LT₄ is a convenient therapy for hypothyroidism. Monotherapy with this product is the most commonly employed treatment for hypothyroidism today. LT₄ is chemically stable with relatively modest product deterioration during storage. The manufacturing process is expected to maintain consistent potency and minimize batch-to-batch variability through standardization and quality control. Absorption after oral administration is acceptable and the half-life of a week allows once daily dosing. LT₄, as the sodium salt of T₄, is actually a prohormone and is converted into the active triiodothyronine (T₃), which binds to either the alpha or beta forms of the thyroid hormone receptor. The T₃-receptor complex interacts with target genes and regulates gene transcription. The different isoforms of the receptor allow tissue specific actions of T₃ to ensue. The ratio of T₄ to T₃ in thyroid glandular secretion is approximately 15:1 (13). Multi-compartment analyses in humans with normal thyroid function show that 100 mcg of T₄ and 29 mcg of T₃ are produced daily (14). T₄ is secreted by the thyroid gland itself. T₃ primarily results from deiodination of T₄ to T₃ in the liver and peripheral tissues (23 mcg), with the remainder (6 mcg) being generated from thyroidal production, in proportions of 80% and 20%, respectively.

When LT₄ therapy is administered to individuals with hypothyroidism and little or no endogenous thyroid function, T₃ is generated solely by deiodination of T₄ in peripheral tissues. Relatively stable serum concentrations of both T₄ and T₃ are achieved (15,16). It is clear that in athyreotic patients taking LT₄, the serum T₄ levels required to maintain a normal TSH are higher than the T₄ levels seen in euthyroid subjects (17,18,19,20). This results in a higher T₄/T₃ ratio in LT₄-replaced patients. However, there are conflicting data regarding whether comparable T₃ concentrations are achieved. Several studies (18,19,21,22), including one using patients as their own controls (20), suggest that serum T₃ levels are maintained in LT₄-treated patients (see Fig. 46.1). Other studies have demonstrated that serum T3 levels were lower in patients taking LT₄ (17,23).

Many different LT₄ products are available that are thought to have different absorption because of different excipients (color agents and fillers) (24,25,26). Bioequivalence is a measure of absorption or bioavailability that the Food and Drug Administration (FDA) uses to predict therapeutic efficacy. Bioavailability is determined by studying the pharmacokinetics of large oral doses of LT₄ in volunteers who have normal endogenous thyroid function. Doses of 400 to 600 mcg of the LT₄ products to be tested are administered and the maximum serum concentration (Cmax), time to Cmax, and area under the concentration–time curve (AUC) are determined (Fig. 46.2A) (27). Two products are studied in a cross-over design. The AUC and Cmax are logarithmically transformed. If the two 90% confidence intervals from the natural logarithms of the AUC at 48 hours and the Cmax are both within the 80% to 125% range, the products are deemed bioequivalent by the FDA (Fig. 46.2B), and can be substituted for each other. Measures of systemic exposure (AUC, Cmax) are used in this testing, rather than using clinical endpoints such as serum TSH levels (28). Representatives of the major endocrine societies have expressed their concern about this methodology (29,30). The concerns voiced include the inability to study serum TSH because of the use of supraphysiologic doses of LT₄ and the fact that the situation does not reflect steady state conditions. In addition, bioequivalence
methodology appears not to be capable of detecting LT₄ doses with 12.5% difference from each other (26). Thus, referring to Table 46.1, an increase in dose from 100 to 112 mcg (12%) and a decrease in dose from 100 to 88 mcg (12%) may not be detected. Differences in dosage strengths in the 25% range are known to produce clinically relevant changes (11), and potentially result in iatrogenic hyperthyroidism or hypothyroidism.

An additional issue with respect to treating patients with hypothyroidism is whether tissue levels, rather than simply serum levels, of T₃ are normal in patients receiving replacement with T₄ alone. A relative T₃ deficiency might prompt consideration of combination therapy. If combination therapy with both T₄ and T₃ is considered, options for delivering such therapy include use of liotrix, which contains T₄ and T₃ in a 4:1 ratio, and addition of liothyronine to LT₄ in doses and ratios selected by the prescribing physician. If the intention were to replicate the molar ratio of T₄:T₃ achieved by endogenous thyroid functioning in humans, the prescribed ratio would be approximately 15:1 (13,14).

