Complementary Therapies in Medicine 48 (2020) 102245

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Complementary Therapies in Medicine

journal homepage: www.elsevier.com/locate/ctim

Efficacy of Salvia officinalis extract on the prevention of insulin resistance in T

euglycemic patients with polycystic ovary syndrome: A double-blinded
placebo-controlled clinical trial
Leila Amini (PhD)a,1, Faraz Mojab (PhD)b,2, Shayesteh Jahanfar (PhD)c,3,
Mahdi Sepidarkish (PhD)d,4, Zahra Raoofi (MD)e,5, Arezoo Maleki-Hajiagha (MSc)a,f,*
a
Department of Midwifery, School of Nursing and Midwifery, Iran University of Medical Sciences, Tehran, Iran
b
Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
c
Department of Public Health, the Herbert H. & Grace A. Dow College of Health Professions, Central Michigan University, United States
d
Department of Biostatistics and Epidemiology, Babol University of Medical Sciences, Babol, Iran
e
Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
f
Research Development Center, Arash Women’s Hospital, Tehran University of Medical Sciences, Tehran, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Objectives: At the present study, we aimed at evaluating the effect of Salvia officinalis (S. officinalis) extract on
Polycystic ovary syndrome "anthropometric indices" and "insulin resistance markers" in Polycystic Ovary Syndrome (PCOS) patients.
Metabolism disorders Design and setting: This was a randomized, triple-blinded, controlled trial performed in gynecology hospitals
Insulin resistance affiliated to Iran University of Medical Sciences.
Obesity
Participants: Sixty PCOS patients diagnosed according to Rotterdam criteria.
Salvia officinalis
Interventions: Consumption of the 330 mg oral S. officinalis extract or placebo capsules daily for eight weeks.
Common sage
Main outcome measures: Body mass index (BMI), waist to hip ratio (WHR), blood pressure, homoeostatic model
assessment-insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI).
Results: Results showed a statistically significant decrease in the BMI (P = 0.001) in S. officinalis group, but, there
were no significant differences between the two groups for WHR (P = 0.164). Although we failed to find a
significant effect of S. officinalis extract on systolic blood pressure (P = 0.283) but using a multivariate model
showed a significant difference between two groups regarding diastolic blood pressure (P = 0.025). Also, the
consumption of S. officinalis extract, compared to the placebo, resulted in a significant decrease in Insulin levels
(P < 0.001), and HOMA-IR (P < 0.001). As well as, S. officinalis extract supplementation resulted in a greater
increase in QUICKI (P < 0.001) compared with placebo groups.
Conclusion: S. officinalis extract at a dose of 330 mg/day could decrease BMI and systolic blood pressure, and it
could enhance insulin resistance markers in euglycemic PCOS patients.
Trial Registration: Iranian Registry of Clinical Trials (IRCT201504146917N2, 2015-10-03).

1. Background
Polycystic ovary syndrome (PCOS) is the most common en-
docrinopathy in women of reproductive age.1 Irregular menstrual cy-
cles, clinical or biochemical hyperandrogenemia, anovulatory
infertility, and metabolic risk factors are common complications of this
syndrome. 2,3 Women with PCOS are found to have an increased pre-
valence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM),
4
and insulin resistance. 5
Management of underlying metabolic abnormalities and reduction

⁎
Corresponding author at: Arash Women’s Hospital, Eastern 162th St., Baghdarnia st., Resalat Highway, Tehranpars, Tehran, Iran.
E-mail addresses: amini.l@iums.ac.ir (L. Amini), sfmojab@sbmu.ac.ir (F. Mojab), jahan2s@cmich.edu (S. Jahanfar),
mahdisepidarkish@gmail.com (M. Sepidarkish), raoofi.z@iums.ac.ir (Z. Raoofi), a-maleki@farabi.tums.ac.ir (A. Maleki-Hajiagha).
1
Iran School of Nursing & Midwifery, Rashid Yasemi St., Valiasr St., Tehran, Iran.
2
Shahid Beheshti School of Pharmacy, Niayesh Highway, Valiasr Ave, Tehran, Iran.
3
Dow College of Health Professions,Central Michigan University,1280 E Campus, Dr Mount Pleasant, MI 48859.
4
Babol University of Medical Sciences, Ganjafrooz Street, Babol, Mazandaran, Iran.
5
Firoozgar Hospital, Beh Afarin St.,Karim Khan Zand Ave. Tehran, Iran.

