Farhangi et al.

BMC Complementary and Alternative Medicine (2016) 16:471

DOI 10.1186/s12906-016-1432-2

RESEARCH ARTICLE Open Access

The effects of Nigella sativa on thyroid

function, serum Vascular Endothelial
Growth Factor (VEGF) – 1, Nesfatin-1 and
anthropometric features in patients with
Hashimoto’s thyroiditis: a randomized
controlled trial
Mahdieh Abbasalizad Farhangi1*, Parvin Dehghan1, Siroos Tajmiri2 and Mehran Mesgari Abbasi3

Abstract
Background: Hashimoto’s thyroiditis is an autoimmune disorder and the most common cause of hypothyroidism.
The use of Nigella sativa, a potent herbal medicine, continues to increase worldwide as an alternative treatment of
several chronic diseases including hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM). The aim of the
current study was to evaluate the effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth
Factor (VEGF) – 1, Nesfatin-1 and anthropometric features in patients with Hashimoto’s thyroiditis.
Methods: Forty patients with Hashimoto’s thyroiditis, aged between 22 and 50 years old, participated in the trial
and were randomly allocated into two groups of intervention and control receiving powdered Nigella sativa or
placebo daily for 8 weeks. Changes in anthropometric variables, dietary intakes, thyroid status, serum VEGF and
Nesfatin-1 concentrations after 8 weeks were measured.
Results: Treatment with Nigella sativa significantly reduced body weight and body mass index (BMI). Serum
concentrations of thyroid stimulating hormone (TSH) and anti-thyroid peroxidase (anti-TPO) antibodies decreased
while serum T3 concentrations increased in Nigella sativa-treated group after 8 weeks. There was a significant
reduction in serum VEGF concentrations in intervention group. None of these changes had been observed in
placebo treated group. In stepwise multiple regression model, changes in waist to hip ratio (WHR) and thyroid
hormones were significant predictors of changes in serum VEGF and Nesgfatin-1 values in Nigella sativa treated
group (P < 0.05).
Conclusions: Our data showed a potent beneficial effect of powdered Nigella sativa in improving thyroid status
and anthropometric variables in patients with Hashimoto’s thyroiditis. Moreover, Nigella sativa significantly reduced
serum VEGF concentrations in these patients. Considering observed health- promoting effect of this medicinal plant
in ameliorating the disease severity, it can be regarded as a useful therapeutic approach in management of
Hashimoto’s thyroiditis.
Trial registration: Iranian registry of clinical trials (registration number IRCT2015021719082N4- Registered
March-15-2015).
Keywords: Hashimoto’s thyroiditis, Nigella sativa, VEGF, Nesfatin-1

* Correspondence: abbasalizad_m@yahoo.com
1
Nutrition Research Center, Department of Community Nutrition, School of
Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
Full list of author information is available at the end of the article

© The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Farhangi et al. BMC Complementary and Alternative Medicine (2016) 16:471 Page 2 of 9

