hipertiroid hamil speroff

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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 factorThe 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 adeuate 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%idied 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, thecolloid 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 .2 is converted to the

inactive, reverse T/ 3bout 42 of the T/ generated is derived outside the thyroid gland, chiefly in the

liver and kidney T / is /5 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 times the rate of T/, it is T/ that is responsible for mostif 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 reuire 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 increases8irculating thyroid hormones are present in the circulation mainly bound to proteins 3ppro%imately

<2 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 /2 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 synthesied 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 ) The thyroid hormone receptor

e%ists in several forms, the products of 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 ubiuitous, 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 antagonies normal receptors, a syndrome of thyroid resistance

characteried by elevated thyroid hormone levels T$+ iselevated 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 utiliing monoclonal antibodies, usually in a techniue

that uses two antibodies, one directed at the a*subunit and onedirected 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 1 @;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 utilies iodine, radioisotopes of iodine can be used as

a measure of thyroid gland activity and to localie activity

within the glandThe 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$+ reuires the measurement of free T. to confirm the diagnosis of

hypothyroidism

f the initial T$+ is low, especially less than 4 @;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 emphasiing 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 women 6 ;p to .52 of thyroid glands

from women over age 6 show evidence of thyroiditis < The

incidence of antithyroglobulin antibodies is <.2 in women over age <5 years, while 16B2 of women

age 6 and 1<.2 of women over age <5 have elevated T$+levels n women admitted to geriatric wards, .2 have clinically apparent hypothyroidism

Therefore, hypothyroidism is freuent 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

years beginning at age 6, 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 6, and 52 of older women with

hyperthyroidism present with an apathetic or atypical syndrome

=raves7 disease is characteried by the triad of hyperthyroidism, e%ophthalmos, and pretibialmy%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 .2 $inus tachycardia occurs in less than half, but atrial fibrillation occurs in .2

and is resistant to cardioversion or spontaneous reversion tosinus 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 +yperthyroidismThe diagnosis of hyperthyroidism reuires 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 freuently 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 15@;A9 by general illnesses and drugs such as glucocorticoids, dopamine, and anticonvulsants> however,

this suppression does not e%tend below 1 @;A9 Galues

below 1 @;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 reuired 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 (15 @;A9) need not be

treated, but T$+ measurement is warranted every 6 months

'rogression to overt hyperthyroidism is uncommonTreatment 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 hyperthyroidism 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 reuires a full 4*week

interval for stabiliation of the hypothalamic*pituitary*thyroid

system

3ntithyroid :rugsThe drug of choice in most circumstances will be methimaole because it has fewer adverse effects

The drug inhibits organification of iodide and decreases

production of T. and T/ The oral dose is 1 mg daily The onset of effect takes . 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 .4 weeks The dose can be titrated

down once the disease is controlled to a maintenance dose of 51

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 . mg, every 1 hours, orally, and the dose is titrated to

maintain a heart rate of about 1 beatsAminute The drug may cause bronchospasm, worsening

congestive heart failure, fatigue, and depression 0arely inorganiciodine will be needed to block release of hormone from the gland 9ugol7s solution, drops in water

daily, is sufficient The onset of effect is 1 days, with ma%imal

effect in /< days There may be an escape from protection in 6 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 reuire surgery because of

the sie 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 theonset of hypothyroidism

Dsteoporosis and ?%cessive Thyro%ine

"ecause postmenopausal women are at increased risk for osteoporosis, and freuently develop

hyperthyroidism or receive levothyro%ine treatment for

hypothyroidism, the clinician needs to understand how thyroid hormone affects bones 1 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 ionied 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 subseuent decrease in bone density I osteoporosis

These effects become more clinically important in prolonged e%posure to e%cessive thyroid hormone

/ Women who have had hyperthyroidism e%perience

postmenopausal fractures earlier than usual .

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 subseuently was documented5 "one density has been found to be reduced (B2) in

premenopausal women receiving enough thyro%ine to suppress T$+

for 1 years or more6 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 <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 reuire

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 4

Thyroid &odulesThe ma#or concern with thyroid nodules is the potential for thyroid cancer B $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), 12 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 12 overall) The carcinogenic risk has

been estimated to be 12 per 1 rads in 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 characteriation of the nodule,e%amination of the lymph nodes, and inuiry 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 reuire 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 utilied to more accurately establish sie

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 isuniue 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 /

!ine*&eedle 3spiration

!ine*needle aspiration biopsy has a 4/2 sensitivity and B2 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 1 @;A9) for one year with close observation for growth of the nodule / =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 sie, 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 reuires no anesthetic ;sing sterile techniue and a /*

gauge needle on a 1 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 mm in the

nodule $uction is stopped when biopsy material becomes visible in the hub of the needle Thecontents of the needle should be e%pelled onto a slide and fi%ed for

pathology =entle pressure is applied over the nodule for 1 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

sie 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 reuire 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 deficiencyThe 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

euilibrium 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.th 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 1 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, . t is well recognied 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 directionsndeed, 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, . 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 synthesie hormone

between 4 and 1 weeks of gestation, the same time that the

pituitary begins to synthesie T$+ .5, .6 $ome thyroid development and hormone synthesis are

possible in the absence of the pituitary gland, but optimal function

reuires T$+ "y 11. weeks, development of the pituitary*thyroid system is complete !unction is

minimal, however, until an abrupt increase in fetal T$+ occurs at

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 4 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, parallelingthe 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 stateof T3 thyrotoxicosis. Shortly after birth serum TSH concentrations increase rapidlytoa peak at 30 minutes of ae. They fall to baseline values by !"#$% hours. &nresponse 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 thatboth are increased in response to T(H. The T(H sure is thouht to be aresponseto rapid neonatal coolin. ) pu**le is the fact that the early increase in T 3 isindependent of TSH and is tied in some way to cuttin of the umbilical cord.+elayin cordcuttin delays the increase in T 3, but TSH levels still reach their peak at 30minutes. &n some way cord cuttin auments peripheral larely liver- conversionof T ! toT3. The later increases in T3 and T! after % hours- are due to increased thyroidland activity. These thyroid chanes after birth probably represent defense

mechanisms aainst the sudden entry into the cold world. The hih (T 3 levelsdurin prenancy continue durin the first 3# days of life, and then fall raduallytonormal levels by % weeks.Summary of Fetal and Newborn Thyroid Changes/. TSH and T4 appear in the fetus at 10–13 wees! "e#els are low until anabrupt 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 tohypothyroid 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 &aloriemalnutrition!. )fter deli#ery' TSH peas at 30 minutes of age' followed by a T3 pea at$4 hours and a T4 pea at $4–4* 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 . 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 conseuence of adelay 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

diagnosis5 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

conseuence of the demands of pregnancy superimposed upon the hyperdynamic cardiovascular state

induced by the increased thyroid hormone 5

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 methimaole are eually

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 1 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, pregnantwomen 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 freuent in women with significant hypothyroidism 5B, 6 and 61 There is also

reason to believe that patients with hypothyroidism have an increased rate

of spontaneous abortion6 The mechanism may be impaired ability of important organs such as the

endometrium and the corpus luteum Women being treated for

hypothyroidism reuire an increase (52) in thyro%ine during pregnancy 6/, 6. T$+ should bemonitored 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 (512), usually /6 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*reuiring diabetesmellitus 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 1/ months, and almost all women return to normal

thyroid function 'ostpartum thyroiditis tends to recur with subseuent

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 1 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

hipertiroid hamil speroff

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