https://doi.org/10.1016/j.ctim.2019.102245
Received 23 July 2019; Received in revised form 19 October 2019; Accepted 12 November 2019
Available online 13 November 2019
0965-2299/ © 2019 Elsevier Ltd. All rights reserved.
L. Amini, et al.
of risk factors for insulin resistance, T2DM, and cardiovascular diseases
(CVD) is one of the main goals in the treatment of women with PCOS.
According to the literature, for most women with PCOS, weight loss is
the first-line of the interventions because it can restore ovulatory cycles
and improve metabolic risk. 6 Evidence suggests that lifestyle inter-
ventions (structured dietary, exercise, or behavioral intervention) are
effective for improvement of body composition, hyperandrogenism,
and insulin resistance in women with PCOS. 7 However, treatment
adherence is often low, drop-out rates are high, and most of the initial
weight loss is regained within one year. The success of lifestyle inter-
ventions depends on the patient's adherence to the weight loss program.
The manifestations of PCOS can return if the patient regains the lost
weight. 8,9 Therefore, pharmacotherapeutic support with antiglysemic
and weight lowering agents like metformin, orlistat, acarbose, and
thiazolidinediones may be helpful in these patients because of their
potential abilities in boosting metabolism and lowering insulin and
glucose levels. 10–12 However, most of these drugs have various side
effects, such as gastrointestinal disturbances that limit long-term use. 13
Also, clinical data do not support the use of metformin for women with
normal glucose tolerance, and it is not approved for use in prediabetes
or PCOS, although it is often prescribed in these cases. 14,15 Finally,
after extensive studies, there is a lack of long-term, effective, and safe
intervention for the prevention of metabolic complications in patients
with PCOS.
Medicinal plants have been used in Iranian traditional medicine for
centuries. Recent studies provided growing evidence that medicinal
plants, especially phytoestrogens, can regulate ovarian function and
metabolic status in women with PCOS. 16–18 Salvia officinalis (S. offici-
nalis) or common Sage from Lamiaceae family is among herbal agents
that consist of compounds with potential insulin-sensitizing and glu-
cose-lowering effects such as carnosic acid, rosmarinic acid, diterpe-
noids, triterpenoids, flavonoids, polyphenols, and phenolic glyco-
sides.19–24 It is also hypothesized that S. officinalis can prevent the onset
of diabetes in healthy non-diabetic people due to its metformin like
activity. 25 Although according to our literature search, the effect of S.
officinalis in women with PCOS has not yet been evaluated, its anti-
diabetic and metabolism-enhancing properties have been shown in
various studies, and this herb is known to be an effective herbal remedy
for the treatment and prevention of diabetes and dysmetabolism. 26–30
It is worth noting that some methodological flaws limit the strength of
the previous trials.
Our hypothesis in this study is based on the anti-diabetic and me-
tabolism-boosting properties of S. officinalis. We aimed at evaluating
the effect of S. officinalis extract on anthropometric indices and insulin
resistance markers in patients with PCOS to determine the possible role
of this plant in preventing metabolic complications, like insulin re-
sistance, in newly diagnosed PCOS patients.
2. Methods
This study was a randomized triple-blinded placebo-controlled
clinical trial with parallel groups. We evaluated the effect of S. offici-
nalis extract on anthropometric indexes and insulin resistance markers
in patients diagnosed with PCOS according to Rotterdam criteria. 14
2.1. The calculation of sample size
We calculated sample size based on the mean difference of FBS
between two groups of intervention and control. It was assumed that a
total sample of 70 subjects (35 women per group), which included a 15
% dropout factor, would provide 80 % power to detect a clinical sig-
nificance difference in mean of FBS between the intervention and pla-
