Treatment of Primary Hypothyroidism in Adults - UpToDate

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5/2/22 17:31 Treatment of primary hypothyroidism in adults - UpToDate

Author: Douglas S Ross, MD


Section Editor: David S Cooper, MD
Deputy Editor: Jean E Mulder, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2022. | This topic last updated: May 20, 2021.

INTRODUCTION

In most patients, hypothyroidism is a permanent condition requiring lifelong treatment. Therapy


consists of thyroid hormone replacement, unless the hypothyroidism is transient (as after painless
thyroiditis or subacute thyroiditis) or reversible (due to a drug that can be discontinued). (See
"Disorders that cause hypothyroidism".)

The goal of therapy is restoration of the euthyroid state, which can be readily accomplished in
almost all patients by oral administration of synthetic thyroxine (T4, levothyroxine). Appropriate
treatment reverses all the clinical manifestations of hypothyroidism.

This topic will review the major issues that must be addressed in the treatment of adults with overt
primary hypothyroidism. The treatment of subclinical and central hypothyroidism, as well as
hypothyroidism in children (congenital or acquired), is discussed separately.

● (See "Subclinical hypothyroidism in nonpregnant adults".)


● (See "Central hypothyroidism".)
● (See "Treatment and prognosis of congenital hypothyroidism".)
● (See "Acquired hypothyroidism in childhood and adolescence".)

APPROACH TO TREATMENT

Our approach described below is largely consistent with the American Thyroid Association (ATA)
Guidelines for the Treatment of Hypothyroidism [1].

Defining hypothyroidism

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● Overt primary hypothyroidism is characterized biochemically by a high serum thyroid-


stimulating hormone (TSH) concentration and a low serum free thyroxine (T4) concentration.
The clinical manifestations are highly variable, depending upon the age at onset and the
duration and severity of thyroid hormone deficiency. (See "Clinical manifestations of
hypothyroidism" and "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)

● Subclinical hypothyroidism is characterized biochemically by a high serum TSH concentration


and a normal serum free T4 concentration. Most patients are asymptomatic. The diagnosis
and management of subclinical hypothyroidism are reviewed separately. (See "Subclinical
hypothyroidism in nonpregnant adults".)

● Central hypothyroidism caused by hypothalamic or pituitary disease is characterized by a low


serum T4 concentration and a serum TSH concentration that is not appropriately elevated.
TSH may be low, normal, or even slightly elevated (up to approximately 10 mU/L). The clinical
manifestations of central hypothyroidism are similar to but sometimes milder than those of
primary hypothyroidism. The diagnosis and management of central hypothyroidism are
reviewed separately. (See "Central hypothyroidism".)

All patients with overt primary (or central) hypothyroidism require treatment (regardless of
symptoms), unless the hypothyroidism is transient (as after painless thyroiditis or subacute
thyroiditis) or reversible (due to a drug that can be discontinued). (See "Disorders that cause
hypothyroidism", section on 'Transient hypothyroidism'.)

Thyroid hormone should not be prescribed to biochemically euthyroid individuals with nonspecific
symptoms (eg, fatigue, weight gain, depression). Thyroid hormone has been administered to
euthyroid patients with several clinical problems in whom it was hoped that outcome would be
improved. These include T3 therapy in patients undergoing coronary artery bypass graft surgery [2]
and in those with refractory depression in an attempt to enhance the response to antidepressant
drug therapy. A meta-analysis on the efficacy of thyroid hormone therapy in depressed patients was
equivocal [3]. Although there was evidence for overall benefit, the analysis limited to randomized,
double-blind trials revealed no benefit of synthetic T3. In addition, T3 did not help in an open-label
study of patients with severe depression [4]. Finally, T4 therapy in euthyroid patients with
"hypothyroid symptoms" was no more effective than placebo in ameliorating symptoms [5].

Goals of therapy — The goals of therapy are:

● Amelioration of symptoms
● Normalization of serum TSH secretion
● Reduction in the size of goiter (if present)
● Avoidance of overtreatment (iatrogenic thyrotoxicosis)
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We aim to keep serum TSH within the normal reference range (approximately 0.5 to 5.0 mU/L).
However, it is important to note that there is an age-related shift towards higher TSH concentrations
in older patients, with an upper limit of normal of approximately 7.5 mU/L in 80 year olds. Among
patients with goiter, approximately 50 percent will have some decrease in goiter size, which lags
behind the fall in TSH secretion [6,7].

There is considerable controversy as to the appropriate upper limit of normal for serum TSH [8].
Most laboratories have used values of approximately 4.5 to 5.0 mU/L. However, others have argued
that the upper limit of normal of the euthyroid reference range should be reduced to 2.5 mU/L
because 95 percent of rigorously screened, young, euthyroid volunteers have serum values
between 0.4 and 2.5 mU/L [9]. In contrast, others have reported that age-adjusted upper limits of
normal for TSH should be higher than 4.5 to 5 mU/L, especially for patients over age 70 [10]. Until
there are data demonstrating an adverse biologic impact for serum TSH values between 2.5 and 5.0
mU/L, the wisdom of labeling such patients as hypothyroid is questionable [11]. This topic is
reviewed in detail separately. (See "Laboratory assessment of thyroid function", section on 'Serum
TSH'.)

The approach to patients with persistent symptoms of hypothyroidism despite a normal serum TSH
level is reviewed below. (See 'Persistent symptoms' below.)

STANDARD REPLACEMENT THERAPY

The treatment of choice for correction of hypothyroidism is synthetic thyroxine (T4, levothyroxine).
T4 is a prohormone with very little intrinsic activity. It is deiodinated in peripheral tissues to form T3,
the active thyroid hormone. This deiodination process accounts for approximately 80 percent of the
total daily production of T3 in normal subjects. Approximately 70 to 80 percent of a dose of T4 is
absorbed and, because the plasma half-life of T4 is long (seven days), once-daily treatment results
in nearly constant serum T4 and triiodothyronine (T3) concentrations when a steady state is
reached [12].

T4 formulations — T4 is available in tablet, soft gel, and liquid formulations. Either a generic or a
brand-name formulation of T4 is acceptable. The brand-name and most generic formulations are
available in color-coded tablets at small increments in hormone content to allow precise titration of
the dose according to the serum concentration of TSH.

● Tablet versus soft gel capsule or liquid – Most patients are treated with a T4 tablet. While
in one study, the pharmacokinetics of the soft gel capsule were similar to tablets in healthy
individuals [13], in other studies, the soft gel capsule was less dependent upon gastric pH than

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a branded tablet [14,15]. Thus, the soft gel capsule or liquid is an option for patients with
suspected poor absorption of the standard solid tablet, especially in the presence of atrophic
gastritis. It may also be better absorbed after bariatric surgery [16]. However, another, less
costly option is to increase the dose of a generic T4 tablet with monitoring of TSH.

● Generic versus brand name – Either a generic or a brand-name formulation of T4 is


acceptable [17].

If a switch from one manufacturer to another is made by the pharmacy and the patient is
concerned regarding equivalent efficacy of the preparations, we measure a serum TSH six
weeks after changing preparations to document that the serum TSH is still within the
therapeutic target. In a study from the Netherlands during an unexpected shortage of one
branded levothyroxine product, a higher percentage of patients who switched brands had
abnormal TSH levels, especially if their dose exceeded 100 mcg/day [18].

There has been considerable controversy about the bioequivalence of the various T4
formulations. In the past, variation in the T4 content of brand-name and generic formulations
led many experts to prefer a specific preparation [19]. In 1997, a study of two brand-name and
two generic formulations of T4, using US Food and Drug Administration (FDA)-recommended
methodology for determining bioequivalence, reported that all four preparations were
equivalent [20]. The methodology used to determine bioequivalence in the study is considered
by some to be flawed since endogenous T4 concentrations were not taken into account [21].

Although the use of brand-name T4 products might be preferred theoretically to avoid the
issue of variable bioavailabilities when there is interchange of different generic preparations by
the pharmacy, often this is not possible, because of cost considerations. In addition, it has yet
to be shown that switching among various generic manufacturers is a clinical problem. In the
United States, the manufacturer of the generic preparation is included on the label.

