Androgens and anabolic steroids:
Androgens when used as replacement therapy in hypogonadal men or in supraphysiological doses for anabolic effects in athletes of both sexes, result in decreased TBG, TT4 and TT3 levels without affecting FT4 and TSH levels.58–61 The rise starts within one week, reaching a maximum in two to three weeks.60
This effect has also been observed with danazol used in its usual dose of 800 mg daily for treatment of endometriosis.62Androgen therapy with the non-aromatizable oral fluoxymesterone for metastatic, hormone-sensitive breast cancer, decreased serum levels of TT4 and TBG in four weeks. Normalisation occurs within six to twelve weeks of therapy cessation. In hypothyroid women, on levothyroxine supplementation, the decrease in TBG caused clinical thyrotoxicosis (with elevated FT4 and suppressed TSH), requiring 25 to 50% dose reduction in thyroid hormone doses. This effect reversed after 8-10 weeks of cessation of androgen therapy.63 In euthyroid female-to-male transsexuals, administration of testosterone esters at a dose of 250 mg intramuscular every two weeks, was associated with a 14% decrease in TBG but serum FT4 and TSH levels remained unchanged. This study also reported an increase in T3/ T4 ratio indicating a probable upregulation of deiodinase activity by testosterone.29
Though the exact mechanism involved is unclear; but it is believed that androgens cause desialylation of TBG making it susceptible to degradation.63 The net effect of a particular androgen on TBG levels depends on its aromatisation rate to estrogen.60 Adequacy of liver function also influences this effect, as observed in a study in males with alcoholic cirrhosis. Oral testosterone treatment resulted in TBG decrease in men with alcoholic cirrhosis and mild liver dysfunction (Child-Turcotte’s group A) and not in those with more advanced liver disease (Child-Turcotte’s group B or C). This could be due to inadequate expression of sex hormone receptors in the liver, increase in serum estrogen concentration and use of antiandrogenic medication like spironolactone.64Short term studies have suggested a possible shift of T4 binding from TBG to transthyretin during therapy with norethandrolone due to lower TBG levels.65 From a clinical perspective, androgen therapy may unmask or worsen mild hyperthyroidism due to reduction of TBG levels.66
Chronic glucocorticoid therapy: Endogenous glucocorticoid hypersecretion or exogenous glucocorticoid administration, at a rate of 2-20 times the basal adrenal glucocorticoid secretion, results in decreased TBG levels.67–69 While it can occur with any route of administration, it depends on the dose and duration of the glucocorticoid therapy.69 It is unclear how glucocorticoids cause this change, it is probably mediated through a decrease in the hepatic synthesis of TBG perhaps at a transcriptional level.68
L-asparaginase: L-asparaginase has been reported to decrease TBG levels, with a return to normal after withdrawal. It is believed to be due to the dose-dependent suppression of hepatic synthesis of the glycoprotein as demonstrated in in-vitro studies of cultured human hepatoma (HEP G2) cell lines.70 During the induction phase of acute lymphoblastic leukemia (ALL) treatment, L-asparaginase causes a reduction in TT4 and TBG.71–73 It occurs within two days to two weeks after administration and resolves in two to four weeks after cessation of medication. Two cases of transient hyperthyroidism occurring after l-asparaginase therapy for ALL, have been reported. There was an increase in FT4 along with TSH suppression accompanied by clinical features of thyrotoxicosis in both the cases.74
The mechanism involved is presumed to be due to the general ability of l-asparaginase to inhibit protein synthesis in the liver including suppressing the production of TBG.70 The mechanism of the single reported observation of an increase in FT4 is unexplained.
Nicotinic acid: Nicotinic acid can result in decreased TBG and TT4 levels without affecting FT4 and TSH values.75–78O’Brien et al. proposed nicotinic acid associated hepatitis or subclinical liver dysfunction, while Drinka et al. attributed a direct drug effect as the cause for the change in TBG.76,77Shakir et al. ascribed mobilisation of fatty acids from the periphery, with subsequent interference to binding of thyroid hormones to TBG as another mechanism.75 The exact mechanism is still not clearly understood.
Drugs altering the binding of thyroid hormone to thyroid binding proteins
Displacement of thyroid hormones from TBPs like TBG and TTR can alter thyroid test results.
Salicylates and non-steroidal anti-inflammatory drugs(NSAIDs):Salicylates and salsalate inhibit binding of T4 to all three TBP with maximum effect on TBG.79,80 This occurs at doses of more than 2 g daily of salicylates and 1.5-3 g daily of salsalate. There is an initial and transient increase in FT4 levels at drug initiation, which is then followed by a decrease in TT4 and normalisation of FT4 levels as therapeutic concentrations are maintained.81Salsalate may produce a more significant decline in T4 levels as compared to salicylate (30-40% vs 20-30%).80,82
An analysis of different NSAIDs revealed that ibuprofen, naproxen and indomethacin did not alter hormone levels, aspirin caused a decrease in TT4, TT3, TSH after one week and salsalate affected a drop of , FT4 levels (probably due to dilutional artefact). Meclofenamate caused transient fluctuation of hormone levels which normalised in a week. All subjects remained clinically euthyroid during the one week study period, and TSH remained within normal range.83
Frusemide: Frusemide displaces thyroid hormones from TBG, TTR and albumin, causing a transient increase in FT4 and decrease in TT4.84 This effect occurs at large intravenous doses of more than 80 mg and not at usual therapeutic doses.67,85 The changes depend on the interval between drug administration and sample collection, occurring two to five hours after frusemide doses of 80,120 or 250 mg.86 Other factors involved are the renal drug clearance rate and serum concentration of albumin, which also binds frusemide.67,85
Phenytoin and Carbamazepine: Phenytoin and carbamazepine have been shown to lower T4, T3, FT3 and FT4 levels without affecting serum TSH levels, in euthyroid individuals.86 These drugs at therapeutic levels displace thyroid hormones from thyroid-binding proteins. This is distinct from the class effect of augmented T4 and T3 metabolism, by induction of hepatic microsomal P-450 enzymes. Low FT4 levels are presumably artefactual, and is believed to occur due to serum dilution during the estimation process.87 Direct measurement of FT4 by equilibrium dialysis or indirect assessment by measuring FT4 index can overcome this inaccuracy.88