cebo groups. Assuming means of 80 (mg/dl) in the intervention and 100
(mg/dl) in the placebo group; a standard deviation (SD) of 30; and a
two-sided test having a type I error of 0.05.
2
Complementary Therapies in Medicine 48 (2020) 102245
2.2. Preparations of the S. officinalis extract capsules and the placebo
capsules
The S. officinalis samples were taken from the central herbal market
of Tehran city and were verified by pharmacognosy experts in the
School of Pharmacy, Shahid Beheshti University of Medical Sciences.
We selected the dosage based on the dosage recommended in Iranian
Traditional Medicine (ITM) and also Physician's Desk Reference (PDR)
for Herbal Medicines. According to this two reference, the average daily
internal dose should be 4–6 g of the drug, equal to 150–350 g of the
extract, 31,32 so we selected an average dose of 330 mg of extract per
day. We grounded plant ailment parts by the electrical grinder and
combined the powder with ethanol 96 % (maceration ×3). Then, we
mixed the extract with corn starch and, and manually placed 330 mg of
powdered extract into each capsule (size 0). For the placebo, we filled
the capsules with corn starch alone.
The intervention group received capsules containing 330 mg S. of-
ficinalis extract, and the placebo group received capsules containing
corn starch. The pharmacologist coded each drug box according to the
randomization list. The identities of the codes were only available to
the pharmacognosy expert; therefore, the outcome investigators, par-
ticipant, and the statistician were unaware of the type of intervention
until the end of the study.
2.3. Ethics
The entire process of the study followed the declaration of Helsinki.
All participants signed an informed consent before entering the study.
This research was conducted with the approval of the ethics committee
of Iran University of Medical Sciences (code of ethics is
IR.IUMS.REC.1394.9211373221), and its protocol was registered at the
Iranian website for registration of clinical trials (http://www.irct.ir:
IRCT201504146917N2).
2.4. Study design
The study community was women with PCOS attending to the gy-
necology, infertility, or endocrinology outpatient clinics affiliated to
Iran University of Medical Sciences, Tehran, Iran (2015–2017). The
Iranian, married female, aged 15–40 years, with newly diagnosed
PCOS, according to the Rotterdam criteria, were included in the study.
The Rotterdam criteria require the presence of two of the following
symptoms: 1.oligomenorrhea or amenorrhea, 2.clinical (hirsutism) or
biochemical signs of hyperandrogenism, and 3.polycystic ovaries di-
agnosed with ultrasound. 33 We defined hirsutism as a Ferriman-
Gallwey score greater than eight. 34 We also excluded participants who
use multivitamins or other herbs, oral contraceptives or any other
steroid, and glucose and lipid metabolism affecting agents; patients
with medical and metabolic disorders or a history of vertigo and sei-
zure; pregnant women; women planning for pregnancy; and breast-
feeding women.
Seventy eligible women signed an informed consent form and par-
ticipated in the trial. A group of 35 patients took the S. officinalis extract
at a dose of 330 mg orally once a day for eight weeks, and another
concurrently parallel group of 35 patients took the placebo capsules
once a day for eight weeks. There are conflicting results on the effect of
hormonal agents such as oral contraceptives pills (OCP) on metabolic
status and insulin sensitivity in women with PCOS. 35–37 Therefore,
regarding to control for the confounding effect of such treatments on
the outcome, we used the Salvia officinalis or placebo capsules in all
patients, and any patient who was using medications with potential
metabolic effect (like OCPs, antihyperglycemic or antihyperlipidemic
agents) were excluded from our study.
An independent investigator randomly allocated participants to in-
tervention and control groups by using a random number sequence
generated with STATA software, according to the block randomization
L. Amini, et al.
method. The size of the blocks was six. The randomization list was
