Central Hypothyroidism: Pathogenic, Diagnostic, and Therapeutic Challenges

Central Hypothyroidism: Pathogenic, Diagnostic, and
Therapeutic Challenges
Luca Persani
Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy; and
Division of Endocrine and Metabolic Diseases, San Luca Hospital, Istituto Auxologico Italiano, 20149
Milan, Italy
Context: Central hypothyroidism (CH) is a particular hypothyroid condition due to an insufficient
stimulation by TSH of an otherwise normal thyroid gland. This condition raises several challenges
for clinicians; therefore, a reviewof the most relevant findings onCHepidemiology, pathogenesis,
and clinical management has been performed.
Methodology: Therelevant papers wereselectedbyaPubMedsearchusingappropriatekeywords.
Main Findings: CHcan be the consequence of various disorders affecting either the pituitary gland
or the hypothalamus, but most frequently affectingbothof them. CHis about 1000-foldrarer than
primary hypothyroidism. Except for the neonatal CH due to biallelic TSH mutations, the thyroid
hormone defect is rarely as profound as can be observed in some primary forms. In contrast with
primary hypothyroidism, CH is most frequently characterized by low/normal TSH levels, and ade-
quate thyroid hormone replacement is associated with the suppression of residual TSH secretion.
Thus, CHoften represents a clinical challenge because physicians cannot rely on the systematic use
of the reflex TSHstrategy. The clinical management of CHis further complicatedby the frequent
combination with other pituitary deficiencies and their substitution. (J Clin Endocrinol Metab 97:
30683078, 2012)
C
entral hypothyroidism(CH) is a disease characterized
by a defect of thyroid hormone production due to
insufficient stimulation by TSH of an otherwise normal
thyroid gland (14). This condition is the consequence of
an anatomic or functional disorder of the pituitary gland
or the hypothalamus, resulting in variable alterations of
TSH secretion.
TSH is a glycoprotein dimeric hormone composed of
two subunits (-GSU and TSH) and normally secreted
with a circadian pattern, characterized by a nocturnal
surge occurring during the first hours of the night (14).
TSH secretion is mainly regulated by the negative feed-
back of thyroid hormone and the positive action of TRH.
TSH secretion is directly influenced by other factors, in-
cluding the negative effects of hypothalamic somatostatin
and dopamine and of glucocorticoids. Signals from the
peripheral tissues able to indirectly affect the thyrotrope
secretioninclude gonadal hormones, leptin, andother fac-
tors correlated with feeding behavior or sleep. Derange-
ments in these regulatory mechanisms are involved in the
pathogenesis of CH (14).
Although an isolated failure of thyrotrope cells can be
observed, the defective TSH secretion is more frequently
part of combined pituitary hormone deficiencies (CPHD),
andthe hypothyroidmanifestations may be maskedby the
concomitant pituitary defects. Diagnosis is usually made
biochemically with low circulating free T
4
(FT4) concen-
trations associated with low/normal serum TSH levels.
Therefore, CH represents a major false-negative result of
the reflex TSH strategy, which is a worldwide diffuse
method to screen thyroid function by the first-line TSH
measurement (5). CH itself does not severely reduce life
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright 2012 by The Endocrine Society
doi: 10.1210/jc.2012-1616 Received March 8, 2012. Accepted June 11, 2012.
First Published Online July 31, 2012
Abbreviations: CH, Central hypothyroidism; CPHD, combined pituitary hormone deficien-
cy; FT3, free T
3
; FT4, free T
4
; NTI, nonthyroidal illness; PRL, prolactin; rhGH, recombinant
human GH; TBG, T
4
binding globulin.
S P E C I A L F E A T U R E
C l i n i c a l R e v i e w
3068 jcem.endojournals.org J Clin Endocrinol Metab, September 2012, 97(9):30683078
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 26 May 2014. at 06:12 For personal use only. No other uses without permission. . All rights reserved.
expectancy, but the quality of life can be severely affected
at all ages by the hypothyroid state. Therefore, the exis-
tence of mild forms of CH should always be suspected in
patients with hypothalamic-pituitary disorders.
Epidemiology of CH: Is It So Rare?
