INTRODUCTION — The overwhelming majority of patients who have hypothyroidism have thyroid disease (primary hypothyroidism). Central hypothyroidism refers to thyroid hormone deficiency due to a disorder of the pituitary, hypothalamus, or hypothalamic-pituitary portal circulation, resulting in diminished thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), or both. Pituitary TSH production is regulated in part by TRH, which is secreted from the paraventricular nucleus in the hypothalamus . TRH is released into portal blood vessels and transported to the anterior pituitary gland where it regulates the synthesis, glycosylation, and release of TSH (figure 1). TSH stimulates the synthesis and secretion of triiodothyronine (T3) and thyroxine (T4). (See "Thyroid hormone synthesis and physiology".)
The clinical features, diagnosis, and treatment of central hypothyroidism will be reviewed here. The approach to patients with primary, subclinical, and congenital hypothyroidism is reviewed separately. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Treatment of primary hypothyroidism in adults" and "Subclinical hypothyroidism in nonpregnant adults" and "Clinical features and detection of congenital hypothyroidism" and "Treatment and prognosis of congenital hypothyroidism".)
ETIOLOGY — Central hypothyroidism is a rare cause of hypothyroidism, estimated to occur in 1:20,000 to 1:80,000 in the general population . The causes of central hypothyroidism are the same as the causes of hypopituitarism (table 1) [3,4]. Patients with central hypothyroidism frequently have other pituitary hormone deficiencies. (See "Causes of hypopituitarism".)
Pituitary mass lesions, especially pituitary adenomas, are the most common cause of central hypothyroidism . Pituitary tumors can cause central hypothyroidism by compressing pituitary thyrotrophs, which results in a decrease in TSH secretion; by interrupting the hypothalamic-pituitary portal blood flow, which results in disruption of the signaling between the hypothalamus and pituitary; or, rarely, by acute hemorrhage or infarction, resulting in pituitary apoplexy [3,4]. Other mass lesions that can cause central hypothyroidism include cysts and abscesses, meningiomas and dysgerminomas, metastatic tumors, and craniopharyngiomas, which may enter the sella or remain suprasellar.
In addition, surgery or radiation therapy for pituitary adenomas or other mass lesions can cause central hypothyroidism. Radiation in high doses (≥30 to 40 Gray) to the brain, orbits, infratemporal, nasopharyngeal, or oropharyngeal regions can affect the pituitary gland or hypothalamus [6,7]. (See "Delayed complications of cranial irradiation", section on 'Endocrinopathies'.)
Other causes of central hypothyroidism include:
●Infiltrative disorders affecting the pituitary or hypothalamus (eg, hemochromatosis, lymphocytic hypophysitis, tuberculosis, syphilis, sarcoidosis, fungal infections, toxoplasmosis, and histiocytosis)
●Traumatic brain injury with injury to the pituitary stalk , stroke, subarachnoid hemorrhage
●Sheehan syndrome (postpartum pituitary necrosis).
●Developmental abnormalities, internal carotid aneurysms, and other central nervous system (CNS) tumors, which may cause hypothalamic damage
●Drug-induced endocrinopathies (eg, checkpoint inhibitor-induced hypophysitis) (see "Toxicities associated with immune checkpoint inhibitors", section on 'Hypophysitis')
Idiopathic isolated TSH or thyrotropin-releasing hormone (TRH) deficiency is a rare cause of central hypothyroidism [9,10]. One cause of the former is treatment (of patients with lymphoma) with a retinoid X receptor ligand (bexarotene) that selectively inhibits TSH secretion [11,12].
Several rare genetic defects have also been described [13,14]:
●Central hypothyroidism may occur due to mutations in the TSH-beta subunit gene, the TRH receptor gene, in TBL1X (the gene encoding the subunit of the nuclear receptor co-repressor of the thyroid hormone receptor complex), in the IGSF-1 gene (which also causes macroorchidism, by negative modulation of the TGFb1- and activin-Smad pathways), and in the IRS4 (insulin receptor substrate 4) gene by an unknown mechanism.