Dose and monitoring

Initial dose — The average full replacement dose of T4 in adults is approximately 1.6 mcg/kg
body weight per day (112 mcg/day in a 70-kg adult), but the range of required doses is wide, varying
from 50 to ≥200 mcg/day. T4 requirements correlate better with lean body mass than total body
weight [22]. In one study, the average full replacement dose after thyroidectomy was 1.76 mcg/kg
body weight for body mass index (BMI) <25 kg/m2, 1.47 mcg/kg for BMI 25 to 29 kg/m2, 1.42
mcg/kg for BMI 30 to 34 kg/m2, 1.27 mcg/kg for BMI 35 to 39 kg/m2, and 1.28 mcg/kg for BMI over
40 kg/m2 [23].

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The initial dose can be the full anticipated dose (approximately 1.6 mcg/kg/day) in young, healthy
patients ( algorithm 1). Older patients or those with coronary heart disease, in whom the duration
of hypothyroidism is unknown, should be started on a lower dose (25 to 50 mcg daily). If the
duration of hypothyroidism is known to be short, eg, less than approximately two months, starting
doses in older patients or in those with coronary heart disease can be two-thirds to three-quarters of
the anticipated dose needed to achieve a euthyroid state. (See 'Older patients or those with
coronary heart disease' below.)

In one prospective study of different starting doses of T4, 50 hypothyroid patients (mean age 47
years but some patients were in their 70s and 80s) were randomly assigned to receive a full starting
dose of T4 (1.6 mcg/kg/day) or T4 25 mcg/day with dose adjustments every four weeks.
Euthyroidism was achieved more rapidly in the full-dose group, but signs and symptoms of
hypothyroidism and quality of life improved at a similar rate in the two groups. No adverse cardiac
effects were seen in either group, but the subjects in the study, including the older patients, had
been carefully screened to rule out cardiovascular disease prior to enrollment [24].

Timing of dose

● T4 (tablets, gel capsules, or liquid) should be taken on an empty stomach with water, ideally
30 to 60 minutes before breakfast.

● T4 (tablets, gel capsules, or liquid) should not be taken with other meds that interfere with its
absorption (eg, bile acid resins, calcium carbonate, ferrous sulfate). (See "Drug interactions
with thyroid hormones", section on 'Drugs that affect gastrointestinal absorption of thyroid
hormone'.)

● Some patients take their T4 at bedtime (at least two hours after their last meal, ideally longer).

Few patients are able to wait a full hour before eating breakfast. The proximity to food ingestion,
rather than time of day, is the more critical parameter. A meta-analysis demonstrated no difference
in effectiveness of morning versus bedtime dosing based on TSH measurements [25]. In some
studies, serum TSH concentrations were lower and less variable with standard fasting
administration of T4 than with nonfasting administration (eg, mean serum TSH 1.06±1.23,
2.93±3.29, and 2.19±2.66 mU/L if taken one hour before breakfast, with breakfast, or at bedtime two
hours after the last meal, respectively) [26,27]. In another small study, there was no difference in
serum TSH levels after ingestion of liquid T4 at breakfast compared with the same dose 30 minutes
prior to breakfast [28]. In two small studies, espresso coffee, in comparison with water, appeared to
interfere with T4 absorption of levothyroxine tablets [29] but not soft gel capsules [30].

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Initial monitoring and dose adjustments — Patients who are treated with T4 usually begin to
improve symptomatically within two weeks, but complete recovery can take several months in those
with severe hypothyroidism. Although symptoms may begin to resolve after two to three weeks,
steady-state TSH concentrations are not achieved for at least six weeks. Serum thyroid hormone
concentrations increase first and then TSH secretion begins to fall because of the negative
feedback action of T4 on the pituitary and hypothalamus.

After initiation of T4 therapy:

● The patient with symptomatic improvement should be re-evaluated and serum TSH measured
in four to six weeks ( algorithm 1). If the TSH remains above the reference range, the dose
of T4 can be increased by 12 to 25 mcg/day in older patients, or it can be increased by a
higher dose in younger patients based on the degree to which the initial dose increased free
T4 concentrations and reduced TSH concentrations. The patient will require a repeat TSH
measurement in six weeks. (See 'Adjustment of maintenance dose' below.)

● The patient with persistent symptoms after two to three weeks should be reevaluated and a
serum free T4 and TSH measured in three weeks. If the serum free T4 is below normal, the
dose can be increased at three weeks without additional testing, but it should be recognized
that serum T4 (and TSH) concentrations at this time are not steady-state values, and serum
TSH levels may still be falling despite normal (or even high) serum T4 concentrations. Given
the one-week plasma half-life of T4, it takes approximately six weeks (six half-lives) before a
steady state is attained after therapy is initiated or the dose is changed.

This process of increasing the dose of T4 every three to six weeks (depending upon the patient's
symptoms) should continue, based upon periodic measurements of serum TSH (and free T4 if
steady-state conditions have not yet been achieved), until the high values of TSH in patients with
primary hypothyroidism return to the reference range. (See 'Goals of therapy' above.)

The maintenance dose may vary according to the cause of hypothyroidism. In a study of patients
receiving chronic T4 therapy who were clinically euthyroid and had serum free T4 index values
within the upper half of the normal range and normal serum TSH concentration, 73 patients with
hypothyroidism caused by chronic autoimmune thyroiditis or radioiodine therapy were receiving less
T4 (118 mcg/day, 1.6 mcg/kg/day) than 36 patients with thyroid cancer after near-total
thyroidectomy (152 mcg/day, 2.1 mcg/kg/day) [31]. In 36 patients with central hypothyroidism and
similar serum free T4 index values, the T4 dose was higher (155 mcg/day, 1.9 mcg/kg/day). These
results suggest that both normal amounts of TSH and the presence of residual thyroid tissue are
determinants of T4 dose in patients with hypothyroidism. In general, doses >2 mcg/kg/day suggest

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T4 malabsorption or poor adherence to the medication regimen. (See 'Persistent elevation in TSH'
below.)

Adjustment of maintenance dose — After identification of the proper maintenance dose, the


patient should be examined and serum TSH measured once yearly or more often if there is an
abnormal result or a change in the patient's status ( algorithm 1). Further dose adjustment is
usually not required, but there are situations in which a different dose may be needed. When drugs
that affect the absorption of T4 are begun for coexisting medical conditions ( table 1), serum TSH
should be measured four to six weeks later to confirm that the T4 dose is still adequate. The dose
should be increased if the serum TSH value is high. Medications that interfere with T4 absorption
should be taken several hours after the T4 dose. (See "Drug interactions with thyroid hormones",
section on 'Drugs that affect gastrointestinal absorption of thyroid hormone'.)

In addition, increases in dose may be required in the following settings ( table 2):

● Pregnancy, and if increased, the dose should be reduced to the prepregnancy maintenance
dose postpartum. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis,
and treatment", section on 'Preexisting treated hypothyroidism'.)

● Weight gain of more than 10 percent of body weight.

● Diminished thyroid hormone absorption (patients with impaired acid secretion or other
gastrointestinal disorders [eg, uncontrolled celiac disease]). (See "Diagnosis of celiac disease
in adults".)

● Increased thyroid hormone excretion (nephrotic syndrome). (See "Endocrine dysfunction in


the nephrotic syndrome".)

● Increased rate of thyroid hormone metabolism (therapy with rifampin, carbamazepine,


phenytoin, or phenobarbital). (See "Drug interactions with thyroid hormones", section on
'Drugs that affect thyroid hormone metabolism'.)

If the TSH is slightly elevated (eg, 5 to 10 mU/L), a small increase of 12 to 25 mcg/day is usually
sufficient. If the TSH is ≥10 mU/L, a larger dose increase (eg, 25 to 50 mcg/day) is usually
necessary. Because of the seven-day half-life of levothyroxine, another method of changing the
dose without the need for a new prescription is to recommend increasing the dose by 15 percent by
adding one tablet a week. For example, if a patient is taking 100 mcg/d (1 tablet a day), if they were
to take 8 tablets a week (eg, 1 tablet a day for 6 days and 2 tablets on 1 day), this is equivalent to
114 mcg a day ([(100 x 8)/7 = 114]).

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Free T4 measurements can help determine an appropriate dose increase when TSH is very high
(eg, ≥20 mU/L) since the magnitude of TSH elevation in hypothyroid patients is quite variable. For
example, if steady-state conditions exist and the TSH exceeds 20, and the free T4 measurement is
only half the mean value of the normal reference range (for example, a free T4 of 0.7 ng/dL in an
assay with a normal range of 0.9 to 1.9 ng/dL), the dose could initially be doubled to target a mid-
normal free T4 (a free T4 of 1.4 ng/dL in the example given). If the free T4 measurement is in the
lower third of the normal range (for example, a free T4 1.2 ng/dL in the example above), a 20
percent increase in dose would target a mid-normal free T4. Further dose adjustments may be
needed. The normal range for free T4 is assay dependent, and the target free T4 level may be
higher than the average level, for example, in patients with thyroid cancer.

