ISSN: 0975 -8542

Journal of Global Pharma Technology

Available Online at www.jgpt.co.in

RESEARCH ARTICLE

Effect of Thyroxine Tablets Treatment on the Oxidative Stress in

Hypothyroid Women
Al-Shimaysawee Sadeq*, Ghufran Mohammed Hussein*

Pathological Analysis Technical Department, College of Medical Technologies, TheIslamic University in

Najaf-Iraq.

*Corresponding Author: Email: sadeqhalshimaysawee@iunajaf.edu.iq, ghufranasal@iunajaf.edu.iq

Abstract

Objective: Although some researches informed increased oxidative stress (OS) in hypothyroidism, the
influence of treatment with levothyroxine is did not considered widely. Hence, we directed this article to
examine the influence of levothyroxine therapy on oxidative stress in hypothyroid women. Methods: The
current study included 42 women hypothyroid patients treated with thyroxine& 25 untreated in addition
to 40, age matched healthy females used as a control group. The thyroid function test, serum reduced
glutathione (GSH), catalase (CAT) and glutathione-S-transferases (GST) levels were measured. Results:
The results showed that serum GSH level revealed significant increases in hypothyroid untreated
patients. In contrast, GSH treated level showed nonsignificant increases when compared with those of
the control group, but the results of CAT levels failed to indicate significant variation in the two groups
while the serum GST level revealed significant decreases in hypothyroid untreated patients in contrast,
GST treated level showed nonsignificant increases when compared with those of the control group.
Highly significant (p<0.01) positive correlation was obtained for GSH levels with thyroxine in treated
hypothyroid women whereas CAT levels failed to exhibit significant correlation with throxine tablets
treatment also Significant (p<0.05) positive correlation was obtained for GST levels with thyroxine in
treated hypothyroid women. Conclusions: Hypothyroidism is associated with elevated oxidative stress
and thyroxine tablets are modulate the oxidative stress in treated hypothyroid women patients.

Keywords: Thyroxine Tablets, Oxidative Stress, Hypothyroid Women.

Introduction
Wharton introduced the word thyroid,
meaning shield-shaped, in his description of
the thyroid gland .He attributed a solely
cosmetic function to it like many before him,
because of further numerous incidence of
enlarged glands in women giving the throat
area a more beautiful roundness [1].
The thyroid gland is highly vascular, flat
structure located in the upper portion of the
trachea, just below the larynx. It composed of
fundamentally different types of hormones,
Thyroxine (T4) and Triiodothyronine (T3) [2].
Both hormones are vital for normal growth
and development and control essential
functions, such as energy metabolism and
protein synthesis [3].
Action of Thyroid Hormones
Thyroid hormones are essential for normal
growth, mental development and sexual
maturation and increase the sensitivity of the
cardiovascular and central nervous system to
catecholamine, there by influencing cardiac
output and heart rate [4].
Disorders of the Thyroid Gland
The most common presenting clinical
features of thyroid disease are the result of:
hypothyroidism due to deficient thyroid
hormone secretion, and hyperthyroidism due
to excessive thyroid hormone secretion [5].
Hypothyroidism
Hypothyroidism is caused by suboptimal
circulating concentration of thyroid
hormones. It becomes more prevalent with
age, affecting about 6 per cent of people over
60 years. It is more common in women.
Hypothyroidism is classified into primary
and secondary disorders. The most common
type is the primary hypothyroidism [6].

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 Al-Shimaysawee Sadeq et. al.| Journal of Global Pharma Technology| 2018; 10(08):57-66

However the secondary hypothyroidism is  Neck radiation to treat cancer.

