Thomas Wharton, in 1656, gave the thyroid gland its modern name (meaning oblong shield) because

he believed the function of the thyroid was to fill vacant spaces

and contribute to the shape and beauty of the neck, especially in women 1 !or unknown reasons,
thyroid disease is more common in women than in men "ecause
most thyroid disease is autoimmune in nature, an increased susceptibility to autoimmune diseases,
perhaps secondary to the female endocrine environment, is a
likely contributing factor
The clinical ob#ective is to detect and treat thyroid disease before the symptoms and signs are
significant and intense $ubtle thyroid disease is easily diagnosed by
the sensitive laboratory assessments now available Therefore, the key to early diagnosis is to maintain
a high inde% of suspicion and to readily screen for the
presence of abnormal thyroid function
&ormal Thyroid 'hysiology
Thyroid hormone synthesis depends in large part on an ade(uate supply of iodine in the diet )n the
small intestine, iodine is absorbed as iodide that is then
transported to the thyroid gland 'lasma iodide enters the thyroid under the influence of thyroid*
stimulating hormone (T$+), the anterior pituitary thyrotropin hormone
Within the thyroid gland, iodide is o%idi,ed to elemental iodine, which is then bound to tyrosine
-onoiodotyrosine and diiodotyrosine combine to form thyro%ine (T .)
and triiodothyronine (T /) These iodinated compounds are part of the thyroglobulin molecule, the
colloid that serves as a storage depot for thyroid hormone T$+
induces a proteolytic process that results in the release of iodothyronines into the bloodstream as
thyroid hormone
0emoval of one iodine from the phenolic ring of T . yields T/, while removal of an iodine from the
nonphenolic ring yields reverse T / (0T/) which is biologically inactive
)n a normal adult, about one third of the T . secreted each day is converted in peripheral tissues,
largely liver and kidney, to T /, and about .12 is converted to the
inactive, reverse T/ 3bout 412 of the T/ generated is derived outside the thyroid gland, chiefly in the
liver and kidney T / is /55 times more potent than T., and
virtually all the biologic activity of T . can be attributed to the T/ generated from it 3lthough T. is
secreted at 61 times the rate of T/, it is T/ that is responsible for most
if not all the thyroid action in the body T / is more potent than T. because the nuclear thyroid
receptor has a ten*fold greater affinity for T / than T. While T . may have
some intrinsic activity of its own, it serves mainly as a prohormone of T / )t is hard to think of a body
process or function that doesn7t re(uire thyroid hormone for its
normal operation, not only metabolism but also development, steroidogenesis, and most specific tissue
activities
8arbohydrate calories appear to be the primary determinant of T / levels in adults 3 reciprocal
relationship e%ists between T / and 0T/ 9ow T/ and elevated 0T/ are
seen in a variety of illnesses such as febrile diseases, burn in#uries, malnutrition, and anore%ia nervosa
The metabolic rate is determined to a large degree by the
relative production of T/ and 0T/ :uring periods of stress, when a decrease in metabolic rate would
conserve energy, the body produces more 0T / and less T/, and
metabolism slows ;pon recovery, this process reverses, and metabolic rate increases
8irculating thyroid hormones are present in the circulation mainly bound to proteins 3ppro%imately
<12 of thyroid hormones are bound to thyro%ine*binding globulin
(T"=), which, therefore, is the ma#or determining factor in the total thyroid hormone concentration in
the circulation The remaining /12 is bound to thyro%ine*binding
prealbumin and albumin The binding proteins have a greater affinity for T . and thus allow T/ to
have greater entry into cells T"= is synthesi,ed in the liver, and this
synthesis is increased by estrogens
The nuclear receptor for thyroid hormone is a member of the super family that includes the steroid
hormone receptors ( 8hapter 6)6 The thyroid hormone receptor
e%ists in several forms, the products of 6 genes located on different chromosomes The a receptor is on
chromosome 1<, and the b receptor is on chromosome / The
nuclear T/ receptor is truly ubi(uitous, indicating the widespread actions of thyroid hormone
throughout the body -utations in the gene for the thyroid receptor lead to
the synthesis of a receptor that actually antagoni,es normal receptors, a syndrome of thyroid resistance
characteri,ed by elevated thyroid hormone levels T$+ is
elevated as well because of the impairment in thyroid hormone action