Decreases in dose may be required in the following settings [32,33]:

● Normal aging
● Weight loss of roughly more than 10 percent of body weight
● Initiation of androgen therapy

If the TSH is slightly below normal (eg, 0.05 to 0.3 mU/L), a small dose reduction of 12 to 25
mcg/day is usually sufficient. An alternative is to reduce the dose by 15 percent by omitting one pill
a week. Lower TSH values may require larger dose reductions. For TSH values below 0.05 mU/L
(below 0.1 mU/L in a second-generation assay), measurement of free T4 can help determine the
estimated dose reduction. For example, using the free T4 assay described above, if the free T4 is
2.8 ng/dL, which is twice the average free T4, the necessary dose reduction may be as high as 50
percent if the target is a mid-normal free T4. However, in young patients with longstanding
overtreatment, a stepwise reduction in dose over three to four months might be better tolerated.
When TSH is suppressed to <0.05 mU/L, it will occasionally take longer than eight weeks for
steady-state levels to be re-established.

The serum TSH should be remeasured six to eight weeks after any change in dose. (See 'Goals of
therapy' above.)

Adverse effects — Adverse effects of T4 replacement are rare as long as the correct dose is
given. (See 'Over-replacement' below.)

Rare patients have an allergy to the dye or excipients (filler) in the tablets. For dye sensitivities,
multiples of the white 50 mcg tablets can be given. For allergies to excipients (except gelatin), the
soft gel capsule (which contains T4 as a liquid) can be given. The liquid formulation contains
glycerol and water.

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Long-term outcomes — Successful treatment reverses all the symptoms and signs of


hypothyroidism, although some neuromuscular and psychiatric symptoms may not disappear for
several months. Long-term treatment of hypothyroidism is not associated with impaired cognitive
function or depressed mood in some studies [34], but other studies have documented a persistent
defect in psychological well-being that was not corrected with adequate amounts of T4 [35]. Limited
evidence also suggests no increase in all-cause mortality among patients with treated
hypothyroidism [36,37].

In contrast, infants with congenital hypothyroidism in whom treatment is inadequate or delayed for
several months may have permanent brain damage, even if they are adequately treated several
months later. (See "Treatment and prognosis of congenital hypothyroidism".)

Persistent symptoms — Because many symptoms of hypothyroidism are nonspecific, patients


often think that their T4 dose is inadequate when they feel tired or gain weight. The possibility of an
inadequate current T4 dose should be verified by measuring serum TSH before the dose is
increased. In addition, clinicians should evaluate for alternative causes of the symptoms.

The dose of T4 need not be altered in patients who are clinically euthyroid if their serum TSH
concentration is normal or only slightly above (or below) the reference range. TSH values may be
slightly high (or low) because of laboratory error or normal circadian fluctuations in TSH secretion,
so a slightly high (or low) value should be confirmed with repeat measurement before the dose is
changed. On the other hand, if a patient has possible hypothyroid symptoms and the serum TSH is
confirmed by repeat measurement to be at the upper limits or above the reference range, it is
reasonable to increase the dose and to aim for a serum TSH value in the lower half of the reference
range. However, it is important to note that there is an age-related shift towards higher TSH
concentrations in older patients, with an upper limit of normal of approximately 7.5 mU/L in 80 year
olds. (See "Laboratory assessment of thyroid function", section on 'Serum TSH'.)

Additionally, it is likely that improved symptoms with higher doses are due to the expectation of
feeling better on a higher dose of levothyroxine, rather than a true physiologic benefit. In one study
of 697 patients on thyroid hormone replacement, psychological well-being assessed by the General
Health Questionnaire (GHQ)-12 correlated positively with serum free T4 and negatively with serum
TSH for TSH values between 0.3 to 4.0 mU/L [38]. More specifically, psychological well-being was
better in patients with lower serum TSH concentrations. However, in a blinded, placebo-controlled,
crossover trial, patients could not distinguish between their usual T4 dose and doses that were 25 to
50 mcg/day higher, ie, they could not distinguish between TSH values that averaged 2.8 mU/L from
those that averaged 0.3 mU/L [39], and in a second double-blinded trial, patients had no preference
after varying doses of levothyroxine that resulted in average TSH levels between 1.85 and 9.49
mU/L [40].
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Persistent symptoms of hypothyroidism despite a normal serum TSH level may be due to
inadequacy of T4 to physiologically restore tissue thyroid hormone levels to normal or to factors
unrelated to hypothyroidism, such as inflammation in other tissues from autoimmune disease [41].

● The question of whether a subset of hypothyroid patients with persistent symptoms may
benefit from substitution of some T3 (liothyronine) for T4 is reviewed below. (See 'Combination
T4 and T3 therapy' below.)

● The question of whether thyroid peroxidase (TPO) antibodies themselves, or associated


immunologic modulators, cause inflammation in other tissues was evaluated in a trial from
Norway, in which 150 patients with Hashimoto's thyroiditis and persistent symptoms (eg,
fatigue, joint and muscle tenderness, dry mouth and eyes) despite normal TSH and free T4
were randomly assigned to total thyroidectomy or medical management (with optimally titrated
thyroid hormone replacement in both groups) [42]. After 18 months, there was a greater
decrease in TPO antibody levels and a greater improvement in the primary outcome (SF-36
general health score) in the patients who received surgery (+26 versus -3 points in the
medical management group). The absence of a sham surgical group limits the validity of this
study, however it is unlikely that the study can be repeated with an appropriate control group,
and this provocative finding is likely to remain controversial. Thyroidectomy has surgical
complications (in this trial, infection [4.1 percent], hypocalcemia [4.1 percent], and recurrent
laryngeal nerve palsy [5.5 percent]) and is currently not a recommended treatment for
autoimmune-mediated thyroiditis.

Persistent elevation in TSH — Occasionally a patient will insist they are taking T4, but TSH will
be quite high. Often these patients are taking larger doses of T4 than expected. This finding may be
due to poor compliance or to poor absorption of T4.

Patients with autoimmune gastritis have higher T4 requirements (especially tablet preparations). In
one study, the T4 dose was 17 percent higher in patients with parietal cell antibodies [43]. A similar
effect can be seen in patients with occult celiac disease [44]. In this setting, free T4 levels are
typically low or low-normal. In contrast, poorly compliant patients may have free T4 concentrations
that are low, normal, or high, depending on how much T4 they have taken and when they have
taken it (some poorly compliant patients take extra T4 in the days leading up to the appointment
with their clinician and may have a high-normal or even an elevated free T4 with a TSH that hasn't
had time to fall into the normal or subnormal range).

In patients with persistently elevated TSH despite what appears to be an adequate dose of T4, it
should be confirmed that T4 is taken daily on an empty stomach with water, ideally an hour before

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breakfast, and that medications that interfere with T4 absorption ( table 1) are taken several
hours after the T4 dose.

If the TSH remains elevated, and noncompliance is not acknowledged, adequate T4 absorption can
be assessed by a T4 absorption test. Patients are administered their weight-based weekly oral dose
of T4 (eg, 1.6 mcg/kg body weight times 7), and free T4 is measured at baseline and at two hours.
In one study, the average normal increase in free T4 at 120 minutes was 54 percent [45]. Values
well below this suggest malabsorption, whereas values similar to this suggest poor compliance.
Only 1 of 16 tests done at one institution over a four-year period documented malabsorption [46].
(See 'Poorly compliant patients' below.)

In patients with celiac disease, a gluten-free diet improves T4 absorption [44]. Other options for
patients with poor T4 absorption include increasing the dose of T4 tablets or switching to a soft gel
or liquid preparation. In one study, patients who appeared to be resistant to levothyroxine
administration did not absorb T4 tablets well but absorbed T4 tablets after they were pulverized [47].
(See 'T4 formulations' above.)