Background with cardiac dysfunction, left ventricular hypertrophy

Hashimoto’s thyroiditis (HT) is an organ-specific T-cell [18, 19] and rapid bone loss [20]. Nigella sativa is one of
mediated disease that affects the thyroid glands and is the medicinal plants and belongs to the Ranunculaceae
one of the most common human autoimmune disorders family [21]. The seeds of the Nigella sativa are the main
[1]. The disease affects 2% of general population and is source of its active ingredients with considerable health
ten times more prevalent in women than in men [2, 3]. promoting effects including antioxidant, anti-inflammatory
A significant proportion of patients have asymptomatic and immune-modulatory properties and no side effects
chronic autoimmune thyroiditis and 8% of woman (10% [21, 22]. Numerous researches have extensively studied
of woman over 55 years of age) and 3% of men have therapeutic actions of Nigella sativa in improving chronic
subclinical hypothyroidism [4]. disease status including diabetes, hyperlipidemia, hyperten-
Hashimoto’s thyroiditis is characterized by the presence sion and gastritis especially in animal models; while human
of thyroid auto-antibodies such as anti-thyroid peroxidase studies in this filed are scarce and limiting [23, 24]. More-
(TPO-Ab) and anti-thyroglobulin (TG-Ab) antibodies in over the health effects of Nigella sativa in Hashimoto’s
the serum while these antibodies have potential ability to thyroiditis has been studied in only one animal model indi-
deteriorate thyroid cells [5, 6]. The disease is characterized cating its protective role in reversing hypothyroid status
by gradual thyroid failure and occasional goiter develop- and ameliorating oxidative stress and thyroid cell dam-
ment and the untreated forms of Hashimoto’s thyroiditis age in propylthiouracil (PTU)-induced hypothyroidism
can ever lead to papillary thyroid cancer and thyroid in rats [25]. In the current randomized clinical trial we
carcinoma [7, 8]. aimed to evaluate the potential therapeutic effects of
From pathological point of view, thyroid enlargement Nigella sativa powder on thyroid function and serum
and hyper-function in Hashimoto’s thyroiditis is accom- VEGF and Nesfatin-1 concentrations in patients with
panied by a markedly increased blood flow and increased Hashimoto thyroiditis.
vascularization [9]. A number of growth and vasoactive
factors are produced in thyroid and are considered to be Methods
potentially responsible for changes in thyroid microvas- Patients
culature and blood flow; vascular endothelial growth fac- In the current double-blinded placebo-controlled trial,
tors (VEGF) is a hemodynamic glycoprotein with potent 40 patients with Hashimoto’s thyroiditis were enrolled
angiogenic and vascular permeability enhancing activ- (Fig. 1). Subjects were recruited from outpatient endo-
ities [10]. It has been proposed that VEGF and its recep- crinology and metabolism clinics of Isfahan University of
tors are present in epithelial cells of the thyroid and Medical Sciences. Inclusion criteria were as follows: age
contribute in regulation of development and function of between 20 and 50 years and having Hashimoto’s thy-
thyroid epithelial cells [10]. In fact VEGF is unique among roiditis according to physician diagnosis. Exclusion cri-
angiogenic factors because it is both vascular endothelial teria were as follows: taking any nutritional supplements
cell-specific mitogen and is secreted by thyroid cancer for at least 3 months prior participation or during the
cells and high thyroid stimulating hormone (TSH) con- trial, any history of autoimmune disease, cardiovascular
centrations in Hashimoto’s thyroiditis promotes VEGF events, other thyroid abnormalities including Grave’s
secretion from thyroid cancer cell lines [11]. disease, being pregnant or lactating, any history of thyroid
Nesfatin-1, a peptide secreting from peripheral tissues, surgeries and being on any dietary regimens during and 3
central and peripheral nervous system, is involved in the months before recruitment in the trial. Participants were
regulation of energy homeostasis related with food con- treated with levothyroxine while the drug dosage was
sumption mostly by passing through the blood–brain bar- stable from 6 weeks prior participation in the study to the
rier [12]. Moreover, several recent studies have proposed end of the trial. The average full replacement dose of
the possible role of Nesfatin-1 in in thyroid dysfunction levothyroxine sodium was approximately 1.7 mcg/kg/day
[13, 14]. Liu et al. [15] reported that plasma Nesfain-1 (e.g., 100–125 mcg/day for a 70 kg adult).
levels are independently correlated with serum TSH con-
centrations in patients with T2DM. The Nesfatin-1 Study design
immuno-positive neurons have been reported to be co- From 100 recruited subjects, 53 participants were ex-
localized with thyrotropin releasing hormone (TRH) cluded because of not meeting the inclusion criteria or
neurons in the paraventricular nucleous (PVN) and the decline to participate. Among remaining 47 patients,
central Nesfatin-1 affects the membrane potential of TRH random permuted block procedure was performed and
neurons suggesting the possible role of Nesfatin-1 in regu- participants were randomly allocated into Nigella sativa-
lation of thyroid hormone function [16, 17]. treated (n = 23) or placebo-treated (n = 24) groups. Dur-
Levothyroxine sodium is the treatment of choice for ing the trial, three patients in Nigella sativa-treated
Hashimoto’s thyroiditis; however its chronic use is related group were excluded from the study because of itching
Farhangi et al. BMC Complementary and Alternative Medicine (2016) 16:471 Page 3 of 9