The thyroid a%is is stimulated by the hypothalamic factor, thyrotropin*releasing hormone (T0+) and
inhibited by somatostatin and dopamine Thyroid hormones
regulate T$+ by suppressing T0+ secretion, but primarily affecting the pituitary sensitivity to T0+
(by reducing the number of T0+ receptors) 'ituitary secretion of
T$+ is very sensitive to changes in the circulating levels of thyroid hormone> a slight change in the
circulating level of T . will produce a many*fold greater response in
T$+ T$+*secreting cells are regulated by T ., but only after the T. is converted to T/ in the pituitary
cells 3lthough modulation of thyroid hormone occurs at the
pituitary level, this function is permitted by the hypothalamic releasing hormone, T0+ 3lthough
some tissues depend mainly on the blood T / for their intracellular T /, the brain and the pituitary
depend on their own intracellular conversion of T . The measurement of T. and T$+, therefore,
provides the most accurate assessment of
thyroid function
The T$+ response to T0+ is influenced mainly by the thyroid hormone concentration in the
circulation> however, lesser effects are associated with dopamine agonists
(inhibition), glucocorticoids (inhibition), and dopamine antagonists (stimulation) ?strogen increases
the T0+ receptor content of the pituitary> hence, the T$+
response to T0+ is greater in women than in men, and greater in women taking combined oral
contraceptives
T0+ also stimulates prolactin secretion by the pituitary The smallest doses of T0+ that are capable of
producing an increase in T$+, also increase prolactin levels,
indicating a physiologic role for T0+ in the control of prolactin secretion +owever, e%cept in
hypothyroidism, normal physiologic changes as well as abnormal
prolactin secretion can be understood in terms of dopaminergic inhibitory control, and T0+ need not
be considered
!unctional 8hanges With 3ging
Thyro%ine metabolism and clearance decrease in older people, and thyro%ine secretion decreases in
compensation to maintain normal serum thyro%ine
concentrations/ With aging, conversion of T . to T/ decreases, and T$+ levels increase The T$+
response to T0+ is normal in older women T"= concentrations
decrease slightly in postmenopausal women but not enough to alter measurements in serum
Thyroid !unction Tests
!ree Thyro%ine (!T.)
3ssays that measure free T. are usually displacement assays using an antibody to T . The result is not
affected by changes in T"= and binding The free T . level has
a different range of normal values from laboratory to laboratory
Total Thyro%ine (TT .)
The total thyro%ine, both the bound portion to T"= and the free unbound portion, is measured by
displacement assays, and in the absence of hormone therapy or
other illnesses, estimates the thyro%ine concentration in the blood +owever, the free T . is unaffected
by factors that influence T"= and is preferred
!ree Thyro%ine )nde% (!T) or T<)
The free thyro%ine inde% is calculated from the TT . and the T/ resin uptake measurements This test
too has been replaced by the free T . assay
Total T/ and 0everse T/
"oth of these thyronines can be measured by sensitive immunoassays +owever, in most clinical
circumstances they add little to what is learned by the free T . and
T$+ measurements The clinical situations where measurement will be useful will be discussed under
the specific diseases and indicated on the algorithm
Thyroid*$timulating +ormone (T$+)
T$+ is measured by highly sensitive assays utili,ing monoclonal antibodies, usually in a techni(ue
that uses two antibodies, one directed at the a*subunit and one
directed at the b*subunit of T$+ The normal levels vary from laboratory to laboratory, but the
sensitive T$+ assay can detect concentrations as low as 111 @;A9
T$+ is a very sensitive indicator of thyroid hormone action at the tissue level because it is dependent
upon the pituitary e%posure to T . )n the absence of
hypothalamic or pituitary disease, the sensitive T$+ assays will provide the best indication of e%cess
or deficient thyro%ine> slight changes in T . are reflected in a
many*fold greater response in T$+ &early all women with elevated T$+ levels have hypothyroidism
Transient changes in T$+ can be caused by systemic illnesses,
ma#or psychiatric disturbances, and pharmacologic treatment with glucocorticoid agents or dopamine
0adioactive )odine ;ptake
"ecause the thyroid gland is the only tissue that utili,es iodine, radioisotopes of iodine can be used as
a measure of thyroid gland activity and to locali,e activity
within the gland
The 9aboratory ?valuation The algorithm represents a cost*effective and accurate clinical strategy .
