The future endocrine patient. Reflections on the future of clinical endocrinology

In recent years the future position of clinical endocrinology has been extensively discussed by Western European endocrine societies. Clinical endocrinology seems to suffer from being too intellectual, generating too little income, and lacking too few spectacular interventions. In this manuscript we describe 'the endocrine patient' of the past, the present, and the future. Complete therapeutic breakthroughs resulting in 'cure' are compared with 'halfway technologies' which help in creating the (life-long) chronic endocrine patient. The potential use of molecular diagnostics in optimalizing hormone replacement therapy is discussed. Clinical endocrinology is at risk of developing into a subspecialty where life-style drugs created for new diseases or conditions are offered, but also actively pursued by otherwise healthy individuals (e.g. in normal short stature, regulation of appetite, body composition, sexuality, reproduction and aging). The potential opportunities and risks for clinical endocrinology in creating 'the endocrine patient' of the future are discussed

Aberrant levels of hematopoietic/neuronal growth and differentiation factors in euthyroid women at risk for autoimmune thyroid disease

Background Subjects at risk for major mood disorders have a higher risk to develop autoimmune thyroid disease (AITD) and vice-versa, implying a shared pathogenesis. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors is observed, suggesting that growth/differentiation abnormalities of these cell lineages may predispose to mood disorders. The first objective of our study was to investigate whether an aberrant profile of these hematopoietic/neuronal growth factors is also detectable in subjects at risk for AITD. A second objective was to study the inter relationship of these factors with previously determined and published growth factors/cytokines in the same subjects. Methods We studied 64 TPO-Ab-negative females with at least 1 first-or second-degree relative with AITD, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. Subjects were compared with 32 healthy controls (HCs). We measured serum levels of brain-derived neurotrophic factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF) and IL-7 at baseline. Results BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001), while EGF (506.9 vs 307.6 pg/ml, P = 0.003) and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028) were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1β, IL-6 and CCL-3, of which high levels also prec

Differential diagnosis in spinal and bulbar muscular atrophy clinical and molecular aspects

Kennedy disease is caused by an enlarged trinucleotide repeat sequence within the androgen receptor gene. We report here seven male patients with a benign motor neuron syndrome highly analogous to Kennedy disease but with a normal trinucleotide repeat

The 2021 European group on graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of graves’ orbitopathy

Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves’ hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations

The role of thyroid hormone nuclear receptors in the heart: evidence from pharmacological approaches

This review evaluates the hypothesis that the cardiac effects of amiodarone can be explained—at least partly—by the induction of a local ‘hypothyroid-like condition’ in the heart. Evidence supporting the hypothesis comprises the observation that amiodarone exerts an inhibitory effect on the binding of T3 to thyroid hormone receptors (TR) alpha-1 and beta-1 in vitro, and on the expression of particular T3-dependent genes in vivo. In the heart, amiodarone decreases heart rate and alpha myosin heavy chain expression (mediated via TR alpha-1), and increases sarcoplasmic reticulum calcium-activated ATPase and beta myosin heavy chain expression (mediated via TR beta-1). Recent data show a significant similarity in expression profiles of 8,435 genes in the heart of hypothyroid and amiodarone-treated animals, although similarities do not always exist in transcripts of ion channel genes. Induction of a hypothyroid cardiac phenotype by amiodarone may be advantageous by decreasing energy demands and increasing energy availability

Impact of month of birth on the development of autoimmune thyroid disease in the United Kingdom and Europe

CONTEXT: Viral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves' disease (GD) and Hashimoto's thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life. OBJECTIVE: Month of birth effects were investigated in three independent European Caucasian AITD datasets. DESIGN: Variation in GD and HT onset was compared across months and seasons, with fluctuations across all 12 months analyzed using a Walter-Elwood test. SETTING: The study was conducted at a research laboratory. PATIENTS: National UK Caucasian AITD Case Control Collection (2746 GD and 502 HT compared with 1 423 716 UK births), National UK Caucasian GD Family Collection (239 GD and 227 unaffected siblings), and OXAGEN AITD Caucasian Family Collection (885 GD, 717 HT, and 794 unaffected siblings of European Caucasian decent). MAIN OUTCOME MEASURES: Case-control and family-based association studies were measured. RESULTS: No consistent month of birth effects were detected in GD females or males across all three collections. In HT females from the OXAGEN AITD Caucasian Family Collection, slightly higher birth rates were detected in autumn (Walter's test statistic = 7.47, P = .024) however, this was not seen in the HT females from the case-control cohort. CONCLUSION: Our results suggest in UK/Northern European Caucasian GD subjects, month of birth does not impact on AITD development. Although some month of birth effects for HT females in one collection cannot be excluded, only further work in larger European Caucasian AITD collections can confirm these effects

Do we need still more trials on T-4 and T-3 combination therapy in hypothyroidism?

Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine replacement. It is unlikely that slight over- or under-treatment with thyroxine (T-4) explains remaining complaints Meta-analysis of randomized clinical trials shows no advantage of T-4/tri-iodothyronine (T-3) combination therapy over T-4 monotherapy However, each of these trials can be criticized, and none is perfect: most of them failed to mimic the physiological ratio of serum free T-4 (FT4) to free T-3 (FT3) concentrations. Development of a sustained-release T-3 preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT4-FT3 ratio's throughout 24 h Genetic polymorphisms in deiodinase 2 and thyroid hormone transporters have been associated with well-being, fatigue, depression, and greater improvement on combination therapy. Future trials should target carriers of these polymorphisms to see whether they do better on T-4/T-3 combination therapy than on T-4 monotherap

Advances in treatment of active, moderate-to-severe Graves' ophthalmopathy

Graves' ophthalmopathy is defined as autoimmune inflammation of extraocular muscles and orbital fat or connective tissue, usually in patients with Graves' disease. About one in 20 patients with Graves' hyperthyroidism has moderate-to-severe Graves' ophthalmopathy. Corticosteroids have been the mainstay of treatment, but new evidence about immune mechanisms has provided a basis to explore other drug classes. Intravenous methylprednisolone pulses are more effective and better tolerated than oral prednisone in the treatment of active, moderate-to-severe Graves' ophthalmopathy. Rituximab has also been suggested as a possible replacement for intravenous corticosteroids. Two randomised controlled trials of rituximab reached seemingly contradictory conclusions-rituximab was not better with respect to the primary outcome (clinical activity score) than placebo in one trial (which, however, was confounded by rather long Graves' ophthalmopathy duration), but was slightly better than intravenous methylprednisolone pulses in the other (disease flare-ups occurred only in the latter group). On the basis of evidence published so far, rituximab cannot replace intravenous methylprednisolone pulses, but could have a role in corticosteroid-resistant cases. Open-label studies of tumour-necrosis-factor-a blockade had limited efficacy, but other studies showed that interleukin-6 receptor antibodies were effective. Results of randomised controlled trials investigating the efficacy of the IGF-1 receptor antibody teprotumumab and the interleukin-6 receptor antibody tocilizumab are expected shortly. Approaches that target the causal mechanism of Graves' ophthalmopathy (antibodies or antagonists that block thyroid-stimulating-hormone receptors) also look promisin