Over-replacement — Over-replacement with T4 should be discouraged. Over-replacement


causes subclinical hyperthyroidism (normal serum T4 and T3 and low serum TSH concentrations)
or even overt hyperthyroidism. Atrial fibrillation is the main risk of subclinical hyperthyroidism, and it
occurs three times more often in older patients with serum TSH concentrations <0.1 mU/L than in
normal subjects ( figure 1) [48]. Patients with iatrogenic subclinical hyperthyroidism, particularly
postmenopausal women, may also have accelerated bone loss. It is therefore important to educate
patients about the potential adverse effects of overtreatment with T4. (See "Bone disease with
hyperthyroidism and thyroid hormone therapy".)

The risks associated with over-replacement of thyroid hormone are greatest in those with the most
suppressed TSH concentrations. This was illustrated by the findings from a cohort study of 17,684
patients taking T4 replacement therapy. Patients with TSH concentrations between 0.04 and 0.4
mU/L were not at risk for arrhythmias or fractures compared with those with a TSH in the normal
reference range. However, patients with more severe iatrogenic thyrotoxicosis (TSH <0.03 mU/L)
had a significantly increased risk of arrhythmia (hazard ratio [HR] 1.6) and fractures (HR 2.0) [49].
(See 'Adjustment of maintenance dose' above.)

COMBINATION T4 AND T3 THERAPY

Is there a role for T3? — For the vast majority of patients with hypothyroidism, we suggest not
using combination T4-T3 therapy. However, a therapeutic trial using doses of T4 and T3 that

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attempt to mimic normal physiology (ratio T4-to-T3 of 13:1 to 16:1) while maintaining a normal TSH
is an option in selected patients. (See 'Candidates for combined T4 and T3 therapy' below.)

There is controversy as to whether T4 replacement alone can mimic normal physiology. T4 is


deiodinated in peripheral tissues to form T3, the active thyroid hormone. The prohormone nature of
T4 is an advantage over other thyroid hormone preparations because the patient's own physiologic
mechanisms control the production of active hormone. In some [12,50], but not all [51,52], studies,
mean serum T3 concentrations were within the normal range in hypothyroid patients receiving
adequate T4 therapy. In a prospective study of recently athyreotic patients receiving T4 therapy to
normalize serum TSH concentrations, serum T3 concentrations on treatment were, in most, but not
all cases, comparable with the patients' preoperative T3 values [50]. However, in another study, 15
percent of athyreotic patients taking T4 monotherapy had serum T3 levels below the reference
range for individuals with intact thyroid glands [52].

Some hypothyroid patients remain symptomatic in spite of T4 replacement and normal serum TSH
concentrations [53]. In a large, community-based questionnaire study of patients taking T4 who had
normal serum TSH concentrations, 9 to 13 percent more patients had impaired psychological well-
being as compared with normal subjects [35]. This observation raises the question of whether
hypothyroid patients might benefit from substitution of some T3 for T4, an idea that has now been
evaluated in multiple randomized trials, almost all of which showed that combination T4-T3 therapy
does not appear to be superior to T4 monotherapy for the management of hypothyroid symptoms
[54-65]. (See 'Efficacy' below.)

Well-designed, blinded studies are still needed to address this ongoing controversy [66]. The normal
ratio of T4-to-T3 secretion by the thyroid gland is approximately 13:1 to 16:1 (mcg T4 to mcg T3)
[41]. The majority of the randomized, controlled trials used excessive and nonphysiologic amounts
of T3 when assessing combination therapy. In addition, a slow-release T3 preparation, which may
avoid supraphysiologic peaks in serum T3 concentrations, is not yet commercially available [67]. A
combination T4-slow release T3 preparation may better replicate physiologic T4-T3 production.

Efficacy — In a systematic review of nine randomized trials, only one trial reported beneficial
effects of combination T4-T3 therapy on mood, quality of life, and psychometric performance when
compared with T4 therapy alone [68]. A subsequent meta-analysis of 11 published randomized trials
including 1216 patients showed that there was no benefit (fatigue, bodily pain, anxiety, depression,
quality of life) of combined therapy [69].

In some trials, patients preferred combined therapy to T4 monotherapy [70]. In some [63], but not all
[61,71], of these trials, patients were given overzealous doses of T3, resulting in mild
hyperthyroidism. As examples:

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● In one trial comparing T4 alone with T4 and T3 in a molar ratio of 10:1 or 5:1, there were
similar improvements in mood, fatigue, psychological symptoms, or neurocognitive testing
[63]. However, patients preferred combined therapy to T4 alone. Forty-four percent of the
patients who preferred combined therapy had TSH values less than 0.11 mU/L. In addition,
those patients taking T4:T3 in a molar ratio of 5:1 had a 1.8 kg weight loss, which correlated
with a preference for the combined treatment, and 54 percent of these patients had subnormal
serum TSH concentrations.

● In one small, well-designed study, women taking 100 mcg of T4 were changed to 75 mcg T4
and 5 mcg T3 (ratio 15:1) [61]; while no benefit was found using standardized questionnaires,
patients preferred combination therapy over monotherapy despite a higher TSH within the
normal range in the group receiving combination therapy.

● In a double-blind, crossover trial comparing T4 and desiccated thyroid extract (T4-to-T3 ratio
4:1), there were no differences in symptoms and neurocognitive measurements between the
two groups, but 49 percent of the patients preferred thyroid extract over T4 (19 percent
preferred T4 and 33 percent had no preference), and those who preferred thyroid extract had
lost on average 1.8 kg during the study [71]. In this trial, thyroid medications were adjusted to
maintain a TSH level between 0.5 and 3.0 mU/L (mean achieved TSH levels were 1.30 and
1.67 mU/L for T4 and desiccated thyroid extract, respectively).

Whether a combination of T4 and T3 is beneficial in a subset of hypothyroid patients has also been
studied. One analysis suggested patients with a polymorphism in the type 2 deiodinase, which
converts T4 to T3, might benefit from combination therapy [72]. Sixteen percent of the population
studied had the CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2); these
patients had worse baseline quality-of-life scores and showed greater improvement after T4-T3
therapy compared with T4 alone. However, a smaller study was unable to show a difference in
response to combined T4-T3 therapy based on DIO2 genotype [73]. In addition, a large population-
based study showed lower health-related quality-of-life scores in levothyroxine-treated hypothyroid
patients compared with controls, but this did not differ among individuals who did or did not have the
rs225014 polymorphism [74].

Some thyroidectomized patients who have no residual endogenous T3 production might derive
benefit from the addition of T3. In one study, serum T3 levels were more uniformly restored to
preoperative levels when T4 doses were high enough to suppress the serum TSH (≤0.3 mU/L) [51].
However, in another study, traditional T4 therapy that resulted in a TSH level of ≤4.6 mU/L resulted
in normal T3 levels in most but not all patients [50].

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Candidates for combined T4 and T3 therapy — The majority of patients do well on T4


monotherapy, and we do not suggest the routine use of combined T4 and T3 therapy for the
treatment of hypothyroidism. This is in agreement with the 2014 American Thyroid Association
(ATA) guidelines, which found insufficient evidence to support the routine use of a combination of T4
and T3 therapy in patients unhappy with T4 monotherapy [1].

However, a therapeutic trial using doses of T4 and T3 that attempt to mimic normal physiology (ratio
T4-to-T3 of 13:1 to 16:1) while maintaining a normal TSH is reasonable in selected patients.
Candidates for combined therapy include patients who have not felt well on T4 monotherapy:

● Since thyroidectomy
● Since ablative therapy with radioiodine
Or
● Who have serum T3 at or below the lower end of the T3 reference range

Patients who have previously felt well on T4 monotherapy but now feel poorly and patients with mild
hypothyroidism on low doses of T4 who have persistent endogenous thyroid function are not likely
to improve with combined therapy. In addition, we discourage the use of combined therapy in older
patients, patients with underlying cardiovascular disease in whom excessive T3 levels might
precipitate an arrhythmia, and in pregnant women.

An important caveat for women of childbearing age using combined T4 and T3 treatment is that
fetal neurogenesis is primarily dependent upon maternal free T4 concentrations until week 16 to 18
of gestation [75]. Regimens containing excessive T3 cause hypothyroxinemia, which has been
associated with impaired neurologic development. For example, patients taking desiccated thyroid
extract in the trial noted above [71] had a mean free T4 of 0.85 ng/dL (normal 0.89 to 1.76 ng/dL).