accounted to be rare among cases of the
 Drugs (amiodarone and lithium).
disease. The female: male ratio is
approximately 6:1. The prevalence of primary  Family members’ thyroid disease.
hypothyroidism is 1:100, but increases to
 TSH measurement: This is the most
5:100 if patients with subclinical
important and sensitive test for
hypothyroidism (normal T4, raised TSH) are
hypothyroidism. An abnormally high TSH
included [7].
means hypothyroidism.
Primary Hypothyroidism
 T4 measurement [13].
Autoimmune: Hashimoto's thyroiditis,
Treatment
spontaneous atrophic hypothyroidism.
Transient thyroiditis: Lymphocytic With the exception of certain conditions, the
thyroiditis (which may occur after treatment of hypothyroidism requires life-
hyperthyroidism or post-partum) [8]. long therapy. The average dose of T4
Iatrogenic: Thyroid destruction (from replacement in adults is approximately 1.6
radioactive iodine or surgery), medications micrograms per kilogram per day. This
with amiodarone, lithium, carbimazole, translates into approximately 100 to 150
methimazole and propylthiouracil. Severe micrograms per day. Ideally, synthetic T4
iodine deficiency: e.g. in mountainous regions replacement should be taken in the morning,
[9]. 30 minutes before eating [14].
Secondary Hypothyroidism Oxidative Stress
Pituitary or hypothalamic problems (TSH Oxidative Stress is a condition of increased
deficiency) include: pituitary adenoma, oxidant production in cells characterized by
tumors impinging on the hypothalamus, the release of free radicals and resulting in
history of brain irradiation and drugs (eg, cellular degeneration. Oxidative stress can
dopamine, lithium) [10]. result from a lack of antioxidants or from an
overabundance of free radicals. It is caused
Signs and Symptoms
by an imbalance between the production of
When thyroid hormone levels are too low, the reactive oxygen species (ROS) and a
body's cells can't get enough thyroid hormone biological system's ability to readily detoxify
and the body's processes start slowing down. such species or easily repair the resulting
For example, the body makes less heat and damage [15].
less energy, and organs like the brain and
Free Radicals
bowels move more slowly [3]. As the body
slows, one may notice that a patient feel A free radical is any chemical species capable
colder, tire more easily, skin is getting drier, of independent existence possessing one or
becoming forgetful and depressed, and starts more unpaired electrons. Biological free
to get constipation several body changes are radicals are thus highly unstable molecules
taken place. For example cholesterol is that have electrons available to react with
building in the body and plaques are various organic substrates [16]. Free radicals
hardening arteries, increasing the risk of accumulate in tissues due to intracellular
heart attack [11]. and extracellular processes.
Diagnosis Free radicals react with key organic
substrates such as lipids, proteins, and DNA.
The correct diagnosis of hypothyroidism
Oxidation of these bio molecules can damage
depends on the following.
them, disturbing normal functions and may
 Symptoms. Hypothyroidism doesn’t have contribute to a variety of disease states [17].
any characteristic symptoms. Endogenous Antioxidants
There are no symptoms that people with
 Catalase (CAT)
hypothyroidism always have and many
symptoms of hypothyroidism can occur in  Glutathione Peroxidase (GPx)
people with other diseases [12].  Glutathione Reductase (GR)
 Medical and family history.  Glutathione-S-transferase (GST)
 Thyroid surgery.  Reduced Glutathione (GSH)

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 Al-Shimaysawee Sadeq et. al.| Journal of Global Pharma Technology| 2018; 10(08):57-66

 Superoxide Dismutase (SOD) [18] principle combine an enzyme immunoassay

Exogenous Antioxidants
 Ascorbic Acid
 Tocopherol
 Carotenoids [19]
THE Aims of the Study
To demonstrate the impact of thyroxine oral
tablets treatment of the hypothyroidism on
oxidative stress markers (GSH, CAT and
GST) in hypothyroidism women patients.
Patients and Control Group
The groups of patients were obtained
randomly consisted of 42 patients treated
with thyroxine& 25 untreated, in addition to
forty; age matched healthy females used as a
control group. The enrolled females were
neither smoking nor suffering from a disease
other than hypothyroidism. The thyroid
function tests, were measured by the assay
Table-1: Levels of serum reduced glutathione (GSH), catalase (CAT), glutathione-S-transferase (GST) in treated and
untreated hypothyroidism female patients and the control group
Parameter Type of group
competition method for T3& T4, while a one-
step enzyme immunoassay sandwich method
for TSH with a final fluorescent detection
(ELFA).GSH was measured by Ell
man's reaction [20], CAT activity was
measured following the method of AebiH
[21], and GST activity was assessed
according to the method of Habiget. Al [22].
Results &Discussion
The estimation of serum GSH and GST levels
revealed significant increases and decreases
respectively in untreated hypothyroid female
patients when compared with those of the
control group .While non-significant increase
of serum GSH and GST levels for treated
groups when matched with those of the
control group. In contrast, serum CAT levels
showed nonsignificant decreases in untreated
and treated hypothyroid female patients
groups in comparison with the control group
Table-1.
Mean± SD Range P-value