!or screening purposes, or when there is a relatively low
clinical suspicion of thyroid disease, the initial step is to measure the T$+ by a sensitive assay 3
normal T$+ essentially e%cludes hypothyroidism or
hyperthyroidism 3 high T$+ re(uires the measurement of free T. to confirm the diagnosis of
hypothyroidism
)f the initial T$+ is low, especially less than 114 @;Am9, then measurement of a high T . will
confirm the diagnosis of hyperthyroidism )f the T . is normal, the T/ level
is measured, since some patients with hyperthyroidism will have predominantly T / to%icosis )f the
T/ is normal, it implies that thyro%ine secretion is autonomous from
T$+, and this is called subclinical hyperthyroidism $ome of these patients will eventually have
increased T . or T/ levels with true hyperthyroidism
+ypothyroidism
)n most cases of hypothyroidism, a specific cause is not apparent )t is believed that the
hypothyroidism is usually secondary to an autoimmune reaction, and when
goiter formation is present, it is called +ashimoto7s thyroiditis 5 ;nless abnormal thyroid function can
be documented by specific laboratory assessment, empiric
treatment with thyroid hormone is not indicated, and it is especially worth emphasi,ing that thyroid
hormone treatment does not help infertility in euthyroid women )t is
uncertain whether hypothyroidism can be a cause of recurrent miscarriages, but an assessment of
thyroid function is worthwhile in these patients
+ypothyroidism increases with aging and is more common in women6 ;p to .52 of thyroid glands
from women over age 61 show evidence of thyroiditis < The
incidence of antithyroglobulin antibodies is <.2 in women over age <5 years, while 16B2 of women
age 61 and 1<.2 of women over age <5 have elevated T$+
levels )n women admitted to geriatric wards, 65.2 have clinically apparent hypothyroidism
Therefore, hypothyroidism is fre(uent enough to warrant
consideration in most older women, #ustifying screening even in asymptomatic older women We
recommend that older women be screened with the
highly sensitive T$+ assay every 5 years beginning at age /5, then every
6 years beginning at age 61, or with the appearance of any symptoms suggesting
hypothyroidism4
+yperthyroidism
The two primary causes of hyperthyroidism are =raves7 disease (to%ic diffuse goiter) and 'lummer7s
disease (to%ic nodular goiter) 14 'lummer7s disease is usually
encountered in postmenopausal women who have had a long history of goiter Twenty percent of
hyperthyroid patients are over 61, and 652 of older women with
hyperthyroidism present with an apathetic or atypical syndrome
=raves7 disease is characteri,ed by the triad of hyperthyroidism, e%ophthalmos, and pretibial
my%edema and is believed to be caused by autoantibodies that have
T$+ properties and, therefore, bind to and activate the T$+ receptor -enstrual changes associated
with hyperthyroidism are unpredictable, ranging from
amenorrhea to oligomenorrhea to normal cycles (hence, the amenorrhea in a thyroto%ic woman can be
due to pregnancy)
The classic symptoms of thyroto%icosis are nervousness, heat intolerance, weight loss, sweating,
palpitations, and diarrhea These symptoms are associated with
typical findings on physical e%aminationC proptosis, lid lag, tachycardia, tremor, warm and moist skin,
and goiter Women in the reproductive years usually present with
the classic picture )n postmenopausal women, symptoms are often concentrated in a single organ
system, especially the cardiovascular or central nervous system
=oiter is absent in .12 $inus tachycardia occurs in less than half, but atrial fibrillation occurs in .12
and is resistant to cardioversion or spontaneous reversion to
sinus rhythm )n old women, there is often a coe%istent disease, such as an infection or coronary heart
disease that dominates the clinical picture
The triad of weight loss, constipation, and loss of appetite, suggesting gastrointestinal malignancy,
occurs in about 152 of older patients with hyperthyroidism
Dphthalmopathy is rare in older patients +yperthyroidism in older women is sometimes described as
Eapathetic hyperthyroidismF because the clinical manifestations
are different The clinician should consider the diagnosis in older patients with Efailure to thrive,F in
patients who are progressively deteriorating for une%plained reasons, and in patients with heart
disease, une%plained weight loss, and mental or psychologic changes
'sychologic changes are not unusual in hyperthyroid women Women who complain of emotional
lability and nervousness should be screened for hyperthyroidism
:iagnosis of +yperthyroidism
The diagnosis of hyperthyroidism re(uires laboratory testing 3 suppressed T$+ with a high T . or a
high T/ confirms the diagnosis +yperthyroidism caused by high
levels of T/ is more common in older women -ost patients should have a radioactive iodine thyroid
uptake and scan after laboratory confirmation of the diagnosis )f
the uptake is suppressed then drug therapy is indicated The scan will indicate whether the patient has
a diffuse to%ic goiter, a solitary hot nodule, or a hot nodule in a
multinodular gland To%ic multinodular goiters occur more fre(uently in the elderly T$+
hypersecretion as a cause of hyperthyroidism is e%tremely rare> the
combination of a normal or elevated T$+ and elevated thyroid hormone will be the clue to this
possibility
$ubclinical +yperthyroidism