●Central hypothyroidism also occurs with combined pituitary hormone deficiencies due to mutations in multiple genes including pituitary transcription factors such as POU1F1 (PIT1), PROP1, HESX1, SOX3, SOX2, and others. (See "Causes of hypopituitarism", section on 'PIT-1'.)
Growth hormone replacement therapy in growth hormone-deficient adults may unmask central hypothyroidism [15,16]. In one study of 84 patients with growth hormone deficiency, all of whom were initiating growth hormone therapy, 30 (36 percent) subsequently required levothyroxine (T4) therapy because of reduced serum T4 concentrations .
Clinical manifestations — The clinical manifestations of central hypothyroidism are similar to, but sometimes milder than, those of primary hypothyroidism. Common symptoms of central hypothyroidism include fatigue, cold intolerance, muscle cramps, headache, and weight gain (table 2). Goiter is not a typical finding. (See "Clinical manifestations of hypothyroidism".)
Most patients with central hypothyroidism have a history of previous hypothalamic or pituitary disease, cranial irradiation, infiltrating disease, or trauma, with accompanying symptoms of deficiency or excess of other pituitary hormones . In patients with coexisting pituitary hormone abnormalities, the symptoms of hypothyroidism may be less obvious. As an example, hot flashes due to hypogonadism may mask the cold intolerance of hypothyroidism. The coexistence of hypothyroidism and adrenal insufficiency may result in anorexia and weight loss, while hypothyroid, acromegalic patients may complain of sweating. Children may present with growth retardation and delayed sexual maturation, precocious puberty, or dwarfism and cretinism. The presence of polyuria and polydipsia suggests diabetes insipidus and posterior pituitary or hypothalamic involvement (eg, due to a craniopharyngioma).
Thyroid function tests — In patients with central hypothyroidism, serum free T4 is low or low-normal, but serum TSH may be low, normal, or even slightly elevated (up to approximately 10 mU/L) (table 3). In a retrospective study of 108 adult patients with central hypothyroidism (childhood onset, n = 26; adult onset, n = 82), initial free T4 results were in the low-normal range in only 18 percent of patients with adult onset (the remainder having levels below normal), compared with 65 percent of patients with childhood-onset central hypothyroidism . In 51 patients, TSH was measured with a sensitive immunoradiometric assay, and the following results were noted:
●8 percent of patients had low (<0.2 mU/L) serum TSH concentrations
●84 percent had normal values
●8 percent had high (>3.5 mU/L) values
Normal or high serum TSH concentrations in some patients with central hypothyroidism is due, in part, to the secretion of TSH that has reduced biologic activity but normal immunoactivity [18,19]. Reduced bioactivity is due to abnormalities in glycosylation of the TSH subunits, which is under the control of thyrotropin-releasing hormone (TRH) [18,20].
There is a diurnal rhythm in TSH secretion, with a surge late in the evening. This appears to be under hypothalamic control and is absent in many patients with central hypothyroidism [21,22]. Thus, TSH measurements may be normal during the daytime, but the absence of a nocturnal rise in TSH reduces the overall quantity of TSH secreted by the pituitary gland, causing clinical hypothyroidism.
In patients with central hypothyroidism, serum total and free T3 levels may be normal or low [17,23].
TRH stimulation test — Although thyrotropin-releasing hormone (TRH) is not currently available in the United States, it is widely available in other countries. A TRH stimulation test involves the intravenous administration of TRH (200 mcg) with measurement of serum TSH at baseline and then 20 and 60 minutes after TRH administration. The normal increment in TSH at 20 minutes is 5 to 30 mU/L, with a subsequent decrease at 60 minutes . Classically, one would expect no serum TSH response to TRH in patients with pituitary disease and a delayed response in patients with hypothalamic disease (figure 1). In fact, the response to TRH is highly variable in these circumstances, limiting the utility of this test in distinguishing between pituitary and hypothalamic disease as a cause of central hypothyroidism .
