Effects of oral contraceptives on thyroid function and vice versa

Abstract

Background
Thyroid gland dysfunction represents an epidemiologically relevant disease in the female gender, where treatment with oral contraceptives (OCs) is frequently prescribed. Although OCs are able to impact the thyroid gland function, scanty data have been released on this matter so far.AimThe aim of this article was to review how hormonal OCs, including estrogen- or progesterone-only containing medications, interact with the hepatic production of thyroid-binding globulin (TBG) and, consequently, their effects on serum levels of thyroxine (T4) and triiodothyronine (T3). We also reviewed the effect of Levo-T4 (LT4) administration in women taking OCs and how they influence the thyroid function in both euthyroid women and in those receiving LT4.ReviewThe estrogenic component of the pills is capable of increasing various liver proteins, such as TBG, sex hormone-binding protein (SHBG) and coagulation factors. On the other hand, the role of progestogens is to modulate estrogen-dependent effects mainly through their anti-androgenic action. In fact, a reduction in the effects of androgens is useful to keep the thromboembolic and cardiovascular risks low, whereas OCs increase it especially in women with subclinical hypothyroidism or in those treated with LT4. Accordingly, subclinical hypothyroidism is known to be associated with a higher mean platelet volume than normal and this increases cardiovascular risk due to platelet hyperactivity caused by incomplete thrombocytopoietic maturation.

Full text

1 23
Journal of Endocrinological
Investigation
Official Journal of Italian Society of
Endocrinology (SIE)
e-ISSN 1720-8386
J Endocrinol Invest
DOI 10.1007/s40618-020-01230-8
Effects of oral contraceptives on thyroid
function and vice versa
F.Torre, A.E.Calogero,
R.A.Condorelli, R.Cannarella,
A.Aversa & S.La Vignera

1 23
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Vol.:(0123456789)
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Journal of Endocrinological Investigation
https://doi.org/10.1007/s40618-020-01230-8
REVIEW
Eects oforal contraceptives onthyroid function andviceversa
F.Torre1· A.E.Calogero1· R.A.Condorelli1· R.Cannarella1· A.Aversa2· S.LaVignera1
Received: 2 January 2020 / Accepted: 17 March 2020
© Italian Society of Endocrinology (SIE) 2020
Abstract
Background Thyroid gland dysfunction represents an epidemiologically relevant disease in the female gender, where treat-
ment with oral contraceptives (OCs) is frequently prescribed. Although OCs are able to impact the thyroid gland function,
scanty data have been released on this matter so far.
Aim The aim of this article was to review how hormonal OCs, including estrogen- or progesterone-only containing medica-
tions, interact with the hepatic production of thyroid-binding globulin (TBG) and, consequently, their effects on serum levels
of thyroxine (T4) and triiodothyronine (T3). We also reviewed the effect of Levo-T4 (LT4) administration in women taking
OCs and how they influence the thyroid function in both euthyroid women and in those receiving LT4.
Review The estrogenic component of the pills is capable of increasing various liver proteins, such as TBG, sex hormone-
binding protein (SHBG) and coagulation factors. On the other hand, the role of progestogens is to modulate estrogen-
dependent effects mainly through their anti-androgenic action. In fact, a reduction in the effects of androgens is useful to
keep the thromboembolic and cardiovascular risks low, whereas OCs increase it especially in women with subclinical hypo-
thyroidism or in those treated with LT4. Accordingly, subclinical hypothyroidism is known to be associated with a higher
mean platelet volume than normal and this increases cardiovascular risk due to platelet hyperactivity caused by incomplete
thrombocytopoietic maturation.
