Implementing reference systems for thyroid function tests - A collaborative effort.

Measurements of thyroid stimulating hormone (TSH) and free thyroxine (fT4) are critical for the early detection of thyroid diseases and for monitoring treatment. The IFCC Committee for Standardization of Thyroid Function Tests (C-STFT) established reference systems for TSH harmonization and FT4 standardization, and is now working national partners on implementing these reference systems. These implementation activities include the maintenance of the reference systems, their use to standardize and harmonize assays, and educational activities to inform stakeholders about anticipated changes in measurement values as a result of standardization and harmonization. The IFCC C-STFT formed a network of reference laboratories for FT4 and is creating a new harmonization panel for TSH. The U.S. Centers for Disease Control and Prevention is a member of the reference laboratory network and is launching a formal standardization program for FT4. In Japan, national organizations successfully implemented TSH harmonization and established harmonized reference intervals for TSH. The C-STFT made available on its website research findings about potential concerns, communication needs and benefits of FT4 standardization and is assisting local organizations with communicating changes related to these standardization and harmonization efforts. Implementation of fT4 standardization and TSH harmonization is a complex, continuous task that requires collaboration with IVD manufacturers, laboratories, physicians and health care providers. C-STFT is working successfully with national organizations and local groups on improving FT4 and TSH measurements.

French Endocrine Society Guidance on endocrine side effects of immunotherapy.

The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPIs). However, the use of ICPI has a risk of side effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, and we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side effects in oncology using 'common terminology criteria for adverse events' (CTCAE) and the difficulties in applying this to endocrine side effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side effects (high-dose corticosteroids, contraindicated in ICPI for example) and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high-dose glucocorticoid intake.

ALK7 expression in prolactinoma is associated with reduced prolactin and increased proliferation.

Prolactinoma represents the most frequent hormone-secreting pituitary tumours. These tumours appear in a benign form, but some of them can reach an invasive and aggressive stage through an unknown mechanism. Discovering markers to identify prolactinoma proliferative and invading character is therefore crucial to develop new diagnostic/prognostic strategies. Interestingly, members of the TGFß-Activin/BMP signalling pathways have emerged as important actors of pituitary development and adult function, but their role in prolactinomas remains to be precisely determined. Here, using a heterotopic allograft model derived from a rat prolactinoma, we report that the Activins orphan type I receptor ALK7 is ectopically expressed in prolactinomas-cells. Through immunohistological approaches, we further confirm that normal prolactin-producing cells lack ALK7-expression. Using a series of human tumour samples, we show that ALK7 expression in prolactinomas cells is evolutionary conserved between rat and human. More interestingly, our results highlight that tumours showing a robust expression of ALK7 present an increased proliferation as address by Ki67 expression and retrospective analysis of clinical data from 38 patients, presenting ALK7 as an appealing marker of prolactinoma aggressiveness. Beside this observation, our work pinpoints that the expression of prolactin is highly heterogeneous in prolactinoma cells. We further confirm the contribution of ALK7 in these observations and the existence of highly immunoreactive prolactin cells lacking ALK7 expression. Taken together, our observations suggest that Activin signalling mediated through ALK7 could therefore contribute to the hormonal heterogeneity and increased proliferation of prolactinomas.

Follow-up of differentiated thyroid carcinoma.

The aim of follow-up of differentiated thyroid carcinoma (CTD) is the assessment of remission, and, in further steps, the early recognition of patients who develop a recurrence. Tools for the follow-up of CTD include the assessment of thyroglobulin and imaging procedures. Thyroglobulin (Tg) is a strong marker of persistent or recurrent disease, but it must be known that Tg antibodies may give falsely low Tg concentration. TSH stimulation, mainly by the mean of recombinant human TSH, improves the sensitivity of Tg determination. New highly sensitive assays may preclude the need for TSH stimulation, at least in some situations. In the last decades, (131)iodine whole body scan gave place to neck ultrasonography (US) as the most performing imaging procedure in the follow-up of CTD. Criteria to identify cervical lymph node suspect of metastasis have been described, and standardized procedures proposed. Finally, the proof of tumoral invasion is brought by cytological analysis of fine needle biopsies of suspicious lymph nodes. (18)FDG PET is a valuable tool for diagnosis and prognosis in metastatic patients, especially with negative (131)I WBS. Initial response to therapy, assessed by Tg determination and neck US, allows re-stratification of the risk of relapse. According to this "reassessed risk", adapted rhythms and modalities of follow-up have been recently proposed.

