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Central hypothyroidism

The right clinical information, right where it's needed

Last updated: Jun 10, 2016

Table of Contents
Summary

Basics

Definition

Epidemiology

Aetiology

Pathophysiology

Prevention
Screening

Diagnosis

6
6
7

Case history

Step-by-step diagnostic approach

Risk factors

History & examination factors

Diagnostic tests

11

Differential diagnosis

12

Treatment

15

Step-by-step treatment approach

15

Treatment details overview

16

Treatment options

17

Emerging

19

Follow up

20

Recommendations

20

Complications

20

Prognosis

21

Guidelines

22

Diagnostic guidelines

22

Treatment guidelines

22

References

24

Disclaimer

29

Summary

Symptoms of central hypothyroidism include those of primary hypothyroidism (fatigability, cold intolerance,
weight gain), with or without other symptoms of hypopituitarism, including hypogonadism and secondary adrenal
insufficiency.

Signs on physical examination may indicate hypothyroidism, including skin changes, hair loss, and bradycardia.

Signs indicating a sellar or parasellar mass include papilloedema and visual field deficits (a bitemporal hemianopia).

Diagnostic evaluation of central hypothyroidism includes serum TSH and free T4. In central hypothyroidism,
free T4 is low and TSH may be low, normal, or minimally elevated. MRI may reveal sellar or parasellar pathology.

Treatment of central hypothyroidism is by thyroid hormone replacement (levothyroxine).

Complications of treatment may include thyrotoxicosis and osteoporosis.

Central hypothyroidism

Basics

BASICS

Definition
Hypothyroidism is a clinical syndrome resulting from a deficiency of thyroid hormones, which results in a generalised
slowing of metabolic processes. Central hypothyroidism is the result of anterior pituitary or hypothalamic hypofunction.
It may be the result of congenital, neoplastic, inflammatory, infiltrative, traumatic, or iatrogenic aetiologies. It is
characterised by decreased TSH secretion in turn causing decreased thyroid hormone synthesis and release.

Epidemiology
The incidence of central hypothyroidism is low, estimated to be anywhere from 0.0006% to 0.006%.[1] [2] Pituitary
adenomas are the most common cause of central hypothyroidism. Secreting adenomas (prolactinomas) are the most
common pituitary adenomas (58%), followed in frequency by growth hormone-secreting adenomas (23%) and
non-secretory adenomas (10%).[3] Prolactinomas are most common in women in the second to fifth decades.[4] Growth
hormone-secreting and non-secretory adenomas are more common in men.[4]

Aetiology
Aetiologies for central hypothyroidism are numerous and reflect dysfunction of the pituitary, hypothalamus, or
hypothalamic-pituitary portal circulation. Pituitary mass lesions, especially pituitary adenomas, are the most common
cause.[5] Other mass lesions include primary tumours, such as growth hormone (GH)- or ACTH-secreting adenomas,[6]
as well as cysts, meningiomas, dysgerminomas, craniopharyngiomas, and tumour metastases.
Infiltrative disorders may affect hypothalamic/pituitary function, including infectious (tuberculosis, syphilis, fungal
infections, toxoplasmosis) and non-infectious aetiologies (sarcoidosis, haemochromatosis, histiocytosis).[7] [8] [9]
Catastrophic causes of central hypothyroidism include head trauma, pituitary apoplexy, and Sheehan's syndrome
(postpartum pituitary necrosis).[10] [11] [12] [13] Iatrogenic causes include pituitary surgery or radiation.[14] Several
rare genetic defects may also cause central hypothyroidism.[15] [16] [17] [18] [19] [20] [21] Lymphocytic hypophysitis
is a rare aetiology.[22]

Pathophysiology
Pituitary thyroid-stimulating hormone (TSH) is a glycoprotein that is produced and secreted by the anterior pituitary.[23]
TSH stimulates thyroidal biosynthesis and secretion of thyroid hormones (T3 and T4). TSH secretion is regulated by the
hypothalamic thyrotropin-releasing hormone (TRH), as well as by thyroid hormones. TRH is a tripeptide released into the
hypothalamic-pituitary portal vessels and transported to the anterior pituitary, where it promotes the synthesis and
secretion of TSH.[24] Conversely, T3 and T4 act on the anterior pituitary in a negative feedback loop, inhibiting the
synthesis and secretion of TSH. T3 and T4 also act at the hypothalamic level to inhibit the secretion of TRH.[25] Other
soluble factors that affect TSH secretion include dopamine, glucocorticoids, and somatostatin. Central hypothyroidism
is caused by a deficiency of TSH because of hypothalamic and/or pituitary dysfunction. This can occur as a result of
deficient stimulation of the anterior pituitary by TRH, deficient synthesis and secretion of TSH by the anterior pituitary,
or secretion of biologically ineffective TSH, as in some genetic diseases.[15] [16] [18] [19] [20] [26]
The clinical manifestations of central hypothyroidism are related to a deficiency of T3 and T4 and therefore are similar
to primary hypothyroidism. Pathologically, the most characteristic symptom in primary and to a lesser extent central
hypothyroidism is the accumulation of glycosaminoglycans in interstitial tissues, because of their decreased metabolism.