A TRH stimulation test may be useful in distinguishing nonthyroidal illness from central hypothyroidism due to pituitary disease. Patients with nonthyroidal illness have a blunted nocturnal rise in serum TSH concentrations, but they usually have a normal serum TSH response to TRH. (See 'Transient central hypothyroidism' below.)
Other — In patients with pituitary tumors, there may be laboratory evidence of deficiency or excess of other pituitary hormones, such as hypogonadism or hyperprolactinemia. (See "Causes, presentation, and evaluation of sellar masses".)
DIAGNOSIS — The diagnosis of central hypothyroidism is based upon clinical manifestations and thyroid function tests. The majority of patients with central hypothyroidism have coexisting deficiencies in other pituitary hormones, although isolated TSH deficiency may also occur. Central hypothyroidism should be suspected in the following circumstances:
●There is known hypothalamic or pituitary disease
●A mass lesion is present in the pituitary
●When symptoms and signs of hypothyroidism are associated with other hormonal deficiencies
In hypothyroidism caused by hypothalamic or pituitary disease, TSH secretion does not increase appropriately as T4 secretion falls. Thus, we measure both serum TSH and free T4 if pituitary or hypothalamic disease is suspected. We also measure free T4 if the patient has convincing symptoms of hypothyroidism despite a normal TSH result.
In patients with central hypothyroidism, the serum free T4 value is low normal or low and serum TSH may be frankly low, inappropriately normal (for the low T4), or slightly high (5 to 10 mU/L) due to secretion of biologically inactive TSH (table 3). In patients being monitored for central hypothyroidism (eg, irradiated childhood brain tumor survivors), a progressive decline in free T4 during surveillance is suggestive of central hypothyroidism . (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Secondary and tertiary (central) hypothyroidism'.)
It is not necessary to measure T3 in most patients with suspected central hypothyroidism. However, it may be helpful to measure T3 when the diagnosis of central hypothyroidism is uncertain. As an example, patients who are taking liothyronine (T3) supplements or who have autonomous thyroid nodules may have suppressed TSH and low free T4 levels, similar to that seen in patients with central hypothyroidism; however, serum T3 levels are usually elevated or high normal, rather than normal or low. (See 'TSH low' below.)
DIFFERENTIAL DIAGNOSIS — For patients with a history of previous hypothalamic-pituitary disease, with accompanying symptoms of deficiency or excess of other pituitary hormones, and a low or low-normal free T4 with a low or inappropriately normal TSH, the diagnosis of central hypothyroidism is straightforward. However, for patients without previous hypothalamic/pituitary disease, it may be difficult to distinguish mild central hypothyroidism from mild primary hypothyroidism or subclinical hyperthyroidism. Some drugs can affect thyroid hormone metabolism, mimicking the thyroid function test abnormalities seen in patients with central hypothyroidism. In addition, transient central hypothyroidism may occur in some settings.
TSH slightly high
●Central versus primary hypothyroidism – A patient with a low serum total or free T4 concentration (eg, free T4 0.7 to 0.9 ng/dL [normal range 0.9 to 1.8 ng/dL]) and a slightly high serum TSH concentration (eg, 5 to 10 mU/L [normal range 0.5 to 5.0 mU/L]) could have either primary or central hypothyroidism. A higher serum TSH value would be expected if the patient had primary hypothyroidism, but since patients with central hypothyroidism may have elevations of biologically inactive TSH, definitive diagnosis requires further evaluation.
In this setting, we measure anti-thyroid peroxidase (TPO) antibodies; follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol in premenopausal women with amenorrhea; FSH in postmenopausal women; and LH and testosterone in men. A high serum TPO antibody concentration suggests chronic autoimmune (Hashimoto's) thyroiditis and primary hypothyroidism, whereas absence of anti-TPO antibodies and abnormalities in other pituitary hormones favors central hypothyroidism. Amenorrhea in premenopausal women, the absence of high serum FSH concentrations in postmenopausal women, and low serum testosterone and normal or low LH concentrations in men suggest the presence of secondary hypogonadism. Hyperprolactinemia may be present in both central and primary hypothyroidism.