Fig. 1 CONSORT Flow diagram of subject recruitment

and nausea; while four patients in control group refused two capsules daily, taking it immediately before lunch
to continue the trial. Therefore, totally 20 patients in and dinner respectively.
each group completed the study. Patients in the inter- Randomization procedure was performed by a third
vention group received a daily dose of 2 g Nigella sativa investigator who had no clinical involvement in the trial
powder per day and placebo group received 2 g starches to ensure complete blinding in the randomization process.
per day for 8 weeks. The dose of the Nigella sativa and Randomization was done according to computer- gener-
time period of the study had been selected according to ated numbers and was kept in consecutively numbered
review of the previous studies indicating the effective- envelopes opened at the moment of participant enroll-
ness of 2 g of Nigella sativa or even lesser doses and ment into the study. A follow-up procedure was done with
8 weeks study duration in treatment of numerous meta- weekly telephone contacts to ensure that subjects con-
bolic disorders including immune disturbances and lipid sumed the supplements regularly.
abnormalities [26, 27].
Black seed powders were obtained from corns grown Anthropometric and nutritional assessments
in Isfahan bought by a local market (Sad-Giah market, Body weight and height were measured with a calibrated
Isfahan, Iran) and were prepared by the Goldaroo digital scale and stadimeter respectively. BMI was calcu-
pharmaceutical company (Goldaro Pharmaceutical Co. lated as weight (kg) divided by height (cm) squared. Waist
Isfahan, Iran). The black seeds were milled in a grinder circumference (WC) was measured in horizontal plane,
and a purified powder was prepared. The seeds were midway between the lowest rib and the iliac crest with a
identified and authenticated by Dr. Mahdieh Abbasalizad measuring tape in centimeter. Waist to hip ratio (WHR)
Farhangi, supervisor of the project from Department of was calculated by WC divided by hip circumference (HC).
Nutrition, Tabriz University of Medical Sciences, Tabriz, The dietary assessments were performed using a 3-day
Iran. Thereafter, Nigella sativa seeds were processed into food record, covering two weekdays and one weekend
pharmaceutical grade capsules containing Nigella sativa day, to estimate total energy, carbohydrate, protein, fat
powder and bottled according to Good Manufacturing and antioxidant vitamins consumption. Because of the
Practices (GMP). Each capsule was prepared containing antioxidant nature of Nigella sativa the intake of vitamin E
1 g powder of Nigella Sativa, and each bottle contained and C were specifically evaluated to ensure that no change
112 capsules, for 8 weeks period of the study. While for in their consumption has been occurred throughout the
the placebo, we used starch bought from the same trial and to rule out their possible confounding effect on
market and the entire processes of its capsulation was study parameters. Nutrient analysis of the 3-day food
similar to Nigella sativa seeds preparation. Partici- record was performed using the Nutritionist IV software
pants in intervention and placebo groups received (N-squared Computing, Salem, OR, USA).
Farhangi et al. BMC Complementary and Alternative Medicine (2016) 16:471 Page 4 of 9