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Central hypothyroidism

Basics

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BASICS

Patients with central hypothyroidism often have concomitant derangements in one or more pituitary hormones, including
ACTH, gonadotrophin (LH and FSH), growth hormone, and prolactin deficiencies. Concomitant dysfunction of the posterior
pituitary results in diabetes insipidus because of ADH deficiency. If central hypothyroidism is caused by a functioning
pituitary adenoma, symptoms of ACTH, growth hormone, or prolactin excess may be present.

Central hypothyroidism

Prevention

Screening
There are differences in recommendations from various expert panels regarding screening for thyroid dysfunction in the
general population. For example, the American Thyroid Association (ATA) recommends screening every 5 years for all
newborn children and adults aged over 35 years.[47] [48] However, the US Preventive Services Task Force (USPSTF) do
not recommend routine screening in non-pregnant, asymptomatic adults as the current evidence is insufficient to assess
the benefits and harms.[49]
In the UK, all newborn children are screened for hypothyroidism. There is currently no screening programme for adults.
Most programmes that screen for congenital hypothyroidism use serum TSH measurements, supplemented by T4
measurements in infants with elevated TSH values. With this approach, central hypothyroidism will be missed. Programmes
that employ primary measurement of serum T4 with back-up measurement of serum TSH or a combined serum TSH
and T4 approach can identify infants with central hypothyroidism.[50]

PREVENTION

Thyroid function tests should be assessed regularly in patients with hypothalamic/pituitary disorders.

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Central hypothyroidism

Diagnosis

Case history
Case history #1
A 40-year-old woman visits her physician with a 4-month history of chronic headaches and visual problems. She has
no past medical history. Review of symptoms reveals easy fatigability, cold intolerance, galactorrhoea, and amenorrhoea
for the past 6 months. Physical examination findings include a bitemporal hemianopia, periorbital oedema, normal-sized
thyroid, bradycardia, galactorrhoea, and vaginal atrophy.

Step-by-step diagnostic approach


Hypothyroidism is caused by a deficiency of thyroid hormone (T4 and T3) and generally presents with cold intolerance,
fatigue, depression, and generalised weakness. The diagnosis of central hypothyroidism requires low serum free T4 and
low, normal, or slightly elevated TSH.[33] [34]

History
Clinical features of central hypothyroidism are similar to those of primary hypothyroidism. These include the following:
weakness, fatigue, lethargy, headaches, cold intolerance, hearing impairment, constipation, muscle cramps, modest
weight gain, galactorrhoea, decreased memory, and depression.
Features in the history that support a central, rather than peripheral, hypothyroidism include symptoms consistent
with deficiency or excess of other pituitary hormones including prolactin, ACTH, growth hormone, LH, and FSH.
Symptoms of diabetes insipidus may indicate posterior pituitary dysfunction. A history of headaches, diplopia, or
diminished peripheral vision may indicate a sellar or suprasellar mass. A past medical history of brain or metastatic
cancer, haemochromatosis, sarcoidosis, recent pregnancy, or pituitary surgery or radiation may indicate a probable
aetiology. A family history of central hypothyroidism may suggest a genetic disorder in rare cases.

Physical examination

Laboratory evaluation
If hypothyroidism is suspected, serum TSH and free T4 should be ordered. Central hypothyroidism is characterised
by a low free T4 in association with a non-elevated TSH. Non-thyroidal illness is an important differential diagnosis
that must be excluded. Urgent referral to an endocrinologist is advised for further assessment of pituitary function.
Appropriate baseline endocrine investigations include a serum cortisol, prolactin, gonadotrophins (FSH, LH), and a
total testosterone. Low/normal serum gonadotrophins in post-menopausal women and low serum gonadotrophins
in combination with a low serum total testosterone in men indicate hypogonadotrophic hypogonadism.