concealed from all research staff involved in enrollment and assess-
ment.
All blood samples were collected after fasting for 12 h in the early
morning. After placing blood samples at the room temperature for
20−30 min, the samples were centrifuged at 2500−3500 rpm for
10−15 min. Blood serum was isolated and stored at eighty degrees
below zero for later assessment. Levels of fasting blood sugar (FBS)
(mg/dl) have been measured by Pars Azmoon company enzymatic kits
(Tehran, Iran) and Hitachi 912 autoanalyzer (Japan), and the serum
insulin (mIU/l) levels were determined by ELISA method using the
commercial kit (Insulin: Monobind Inc., Lake Forest, CA, USA) with an
automated microplate reader (Hyperion Inc, USA). Homoeostatic model
assessment-insulin resistance (HOMA-IR) was used to determine the
level of insulin resistance using the following formula: HOMA-IR =
(fasting insulin (μIU/ml) × fasting blood glucose (mg/dl)) / 405·
Quantitative insulin sensitivity check index (QUICKI) was used to de-
termine the degree of insulin sensitivity using the following formula: 1/
(log fasting glucose + log fasting insulin). Height was recorded by a
wall-mountable height rod with an accuracy of 0.1 cm, and weight was
measured by Seca 760 scale with an accuracy of 1 kg. Body mass index
(BMI) was calculated based on the following formula: body weight in
kilograms divided by height in meters squared. An inflexible measuring
tape was used to determine waist circumference (WC) and hip cir-
cumference (HC) with an accuracy of 0.1 cm. The HC was measured at
its maximum over the buttocks, the WC was measured in place of the
smallest circumference between the rib margin and the iliac crest, and
the waist-to-hip ratio (WHR) was calculated by dividing WC to HC. 38
All these variables were measured twice; once before the intervention,
and once eight weeks after starting the intervention.
Participants were reminded to keep their daily routine physical
activity and diet constant throughout the study and not to use any other
herbal remedies, multivitamins, and antioxidants. We monitored the
patients’ compliance by a paper-based table to record their daily intake
of the assigned intervention. We excluded participants who have not
consumed more than 15 % of the capsules from the study. Also, we
followed the participants to check probable complications and com-
pliance with the allocated treatment by a weekly phone call.
2.5. Statistical analysis
The analysis was performed in all randomized women according to
the intention-to-treat approach. We checked the normal distribution by
graphical methods and Kolmogorov–Smirnov test. Baseline demo-
graphic and clinical characteristics were compared between two in-
tervention groups using the student t-test for continuous variables and a
chi-square test for categorical variables. The changes in anthropometric
and insulin resistance indexes of the patients between the beginning
and end of the intervention were compared by analysis of covariance
(ANCOVA). The independent variables were the treatment group, BMI,
parity, and age. The magnitude of effect size presented as the mean
difference with 95% confidence interval. All statistical analyses were
performed with Stata software (Stata Corporation, College Station,
Texas, version 13).
3. Results
We randomly assigned 35 patients to the intervention and 35 pa-
tients to the control group; however, as described in Fig. 1, five patients
in the intervention group and five patients in the control group were
excluded from the study.
Table 1 summarizes the baseline characteristics of 70 PCOS women
enrolled in the study. Random allocation produced a balance between
two arms regarding demographic, reproductive, and lifestyle variables.
There were no statistically significant differences in anthropometric
measurements and demographic parameters between the treatment and
3
Complementary Therapies in Medicine 48 (2020) 102245
placebo groups at baseline.
Table 2 and Table 3 present baseline, post-intervention, and values
of changes for anthropometric indices and insulin resistance markers in