●Central hypothyroidism versus subclinical hyperthyroidism – A patient with a low-normal serum total or free T4 value and a detectable but subnormal serum TSH concentration (eg, free T4 0.9 to 1.1 ng/dL, TSH 0.2 to 0.5 mU/L) could have either central hypothyroidism or subclinical hyperthyroidism.
In this setting, serum T3 should be measured. Rarely, patients with subclinical hyperthyroidism who have low-normal free T4 values can have high-normal T3 values. The finding of a normal or high-normal serum T3 is consistent with subclinical hyperthyroidism. We then obtain a thyroid scan and uptake, looking for thyroid autonomy. If the scan shows areas of autonomy and the 24-hour uptake is normal or high-normal, autonomously functioning thyroid nodules or multinodular goiter are the most likely cause of subclinical hyperthyroidism.
If the T3 is normal or low-normal, we evaluate for coexisting pituitary hormone abnormalities as described above.
●Central hypothyroidism versus euthyroid hypothyroxinemia – Many conditions result in increases or decreases in serum total T4 and T3 concentrations, but little change in serum free T4 and T3 concentrations and no symptoms or signs of thyroid dysfunction. Thus, in patients with a normal TSH and low total T4 concentrations, the serum free T4 should be measured. The detection of a normal serum TSH concentration associated with a low serum total T4 and normal free T4 concentration should alert the clinician to search for one of the causes of euthyroid hypothyroxinemia, especially if the patient has no symptoms or signs of hypothyroidism. (See "Euthyroid hyperthyroxinemia and hypothyroxinemia", section on 'Euthyroid hypothyroxinemia due to binding protein abnormalities'.)
●Drug interaction – In patients with low serum total and free T4 concentrations (with a normal TSH concentration), central hypothyroidism is possible. However, certain drugs, especially antiseizure medications, such as phenytoin and carbamazepine, may be associated with an artifactually low serum free T4 and a normal serum TSH, mimicking central hypothyroidism . In this case, assessment of other pituitary functions and pituitary imaging may be required to definitively rule out central hypothyroidism. In addition, thyrotropin-releasing hormone (TRH) testing, where available, can be very helpful in ruling out central hypothyroidism . Patients with phenytoin-induced reductions in serum total and free T4 would have a normal TSH response to TRH administration, whereas patients with central hypothyroidism would have an absent or delayed response. Mitotane, a drug used to treat adrenocortical cancer, is also associated with a low free T4 and normal TSH, but unlike phenytoin, the TSH response to TRH is blunted. (See "Drug interactions with thyroid hormones".)
Transient central hypothyroidism — There are three clinical situations in which the laboratory finding of central hypothyroidism is transient:
●After treatment of hyperthyroidism with an antithyroid drug, radioiodine, or surgery, serum TSH concentrations remain low for approximately 25 days. Serum free T4 values may fall to below normal during this period . (See "Laboratory assessment of thyroid function", section on 'Monitoring treatment of hyperthyroidism' and "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Choice of therapy'.)
●Serum TSH concentrations may remain low for a similar period after T4 suppressive therapy is discontinued in a patient with a nodular goiter  or a history of thyroid cancer.
●Patients with severe, nonthyroidal illness have transient central hypothyroidism. Thus, permanent central hypothyroidism should not be diagnosed in the presence of an underlying medical disease. (See "Thyroid function in nonthyroidal illness".)
In these settings, clinical status and thyroid function tests (TSH, free T4) should be monitored serially (every four to six weeks) until thyroid tests return to normal. Additional evaluation is generally unnecessary.
EVALUATION — Patients with biochemical evidence of central hypothyroidism require neuroradiologic studies (preferably magnetic resonance imaging [MRI]) to assess the hypothalamic-pituitary region. If MRI is unavailable, a computed tomography (CT) scan with coronal views through the pituitary is a reasonable alternative.