Imaging
Large pituitary tumours are common in the setting of central hypothyroidism. Thus, imaging of the pituitary is essential.
MRI is the single best imaging procedure for sellar masses. If MRI is unavailable, CT scan with coronal views through
the pituitary is a reasonable alternative.[35] [36] [37]
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DIAGNOSIS

The examination findings in patients with central hypothyroidism are similar to those found in primary hypothyroidism.
Patients may have dry, coarse skin, impassive facial expression, bradycardia, reduced body and scalp hair, and delayed
relaxation of deep tendon reflexes. Physical examination findings that support a central rather than peripheral
hypothyroidism include findings consistent with a deficiency or excess of other pituitary hormone(s), such as skin
depigmentation, atrophic breasts, galactorrhoea, Cushing's syndrome, or acromegaly.

Central hypothyroidism

Diagnosis

Risk factors
Strong
multiple endocrine neoplasia (MEN) type I
Patients with MEN type 1 have an increased risk of parathyroid, pancreatic islet, and anterior pituitary tumours.[3]
Anterior pituitary tumours may cause central hypothyroidism, hypogonadism, and secondary adrenal insufficiency.

head and neck irradiation


Following conventional irradiation for pituitary tumours, the incidence of central hypothyroidism is observed in 3%
to 6% of patients.[28] In another study of patients undergoing irradiation for extracranial head and neck tumours,
27.4% of those screened developed subclinical central hypothyroidism.[29]

traumatic brain injury (TBI)


Central hypothyroidism was observed in 10% to 30% of cases following TBI.[30] [13]

Weak
age - between 5 and 14 years and older than 65 (craniopharyngiomas)
Craniopharyngiomas have a bimodal age distribution with a peak between 5 and 14 years of age and a second peak
in adults older than 65.[4]

age - second to fifth decades (prolactinomas)


Prolactinomas occur most commonly in the second to fifth decades.[4]

age - fourth to eighth decades (non-functioning pituitary adenomas)


Non-functioning pituitary adenomas are more common in the fourth to eighth decades.[4]

DIAGNOSIS

sarcoidosis
Affects the CNS in 5% to 16% of patients.[27]
Hypothalamic dysfunction and hypopituitarism are the most common neuroendocrine manifestations; however,
isolated central hypothyroidism is rarely observed.[27]

histiocytosis
Hypothalamic/pituitary involvement is a well-described feature of Langerhans' cell histiocytosis (LCH).
Hypopituitarism has been reported in up to 20% of patients with LCH.[9] Evidence comes from case reports.

haemochromatosis
Hypopituitarism, particularly hypogonadotrophic hypogonadism, is a prominent manifestation of iron storage
disease.
Hypogonadism, if diagnosed early, may be reversible with iron depletion. Central hypothyroidism is generally not
found until the later stages of haemochromatosis, at which time it is irreversible.

pregnancy
Sheehan's syndrome occurs as a result of ischaemic pituitary necrosis due to postpartum haemorrhage and is
associated with central hypothyroidism in the majority of cases.[31] Lymphocytic hypophysitis is a potential cause
of hypopituitarism and demonstrates a temporal association with pregnancy.[32]

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Central hypothyroidism

Diagnosis

family hx of central hypothyroidism


Generally due to a homozygous mutation of TSH resulting in congenital central hypothyroidism and familial
clustering. However, pituitary-selective genes encoding the TRH receptor, the beta-subunit of TSH, and the
immunoglobulin superfamily factor 1 (IGSF1) have been associated with isolated central hypothyroidism.[18] [19]
[20] [26]

History & examination factors


Key diagnostic factors
presence of risk factors (common)
Key risk factors include multiple endocrine neoplasia (MEN) type I, head and neck irradiation, and traumatic brain
injury.

weakness (common)
is a diagnostic factor

fatigue (common)
is a diagnostic factor

cold intolerance (common)


is a diagnostic factor

Other diagnostic factors


decreased memory (common)
is a diagnostic factor

DIAGNOSIS

constipation (common)
17% prevalence among those with primary hypothyroidism.[39]

muscle cramps (common)


34% prevalence among those with primary hypothyroidism.[39]

weight gain (common)


The result of both fluid retention and decreased metabolism. Weight gain is usually modest. Marked obesity is not
characteristic of hypothyroidism.

depression (common)
is a diagnostic factor

dry, coarse skin (common)


is a diagnostic factor

oligomenorrhoea/amenorrhoea (common)
May result from hypothyroidism and/or accompanying hypogonadism.

