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Journal of Psychosomatic Obstetrics & Gynecology

ISSN: 0167-482X (Print) 1743-8942 (Online) Journal homepage: http://www.tandfonline.com/loi/ipob20

Comparison of myo-inositol and metformin on


mental health parameters and biomarkers of
oxidative stress in women with polycystic ovary
syndrome: a randomized, double-blind, placebo-
controlled trial

Hamidreza Jamilian, Mehri Jamilian, Fatemeh Foroozanfard, Faraneh Afshar


Ebrahimi, Fereshteh Bahmani & Zatollah Asemi

To cite this article: Hamidreza Jamilian, Mehri Jamilian, Fatemeh Foroozanfard, Faraneh Afshar
Ebrahimi, Fereshteh Bahmani & Zatollah Asemi (2017): Comparison of myo-inositol and metformin
on mental health parameters and biomarkers of oxidative stress in women with polycystic ovary
syndrome: a randomized, double-blind, placebo-controlled trial, Journal of Psychosomatic
Obstetrics & Gynecology, DOI: 10.1080/0167482X.2017.1383381

To link to this article: http://dx.doi.org/10.1080/0167482X.2017.1383381

Published online: 05 Oct 2017.

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JOURNAL OF PSYCHOSOMATIC OBSTETRICS & GYNECOLOGY, 2017
https://doi.org/10.1080/0167482X.2017.1383381

ORIGINAL ARTICLE

Comparison of myo-inositol and metformin on mental health parameters


and biomarkers of oxidative stress in women with polycystic ovary
syndrome: a randomized, double-blind, placebo-controlled trial
Hamidreza Jamiliana, Mehri Jamilianb, Fatemeh Foroozanfardc, Faraneh Afshar Ebrahimic,
Fereshteh Bahmanid and Zatollah Asemid
a
Department of Psychiatry, Arak University of Medical Sciences, Arak, Iran; bEndocrinology and Metabolism Research Center,
Department of Gynecology and Obstetrics, School of Medicine, Arak University of Medical Sciences, Arak, Iran; cDepartment of
Gynecology and Obstetrics, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; dResearch Center for
Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran

ABSTRACT ARTICLE HISTORY


Downloaded by [University of Connecticut] at 06:36 06 October 2017

Introduction: Data on comparison of myo-inositol and metformin on mental health parameters Received 7 July 2017
and biomarkers of oxidative stress in subjects with polycystic ovary syndrome (PCOS) are scarce. Revised 3 September 2017
This purpose of this study was to compare of myo-inositol and metformin on mental health Accepted 15 September 2017
parameters and biomarkers of oxidative stress in subjects with PCOS.
Methods: This randomized controlled trial was conducted among 60 subjects diagnosed with KEYWORDS
PCOS according to the Rotterdam criteria. Subjects were randomly assigned into two groups to Myo-inositol; metformin;
intake either myo-inositol (n ¼ 30) or metformin (n ¼ 30) for 12 weeks. Parameters of mental polycystic ovary syndrome;
health were recorded at baseline and after the 12-week intervention. Fasting blood samples mental health; oxidative
were obtained at baseline and the end of the study to determine biomarkers of biomarkers of stress
oxidative stress.
Results: After the 12-week intervention, changes in beck depression inventory total score
(1.0 ± 1.7 vs. 0.3 ± 0.7, p ¼ 0.03), general health questionnaire scores (1.7 ± 2.9 vs. 0.5 ± 1.2,
p ¼ 0.02), depression anxiety and stress scale scores (3.9 ± 6.4 vs. 0.9 ± 1.9, p ¼ 0.01) and
plasma total antioxidant capacity (TAC) concentrations (þ106.1 ± 69.6 vs. þ2.1 ± 132.4 mmol/L,
p < 0.001) in the myo-inositol group were significantly different from the changes in these indi-
cators in the metformin group. Myo-inositol supplementation for 12 weeks among patients with
PCOS did not affect plasma glutathione and malondialdehyde levels.
Conclusions: Overall, our data supported that myo-inositol supplementation for 12 weeks among
patients with PCOS had favorable effects on parameters of mental health and plasma TAC levels.