Biochemical assessment of other pituitary hormone deficiencies, particularly secondary adrenal insufficiency, should be performed. Administration of levothyroxine (T4) to patients with unsuspected and untreated secondary adrenal insufficiency can precipitate an acute adrenal crisis. Thus, pituitary-adrenal function should be assessed, usually by a corticotropin (ACTH) stimulation test, before T4 therapy is begun in all patients with central hypothyroidism. If adrenal insufficiency is present, glucocorticoid therapy should be given concomitantly with T4. (See "Diagnosis of adrenal insufficiency in adults".)
Evaluation of other hypothalamic-pituitary hormonal function (gonadotropins, testosterone, estradiol, prolactin, insulin-like growth factor-1 [IGF-1]) to diagnose hormonal hypersecretion or hyposecretion is necessary in patients with a sellar mass on MRI. (See "Causes, presentation, and evaluation of sellar masses", section on 'Evaluation of a sellar mass'.)
In patients with normal findings on MRI, clinical and biochemical assessment of hypothalamic-pituitary hormonal function may be useful to differentiate central from mild primary hypothyroidism. (See 'TSH slightly high' above.)
TREATMENT — Pituitary-adrenal function should be assessed, usually by a corticotropin (ACTH) stimulation test, before levothyroxine therapy is begun in all patients with central hypothyroidism. If adrenal insufficiency is present, glucocorticoid therapy should be given concomitantly with T4. (See "Diagnosis of adrenal insufficiency in adults" and "Diagnostic testing for hypopituitarism".)
●Dosing – The treatment of choice for correction of central hypothyroidism is synthetic levothyroxine. We suggest starting with a weight-based levothyroxine dose of 1.6 mcg/kg . Another approach is to start with a lower dose and titrate to an endpoint slightly higher than the average normal free T4 value (ie, slightly higher than mid-normal); this approach is preferred in older patients or patients with underlying cardiovascular disease.
●Monitoring – The dose of levothyroxine should be adjusted according to the patient's symptoms and serum free T4 values. The goal should be an average free T4 value for patients taking levothyroxine monotherapy. Since patients taking levothyroxine monotherapy have slightly higher serum T4 concentrations to compensate for the small deficit in T3, the free T4 should be slightly higher than mid-normal.
Serum TSH cannot be used to monitor therapy, as it is suppressed to <0.1 mU/L in nearly all patients taking doses of levothyroxine that raise their serum free T4 concentrations to normal .
In patients with pituitary tumors, central hypothyroidism may be reversible. Surgery may occasionally lead to an improvement in anterior pituitary function (see "Causes of hypopituitarism", section on 'Mass lesions'). Thyroid function (TSH, free T4) should be measured six to eight weeks after surgery. If a previously undetectable TSH becomes detectable, one can consider trying to taper the levothyroxine dose while monitoring free T4 and TSH at four- to six-week intervals.
There is controversy regarding the goal for free T4 in patients with central hypothyroidism taking levothyroxine. In a randomized, crossover trial comparing thyroid hormone replacement regimens in patients with central hypothyroidism, higher dose T4 (1.6 mcg/kg) was superior to lower dose (1 mcg/kg) with respect to body mass index (BMI), lipid profile, and symptoms . The resultant serum free T4 levels were at or slightly above the upper limit of normal. The widely accepted conclusion from this study is that the levothyroxine dose should be adjusted according to the patient's symptoms and serum free T4 values, aiming to maintain the serum free T4 concentration in the upper part of the normal range. However, it is well known that patients with primary hypothyroidism who take doses of levothyroxine that suppress TSH may have improved mental health and mood  and improved well-being  despite the cardiovascular and skeletal risks of iatrogenic subclinical hyperthyroidism (see "Subclinical hyperthyroidism in nonpregnant adults"). An analysis of a United Kingdom database of 525 patients with pituitary tumors found that 39 percent of those with central hypothyroidism taking levothyroxine had free T4 values less than 13 pmol/L (1.0 ng/dL; normal range 9 to 25 pmol/L [0.7 to 1.9 ng/dL]), compared with 13 percent of patients with primary hypothyroidism taking T4, suggesting the possibility that many patients with central hypothyroidism are undertreated .
