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.
- 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
- 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
- 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