REVIEW

Levothyroxine Dose Adjustment to Optimise TherapyThroughout a Patient’s Lifetime

Leonidas H. Duntas . Jacqueline Jonklaas

Received: August 16, 2019 / Published online: September 4, 2019� The Author(s) 2019

ABSTRACT

Levothyroxine is the standard therapy forpatients with hypothyroidism, a condition thataffects up to 5% of people worldwide. Whilelevothyroxine therapy has substantiallyimproved the lives of millions of hypothyroidpatients since its introduction in 1949, thecomplexity of maintaining biochemical andclinical euthyroidism in patients undergoingtreatment with levothyroxine cannot beunderestimated. Initial dosing of levothyroxinecan vary greatly and may be based on theamount of residual thyroid function retained bythe patient, the body weight or lean body massof the patient, and thyroid-stimulating hor-mone levels. As levothyroxine is usuallyadministered over a patient’s lifetime, physio-logical changes throughout life will affect thedose of levothyroxine required to maintaineuthyroidism. Furthermore, dose adjustments

may need to be made in patients with con-comitant medical conditions, in patients takingcertain medications, as well as in elderlypatients. Patients who have undergone anyweight or hormonal changes may require doseadjustments, and the majority of pregnantwomen require increased doses of levothyrox-ine. Optimal treatment of hypothyroidismrequires a partnership between patient andphysician. The physician is tasked with vigilantappraisal of the patient’s status based on athorough clinical and laboratory assessmentand appropriate adjustment of their levothy-roxine therapy. The patient in turn is taskedwith medication adherence and reporting ofsymptomatology and any changes in theirmedical situation. The goal is consistent main-tenance of euthyroidism, without the patientexperiencing the adverse events and negativehealth consequences of under- or overtreat-ment.Funding Merck.Plain Language Summary Plain languagesummary available for this article.

Keywords: Dose adjustment; Endocrinology;Hypothyroidism; Levothyroxine; Lifespan;Medical conditions; Medications

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.9706403.

L. H. Duntas (&)Unit of Endocrinology, Diabetes, and Metabolism,Thyroid Section, Evgenidion Hospital, Athens,Greecee-mail: ledunt@otenet.gr

J. JonklaasDivision of Endocrinology, Georgetown University,Washington, DC, USA

Adv Ther (2019) 36:S30–S46

https://doi.org/10.1007/s12325-019-01078-2

PLAIN LANGUAGE SUMMARY

Hypothyroidism, a reduction in thyroid hor-mone levels, is one of the most common dis-eases worldwide. The medication most used totreat hypothyroidism is levothyroxine, a com-pound that acts as a replacement for a person’sthyroid hormone. People with hypothyroidismwill often need to take levothyroxine for a longtime, typically for the rest of their life, so it isimportant that their treatment is monitoredclosely and the dose is adjusted for the besteffect as needed. As a person progresses throughlife, their dose may need to be adjusted becauseother diseases or medications can affect thedose needed for effective treatment. Pregnancyor weight gain can also affect the dose oflevothyroxine needed by the patient, sopatients and physicians need to work in part-nership to ensure that the treatment is workingas well as it can. The goal of this partnership isto maintain normal thyroid hormone levelswithout the patient experiencing any sideeffects or negative health consequences of tak-ing too much or too little levothyroxine.

INTRODUCTION

Thyroxine was isolated on Christmas Day 1914by Kendall. Its chemical structure was deter-mined in 1926 by Harington, and it was syn-thesised in 1927 by Harington and Barger [1, 2].The acidity of the thyroxine molecule, whichcaused diminished absorption resulting in lowbioavailability, was an unresolved problem formore than 20 years following its discovery [3].In 1949, a commercial product containingsynthesised sodium thyroxine was launched inthe USA and some years later in Europe, sig-nalling a new era in the treatment of hypothy-roidism, which had advanced from partiallypurified extracts of bovine thyroid gland anddesiccated thyroid extracts from sheep and pigsto fully synthesised thyroxine [4, 5]. The man-ufacture of sodium thyroxine (levothyroxine)thus resulted in a major pharmacologicalachievement in endocrinology, giving a morestable and effective thyroid hormone com-pound that, over the last few decades, has

considerably improved the lives of millions ofpatients with various forms of hypothyroidism.