Keyword TBG· Hormonal contraception· Hypothalamic· Pituitary· Thyroid axis
Abbreviations
APC Active protein c
CVD Cardiovascular disease
OC Oral contraceptive
DNG Dienogest
EE Ethinyl estradiol
EV Estradiol valerate
FT4 Free thyroxine
FT3 Free triiodothyronine
LNG Levonorgestrel
LT4 Levothyroxine
MI Myocardial infarction
MPV Mean platelet volume
PDW Amplitude of platelet distribution
PLT Platelet count
T3 Triiodothyronine
T4 Thyroxine
TSH Thyroid-stimulating hormone
TRH Thyrotropin-releasing hormone
TBG Thyroxine-binding globulin
TG Triglycerides
TTR Transthyretin
SCH Subclinical hypothyroidism
VTE Venous thromboembolism
Introduction
The metabolism of body proteins is strictly regulated by thy-
roid hormones, which, in turn, are closely related to the pro-
cesses of development and growth [1–4]. The thyroid gland
synthesizes and releases thyroxine (T4) and triiodothyronine
(T3), both being iodine-containing hormones. T4 is the main
product of thyroid secretion. Thyroid hormone synthesis is
controlled by thyroid-stimulating hormone (TSH) secreted by
the anterior pituitary in response to hypothalamic thyrotropin-
releasing hormone (TRH). Local deiodination in peripheral
* S. La Vignera
sandrolavignera@unict.it
1 Department ofClinical andExperimental Medicine,
University ofCatania, Via S. Sofia 78, 95123Catania, Italy
2 Department ofExperimental andClinical Medicine, “Magna
Graecia” University, Catanzaro, Italy
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Journal of Endocrinological Investigation
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tissues produces T3, the biologically active thyroid hormone.
T4 and T3 circulate into the blood stream bound to thyroxin-
binding globulin (TBG), a protein produced by the liver [5].
The fraction of T4 and T3 free from protein binding (FT4 and
FT3, respectively) exert negative feedback on the synthesis and
release of TSH and TRH to maintain the circulating thyroid
hormone levels in the required range [5].
Hyperthyroidism and hypothyroidism represent pathologic
conditions where an excessive or insufficient hormone synthe-
sis occur. In both cases, the hormone imbalance has relevant
consequences on the metabolic environment: hyperthyroidism
causes metabolic hyperactivity, increased energy expenditure
at rest, weight loss, reduced cholesterol levels, increased lipol-
ysis and gluconeogenesis [6, 7]. On the contrary, the decline
in metabolic activity typical of hypothyroidism configures a
lower energy expenditure at rest with consequent weight gain,
hypercholesterolemia and reduced gluconeogenesis [8]. The
hormonal profile of the hypothyroid and/or hyperthyroid male
or female patients have a negative impact also on gonadal hor-
monal profile. Accordingly, alterations are found in the serum
levels of sex hormone-binding globulin, 17β-estradiol, testos-
terone, free-androgen index, progesterone, dehydroepiandros-
terone, luteotropic hormone, follicle-stimulating hormone, etc.
[8].
More than 99.8% of the circulating thyroid hormone is
bound to three plasma proteins: TBG, Transthyretin (TTR),
and albumin. TBG is the most quantitatively important and
represents over 70% of the total hormone bound to proteins
(both T4 and T3). About 10–15% of circulating T4 and 10%
of circulating T3 are bound to TTR and almost equal quanti-
ties are bound to albumin. TBG carries most of the hormones,
but all three proteins bind T4 with at least a 10-time grater
affinity than T3, thus the free and unbound concentrations of
T3 and T4 are almost equal. The molecular weight of hor-
mone binding proteins is large enough to not be filtered by the
kidneys; therefore, no thyroid hormone is found in the urine.
This confirms that plasma proteins also act as a substantial
reservoir of extra thyroid hormone [9]. It is clear that at the
serum level there is a fine balance between the free and bound
to protein fractions that can be altered by oral contraceptives
(OCs) made up of estrogens and/or progestins. These drugs
could influence this ratio either by increasing or decreasing
the concentration of thyroid hormone-binding proteins. There-
fore, the purpose of this review is to answer two fundamental
questions: (a) Does OCs intake affect thyroid function? (b)
Does the intake of LT4 affects the efficacy and safety of oral
hormonal contraception?
Drugs increasing thyroxin‑binding globulin
concentration andinuencing T4 andT3
transport intothebloodstream
The most common causes of increased serum TBG levels are
the raise in estrogen production or administration, either as a
component of an OC or as a replacement therapy [10]. TBG
is a glycoprotein synthesized by the liver. Natural estrogens
causes an increase in the salicylation, which, in turn, decreases
its clearance rate and increases its serum concentration [11].
The usual doses of ethinyl-estradiol (20–35µg per day) and
conjugated estrogens (0.625mg per day) increase serum
TBG concentrations by approximately 30–50% and serum T4
concentrations by 20–35% [12]. The increases begin within
two weeks and a new steady state is reached in 4–8weeks. In
women with hypothyroidism treated with T4 and in pregnant
women, on average, a 45% increase of the dose is required to
maintain normal serum TSH concentrations [13]. Thus, the
increase in total estrogen-induced serum T4 concentrations
occurs as a result of at least a transient increase in T4 secre-
tion (Fig.1).