GSH (µM) Untreated(25)* 27±29.7 (1.25-90) 0.05

Treated (42)* 19.7±26.4 (1.25-95) N.S

Control (40)* 18.4±16.9 (1.25-60)

CAT (K/min) Untreated(25)* 4.7±3.5 (1.7-15.1) N.S

Treated (42)* 4.9±3.9 (0.93-17.7) N.S

Control (40)* 4.9±2.9 (1.5-13.7)

GST (U/ml) Untreated(25)* 2.6±1.3 (0.5-6.2) 0.05

Treated (42)* 3.9±1.1 (0.94-6.4) N.S

Control (40)* 3.3±1.3 (0.88-5.5)

* = Number
N.S = Non-significant

Thyroid hormones are associated to the
oxidative and anti-oxidative status of the
organism. Depression of metabolism due to
hypothyroidism has been reported to
decrease oxidant production and thus
protects tissues against oxidative damage.
Oxidative stress, cherished by an elevation in
the steady-state concentration of reactive
oxygen species (ROS), has been involved in a
wide range of biological and pathological
conditions [23].
However, data on the oxidative status of
hypothyroidism are limited and controversial
[24] and the mechanism linking
hypothyroidism with oxidative stress and
antioxidants is unknown [25].
The role of thyroid in the regulation of the
antioxidant systems has been recently
reviewed in the context of the reproductive
endocrinology [26]. It is well known that
thyroid function influences the ovarian
activity. ROS play physiological roles in the
ovary and hypothyroidism, or a lowT3
syndrome, can induce ovaryandys function by
interfering with the antioxidant systems.
Oxidative stress has been shown to be
associated with both hyperthyroidism and
hypothyroidism [27].
However; the mechanisms by which O Sis
generated in these two clinical conditions are
different: increased ROS production in
hyperthyroidism and low availability of

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 Al-Shimaysawee Sadeq et. al.| Journal of Global Pharma Technology| 2018; 10(08):57-66

antioxidants in hypothyroidism. Some <0.001) decreased in hypothyroid women, but

complications of hyperthyroidism in target
tissues are caused by OS [28].
Thyroid hormones per se can act as oxidants
and produce DNA damage (contrasted by
CAT), probably through the phenolic group,
which is similar to that of steroidal estrogens
[29]. The increment of GSH in this study is
corresponding to the Mogulkoc R, ET. al.
2005, results [30], also the results of GSH are
similar with ZS Saičić et. al. but differed with
them in the results of CAT and GST [31].
The estimation of serum GSH level revealed
significant increases in hypothyroid
untreated patients. In contrast, GSH treated
level showed nonsignificant increases when
compared with those of the control group
Figure-1.This results of GSH levels in this
study are different from A A Al-Fahham
2015, who is show that a high significant (p
parallel with him about the activity of CAT
who showed a significant decrease (p <0.05)
in the hypothyroid women group when
compared with the control group while non-
significant decrease of CAT activity in this
study [32]. The levels of glutathione and
thyroid health are intermittently linked.
Glutathione is an antioxidant that protects
cells from damage caused by oxidation and
inflammation.
Thus, it is one of the most important
antioxidants needed by the body. Glutathione
is also vital in the launch of the autoimmune
response. Therefore, maintaining a healthy
glutathione level is critical in patients with
Hashimoto’s thyroidit is as well as those who
suffer from hypothyroidism. Maintain your
body’s defenses against autoimmune disease,
inflammatory disorders, chemical
sensitivities, and a leaky gut by making sure
your glutathione levels are healthy [33].

30
25
GSH (uM)

20
15
10
5
0
18.4 19.7 27

control treated untreated

Figure-1: Reduced glutathione (GSH) levels in treated, untreated hypothyroidism patients and the control group.

The results of CAT levels failed to indicate significant variation in the two groups
Figure-2.

4.95
4.9
4.85
4.8
CAT (K/min)

4.75
4.7
4.65
4.6
4.55
4.5
4.45
control treated untreated

Figure-2: Catalase (CAT) levels in treated, untreated hypothyroidism patients and the control group.