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Central hypothyroidism

Diagnosis

bradycardia (common)
Caused by a decrease in thyroid hormone.

reduced body and scalp hair (common)


is a diagnostic factor

delayed relaxation of deep tendon reflexes (common)


is a diagnostic factor

hearing impairment (uncommon)


May be present in up to 85% of cases of hypothyroidism and may be due to changes in sensorineural, central, or
conductive components.[38]

impassive facial expression (uncommon)


is a diagnostic factor

diabetes insipidus (DI) (uncommon)


DI is caused by decreased secretion of antidiuretic hormone (ADH). It is more frequently associated with hypothalamic
pathology. Lesions of the posterior pituitary rarely cause permanent DI.

headache (uncommon)
May be indicative of an intra- or suprasellar mass lesion.

diplopia (uncommon)
May be indicative of an intra- or suprasellar mass lesion.

decreased peripheral vision (uncommon)

DIAGNOSIS

A pituitary adenoma compressing on the optic chiasm may cause a bitemporal hemianopia.

skin depigmentation (uncommon)


Caused by mass effect and changes in ACTH release by the pituitary gland.

atrophic breasts (uncommon)


is a diagnostic factor

galactorrhoea (uncommon)
Functional pituitary adenomas may result in an elevation of prolactin.[40]

10

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Diagnosis

Central hypothyroidism

Diagnostic tests
1st test to order
Test

Result

serum free T4

low

Serum TSH and free T4 should be ordered as an initial diagnostic step in any
patient suspected of central hypothyroidism. Low free T4 is observed in both
primary and central hypothyroidism.
Free T4, free T3, and TSH values may be abnormal in the context of
non-thyroidal illness, depending upon disease duration and severity.
serum TSH
Serum TSH and free T4 should be ordered as an initial diagnostic step in any
patient suspected of central hypothyroidism.
Free T4, free T3, and TSH values may be abnormal in the context of
non-thyroidal illness, depending upon disease duration and severity.

inappropriately low to normal


TSH in the setting of low serum
free T4

Other tests to consider


Test

Result

MRI of brain

may reveal a variety of lesions,


most commonly pituitary
adenomas

MRI should be obtained in any patient with biochemical evidence of


hypothalamic or pituitary dysfunction, or in any patient with physical
examination findings strongly suggestive of a pituitary lesion (e.g., a bitemporal
hemianopia).
MRI of pituitary microadenomas has a sensitivity of 82 to 94%.[36] [37]
If MRI is unavailable, a CT scan with coronal views through the pituitary is a
reasonable alternative.[41]
CT head

prolactin (PRL)

may be elevated

If levels are mildly elevated, differential diagnoses include pituitary stalk


pathologies and drugs with dopamine antagonistic effects.
A serum PRL >8696 picomol/L (>200 micrograms/L) is highly suggestive of a
PRL-secreting pituitary adenoma (prolactinoma). If levels are elevated to a
lesser degree, the differential diagnosis includes a number of aetiologies
including drug and end-organ dysfunction.[43]
Primary hypothyroidism may itself be associated with modest
hyperprolactinaemia.

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11

DIAGNOSIS

may reveal a mass of the sellar


MRI is the single best imaging procedure for sellar masses. If MRI is unavailable, and parasellar area
CT scan with coronal views through the pituitary is a reasonable alternative.[35]
[36] [37] [42]

Diagnosis

Central hypothyroidism

Test

Result

9 a.m. serum cortisol

low in the presence of ACTH


ACTH deficiency causes adrenal atrophy and ACTH-receptor downregulation. deficiency
An abnormal ACTH stimulation test in the setting of hypothyroidism may
indicate hypopituitarism. A standard 250 microgram or a 1 microgram
corticotrophin test can be used to establish adrenal insufficiency.[44] The latter
may be more accurate in the acute or subacute presentation. Endocrinology
advice should be sought.
Most normal individuals have cortisol levels above 497 nanomols/L (18
micrograms/dL) at 30 and/or 60 minutes after intravenous or intramuscular
ACTH 250 micrograms.

serum testosterone

low in the presence of


A serum testosterone level of <5.2 nanomol/L (<150 nanograms/dL) in men gonadotrophin deficiency
is associated with pituitary tumours, especially when associated with clinical
signs of headache and diplopia, or laboratory evidence of other hormone
abnormality - most commonly, PRL elevation.

serum gonadotrophins

may be low

Low/normal serum gonadotrophins in post-menopausal women and low serum


gonadotrophins in combination with a low serum total testosterone in men
indicate hypogonadotrophic hypogonadism.

Differential diagnosis
Condition

DIAGNOSIS

Primary hypothyroidism

Differentiating signs /
symptoms
Absence of symptoms and signs
of hypopituitarism such as CNS
involvement (headaches, visual
disturbances) or pituitary
hormone excess (galactorrhoea,
acromegaly, Cushing's syndrome).