"y definition, patients with subclinical hyperthyroidism have normal T . and T/ levels, but subnormal
concentrations of T$+ T$+ levels can be suppressed to 11515
@;A9 by general illnesses and drugs such as glucocorticoids, dopamine, and anticonvulsants> however,
this suppression does not e%tend below 11 @;A9 Galues
below 11 @;A9 are regarded as nondetectable, and patients with overt hyperthyroidism usually have
undetectable T$+ $ubclinical hyperthyroidism is half as
common in older people as subclinical hypothyroidism (e%cluding the most common cause, treatment
with e%cessive doses of thyro%ine) Heep in mind that the dose of
thyro%ine re(uired to treat hypothyroidism declines with age (because of the decrease in metabolic
clearance with age)> all patients being treated with thyroid
hormone should have their T$+ levels assessed every year 3trial fibrillation is a common
cardiovascular problem associated with subclinical hyperthyroidism 1B )f
subclinical hyperthyroidism persists, it should be treated, especially in postmenopausal women,
because of the cardiac complications and the loss of bone associated
with e%cess thyroid hormone T$+ levels that are low but not undetectable (11551 @;A9) need not be
treated, but T$+ measurement is warranted every 6 months
'rogression to overt hyperthyroidism is uncommon
Treatment of +yperthyroidism
There are multiple ob#ectives of therapyC control of thyroid hormone effects on peripheral tissues by
pharmacologic blockade of beta*adrenergic receptors, inhibition of
thyroid gland secretion and release of thyroid hormone, and specific treatment of nonthyroidal
systemic illnesses which can e%acerbate hyperthyroidism or be
adversely affected by hyperthyroidism61 3ntithyroid drugs are usually administered first to achieve
euthyroidism, then definitive therapy is accomplished by
radioactive iodine treatment Df course, it is important to make sure a woman is not pregnant before
treatment with radioactive iodine, and pregnancy should be
postponed for several months after treatment -onitoring treatment response re(uires a full 4*week
interval for stabili,ation of the hypothalamic*pituitary*thyroid
system
3ntithyroid :rugs
The drug of choice in most circumstances will be methima,ole because it has fewer adverse effects
The drug inhibits organification of iodide and decreases
production of T. and T/ The oral dose is 11561 mg daily The onset of effect takes 65. weeks
0emember that the half*life of thyro%ine is about one week, and the
gland usually has large stores of T . -a%imal effect occurs at .54 weeks The dose can be titrated
down once the disease is controlled to a maintenance dose of 5511
mg daily The ma#or side effects are rash, gastrointestinal symptoms, and agranulocytosis (an
idiosyncratic reaction) 'ropranolol and other beta*blockers are
effective in rapidly controlling the effects of thyroid hormone on peripheral tissues The dose is
usually 615.1 mg, every 16 hours, orally, and the dose is titrated to
maintain a heart rate of about 111 beatsAminute The drug may cause bronchospasm, worsening
congestive heart failure, fatigue, and depression 0arely inorganic
iodine will be needed to block release of hormone from the gland 9ugol7s solution, 6 drops in water
daily, is sufficient The onset of effect is 156 days, with ma%imal
effect in /5< days There may be an escape from protection in 656 weeks, and the drug can cause rash,
fever, and parotitis )odine precludes radioiodine
administration for several months
3fter the symptoms are controlled, and the patient is euthyroid, a dose of radioactive iodine can be
selected, the thiouracil withheld temporarily, and definitive therapy
accomplished 'atients with solitary nodules will be treated in the same fashion $ome patients with
hot nodules in multinodular glands will re(uire surgery because of
the si,e of the gland and because the hyperthyroidism tends to recur in new nodules after the ablation
of the original hot nodule This can result in repetitive
treatments with substantial doses of radioactive iodine, and surgery may be preferable 3ll patients
definitively treated for hyperthyroidism must be monitored for the
onset of hypothyroidism
Dsteoporosis and ?%cessive Thyro%ine
"ecause postmenopausal women are at increased risk for osteoporosis, and fre(uently develop
hyperthyroidism or receive levothyro%ine treatment for
hypothyroidism, the clinician needs to understand how thyroid hormone affects bones 61 Thyroid
hormone e%cess alters bone integrity via direct effects on bone and
gut absorption and indirectly through the effects of vitamin :, calcitonin, and parathyroid hormone
Thyroid hormone increases bone mineral resorption )n addition, total and ioni,ed calcium increase in
hyperthyroid women, leading to increases in serum
phosphorous, alkaline phosphatase, and bone =la protein (osteocalcin), a marker of bone turnover
'arathyroid hormone decreases in response to the increased
serum calcium, and this results in decreased hydro%ylation of vitamin : )ntestinal calcium and
phosphate absorption decrease, while urinary hydro%yproline and
calcium e%cretion increase The net effect is increased bone resorption and a subse(uent decrease in
bone density I osteoporosis 66
These effects become more clinically important in prolonged e%posure to e%cessive thyroid hormone
6/ Women who have had hyperthyroidism e%perience
postmenopausal fractures earlier than usual 6.