Temporary treatment with T3 monotherapy is appropriate in patients with thyroid cancer who are to
undergo radioiodine imaging and possible treatment. To shorten the period of hypothyroidism, the
patient's T4 therapy is discontinued, and T3 is substituted for three to four weeks until the T4 is
cleared. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Thyroid hormone
withdrawal'.)

Dosing and available preparations — There are several commercial thyroid hormone


preparations containing T3 alone or in combination with T4 ( table 3).

● We do not use combined T4 and T3 therapy when the ratio of T4 to T3 is not physiologic (ie,
when T3 doses are excessive). The normal ratio of T4-to-T3 of 13:1 to 16:1.

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● We do not use desiccated thyroid extract, which has a T4-to-T3 ratio of 4:1. (See 'Converting
from desiccated thyroid extract to T4' below.)

Although for most patients with hypothyroidism we do not suggest treatment with T3, if combined
therapy is given, the doses of T4 and T3 should mimic normal physiology as closely as possible. T3
alone is available as 5 and 25 mcg tablets, so available doses utilizing half tablets are 2.5, 5, 7.5,
10, and 12.5 mcg. When possible, the dose of T3 should be divided into morning and afternoon
doses. One can calculate an optimal dose by considering that T3 is three to four times more potent
metabolically than T4 and aiming for a T4-to-T3 ratio of approximately 13:1 to 16:1 [41]. The table is
offered as a guide for the conversion of T4 monotherapy to combined T4 and T3 therapy ( table 4
). This approach is consistent with the European Thyroid Association (ETA) guidelines on the use of
combination therapy, published with the intent of enhancing its safety [41].

Monitoring combined therapy — In patients taking combined therapy, we typically monitor TSH
six weeks after initiating therapy. TSH levels in steady-state conditions will reflect adequacy of
therapy. Serum free T4 can be useful, especially in non-steady-state conditions, in patients
receiving combined T4 and T3 therapy at a physiologic ratio of 13:1 to 16:1 but may be misleading
(due to low values) in patients receiving combined therapy where the ratio is low. For example, over
half of patients receiving desiccated thyroid extract (T4:T3 ratio 4:1) will have subnormal T4
concentrations despite normal serum TSH [71].

We do not monitor T3 levels. Patients treated with currently available T3-containing preparations
have wide fluctuations in serum T3 concentrations throughout the day due to its rapid
gastrointestinal absorption and its relatively short half-life in the circulation (approximately one day).
In fact, T3 serum levels may be elevated three to four hours after the last dose (eg, at noon if the
dose is taken at 8 AM) and low if T3 is measured before the next dose. Thus, T3 measurements
primarily reflect the interval since the dose was administered and should not be used for monitoring.

Converting from desiccated thyroid extract to T4 — For patients who are taking desiccated
thyroid, we prefer to switch them to T4.

By US Food and Drug Administration (FDA) mandate, 1 grain of desiccated thyroid extract (60 mg)
should contain approximately 38 mcg T4 and 9 mcg T3. Using a conversion of 9 mcg T3 is
equivalent to approximately 36 mcg T4, 1 grain would be equivalent to approximately 74 mcg T4.
However, in a randomized trial comparing T4 with desiccated thyroid extract, 1 grain (60 mg) of
extract was equivalent to 88 mcg of T4 [71]. Both of these conversions result in lower amounts of T4
than traditionally recommended; the United States Pharmacopeia Drug Information suggests 1 grain
(60 mg) is equivalent to 100 mcg [71]. Thus, many clinicians use a simple conversion factor of 1
grain = 100 mcg T4. For a patient who is taking 1.5 grains (90 mg) of desiccated thyroid, an

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equivalent T4 dose ranges from 112 to 150 mcg. Some clinicians prefer to begin with the higher
dose (150 mcg) and slowly taper the dose if the TSH measured six weeks after switching remains
below the reference range.

Converting from combined T4 and T3 therapy to T4 monotherapy — For patients converting


from T4-T3 combination preparations back to T4 monotherapy, the equivalent dose of T4 can be
calculated by considering that T3 is three to four times more potent metabolically than T4. As an
example, for a patient who is taking a preparation of 12.5 mcg T3 combined with 50 mcg T4, the
equivalent dose of T4 is approximately 100 mcg (50 mcg T4 plus four times the dose of T3).

SPECIAL TREATMENT SITUATIONS

There are several situations in which therapy should be more conservative or the dose may need
modification:

Older patients or those with coronary heart disease — Older patients (>60 years), patients with
coexisting cardiopulmonary problems, or patients with a history of coronary heart disease, should
initially be treated with 25 to 50 mcg T4 (levothyroxine)/day ( algorithm 1). Patients with coronary
artery disease without other cardiopulmonary problems who have had recent successful
interventions to treat ischemia (eg, coronary artery bypass grafting [CABG] or coronary artery
stenting) can initially receive up to 80 percent of their weight-based dose (1.6 mcg/kg/day).

The dose can be increased by 12 to 25 mcg/day every three to six weeks until replacement is
complete, as determined by a normal serum TSH concentration or an increase in dose results in
cardiac symptoms, in which case something less than full replacement may have to be accepted. It
is important to note that there is an age-related shift towards higher TSH concentrations in older
patients, with an upper limit of normal of approximately 7.5 mU/L in 80 year olds. (See 'Goals of
therapy' above.)

Thyroid hormone increases myocardial oxygen demand, which is associated with a small risk of
inducing cardiac arrhythmias, angina pectoris, or myocardial infarction in older patients. A 1961
report remains the largest and best study of the effects of beginning thyroid hormone on chest pain
in patients with hypothyroidism [76,77]. Among 1503 hypothyroid patients, the following findings
were noted:

● Fifty-five had angina before thyroid hormone replacement therapy. During therapy, 21
improved, 25 had no change, and 9 had more angina.

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● Thirty-five patients developed new angina during therapy, 6 during the first month, 6 during the
first year, and 23 after one year.

Thus, angina may improve with T4 treatment, and it does not often first appear during T4
replacement therapy.

Many older patients receiving thyroid hormone replacement are over- or undertreated, as illustrated
by a community survey that identified 339 individuals over age 65 years taking thyroid hormone
[78]. Forty-one percent of patients had a subnormal TSH, 16 percent had a high TSH, and only 43
percent were euthyroid [78]. Patients with low body weight were more likely to have a subnormal
TSH, while those with diabetes were at risk for having low and high serum TSH. (See 'Goals of
therapy' above.)

The clinical manifestations and consequences of hypothyroidism (subclinical and overt) in older
adults are discussed in detail elsewhere. (See "Clinical manifestations of hypothyroidism" and
"Subclinical hypothyroidism in nonpregnant adults", section on 'Consequences of subclinical
hypothyroidism'.)

Pregnancy — Women need more thyroid hormone during pregnancy and, unlike normal women,
those with hypothyroidism are unable to increase thyroidal T4 and T3 secretion. Approximately 75
to 85 percent of women with preexisting hypothyroidism need a higher dose of T4 during pregnancy
to maintain normal TSH secretion. The increase in T4 requirements occurs as early as the fifth
week of gestation and plateaus by week 16 to 20. The treatment of hypothyroidism during
pregnancy is reviewed separately. (See "Hypothyroidism during pregnancy: Clinical manifestations,
diagnosis, and treatment", section on 'Preexisting treated hypothyroidism'.)

Euthyroid women with TPO antibodies who become pregnant are also discussed separately. (See
"Overview of thyroid disease and pregnancy", section on 'Thyroid peroxidase antibodies in
euthyroid women'.)

Estrogen therapy — In women receiving T4 therapy, estrogens increase serum thyroxine-binding


globulin (TBG) concentrations, as they do in normal women, and may increase the need for T4. In a
study of postmenopausal women (25 women with hypothyroidism and 11 normal women) treated
with 0.625 mg conjugated estrogens daily for 48 weeks, serum T4 and TBG concentrations
increased in both the hypothyroid and normal women. Serum free T4 and TSH concentrations did
not change in the normal women but decreased and increased, respectively, in the hypothyroid
women [79]. Among the latter, seven women had serum TSH concentrations >7 mU/L and were
given more T4. These data suggest that serum TSH should be measured approximately 6 to 12
weeks after starting estrogen therapy in postmenopausal women receiving T4 therapy to determine
if an increase in T4 dose is needed. Whether younger hypothyroid women receiving oral
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contraceptives require dose adjustments is uncertain. Such patients may require dose adjustments,
especially when oral contraceptives are initiated because of hypoestrogenic states.