The objective of this review is to provide anoverview of (1) when administration oflevothyroxine is necessary, (2) initial dosingand subsequent adjustment of levothyroxine,(3) the importance of avoiding under- and over-treatment with levothyroxine, (4) the need forlevothyroxine dose adjustment through variousphases of life, (5) medical conditions and med-ications necessitating levothyroxine doseadjustments, as well as (6) controversies abouttreatment with products other than levothy-roxine. Diligent monitoring of patients takinglevothyroxine and regular dose adjustment toachieve optimised treatment and avoidance ofadverse events are particularly emphasised.

METHODS

A search of the literature was conducted usingthe PubMed and CENTRAL (Cochrane) data-bases. Keywords relating to levothyroxine,hypothyroidism, treatment, levothyroxine doseadjustments, levothyroxine and concomitantconditions, levothyroxine and concomitantmedications, and combined treatment withlevothyroxine and liothyronine versuslevothyroxine were searched. Only reviews andarticles providing clinical data, particularly themost recent, were considered. Potential articlesof interest were identified by title and abstract,and citation lists of articles of interest were usedto identify additional literature. This article isbased on previously conducted studies and doesnot contain any studies with animals performedby any of the authors. Some of the studies citedinclude analyses, or studies with human par-ticipants, performed by the authors and com-pleted prior to the initiation of this manuscript.

WHEN LEVOTHYROXINEADMINISTRATION IS A NECESSITY

Thyroxine is secreted by the thyrocytes and isthe main thyroid hormone in the circulation.Thyroxine is actively transported to the variousorgans where it is converted to triiodothyronine

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by the activity of the deiodinases [6]. Tri-iodothyronine, the active form of thyroid hor-mone, is secreted in small amounts by thethyroid but is mainly generated via extrathy-roidal conversion of the prohormone thyrox-ine. Hypothyroidism is a common endocrinedisease that requires timely and lifelong treat-ment since, if left untreated, it can contribute tohypertension, dyslipidaemia, and heart failureand induce reversible dementia and infertility,as well as neurosensory, musculoskeletal, andgastrointestinal symptoms [7]. There is cur-rently no other treatment for hypothyroidism,other than providing thyroid hormonereplacement. Due to its long half-life of about7 days, in patients in the clinically euthyroidstate, levothyroxine is the preferred first-linetreatment for primary hypothyroidism and hasbeen the most commonly prescribed treatmentsince the 1980s [8].

INITIAL DOSING AND DOSEADJUSTMENT OF LEVOTHYROXINEDURING THERAPY

Initial Dosing

The levothyroxine dose initially required by apatient depends primarily on three factors: theamount of residual thyroid function retained bythe patient, the body weight or lean body massof the patient, and the target thyrotropin orthyroid-stimulating hormone (TSH) level to beachieved during therapy [8]. Additional factorssuch as patient age, patient sex, and menopau-sal status may have an influence that is gener-ally of lesser magnitude. Other physiologicalfactors such as pregnancy and gastrointestinalfunctioning may be important factors in speci-fic patients or at specific times [8].

When commencing levothyroxine therapy,initial dose requirements can vary greatly fromsmall doses such as 25–50 lg in an individualwith mild or subclinical disease, where thetherapy may be supplementing endogenousfunction, to larger doses of 88–175 lg in cases ofpatients with negligible endogenous thyroidfunction. In keeping with this concept, the

