients (34-57%), 5-22% were severely deficient (<10 ng/ml), 28-38% insufficient (20-30 ng/ml) and only 7-14% sufficient (>30 ng/ml). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (p = 0.03/0.003 and p = 1 x 10-5/< 1 x 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/ml), AAD patients remained largely deficient (18.0 to 21.2 ng/ml) and synthesize less 1,25(OH)2D3.

CONCLUSION

Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year.

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Olaf M Dekkers and Rolf H H Groenwold

Immortal time bias should always be considered in an observational study if exposure status is determined based on a measurement or event that occurs after baseline. This bias can lead to an overestimation of an effect, but also to an underestimation, which is explained. Several approaches are illustrated that can be used to avoid immortal time bias in the analysis phase of the study; a time-dependent analysis to avoid immortal time bias optimizes the use of available information.

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J C Naafs, P H Verkerk, E Fliers, A S P van Trotsenburg, and N Zwaveling-Soonawala

Objective

To evaluate clinical characteristics of patients with central congenital hypothyroidism (CH), detected in the Dutch neonatal screening program. This included patients with isolated central CH but the majority have multiple pituitary hormone deficiencies (MPHD).

Design

Nationwide, cross-sectional study.

Methods

Data was collected on clinical characteristics, endocrine tests and neuroimaging of central CH patients, detected by the Dutch neonatal screening and born between 1 January 1995 and 1 January 2015. Height and pubertal status were assessed during a study visit. Isolated central CH patients without a confirmed genetic diagnosis were offered genetic (re-)testing.

Results

During the 20-year period 154 central CH patients were detected (incidence of permanent central CH 1:25 642). After excluding deceased (15), severe syndromic (7) and transient patients (6), 92 of 126 eligible patients were included (57 MPHD; 79% male). Sixty-one patients (50 MPHD) had been hospitalized before screening results were reported, but central CH was diagnosed on clinical grounds in only three of them (5%). MRI abnormalities consistent with pituitary stalk interruption syndrome were seen in 50 (93%) MPHD patients. Among isolated central CH patients, 27 (84%) had an IGSF1, TBL1X or IRS4 gene variant (53, 16 and 16%, respectively).

Conclusion

Many patients with central CH have neonatal health problems, especially MPHD patients. Despite hospital admission of two-thirds of patients, almost none were diagnosed clinically, but only after the notification of an abnormal screening result was received. This indicates that central CH, especially if isolated, is an easily missed clinical diagnosis.

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Giulia Gava, Ilaria Mancini, Stefania Alvisi, Renato Seracchioli, and Maria Cristina Meriggiola

Objective

The impact of different combinations of long-term gender-affirming hormone therapy (GAHT) in transwomen (TW) is largely unknown. To assess the effects of 5-year administration of cyproterone acetate (CPA) or leuprolide acetate (Leu) plus transdermal or oral estradiol (E).

Design

Cohort study based on prospectively collected data. Fifty TW received 50 mg CPA daily orally (n = 25; CPA+E group) or 3.75 mg Leu i.m. monthly (n = 25; Leu+E group) with 1 or 2 mg E daily for 5 years. Reproductive hormones, biochemical and anthropometric parameters, body composition and bone mineral density (BMD) were assessed.

Results

LH, FSH and total testosterone levels were similarly and significantly suppressed in both groups. Prolactin increased only in the CPA+E group (P = 0.002). Fasting insulin resistance and glucose progressively increased in the CPA+E group only (treatment × time effect P = 0.002 and P = 0.043, respectively). Total cholesterol increased more in the Leu+E group than in the CPA+E group and HDL-cholesterol decreased in the CPA+E group (time × treatment interaction effect, P = 0.007). Lumbar and total body BMD increased in both groups after 3 years. No serious adverse events were recorded.

Conclusions

Both regimens were effective in suppression of T production. CPA+E worsened the metabolic profile with a slight increase in PRL levels. All subjects presented an increase in BMD regardless of treatment. These preliminary data could have clinical implications in the choice of GAHT, in particular for those TW not requiring gender-affirming surgery.

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Maria-Elina Mosorin, Annina Haverinen, Meri-Maija Ollila, Tanja Nordström, Jari Jokelainen, Sirkka Keinänen-Kiukaanniemi, Katri Puukka, Aimo Ruokonen, Juha Auvinen, Terhi Piltonen, Laure Morin-Papunen, and Juha S Tapanainen

Objective

The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial.

Design

The study is a prospective longitudinal population-based cohort study.

Methods

The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884).

Results

In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3–3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1–9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3–3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5–13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2–3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status.

Conclusions

CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

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Elisa Giannetta, Valentina Guarnotta, Barbara Altieri, Concetta Sciammarella, Elia Guadagno, Pasqualino Malandrino, Giulia Puliani, Tiziana Feola, Andrea M Isidori, Annamaria Anita Livia Colao, and Antongiulio Faggiano

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10–100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or <two-fold response to stimulation. The measurement of calcitonin in fine-needle aspirate washout (FNA-CT) and calcitonin immunocytochemical staining from thyroid nodules are ancillary methods that may significantly improve MTC diagnosis. The present review examines the gray areas in the interpretation of calcitonin measurement in order to provide a tool to clarify the origin of calcitonin secretion and differentiate the behavior of the two-faced Janus of neuroendocrinology: intra-thyroid (MTC) and extra-th9yroid NENs.

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Hei Man Fan, Alice Louisa Mitchell, and Catherine Williamson

Bile acids are lipid-solubilising molecules that also regulate metabolic processes. Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are two bile acid receptors with key metabolic roles. FXR regulates bile acid synthesis in the liver and influences bile acid uptake in the intestine. TGR5 is mainly involved in regulation of signalling pathways in response to bile acid uptake in the gut and therefore prandial response. Both FXR and TGR5 have potential as therapeutic targets for disorders of glucose and/or lipid homeostasis. Gestation is also known to cause small increases in bile acid concentrations, but physiological hypercholanaemia of pregnancy is usually not sufficient to cause any clinically relevant effects. This review focuses on how gestation alters bile acid homeostasis, which can become pathological if the elevation of maternal serum bile acids is more marked than physiological hypercholanaemia, and on the influence of FXR and TGR5 function in pregnancy on glucose and lipid metabolism. This will be discussed with reference to two gestational disorders: intrahepatic cholestasis of pregnancy (ICP), a disease where bile acids are pathologically elevated, and gestational diabetes mellitus (GDM), characterised by hyperglycaemia during pregnancy.

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Stefan M Constantinescu, Natacha Driessens, Aurélie Lefebvre, Raluca M Furnica, Bernard Corvilain, and Dominique Maiter