Although familial cases can seldom be observed, CH oc-
curs as a sporadic form of hypothyroidism in most of the
cases. CH can affect patients of all ages, and unlike what
is observed in primary hypothyroidism, there is no female
prevalence. CH apparently accounts for about one of
1,000 hypothyroid patients because its prevalence was es-
timated to range from1:20,000 to 1:80,000 in the general
population (5). Neonatal screening programs for hypo-
thyroidism based on the recall of babies with TSH or T
4
values falling in the hypothyroid range reported a case of
congenital hypothyroidism of central origin in 1:160,000
live newborns in Japan (6). Similar findings recently sug-
gested abandoning the combined TSH/T
4
determination
and shifting to the reflex TSH strategy in the neonatal
screeningprograminIndiana(7). However, acomplicated
algorithm based on the combined T
4
/TSH/T
4
binding
globulin (TBG) evaluation would allow the diagnosis of
milder forms of CH with an incidence of 1:16,000 new-
borns in The Netherlands (8). Because almost all of these
cases are genetic forms of CPHD, the CH findings would
allow the early diagnosis of combined GH and/or ACTH
deficiencies, thus preventing the risk of life-threatening
hypoglycemia.
Pathogenesis: A Matter of Quantity and
Quality
The mechanisms underlying CHpathogenesis variably in-
volve both hypothalamic and pituitary cells, but they are
still inexplicable in a large number of cases. The major
causes of CH are listed in Table 1, and a list of genetic
forms of CHwith their typical phenotypic manifestations
is provided in Table 2. Indeed, isolated CH is mainly due
to specific genetic defects, including TSH-subunit and
TRH receptor gene mutations.
Defects in TSH secretion may be quantitative (the so-
called reduced TSH reserve) and/or qualitative (14,
911). Indeed, serum TSH is low in most cases of genetic
CH, a typical example being TSH gene mutations that
result in the synthesis of a truncated subunit unable to
dimerize with the -GSU (4, 12, 13). In contrast, in ac-
quired CH, the quantitative defect in TSH-producing cells
is frequently associated with a qualitative defect in the
secreted TSH isoforms that conserve immunoreactivity
but displayasevere impairment inintrinsic bioactivityand
ability to stimulate TSHreceptors. The secretion of bioin-
active TSHhas been reported in several forms of acquired
CH mainly affecting the hypothalamic function and as-
sociated with normal or even slightly elevated immuno-
reactive TSH concentrations (8, 10, 1418). Therefore,
the existence of this qualitative defect in TSH secretion
provides an explanation for the lack of correlation be-
tween circulating thyroid hormone and TSH concentra-
tions in patients with CH (Fig. 1). It is well documented
that glycosylation plays a fundamental role in modulating
the biological features of glycoprotein hormones (4, 9, 11,
1820). Impaired control of TSH synthesis and secretion
by TRH and other neuroendocrine or paracrine factors
may be associated with alterations of posttranslational
processing of the molecule, resulting in the release of TSH
forms with altered glycosylation and variable bioactivity
(9, 17, 20). Because TSH levels measured in sera of CH
patients are the likely result of the maximal secreting ac-
tivity fromthe conserved thyrotrope cells, the secretion of
highly sialylated molecules with a prolonged half-life but
an impaired bioactivity appears prevalent in such extreme
conditions (10).
The relevant contribution of both reduced thyrotrope
population and decreased biological activity of secreted
TSHwas confirmedbythe findings inTRHknockout mice
TABLE 1. Known causes of CH in a tentative order of
frequency
Invasive or compressive lesions
Pituitary macroadenomas
Craniopharyngiomas
Meningiomas or gliomas
Rathke cleft cysts
Metastases
Empty sella
Carotid aneurysm
Iatrogenic factors
Cranial surgery or irradiation
Drugs (e.g. RXR selective ligands)
Injuries
Head traumas
Traumatic delivery
Vascular accidents
Pituitary apoplexy
Postpartum pituitary necrosis (Sheehan syndrome)
Subarachnoid hemorrhage
Autoimmune disease
Lymphocytic hypophysitis
Polyglandular autoimmune diseases
Infiltrative lesions
Iron overload (hemochromatosis, thalassemia major)
Sarcoidosis
Histiocytosis X
Inherited diseases
CPHD: pituitary transcription factor defects; LEPR mutations
Isolated CH: TSH or TRHR mutations
Infective diseases
Tuberculosis
Mycoses
Syphilis
J Clin Endocrinol Metab, September 2012, 97(9):30683078 jcem.endojournals.org 3069
(21). This animal model of pure hypothalamic hypothy-
roidism confirmed that TRH action is a prerequisite for a
normal thyroid stimulation (22). No TRHgene defect has
been documented so far in humans, but defective TRH
action due to natural mutations in the TRHR gene has
been described in two families (23, 24). Interestingly, the
early development of patients with complete TRH resis-
tance appeared uneventful, and the diagnosis in the male
probandwithhomozygous TRHRmutations was reached
because of delayed growth accompanied by lethargy and
fatigue at 11 yr of age (24). Unexpectedly, the same diag-
nosis was reachedinthe sister by genetic testing during her
second pregnancy when she was 33 yr old. This woman
with complete TRH resistance had reached her target
height and normal IQ and has presently delivered three
heterozygous babies with normal pre- and postnatal
growth. In none of these cases, she experienced any lac-
tating defect. This study showed that the hypothalamic
hormone is required to set the pituitary feedback mecha-
nism at a level adequate to maintain FT4 levels in the
normal range, and that the bioactivity of circulating
TSH is not completely damaged in the absence of TRH
action. In addition, the conservation of a significant
nocturnal TSH surge in this condition indicates that
TRH action influences the amplitude, but additional
sleep-related factors account for the determination of
the circadian oscillation (24).