The addition of progesterone to estrogen therapy does not
alter the estrogen-induced increase in serum TBG concentra-
tions and progesterone alone has no effect. Oral estrogens,
commonly used for replacement therapy rather contraception,
have a first-pass effect on the liver; transdermal administration
of estrogens does not increase serum concentrations of TBG
or T4, although estrogen serum concentrations are comparable
to those measured after oral administration [14]. The second
question to be analyzed, namely whether the intake of levo-T4
(LT4) can affect the efficacy and safety of OCs, is inspired
by an in-vitro and in-vivo study that showed how thyroid
hormones affect the action of estrogen [15]. The binding of
thyroid hormones to their receptors induces a transcriptional
facilitation of estrogen receptor genes. It seems that this fine
gene regulation takes into account seasonal phenomena linked
to reproduction. The treatment with estrogens influences the
hepatic synthesis and/or secretion of different proteins involved
in clinically important pathological processes such as athero-
sclerosis, hypertension, and thrombosis. After performing a
thyroidectomy in female mice, a decreased hepatic expression
of estrogen receptors by 70% was found; the administration
of T3 (1µg/day) normalized both mRNA expression as well
as the receptor protein [6]. This suggests that euthyroidism is
important for the effectiveness of OCs.
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Eects ofcombined oral contraceptive pills
onthyroid function
The use of contraceptive pills exploits pharmacodynamic
properties of the progestin component. Many progestins
have other partial effects (Table1).
Dienogest (DNG) has a higher anti-androgenic profile
than Levonorgestrel (LNG), which has a more andro-
genic profile. The estrogen profile of the DNG is slightly
higher than that of LNG, while the anti-estrogenic action
is scarcer. An important aspect is that there are no differ-
ences from the point of view of the anti-mineralocorticoid
and glucocorticoid action. The use of combined contra-
ceptives should also take into account the pleiotropic
effects of the estro-progestin synergy. For example, in a
state of hyperestrogenism, including pregnancy, there is an
increase in the proportion of sialic acid that decreases its
renal clearance [16]. This results in a decreased TBG real
clearance and, at the same time, leads to a greater capacity
to bind thyroid hormones [9].
Fig. 1 In women with hypothyroidism treated with thyroxin (T4)
and in pregnant women, on average, a 45% increase in the dose is
required to maintain normal serum TSH concentrations. The reduced
renal clearance of thyroxin-binding protein (TBG) due to its hyper
sialylation creates a sequestering effect of T4, which increases TSH
synthesis. A. Excessive stimulation in hypothyroid patients requires
close monitoring of hormonal therapy
Table 1 Effects of progesterone and progestins on thyroid function [57]
N not changed
Progesto-
genic
activity
Gluco-
corticoid
activity
Andro-
genic
activity
Anti-
androgenic
activity
Anti-mineralo-
corticoid
activity
TSH FT4 FT3 TBG SHBG Reference(s)
Progesterone + − − ( +) + ↓ ↑ N – ↑[20]
Dienogest + − − + − – N/↑N/↑ ↑ – [9, 17]
Drospirenone + + − + + N/↑N↑[7]
Levonorgestrel + − + − − – N/↑N/↑ ↑ – [9, 17]
Gestodene + + + − + – ––↑ ↑ [58]
MPA + + ( +) − − – ↑– – – [19]
Norgestimate + − + − − – – – – – –-
Norethisterone + − + − − N N – ↑– [59]
Desogestrel + − + − − – – – ↑ ↑ [58]
Cyproterone acetate + + − + + − N/↑N↑– [7]
Chlormadinone acetate + + − + − – – – – – [60]
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In a double-blind, controlled, randomized, four-arm clini-
cal trial, the effect of four OCs on thyroid hormones, cortisol,
aldosterone, endothelin-1, and angiotensin II was investi-
gated. Four groups of 25 volunteers each (aged between 18
and 35years) were treated for six cycles with monophasic
combinations containing 21 tablets with 30μg ethinyl estra-
diol (EE) + 2mg DNG (30 EE/DNG), 20μg EE + 2mg of
DNG (20 EE/DNG), 10μg of EE + 2mg of estradiol valerate
(EV) + 2mg of DNG (EE/EV/DNG) or 20μg EE + 100μg
of LNG (EE/LNG). A significant increase of T3 and T4 by
20–40% in all treatment cycles was reported, whereas TSH
significantly increased only with EE/EV/DNG [17].
