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Table of Contents
Summary
Basics
Definition
Epidemiology
Aetiology
Pathophysiology
Prevention
Screening
Diagnosis
6
6
7
Case history
Risk factors
Diagnostic tests
11
Differential diagnosis
12
Treatment
15
15
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.
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.
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.
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]
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
weakness (common)
is a diagnostic factor
fatigue (common)
is a diagnostic factor
DIAGNOSIS
constipation (common)
17% prevalence among those with primary hypothyroidism.[39]
depression (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.
headache (uncommon)
May be indicative of an intra- or suprasellar mass lesion.
diplopia (uncommon)
May be indicative of an intra- or suprasellar mass lesion.
DIAGNOSIS
A pituitary adenoma compressing on the optic chiasm may cause a bitemporal hemianopia.
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.
Result
MRI of brain
prolactin (PRL)
may be elevated
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11
DIAGNOSIS
Diagnosis
Central hypothyroidism
Test
Result
serum testosterone
serum gonadotrophins
may be low
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
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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
de Quervain's thyroiditis
Depression
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13
DIAGNOSIS
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.
DIAGNOSIS
Fibromyalgia
Differentiating signs /
symptoms
14
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Central hypothyroidism
Treatment
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]
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
Ongoing
Patient group
all patients
Tx line
1st
Treatment
levothyroxine
adjunct
adjunct
corticosteroids
TREATMENT
( 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
17
TREATMENT
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]
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
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]
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.
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
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
Treatment guidelines
Europe
Thyroid function disorders: guidelines of the Netherlands Association of Internal Medicine
Published by: Netherlands Association of Internal Medicine
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
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
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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Mathioudakis N, Thapa S, Wand GS, et al. ACTH-secreting pituitary microadenomas are associated with a higher
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Stuart CA, Neelon FA, Lebovitz HE. Hypothalamic insufficiency: the cause of hypopituitarism in sarcoidosis. Ann
Intern Med. 1978;88:589-594. Abstract
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Charbonnel B, Chupin M, Le Grand A, et al. Pituitary function in idiopathic haemochromatosis: hormonal study in
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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.