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 Al-Shimaysawee Sadeq et. al.| Journal of Global Pharma Technology| 2018; 10(08):57-66
The non-significant decrease of CAT activity
in untreated hypothyroid patients and
treated group when compared with control
group are identical to the outcomes of B
Pereira et. al., that hypothyroidism tended to
diminish lipid peroxidation. Low levels of
thyroid hormones tended to diminish Mn-
SOD and glutathione peroxidase activities.
These findings show that the thyroid
hormones might be able to regulate the
catalase in the lymphoid organs and skeletal
muscles [34]. Specifically, observations
indicate that catalase (CAT) is required to
degrade H2O2at a higher concentration. It is
thus possible that the lower activities of CAT
lead to H2O2-induced apoptosis of thyroid
cells in Hashimoto's thyroiditis patient’s .In
4.5
4
3.5
3
GST (U/Ml)
2.5
2
1.5
1
0.5
0
control
Figure 3: Glutathione-S-transferase (GST) levels in treated, untreated hypothyroidism patients and the control
group.
The activities of the enzymatic antioxidant
GST in this study are identical to the Z S
Saičić, et. al., DGO Al-Watify and Pasupathi
P et. al., which exhibited significantly lower
GST activities in hypothyroid patients when
compared with healthy subjects [31, 36, 38].
However, the outcomes of the GST for this
study are different from K. Das, et. al.,
whom indicate that in mammalian system;
low molecular weight isoenzymes of GST
exhibit GST activities increased following the
hypothyroid state, whereas the decreased
GST activity of the hypothyroid state with
treatment by T3 supplementation [39].
©2009-2018, JGPT. All Rights Reserved
an in vitro study by Demelash et. al., [35].
This data are also corresponding to the
possibility that reduced CAT activities in
hypothyroid patients might participate in
initiation of the autoimmune process might
lead to H2O2-induced damage of thyroid cells
related to cystolic oxidative stress [36].
However, the CAT activity results in this
study are unlike to Saeed Naazeri et. al., that
showed a significant increase for CAT in
hypothyroidism compared to the control
group [37]. The estimation of serum GST
level revealed significant decreases in
hypothyroid untreated patients. In contrast,
GST treated level showed nonsignificant
increases when compared with those of the
control groupFigure-3.
treated untreated
To verify the relevance of the thyroxine
tablets treatment of hypothyroidism with
GSH, CAT and GST level alterations, the
data of patients with thyroxine tablets
treatment were evaluated by the linear
regression analysis.
Table-2 demonstrate highly significant
(p<0.01) positive correlation for GSH and
significant (P<0.05) positive correlation for
GST with the weight of thyroxine tablets
treatments for hypothyroidism in the
enrolled patients. On the other hand, CAT
levels did not exhibit significant correlation
during a similar assessment.
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Table-2: Univarate analysis of thyroxine tablets treatment with reduced glutathione (GSH), catalase (CAT),
glutathione-S-transferase (GST) in hypothyroidism women patients
Parameter r p-value

GSH (μM) 0.45 0.01

CAT (K/min) 0.09 N.S

GST(U/ml) 0.31 0.05

Highly significant (p<0.01) positive Figure 4. This result is like to Ihsan Ates,
correlation was obtained for GSH levels with et.al.2016 that suggest levothyroxine therapy
thyroxine in treated hypothyroid women reductions oxidant status and rises
antioxidant status [40].

100
90
80
70
GSH (uM)

60
50
40
30
20
10
0
0 25 50 75 100 125 150 175 200 225 250
Thyroxine ug

Figure 4: Correlation of serum reduced glutathione (GSH) with thyroxine tablets of treated hypothyroid women
patients.

Conversely, A S R Araujo et. al., establish tablets treatment Figure 5. The outcomes
declined GSH activities next 4-weekstherapy nonsignificant increases of CAT with
i. e. different our results in this research [41]. thyroxine tablets are somewhat similar to the
The GSH is a substrate for antioxidant results of Saeed Naazeri et. al., showed that
enzymes like glutathione peroxidase (GPx), catalase activity in hypo-and
glutathione-S-transferase (GST) and hyperthyroidism were significantly increased
glutathione reductase (GRx). The decrease in compared with healthy controls (p=0.005)
the concentrations may be due to the [37]. But our results that nonsignificant
increased turnover of GSH in preventing increase of CAT with thyroxine tablets are
oxidative damage in these cases [42]. dissimilar to Panda Sand Kar A, 2007, that
Therefore when increased the concentration indicated although levothyroxine (L-T4)
of thyroxine increased concentration of GSH administration increased serum levels of
that is mean decreased OS by increasing of thyroid hormones, it decreased the activities
thyroxine tablets weight. CAT levels failed to of anti-oxidant enzymes, such as SOD, CAT
exhibit significant correlation with throxine and GSH [43].

