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