the treatment and placebo group, respectively. Anthropometric out-
comes at eight weeks found a statistically significant change (mean
difference = MD) between groups of women taking S. officinalis extract
compared with placebo. These differences included body weight (kg)
(MD= -1.67, 95% CI: -2.60 to -0.74), BMI (kg/m2) (MD= -0.64, 95%
CI: -1.00 to -0.28) and WC (cm) (MD= -1.26 kg, 95% CI: -2.47 to -0.06).
HC (cm) (MD= -0.25, 95% CI: -1.44 to 0.94) and WHR (MD= -0.008,
95% CI: -0.020 to 0.003) were identical between two groups after in-
tervention. Also, results of linear mixed-effects models showed statis-
tically significant differences between the two groups regarding body
weight (P = 0.001), BMI (P = 0.001), and WC (P = 0.036) at the end of
the study, adjusted for BMI, maternal age, and baseline values. But
there was no significant difference for HC (P = 0.552) and WHR
(P = 0.164). Although we failed to find a significant effect of S. offici-
nalis extract on systolic blood pressure (Change Mean Difference: -4.46,
95%CI: -12.72 to 4.78, P = 0.283 there was a significant difference
between two groups regarding diastolic blood pressure (P = 0.025)
using multivariate model. Consumption of S. officinalis extract, com-
pared to the placebo, resulted in a significant decrease in FBS value
(Change Mean Difference: -4.23, 95%CI: -5.27 to -3.19, P < 0.001),
Insulin levels (Change Mean Difference: -2.81, 95%CI: -3.59 to -2.02,
P < 0.001), and HOMA-IR (Change Mean Difference: -0.69, 95%CI:
-0.87 to -0.51). Moreover, S. officinalis extract supplementation resulted
in a greater increase in QUICKI (Changed MD of 0.021, 95%CI: 0.015 to
0.026, P < 0.001) compared with placebo groups.
4. Discussion
As mentioned in previous sections, weight loss and prevention of
PCOS-related metabolic abnormalities like insulin resistance are two of
the main treatment strategies in women with PCOS. 6,7 Our study
showed that S. officinalis extract at a dose of 330 mg per day for eight
weeks, has favorable effects on anthropometric indexes and insulin
resistance markers in women with PCOS. Results showed a statistically
significant decrease in body weight, BMI, WC, and diastolic blood
pressure level, although changes in HC, WHR, and systolic blood
pressure were not significant. Also, we found that the consumption of S.
officinalis extract could lead to significant improvements in insulin
sensitivity and glycemic control since the levels of FBS, insulin, and
HOMA-IR were considerably decreased, and the QUICKI was increased
in the intervention group.
It is hard to precisely explain how S. officinalis extract could induce
hypoglycemic effects in women with PCOS at the molecular level. In a
physiological state, there must be a balance between glucose produc-
tion by hepatocytes and its uptake and metabolism by extrahepatic cells
(adipose, skeletal muscle, renal, and brain cells). This balance has been
established by multiple plasma membrane glucose transporters
(GLUT1, GLUT2, and GLUT4), hormonal (insulin and glucagon), and
neuronal signals in healthy people. In principle, most of the blood
glucose reduction strategies are based on the regulation of these signals
and transporters, and as a result, restoration of bodily homeostasis.
Also, pharmacotherapeutic interventions affecting the activity of di-
gestive enzymes, like pancreatic and intestinal lipase, sucrose, and
maltase, which are involved in the digestion and absorption of mac-
ronutrients, became an attractive approach for weight loss and treat-
ment of dysmetabolism in recent years. 39
Orlistat is the only pharmacologic agent clinically approved in
Europe with pancreatic lipase inhibitory effects that its positive impact
on obesity in patients with PCOS has been shown in various studies.
40,41
Of course, two issues limit Orlists’s routine use in these patients;
digestive complications and reduced absorption of lipid-soluble vita-
mins and, consequently, deficiency. 42–44 Along with the above-men-
tioned drugs, several herbal compounds have been found to have
L. Amini, et al. Complementary Therapies in Medicine 48 (2020) 102245