The ma#or concern is that mild chronic e%cess thyroid hormone replacement, especially in
postmenopausal women, might increase the risk of osteoporosis, and
indeed this subse(uently was documented65 "one density has been found to be reduced (B2) in
premenopausal women receiving enough thyro%ine to suppress T$+
for 11 years or more66 3 meta*analysis of the literature on this sub#ect concluded that premenopausal
women treated for long durations did not suffer a clinically
significant loss of bone (probably because of the protective presence of estrogen)> however,
postmenopausal women lose an e%cess of bone if thyroid treatment
results in T$+ levels below the normal range 6<
Thus, e%posure to e%cessive thyro%ine must be added to the risk factors for osteoporosis )t makes
sense to monitor patients (both premenopausal women and
especially postmenopausal women) receiving thyro%ine with the sensitive T$+ assay to ensure that
levothyro%ine doses are EphysiologicF $ome patients who re(uire
T$+ suppressive doses of thyro%ine, such as patients with nodules, goiters, and cancer, must be
considered at increased risk of osteoporosis )t would be wise to
assess bone density in women on long*term thyroid treatment and in women receiving high*dose
thyro%ine suppression of T$+ The use of hormone therapy, e%ercise
programs, and possibly biphosphate treatment must be seriously considered for these patients )n a
cross*sectional study of elderly women, the bone loss associated
with long*term thyroid treatment was avoided in those women also taking estrogen 64
Thyroid &odules
The ma#or concern with thyroid nodules is the potential for thyroid cancer 6B $ingle nodules are .
times more common in women, and carcinoma of the thyroid is
nearly / times more common in women than in men The incidence rises steadily from the age of 55
-ortality from thyroid cancer occurs predominantly in the
middle*aged and the elderly There are . ma#or types of primary thyroid carcinomaC papillary,
follicular, anaplastic, and medullary )n solitary nodules that are EcoldF
(those that do not take up radioactive iodine or pertechnetate on thyroid scan), 162 prove to be
malignant This also means that the ma#ority are benign $urgical
e%cision of nodules can result in vocal cord paralysis, hypoparathyroidism, and other complications
Therefore, the goal is to select patients for curative surgery who
have the greatest likelihood of having cancer in the nodule
?pidemiologic and 8linical :ata
The ma#or risk factors for thyroid cancer are family history of this disease and a history of irradiation
to head or neck )n those who have received thyroid irradiation,
about one*third will have thyroid abnormalities, and about one*third of those with abnormalities will
have thyroid cancer (about 112 overall) The carcinogenic risk has
been estimated to be 12 per 111 rads in 61 years 3 rapidly growing nodule, a hard nodule, the
presence of palpable regional lymph nodes, or vocal cord paralysis
greatly increase the probability of thyroid cancer
Thyroid nodules in multinodular thyroid glands, not previously e%posed to thyroid irradiation, have no
greater risk of thyroid carcinoma than normal glands Therefore,
predominant thyroid nodules in multinodular glands should be followed and, if a nodule grows, then
biopsy or surgery should be considered
:iagnostic $trategy
)n patients with a thyroid nodule, laboratory assessment of thyroid function is essential When
abnormal thyroid function is present, the nodule is almost always
benign :etection of a thyroid nodule is followed by clinical characteri,ation of the nodule,
e%amination of the lymph nodes, and in(uiry regarding rapid growth, family
history, and history of thyroid irradiation )n the presence of any of these findings, surgery is
recommended for e%cision of the nodule )f none of these is present,
proceed directly to fine needle aspiration biopsy or thyroid scan
)f a scan is chosen, hot nodules are evaluated independently 8old nodules re(uire a surgical diagnosis
)f the patient prefers, one can treat with suppressive doses of
levothyro%ine and evaluate over time ;nfortunately, many of these thyroid nodules do not regress
with thyroid treatment, but it is very reassuring if they do =rowth or
lack of disappearance with thyroid suppression is an indication for fine needle aspiration biopsy
Thyroid ultrasound can be utili,ed to more accurately establish si,e
for comparison over time
3lthough accounting for only 52 of thyroid cancers, medullary carcinoma is associated with early
spread and poor survival rates -edullary carcinoma of the thyroid is
uni(ue in having the serum calcitonin as a very sensitive and specific tumor marker -easuring the
serum calcitonin is recommended for older patients with solitary
nodules in order to achieve earlier diagnosis of medullary carcinoma /1
!ine*&eedle 3spiration
!ine*needle aspiration biopsy has a 4/2 sensitivity and B62 specificity in diagnosing thyroid
malignancy /1 When EindeterminateF by biopsy, about one*third prove to
be malignant at thyroidectomy )f the fine*needle aspiration biopsy reveals suspicious cells or is
indeterminate, a subtotal thyroidectomy should be performed for
diagnosis and treatment )f the aspiration biopsy is benign some would repeat the biopsy in one year to