Surgical patients — Patients receiving chronic T4 therapy who undergo surgery and are unable to
eat for several days need not be given T4 parenterally. If oral intake cannot be resumed in five to
seven days, then T4 should be given intravenously. The dose should be approximately 70 to 80
percent of the patient's usual oral dose because that is approximately the fraction of oral T4 that is
absorbed [12,80]. We typically give 80 percent.

Several studies have investigated the safety of general anesthesia and surgery in patients with
untreated or inadequately treated hypothyroidism. This topic is reviewed in detail elsewhere. (See
"Nonthyroid surgery in the patient with thyroid disease", section on 'Hypothyroidism'.)

Poorly compliant patients — Some patients do not take their T4 regularly and do not respond to
efforts to improve compliance. These patients may be given their total weekly dose of T4 once per
week. The efficacy of this approach was evaluated in a crossover trial of 12 patients [81]. The mean
serum TSH concentration one week after a single weekly dose was slightly higher than when the
usual dose was given daily (6.6 versus 3.9 mU/L), but the raised value returned to normal one day
after the next weekly dose. There was no difference in symptoms between daily or weekly dosing.
Weekly dosing should probably not be used in patients with coronary heart disease.

Thyroid cancer — Patients who have had a thyroidectomy for thyroid cancer, with or without
additional treatment with radioiodine (I-131), need to take T4 not only for treatment of
hypothyroidism but also to prevent recurrence of their thyroid cancer, especially those with higher
risk disease. (See "Differentiated thyroid cancer: Overview of management", section on 'Thyroid
hormone suppression'.)

Myxedema coma — Myxedema coma is defined as severe hypothyroidism leading to decreased


mental status, hypothermia, and other symptoms. It is a medical emergency with a high mortality
rate. Fortunately, it is now a rare presentation of hypothyroidism, probably because of earlier
diagnosis. The clinical presentation, diagnosis, and treatment of myxedema coma are reviewed
separately. (See "Myxedema coma".)

Selenium deficiency — Selenium is required for deiodinase activity (the enzyme is a


selenoprotein), and it has important effects on immune function. The effects of selenium deficiency
on normal thyroid function are not well described. However, selenium deficiency has been shown to
exacerbate both autoimmune thyroid disease and endemic cretinism [82]. Selenium
supplementation in some studies reduces antithyroid peroxidase antibody levels, improves the
ultrasound structure of the thyroid gland, and reduces the occurrence of postpartum thyroiditis in
pregnant women with TPO antibodies, but a meta-analysis failed to show any improvement in
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thyroid function when selenium is given to hypothyroid individuals [83]. (See "Postpartum
thyroiditis", section on 'Prevention'.)

When the diagnosis of hypothyroidism is uncertain — Some patients have been prescribed


thyroid hormone for questionable indications (eg, obesity or hypercholesterolemia) or the diagnosis
of hypothyroidism is uncertain. In such a patient, a high serum TSH concentration suggests that the
patient is hypothyroid, and the T4 dose should be increased accordingly. If, however, the serum
TSH values are normal or low, the dose of thyroid hormone can be reduced by one-half and serum
TSH measured again in four to six weeks. If the value is normal, the dose can be reduced further or
stopped. Most patients with hypothyroidism have symptoms and a high serum TSH concentration
within one month after discontinuing therapy. In a meta-analysis of 1082 patients from 16 studies,
37 percent of putatively hypothyroid patients had their levothyroxine successfully discontinued [84].

Many of these patients are reluctant to discontinue their thyroid hormone, especially if they have
taken it for many years. In the meta-analysis noted above, two-thirds of patients restarted
levothyroxine [84]. In this case, the goal should be to provide an appropriate dose of T4 (adjusted to
maintain a normal serum TSH concentration) to avoid the potential adverse cardiac and skeletal
effects of overtreatment.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Hypothyroidism".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics."
The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
These articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)

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● Basics topics (see "Patient education: Hypothyroidism (underactive thyroid) (The Basics)")

● Beyond the Basics topics (see "Patient education: Hypothyroidism (underactive thyroid)
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Overt primary hypothyroidism is characterized biochemically by a high serum thyroid-


stimulating hormone (TSH) concentration and a low serum free thyroxine (T4) concentration.
All patients with overt primary hypothyroidism require treatment (regardless of symptoms),
unless the hypothyroidism is transient (as after painless thyroiditis or subacute thyroiditis) or
reversible (due to a drug that can be discontinued). (See 'Defining hypothyroidism' above and
"Disorders that cause hypothyroidism", section on 'Transient hypothyroidism'.)

● The goals of therapy are amelioration of symptoms, normalization of TSH secretion, reduction
in size of goiter (if present), and avoidance of overtreatment (iatrogenic thyrotoxicosis). We
aim to keep serum TSH within the normal reference range (approximately 0.5 to 5.0 mU/L). It
is important to note that there is an age-related shift towards higher TSH concentrations in
older patients, with an upper limit of normal of approximately 7.5 mU/L in 80 year olds. (See
'Goals of therapy' above.)

● The treatment of choice for correction of hypothyroidism is synthetic thyroxine (T4,


levothyroxine). For the vast majority of patients with hypothyroidism, we suggest not using
combination T4-triiodothyronine (T3) therapy (Grade 2B). However, T4-T3 therapy may
improve symptoms in selected patients (eg, after thyroidectomy or ablative therapy with
radioiodine). We discourage the use of combined therapy in older patients, patients with
underlying cardiovascular disease in whom excessive T3 levels might precipitate an
arrhythmia, and in pregnant women. (See 'Standard replacement therapy' above and
'Candidates for combined T4 and T3 therapy' above.)

When T4-T3 therapy is used, the T4-to-T3 ratio should be approximately 13:1 to 16:1 (
table 4). (See 'Dosing and available preparations' above.)

● We suggest that patients remain on the same formulation of T4 (Grade 2C). Either a generic
or a brand-name formulation is acceptable. If a switch from one manufacturer to another is
made by the pharmacy and the patient is concerned regarding equivalent efficacy of the
preparations, we measure a serum TSH six weeks after changing preparations to document
that the serum TSH is still within the therapeutic target. (See 'T4 formulations' above.)

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● The initial dose can be the full anticipated dose (1.6 mcg/kg/day) in young, healthy patients,
but older patients and those with coronary heart disease should be started on a lower dose
(25 to 50 mcg daily) ( algorithm 1). T4 should be taken on an empty stomach, ideally 30 to
60 minutes before breakfast. (See 'Initial dose' above and 'Timing of dose' above.)

● After initiation of T4 therapy, the patient should be reevaluated and serum TSH should be
measured in six weeks and the dose adjusted accordingly. Symptoms may begin to resolve
after two to three weeks, but steady-state TSH concentrations are not achieved for at least six
weeks. (See 'Initial monitoring and dose adjustments' above.)

● If a patient has possible hypothyroid symptoms and the serum TSH is confirmed by repeat
measurement to be at the upper limits or above the reference range, it is reasonable to
increase the dose and to aim for a serum TSH value in the lower half of the normal range;
however, improved symptoms with higher doses may be based on expectation of benefit
rather than a true physiologic advantage. (See 'Persistent symptoms' above.)

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REFERENCES
1. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism:
prepared by the american thyroid association task force on thyroid hormone replacement.
Thyroid 2014; 24:1670.

2. Mullis-Jansson SL, Argenziano M, Corwin S, et al. A randomized double-blind study of the


effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery. J
Thorac Cardiovasc Surg 1999; 117:1128.

3. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment
of refractory depression. A meta-analysis. Arch Gen Psychiatry 1996; 53:842.

4. Birkenhäger TK, Vegt M, Nolen WA. An open study of triiodothyronine augmentation of


tricyclic antidepressants in inpatients with refractory depression. Pharmacopsychiatry 1997;
30:23.

5. Pollock MA, Sturrock A, Marshall K, et al. Thyroxine treatment in patients with symptoms of
hypothyroidism but thyroid function tests within the reference range: randomised double blind
placebo controlled crossover trial. BMJ 2001; 323:891.

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5/2/22 17:31 Treatment of primary hypothyroidism in adults - UpToDate

6. Hegedüs L, Hansen JM, Feldt-Rasmussen U, et al. Influence of thyroxine treatment on thyroid


size and anti-thyroid peroxidase antibodies in Hashimoto's thyroiditis. Clin Endocrinol (Oxf)
1991; 35:235.