Introduction To treat the long-term health consequences among


PCOS women, in addition to lifestyle changes [7], the
Polycystic ovary syndrome (PCOS) is one of the most
use of insulin-sensitizers [8] has been proposed.
common hyperandrogenic and dysmetabolic disorder
of reproductive-aged women [1]. The prevalence of However, metformin intake may have metabolic and
PCOS is ranging from 5.5% to 16%, depending on the reproductive benefits, such as weight reduction,
diagnostic criteria used [2]. Prior studies have shown improved androgen levels, restoration of a normal
that PCOS women suffer from impaired emotional menstrual cyclicity and ovulation [9], the consumption
well-being, including anxiety and depression [3], and of it in PCOS women may be limited by gastrointes-
reduced quality of life [4]. However, the relationship tinal side effects [10]. Unlike with metformin, no side
between the biochemical features of PCOS and the effects have been reported following the intake of
severity of the psychological disorders remains unclear. myo-inositol [11]. Inositol is a precursor in the phos-
Nonetheless, the role of physical appearance, such as phatidyl-inositol secondary messenger pathway acti-
hirsutism and obesity [5], and acne [6] has been rela- vated by several neurotransmitters [12]. In the last two
tively well-established in psychological dysfunction in decades, inositols were found to have important
PCOS patients. effects in the treatment of disease associated to insulin

CONTACT Zatollah Asemi asemi_r@yahoo.com Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical
Sciences, Kashan, Iran
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
2 H. JAMILIAN ET AL.

resistance such as PCOS, gestational diabetes, and and was recorded in the Iranian website for registra-
metabolic syndrome [13–14]. In addition, other studies tion of clinical trials (http://www.irct.ir:
underlined the importance of two inositol isoforms, IRCT201706065623N118).
myo- and D-chiro-, in metabolism and ovarian function
in PCOS women [15,16]. In a study by Chengappa
Study design
et al. [17] it observed that inositol intake at a dosage
of 12 g/day for six weeks in patients with bipolar Participants were randomly assigned into two groups
depression improved Hamilton Depression Rating to intake either 500 mg of metformin three times a
Scale and Clinical Global Improvement scores. In add- day (n ¼ 30) or myo-inositol containing 2 g of myo-
ition, the beneficial effects of folate supplementation inositol plus 200 mg of folate twice a day (n ¼ 30) for
on biomarkers of oxidative stress in patients with 12 weeks. Myo-inositol and metformin were manufac-
PCOS [18] and type 2 diabetes mellitus [19] have pre- tured by LO.LI. Pharma (Rome, Italy) and Tehran Darou
viously reported. Pharma (Tehran, Iran), respectively. Participants were
Although there is evidence to indicate that myo- asked not to alter their routine physical activity or
inositol intake may improve mental health parameters usual dietary intakes during the study and not to con-
and biomarkers of oxidative stress in PCOS women, sume any supplements and medications that might
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the beneficial effects of myo-inositol intake in PCOS influence related markers during the study or the pre-
women on these variables compared with the metfor- vious three months (wash-out). All participants pro-
min, to our knowledge, has not yet been firmed. vided three-day dietary records and three physical
Therefore, we hypothesized that myo-inositol intake activity records. Both dietary records and physical
might improve mental health parameters and bio- activity were taken at baseline, weeks of 3, 6, 9 and 12
markers of oxidative stress of PCOS women. The pur- of the intervention. To obtain information on partici-
pose of this study was to compare myo-inositol and pant nutrient intake based on these three-day food
metformin on mental health parameters and bio- diaries, we used Nutritionist IV software (First
markers of oxidative stress among women with PCOS. Databank, San Bruno, CA, USA) modified for Iranian
foods.