avoid false negatives -ost would provide thyroid hormone
suppressive therapy (aiming for a T$+ level below 11 @;A9) for one year with close observation for
growth of the nodule /6 =rowth or lack of disappearance indicates
the need for biopsy or surgery )f the nodule shrinks during suppression, after one year a choice is
made between no treatment or maintenance of the T$+ level at the
lower end of normal )n some cases, especially in older women, nodules can be followed with no
therapy and little risk )f the nodule increases in si,e, suppressive
therapy is recommended Dne of the reasons many are treated with levothyro%ine is because of the
known growth*promoting effects of T$+ in carcinoma of the
thyroid and the hope that T$+ suppression will inhibit the growth of early carcinoma
The method for fine*needle aspiration biopsy re(uires no anesthetic ;sing sterile techni(ue and a 6/*
gauge needle on a 11 m9 syringe, the nodule is fi%ed with two
fingers of one hand and the nodule entered 3spiration is performed with the syringe while several
passes are made through a vertical distance of about 6 mm in the
nodule $uction is stopped when biopsy material becomes visible in the hub of the needle The
contents of the needle should be e%pelled onto a slide and fi%ed for
pathology =entle pressure is applied over the nodule for 11 minutes Dccasionally, a patient will have
some bleeding into the nodule or surrounding tissues, but it is
usually self*limiting
The Thyroid =land and 'regnancy
)n response to the metabolic demands of pregnancy, there is an increase in the basal metabolic rate
(which is mainly due to fetal metabolism), iodine uptake, and the
si,e of the thyroid gland caused by hyperplasia and increased vascularity // +owever, a pregnant
woman is euthyroid with normal levels of T$+, free T., and free T/>
thyroid nodules and goiter re(uire evaluation :uring pregnancy, iodide clearance by the kidney
increases !or this reason (plus the iodide losses to the fetus), the
prevalence of goiter is increased in areas of iodine deficiency /. This is not a problem in the ;$, and
any goiter should be regarded as pathologic )n many parts of
the world, iodine is not sufficiently available in the environment, and pregnancy increases the risk of
iodine deficiency
The increase in thyroid activity in pregnancy is compensated by an marked increase in the circulating
levels of T"= in response to estrogen> therefore, a new
e(uilibrium is reached with an increase in the bound portion of the thyroid hormone The mechanism
for the estrogen effect on T"= is an increase in hepatic
synthesis and an increase in glycosylation of the T"= molecule that leads to decreased clearance
The increase in thyroid activity is attributed to the thyrotropic substances secreted by the placentaC a
chorionic thyrotropin and the thyrotropic activity in human
chorionic gonadotropin (+8=)/5 )t has been calculated that +8= contains appro%imately 1A.111th of
the thyrotropic activity of human T$+ )n conditions with very
elevated +8= levels, the thyrotropic activity can be sufficient to produce hyperthyroidism, and this
can even be encountered in normal pregnancy /6
T"= levels reach a peak (twice nonpregnant levels) at about 15 weeks, which is maintained
throughout the rest of pregnancy /< T. undergoes a similar change, but T /
increases more markedly "ecause of the increase in T"=, free T . and T/ levels actually decrease,
although they remain within the normal range /4 There is an
inverse relationship between maternal circulation levels of T$+ and +8= /< T$+ reaches a nadir at
the same time that +8= reaches a peak at 11 weeks of
pregnancy T$+ levels then increase as +8= levels drop to their stable levels throughout the rest of
pregnancy These changes support a role for +8= stimulation of
the maternal thyroid gland during early pregnancy /<, /B, .1 )t is well recogni,ed that patients who
have conditions associated with very high levels of +8=
(trophoblastic disease, +8=*secreting cancers) can develop hyperthyroidism The thyroid*stimulating
activity of +8= is e%plained by the molecular homology
between +8= and T$+, and between their receptors
)n normal pregnancies, placental transfer of T$+, T ., and T/ is severely limited in both directions
)ndeed, the placenta is essentially impermeable to these substances
no matter whether the fetus is euthyroid or hypothyroid $light transfer of T . and T/ can occur,
however, when maternal levels are very high or when fetal levels are
substantially lower than the maternal levels
The ma#ority of patients with hyperemesis gravidarum have laboratory values consistent with
hyperthyroidism, and the severity of the hyperemesis correlates with the
degree of hyperthyroidism.1, .6 These patients have higher levels of +8=, and the transient
hyperthyroidism and severity of the hyperemesis may be mediated by the
thyrotropic and steroidogenic activity of the +8= These clinical manifestations in normal
pregnancies may be linked to a specific subpopulation of +8= molecules
with greater thyrotropic bioactivity (because highly purified, standard +8= has only trivial T$+*like
activity) ./ $pecifically, +8= with reduced sialic acid content is
increased in pregnant patients with hyperemesis and hyperthyroidism ..