A study performed in rodents showed that with intravenous infusion of T₄ alone, tissue levels of T₃ were lower in some tissues than in control animals (31). However, with an infusion of both T₄ and T₃, levels of T₃ could be normalized in all tissues (32). A study in euthyroid patients undergoing thyroidectomy, who were subsequently treated with T₄ monotherapy, showed that serum T₃ concentrations were maintained in the pre-thyroidectomy range (20). However, patient satisfaction, patient performance, and tissue indices of thyroid status were
not examined. Many studies of hypothyroid patients examining the issue of combination therapy have been performed since an initial study in 1970 (33). For example, in one trial of combination therapy, LT₄ alone was compared with combination therapy by substituting 50 mcg of T₄ with 7.5 mcg of T₃ (34). This study demonstrated no beneficial changes in body weight, serum lipid levels, hypothyroid symptoms as measured by a health-related quality of life questionnaire, and standard measures of cognitive performance. The available studies (33,34,35,36,37,38,39,40,41,42,43) had variable designs with respect to the outcomes studied, the use of cross-over or parallel groups, blinding methodology, and the ratio of T₄ to T₃ employed. However, autoimmune hypothyroidism was the predominant diagnosis in most. With minor exceptions, or exceptions within subgroups (35,40,43), these studies failed to demonstrate a benefit of T₃ combination therapy. The exceptions included patient preference for combination therapy (35,39,40) and improved mood scores and measures of cognition (35,40,43). Two meta-analyses of the 11 or so accumulated studies have also concluded that there is no advantage to combination therapy (44,45). An additional study published after the completion of these meta-analyses, however, did report that combination therapy had a favorable effect on quality of life and was preferred by patients (46). Simulation studies of thyroid hormone replacement after thyroidectomy using a nonlinear feedback system on the basis of human data suggest that either combination therapy with T₄/T₃ or T₄ therapy alone could each normalize plasma and tissue T₃ levels. The daily T₄ doses that were predicted were 103 mcg and 162 mcg, respectively (16).

Rat and human thyroid physiology differ with respect to the molar ratio of T₄:T₃, the proportion of thyroid hormones bound to transport proteins, and presumably the regulation of tissue thyroid hormone concentration by deiodinases. Putting aside species differences, the rodent studies cited above (31,32) might suggest that local production of T₃ is regulated in a tissue-specific manner, and that specific tissues may have differential dependence on circulating T₃ levels on the basis of their deiodinase activity (see discussion in Chapter 7). The type 2 deiodinase enzyme is responsible for the conversion of T₄ to T₃ in many tissues, and several polymorphisms in the type 2 deiodinase gene have been described in humans. The Thr92Ala polymorphism, which is associated with a threonine to alanine substitution at codon 92, does not lead to altered thyroid hormone concentrations. A recent analysis, which examined the impact of combination therapy according to the type 2 deiodinase polymorphism status of the treated patients, suggested that individuals harboring the Thr92Ala polymorphism had a poorer psychological response to LT₄ therapy and a better response to combination therapy with both T₄ and T₃ (47). A smaller study had previously failed to show this differential response, but may have been underpowered (48). Thus, it is possible that individuals with the Thr92Ala polymorphism, which is present in 16% of the population, may account for the subset of patients who do not derive the expected benefit from T₄ monotherapy. A prospective trial designed to test this hypothesis has not yet been reported.

Desiccated thyroid extracts, described as “the cleaned, dried, and powdered thyroid gland,” derived from domesticated animals (hog, beef, or sheep) are preferred by some patients. Thyroid extracts from porcine sources are the most commonly available. The United States Pharmacopeia (USP) requires thyroid extracts to contain approximately 38 mcg (±15%) of T₄ and 9 mcg (±10%) of T₃ for each 60 to 65 mg (1 grain) tablet. As an animal protein–derived product, thyroid extracts have a characteristic odor and in theory could be antigenic. Although allergy or sensitivity to thyroid extract may be anecdotally described, this problem has rarely been reported (49). Such products may be associated with problems such as variable supply and batch-to-batch variability in the non-thyroid hormone constituents of the animal glands. In addition, it is difficult to maintain euthyroidism in treated patients due to the high proportion of T₃ in the thyroid USP preparations (T₄:T₃ ratio of 4:1). Even though desiccated thyroid is inexpensive, its limitations, particularly the non-physiologic proportion of T₃, preclude it from being considered a drug of choice for hypothyroid patients.

Options available for T₃-based therapy are the previously mentioned liotrix and thyroid USP, which both contain T₃ and T₄ in a ratio of approximately 1:4, and liothyronine sodium, which is T₃ alone. T₃ is well absorbed in the gastrointestinal tract and liothyronine is available in three dosages of 5, 25, and 50 mcg. The major disadvantage of T₃ therapy is that, due to its short half-life of 1 day, its use is associated with peaks and troughs in its serum concentration (15), unless it is administered multiple times daily. This is in contrast to the steady T₃ concentrations that are achieved with T₄ therapy (15,16). Peak serum levels, which are attained within 4 hours of administration, can be associated with hyperthyroid symptoms such as anxiety, tremors, and palpitations. Recently, a small trial compared serum TSH concentrations achieved with either T₄ or T₃ therapy each delivered three times daily (50). Relatively stable T₄ and T₃ concentrations and similar TSH concentrations could be achieved, but a lengthy adjustment period, with a mean duration of 32 weeks, was required to achieve the stated TSH goal of 0.5 to 1.5 mIU/L, perhaps suggesting that adherence to a thrice daily regimen was difficult. This study demonstrated that 40 mcg T₃ or 115 mcg T₄ (1:3 ratio) produced similar mean TSH concentrations of 1.4 and 1.2 mIU/L.