Biochemical assays change in placebo-treated group has been occurred

Fasting blood samples were obtained from all of the (Table 1). Dietary energy and nutrient intakes before and
participants at the beginning and end of the trial. The after intervention are presented in Table 2. Energy and
serum and plasma samples were separated by centrifuga- nutrient intakes were similar between groups before inter-
tion at 2500 rpm for 10 min (Beckman Avanti J-25; vention and no significant change was observed after inter-
Beckman Coulter, Brea, CA, USA) at room temperature. vention. Serum TSH and anti-TPO concentrations reduced
The serum samples were stored at −70 °C immediately while serum T3 increased in Nigella sativa treated group
after centrifugation until their assays. Serum thyroid- (P < 0.05). Moreover, serum VEGF reduced significantly
stimulating hormone (TSH), total triiodothyronine (T3) after 8 weeks of Nigella sativa supplementation (P = 0.02,
and total thyroxine (T4) were analyzed by enzyme linked Table 3). In stepwise multiple linear regression analysis
immunosorbent assay (ELISA Kit, Pishtaz Tebe Co., when change in serum VEGF concentrations was entered
Tehran, Iran) according to the manufacturer’s instruc- as dependent variable and change in anthropometric vari-
tions. Anti-thyroid peroxidase antibody was measured ables and thyroid hormones as independent variables
by the commercially solid-phase ELISA kit (Aeskulisa, (Table 4) one model was obtained indicating change in
Wendelsheim, Germany). Serum concentration of VEGF WHR as predictor of change in VEGF concentrations. In
and Nesfatin-1 were measured by commercial ELISA kits similar procedure when change in serum Nesfatin-1 was
(Hangzhou East biopharm Co, USA). The sensitivity of entered as dependent variable, change in WHR, TSH and
these assays was 10.42 ng/l and 0.15 ng/ml respectively. T3 were its predictors (P < 0.05).

Statistical assays Table 1 General characteristics and anthropometric variables in

Statistical analysis was performed by SPSS™ statistical treatment groups before and after intervention
software (SPSS Inc., Chicago, IL, USA). Quantitative data N Nigella sativa Placebo P†
were presented as mean ± standard deviation (SD), and N = 20 N = 20
qualitative data were demonstrated as frequency and Age (years) 35.70 ± 8.18 33.95 ± 8.72 0.52
percent. One-sample Kolmogorov-Smirnov test was
Levothyroxine (mcg/d) 119.85 ± 24.12 118.46 ± 22.12 0.91
used to assess the normality of data. Between groups
comparisons of continuous variables were performed by Female [n (%)] 17 (85) 17 (85) 0.89
independent sample t-test. Paired t-test was used for before Weight (kg)
and after intervention comparisons. Analysis of covariance Before 70.52 ± 12.27 69.63 ± 11.75 0.81
(ANCOVA) was used to identify any differences between After 69.39 11.84 69.62 11.80 0.95
two treatment groups after intervention adjusting for the P‡ 0.004 0.91
confounding effects of baseline concentrations of para-
BMI (kg/m2)
meter, age and gender. Stepwise multivariate linear regres-
sion model was used to evaluate the predictors of changes Before 27.10 ± 4.63 25.93 ± 4.07 0.40
in VEGF and Nesfatin-1 concentrations. P-values less than After 26.63 4.42 25.95 4.11 0.61
0.05 were considered to be significant. Sample size calcula- P‡ 0.002 0.65
tion was performed based on 80% power and an α-error of Waist Circumference (cm)
5% to detect treatment effect of Nigella sativa on serum Before 88.56 ± 7.29 88.69 ± 7.41 0.95
TSH. Totally, 14 individuals were calculated. Allowing for
After 87.72 ± 6.92 88.57 ± 7.35 0.71
30% drop-out over 8 weeks of intervention, the total sample
size required for the study was 40 individuals. P‡ 0.006 0.17
HC (cm)
Results Before 102.85 ± 6.25 101.77 ± 6.84 0.61
The flowchart of the study is given in Fig. 1. A total of After 101.56 ± 5.51 101.56 ± 7.02 0.99
40 patients completed the study. Three patients in P‡ 0.001 0.08
Nigella sativa-treated group were excluded from the
WHR
study because of itching and nausea; while four patients
in control group refused to continue the trial. No other Before 0.86 ± 0.052 0.87 ± 0.053 0.53
side effects were observed in the current study. After 0.86 ± 0.05 0.87 ± 4.11 0.61
At baseline, there was no significant difference in P‡ 0.38 0.53
general characteristics among groups. Nigella sativa BMI body mass index, WC waist circumference, HC hip circumference, WHR
supplementation significantly reduced anthropometric waist to hip ratio, †P values for ANOCOVA after adjustment for age, gender,
duration of the disease and variable’s baseline value; ‡P values for paired
variables including weight, BMI, WC and HC in patients t-test. Data are presented as mean ± SD or number (percent), the bolded
with Hashimoto’s thyroiditis (P < 0.05); while no significant P values are statistically significant
Farhangi et al. BMC Complementary and Alternative Medicine (2016) 16:471 Page 5 of 9