Pituitary macroadenomas, such as nonfunctioning pi-
tuitary adenomas and prolactin (PRL) or somatotrope
(GH)-secreting tumors, represent the most frequent cause
of acquiredCHandaccount for more thanhalf of the cases
(1, 2, 25). Varying degrees of hypopituitarism may result
from compression of normal pituitary cells, the pituitary
stalk, and/or the hypothalamus. Craniopharyngioma is
the most frequent extrasellar brain tumor causing hypop-
ituitarism, especially in younger patients (26, 27).
TABLE 2. Genetic forms of CH
Gene (MIM no.) Clues for diagnosis (MIM phenotype no.) Inheritance
TSH (188540) Severe isolated CH of neonatal onset with high -GSU, pituitary
hyperplasia (275100)
Recessive
TRH-R (188545) Isolated CH with blunted TSH/PRL response to TRH and
apparently uneventful infantile development, and with delayed
diagnosis from childhood (growth retardation) to adulthood
Recessive
POU1F1 (173110) Moderate/severe CH of neonatal to infantile onset combined
with GH and PRL defects, prominent forehead, mid face
hypoplasia, depressed nose (613038)
Dominant or recessive
PROP1 (601538) Moderate/severe CH of neonatal to infantile onset, combined
with GH, PRL, LH/FSH defects, and delayed ACTH deficiency,
pituitary hypo-/hyperplasia (262600)
Recessive
HESX1 (601802) Severe panhypopituitarism associated with septooptical dysplasia,
supernumerary/hypoplastic digits (182230)
Dominant or recessive
LHX3 (600577) Hypopituitarism with conserved ACTH function and associated
with pituitary hypo- or hyperplasia, short/rigid cervical spine,
vertebral abnormalities, and variable deafness or mental
retardation (221750)
Recessive
LHX4 (602146) Combined anterior pituitary defects associated with abnormalities
of cerebellum and small sella turcica (262700)
Dominant
LEPR (601007) Severe obesity and hyperphagia combined with delayed puberty
and mild thyrotropin defect
Recessive
The reference numbers on the NCBI web site (http://www.ncbi.nlm.nih.gov/omim) are reported for each gene and phenotype (4).
FIG. 1. Serum levels of FT4 and immunoreactive TSH in 50 patients with
CH. Full symbols indicate the patients with a prevalent hypothalamic
disease as indicated by a TSH response to TRH of 4 mU/liter or greater.
Open symbols identify the patients with a prevalent pituitary disease as
indicated by a blunted TSH response (4 mU/liter). Dotted lines indicate
the limit of the normal ranges. Patients with a prevalent pituitary disease
tend to have a more severe hypothyroid state, thus supporting the role of
a reduced pituitary reserve in the determination of CH. However, the lack
of correlation between the TSH and FT4 values is consistent with a
reduced bioactivity of circulating TSH molecules. [Modified from L. Persani
et al.: Circulating TSH bioactivity in sporadic central hypothyroidism. J Clin
Endocrinol Metab 85:36313635, 2000 (11), with permission. The
Endocrine Society.]
3070 Persani Clinical Challenges of Central Hypothyroidism J Clin Endocrinol Metab, September 2012, 97(9):30683078
Therapeutic interventions on sellar and extrasellar tu-
mor masses represent an additional risk for CH. Hypo-
thyroidism resulting from pituitary or hypothalamic dys-
function had been reported in 2050% of patients
irradiated for nasopharyngeal or paranasal sinus tumors
(28) and in about 65% of patients irradiated for brain
tumors (28, 29). Overall, the risk of the development of
CH is related to the total radiation dose (29, 30) and the
biological effective dose given to the area (31). In the case
of head-and-neck tumors, mixed forms of primary and
central hypothyroidism can also occur after radiation
therapy (3, 31, 32). The technical improvements in radio-
therapy instrumentation and earlier diagnosis are ex-
pected to reduce the development of CH in a number of
cancer survivor patients (3). TSHdeficiencycanalsoresult
fromdirect irradiation or surgical therapy of pituitary tu-
mors. The dimension and extrasellar extension of the pi-
tuitary mass, as well as the operators expertise, are critical
factors in this context.