Therapy with sustained release T₃ is postulated to be an attractive option (51,52) as it might ensure adequate T₃ concentrations at the tissue level, albeit bypassing the opportunity for regulation by type 2 deiodinases. Use of T₄/T₃ combination therapy containing an in-house sustained release T₃ preparation was described in a 2004 publication (53). Subjects had similar TSH values during T₄ therapy and during combination therapy, and the combination therapy containing the sustained release T₃ achieved steady maintenance of concentrations of T₃ over a 10-hour period. There do not appear to be further descriptions of sustained release T₃ therapy in the scientific literature since this report.

It is possible to obtain various thyroid hormone preparations from compounding pharmacies. Such pharmacies are described by the FDA as being engaged in “combining, mixing, or altering of ingredients to create a customized medication for an individual patient.” They thus mix drugs for various specific needs, including provision of the exact dose required by the patient. For example, a compounding pharmacy may mix T₃ with methylcellulose and dispense tablets designed to have a sustained release profile. Compounding pharmacies are regulated by their respective states, but the issue of whether there is also federal jurisdiction over compounding pharmacies has been argued in the courts without a clear resolution (54).

A LT₄ preparation has recently become available in which the T₄ is dissolved in glycerin and contained within a gelatin capsule. This preparation is reported by the manufacturer to have 100% absorption from the gastrointestinal tract, compared with 40% to 80% absorption reported by manufacturers of other LT₄ preparations. The dissolution of this preparation appears to be relatively unaffected by pH (55). Therefore, its absorption, in theory, might be less affected by the altered pH of the gastric environment associated with food consumption, gastritis, and use of proton pump inhibitors than other LT₄ products (see section Factors Affecting Absorption of Levothyroxine). Nevertheless, under the fasting conditions of FDA-approved bioequivalence methodology this product appears to satisfy criteria for bioequivalence to a brand name tablet (56).

It is well established that the etiology of a patient’s hypothyroidism, which is closely linked to the amount of residual thyroid function, affects the dose of LT₄ that will result in a normal TSH in a treated patient (57,58). Patients who are athyreotic as a consequence of thyroidectomy generally require a higher LT₄ dose than patients with Hashimoto’s thyroiditis. Patients who have received radioiodine therapy for Graves’ hyperthyroidism may have a variable need for LT₄, depending on whether they have remaining functional thyroid tissue.

The medications that may necessitate an adjustment in LT₄ dose by virtue of altering T₄ metabolism or changing the concentration of T₄-binding globulin are shown in Table 46.2 (59). T₄ and T₃ are primarily metabolized by deiodination, but are also metabolized by conjugation with glucuronates and sulfates in the liver. The major enzymes involved in the conjugation are the mixed function oxidases and uridine diphosphate glucuronosyltransferases. Drugs that have either been shown to increase hepatic metabolism of T₄ and T₃ via their induction of these enzymes, or are presumed to have this effect, include phenobarbital (60), phenytoin (61), carbamazepine (62), rifampin (63), sertraline (64), and imatinib (65). Patients taking these medications may need to have their LT₄ doses increased substantially above the usual replacement doses (59). Hypothyroid patients receiving treatment may also require an increased dose of LT₄ to maintain a normal serum TSH when therapy with amiodarone is initiated (66). In this case the mechanism is not thought to be related to altered conjugation, but is postulated to be due either to decreased conversion of T₄ to T₃ in the pituitary and other tissues, or to decreased entry of T₃ into pituitary thyrotrophs.

If drugs that increase the serum T₄–binding globulin concentrations, and thus increase total T₄ levels, are started in hypothyroid patients receiving LT₄, their TSH levels may rise above the normal range, thus signaling the need for a higher dose of LT₄ to compensate and restore the steady state. Examples of drugs that increase serum T₄–binding globulin from insignificant to significant degrees (59) include estrogen (67), tamoxifen (68), raloxifene (69), clofibrate (70), opioids (71), mitotane (72), fluorouracil (73), and capecitabine (74). With respect to the classic case of estrogen treatment in post-menopausal women, such therapy was associated with an increase in mean TSH concentration from 0.9 mIU/L to approximately 3.2 mIU/L 12 weeks after initiation of estrogen therapy (67). Other drugs, such as androgens (75), anabolic steroids (76), and glucocorticoids (77) may have the opposite effect and decrease the serum T₄–binding globulin concentrations, and thus typically necessitate a decrease in LT₄ dose (59).

Another factor affecting the LT₄ dose that a patient requires is the TSH goal of their therapy. Patients who are being treated to achieve a normal TSH require a lower dose of LT₄ than those with differentiated thyroid cancer being treated to achieve subnormal TSH values. The latter patient group requires higher doses (18,58,78). Normalization of TSH, in most studies, is achieved by doses in the range of 1.6 to 1.8 mcg LT₄ per kilogram, whereas TSH suppression is achieved by doses of approximately 2.0 to 2.2 mcg/kg.