Fig. 1. The CONSORT Flow Diagram.

Table 1 compounds with inhibitory activities against enzymes like α-glycosides

Patient’s characteristic after random assignment. that are involved in the digestion of carbohydrates. 46 Acarbose is a type
Groups P
of α-glycoside inhibitor that is widely used in the treatment of T2DM,
and it is supposed to be able to lower body weight and improve me-
Intervention Placebo tabolic status in women with PCOS. 47,48 S. officinalis acts just like
(n = 35) (n = 35) acarbose in animal models and can reduce postprandial blood glucose
Age (years) Mean ± SD 28.07 ± 4.18 29.23 ± 5.44 0.356†
in a dose-dependent manner in a short time through inhibiting in-
Median (range) 27.50 (22 to 30 (17 to 39) testinal α-glycoside activity. 49
38) Along with inhibitory activities on digestive enzymes and short time
BMI (Kg/m2) Mean ± SD 25.55 ± 3.69 24.94 ± 3.35 0.504† hypoglycemic effects, S. officinalis can apply a significant modulatory
Median (range) 24.84 (20.70 24.43 (19.78
effect on glucose metabolism and insulin sensitivity in long-term use. 49
to 34.24) to 32.53)
Gravidity Mean ± SD 0.87 ± 1.22 1.03 ± 1.35 0.619† Quercetin, lutein, and kaempferol are derivatives from S. officinalis that
Median (range) 0 (0 to 5) 0 (0 to 4) inhibit glucokinase and glucose 6-phosphatase enzymes activities, and
Parity Mean ± SD 0.67 ± 0.95 0.83 ± 1.08 0.619† subsequently, inhibit gluconeogenesis and increase hepatocyte sensi-
Median (range) 0 (0 to 3) 0 (0 to 3) tivity to insulin. 21,50 Also, Lima et al. showed that S. officinalis acts like
Infertility Yes 2 (6.7%) 5 (16.7%) 0.696*
No 28 (93.3%) 25 (83.3%)
the metformin. It can lower glucose production in hepatocyte cells
Oligomenorrhea Yes 23 (76.7%) 17 (56.7%) 0.100* isolated from rats and reduce fasting blood glucose, through inhibition
No 7 (23.3%) 13 (43.3%) of gluconeogenesis. 25
Dysmenorrhea Yes 5 (16.7%) 4 (13.3%) 0.718* Another supposed mechanism for modulatory effects of S. officinalis
No 25 (73.3%) 26 (86.7%)
on metabolism is related to its ability to activate the peroxisome pro-
Ferriman–Gallwey Mean ± SD 15.58 ± 4.78 14.50 ± 3.57 0.347†
Score Median (range) 15.50 (8 to 23) 14 (8 to 22) liferator-activated receptor gamma (PPAR-γ). 51,52 PPAR-γ is a member
of the nuclear receptor superfamily, which controls glucose and lipid
†
Based on t-test. metabolism and is one of the potential therapeutic targets in the
* Based on Chi-Square test. treatment of metabolic disorders. 53
In addition to the above mechanisms, there is a hypothesis that S.
similar effects on digestive enzymes, but with much fewer side effects. officinalis can regulate the expression of genes involved in cellular
Carnosic acid, Carnosol, Royleanonic Acid, and 7-methoxy-rosmanol glucose absorption and metabolism. As mentioned above, plasma
are four abietane-type diterpenes components from S. officinalis that membrane glucose transporters are one of the important parts of glu-
exhibit a potential inhibitory effect on pancreatic lipase. Ninomiya cose homeostasis. GLUT4 is a protein in the membrane surface of the
et al. found that the inhibitory effect of carnosic acid is even equivalent cell, which provides a glucose-facilitated release to muscle and fat cells.
to orlistat, and it reduces weight and body visceral fat in high-fat diet- It has been reported that the amount of adipocyte GLUT4 transporters is
fed mice. 45 lower in PCOS patients than normal subjects, 54 and its up-regulation
Also, it is known that S. officinalis contains some phenolic can play a considerable roll in the treatment of PCOS related

4
L. Amini, et al. Complementary Therapies in Medicine 48 (2020) 102245

Table 2
Comparison of anthropometric indices between two groups.
Intervention Control Diff# 95% CI P