Traumatic brain injuries and cardiovascular accidents,
such as subarachnoid hemorrhage or infarcts, were re-
ported as causes of CH with increasing prevalence (33
35). Although a significant number of cases may be tran-
sient (36), hypopituitarism should always be suspected
due to the increasing number of patients surviving these
accidents. In contrast, the occurrence of postpartum pi-
tuitary necrosis (Sheehans syndrome) nowadays is far less
commonineconomically advancedcountries due toa gen-
eral improvement in standard health care, but it is still a
prominent yet underreported disease in developing coun-
tries (16, 37).
An increased awareness and technological advance-
ments are leading to an increased number of patients di-
agnosedwithlymphocytic hypophysitis. The autoimmune
pituitary process may be isolated or part of a polyglandu-
lar autoimmune syndrome, but it is generally associated
with variable CPHD (38, 39). All the other causes of
CPHD are infrequent and involve either infective or infil-
trative granulomatous diseases or iron overload in pa-
tients with hemochromatosis or thalassemia (40, 41).
Transient or reversible forms of CH can be observed
with drugs affecting the neuroendocrine TSH regulation
or during recovery from prolonged thyrotoxicosis or se-
vere chronic diseases. Somatostatin analogs, glucocorti-
coids, or dopaminergic compounds may acutely inhibit
TSH secretion, but the subsequent reduction of thyroid
stimulation and thyroid hormone levels activates the thy-
roid hormone feedback mechanism, thus keeping ade-
quate thyroid stimulation in the long term(42). Transient
CH may be induced in neonates by drugs, such as corti-
costeroids or dopamine, giventothe mother during a com-
plicated pretermdelivery (4345). Moreover, the passage
of relevant amounts of TSHreceptor-stimulating antibod-
ies or thyroid hormones from a thyrotoxic mother to the
fetus may lead to the prolonged suppression of TSH se-
cretion and CH in the neonate that may persist up to 6
months after birth (46). The presence of an intermittent
autonomous thyroidsecretionmayalsobe associatedwith
transient CH phases. The more prolonged and severe the
thyrotoxicosis, the longer is the following CHperiod (47).
Antineoplastic agents acting through the retinoid X nu-
clear receptor can cause profound TSH inhibition that is
reversible upon drug discontinuation (42). Finally, non-
thyroidal illnesses (NTI) cause a suppression of hypotha-
lamic TRH synthesis and produce a variant of CH (48,
49). Although controversy exists on the significance of
NTI (5052), this mechanismis generally considered pro-
tective against an unwanted thyroid hormone-mediated
metabolic stimulation.
An Intricate Diagnosis
Inheritable CH
Inheritable forms of CH(e.g. biallelic TSHmutations)
are frequently associated with severe neonatal onset and
characterized by the typical manifestations of congenital
primary hypothyroidism (jaundice, macroglossia, coarse
cry, failure to thrive and retarded growth, umbilical her-
nia, hypotonia, etc.). If untreated with levothyroxine
(LT
4
) within the first 6 wk of life, these patients may de-
velop cretinism(12, 13). In the neonates, CHcan be iden-
tified only by screening programs based on concomitant
TSH and total T
4
measurements on the blood spot (6, 8,
5355). CH confirmation by serum FT4 and abnormal
TSHresponse toTRHtesting may reveal the riskof CPHD
and impending adrenal crisis (8, 56). In pituitary tran-
scription factor defects, CHcan also have a delayed onset
and be associated with hypoglycemia, typical craniofacial
abnormalities, and severity of growth retardation (1, 2,
12, 57). The association of CH with high -GSU levels in
an infant is invariably indicative of a TSHdefect (13). As
discussed above, complete TRHresistance does not cause
severe neonatal hypothyroidism, and this defect can be
suggested by the blunted TSHand PRL responses to TRH
testing (23, 24).
Acquired CH forms
The hypothyroid state is mild to moderate in most pa-
tients with acquired CHbecause the pituitary TSHreserve
is infrequently depleted and a residual thyroid hormone
secretionmay occur by the constitutive activity of the TSH
receptor (58, 59). Although manifestations of CHare sim-
ilar to those of primary hypothyroidism, they can be
masked by symptoms of CPHD(8, 60, 61). CHrepresents
a major false-negative result of the reflex TSH strategy
for the diagnosis of thyroiddysfunction(5, 62, 63). There-
fore, the diagnosis of acquired CH is generally made bio-
chemically in patients being evaluated for hypothalamic/
pituitary disease. On serum samples, the diagnosis of CH
is usually suggested by the finding of low FT4 concentra-
tions associated with low/normal TSH levels (60, 61).