Subjects and methods


Treatment adherence
Trial design
To evaluate the compliance, participants were asked
The current study was a prospective randomized con- to bring the medication container. In addition, partici-
trolled trial. pants received a daily reminder message on their cell
phones to take their supplements regularly.
Participants
The current study was carried out at the Kosar clinic Assessment of anthropometric measures
affiliated to Arak University of Medical Sciences Weight and height of participants were determined in
(AUMS), Arak, Iran between July 2016 and December an overnight fasting status using a standard scale
2016. Inclusion criteria were women with PCOS accord- (Seca, Hamburg, Germany) at the onset of the study
ing to the Rotterdam criteria [20] and aged and after the 12-week intervention. BMI was calculated
25–65 years. Smokers, the intake of folate supplements as weight in kg divided by height in meters squared.
within the last 3 months, pregnant women, individuals
with metabolic diseases, thyroid disease, hyperprolacti-
nemia and hypercortisolemia were excluded in the
Assessment of outcomes
study. Parameters of mental health were considered as the
primary outcome and biomarkers of oxidative stress
were considered as the secondary outcomes.
Ethics statements
This study was conducted in accordance with the
Assessment of mental health
Declaration of Helsinki and Good Clinical Practice
guidelines as well as written informed consent were Mental health was judged with beck depression inven-
obtained from all participants. The study was tory (BDI), general health questionnaire-28 (GHQ-28)
approved by the research ethics committee of AUMS and depression anxiety and stress scale (DASS) at
JOURNAL OF PSYCHOSOMATIC OBSTETRICS & GYNECOLOGY 3

baseline and the end of treatment. BDI is a self-com- sample t-test was used to establish changes in
piled questionnaire of 21 items in multiple choice for- anthropometric measures and dietary intakes between
mat [21]. The GHQ-28 comprises 28-item consisting of the two groups. To compare the effects of myo-inosi-
four subscales: somatic symptoms, anxiety and insom- tol and metformin on mental health and oxidative
nia, social dysfunction and severe depression [22]. stress parameters, we used one-way repeated meas-
DASS questionnaire consists of three 14-item self- ures analysis of variance. Adjustment for changes in
report scales that measure depression, anxiety and baseline values of biochemical parameters, age and
stress [23]. baseline BMI was conducted by analysis of covariance.
p < 0.05 were considered statistically significant. All
statistical analyzes conducted using the Statistical
Biochemical assessment
Package for Social Science version 18 (SPSS Inc.,
Ten milliliters fasting blood samples were taken at Chicago, IL, USA).
baseline and after the 12-week intervention at Arak
reference laboratory, Arak, Iran. Serum high sensitivity
Results
C-reactive protein (hs-CRP) levels were assessed using
available ELISA kits (LDN, Nordhorn, Germany). Thirty participants in both groups completed the trial
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Spectrophotometric methods were used to assess out of 65 subjects which were recruited in our study
nitric oxide (NO) [24]. Plasma total antioxidant capacity (five subjects were excluded from the study because
(TAC) by the method of ferric reducing antioxidant of not meeting inclusion criteria) (Figure 1). On aver-
power developed by Benzie and Strain [25], total age, higher than 90% of myo-inositol and metformin
glutathione (GSH) using the method of Beutler et al. were taken in both groups.
[26] and malondialdehyde (MDA) concentrations by Mean age, height, weight and BMI at baseline and
the thiobarbituric acid reactive substances spectro- end-of-trial were not statistically different between the
photometric test [27] were determined. two groups (Table 1).
Considering the three-day dietary records obtained
at baseline, weeks of 3, 6, 9 and 12 of the intervention,
Sample size
there was no statistically significant difference in terms
Considering the following values: effect size ¼ 0.5, of dietary macro- and micro-nutrient intakes between
a ¼ 0.05, b ¼ 0.20, to the power of 80% and using a myo-inositol and metformin groups (data not shown).
formula suggested for clinical trials, the sample size After the 12-week intervention, compared with met-
was estimated at 25 subjects in each group. formin, myo-inositol supplementation led to significant
Considering the possible losses, the sample size was improvements in BDI score (1.0 ± 1.7 vs. 0.3 ± 0.7,
set at 30 subjects in each group finally. p ¼ 0.03), GHQ scores (1.7 ± 2.9 vs. 0.5 ± 1.2, p ¼ 0.02)
and DASS scores (3.9 ± 6.4 vs. 0.9 ± 1.9, p ¼ 0.01)
(Table 2). In addition, change in plasma TAC concentra-
Randomization
tions (þ106.1 ± 69.6 vs. þ2.1 ± 132.4 mmol/L, p < 0.001)
Randomization assignment was conducted using com- in myo-inositol group were significantly different from
puter-generated random numbers. At the time of ran- the change in this indicator in metformin group. Myo-
domization, sequentially numbered, sealed envelopes inositol supplementation for 12 weeks among patients
were opened. Allocation to study group was concealed with PCOS did not affect plasma GSH and MDA levels.
until consent was obtained and inclusion/exclusion cri- Baseline levels of MDA (p ¼ 0.01) were significantly
teria verified. Allocation of the subjects was conducted different between the two groups. Therefore, we con-
by a trained staff at the gynecology clinic that was trolled the analyzes for the baseline values of bio-
blinded to the randomization schedule. Because com- chemical parameters, age and baseline BMI. When we
mercially available myo-inositol and metformin were adjusted the analysis for baseline values of biochem-
used, there was no blinding after randomization; con- ical variables, age and baseline BMI, BDI scores
sequently, researchers and participants could identify (p ¼ 0.05) and GHQ scores (p ¼ 0.06) became non-sig-
the actual treatment. nificant, and other findings did not alter (Table 3).