Recommendations for investigation of hyperandrogenism.

1. Total testosterone assay is recommended as the first-line approach. 2. Radioimmunological assay following prior treatment of the sample (extraction or extraction + chromatography) is the recommended method pending wider experience with mass spectrometry. 3. Where testosterone is twice the upper limit of normal, it is recommended that DHEAS assay be performed. DHEAS is primarily of cortico-adrenal origin in women. Thus, a DHEAS level over 600 mg/dl indicates a diagnosis of androgen-secreting adrenal cortical adenoma.. If DHEAS is normal, the diagnosis could be either ovarian hyperthecosis, normally associated with insulin resistance, or androgen-secreting ovarian tumour. 4. More rarely, elevated testosterone is associated with a marked elevation of SHBG possibly as the result of use of medication having an estrogenic effect (tamoxifen, raloxifene, Op'DDD), or of hyperthyroidism or liver disease. 5. Normal testosterone levels in patients with clear clinical symptoms of hyperandrogenism (hirsutism, seborrhoeic acne) must be interpreted with care. SHBG is normally reduced in the event of overweight, metabolic syndrome or familial history of diabetes.

Sex hormone-binding globulin predicts the incidence of hyperglycemia in women: interactions with adiponectin levels.

OBJECTIVE: Previous evidence has suggested that a low sex hormone-binding globulin (SHBG) concentration is associated with insulin-resistance and a low adiponectin concentration. We investigated the association between SHBG and the risk of hyperglycemia in each sex and we determined potential interactions between SHBG and adiponectin levels in the development of dysglycemia. DESIGN: We used a nested case-control design in the large prospective study, Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR). We studied 227 men and women who were normoglycemic at baseline but hyperglycemic at 3 years (glycemia > or = 6.1 mmol/l or type 2 diabetes). They were matched for sex, age, and body mass index with 227 subjects who remained normoglycemic at 3 years. RESULTS: At baseline, the concentration of SHBG was significantly lower in women who subsequently developed hyperglycemia than in those who remained normoglycemic, with no difference for men. In multiple regression, SHBG at baseline was as an independent determinant of plasma adiponectin levels, in both women (P<0.0001) and men (P=0.002). In multivariate conditional logistic regression taking into account physical activity and changes in waist circumference over the follow-up, plasma SHBG remained significantly associated with the development of hyperglycemia in women but not in men. These associations persisted after adjustment for fasting insulinemia, high fasting glucose, and adiponectin levels. CONCLUSIONS: These findings suggest that a low SHBG level is a strong risk marker for dysglycemia in women, independently of both adiponectinemia and insulinemia. SHBG may therefore improve the identification of women at risk of diabetes.

Reliability and validity of commercially available, direct radioimmunoassays for measurement of blood androgens and estrogens in postmenopausal women.

In large-scale epidemiological studies on endogenous sex steroids and cancer risk, direct immunoassays of circulating hormone levels have the advantage of being fast and comparatively inexpensive while requiring only small sample volumes. On the other hand, indirect assays after organic extraction and chromatographic prepurification have the advantage of reducing specific interferences and matrix effects and hence are thought to have better validity. We compared direct assays of testosterone (T, six different assays), Delta4-androstenedione (A, four assays), estrone (E(1), one assay), and 17beta-estradiol (E(2), five assays) with measurements obtained by an indirect assay in a representative subset of 20 postmenopausal women who were part of a large prospective cohort study. Within-batch reproducibilities of the subject rankings by relative hormone levels were good (intraclass correlations >0.89) for all direct assays tested. Between batches, reproducibilities generally were also acceptable (r > 0.80) to good (r > 0.90) in terms of Pearson's correlations. The between-batch reproducibility in terms of intraclass correlations was systematically lower in terms of Pearson's correlations, however, because of between-batch variations in the absolute scale of measurements. The relative validity of direct versus indirect assays in terms of the subjects' ranking by relative hormone levels was also high for most of the kits tested for T, A, and E(1) (Pearson's correlations between 0.70 and 0.89) but was high for only two kits of five tested for E(2) (correlations of 0.86 and 0.84). On an absolute scale, mean measurement values were generally higher for direct assays than for the indirect assay and, for each hormone, varied substantially, depending on the kit used. Overall, the results of this study show that, with careful selection, commercial kits for direct radioimmunoassays of steroid hormones in postmenopausal serum can be found that may allow a reliable estimation of relative risks in epidemiological studies. However, standardization of the absolute scale of assays remains problematic.