The authors of another study suggest that patients with central hypothyroidism may need more levothyroxine to achieve serum T4 values in the upper half of the normal range than patients with primary hypothyroidism caused by chronic autoimmune thyroiditis or radioiodine therapy. In this study of clinically euthyroid patients with serum free T4 index values in the upper half of the normal range, 36 patients with central hypothyroidism were receiving more levothyroxine (155 mcg/day, 1.9 mcg/kg/day) than 73 patients with hypothyroidism caused by chronic autoimmune thyroiditis or radioiodine therapy (118 mcg/day, 1.6 mcg/kg/day) . It is unclear from this study whether aiming for a high normal free T4 in patients with central hypothyroidism results in excessive replacement therapy. In another study, women taking estrogen replacement therapy, men initiating growth hormone therapy, and patients with childhood-onset central hypothyroidism needed a higher dose of levothyroxine to maintain the free T4 in the upper half of the normal range .
There are insufficient data to determine whether combined levothyroxine (T4) and T3 (in physiologic doses) is superior to levothyroxine monotherapy for patients with central hypothyroidism. Patients with central hypothyroidism may have low serum free T3 concentrations despite normal or upper normal free T4 values [17,23]. The potential benefit of combined T4-liothyronine (T3) treatment in 29 patients with central hypothyroidism was evaluated in a five-week, crossover trial comparing thyroid replacement regimens . Although compared with T4 alone (1.6 mcg/kg), patients receiving combined T3 (0.16 mcg/kg) and T4 (1.44 mcg/kg) had a small but significant improvement in total cholesterol (198 versus 194 mg/dL) and normalization of ankle reflex time (380 versus 364 msec); the combined regimen resulted in supraphysiologic free T3 levels, suggesting hyperthyroidism. A full discussion of this topic can be found elsewhere. (See "Treatment of primary hypothyroidism in adults", section on 'Combination T4 and T3 therapy'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypothyroidism".)
SUMMARY AND RECOMMENDATIONS
●Central hypothyroidism refers to thyroid hormone deficiency due to a disorder of the pituitary, hypothalamus, or hypothalamic-pituitary portal circulation (figure 1). The prevalence of central hypothyroidism is much lower than that of primary hypothyroidism. Pituitary mass lesions, especially pituitary adenomas, are the most common cause of central hypothyroidism. Other mass lesions that can cause central hypothyroidism include cysts and abscesses, meningiomas and dysgerminomas, pituitary adenocarcinomas and metastatic tumors, and craniopharyngiomas, which may enter the sella or remain suprasellar (table 1). (See 'Introduction' above and 'Etiology' above.)
●The clinical manifestations of central hypothyroidism are similar to, but sometimes milder than, those of primary hypothyroidism. Common symptoms of hypothyroidism include fatigue, cold intolerance, muscle cramps, and weight gain. The majority of patients with central hypothyroidism have coexisting deficiency or excesses of other pituitary hormones, although isolated thyroid-stimulating hormone (TSH) deficiency may also occur. In patients with coexisting pituitary hormone abnormalities, the symptoms of hypothyroidism may be masked by other symptoms of hypopituitarism. (See 'Clinical manifestations' above.)
●In hypothyroidism caused by hypothalamic or pituitary disease, TSH secretion does not increase appropriately as thyroxine (T4) secretion falls. In patients with central hypothyroidism, serum free T4 is low or low normal, but serum TSH may be low, normal, or even slightly elevated (up to approximately 10 mU/L) (table 3). In patients with pituitary tumors, there may be laboratory evidence of deficiency or excess of other pituitary hormones, such as hypogonadism or hyperprolactinemia. (See 'Laboratory findings' above.)