Statistical methods Discussion


The Kolmogorov–Smirnov test was applied to control In this study, we compared the effects of myo-inositol
the normal distribution of variables. Independent and metformin on mental health parameters and
4 H. JAMILIAN ET AL.

Assessed for eligibility (n=65)

Enrollment
Excluded (n=5)
- Not meeting inclusion criteria (n=5)

Randomized (n=60)
Allocation

Allocated to placebo (n=30) Allocated to intervention (n=30)


Follow-up

Lost to follow-up (n=0) Lost to follow-up (n=0)


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Analysis

Analyzed (n=30) Analyzed (n=30)

Figure 1. Summary of patient flow.

significantly associated with improved insulin sensitiv-


Table 1. General characteristics of study participants. ity [33]. In addition, D-chiro-inositol supplementation
Metformin Myo-inositol for 6 months among patients with PCOS was effective
group group
(n ¼ 30) (n ¼ 30) pa in improving ovarian function and metabolic factors,
Age (y) 27.7 ± 3.4 28.5 ± 4.7 0.43 including total testosterone, free testosterone, 4-andro-
Height (cm) 160.7 ± 5.4 160.6 ± 3.5 0.95 stenedione, prolactin, and insulin resistance [34]. In
Weight at study baseline (kg) 72.5 ± 16.0 71.3 ± 11.9 0.74
Weight at end-of-trial (kg) 72.2 ± 16.5 70.7 ± 11.5 0.69 another study, both the isoforms of inositol were
Weight change (kg) 0.3 ± 1.1 0.5 ± 1.6 0.44 effective in improving ovarian function and metabolic
BMI at study baseline (kg/m2) 28.1 ± 6.4 27.6 ± 4.2 0.71
BMI at end-of-trial (kg/m2) 28.0 ± 6.5 27.4 ± 4.1 0.66 factors in subjects with PCOS, although myo-inositol
BMI change (kg/m2) 0.1 ± 0.4 0.2 ± 0.6 0.49 showed the most marked effect on the metabolic pro-
Data are means ± SDs. files, whereas D-chiro-inositol decreased hyperandro-
a
Obtained from independent t-test.
genism better [35]. Interestingly, it has been
documented that in PCOS women metformin improves
biomarkers of oxidative stress in subjects with PCOS. insulin action at least in part by increasing insulin-
Our data documented that myo-inositol supplementa- mediated release of D-chiro-inositol phosphoglycan
tion for 12 weeks among patients with PCOS had [36].
beneficial effects on parameters of mental health, and We found that myo-inositol supplementation
plasma TAC levels, but did not affect GSH and MDA among PCOS women for 12 weeks resulted in a signifi-
concentrations. To our knowledge, this study is the cant improvement in mental health parameters com-
first report of the effects of myo-inositol and metfor- pared with the metformin. However, few studies have
min intake on mental health parametres and bio- evaluated the effects of myo-inositol intake on mental
markers of oxidative stress in patients with PCOS. health parameters among patients without PCOS; data
Subjects with PCOS are susceptible to mental health on the effects of myo-inositol supplementation, com-
disorders [28,29] and increased biomarkers of oxidative pared with metformin, on mental health parameters in
stress [30,31]. During the last decades, inositol admin- PCOS women are scarce. Two previous studies of
istration has gained as novel promising treatment for adjunctive inositol yielded conflicting results. One
a wide range of pathological conditions namely gyne- study has randomized subjects with bipolar depression
cological diseases, insulin resistance, psychiatric illness, to receive 12 g of inositol or placebo for six weeks
and even cancer [32]. It has been shown that in PCOS [17]. Patients receiving inositol had at least a 50%
patients, the increased release of D-chiro-inositol is improvement in depressive symptoms, as well as
JOURNAL OF PSYCHOSOMATIC OBSTETRICS & GYNECOLOGY 5