20
18
16
14
CAT (K/min)

12
10
8
6
4
2
0
0 25 50 75 100 125 150 175 200 225 250
Thyroxine ug

Figure-5: Correlation of serum catalase (CAT) with thyroxine tablets of treated hypothyroid women patients.

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 Al-Shimaysawee Sadeq et. al.| Journal of Global Pharma Technology| 2018; 10(08):57-66
Hormones of thyroid gland are believed to
involve for free oxygen radical purification by
rising non-enzymatic antioxidant particles
[44] which altered antioxidant enzyme levels
like superoxide dismutase, catalase, and
glutathione peroxidase [45]. Finally, during
thyroid hormone synthesis in thyroid
epithelial cells H2O2, an oxidant radical is
needed for the oxidation of iodide [46].
Consequently, when decrease thyroid
hormone synthesis in hypothyroidism the
H2O2 is accumulation so catalase will rise to
direct hydrogen peroxide, break down and
transfer it into water and oxygen. Increase
oxidative stress is also thought for extreme
autoimmune response by amplifying
inflammation or causing a fall in thyroid
hormone production by means of raising
7
6
5
GST (U/ml)
4
3
2
1
0
0 25 50
Figure-6: Correlation of serum glutathione-S-transferase (GST) in hypothyroidism women patients.
The enzyme catalase is not the only way to
clear the hydrogen peroxide buildup
associated with Hashi’s. There was an
interesting article published May 2017 in
Thyroid, The Official Journal of the American
Thyroid Association. Researchers evaluated
participants with Hashimoto’s. They looked
at various biomarkers especially iron (in
menstruating women), selenium, and vitamin
D status.
They found that selenium is essential to
thyroid action. And the reason was that the
selenium helped form glutathione which …
and I’ll quote them, “protect the thyroid by
removing excessive hydrogen peroxide.” Their
study suggested that some selenium would be
helpful, especially in iodine-deficient areas.
The researchers recommended about 50-100
mcg per day.
©2009-2018, JGPT. All Rights Reserved
tissue injury. There are a few information to
determine effects of levothyroxine therapy on
oxidant and antioxidant molecules because
lack of articles in the literature [47].
Significant (p<0.05) positive correlation was
obtained for GST levels with thyroxine in
treated hypothyroid women Figure-6. This
result is consistent with P Pasupathi et. al.,
that attributed the decrease the GST activity
in hypothyroidism and increases with
thyroxine [48]. While our result is different
from Gupta BL et. al.,that recognized
thyroxine treatment resulted in maintaining
the GST activity at control levels [49].
Nevertheless, this outcome is change from
Coeckes et. al., that identify the Tri-
iodothyronine (T3), and thyroxine (T4)
reduced GST activities [50].
75 100 125 150 175 200 225 250
Thyroxine ug
They also recommended that clinicians check
patients’ iron (particularly in menstruating
women) and Vitamin D status to correct any
deficiencies [51]. Our results recommend that
levothyroxine therapy reductions oxidant
status and rises antioxidant status.
This situation support to believe that
deficiency of thyroid hormone may be
efficient in raising the oxidative stress of
hypothyroid patients. In the rational
regression analysis, evaluation of oxidative
stress index (OSI) as an independent hazard
factors for the hypothyroidism further more
assist this fact. More researches are
necessary to explain whether the oxidative
stress is a source or outcome of
hypothyroidism [52].
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These results are supports by Ricardo  Hypothyroidism is associated with elevated

Gredilla, et. al., that indicate thyroid oxidative stress.
hormones modulate oxidative damage to
lipids and DNA, and cellular redox potential  Thyroxine tablets are modulate the
in the mouse heart [53]. oxidative stress in treated hypothyroid
women patients.
Conclusions

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