Table 2 Dietary intakes of energy and nutrients in treatment Table 3 Metabolic parameters in treatment groups before and
groups before and after intervention after intervention
N Nigella sativa Placebo P† N Nigella sativa Placebo P†
N = 20 N = 20 N = 20 N = 20
Total calories (kcal/d) TSH (mIU/l)
Before 2251.90 ± 349.58 2208.95 ± 327.80 0.69 Before 6.42 ± 3.86 8.14 ± 7.28 0.35
After 2236.40 ± 248.27 2265.45 ± 270.73 0.72 After 4.13 ± 2.35 8.27 ± 7.21 0.02
P‡ 0.77 0.32 P‡ 0.03 0.40
Carbohydrate (%) T3 (mmol/l)
Before 57.11 ± 2.90 57.07 ± 3.78 0.97 Before 0.92 ± 0.27 1.18 ± 0.36 0.017
After 57.24 ± 2.71 57.58 ± 3.32 0.72 After 1.06 ± 0.34 1.16 ± 0.35 0.39
P‡ 0.26 0.67 P‡ 0.008 0.15
Protein (%) T4 (mmol/l)
Before 15.73 ± 1.68 15.07 ± 1.29 0.17 Before 8.07 ± 2.56 7.97 ± 3.11 0.91
After 15.77 ± 1.36 15.10 ± 1.81 0.19 After 8.89 ± 1.43 7.63 ± 2.23 0.04
P‡ 0.94 0.94 P‡ 0.21 0.32
Fat (%) Anti-TPO (IU/ml)
Before 27.34 ± 2.15 26.57 ± 2.32 0.28 Before 294.55 ± 210.05 278.10 ± 170.77 0.78
After 26.56 ± 1.96 26.13 ± 2.48 0.55 After 147.99 ± 158.33 274.30 ± 167.20 0.01
P‡ 0.51 0.51 P‡ 0.019 0.28
Vitamin E (mg/d) Nesfatin-1 (ng/ml)
Before 2.98 ± 1.08 3.43 ± 1.48 0.36 Before 41.80 ± 28.33 25.86 ± 20.91 0.049
After 2.89 ± 1.64 3.40 ± 1.19 0.28 After 37.63 ± 5.91 26.75 ± 23.95
P‡ 0.80 0.96 P‡ 0.34 0.69
Vitamin C (mg/d) VEGF (ng/L)
Before 79.75 ± 22.69 75.67 ± 17.24 0.52 Before 3521.13 ± 395.95 2101.73 ± 339.29 0.17
After 28.37 ± 11.84 75.45 ± 15.36 0.59 After 2100.17 ± 36,082 2100.17 ± 360.82 0.25
P‡ 0.77 0.91 P‡ 0.02 0.99
Data are presented as mean ± SD, †P values for ANOCOVA after adjustment for Data are presented as mean ± SD. † P values for ANOCOVA after adjustment
age, gender, duration of the disease and variable’s baseline value; ‡P values for age, gender and baseline concentration of parameter; ‡P values for paired
for paired t-test t-test. TSH, thyroid-stimulating hormone; T3 triiodothyronine, T4 thyroxine,
VEGF vascular endothelial growth factor, the bolded P values are statistically
significant
Discussion
In the current study we showed a meaningful impact of 8
weeks treatment with Nigella sativa on thyroid function,
anthropometric features and serum VEGF concentrations Table 4 Stepwise multivariate linear regression analysis in Nigella-
in patients with Hashimoto’s thyroiditis. However changes sativa treated group with changes in VEGF and Nesfatin-1 as
in serum Nesfatin-1 concentrations were not significant. dependent variables and changes in anthropometric variables and
These findings were in accordance of findings of two ani- thyroid hormones as dependent variables
mal studies; in one study by Khalawi AA [25] Nigella B SE β t P
sativa oil improved hypothyroid status and decreased Δ Nesfatin (as dependent variable)
serum TSH concentrations in rats; in other animal study Δ WHR 387.54 183.92 0.24 2.10 0.05
by Al-Asoom et al. [28] daily oral administration of Δ TSH 1.34 0.63 0.30 2.11 0.05
800 mg/kg Nigella sativa in male Wistar rats reduced
ΔT3 −59.11 14.49 −0.63 −4.07 0.001
serum thyroxine concentrations. However in our study,
Δ VEGF (as dependent variable)
for the first time, we clearly demonstrated its beneficial
role on improving thyroid function in human. ΔWHR 35449.84 18234.88 0.31 1.94 0.05
The seeds of Nigella sativa known as black seeds or WHR waist to hip ratio, TSH thyroid-stimulating hormone, T3 triiodothyronine,
T4 thyroxine, VEGF vascular endothelial growth factor, B unstandardized coefficient,
black cumin have long been used in folk medicine in the SE standard error, β standardized coefficient, t the student’s t distribution, P level
middle and Far East as a traditional medicine for a wide of significance
Farhangi et al. BMC Complementary and Alternative Medicine (2016) 16:471 Page 6 of 9