Differentiating tests

Non-thyroidal illness

12

Abnormal findings on thyroid


function tests that occur in the
setting of a systemic
non-thyroidal illness (NTI) without
pre-existing
hypothalamic/pituitary
dysfunction.
The key characteristics are those
of the primary disorder.

Low free T4 is observed in both


primary and central
hypothyroidism.
A high TSH would be expected in
primary hypothyroidism, whereas
in central hypothyroidism TSH is
low, normal, or mildly elevated
(normal 0.5 to 5.0 mU/L).
A high serum antithyroid
peroxidase antibody
concentration suggests primary
hypothyroidism.
The most prominent alteration is
low serum T3.
TSH, T4, and free T4 are also
affected in variable degrees based
on the severity and duration of
the NTI.
As the severity of the NTI
increases, both serum T3 and T4
levels drop and then gradually
normalise as the patient recovers.

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Diagnosis

Central hypothyroidism

Condition
Iodine deficiency

Differentiating signs /
symptoms
Affected patients come from
geographical regions where
iodine deficiency disorders are
endemic.
Patients present with goitre,
cretinism, and mental retardation.

Differentiating tests

Occurs when dietary iodine intake


is inadequate for thyroid hormone
synthesis.
TSH levels are increased, and
there is an increase in the T3 to
T4 ratio.
A low 24-hour urine iodine
collection <394 nanomol/L (<50
micrograms/L) is consistent with
moderate deficiency.

Patients with both


hypothyroidism and chronic
fatigue syndrome may experience
prolonged fatigue as well as
cognitive slowing and memory
problems.
Symptoms such as cold
intolerance, weight gain,
weakness, headaches, and visual
disturbances suggest central
hypothyroidism.
Signs such as bradycardia, skin
changes, and hair thinning are
more consistent with
hypothyroidism.

Thyroid hormone levels are


normal.

de Quervain's thyroiditis

Symptoms of hypothyroidism are


typical in de Quervain's thyroiditis,
although most are transient. Local
symptoms observed in de
Quervain's thyroiditis, such as pain
over the thyroid area and
dysphagia, are not observed in
central hypothyroidism.
On physical examination, thyroid
tenderness, enlargement, or
firmness may be present in de
Quervain's thyroiditis, but is not
consistent with central
hypothyroidism.

TSH is typically elevated in the


hypothyroid period of de
Quervain's thyroiditis.
Serum thyroglobulin and ESR are
almost always markedly elevated
in de Quervain's thyroiditis,
especially in the initial
inflammatory phase.

Slow mentation, fatigue,


decreased memory, and somatic
complaints are common in both
depression and hypothyroidism.
Physical examination findings
such as dry, coarse skin,
periorbital puffiness, bradycardia,
and delayed relaxation of deep
tendon reflexes are not
characteristic of depression.
Comorbid psychiatric disorders
are more common in those with
depression.

Depression

Thyroid hormone levels are


normal.

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13

DIAGNOSIS

Chronic fatigue syndrome

Diagnosis

Central hypothyroidism

Condition
Eosinophilia-myalgia syndrome
(EMS)

Differentiating tests

Symptoms common to
hypothyroidism and EMS include
myalgias, arthralgias, skin changes
(thickening of the skin), weakness,
and fatigue, as well as difficulty
with concentration and
memory.[45] [46]
A history of acute inflammatory
symptoms or prominent
pulmonary symptoms suggests
EMS.

Symptoms common to central


hypothyroidism and fibromyalgia
include fatigue, depression,
myalgias, and headaches (if
central hypothyroidism is caused
by a mass lesion).
A history of generalised pain with
specific tender points suggests
fibromyalgia.

The presence of blood


eosinophilia is essential for the
diagnosis of EMS.[45] [46] A
polymorphonuclear leukocytosis
is also common.
Thyroid function tests are normal.

Thyroid hormone levels are


normal.

DIAGNOSIS

Fibromyalgia

Differentiating signs /
symptoms

14

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Central hypothyroidism

Treatment

Step-by-step treatment approach


The treatment of central hypothyroidism is thyroxine replacement, and assessment and management of the underlying
pituitary pathology.[34] [51] A specialist endocrine opinion should be sought urgently.