Treatment with DNG-containing OCs did not cause vari-
ations in FT4 and a transient decrement of FT3 serum lev-
els during the first cycle. EE/LNG administration slightly
increases FT4, whereas FT3 remained stable. This could prob-
ably be related to the slight anti-estrogenic effects of LNG
compared to DNG. In addition, DNG has an anti-estrogenic
action, although bland. Furthermore, DNG has also an anti-
androgenic effect that could explain the serum TBG increase
and the consequent maintenance of FT4 concentrations. These
results suggest that the three low-dose DNG or LNG-contain-
ing OCs may increase T4, T3 and cortisol due to an increased
binding to serum globulins. The amount of free hormones does
not or slightly change. Therefore, these OCs have only minor
effects on thyroid function and adrenal parameters [17].
Eects ofestrogen orprogesterone‑only
containing drugs onthyroid function
To date, few data have been published on the effects of drugs
containing only estrogen or progesterone on thyroid func-
tion. A dose–response study in 23 post-menopausal women
assessed the effects of 25, 50, 100 and 200µg of transder-
mal estradiol administered daily on TBG, compared to that of
conjugated estrogens. While treatment with conjugated estro-
gens increased TBG serum levels, transdermal estrogens did
not [18]. In contrast, the use of depot medroxyprogesterone
acetate (DMPA) significantly increased FT4 levels more than
the copper intrauterine device (IUD) did [19]. Accordingly, a
randomized placebo-controlled 12-week trial found that oral
micronized progesterone at the daily dose of 300mg decreased
TSH, increased FT4 and did not have any effect on FT3 serum
levels, compared to placebo [20]. This evidence suggests a
greater role for progestins in influencing thyroid function when
OCs are given.
Contraceptives andthevenous thrombotic
risk
Raps etal. [7] treated 231 women with OCs and evaluated
the following parameters: TBG, FT4, TSH and activated
protein C resistance (APCR). The results showed that TSH
and FT4 did not change significantly. Increases in TBG
levels in patients receiving more thrombogenic molecules,
such as cyproterone acetate, drospirenone, etc. were found.
On the contrary, the administration of less thrombogenic
progestins (e.g. LNG) resulted in lower TBG levels. The
study showed a positive correlation between increases in
TBG and in the thrombogenic protein APCR, thus leading
to a higher thromboembolic risk. The use of combined
OCs is associated with a higher risk of venous thrombo-
embolism (VTE), increased from three to eight times com-
pared to non-use [7]. The thrombotic risk depends on the
dose of estrogen and the type of progestin. The use of OCs
leads to resistance to activated protein C (APC), which can
serve as a marker for the risk of VTE.
As the Practice Committee of the American Society for
Reproductive Medicine (ASRM) reports, the incidence of
VTE has been esteemed to be as high as 16–22 cases per
10,000 women per year [21]. Several epidemiologic stud-
ies confirm the increased thrombotic risk in patients tak-
ing drugs containing only estrogens [21]. The “ET trial”,
carried on patients treated with estrogen-only medica-
tions, reported 30 and 22 thrombotic events per 10,000
women per year in the estrogen-treated group and in the
placebo one, respectively. The risk was high in the first
two years [22]. It was even higher when progesterone was
added to estrogens (1 vs. 2 cases per 1000 women per
year in the estrogen and estrogen plus progesterone groups,
respectively) [22]. A more recent meta-analysis reported
an increased VTE risk among women using oral, but not
transdermal estrogen-only medications [relative risk (RR)
1.48, vs. RR 0.97, respectively] [23]. This suggests that
transdermal estrogens could be preferred in women at
increased VTE risk. Among progestins, the available data
address to medroxyprogesterone acetate a greater safety
compared to other progestins. Based on observational data,
progesterone appears safe with respect to VTE risk [23].
Mean platelet volume andthrombosis
Platelets vary in size. Large platelets are more reactive,
have a greater prothrombotic potential and are more resist-
ant to inhibition with aspirin and clopidogrel (P2Y12).