Nevertheless, some CH patients with a predominant hy-
pothalamic defect have high serum immunoreactive TSH
levels but are devoid of full biological activity. In these
cases, TSHelevations are similar to those generally found
in subclinical or mild primary hypothyroidism and may
lead to the misdiagnosis (Fig. 1) (911, 14, 15).
As pointed out in the Table 3, when a low FT4 is com-
binedwitha normal TSHvalue, the diagnostic workupfor
the confirmation of CH should include the exclusion of
interference in FT4 or TSH measurements (64, 65).
Among the variables of thyroid function (63), the one that
is provided with the highest accuracy for the diagnosis of
CH is the measurement of FT4 (60). Total T
4
levels are
indeed influenced by serumprotein binding (64, 65). TBG
decreases with age and after the testosterone rise at pu-
berty or upon androgen administration, it increases with
estrogen (including contraceptive or tamoxifen) and preg-
nancy, and is altered by malnutrition, hepatic diseases,
and other illness. Thus, a lowT
4
can be normal in a single
subject, and a high TBG might hamper the recognition of
a T
4
deficiency. FT4 is more stable throughout these con-
ditions, but the absolute values are dependent upon the
assay used. FT4 determination is particularly challenging
because the assay should detect a very small fraction
(0.5%) of the total protein-bound hormone. In general,
automated FT4 assays are less reliable than the equilib-
rium dialysis, which is, however, not compatible with the
routine work (64, 65). Nevertheless, FT4 assays involving
two-step immunoextraction (back-titration) are less in-
terferedwithbythyroidautoantibodies or abnormal bind-
ing proteins than are one-step assays. If interference is
suspected, this should be explored by using a two-step
assay or by mass spectrometry. If the problem persists,
hormone measurement after equilibrium dialysis remains
the gold standard for eliminating FT4 assay interfer-
ence. Less frequently, TSH immunometric measurement
can be interfered with by the presence of antianimal an-
tibodies (heterophile antibodies) in a patients serum if
directed against the same species as the assay antibodies;
thus, a heterophile antibody that blocks TSH binding to
either capture or detection antibodies will result in neg-
ative interference in the immunoassay, causing a falsely
low TSH readout and potentially indicating a central in-
stead of a primary hypothyroidism. Although most of the
manufacturers are nowadays providing reagents includ-
ing the preimmune serum from the source animal, hete-
rophile antibodies may still interfere with the TSH deter-
mination in some instances. If interference is suspected,
the discordant TSH concentration should be checked: 1)
by means of an immunoassay using a different antibody
pair; 2) after immunosubtraction by treatment with poly-
ethylene glycol or protein G; or 3) by dilution or recovery
tests.
In the absence of any interference, the finding of low
FT4 combined with an abnormally low TSH accurately
delineates the diagnosis of overt forms of CH, but the
milder defects, characterized by FT4 levels still within the
normal range, remain undiagnosed. Cranial irradiation
can cause hypothalamic defects with TRH secretory ab-
normalities, resulting in either hidden CH (CH with FT4
values includedinthe normal range that canbe recognized
only by the demonstration of abnormal circadian or stim-
ulated TSH secretory kinetics) or manifest CH (most fre-
quently associated with low TSH and FT4) (3). Because
mild CH may be associated with a decreased growth ve-
locity in children surviving cancer, several groups inves-
tigated the possible solutions for the diagnosis of mild or
hidden CH. Rose et al. (66) reported the frequent diag-
nosis of hidden CH in survivors of childhood cancer by
evaluating the nocturnal TSH surge and showed that
TABLE 3. Conditions and findings supporting the
diagnosis of CH
Clinical manifestations
Hypothyroid state
Concomitant or preexisting hypothalamic/pituitary disease
Manifestations suggesting an intracranial lesion (e.g.
recurrent headaches, visual defects)
Alterations in hypothalamus/pituitary imaging
Exclusion of concomitant NTI or Allan-Herndon-Dudley
syndrome or TR1 mutations
Anamnestic data
Positive familial history for CH or pituitary disease
History of head traumas, cardiovascular accidents, or cranial
irradiations
Administration of drugs potentially affecting TSH secretion
Start of rhGH or sex steroid therapies for pituitary defects
Laboratory findings
Low FT4 levels in the absence of interference in the
immunoassay (e.g. abnormal binding proteins)
Significant decrease of circulating T
4
levels along
longitudinal evaluations in a patient with pituitary disease
Low/normal/slightly elevated circulating TSH levels in the
absence of interference in immunoassay (e.g. heterophile
antibodies)
Impaired bioactivity of circulating TSH
Blunted nocturnal TSH surge
Abnormal TSH response at TRH test (blunted or
delayed/exaggerated/prolonged)
Carriers of pathogenic mutations in candidate genes
Thyroid findings
Absent antithyroid autoantibodies or goiter
Homogenous thyroid structure at ultrasound
See Ref. 4.
many patients withmildthyrotrope insufficiency were not
diagnosedonthe basis of basal thyroidfunctionscreening.