initial dose of levothyroxine in patients pre-senting to a clinic with primary hypothyroidismcan be predicted by the patient’s TSH valueprior to initiation of treatment [9]. In the case ofsurgically athyreotic patients, the dose oflevothyroxine required may be slightly higherthan in those with autoimmune thyroid disease[8], presumably reflecting some retained thyroidhormone production in those with autoim-mune thyroid disease. An example of the doserequirement in those with Hashimoto’s thy-roiditis without residual function and post-sur-gical hypothyroidism is approximately 1.6 lg/kg [8]. The dose of levothyroxine required by apatient following thyroidectomy can be pre-dicted by either body weight or body massindex (BMI) [10–12]. Body weight, BMI, idealbody weight, and lean body mass can all predictthe initial dose requirement, with the latterthree parameters providing the more accurateestimates [10, 13]. Various formulae have beenproposed to calculate dose requirement. Theserange from simple formulae based only on bodyweight or BMI to more complex formulae thatalso incorporate other factors such as patientsex [10, 14]. Generally, both a TSH-based esti-mate and a body weight-based estimate yieldsimilar initial estimates of dose requirement(Fig. 1). With respect to age, for patients whoare elderly, have concomitant cardiac disease, ormay have had long-standing untreatedhypothyroidism, it is wise to initiate levothy-roxine therapy with smaller doses such as25–50 lg levothyroxine and incrementallyincrease the dose to full replacement to avoidprecipitating cardiac ischaemia [8].

Dose Adjustment

Regardless of the method used to estimate theinitial levothyroxine dose requirement, doseadjustment is frequently required. This may bedue to multiple factors including limitations inthe dose requirement predictions, inter-patientvariation, levothyroxine absorption, or effectsof concomitant medical conditions or medica-tions [8]. Given the half-life of levothyroxine(approximately 1 week), reassessment of thy-roid status by serum TSH levels, and free

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thyroxine levels if desired, is indicated after6 weeks of therapy when the pharmacokineticsteady state is reached. If the TSH is not at thedesired goal, the levothyroxine dose can beadjusted up or down. TSH values that areslightly out of range may be corrected by asingle dose increment or decrement, such asincreasing from 100 to 112 lg or decreasingfrom 175 to 150 lg. TSH values that are con-siderably out of range may require larger per-centage changes. Levothyroxine absorption ismaximised, at about 75% of the administereddose, when it is ingested upon an empty stom-ach [8]. Therefore, if levothyroxine is taken atother times of the day for convenience, the doserequirement may be greater and potentiallymore variable [15]. Once the desired TSH valuehas been achieved, it could potentially be re-confirmed by laboratory testing in 3–6 months,and then checked on an annual basis thereafter.A stable TSH while receiving levothyroxinetherapy was inversely associated with the mag-nitude of the levothyroxine dose in one study,perhaps suggesting that residual thyroid func-tion provided some buffer against TSH varia-tions in those who required smallerlevothyroxine doses [16].

Simple regimens that involve the same dosetaken daily are ideal with respect to ease ofadherence, although sometimes regimens thatinvolve alternating doses or use of half tabletsare needed to achieve the desired TSH value. Astudy comparing TSH values achieved with useof whole levothyroxine tablets versus splittablets showed comparable TSH values [17], butnevertheless any unnecessary complications toa regimen that patients will be following for alifetime need to be minimised. There do seem tobe a variety of costs, such as utilisation of healthcare resources, and comorbidities, such asdepression and dyslipidaemia, associated withnon-adherence to levothyroxine therapy, asdemonstrated in a study funded by levothy-roxine manufacturers [18]. Non-adherence tolevothyroxine is generally associated with anelevated TSH. However, if missed doses are notreported by the patient, levothyroxine doseincreases can lead to a low TSH if therapy is lateradhered to. If problems with non-adherenceand an elevated TSH are not corrected by edu-cation or treatment of contributing conditionssuch as depression or psychiatric disorders,possible solutions to improve adherenceinclude observed weekly oral levothyroxine

Fig. 1 Example of body weight- and thyroid-stimulating hormone-based levothyroxine initial dose estimates. BMI bodymass index, FT4 free thyroxine, LT4 levothyroxine, TSH thyroid-stimulating hormone

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therapy (Fig. 2) [19, 20] or weekly or twiceweekly parenteral administration (such asintravenous [21], subcutaneous [22], or intra-muscular administration of levothyroxine [23]).