Table 2. Parameters of mental health and biomarkers of oxidative stress at baseline and after the 12-week intervention in sub-
jects with polycystic ovary syndrome that received either myo-inositol or metformina.
Metformin group (n ¼ 30) Myo-inositol group (n ¼ 30)
Baseline End-of-trial Change p b
Baseline End-of-trial Change pb pc
BDI total scores 15.1 ± 3.9 14.8 ± 3.9 0.3 ± 0.7 0.04 15.4 ± 5.2 14.4 ± 5.1 1.0 ± 1.7 0.004 0.03
GHQ scores 49.7 ± 8.4 49.2 ± 8.6 0.5 ± 1.2 0.02 50.2 ± 6.2 48.5 ± 6.6 1.7 ± 2.9 0.004 0.04
DASS scores 86.6 ± 15.7 85.7 ± 15.7 0.9 ± 1.9 0.01 89.1 ± 16.6 85.2 ± 15.8 3.9 ± 6.4 0.002 0.01
TAC (mmol/L) 823.0 ± 152.0 825.1 ± 166.0 2.1 ± 132.4 0.93 868.5 ± 56.2 974.6 ± 60.6 106.1 ± 69.6 <0.001 <0.001
GSH (mmol/L) 586.5 ± 112.9 591.6 ± 143.4 5.1 ± 138.5 0.84 631.3 ± 79.9 663.9 ± 88.0 32.7 ± 80.1 0.03 0.35
MDA (mmol/L) 2.5 ± 0.6 2.8 ± 1.2 0.3 ± 1.4 0.21 2.8 ± 0.3 2.7 ± 0.3 0.1 ± 0.4 0.11 0.10
a
Data are means ± SDs.
b
Obtained from paired-samples t-test.
c
p Values represent the time  group interaction (computed by analysis of the one-way repeated measures ANOVA).
BDI: beck depression inventory; DASS: depression anxiety and stress scale; GHQ: general health questionnaire; GSH: total glutathione; MDA: malondialde-
hyde; TAC: total antioxidant capacity.

Table 3. Mean adjusted changes in parameters of mental psychological disturbances [44,45]. Inositol intake may
health and biomarkers of oxidative stress in patients with improve mental health parameters through to control
polycystic ovary syndrome that received either myo-inositol or intracellular calcium concentration and modulates
metformina.
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serotonin activity [46]. In addition, folate intake may