They are assumed to be immature and their number
increases when there is an increase in the factors affecting
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Journal of Endocrinological Investigation
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platelet turnover. Recent studies have shown that the high
MPV is associated with an increased risk of deep VTE and
myocardial infarction (MI) [24]. A meta-analysis of cohort
studies suggests that MPV could be a useful prognostic
marker in patients with cardiovascular disease (CVD).
MPV was significantly higher in patients with acute MI
and/or coronary angioplasty [25]. High MPV has also been
identified as a predictor of VTE [24].
Cardiovascular risk is also influenced by testosterone.
Ajayi etal. [26] have shown that higher testosterone lev-
els increase human platelet thromboxane A2 receptor den-
sity and aggregation responses. This may contribute to
the thrombogenicity of androgenic steroids. Progesterone
administration can increase SHBG binding capacities and
it can control free testosterone level, decreasing the associ-
ated risks [27].
An important study [28] analyzed the correlation between
MPV and the amplitude of platelet distribution (PDW) in
the attempt to establish a clinicopathological relationship
by examining the thrombocyte parameters in cases of SCH.
Indirect evidence points to an effect of estrogen on plate-
let function. Accordingly, the mean platelet count decreases
in post-menopausal women not on OCs, compared to pre-
menopausal levels. On the contrary, no difference in MPV
values was found. The authors also reported a higher per-
centage of reticulated platelet in group of woman after men-
opause, suggesting a more thrombogenic phenotype [29].
Therefore, the available evidence on the impact of OCs on
platelet function suggests that there is no effect [30, 31].
Thyroid hormones can affect platelet function. Accord-
ingly, overt hyperthyroidism is associated with an increased
risk of VTE, due to increased levels of FT4 that cause a
state of hypercoagulability. In greater details, the T4 recep-
tor is able to interact with the platelet integrin αvβ3, thus
initiating the platelet aggregation cascade. In addition, thy-
roid hormones seem able to enhance the interaction between
platelets and endothelial cells involved in thrombus genera-
tion [32]. Hypothyroidism is also able to influence platelets,
mainly acting on MPV, as discussed subsequently. Particu-
larly, while the evidence on the effects of overt hypothyroid-
ism on MPV is contradictory, SCH has been more clearly
associated with increased MPV values.
SCH is defined as TSH elevation and normal serum FT4
levels. There is much evidence showing the relationship
between SCH and CVD. The risk factors that can be identified
in these patients include changes in the lipid profile, low grade
chronic inflammation, oxidative stress, diastolic hypertension,
changes in coagulation parameters and alterations of the car-
diovascular system [33–36]. MPV is the most commonly used
measure of thrombocyte size and shows a correlation with
thrombocyte activity. PDW is an index that reflects the het-
erogeneous size of thrombocytes. These indices, in particular
MPV and PDW, are related to the functions of thrombocytes
[37, 38]. Therefore, SCH is a condition with a tendency to
cardiac events. The underlying mechanism is that the larger
thrombocytes are more enzymatically or metabolically active
and, therefore, there is a high potential thrombotic activ-
ity [39]. Since high-volume platelets are more hemostaticly
active, they could be a risk factor for possible coronary throm-
bosis and the development of MI. Current data from the study
on the increase in MPV in patients with SCH suggest that they
may have a specific role in the pre-thrombotic events that could
develop in the future [28].
The study by Kim aimed to find a correlation between
MPV and TSH serum concentrations in a population that
included subjects with unsuspected subclinical hypothyroid-
ism (SCH), but also at evaluating the potential predictive
role of MPV in clinically hypothyroid subjects. It was found
that MPV correlated positively with serum TSH levels and
that MPV could contribute to the pro-thrombotic condition
associated with SCH and perhaps also in putative euthyroid
states in which the TSH level is higher than the normal value
[40]. Demerin and colleagues showed that 95% of the 2290
subjects interviewed had a MPV between 7.2 and 11.7 fL
and that patients with a MPV beyond this range should be
carefully evaluated especially for occlusive arterial diseases.