Treatment of concomitant adrenal insufficiency


It is important to assess and treat adrenal hormone deficiency before replacement of thyroid hormone is initiated.
Drugs of choice for the treatment of adrenal insufficiency are hydrocortisone, cortisone, and prednisolone. These
are used primarily to correct glucocorticoid deficiencies. Thyroid hormone replacement in the setting of adrenal
insufficiency may precipitate acute adrenal crisis.

Thyroxine replacement
Treatment can usually be started with the full estimated dose requirement; however, in older people or in those with
known CAD, it is recommended to start at a low dose and gradually titrate to the full calculated dose, based on free
T4 results.[48] [52] [53] Further dose adjustments may be required in patients treated with growth hormone and/or
oestrogen therapy.[54] [55] [56] The main potential adverse effect of thyroxine therapy is overdose.
Absorption of thyroxine can be impaired by malabsorptive disorders such as coeliac disease, inflammatory bowel
disease, and lactose intolerance. Drugs that may impair thyroxine absorption include iron, aluminium-containing
antacids, calcium carbonate, phosphate binders, bile-acid sequestrants, and proton-pump inhibitors. Thyroxine should
be taken at least 4 hours before or after drugs that may interfere with absorption.[57]
Combinations of thyroxine and triiodothyronine should not be used as replacement therapy.[58]

Treatment of pituitary tumour


Medical treatments of responsive tumours may include dopaminergic medications or somatostatin analogues.
Prolactin-secreting pituitary adenomas are managed primarily with dopamine agonist therapy.[59] [60]
Non-prolactin-secreting pituitary adenomas may be managed surgically, depending upon tumour size, extent, and
secretory function. This may be performed via a trans-sphenoidal or trans-frontal approach.[61] [62]
Radiotherapy is an effective treatment for residual or recurrent pituitary adenomas, with excellent rates of tumour
control and normalisation of excess hormone secretion. Technical developments in the delivery of radiotherapy,
stereotactic conformal radiotherapy (SCRT), and stereotactic radiosurgery (SRS) aim to reduce the amount of normal
brain receiving significant doses of radiation.[63]

Laboratory evaluation

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15

TREATMENT

Treatment should be monitored in an endocrine clinic setting. Thyroxine dose titration should be based on the fasting
free T4 value, measured 24 hours after the last thyroxine medication. Adequacy of treatment is usually re-assessed
by clinical assessment and measurement of free T4 levels 4 to 8 weeks after a dose amendment. TSH measurements
are of no use in the management of central hypothyroidism. Clinical effects of thyroid replacement take longer than
biochemical restoration of free T4 levels. Free T4 levels should be titrated to the mid to upper part of the normal
range. Once stable, repeat measurements of free T4 levels may be performed annually.

Treatment

Central hypothyroidism

Treatment details overview


Consult your local pharmaceutical database for comprehensive drug information including contraindications, drug
interactions, and alternative dosing. ( see Disclaimer )

Ongoing
Patient group
all patients

Tx line
1st

Treatment
levothyroxine

adjunct

treatment of underlying pituitary tumour

adjunct

corticosteroids

TREATMENT

presence of adrenal insufficiency

( summary )

16

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Treatment

Central hypothyroidism

Treatment options
Ongoing
Patient group
all patients

Tx line
1st

Treatment
levothyroxine
The American Association of Clinical Endocrinologists
(AACE) and American Thyroid Association (ATA)
advocate the use of a high-quality brand preparation
of levothyroxine.[58] [64] Preferably, the patient should
receive the same brand of levothyroxine throughout
treatment. Desiccated thyroid hormone, combinations
of thyroid hormones, or triiodothyronine should not
be used as replacement therapy.[58]
Therapy is usually initiated in patients younger than
50 years with full replacement dose. For those older
than 50 years, or with CAD, a lower initial dose is
indicated, starting with 25 to 50 micrograms once daily.
Levothyroxine has a narrow therapeutic index. Careful
dosage titration is necessary to avoid the
consequences of over- and under-treatment.
Absorption of levothyroxine can be impaired by
malabsorptive disorders such as coeliac disease,
inflammatory bowel disease, and lactose intolerance.
Drugs that may impair levothyroxine absorption include
iron, aluminium-containing antacids, calcium
carbonate, phosphate binders, bile-acid sequestrants,
and proton-pump inhibitors. Levothyroxine should be
taken at least 4 hours before or after drugs that may
interfere with absorption.[57]
It is important to assess and treat adrenal hormone
deficiency before replacement of thyroid hormone is
initiated.
Primary options
levothyroxine: 1.7 micrograms/kg/day orally,
adjust dose according to response and laboratory
values
Adjust dose according to response and laboratory
values measured 4-8 weeks after a dose
amendment.