AVOIDANCE OF OVER-AND UNDER-DOSINGWITH LEVOTHYROXINE

Generally, hypothyroidism may be effectivelytreated via a constant daily dose of levothyrox-ine, and, for the majority of confirmed aetiolo-gies, this needs to be lifelong. However, in thissetting, there appear to be many cases of bothlevothyroxine over- and under-dosing and itmay be that frequent adjustments of a dose arenecessary. These adjustments need to be han-dled with caution and take into account themany contributing factors, as multiplelevothyroxine dose adjustments evidently resultin a greater burden on healthcare resources [24].This means that it is necessary for clinicians todetermine which patients are truly in need ofdose adjustment. Even more importantly,accumulating evidence suggests that many

patients, for whom the indication for levothy-roxine initiation is not adequately establishedand the diagnosis is not well documented, areremaining on levothyroxine therapy for longerthan necessary. A prospective clinical cohortfollow-up study illustrated this by showing that,among 291 patients (84% females) on levothy-roxine replacement therapy without a soliddiagnosis of hypothyroidism and in whom thetreatment was paused, 114 developedhypothyroidism, while 177 participantsremained euthyroid. The latter results clearlypoint to a significant overuse of levothyroxinetherapy [25].

Overtreatment should particularly be avoi-ded in the elderly. A study seeking to determinewhether levothyroxine pharmacokinetics areaffected by age and weight did not identify anyinfluence of age on the levothyroxine doserequirement, though it was determined thatweight may mediate age-related changes inlevothyroxine pharmacokinetics [26]. In addi-tion, transient changes (e.g., illness), inter- andintra-individual differences in thyroid parame-ters, or ethnic variations may modify the treat-ment target, thus rendering advisable a tailored

Fig. 2 Example of how to address non-adherence tolevothyroxine associated with elevated thyroid-stimulatinghormone levels. 25 (OH) vitamin D 25-hydroxy vitamin

D, FT4 free thyroxine, LT4 levothyroxine, TSH thyroid-stimulating hormone

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assessment of thyroid function. Use of thyroidextract, rather than levothyroxine, may beassociated with overtreatment. In a study of 174reports of adverse events occurring in patientstaking thyroid hormone extract, 91 of thesereports were accompanied by changes in TSHvalues and, of these, 62 patients (68%) haddeveloped new symptoms associated with TSHchanges, with most (65%) having symptomsconsistent with thyrotoxicosis [27].

In a recent case report the authors describetwo female patients with Takotsubo cardiomy-opathy associated with levothyroxine over-re-placement, clearly underlining the necessity toadjust the dose of levothyroxine, particularly inpatients with cardiovascular risks, so as to avoidthe deleterious effects of iatrogenic hyperthy-roidism [28]. Another point to be considered inoverzealously treated patients is the high risk ofaccelerated bone loss, predominantly in post-menopausal women, as well as the risk ofosteoporosis and vertebral fractures [29]. Con-cerning under-dosage, while overtreatment wasnot associated with impairment of health-re-lated quality of life (HRQoL), patients who areundertreated had worse HRQoL than over-treated patients, especially regarding physicaland emotional aspects, independently of thedegree of hypothyroidism [30]. Given thathypothyroidism undertreatment is associatedwith poor patient HRQoL, it is clear thatlevothyroxine therapy must be sufficient tomaintain serum TSH within the reference range.Age-dependent interpretation of TSH values(extending from neonates to the very old), withappropriate consideration of circadian fluctua-tions, body weight, gastrointestinal diseases andmalabsorption, comorbidity, and possibly pitu-itary insufficiency or thyroid hormone resis-tance, is thus crucial for optimal levothyroxinedosage.

Another factor that can be associated withunder- or overtreatment with levothyroxine isswitching between different preparations.Despite the availability of stable compounds oflevothyroxine, over the past few decades,problems have repeatedly emerged concerningpotency, which, according to specificationsissued by the US Food and Drug Administrationin 2007, should not exceed 10% difference from

the stated dose [31]. Furthermore, bioequiva-lence testing allows the 90% confidence intervalof the difference in the areas under the curveand difference of maximum concentrations ofserum T4 derived during pharmacokinetic test-ing to fall within 80–125% of that of a referenceproduct [8] or the more stringent criteria of90–111%. It is well known that dose differencesfalling within this range result in clinically rel-evant dissimilarities in safety and effectiveness.In addition, any method of analysing bioe-quivalence data that does not take into accountendogenous thyroxine concentrations willconfound accurate quantitation and interpre-tation of levothyroxine bioavailability [32].Hence, even products that meet the criteria forbioequivalence could well expose patients tothe development of iatrogenic hyperthyroidismor hypothyroidism. While levothyroxine has anarrow therapeutic index [33], defined as hav-ing a narrow window between effective dosesand those at which they produce adverseevents, as well as a potential variance in thetherapeutic efficacy among various levothyrox-ine preparations, there is at present no viablealternative to this treatment.