Although abnormalities in circadian TSH secretion may
not correlate with FT4 levels (67), the lack of a nocturnal
TSH rise may therefore be useful in the diagnosis of CH
patients (6668) but can be evaluated only in hospitalized
patients. TRH is not available in the United States, but
TRH testing may confirm the suspicion of mild CH and
may be of help in the differential diagnosis between ter-
tiary (hypothalamic) and secondary (pituitary) hypothy-
roidism because the two defects may be associated with
exaggerated/delayed/prolonged or blunted TSH re-
sponses, respectively (13, 37, 6672). However, it must
be underscored that a significant portion of patients with
CHmay still have a normal TSHincrease after TRHstim-
ulation (66, 72), and a clear distinction between the two
forms of CH may be difficult because both sites are af-
fected in most patients (11). The practical utility of TRH
testing is therefore to be limited to the patients with un-
certain diagnosis, in whomthe abnormal TSHresponse to
TRH may confirm the CH. In addition, the lack of a thy-
roid hormone rise despite an exaggerated and prolonged
TSHincrease may be an indirect estimate of the poor bio-
activity of circulating TSH (7, 9, 13).
Interestingly, time-related decreases in circulating FT4
concentrations larger than 20% vs. the initial FT4 deter-
mination were reported to support the diagnosis of CHin
patients with different pituitary diseases followed for sev-
eral years (61). This cutoff value was set on the basis of a
10%variation over time of T
4
levels in normal individuals
(73). Provided that FT4 determination is repeatedly per-
formed in the same laboratory, this approach would then
allow the diagnosis and treatment of mild or hidden hy-
pothyroid states of central origin.
The indexes of peripheral thyroidhormone action, such
as SHBG, bone markers, serum lipids and others, lack
sufficient sensitivity and specificity for the diagnosis of
mild or subclinical hypothyroidism, especially in patients
whopresent withCPHD, whichmayper se affect the levels
of these indexes (60, 61, 74, 75). Very recently, the deter-
mination of parameters of Doppler echocardiography in-
cluding the isovolumic contraction time, isovolumic con-
traction time/ejection time, and myocardial performance
index were, however, demonstrated to correlate with the
presence of CHin a cohort of patients with hypothalamic-
pituitary diseases, thus suggesting a potential use in the
diagnosis of hidden CH (76). Because abnormalities in
cardiac parameters reverted during LT
4
replacement,
these findings may also indicate the requirement for LT
4
treatment eveninmilder forms of the disease, as previously
claimed in subclinical primary hypothyroidism (77).
In the presence of low thyroid hormone levels, the ex-
clusion of a primary thyroid defect may be required either
because CH may sometimes result from an intermittent
thyrotoxic state or because hypothalamic hypothyroidism
may be associatedwithslightly raisedTSHconcentrations
at immunoassay (Fig. 1). Indeed, the exclusion of primary
thyroid disease by biochemical testing and/or ultrasound
examination is the main objective in this differential di-
agnosis, but the possibility to check the thyroid response
after recombinant human TSH administration has also
been explored (78). Conversely, a family history of CHor
the clinical history (e.g. head trauma) or manifestations
(e.g. headaches or visual fielddefects) may be suggestive of
the presence of hypothalamic-pituitary lesions, and the
MRI generally confirms the central origin of hypothyroid-
ism (Table 3).
Patients with NTI have values of thyroid function tests
that largely overlapwiththose of CHpatients (50, 51, 63);
therefore, the presence of concomitant diseases at the time
of blood sampling should always be excluded before sus-
pecting true CH.
Patients with Allan-Herndon-Dudley syndrome, an X-
linked form of mental retardation associated with tissue-
specific resistance to thyroid hormones, can have lowFT4
and normal or slightly elevated TSH levels (79). This dis-
ease is caused by mutations in the MCT8 gene encoding a
membrane thyroid hormone transporter. These patients
can be distinguished from those with CH by the severe
clinical phenotype, including cognitive and psychomotor
retardation, and the typical elevation of T
3
circulating lev-
els that are usually 2- to 3-fold higher than in normal
subjects. Similar biochemical findings can also be found in
patients with heterozygous mutations in the THRA gene,
encoding the thyroid hormone receptor 1 (80). Severe
constipation, growth and mental retardation, and delayed
bone development appear as distinct features of this dis-
ease (80, 81) (Table 3).
Treatment of CH: How Much Is Good?