Mean ± SD Mean ± SD Lower Upper

Weight (kg) Pre 65.98 ± 8.37 64.93 ± 10.05 1.05 −3.73 5.83 0.662†
Post 64.54 ± 7.44 65.16 ± 9.83 −0.62 −5.13 3.88 0.001§
Change −1.44 ± 2.35 0.23 ± 0.98 −1.67 −2.60 −0.74 0.001
BMI (Kg/m2) Pre 25.55 ± 3.69 24.99 ± 3.34 0.61 −1.21 2.43 0.504†
Post 24.99 ± 3.34 25.03 ± 3.24 −0.03 −1.73 1.66 0.001§
Change −0.56 ± 0.90 0.08 ± 0.38 −0.64 −1.00 −0.28 0.001
WC (cm) Pre 89.53 ± 10.81 89.81 ± 9.45 −0.28 −5.53 4.96 0.914†
Post 87.98 ± 10.44 89.53 ± 9.22 −1.55 −6.64 3.54 0.036§
Change −1.55 ± 2.69 −0.28 ± 1.91 −1.26 −2.47 −0.06 0.040
HC(cm) Pre 103.20 ± 11.73 101.87 ± 7.05 1.33 −3.67 6.33 0.596†
Post 102.38 ± 11.07 101.30 ± 6.34 1.08 −3.58 5.74 0.552§
Change −0.81 ± 2.06 −0.56 ± 2.51 −0.25 −1.44 0.94 0.676
WHR Pre 0.86 ± 0.06 0.88 ± 0.05 −0.01 −0.04 0.02 0.501†
Post 0.86 ± 0.07 0.88 ± 0.06 −0.01 −0.05 0.01 0.164§
Change −0.006 ± 0.02 0.002 ± 0.02 −0.008 −0.020 0.003 0.163
Systolic Blood pressure (mmHg) Pre 111.33 ± 6.81 106.37 ± 20.09 4.96 −2.87 12.71 0.205†
Post 109.50 ± 7.91 109.00 ± 9.22 0.50 −3.94 4.94 0.871§
Change −1.83 ± 7.00 2.63 ± 21.47 −4.46 −12.72 3.78 0.283
Diastolic Blood pressure (mmHg) Pre 73.66 ± 6.28 72.00 ± 6.77 1.66 −1.71 5.04 0.200†
Post 70.00 ± 6.82 70.83 ± 8.31 −0.83 −4.76 3.09 0.025§
Change −3.66 ± 7.18 −1.16 ± 7.73 −2.50 −6.35 1.35 0.356

#
Intervention minus control group.
†
tbased on t-test.
§
based on ANCOVA (the included variables were: basic value of dependent variable, treatment type, BMI, parity and age).

Table 3
Comparison of insulin resistance markers between two groups.
Intervention Control Diff# 95% CI P

Mean ± SD Mean ± SD Lower Upper

FBS (mg/dl) Pre 87.13 ± 8.12 86.86 ± 7.12 0.26 −3.68 4.21 0.893†
Post 82.50 ± 7.32 86.46 ± 7.25 −3.96 −7.73 −0.19 0.001§
Change −4.63 ± 2.07 −0.40 ± 1.94 −4.23 −5.27 −3.19 0.001
Insulin (mIU/l) Pre 10.63 ± 2.93 9.50 ± 2.80 1.26 −2.10 4.61 0.458†
Post 7.65 ± 2.72 9.34 ± 2.49 −1.68 −3.03 −0.33 0.001§
Change −2.97 ± 1.95 −0.16 ± 0.86 −2.81 −3.59 −2.02 0.001
HOMA-IR Pre 2.31 ± 0.82 2.01 ± 0.55 0.29 −0.06 0.66 0.103†
Post 1.57 ± 0.65 1.97 ± 0.48 −0.39 −0.69 −0.09 0.001§
Change −0.74 ± 0.44 −0.04 ± 0.20 −0.69 −0.87 −0.51 0.001
QUICKI Pre 0.33 ± 0.01 0.34 ± 0.01 −0.006 −0.014 0.001 0.124†
Post 0.36 ± 0.02 0.34 ± 0.01 0.014 0.005 0.024 0.001§
Change 0.021 ± 0.013 0.001 ± 0.006 0.021 0.015 0.026 0.001

#
Intervention minus control group.
†
tbased on t-test.
§
based on ANCOVA (the included variables were: basic value of dependent variable, treatment type, BMI, parity and age).