In summary, it is necessary in all cases toperiodically verify the need for dose adjustmentand/or continuation of treatment. If there is asuspicion for levothyroxine treatment havingbeen prescribed unnecessarily, this can beinvestigated via a test period incorporating 6- to8-week therapy discontinuation, followed byTSH testing.

FACTORS POTENTIALLYCONTRIBUTING TO THE NEEDFOR LEVOTHYROXINE DOSEADJUSTMENTS THROUGHOUTA PATIENT’S LIFE SPAN

There are many factors encountered by patientsacross their life span that may be associatedwith an altered levothyroxine requirement.Newborns, children, and adolescents typicallyrequire higher levothyroxine doses than adults[8]. Examples of factors affecting the levothy-roxine dose requirements of adults include

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pregnancy, weight changes, hormonal changes,and ageing.

Pregnancy

The dramatic increase in levothyroxine doserequirements associated with pregnancy, andthe subsequent decrease in requirement post-partum are perhaps the best documented alter-ations in levothyroxine requirement [34]. Thereason for the increased requirement is the needfor an increased total body thyroxine poolassociated with increased thyroxine-bindingglobulin concentrations and increased plasmavolume. Increased levothyroxine doses arerequired in approximately 50–85% of pregnantwomen, and the need for an increase occursearly in the first trimester. Requirements tend tostabilise as the patient progresses into the sec-ond and third trimester, with few changesgenerally being required in the third trimester.The percentage increase in levothyroxine doseneeded can be as high as 30–50% and is highestwhen the cause of the hypothyroidism is athyroidectomy or ablation of the thyroid gland[35]. Achieving a serum TSH \ 1.2 mIU/l pre-conception seems to reduce the percentage ofpatients requiring a dose increase [36]. Studiesshow that serum TSH can be maintained at goalduring pregnancy by either increasing thelevothyroxine dose by 29% by increasing from 7to 9 tablets of levothyroxine weekly whenconception is confirmed [37] or ongoing titra-tion based on serum TSH [38]. The lattermethod had the advantage of resulting in fewerpatients having a suppressed TSH during preg-nancy [38]. Women undergoing in vitro fertili-sation have similar needs for increasedlevothyroxine dosages, with 83% of womenrequiring an increase and the average increasebeing 33% [39].

Weight Changes and Hormonal Changes

As mentioned above, levothyroxine doserequirements are affected by body weight, idealbody weight, and lean body mass, with doserequirements increasing as these parametersincrease [8, 13, 40]. However, if actual body

weight is used to calculate the levothyroxinerequirement in obese individuals, the dose maybe overestimated, with ideal body weight beinga better predictor [40]. Moreover, the studiesregarding levothyroxine requirement in obeseindividuals often yield differing results of eitherincreased or decreased requirements, possiblybecause of competing effects of the increasedbody weight and the impaired absorption andaltered levothyroxine kinetics that may be seenwith obesity [41]. Different results have alsobeen reported regarding the altered levothy-roxine requirement associated with the weightloss seen after bariatric surgery. Most studiesshow that such weight loss is associated with areduced levothyroxine requirement [42], possi-bly due to both the reduced weight andimproved absorption. However, bariatric pro-cedures involving jejunoileal bypass may beassociated with an increased levothyroxinerequirement because of reduced, as opposed toimproved, levothyroxine absorption [43]. Incases where levothyroxine absorption isimpaired after bariatric surgery, use of liquidlevothyroxine may improve absorption [44].

With respect to hormonal changes, pre-menopausal women may require higherlevothyroxine doses than postmenopausalwomen [40, 45, 46]. Conversely, oestrogentherapy is associated with a need for higherdoses of levothyroxine to maintain the sameserum TSH [47].