Metformin Myo-inositol improve symptoms of depression by S-adenosylme-
group group
(n ¼ 30) (n ¼ 30) pb thionine and healthy red blood cells production [46].
BDI total scores 0.3 ± 0.2 1.0 ± 0.2 0.05 Our study demonstrated that myo-inositol adminis-
GHQ scores 0.5 ± 0.4 1.6 ± 0.4 0.06 tration among patients with PCOS for 12 weeks
DASS scores 1.1 ± 0.8 3.7 ± 0.8 0.02
TAC (mmol/L) 2.2 ± 18.3 110.3 ± 18.3 <0.001 resulted in a significant increase in plasma TAC com-
GSH (mmol/L) 6.9 ± 19.5 44.7 ± 19.5 0.07 pared with metformin, but unchanged GSH and MDA
MDA (mmol/L) 0.1 ± 0.2 0.1 ± 0.2 0.77
a
levels. Oxidative stress plays a clear detrimental role
All values are means ± SEs.
b
Obtained from analysis of ANCOVA adjusted for baseline values þ age on ovarian functions [47]. Accumulating evidence
and baseline BMI. suggests that myo-inositol, in combination with mela-
BDI: beck depression inventory; DASS: depression anxiety and stress scale;
GHQ: general health questionnaire; GSH: total glutathione; MDA: malon- tonin, is able to decrease oxidative stress and conse-
dialdehyde; TAC: total antioxidant capacity. quently improve oocyte quality during assisted
reproductive technologies [48]. In women with PCOS,
significant improvements in their global illness severity there is an increase of the oxidation of thiol groups
[17]. Unlike, another randomized trial of 17 depressed of follicular proteins, related to a progressive eleva-
individuals with bipolar disorder were allocated to tion of the oxidative stress and that the administra-
receive inositol or placebo for six weeks [37]. Results tion of inositol in these patients seems to reduce the
demonstrated a trend for more participants on inositol oxidation of thiol groups, producing a good quality
to show improvement in depressive symptoms, but of oocytes [49]. In a study by Jiang et al. [50] it
inositol could not show more effective than placebo observed that myo-inositol pre-supplementation did
[37]. About folic acid, several studies have demon- block the toxic effects of copper on the antioxidant
strated a high prevalence of folic acid deficiency system in juvenile Jian carp, and therefore protect
among subjects suffering from psychiatric conditions, enterocytes from copper-induced oxidative damage.
including depression, bipolar disorder and cognitive In another study, both 0.05% and 0.1% pinitol admin-
dysfunction disorders [38,39]. Behzadi et al. [40] carried istration in hamsters fed-high fat and high cholesterol
out a preliminary randomized controlled trial of folate significantly improved antioxidant metabolism [51].
added to sodium valproate for three weeks to treat Moreover, two another studies have reported antioxi-
acute mania. Subjects experienced greater improve- dative, anti-inflammatory and anti-aging effects of
ment with adjunct folate, such that symptoms of D-chiro-inositol [52,53]. D-chiro-inositol also prevented
mania (language, thought disorder, irritability and dis- endothelial dysfunction by inhibiting oxidative stress
ruptive–aggressive behavior) significantly improved and mitochondrial fission in an AMP-activated protein
[40]. Prior studies have demonstrated that depression, kinase-dependent manner [54]. In another study, both
bipolar and anxiety disorders, and binge eating dis- D-chiro-inositol and metformin have showed a statis-
order are more frequent among PCOS women com- tically significant positive effect on follicular milieu by
pared with controls [41,42]. PCOS women with decreasing the oxidative damage on follicular fluid
depression may experience sleep disturbances, fatigue proteins, as well as in recovering good quality
[43], decreased sexual satisfaction and increased oocytes [49]. However, in the above-mentioned study,
6 H. JAMILIAN ET AL.

a natural supplement as D-chiro-inositol and a syn- Funding


thetic drug as metformin had a similar effect on oxi-
The present study was supported by a grant from the Vice-
dative stress status, these results are really interesting chancellor for Research, AUMS, Iran.
because it is well known that many subjects treated
with metformin referred serious side effect such as
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ä Current knowledge on this subject and what this study adds


 Our study supported that myo-inositol supplementation, compared with metformin, for 12 weeks among patients with polycystic ovary syn-
drome had favorable effects on parameters of mental health.

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