adjunct

treatment of underlying pituitary tumour

Non-prolactin-secreting pituitary adenomas may be


managed surgically, depending upon tumour size,
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17

TREATMENT

Medical treatments of responsive tumours may


include dopaminergic medications or somatostatin
analogues. Prolactin-secreting pituitary adenomas are
managed primarily with dopamine agonist therapy.[59]
[60]

Treatment

Central hypothyroidism

Ongoing
Patient group

Tx line

Treatment
extent, and secretory function. This may be performed
via a trans-sphenoidal or trans-frontal approach.[61]
[62]
Radiotherapy is an effective treatment for residual or
recurrent pituitary adenomas, with excellent rates of
tumour control and normalisation of excess hormone
secretion. Technical developments in the delivery of
radiotherapy, stereotactic conformal radiotherapy
(SCRT), and stereotactic radiosurgery (SRS) aim to
reduce the amount of normal brain receiving significant
doses of radiation.[63]

presence of adrenal insufficiency

adjunct

corticosteroids
It is important to assess and treat adrenal hormone
deficiency before replacement of thyroid hormone is
initiated.
Thyroid hormone replacement in the setting of
adrenal insufficiency may precipitate acute adrenal
crisis.
Drugs of choice for the treatment of adrenal
insufficiency are hydrocortisone, cortisone, or
prednisolone.
Gradual withdrawal is required once symptoms
resolve.
Primary options
hydrocortisone: 20-30 mg/day orally
OR
cortisone: 20-25 mg/day orally
OR

TREATMENT

prednisolone: 5 to 7.5 mg/day orally

18

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Central hypothyroidism

Treatment

Emerging
Intensity-modulated radiotherapy (IMRT)
Intensity-modulated radiotherapy has allowed for further dose conformality of pituitary adenomas, potentially allowing
for improved sparing of critical structures and decreasing the morbidity of radiotherapy. Short-term studies have examined
the use of IMRT in those patients with adenomas largely refractory to surgical and/or medical treatments. One such
study demonstrated a 97% clinical progression-free survival, as well as a 100% biochemical response for those with
secretory tumours.[65]

Gamma knife radiosurgery


Stereotactic radiotherapy offers a safe and effective treatment for recurrent or residual pituitary adenomas. Its use may
be appropriate in the initial treatment of select patients as well. Radiosurgery has an approximate growth control rate of
90%; however, reported rates of biochemical normalisation vary widely in the literature.[66]

TREATMENT

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19

Follow up

Central hypothyroidism

FOLLOW UP

Recommendations
Monitoring
Measurement of serum free T4 should be performed 4 to 8 weeks after instituting a new levothyroxine dose. In general,
serum free T4 should be checked yearly thereafter or when symptoms of thyroid hormone deficiency or excess
arise.[2] Additional monitoring should be tailored to the underlying aetiology of hypothyroidism.

Patient instructions
Patients should be instructed that replacement thyroid hormone therapy is life-long. Medication should be taken at
the same time each day, usually in the morning, 45 minutes before breakfast, with water only. It may take several
weeks for the patient to start feeling better. Once the patient starts feeling better they should not stop taking
levothyroxine. The patient should not change brands of levothyroxine or change to a generic drug without first talking
to their physician.

Complications
Complications
adrenal crisis

Timeframe

Likelihood

short term

low

Adrenal crisis may occur if levothyroxine therapy is initiated in the setting of adrenal insufficiency. Patients with adrenal
crisis present with nausea, vomiting, dizziness due to hypotension, and possible loss of consciousness.
Adrenal insufficiency should be treated with glucocorticoids prior to the start of thyroid hormone replacement therapy.

treatment-related bone loss

long term

low

Chronic over-replacement of thyroid hormone may induce osteoporosis, particularly in post-menopausal women.[52]
However, debate stills exists regarding this association. A literature review found that only 9 of 31 studies showed
consistently adverse effects on bone mineral density with use of physiological and/or supraphysiological thyroid
hormone therapy.[69]
Patients, and particularly peri-menopausal women, should follow the general advice of the primary care provider
regarding screening for osteoporosis.

myxoedema coma

variable

low

Myxoedema coma is a rare life-threatening state in which severe hypothyroidism markedly worsens.
In general, it occurs in older people and is usually precipitated by an underlying medical illness.[68]
Patients with myxoedema coma should be treated in the ICU under the supervision of an endocrinologist.

treatment-related thyrotoxicosis

variable

low

Thyrotoxicosis can occur from overdose of levothyroxine.


An appropriate management strategy includes discontinuation for 3 days, followed by resumption of replacement
therapy at a lower dose.