Ageing

Several studies have shown that the levothy-roxine dose requirement is decreased in olderindividuals [8, 48, 49]. However, a recent studysuggests that this decreased requirement may bemediated by the changes in weight that mayaccompany ageing [26]. Other important con-siderations regarding levothyroxine doses inolder individuals include bearing age-adjustedTSH reference ranges in mind [50] and avoidingover-replacement that might potentially exac-erbate other medical conditions [8]. Both ofthese considerations would lead to targeting ofhigher TSH values in older individuals (Fig. 3).

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LEVOTHYROXINE DOSEADJUSTMENTS ASSOCIATEDWITH CONCOMITANT MEDICALCONDITIONS AND MEDICATIONS

Levothyroxine is best absorbed when thestomach environment is acidic and is absorbedmainly in the jejunum and ileum [51]. It isprimarily metabolised by de-iodination, butalso is metabolised by conjugation, decarboxy-lation, and deamination. Based on this routeinto and out of the body, there are many med-ical conditions and medications that canimpact these steps and alter the levothyroxinedose requirement. Two studies illustrate thecombined impact of medical conditions andmedications [52, 53]. A study of a pharmaceu-tical company-sponsored database identifiedgastrointestinal conditions and medicationssuch as iron, calcium, and acid-lowering thera-pies as being associated with difficulty control-ling hypothyroid symptoms and frequentchanges in levothyroxine doses [52]. Gastroin-testinal conditions and interfering medicationswere also identified as being associated with thefinding of patients requiring higher than pre-dicted doses of levothyroxine in an audit of

patients being treated by physicians in thenational health system in Scotland [53].

Medical Conditions

Generally speaking, although other chronicmedical conditions such as cardiac disease,hepatic disease, osteoporosis, or diabetes do notdirectly impact levothyroxine dose require-ments, some individuals with these conditionsmay be elderly or frail and thus extra cautionmay need to be exercised to avoid under- orover-dosing. One specific medical condition inwhich levothyroxine doses that lower serumTSH may be intentionally employed is differ-entiated thyroid cancer [54]. If TSH suppressionis the goal in patients with intermediate- orhigh-risk thyroid cancer, higher doses up to2.2 lg/kg body weight may be needed [8].However, TSH suppression is not necessary inlow-risk patients or in patients who no longerhave a substantial risk of thyroid cancer recur-rence (Fig. 4). Patients with hypothyroidismwho are hospitalised with critical illness mayrequire higher doses of levothyroxine whilehospitalised [55], possibly because of such fac-tors as use of proton pump inhibitors ordecreased absorption associated with enteral

Fig. 3 Example of application of age-adjusted thyroid-stimulating hormone reference ranges to patient treatment. LT4levothyroxine, TSH thyroid-stimulating hormone

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feeding. Decreased absorption caused by enteralfeeding may be circumvented by temporarilyholding tube feeds prior to levothyroxineadministration or using liquid preparations oflevothyroxine [56]. There may also be failure toprescribe levothyroxine appropriately in thehospital setting [57].

A variety of gastrointestinal conditions maybe associated with decreased levothyroxineabsorption and higher serum TSH levels whenthe condition is untreated compared with whenthe condition is treated [51]. These conditionsinclude gastritis, coeliac disease, and lactoseintolerance. Helicobacter pylori-associated gastri-tis is associated with increased levothyroxinerequirement, with the increased requirementresolving with treatment of the gastritis [58, 59].Similarly, untreated coeliac disease is associatedwith a high levothyroxine requirement that isremediated by dietary treatment of the coeliacdisease [60, 61]. The same pattern has beendemonstrated with lactose intolerance [62].While each of these conditions remains in theuntreated state, it appears that levothyroxineabsorption is better when liquid levothyroxineis utilised for patient therapy [63–65]. Nephroticsyndrome is another medical condition associ-ated with a need for an increased dose of

levothyroxine, presumably due to urinary lossesof thyroid hormones, accompanying the uri-nary losses of thyroxine-binding globulin [66].