Thyroid 'hysiology in the !etus and the &eonate
The human fetal thyroid gland develops the capacity to concentrate iodine and synthesi,e hormone
between 4 and 11 weeks of gestation, the same time that the
pituitary begins to synthesi,e T$+ .5, .6 $ome thyroid development and hormone synthesis are
possible in the absence of the pituitary gland, but optimal function
re(uires T$+ "y 1651. weeks, development of the pituitary*thyroid system is complete !unction is
minimal, however, until an abrupt increase in fetal T$+ occurs at
61 weeks 3s with gonadotropin and other pituitary hormone secretion, this thyroid function correlates
with the maturation of the hypothalamus and the development of
the pituitary portal vascular system, which makes releasing hormone available to the pituitary gland
!etal T$+ increases and reaches a plateau at 64 weeks and remains at relatively high levels to term
The free T . concentration increases progressively 3t term, fetal
T. levels e%ceed maternal levels Thus, a state of fetal thyroidal hyperactivity e%ists near term
The ma#or thyroid hormone secreted by the fetus is T. +owever, total T/ and free T/ levels are low
throughout gestation, and levels of 0T / are elevated, paralleling
the rise in T. 9ike T/, this compound is derived predominantly from conversion of T. in peripheral
tissues The increased production of T . in fetal life is compensated
by rapid conversion to the inactive 0T /, allowing the fetus to conserve its fuel resources
With delivery, the newborn moves from a state of relative T 3 deficiency to a state
of T3 thyrotoxicosis. Shortly after birth serum TSH concentrations increase rapidly
to
a peak at 30 minutes of ae. They fall to baseline values by !"#$% hours. &n
response to this increase in TSH, total T ! and free T! increase to peak values by
%!#!"
hours of ae. T3 levels increase even more, peakin by %! hours of ae. 'y 3#!
weeks, the thyroidal hyperactivity has disappeared.
The postnatal sure in TSH is accompanied by a prolactin sure, suestin that
both are increased in response to T(H. The T(H sure is thouht to be a
response
to rapid neonatal coolin. ) pu**le is the fact that the early increase in T 3 is
independent of TSH and is tied in some way to cuttin of the umbilical cord.
+elayin cord
cuttin delays the increase in T 3, but TSH levels still reach their peak at 30
minutes. &n some way cord cuttin auments peripheral ,larely liver- conversion
of T ! to
T3. The later increases in T3 and T! ,after % hours- are due to increased thyroid
land activity. These thyroid chanes after birth probably represent defense
mechanisms aainst the sudden entry into the cold world. The hih (T 3 levels
durin prenancy continue durin the first 3#. days of life, and then fall radually
to
normal levels by % weeks.
Summary of Fetal and Newborn Thyroid Changes
/. TSH and T4 appear in the fetus at 1013 wees! "e#els are low until an
abrupt rise at $0 wees!
%. T4 rises rapidly and e%&eeds maternal #alues at term!
3. T3 le#els rise' but &on&entrations are relati#ely low' similar to
hypothyroid adults!
!. (T3 le#els e%&eed normal adult le#els!
.. The fetal pattern of low T3 and high (T3 is similar to that seen with &alorie
malnutrition!
0. )fter deli#ery' TSH peas at 30 minutes of age' followed by a T3 pea at
$4 hours and a T4 pea at $44* hours! The T3 in&rease is independent of
the TSH &hange!
+! High (T3 le#els persist for 3, days after deli#ery' then rea&h normal
#alues by $ wees!
&ewborn $creening for +ypothyroidism
The incidence of neonatal hypothyroidism is about one in .111 live births, and newborn screening
programs e%ist in most of the world The problem is that congenital
hypothyroidism is not clinically apparent at birth !ortunately, infants with congenital hypothyroidism
have low T . and high T$+ concentrations easily detected in
blood, and early treatment before / months of age is usually associated with normal mental
development .< 9ess than normal development can be a conse(uence of a
delay in treatment or e%tremely low thyroid hormone production in the fetus
There is a familial tendency for hypothyroidism, and if the diagnosis is made in the antepartum period,
intra*amniotic in#ections of thyro%ine can raise fetal levels of
thyroid hormone.4 ;ltrasonographic e%amination of patients with polyhydramnios should include a
search for a fetal goiter )n addition, the fetus should be monitored
for goiter formation in women treated with antithyroid drugs for hyperthyroidism during pregnancy
3mniotic fluid iodothyronines and T$+ reflect fetal plasma levels,
and abnormal values may allow prenatal diagnosis of fetal hypothyroidism by amniocentesis .4, .B
+owever, fetal cord blood sampling is advocated for accurate
diagnosis51 Treatment of fetal hypothyroidism is important because there is a concern that prenatal
hypothyroidism can affect some aspects of development> eg, the
full function of physical skills 3lthough transfer of thyroid hormone from mother to fetus is limited,
even a small amount provides protection, especially to the brain, for
a fetus with hypothyroidism
+yperthyroidism in 'regnancy
;ntreated thyroto%icosis in pregnancy is associated with a higher risk of preeclampsia, heart failure,
intrauterine growth retardation, and stillbirth 51 +eart failure is a
conse(uence of the demands of pregnancy superimposed upon the hyperdynamic cardiovascular state
