Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on 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, intravenous (iv) 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 counselling, a combination of iv methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 grams (g) of iv 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) a second course of iv 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 iv glucocorticoids, d) teprotumumab; e) rituximab and f) tocilizumab. Sight threatening GO is treated with several high single doses of iv 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.

Studies on hypothyroidism and hyperthyroidism implicate that adequate maternal thyroid hormone availability is required for optimal fetal growth and development. Studies on the association of mild thyroid function test abnormalities with birth weight report heterogeneous results. Some studies indicate that high FT4 concentrations are associated with lower birth weight which could have implications for the treatment target in women already on levothyroxine therapy. We searched Medline (Ovid), Embase.com, Web-of-Science, Cochrane CENTRAL and Google Scholar up to March 18 th , 2018 and collected data on serum thyroid function tests and antibody status during pregnancy and birth weight from prospective cohort studies including treatment-naïve pregnant women.

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.