complications. 55 Moradabadi et al. showed in an in-vitro study that S.
officinalis up-regulates GLUT4 gene expression in the heart muscles of
diabetic rats. 49
Our literature review showed that the effects of S. officinalis extract
on different metabolic disorders like diabetes have been investigated
widely in both animal models and in-vitro studies, but few clinical trials
have addressed its effects on metabolic diseases in humans.
Unfortunately, none of them have investigated this herb in people with
PCOS. To the best of our knowledge, our study is the first clinical trial
investigating the effect of S. officinalis extract on metabolic indexes in
women with PCOS.
M.Sá et al. found a contradictory result in their clinical trial. This
study was designed as a non-randomized crossover study and included
six healthy women between the ages of 40 and 50. At the end of this
study, consumption of S. officinalis tea, containing 4 g dried plant ma-
terial boiled in 300 ml of water, twice a day, for four weeks showed no
significant changes in FBS, postprandial glucose, glucose tolerance test,
weight, and blood pressure. Low sample size, non-randomized design,
and lack of a control group are the most important methodological
weaknesses of this study. Also, in this study, S. officinalis was prepared
in the tea form and was used only for four weeks. So, it is unlikely that
the dosage and duration of intervention were sufficient to observe the
anti-glycemic effects of S. officinalis. In an RCT by Behradmanesh et al.,
antiglysemic effects of S. officinalis extract have been evaluated in pa-
tients with poorly controlled T2DM. In this study, S. officinalis extract in
a dose of 150 mg 3 times a day, significantly reduced postprandial
glucose after twelve weeks; however, it doesn’t have a significant effect
on FBS and Hemoglobin A1C. Unfortunately, in this study, the exact
definition of uncontrolled diabetes is not clearly explained, and the
inclusion and exclusion criteria are not well defined, so the homo-
geneity of the studied population is unclear. Also, the type and the
dosage of antidiabetic drugs used along with S. officinalis tablets and the
type of extract used in this study were not mentioned. 56 Kianbakht
et al. used higher doses of S. officinalis alcoholic extract and obtained
results that were consistent with our study results. They showed that
taking 500 mg S. officinalis alcoholic extract three times a day for eight

5
L. Amini, et al.
weeks can improve glycemic control and lipid profile in diabetic pa-
tients newly diagnosed with hyperlipidemia. 28 Moreover, Kianbakht
et al. obtained similar results in another clinical trial. They showed that
using S. officinalis along with antidiabetic drugs and Statins in patients
with uncontrolled hyperlipidemia can be more effective than exclusive
treatment with antidiabetic and Statins. 57 Unfortunately, none of the
previous clinical studies evaluated the effect of S. officinalis on insulin
resistance markers and anthropometric indexes.
Animal model studies have also shown contradictory results. In a
study by Lima et al., S. officinalis tea oral use for fourteen days, reduced
FBS significantly in healthy mice but not in Streptozotocin (STZ) in-
duced type I diabetic subjects. 25 Hajizadeh et al. obtained similar re-
sults and showed that neither aqueous nor ethanolic extracts of S. of-
ficinalis, can apply a hypoglycemic effect in STZ induced diabetic rats
after six days. 58 Also, Alarcon‐Aguilar and co-workers have reported
that S. officinalis water-ethanolic extract after four hours can reduce
glucose levels in normal and mildly alloxan-induced diabetic mice but
not in severely alloxan-induced diabetic animals. 59 Eidi et al. per-
formed two experiments and obtained different results from previous
studies. They showed that glucose-lowering effects of S. officinalis only
occurred in diabetic rats, and healthy rats did not show significant
improvements, either in the short-term (after three hours)30 or long-
term use (two weeks). 29
As noted above, in different studies depending on the treatment
duration, extract dosage, extract type (Aqueous, hydroalcoholic, alco-
holic extracts or essential oil), administration form (tea, dry powder,
capsule, or liquid), and parts of the plant that used, different and
contradictory results have been observed. Also, depending on the lo-
cation where S. officinalis has been cultivated, different effects will be
obtained because the chemical composition and concentration of active
ingredients of the plant would be varied depending on environmental
conditions like climate and altitude. 60
One of the important limitations of this study was that we included
all PCO phenotypes in this study because it is assumed that different
phenotypes of this syndrome may have different degrees of insulin re-
sistance. 61,62 Future studies should address that in which group of
women with PCOS, S. officinalis will be more effective. Also, we re-
commend future studies to compare the effect of S. officinalis with
lifestyle interventions (diet and exercise) as the first line of intervention
in the prevention of metabolic disorders in women with PCOS.
5. Conclusion
Finally, we showed that consumption of S. officinalis extract poses
statistically significant improvements on most anthropometric indices
and insulin resistance markers in patients with PCOS, although it is not
yet clear how much our findings are clinically significant and more
clinical studies with larger sample sizes are still needed.
Funding
This research was supported by Iran University of Medical Sciences,
Tehran, Iran (Grant Number:94-03-28-26521).
Declaration of Competing Interest
The authors declare that they have no competing interests.
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