Medications, Supplements, and Food

Medications may alter a patient’s requirementfor levothyroxine through a variety of mecha-nisms (Table 1). These mechanisms includealtered levothyroxine absorption, altered thy-roid hormone synthesis or release (theoreticallyrelevant for those who still have some residualthyroid function), altered transport of levothy-roxine, altered metabolism of levothyroxine,and altered TSH secretion. A partial list of someof the implicated drugs is shown in Table 1, andmore complete discussion of these drugs can befound in several review articles [8, 51, 67–69]. Inmost cases, the net result is a need for anincreased levothyroxine dose. A classic exampleof a medication that causes an increasedrequirement for levothyroxine is oestrogentherapy [70, 71], which is associated withincreased levels of thyroxine-binding globulin.Tyrosine kinase inhibitors can have multipleeffects, including causing an increased need forlevothyroxine via increasing the metabolism oflevothyroxine (Fig. 5) [68, 72].

Fig. 4 Example of balancing risks and benefits in order to choose a target thyroid-stimulating hormone value for a patient.LT4 levothyroxine, TSH thyroid-stimulating hormone

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If levothyroxine is ingested along with food,its absorption can be impaired [15, 51]. Soy-containing foods are an example of a substancethat can decrease absorption (Fig. 6) [73]. Cal-cium supplements [74, 75] and iron [76, 77] alsoreduce absorption and thereby increase thelevothyroxine dose requirement or increaseserum TSH [52, 53]. Vitamin C stands alone asan example of a supplement that may actuallydecrease the requirement for levothyroxine byenhancing its absorption, at least in patientswith gastritis [78].

CONTROVERSIES ABOUTTREATMENT OTHER THANLEVOTHYROXINE

No consistently strong evidence has been foundfor the superiority of any alternative prepara-tion (e.g., levothyroxine/liothyronine combi-nation therapy, thyroid extract therapy, orothers) over monotherapy with levothyroxinein improving health outcomes [8]. Trials of suchtherapy show mixed results regarding patientpreference for combination therapy or otheralternative therapies [8]. On an anecdotal basis

Table 1 Drugs affecting levothyroxine requirement and the mechanism of altered requirement

Drug Altered LT4requirement

Altered LT4absorption

Altered THsynthesis or release

Alteredtransport

Alteredmetabolism

Altered TSHsecretion

Oestrogen : 9

Androgens ; 9

Glucocorticoids ; 9 9

Phenobarbital : 9

TKI :; 9

Rifampin : 9

Sertraline : 9

Amiodarone :; 9 9

Iodine :; 9

Lithium :; 9

Dopamine,

dobutamine

9

Bexarotene : 9

Calcium

carbonate

: 9

PPI : 9

Ferrous

sulphate

: 9

Cholestyramine : 9

Phosphate

binders

: 9

LT4 levothyroxine, PPI proton pump inhibitors, TH thyroid hormone, THS thyroid-stimulating hormone, TKI tyrosinekinase inhibitors

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some patients may perceive benefit from com-bination therapy, whereas others may not(Fig. 7). However, in some patients, levothy-roxine replacement is associated with signifi-cant impairment in psychological well-being[79], including compared with euthyroid con-trols [80], and as such there is interest in studies

comparing combined levothyroxine/liothy-ronine with levothyroxine monotherapy. Oneexample of a study addressing this controversyis a randomised, double-blind study that wascarried out comparing treatment with levothy-roxine/liothyronine at a ratio of 5:1 or 10:1 withlevothyroxine monotherapy in 141 patients

Fig. 5 Example of how to adjust levothyroxine dose in patients receiving concomitant medications. LT4 levothyroxine, rT3reverse triiodothyronine, T3 triiodothyronine, TSH thyroid-stimulating hormone

Fig. 6 Example of how to adjust levothyroxine dose in patients consuming foods that may impair absorption. LT4levothyroxine, TSH thyroid-stimulating hormone

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(18–70 years old) with primary autoimmunehypothyroidism [81]. It was observed that morepatients on combination therapy displayedelevated triiodothyronine levels. While patientsshowed a preference for the combined treat-ment over levothyroxine therapy (the primarystudy outcome), the positive changes in mood,well-being, fatigue, and neurocognitive func-tions reported (secondary outcomes) occurredin all treatment groups and could not entirelyaccount for the fact that the primary outcomestrongly supported combined therapy. Mean-while, a reduction in body weight, though notin serum TSH, correlated with greater satisfac-tion with the study medication [81]. Finally,among those patients who preferred the com-bined levothyroxine/liothyronine therapy, 44%had serum TSH levels\0.11 mU/l.