●The diagnosis of central hypothyroidism is based upon clinical manifestations and thyroid function tests. We measure both serum TSH and free T4 if central hypothyroidism is suspected. We also measure free T4 if the patient has convincing symptoms of hypothyroidism despite a normal TSH result. In patients with central hypothyroidism, the serum free T4 value is low normal or low and serum TSH may be frankly low, inappropriately normal (for the low T4), or slightly high (5 to 10 mU/L) due to secretion of biologically inactive TSH (table 3). (See 'Diagnosis' above.)
●For patients without previous hypothalamic-pituitary disease, it may be difficult to distinguish mild central hypothyroidism from mild primary hypothyroidism or subclinical hyperthyroidism. Some drugs can affect thyroid hormone metabolism, mimicking the thyroid function test abnormalities seen in patients with central hypothyroidism. In addition, transient central hypothyroidism may occur in some settings. (See 'Differential diagnosis' above.)
●Patients with biochemical evidence of central hypothyroidism require neuroradiologic studies (preferably magnetic resonance imaging [MRI]) to assess the hypothalamic-pituitary region and biochemical assessment of the other pituitary hormones, particularly secondary adrenal insufficiency. Administration of levothyroxine to patients with unsuspected and untreated secondary adrenal insufficiency can precipitate an acute adrenal crisis. Thus, pituitary-adrenal function should be assessed, usually by a corticotropin (ACTH) stimulation test, before levothyroxine therapy is begun in all patients with central hypothyroidism, and glucocorticoid therapy should be given before or with levothyroxine if adrenal insufficiency is present. (See 'Evaluation' above.)
●The treatment for correction of central hypothyroidism is synthetic levothyroxine. We typically start with a weight-based dose of 1.6 mcg/kg. Another approach is to start with a lower dose and titrate to a free T4 slightly higher than the average normal free T4 value. The dose should be adjusted according to the patient's symptoms and serum free T4 values, aiming for a free T4 value that is slightly higher than mid-normal. Serum TSH cannot be used to monitor therapy, as it is suppressed to <0.1 mU/L in nearly all patients taking doses of levothyroxine that raise their serum free T4 concentrations to normal. (See 'Treatment' above.)
1 : The Hypothalamic Paraventricular Nucleus Is the Center of the Hypothalamic-Pituitary-Thyroid Axis for Regulating Thyroid Hormone Levels.
10 : Usefulness of thyrotropin (TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion.
12 : Bexarotene-induced central hypothyroidism assessed by TRH stimulation test in cutaneous T-cell lymphoma patients.
14 : 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism.
15 : Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients.
16 : Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory?
17 : Clinical and hormonal characteristics of central hypothyroidism at diagnosis and during follow-up in adult patients.
18 : Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone.
20 : Concanavalin-A, lentil, and ricin lectin affinity binding characteristics of human thyrotropin: differences in the sialylation of thyrotropin in sera of euthyroid, primary, and central hypothyroid patients.
21 : Patterns of pulsatile pituitary glycoprotein secretion in central hypothyroidism and hypogonadism.
23 : Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism.
24 : Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism.
27 : Normal serum free thyroid hormone concentrations in patients treated with phenytoin or carbamazepine. A paradox resolved.
28 : The effective evaluation of thyroid status in patients on phenytoin, carbamazepine or sodium valproate attending an epilepsy clinic.
29 : Pattern of recovery of the hypothalamic-pituitary-thyroid axis following radioactive iodine therapy in patients with Graves' disease.
30 : Recovery of pituitary thyrotropic function after withdrawal of prolonged thyroid-suppression therapy.
31 : Thyroid hormone replacement for central hypothyroidism: a randomized controlled trial comparing two doses of thyroxine (T4) with a combination of T4 and triiodothyronine.
32 : Thyrotropin suppression by thyroid hormone replacement is correlated with thyroxine level normalization in central hypothyroidism.
34 : Fine adjustment of thyroxine replacement dosage: comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment.
35 : Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of under-replacement with levothyroxine.
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