7. Hayashi Y, Tamai H, Fukata S, et al. A long term clinical, immunological, and histological
follow-up study of patients with goitrous chronic lymphocytic thyroiditis. J Clin Endocrinol
Metab 1985; 61:1172.

8. Waise A, Price HC. The upper limit of the reference range for thyroid-stimulating hormone
should not be confused with a cut-off to define subclinical hypothyroidism. Ann Clin Biochem
2009; 46:93.

9. Baloch Z, Carayon P, Conte-Devolx B, et al. Laboratory medicine practice guidelines.


Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 2003; 13:3.

10. Vadiveloo T, Donnan PT, Murphy MJ, Leese GP. Age- and gender-specific TSH reference
intervals in people with no obvious thyroid disease in Tayside, Scotland: the Thyroid
Epidemiology, Audit, and Research Study (TEARS). J Clin Endocrinol Metab 2013; 98:1147.

11. Surks MI, Goswami G, Daniels GH. The thyrotropin reference range should remain
unchanged. J Clin Endocrinol Metab 2005; 90:5489.

12. Fish LH, Schwartz HL, Cavanaugh J, et al. Replacement dose, metabolism, and bioavailability
of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary
feedback in humans. N Engl J Med 1987; 316:764.

13. Yue CS, Scarsi C, Ducharme MP. Pharmacokinetics and potential advantages of a new oral
solution of levothyroxine vs. other available dosage forms. Arzneimittelforschung 2012;
62:631.

14. Vita R, Benvenga S. Tablet levothyroxine (L-T4) malabsorption induced by proton pump
inhibitor; a problem that was solved by switching to L-T4 in soft gel capsule. Endocr Pract
2014; 20:e38.

15. Vita R, Saraceno G, Trimarchi F, Benvenga S. Switching levothyroxine from the tablet to the
oral solution formulation corrects the impaired absorption of levothyroxine induced by proton-
pump inhibitors. J Clin Endocrinol Metab 2014; 99:4481.

16. Fallahi P, Ferrari SM, Camastra S, et al. TSH Normalization in Bariatric Surgery Patients After
the Switch from L-Thyroxine in Tablet to an Oral Liquid Formulation. Obes Surg 2017; 27:78.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/treatment-of-primary-hypothyroidism-in-adults?search=hipotiroidismo&source=search… 22/29
5/2/22 17:31 Treatment of primary hypothyroidism in adults - UpToDate

17. Brito JP, Ross JS, Sangaralingham L, et al. Comparative Effectiveness of Generic vs Brand-
Name Levothyroxine in Achieving Normal Thyrotropin Levels. JAMA Netw Open 2020;
3:e2017645.

18. Flinterman LE, Kuiper JG, Korevaar JC, et al. Impact of a Forced Dose-Equivalent
Levothyroxine Brand Switch on Plasma Thyrotropin: A Cohort Study. Thyroid 2020; 30:821.

19. Oppenheimer JH, Braverman LE, Toft A, et al. A therapeutic controversy. Thyroid hormone
treatment: when and what? J Clin Endocrinol Metab 1995; 80:2873.

20. Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name
levothyroxine products in the treatment of hypothyroidism. JAMA 1997; 277:1205.

21. Blakesley V, Awni W, Locke C, et al. Are bioequivalence studies of levothyroxine sodium
formulations in euthyroid volunteers reliable? Thyroid 2004; 14:191.

22. Santini F, Pinchera A, Marsili A, et al. Lean body mass is a major determinant of levothyroxine
dosage in the treatment of thyroid diseases. J Clin Endocrinol Metab 2005; 90:124.

23. Papoian V, Ylli D, Felger EA, et al. Evaluation of Thyroid Hormone Replacement Dosing in
Overweight and Obese Patients After a Thyroidectomy. Thyroid 2019; 29:1558.

24. Roos A, Linn-Rasker SP, van Domburg RT, et al. The starting dose of levothyroxine in primary
hypothyroidism treatment: a prospective, randomized, double-blind trial. Arch Intern Med
2005; 165:1714.

25. Pang X, Pu T, Xu L, Sun R. Effect of l-thyroxine administration before breakfast vs at bedtime


on hypothyroidism: A meta-analysis. Clin Endocrinol (Oxf) 2020; 92:475.

26. Bach-Huynh TG, Nayak B, Loh J, et al. Timing of levothyroxine administration affects serum
thyrotropin concentration. J Clin Endocrinol Metab 2009; 94:3905.

27. Perez CL, Araki FS, Graf H, de Carvalho GA. Serum thyrotropin levels following levothyroxine
administration at breakfast. Thyroid 2013; 23:779.

28. Cappelli C, Pirola I, Daffini L, et al. A Double-Blind Placebo-Controlled Trial of Liquid


Thyroxine Ingested at Breakfast: Results of the TICO Study. Thyroid 2016; 26:197.

29. Benvenga S, Bartolone L, Pappalardo MA, et al. Altered intestinal absorption of L-thyroxine
caused by coffee. Thyroid 2008; 18:293.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/treatment-of-primary-hypothyroidism-in-adults?search=hipotiroidismo&source=search… 23/29
5/2/22 17:31 Treatment of primary hypothyroidism in adults - UpToDate

30. Vita R, Saraceno G, Trimarchi F, Benvenga S. A novel formulation of L-thyroxine (L-T4)


reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet
formulations. Endocrine 2013; 43:154.

31. Gordon MB, Gordon MS. Variations in adequate levothyroxine replacement therapy in patients
with different causes of hypothyroidism. Endocr Pract 1999; 5:233.

32. Sawin CT, Herman T, Molitch ME, et al. Aging and the thyroid. Decreased requirement for
thyroid hormone in older hypothyroid patients. Am J Med 1983; 75:206.

33. Arafah BM. Decreased levothyroxine requirement in women with hypothyroidism during
androgen therapy for breast cancer. Ann Intern Med 1994; 121:247.

34. Kramer CK, von Mühlen D, Kritz-Silverstein D, Barrett-Connor E. Treated hypothyroidism,


cognitive function, and depressed mood in old age: the Rancho Bernardo Study. Eur J
Endocrinol 2009; 161:917.

35. Saravanan P, Chau WF, Roberts N, et al. Psychological well-being in patients on 'adequate'
doses of l-thyroxine: results of a large, controlled community-based questionnaire study. Clin
Endocrinol (Oxf) 2002; 57:577.

36. Flynn RW, Macdonald TM, Jung RT, et al. Mortality and vascular outcomes in patients treated
for thyroid dysfunction. J Clin Endocrinol Metab 2006; 91:2159.

37. Bauer DC, Rodondi N, Stone KL, et al. Thyroid hormone use, hyperthyroidism and mortality in
older women. Am J Med 2007; 120:343.

38. Saravanan P, Visser TJ, Dayan CM. Psychological well-being correlates with free thyroxine
but not free 3,5,3'-triiodothyronine levels in patients on thyroid hormone replacement. J Clin
Endocrinol Metab 2006; 91:3389.

39. Walsh JP, Ward LC, Burke V, et al. Small changes in thyroxine dosage do not produce
measurable changes in hypothyroid symptoms, well-being, or quality of life: results of a
double-blind, randomized clinical trial. J Clin Endocrinol Metab 2006; 91:2624.

40. Samuels MH, Kolobova I, Niederhausen M, et al. Effects of Altering Levothyroxine (L-T4)
Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects. J Clin Endocrinol
Metab 2018; 103:1997.

41. Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA Guidelines: The Use of L-T4 + L-T3 in
the Treatment of Hypothyroidism. Eur Thyroid J 2012; 1:55.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/treatment-of-primary-hypothyroidism-in-adults?search=hipotiroidismo&source=search… 24/29
5/2/22 17:31 Treatment of primary hypothyroidism in adults - UpToDate

42. Guldvog I, Reitsma LC, Johnsen L, et al. Thyroidectomy Versus Medical Management for
Euthyroid Patients With Hashimoto Disease and Persisting Symptoms: A Randomized Trial.
Ann Intern Med 2019; 170:453.

43. Checchi S, Montanaro A, Pasqui L, et al. L-thyroxine requirement in patients with autoimmune
hypothyroidism and parietal cell antibodies. J Clin Endocrinol Metab 2008; 93:465.

44. Virili C, Bassotti G, Santaguida MG, et al. Atypical celiac disease as cause of increased need
for thyroxine: a systematic study. J Clin Endocrinol Metab 2012; 97:E419.