20

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Central hypothyroidism

Follow up

Prognosis

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21

FOLLOW UP

Prognosis is dependent on the underlying aetiology of central hypothyroidism. The prognosis for pituitary adenomas is
dependent on the size (micro- versus macroadenoma) and functionality (prolactinoma, growth hormone-secreting,
ACTH-secreting, or non-functional). Long-term remission rates for prolactinomas are good: 54% to 86% after surgery.[67]

Guidelines

Central hypothyroidism

Diagnostic guidelines
Europe
UK guidelines for the use of thyroid function tests
Published by: The Association for Clinical Biochemistry; British Thyroid Association;Last published: 2006
British Thyroid Foundation
Summary: Guidelines for primary care physicians and specialists on the use of thyroid function testing. Guidelines
relate to the significant majority of patients whose hypothyroidism is of primary aetiology. For diagnosis of secondary
hypothyroidism, a combination of TSH and free T4 is required. In order to distinguish secondary hypothyroidism from
non-thyroidal illness, a combination of TSH, free T4, and free T3 is required, along with tests of other pituitary hormones.

GUIDELINES

North America
Screening for thyroid dysfunction (recommendation statement)
Published by: US Preventive Services Task Force

Last published: 2015

Summary: Evidence-based recommendations on routine screening for thyroid disease.

Clinical practice guidelines for hypothyroidism in adults


Published by: American Association of Clinical Endocrinologists; American ThyroidLast published: 2012
Association
Summary: Evidence-based guidelines for the diagnosis of hypothyoridism.

Treatment guidelines
Europe
Thyroid function disorders: guidelines of the Netherlands Association of Internal Medicine
Published by: Netherlands Association of Internal Medicine

Last published: 2008

Summary: Guidelines for secondary care providers on the diagnosis and management of thyroid function disorders,
including diagnosis of secondary and tertiary hypothyroidism.

North America
Guidelines for the treatment of hypothyroidism
Published by: American Thyroid Association

Last published: 2014

Summary: Evidence-based guidelines for the treatment of hypothyroidism.

22

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Central hypothyroidism

Guidelines

North America
Clinical practice guidelines for hypothyroidism in adults
Published by: American Association of Clinical Endocrinologists; American ThyroidLast published: 2012
Association
Summary: Evidence-based guidelines for the treatment of hypothyroidism.

GUIDELINES

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23

Central hypothyroidism

References

REFERENCES

Key articles

Roberts CG, Ladenson PW. Hypothyroidism. Lancet. 2004;363:793-803. Abstract

Persani L. Clinical review: central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol
Metab. 2012;97:3068-3078. Full text Abstract

Baskin HJ, Cobin RH, Duick DS, et al. AACE medical guidelines for clinical practice for the evaluation and treatment
of hyperthyroidism and hypothyroidism. Endocr Pract. 2002;8:457-469. Abstract

Ladenson PW, Singer PA, Ain KB, et al. American Thyroid Association guidelines for detection of thyroid dysfunction.
Arch Intern Med. 2000;160:1573-1575. Full text Abstract

Clarke N, Kabadi UM. Optimizing treatment of hypothyroidism. Treat Endocrinol. 2004;3:217-221. Abstract

Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American
Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 2014;24:1670-1751. Full text Abstract

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4.

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5.

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of this content is subject to our disclaimer. BMJ Publishing Group Ltd 2015. All rights reserved.

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25

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27

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28

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Central hypothyroidism

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29

Contributors:
// Authors:
Jacqueline Gilbert, PhD, MRCP
Consultant Endocrinologist
King's College Hospital NHS Foundation Trust, London, UK
DISCLOSURES: JG declares that she has no competing interests.

// Acknowledgements:
Dr Jacqueline Gilbert would like to gratefully acknowledge Dr Rasa Zarnegar, a previous contributor to this monograph.
DISCLOSURES: RZ declares that he has no competing interests.

// Peer Reviewers:
James Lee, MD
Assistant Professor
Department of Endocrine Surgery, Columbia University, New York, NY
DISCLOSURES: JL declares that he has no competing interests.
James V. Hennessey, MD
Director of Clinical Endocrinology
Beth Israel Deaconess Medical Center, Boston, MA
DISCLOSURES: JVH declares that he has no competing interests.
Anthony Weetman, MD, DSc, FRCP, FMedSci
Sir Arthur Hall Professor of Medicine/Pro Vice Chancellor
University of Sheffield, Sheffield, UK
DISCLOSURES: AW declares that he has no competing interests.