As in primary hypothyroidism, treatment of CH should
restore appropriate serum concentrations of thyroid hor-
mones. The daily administration of LT
4
is the preferred
treatment of CH(82). Recent studies in children and adult
patients with CHfailed to confirmthe superiority of com-
bined T
4
plus T
3
treatment (83, 84).
Adult CH patients
In patients with long-standing hypothyroidismthat are
at risk of untoward effects mainly due to concomitant
heart disease, LT
4
treatment could be started at low daily
dosage and then progressively increased during the fol-
lowing weeks. In patients at risk of CPHD, concomitant
central adrenal insufficiency must be assessedbefore start-
ingLT
4
therapybecause of the riskof triggeringanadrenal
crisis. If adrenal function cannot be excluded before the
start of LT
4
, a prophylactic treatment with corticosteroids
is advised, and assessment of corticotrope function can be
postponed (2, 82).
Several recent papers dealing with substitutive LT
4
therapy in patients with CHhave underlined the difficulty
in achieving optimal replacement. LT
4
replacement is eas-
ily tuned in primary hypothyroidism by evaluating circu-
lating TSH levels, but this index has a limited value for
monitoring LT
4
treatment in CH patients (63, 85). How-
ever, the finding of unsuppressed serumTSHlevels during
LT
4
treatment strongly indicates undertreatment. Indeed,
Ferretti et al. (60) reported that about half of the final LT
4
substitutive dose is sufficient to suppress TSHsecretion in
about 80% of CH patients, despite serum FT4 levels still
in the hypothyroid range in most. Similarly, other authors
observed that the large majority of 135 CH patients had
subnormal serum TSH concentrations during apparently
adequate LT
4
treatment (86). Subsequently, Shimon et al.
(87) suggested that TSH levels above 1.0 mU/liter reflect
an insufficient LT
4
replacement.
The determination of circulating free thyroid hormone
levels is of major significance in monitoring LT
4
treatment
in CH patients (60, 61, 82, 84, 8689). The FT4 mea-
surement has a superior accuracy in hypothyroidism,
whereas free T
3
(FT3) is more accurate in hyperthyroid-
ism. Accordingly, if blood is withdrawn before the morn-
ing administration of LT
4
, low FT4 values may suggest
undertreatment, and high FT3 values are more sensitive to
disclose overtreatment (60). Finally, the evaluation of bio-
chemical indexes of thyroid hormone action at the tissue
level (e.g. SHBG, bone GLA protein, or cholesterol) has
beensuggestedinmonitoringthe efficacyof LT
4
treatment
(60). However, the evaluationof these indexes shouldtake
into account the possible interference by alterations in
somatotrope, gonadal, or adrenal functions (60, 61) and,
except for cholesterol, are generally more effective in doc-
umenting thyrotoxicosis (6365). Mainly due to this lack
of sensitivity and specificity, only longitudinal evaluation
of such indices may be potentially helpful in CH patients.
Very recently, Koulouri et al. (89) divided a large series
of patients with hypothalamic-pituitary lesions into high
risk and lowrisk groups for CH. They then compared FT4
values in these groups of patients with those of patients
withprimary thyroiddisease adequately treatedwithLT
4
,
i.e. those with normal levels of circulating TSH during
replacement therapy. The conclusions were that CH pa-
tients are generally undertreated. Moreover, they suggest
that levels of FT4 in the middle of the normal range might
represent an appropriate target in most treated CH pa-
tients. Althoughthe individual FT4values are quite widely
distributed in normal subjects and genetically determined
(90), this conclusion is similar to the one reached in the
past by other authors, who even suggested to target FT4
values in the upper part of the normal range (84, 88).
Indeed, different authors (60, 61) reported that the large
majority of treated CH patients had circulating levels of
FT4 within the normal range with a mean LT
4
daily dose
of 1.5 0.3 and 1.6 0.5 g/kg body weight/d. Inter-
estingly, these optimal doses are similar to those reported
for primary hypothyroidism(85). As in primary hypothy-
roidism (91), younger CH patients require higher doses
than older patients (60, 61).
Importantly, significant differences in LT
4
doses also
depend on the concomitant treatment for CPHD. Estro-
gens had been reported to increase LT
4
requirements in
hypothyroid patients (61, 92). Because this is a likely con-
sequence of anincrease inTBGlevels (92, 93), the required
adjustment of LT
4
should be carried out to saturate the
increased T
4
-binding capacity of plasma proteins. More-
over, patients onrecombinant humanGH(rhGH) replace-
ment therapy also require significantly higher LT
4
doses
(74, 75, 9498). Accordingly, GH deficiency may mask
subclinical forms of CH that achieve subnormal values
only after institution of rhGH replacement therapy (94
98). The effects of rhGHon thyroid hormone metabolism
and the activity of the hypothalamic-pituitary-thyroid
axis are not transient (74, 75, 96, 98), but are biologically
relevant only in patients with CPHD who already have a
partial impairment of thyrotrope function (99). The rec-
TABLE 4. Recommendations for an adequate LT
4
replacement therapy in patients with CH as derived from
the reviewed Refs. 60, 61, 74, 82, 8489, 9498 and
101103
1. Start therapy only after exclusion of adrenal insufficiency or
give a prophylactic steroid treatment in cases at risk.