45. Walker JN, Shillo P, Ibbotson V, et al. A thyroxine absorption test followed by weekly thyroxine
administration: a method to assess non-adherence to treatment. Eur J Endocrinol 2013;
168:913.

46. Gonzales KM, Stan MN, Morris JC 3rd, et al. The Levothyroxine Absorption Test: A Four-Year
Experience (2015-2018) at The Mayo Clinic. Thyroid 2019; 29:1734.

47. Yamamoto T. Tablet formulation of levothyroxine is absorbed less well than powdered
levothyroxine. Thyroid 2003; 13:1177.

48. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for
atrial fibrillation in older persons. N Engl J Med 1994; 331:1249.

49. Flynn RW, Bonellie SR, Jung RT, et al. Serum thyroid-stimulating hormone concentration and
morbidity from cardiovascular disease and fractures in patients on long-term thyroxine
therapy. J Clin Endocrinol Metab 2010; 95:186.

50. Jonklaas J, Davidson B, Bhagat S, Soldin SJ. Triiodothyronine levels in athyreotic individuals
during levothyroxine therapy. JAMA 2008; 299:769.

51. Ito M, Miyauchi A, Morita S, et al. TSH-suppressive doses of levothyroxine are required to
achieve preoperative native serum triiodothyronine levels in patients who have undergone
total thyroidectomy. Eur J Endocrinol 2012; 167:373.

52. Gullo D, Latina A, Frasca F, et al. Levothyroxine monotherapy cannot guarantee euthyroidism
in all athyreotic patients. PLoS One 2011; 6:e22552.

53. Wekking EM, Appelhof BC, Fliers E, et al. Cognitive functioning and well-being in euthyroid
patients on thyroxine replacement therapy for primary hypothyroidism. Eur J Endocrinol 2005;
153:747.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/treatment-of-primary-hypothyroidism-in-adults?search=hipotiroidismo&source=search… 25/29
5/2/22 17:31 Treatment of primary hypothyroidism in adults - UpToDate

54. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as


compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med
1999; 340:424.

55. Walsh JP, Shiels L, Lim EM, et al. Combined thyroxine/liothyronine treatment does not
improve well-being, quality of life, or cognitive function compared to thyroxine alone: a
randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab
2003; 88:4543.

56. Sawka AM, Gerstein HC, Marriott MJ, et al. Does a combination regimen of thyroxine (T4) and
3,5,3'-triiodothyronine improve depressive symptoms better than T4 alone in patients with
hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol
Metab 2003; 88:4551.

57. Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine
compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial.
JAMA 2003; 290:2952.

58. Siegmund W, Spieker K, Weike AI, et al. Replacement therapy with levothyroxine plus
triiodothyronine (bioavailable molar ratio 14 : 1) is not superior to thyroxine alone to improve
well-being and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf) 2004; 60:750.

59. Bunevicius R, Prange AJ. Mental improvement after replacement therapy with thyroxine plus
triiodothyronine: relationship to cause of hypothyroidism. Int J Neuropsychopharmacol 2000;
3:167.

60. Cooper DS. Combined T4 and T3 therapy--back to the drawing board. JAMA 2003; 290:3002.

61. Escobar-Morreale HF, Botella-Carretero JI, Gómez-Bueno M, et al. Thyroid hormone


replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus
liothyronine with L-thyroxine alone. Ann Intern Med 2005; 142:412.

62. Saravanan P, Simmons DJ, Greenwood R, et al. Partial substitution of thyroxine (T4) with tri-
iodothyronine in patients on T4 replacement therapy: results of a large community-based
randomized controlled trial. J Clin Endocrinol Metab 2005; 90:805.

63. Appelhof BC, Fliers E, Wekking EM, et al. Combined therapy with levothyroxine and
liothyronine in two ratios, compared with levothyroxine monotherapy in primary
hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab
2005; 90:2666.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/treatment-of-primary-hypothyroidism-in-adults?search=hipotiroidismo&source=search… 26/29
5/2/22 17:31 Treatment of primary hypothyroidism in adults - UpToDate

64. Rodriguez T, Lavis VR, Meininger JC, et al. Substitution of liothyronine at a 1:5 ratio for a
portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory
versus treatment with levothyroxine alone. Endocr Pract 2005; 11:223.

65. Nygaard B, Jensen EW, Kvetny J, et al. Effect of combination therapy with thyroxine (T4) and
3,5,3'-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind,
randomised cross-over study. Eur J Endocrinol 2009; 161:895.

66. Jonklaas J, Bianco AC, Cappola AR, et al. Evidence-Based Use of Levothyroxine/Liothyronine
Combinations in Treating Hypothyroidism: A Consensus Document. Thyroid 2021; 31:156.

67. Hennemann G, Docter R, Visser TJ, et al. Thyroxine plus low-dose, slow-release
triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid 2004; 14:271.

68. Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, Morreale de Escobar G.
REVIEW: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J
Clin Endocrinol Metab 2005; 90:4946.

69. Grozinsky-Glasberg S, Fraser A, Nahshoni E, et al. Thyroxine-triiodothyronine combination


therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of
randomized controlled trials. J Clin Endocrinol Metab 2006; 91:2592.

70. Akirov A, Fazelzad R, Ezzat S, et al. A Systematic Review and Meta-Analysis of Patient
Preferences for Combination Thyroid Hormone Treatment for Hypothyroidism. Front
Endocrinol (Lausanne) 2019; 10:477.

71. Hoang TD, Olsen CH, Mai VQ, et al. Desiccated thyroid extract compared with levothyroxine
in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin
Endocrinol Metab 2013; 98:1982.

72. Panicker V, Saravanan P, Vaidya B, et al. Common variation in the DIO2 gene predicts
baseline psychological well-being and response to combination thyroxine plus triiodothyronine
therapy in hypothyroid patients. J Clin Endocrinol Metab 2009; 94:1623.

73. Appelhof BC, Peeters RP, Wiersinga WM, et al. Polymorphisms in type 2 deiodinase are not
associated with well-being, neurocognitive functioning, and preference for combined
thyroxine/3,5,3'-triiodothyronine therapy. J Clin Endocrinol Metab 2005; 90:6296.

74. Wouters HJ, van Loon HC, van der Klauw MM, et al. No Effect of the Thr92Ala Polymorphism
of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and
Cognitive Functioning in a Large Population-Based Cohort Study. Thyroid 2017; 27:147.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/treatment-of-primary-hypothyroidism-in-adults?search=hipotiroidismo&source=search… 27/29
5/2/22 17:31 Treatment of primary hypothyroidism in adults - UpToDate

75. Foeller ME, Silver RM. Combination Levothyroxine + Liothyronine Treatment in Pregnancy.
Obstet Gynecol Surv 2015; 70:584.

76. KEATING FR Jr, PARKIN TW, SELBY JB, DICKINSON LS. Treatment of heart disease
associated with myxedema. Prog Cardiovasc Dis 1961; 3:364.

77. CATZ B, RUSSELL S. Myxedema, shock and coma. Seven survival cases. Arch Intern Med
1961; 108:407.

78. Somwaru LL, Arnold AM, Joshi N, et al. High frequency of and factors associated with thyroid
hormone over-replacement and under-replacement in men and women aged 65 and over. J
Clin Endocrinol Metab 2009; 94:1342.

79. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen
therapy. N Engl J Med 2001; 344:1743.

80. Hays MT, Nielsen KR. Human thyroxine absorption: age effects and methodological analyses.
Thyroid 1994; 4:55.

81. Grebe SK, Cooke RR, Ford HC, et al. Treatment of hypothyroidism with once weekly
thyroxine. J Clin Endocrinol Metab 1997; 82:870.

82. Duntas LH. Selenium and the thyroid: a close-knit connection. J Clin Endocrinol Metab 2010;
95:5180.

83. Winther KH, Wichman JE, Bonnema SJ, Hegedüs L. Insufficient documentation for clinical
efficacy of selenium supplementation in chronic autoimmune thyroiditis, based on a systematic
review and meta-analysis. Endocrine 2017; 55:376.

84. Burgos N, Toloza FJK, Singh Ospina NM, et al. Clinical Outcomes After Discontinuation of
Thyroid Hormone Replacement: A Systematic Review and Meta-Analysis. Thyroid 2021;
31:740.

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