Increase in thyroxine-binding globulin
Estrogen: An elevated TT4 and TT3 level can be seen in patients receiving estrogen, while FT4, FT3 and TSH values remain normal. It causes a dose-dependent increase in TBG, commencing in two weeks of initiation and reaching a new steady-state within four to eight weeks. At routine doses of ethinyl estradiol (20-35 mcg) or conjugated equine estrogen (CEE) (0.625 mg), there is an approximate 30-50% increase in TBG and 20-35% in TT4.23–27 The progesterone component of oral contraceptives (OCs) per se does not alter this estrogen-induced effect; however, the androgenic properties of the progesterone do offset the net effect of the OC on TBG levels. OCs containing anti-androgenic progesterone like dienogest induce a higher rise in TBG (50–60% vs 30%) as compared to those containing androgenic levonorgestrel.28 Transdermal estrogens do not affect TBG levels despite achieving comparable serum levels to oral formulations suggesting the possibility of a portal threshold for estrogenic stimulation of TBG.24,29
Estrogen increases TBG levels predominantly by prolonging its half-life, along with a possible increase in synthesis. It induces a post-translational modification of TBG, resulting in molecules which are more resistant to hepatic degradation, due to the higher terminal sialic acid content.30 The stimulatory effect of estrogen on TBG synthesis, has been observed in in-vitro studies.31,32
Selective estrogen receptor modulators: Selective estrogen receptor modulators (SERMs) are molecules that can act as agonist or antagonist at the estrogen receptors, depending on the target tissue.
  1. Tamoxifen: Tamoxifen has a weak hepatic estrogen-agonistic effect and can cause a mild increase in serum TBG concentrations. The increases are lower than those observed during pregnancy or with estrogen use.33–36
  2. Raloxifene : Raloxifene at a daily dose of 60 mg is used for postmenopausal osteoporosis. Six months of therapy with raloxifene did not significantly affect TBG or TT4 levels.37However when the same dose of raloxifene was administered for one year, it resulted in a small but significant increase in serum TBG.38,39
  3. Droloxifene : In postmenopausal women, droloxifene at a dose of 60 mg daily for six weeks, increased TBG by 41% from baseline. The increase in TBG with CEE (used as the comparator) was twice that observed with droloxifene. Although structurally similar to tamoxifen, droloxifene may have a more profound effect on serum TBG. It is unclear whether this is due to greater estrogen agonistic properties on the liver or is dose-related.40Heroin and methadone : Serum TBG concentrations are increased in about 25- 50% of chronic heroin abusers or those under methadone therapy.41–43 In a large series of 285 euthyroid narcotic addicts, 22% had elevated TT4 and TBG, with normalisation of both parameters after successful stabilisation with methadone therapy.44 Inhalational opium use is also associated with an increase in TT3 levels and TBG as assessed by T3 resin uptake (T3RU).45,46 T3RU is commonly used to evaluate TBG as there is an inverse association between T3RU and TBG.47
The mechanisms involved in these changes have not been clearly understood. The rise in TBG could be related to increased synthesis or decreased degradation or both.
The widely accepted theory is that of concomitant liver dysfunction, as TBG is synthesised in the liver.41,44,48 In methadone treated addicts, high T3 binding ratio has been demonstrated to correlate with the degree of hepatic dysfunction directly.48 The hepatic dysfunction in these patients is multifactorial with contribution from the direct effect of opiates on the liver, dietary deficiencies, chronic and low-grade inflammation due to frequent injections, abuse of other drugs and OC use.48 Liver dysfunction, however, is unlikely to be the sole pathogenetic mechanism as these TBG changes are also seen in addicts (8-25%) with normal liver enzymes.44
The other proposed mechanism is through inhibition of thyroxine-metabolising microsomal enzymes in the liver by morphine (a heroin metabolite), contaminants (like quinine) and methadone.41,42 Alteration in sex steroids by hepatic dysfunction or direct effects of heroin or methadone could also influence TBG levels.41
5-Fluorouracil: 5-Fluorouracil has been associated with an increase in TT4 and TT3, but FT4 and TSH remain unchanged. It is probably due to an increase in TBG levels. There are not many studies reporting this effect of 5-fluorouracil. 49
Mitotane: Long term use of mitotane is associated with an increase in the concentration of TBG and also a smaller increment of sex hormone-binding globulin and cortisol binding globulin. The changes occur as early as one month after commencement of therapy and normalise gradually approximately one year after cessation of medications. The exact mechanisms causing this change in the binding proteins has remained elusive, and presumed to be related to reduced degradation due to enhanced sialylation or increased synthesis.50
Interestingly, unlike the other medications which raise TBG, there is a decrease in TT4 levels by around 38% from the baseline value.50 This is hypothesised to be due to competition of mitotane for binding sites on TBG or due to alteration in T4 binding characteristics.51
There are also reports of reduced FT4 levels with prolonged mitotane use, with an inverse correlation between FT4 levels and serum mitotane concentrations.52,53 While the exact reason for this is unknown, in patients receiving mitotane, high FT3/FT4 ratios have been demonstrated which indicate augmented deiodinase activity aiding the conversion of T4 to T3.52,53 This is considered as a characteristic, compensatory thyroid function change in hypothyroid conditions.54 Changes in FT3 or TSH levels have not been reported.
Clofibrate: Clofibrate, a hypolipidemic agent, has been discontinued since 2002, given the observed excess mortality despite successful cholesterol-lowering.55 Increase in TBG and a small decrease in FT4 and FT3 levels were observed with this medication.56 There was however no relationship between these changes and the lipid response to clofibrates.56,57