induced by the increased thyroid hormone 56
The most common cause of thyroto%icosis in pregnancy is =raves7 disease +owever, the clinician
should always keep in mind that trophoblastic disease can cause
hyperthyroidism due to the T$+ property inherent in human chorionic gonadotropin The maternal
changes with pregnancy can make diagnosis difficult Tachycardia
upon awakening from sleep and a failure to gain weight should make a clinician suspicious
+yperemesis gravidarum is a common presentation of hyperthyroidism in
pregnancy 9aboratory assessment is unaffected by pregnancy and should follow our algorithm
The choice of treatment is between surgery and antithyroid drugs +owever prior to surgery, the
thyroid gland has to be controlled with medical therapy -ost women
can be successfully treated with thioamide drugs 51 'ropylthiouracil and methima,ole are e(ually
safe and effective for pregnant women> however, propylthiouracil is
preferred in breastfeeding patients because it is less concentrated in breast milk 5/
The aim of treatment should be to maintain mild hyperthyroidism in the mother to avoid thyroid
dysfunction in the fetus Treatment of maternal hyperthyroidism with
propylthiouracil, even with moderate doses of 1115611 mg daily, suppresses T . and increases T$+
levels in newborns5. The infants are clinically euthyroid, however,
and their laboratory measurements are normal by the .th to 5th day of life )n addition, follow*up
assessment has indicated unimpaired intellectual development in
children whose mothers received propylthiouracil during pregnancy 55 &evertheless, pregnant
women with thyroto%icosis should be treated with as low a dose of
antithyroid drugs as possible With proper antithyroid drug treatment, very few, if any, deleterious
effects are e%perienced by mother, fetus, or neonate 56 3lthough
small amounts of antithyroid drugs are transmitted in breast milk, the amount has no impact on
neonatal thyroid function, and breastfeeding should be encouraged
'oor control of maternal hyperthyroidism is associated with increased risks of preeclampsia and low*
birth*weight infants 5<
-aternal T$+*like autoantibodies can cross the placenta and cause fetal thyroto%icosis and demise
$ome have advocated fetal cord blood sampling in women with
=raves7 disease who are euthyroid but who have positive titers of T$+*like antibodies to assess the
fetal thyroid status 54 The fetus can be treated by treating the
mother &eonates have to be observed closely until antithyroid drugs are cleared (a few days) and the
true thyroid state can be assessed
Thyroid $torm
This life*threatening augmentation of thyroto%icosis is usually precipitated by stress such as labor,
cesarean section, or infection $tress should be limited as much as
possible in patients with uncontrolled thyroto%icosis
+ypothyroidism in 'regnancy
$erious hypothyroidism is rarely encountered during pregnancy 'atients with this degree of illness
probably do not get pregnant 'atients with mild hypothyroidism
probably never have a laboratory assessment for thyroid function during pregnancy and go undetected
'reeclampsia, intrauterine growth retardation, and fetal
distress are more fre(uent in women with significant hypothyroidism 5B, 61 and 61 There is also
reason to believe that patients with hypothyroidism have an increased rate
of spontaneous abortion66 The mechanism may be impaired ability of important organs such as the
endometrium and the corpus luteum Women being treated for
hypothyroidism re(uire an increase (615512) in thyro%ine during pregnancy 6/, 6. T$+ should be
monitored monthly in the first trimester and again in the
postpartum period, and dosage
should be ad#usted to keep the T$+ level in the normal range
'ostpartum Thyroiditis
3utoimmune thyroid disease is suppressed to some degree by the immunologic changes of pregnancy
Thus, there is a relatively high incidence of postpartum
thyroiditis (55112), usually /56 months after delivery, manifested by either hyperthyroidism or
hypothyroidism, although commonly transient hyperthyroidism is
followed by hypothyroidism65 This condition is due to a destructive thyroiditis associated with
thyroid microsomal autoantibodies 66 Women at high risk for postpartum
thyroiditis are those with a personal or family history of autoimmune disease, and those with a
previous postpartum episode Women with insulin*re(uiring diabetes
mellitus are at particularly high risk 6<
-ost importantly, the symptoms in these women are often attributed to an%iety or depression, and the
obstetrician must have a high inde% of suspicion for
hypothyroidism The symptoms usually last 15/ months, and almost all women return to normal
thyroid function 'ostpartum thyroiditis tends to recur with subse(uent
pregnancies, and eventually hypothyroidism remains 64 The symptoms of hyperthyroidism in this
condition are not responsive to antithyroid medication, and patients
are usually not treated or given beta*adrenergic blocking agents (eg, propranolol in a dose sufficient
to reduce the resting pulse to less than 111 per minute)
"ecause spontaneous remission is common, patients who are treated with hypothyroidism should be
reassessed one year after gradual withdrawal of thyro%ine
'atients who return to normal should undergo periodic laboratory surveillance of their thyroid status