range of disease including infections, obesity, hyperten- Moreover, in the current study, change in WHR was a
sion and gastrointestinal problems [21]. Its most prom- significant positive predictor of changes in serum VEGF
inent constituent with well- known antioxidant, anti- in Nigella sativa treated group. In fact, VEGF is a multi-
inflammatory and anti-cancer properties is thyimoqui- functional cytokine and its elevated concentration has
none [29]. Thyimoquinone has potential cytoprotective been reported previously in several metabolic disorders
and anti-inflammatory effects; it has been reported that including type 2 diabetes mellitus and polycystic ovary
its anti-inflammatory effects are induced by up-regulated syndrome. A positive association between serum VEGF
expression of heme-oxygenase-1 and suppression of the and its different genomic variants with the components
cyclooxygenase-2 (COX-2) expression in different cell lines of metabolic syndrome including central obesity and
[30]. Thyimoquinone also differentially modulated thyroid waist to hip ratio has also been previously reported
hormones and improved thyroid status in rats [31]. Thera- [44, 45]. This relationship arise from this fact that adipo-
peutic effects of Nigella sativa against hypothyroidism is cytes, specially white adipose tissue cells, produce VEGF
mostly attributed to its antioxidant effects which have been which may act as an angiogenic and vascular survival fac-
proved in numerous studies [32–34]. It has also been sug- tor for the omental vasculature and has paracrine or sys-
gested that Nigella sativa protects the hyperplasic changes temic endocrine actions, these might hypothetically
of thyroid parenchyma in hypothyroid rats [25]. Accord- impact on adipose expansion or the vascular comorbidi-
ingly, increment in T3 concentrations after treatment with ties of obesity related disease [46]. In this context, it is in-
Nigella sativa in the current study, has also been reported teresting that Randeva et al. could reported a strong
in the study by Ismail et al. [35] and the authors concluded correlation of serum VEGF with waist-to-hip ratio in a
that Nigella sativa could raise the lowered serum triiodo- considerable cohort of individuals (χ2 = 17.42; P < 0.001)
thyronine concentration without changing the concentra- [47], a measure that, is suggested to be a better marker
tion of serum TSH because of its potential ability in of subclinical arteriosclerosis and endothelial dysfunc-
repairing the thyroid gland and resynthesizing the thyroid tion [48] which are common clinical consequences of
hormone; therefore its therapeutic action could be in part Hashimoto’s thyroiditis [49, 50].
due to antioxidant defense system. Accordingly, reduction Weight reducing effects of Nigella sativa has been ob-
of serum anti-TPO concentrations after treatment with served in previous studies; Zaoui A [51] reported a signifi-
Nigella sativa could be explained by its immunomodulatory cant reduction in body weight in rats after 6 weeks