2. Establish the LT
4
daily dose based on age, sex, and
comorbidities (e.g. concomitant heart disease) (range, 1.2
1.7 or 1015 g/kg body weight, in adults or neonates,
respectively).
3. Keep the levels of circulating FT4 in the central part of the
laboratory reference values, provided that blood for FT4
measurement is obtained before ingestion of the daily dose,
and check regularly the clinical conditions of the patient.
4. Increase the daily LT
4
dose by 0.10.15 g/kg body weight
and/or reassess TSH and FT4 when rhGH or estrogen
replacement is introduced in a patient with CPHD.
5. Reassess TSH and FT4 whenever additional treatment
impacting LT
4
absorption or thyroid hormone metabolism is
introduced or withdrawn.
6. Suspect undertreatment when TSH levels are greater than
0.5 mU/liter or FT4 is below the lower tertile of normal
range.
7. Suspect overtreatment when FT4 and/or FT3 values are
above the upper tertile of normal range.
See Ref. 97.
ommendations for an adequate LT
4
replacement regimen
are summarized in Table 4.
Pediatric CH patients
In normal infants and children, the thyroid hormone lev-
els are higher than in adults (55, 83, 100). Therefore, higher
LT
4
doses are recommended in hypothyroid pediatric pa-
tients, and treatment should be started at full-replacement
doses, especially in patients with neonatal onset, to rapidly
reach adequate circulating FT4 levels and promptly support
neurological development (101). Guidelines recommendini-
tiating treatment of neonatal disorders with 1015 g/kg of
LT
4
and adjusting doses on the basis of FT4 measure-
ments every 24 wk (102). The target range should be
that observed in normal children. LT
4
treatment has
been reported to promote an acceleration of growth
velocity allowing patients to reach the target height (3,
23, 24). Progressively lower doses are required in child-
hood and in transition to adulthood (103).
Perspectives for Future Research
The gaps hampering a more comprehensive understand-
ing and improved treatment of CH are multiple. One is
surely represented by the lack of an explanation for the
several idiopathic CH cases. Therefore, future research
should aim to discover novel molecular mechanisms for
congenital and acquired forms still classified as idiopathic
at present. In this context, the existence of familial forms
of idiopathic CHsuggests the contribution of still uniden-
tified predisposing genes. These predisposing genes are
probably involved in the mechanisms contributing to
the setpoint of thyroid hormone feedback or the circa-
dian TSH oscillation. Among acquired forms, it is pre-
dictable the existence of autoimmune forms which may
be associated with specific antithyrotrope antibodies, a
possibility already put forward for gonadotrope or so-
matotrope defects (104).
An improved understanding of the pathogenic mecha-
nisms will probably provide novel tools or tests for a more
accurate diagnosis of CH, including the milder forms of
the disease. This, together with a more intimate compre-
hension of thyroid hormone metabolismand action at the
tissue level may provide novel markers for a tailored re-
placement therapy, which nowadays can be more easily
achieved in primary thyroid failure by the determination
of serum TSH concentrations. Perhaps in the near future
we will be able to predict the optimal FT4 values in the
various patients with CH under replacement therapy by
testing the genetic loci determining the individual setpoint
of hypothalamus-pituitary-thyroid axis and the interindi-
vidual variations in TSH and FT4 levels (90).
As for other pituitary defects, the cure for CH may
finally be given by the future advent of regenerative med-
icine (105), as recently suggestedby the invitrogeneration
of pituitary cell lineages (106).
Acknowledgments
The author thanks Prof. Paolo Beck-Peccoz for his support, ap-
preciation, and critical advice.
This review is dedicated to the memory of Prof. Giovanni
Faglia, Emeritus Professor of Endocrinology of the University of
Milan and world-renowned expert on pituitary diseases, who
recently passed away.
Address all correspondence and requests for reprints to:
Luca Persani, M.D., Ph.D., San Luca Hospital, Istituto Auxo-
logico Italiano, Piazzale Brescia 20, 20149 Milan, Italy. E-mail:
luca.persani@unimi.it. This work was partially supported by re-
search funds of the University of Milan.
Disclosure Summary: L.P. declares no conflict of interest re-
lated to this work.
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