It has been hypothesised that the Thr92AlaD2 polymorphism may influence the enzymaticactivity of deiodinase II (DIO2), thereby pre-dicting a positive response to combinedlevothyroxine/liothyronine therapy. In a studywith 12,625 participants from the LifeLinescohort study using available genome-widegenetic data, the effects of the Thr92Ala poly-morphism (rs225014) were evaluated in thegeneral population and in 364 individuals

undergoing levothyroxine replacement therapymainly due to primary hypothyroidism [82]. Inboth groups, the D2-Thr92Ala polymorphismwas not associated with differences in TSH, freethyroxine and free triiodothyronine, presenceof metabolic syndrome, other comorbidities,HRQoL, and cognitive functioning [82]. How-ever, new findings in rodents indicate that car-riers of the Thr92Ala-D2 polymorphism mayexhibit lower D2 catalytic activity and dimin-ished thyroid hormone signalling resulting inlocalised/systemic hypothyroidism [83]. Thesefindings, if replicated in humans, may widenthe opportunity for a more personalisedapproach to the treatment of hypothyroidism[84].

A recent survey, which queried the treatmentof hypothyroidism by presenting 13 theoreticalpatients and offering 6 therapeutic options, wasemailed to the members of the American Thy-roid Association (ATA) prior to a satellite sym-posium of their Spring Meeting and also beforethe annual Endocrine Society and ATA Meet-ings. A multivariate analysis of the resultsrevealed that physician characteristics mayaffect prescription patterns, with residents ofNorth America, for example, being moreinclined to prescribe therapies incorporating

Fig. 7 Illustration of potential responses of a patient to a trial of combination therapy with levothyroxine and liothyronine.FT4 free thyroxine, LT3 liothyronine, LT4 levothyroxine, TSH thyroid-stimulating hormone, T3 triiodothyronine

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liothyronine than their colleagues in Europe[85, 86]. However, the study was not designedto investigate whether this was due to physi-cian-patient interaction, specific education fol-lowing the meetings, the influence ofpharmaceutical companies, or media exposure,or a combination of these. The fact that physi-cians indicate their willingness to prescribe aliothyronine-containing treatment may indi-cate a need for more research to understandpatient preferences, which may sway physi-cians’ choices when considering prescribingliothyronine combined with levothyroxine, andthe risks and benefits of such therapy.

CONCLUSION

This review highlights the complexity of main-taining biochemical and clinical euthyroidismin patients undergoing treatment withlevothyroxine. Challenges include the physio-logical changes that occur as adult patientsprogress through the stages of life as well as thealterations in levothyroxine needs that may beassociated with concomitant medical condi-tions and medications. Optimal treatment ofhypothyroidism requires a partnership betweenpatient and physician. The physician is taskedwith vigilant appraisal of the patient’s statusbased on a thorough clinical and laboratoryassessment and appropriate adjustment of theirlevothyroxine therapy. The patient in turn istasked with medication adherence and report-ing of symptomatology and any changes intheir medical situation. The goal is consistentmaintenance of euthyroidism, without thepatient experiencing the adverse events andnegative health consequences of under- orovertreatment.

ACKNOWLEDGEMENTS

This supplement has been sponsored by Merck.

Funding. Sponsorship for this manuscript,the Rapid Service Fees, and the Open Access feewere all funded by Merck.

Medical Writing, Editorial, and OtherAssistance. We would like to thank SimoneTait of Springer Healthcare who edited thismanuscript before submission. This medicalwriting assistance was funded by Merck.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Leonidas H. Duntas and Jac-queline Jonklaas have nothing to disclose rela-ted to this work. This research did not receiveany specific grant from any funding agency inthe public, commercial, or not-for profit sector.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with animalsperformed by any of the authors. Some ofstudies cited include analyses, or studies withhuman participants, performed by the authorsand completed prior to the initiation of thismanuscript.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproductionin any medium, provided you give appropriatecredit to the original author(s) and the source,provide a link to the Creative Commons license,and indicate if changes were made.

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