effects approved previously by its protective roles against treatment with Nigella sativa fixed oil (P < 0.001). In other
several autoimmune disease including type 1 diabetes melli- study 3 month supplementation with 1.5 g per day of
tus and experimental autoimmune encephalomyelitis (EAE) powdered Nigella sativa in central obese men significantly
[36, 37]. The possible underlying mechanisms of immuno- reduced body weight [52]. One suggested mechanism is
modulatory effects of Nigella sativa are reduced synthesis of increasing mean rates of satiety and fullness [53]; although,
auto-antibodies, reduced innate and acquired immune cell we did not observe any change in dietary energy or nutri-
markers and reduction in transforming growth factor ent intakes after intervention. Other possible mechanisms
(TGF)-β and interleukin (IL)-23 concentrations [36–38]. are reduced lipid absorption, increased energy expenditure,
VEGF is minimally expressed in normal human thy- decreased pre-adipocyte differentiation and proliferation,
roid cells [39]; however in pathological situations, en- or decreased lipogenesis and increased lipolysis [54]. The
hanced TSH concentrations, is a potent stimulator of suggested underlying mechanisms of the effects Nigella
VEGF secretion [11]. It has been shown that VEGF and sativa and its major ingredient thymoquinone’s on thyroid
one of its receptors, Flt-1, are present in epithelial cells health and body weight are summarized in Fig. 2.
of the thyroid, and VEGF contributes to the regulation Hashimoto’s thyroiditis is more prevalent among fe-
of development and function of thyroid epithelial cells males compared with males and women are up to 10
[10]. Higher VEGF concentrations are associated with times more likely to develop the disease compared with
increased risk of recurrence and decreased disease-free men [55]. This strong female association remains unex-
survival in papillary thyroid cancer [40]. Strong expres- plained although our hunch is that sex steroids have
sion of VEGF has been reported in thyroiditis and thy- the critical role, as there is compelling evidence for
roid carcinomas [41]; therefore it is a critical cytokine in such effects in animal models of many types of auto-
tumor angiogenesis and will be a potent target of diag- immunity [56]. Other possible explanations include
nosis and therapy. In the current study, Nigella sativa skewed X chromosome inactivation and fetal microchi-
had a strong impact in reducing VEGF concentrations in merism [57]. Accordingly, the number of the female
Hashimoto’s thyroiditis. It is mostly because of anti- participants in the current study was more than men,
angiogenic effects of Nigella sativa and its major bio- but the gender distribution among two groups were
active compound, thyimoquinone, which has been equal. Therefore, the possible confounding effect of
proven previously in different cancer cell lines [42, 43]. gender could be rule out. Moreover, the comparisons
Farhangi et al. BMC Complementary and Alternative Medicine (2016) 16:471 Page 7 of 9

