Guideline sources The following summarized guidelines for the evaluation and management of central hypothyroidism (CeH) are prepared by our editorial team based on guidelines from the European Thyroid Association (ETA 2018), the Endocrine Society (ES 2018; 2016), and the American Thyroid Association (ATA/AACE 2012). 1 2 3 4 Guidelines 1. Screening and diagnosis Indications for screening: As per ES 2018 guidelines: Obtain lifelong annual screening for TSH deficiency in childhood cancer survivors treated for tumors in the region of the hypothalamic-pituitary axis or exposed to 30 Gy hypothalamic- pituitary radiation. B Obtain the same biochemical tests to screen for TSH deficiency in childhood cancer survivors as used in the non-cancer population. Do not obtain serum T3, TSH surge analysis, or thyrotropin-releasing hormone stimulation to diagnose TSH deficiency. B https://web.pathway.md/diseases/recJd5NISKuGq5Y1j 1/5 6/29/23, 3:47 AM Central hypothyroidism Pathway As per ETA 2018 guidelines, obtain screening for CeH in all patients with any of the following, particularly in the presence of hypothyroid manifestations: personal or familial history of hypothalamic-pituitary lesions or diseases moderate-to-severe head trauma stroke previous cranial irradiation hemochromatosis or iron overload. B Show 2 more Indications for testing: As per ETA 2018 guidelines, evaluate for CeH due to IGSF1 defect in adult patients with macroorchidism. B Show 2 more As per ES 2016 guidelines: Monitor euthyroid patients with GH deficiency starting GH therapy for the risk of developing CeH, and initiate levothyroxine therapy if free T4 levels decrease below the reference range. Recognize that patients with GH deficiency and CeH already receiving levothyroxine may require increased levothyroxine doses when starting GH therapy to maintain free T4 levels within target ranges. B Consider treating CeH before obtaining GH-stimulation testing because CeH may impair the accurate diagnosis of GH deficiency. C 2. Diagnostic investigations Thyroid function tests: As per ETA 2018 guidelines, suspect CeH in every subject with low serum concentrations of free T4 and low/normal TSH on a screening examination. B Show 6 more As per ES 2016 guidelines: Measure serum free T4 and TSH for the evaluation of CeH. Consider confirming CeH in case of a free T4 level below the laboratory reference range in conjunction with a low, normal, or mildly elevated TSH in the setting of pituitary disease. A Avoid obtaining dynamic thyroid-stimulating-secretion testing for the diagnose of CeH. D Genetic testing: obtain genetic testing in congenital cases and in cases of CeH onset during childhood, or at any age when CeH remains unexplained, or to support the diagnosis of idiopathic mild forms of CeH (borderline low free T4). B Show 3 more https://web.pathway.md/diseases/recJd5NISKuGq5Y1j 2/5 6/29/23, 3:47 AM Central hypothyroidism Pathway Evaluation for adrenal insufficiency: consider obtaining evaluation for adrenal insufficiency in patients with CeH before initiating levothyroxine therapy. Initiate empiric corticosteroid therapy in patients with CeH initiating levothyroxine therapy until there is a definitive evaluation for adrenal insufficiency. C 3. Medical management Thyroid replacement therapy: As per ETA 2018 guidelines, initiate levothyroxine as first-line therapy for CeH. A Show 6 more As per ES 2016 guidelines, consider initiating levothyroxine therapy in patients with pituitary disease and low/normal free T4 levels suspected to have mild CeH if suggestive symptoms are present, or monitoring free T4 levels over time and initiating treatment if the free T4 level decreases by 20%. C Show 3 more As per AACE 2012 guidelines: Assess serum free T4 levels in patients with CeH to guide therapy and target to exceed the midnormal range value for the assay being used. B Do not use tiratricol for the treatment of CeH. D 4. Perioperative care Perioperative replacement therapy: Initiate levothyroxine therapy before non-emergency pituitary surgery and throughout the perioperative period in cases of preoperative CeH. B Measure free T4 levels 6-8 weeks postoperatively to assess for CeH in patients with intact preoperative thyroid function undergoing pituitary surgery. B 5. Follow-up and surveillance Assessment of treatment response: assess the adequacy of replacement therapy 6-8 weeks after initiation of levothyroxine therapy with concomitant free T4 and TSH measurements in patients with CeH, provided that blood is withdrawn before the morning replacement dose or at least 4 hours after the levothyroxine administration. Aim to maintain free T4 levels above the median value of the normal range. B Show 6 more Serial laboratory assessment: As per ETA 2018 guidelines, monitor free T4 and TSH during childhood at least every 2 years and annually thereafter in patients under follow-up for hypothalamic-pituitary disease. Suspect CeH when serum free T4 falls in the lower quartile of the normal range, in particular when a free https://web.pathway.md/diseases/recJd5NISKuGq5Y1j 3/5 6/29/23, 3:47 AM Central hypothyroidism Pathway T4 decrease > 20% of previous values is seen (provided that the variables are measured by the same assay) despite a low or normal TSH. B Show 2 more As per ES 2016 guidelines, monitor free T4 levels and adjust levothyroxine doses to maintain free T4 levels within target ranges in patients with CeH requiring changes in estrogen therapy. B Show 2 more Clinical findings Symptoms Past medical history Cold intolerance Acromegaly Fatigue Adrenal insufficiency Headache Diabetes inspidus Muscle cramps GH deficiency Sweating Hemochromatosis Weight gain Hypogonadism Hypopituitarism Lab findings Hypothyroidism Pituitary apoplexy serum TSH Pituitary tumor serum free T3 Radiation therapy to the head area serum free T4 thyrotropin-releasing hormone Sheehan's syndrome Stroke TBI Imaging findings Pituitary mass References 1. Maria Fleseriu, Ibrahim A Hashim, Niki Karavitaki et al. Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016 Nov;101 11 3888 3921. Open 2. Persani L, Brabant G, Dattani M et al. 2018 European Thyroid Association ETA Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct;7 5 225 237. Open 3. Sklar CA, Antal Z, Chemaitilly W et al. Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018 Aug 1;103 8 2761 2784. Open https://web.pathway.md/diseases/recJd5NISKuGq5Y1j 4/5 6/29/23, 3:47 AM Central hypothyroidism Pathway 4. Garber JR, Cobin RH, Gharib H et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract. 2012 Nov-Dec;18 6 988 1028. Open https://web.pathway.md/diseases/recJd5NISKuGq5Y1j 5/5