At this point, it is useful to evaluate the association between
platelet count, MPV, and VTE [41]. A meta-analysis of 18
studies was conducted in accordance with the guidelines for
preferred reporting for systematic reviews and meta-analysis
(PRISMA) with primary endpoint aimed at analyzing the
onset of VTE and, as secondary endpoints, platelet count
and MPV assessment. The results showed that patients with
deep VTE were very likely to have a significantly higher
MPV value than the control group [42]. Changes in MPV
also occur under different pathological conditions. An
increased MPV has been observed in cardiovascular dis-
eases, stroke, respiratory diseases, chronic renal failure,
intestinal diseases, rheumatoid diseases, diabetes mellitus,
and various cancers, while a decrease in MPV was observed
in tuberculosis during exacerbation of the disease, ulcerative
colitis, systemic lupus erythematosus in adults and various
neoplastic diseases [43].
In conclusion, while it is accepted that MPV and PDW
increase is a risk factor for CVD, further studies are
needed to confirm the increase in platelet activation and
the increased risk of cardiovascular complications in SCH
patients.
Thyroid dysfunction: inuence onarterial
function andlipid prole
Previous studies have suggested that SCH is associated
with harmful effects on the cardiovascular system [44].
Studies have also suggested an association between SCH
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Journal of Endocrinological Investigation
1 3
and hypertension, which was later confirmed by some, but
not all, large cross-sectional and case–control studies [44].
Over the past 5years, six large cross-sectional studies on this
topic have produced mixed results [45–50]. Three studies
concluded that patients with SCH had a significantly higher
systolic blood pressure than euthyroid subjects (adjusted for
age, gender and body mass index) [45, 49, 50].
In the studies by Kuusi and colleagues [51] and O’Brien
[52], hypothyroidism was found to be associated with an
altered lipid profile [17, 26]. However, the relationship
between SCH and abnormal lipid profile is not yet clear.
Higher serum triglycerides (TG) levels were found in
patients with hypothyroidism compared to euthyroid par-
ticipants in their study. No convincing results were reported
on the association between hypothyroidism and serum TG,
as well as credible mechanisms. Previous studies have found
that LT4 therapy could decrease serum total cholesterol (TC)
or LDL-cholesterol levels, but in those studies serum TG
levels did not change after LT4 administration [53, 54]. This
result indicated that T4 may have limited effects on TG.
Hence, the association between hypothyroidism and TG is
not yet clear. In the meta-analysis by Xiao-Li Liu and col-
leagues [55], patients with SCH showed significantly higher
total cholesterol, TG and LDL-cholesterol values than euthy-
roid subjects.
In the review by La Vignera and his colleagues [56], it
is evident that a thyroid dysfunction due to SCH can cause
long-term alterations in lipid profile and MPV. All of this
can increase the risk of cardiovascular events. This may be
due to endothelial dysfunction; traditional effects can be
added to risk factors that promote atherosclerosis and non-
traditional effects on vascularization. In particular, TSH is
associated with an increase in LDL cholesterol, diastolic
pressure and markers of chronic inflammation (C-reactive
protein) and simultaneously reduces the bioavailability
of nitric oxide to blood vessels and increases angiotensin
receptor expression. Furthermore, LT4 replacement therapy
appears to improve all these aspects.
Finally, OCs prescription needs a careful evaluation of
the thyroid function, taking into account the impact of OCs
and of thyroid dysfunctions on the cardiovascular system
and lipid profile.
Conclusions
From the evidence above reviewed, it can be concluded that
significant changes in T4 and TSH levels are present after
the use of combined OCs. This means that there is a real
effect of OC pills on serum concentrations of thyroid hor-
mones. The increase in T4 and T3 appears to be related to
the increase in TBG level following OCs. FT4 and FT3 are
increased, but the lower TBG clearance and consequently
the increase in thyroid hormone synthesis, could be a
problem especially in patients with overt hypothyroidism
or SCH. In this regard, the prescription of OCs should be
associated with a monitoring of thyroid function (i.e.: serum
TSH levels). Hypothyroidism also requires attention to car-
diovascular risk since the increase in serum TBG correlates
positively with APCR, whose increase, in turn, indicates
both a state of hyper-coagulation and also a pro-aggregating
state. Accordingly, a positive correlation between MPV and
high TBG values in patients with hypothyroidism has been
reported. Since hypothyroidism may lead to lipid altera-
tions (e.g. hypercholesterolemia or hypertriglyceridemia)
and also to systolic/diastolic pressure alterations, both pro-
moting endothelial shear stress and, therefore, deep VTE, it
comes to light the importance to evaluate thyroid function
in patients on OC therapy.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval This article does not contain any studies with human
participants performed by any of the authors.
Informed consent No informed consent.
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