Fig. 2 The probable mechanisms of the effects of Nigella Sativa and its major ingredient Thymoquione on thyroid status and body weight. TSH
thyroid stimulating hormone, T3 triiodotyronin, VEGF vascular endotheilial growth factor

between all of the study parameters are adjusted for the Abbreviations
possible confounding effects of age, gender and vari- BMI: Body mass index; HC: Hip circumference; T3: Triiodotyronine;
T4: Thyroxine; TG-Ab: Thyroglobulin antibody; TPO-Ab: Thyroid peroxidase
able’s baseline values by ANCOVA. antibody; TRH: Thyrotropin releasing hormone; TSH: Thyroid stimulating
In the current study serum Nesfatin-1 did not change hormone; VEGF: Vascular endothelial growth factor; WC: Waist circumference;
after Nigella sativa supplementation in Hashimoto’s thy- WHR: Waist to hip ratio

roiditis patients. The studies regarding the relationship Acknowledgement

between serum Nesfatin-1 concentrations and thyroid The current research was financially supported by a grant from Tabriz University
dysfunction are scarce and conflicting. One study in of Medical Sciences.
children demonstrated its reduced concentrations in
Funding
children with untreated subclinical hypothyroidism [13]; This research has been performed by a grant from Tabriz University of Medical
while, other study by Sahin et al. [58] reported no differ- Sciences (Project number: 93173).
ence in serum Nesfatin-1 concentrations in patients with
Availability of data and materials
hypothyroidism compared with healthy control group.
The data are available for any scientific use with kind permission.
Nesfatin-1 is colocalized with TRH and affects the mem-
brane potential of TRH neurons in the paraventricular Authors’ contributions
nucleus, which is known to be closely related to the MAF conceived and designed the project and wrote the manuscript and
performed the statistical analysis, PD was involved in manuscript revision, ST
regulation of thyroid function [15]. However we did not performed the sampling and data collection and MMA was involved in lab
find any change in its concentrations after treatment works. All authors read and approved the final manuscript.
with Nigella sativa. It could be due to relatively small
sample size or treatment duration. Competing interests
The authors declare that they have no competing interests.

Conclusions Consent for publication

We have demonstrated beneficial effects of Nigella sativa Not applicable.
in improving thyroid status, reducing VEGF and body
Ethics approval and consent to participate
weight in patients with Hashimoto’s thyroiditis. Although All participants signed a written informed consent approved by the Institutional
no significant change in serum Nesfatin-1 concentrations Review Board of Tabriz University of Medical Sciences. The study design and
has been observed, change in anthropometric variables protocol was approved by the ethical committee of Tabriz University of Medical
Sciences (Project number: 93173). The study has also been registered in Iranian
and thyroid hormones were significant predictors of registry of clinical trials (registration number IRCT2015021719082N4- Registered
changes in serum Nesfatin-1 concentrations. March-15-2015).
Farhangi et al. BMC Complementary and Alternative Medicine (2016) 16:471 Page 8 of 9

Author details 22. Dollah MA, Parhizkar S, Latiff LA, Hassan MHB. Toxicity effect of Nigella
1
Nutrition Research Center, Department of Community Nutrition, School of sativa on the liver function of rats. Adv Pharm Bull. 2013;3(1):97–102.
Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran. 2Student 23. Kanter M, Coskun O, Budancamanak M. Hepatoprotective effects of Nigella
Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. 3Drug sativa L and Urtica dioica L on lipid peroxidation, antioxidant enzyme
Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. systems and liver enzymes in carbon tetrachloride-treated rats. WJG. 2005;
11(42):6684–8.
Received: 4 May 2016 Accepted: 2 November 2016 24. Abdel-Sater KA. Gastroprotective effects of Nigella Sativa oil on the formation
of stress gastritis in hypothyroidal rats. Int J Physiol Pathophysiol Pharmacol.
2009;1(2):143–9.
25. Khalawi AA, Al-Robai AA, Khoja SM, Shaker AS. Can Nigella Sativa oil (NSO)
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