International Journal of Reproduction, Contraception, Obstetrics and Gynecology

Chirania K et al. Int J Reprod Contracept Obstet Gynecol. 2017 May;6(5):1814-1820

www.ijrcog.org pISSN 2320-1770 | eISSN 2320-1789

DOI: http://dx.doi.org/10.18203/2320-1770.ijrcog20171563
Original Research Article

A randomised clinical trial comparing myoinositol and

metformin in PCOS
Kishan Chirania, Sujata Misra*, Sandhya Behera

Department of Obstetrics and Gynecology, SCB Medical College, Cuttack, Odisha, India

Received: 27 March 2017

Revised: 05 April 2017
Accepted: 08 April 2017

*Correspondence:
Dr. Sujata Misra,
E-mail: [email protected]

Copyright: © the author(s), publisher and licensee Medip Academy. This is an open-access article distributed under
the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial
use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Background: The medical management of PCOS is fast changing from the combination hormonal pills/progesterone
for cycle regularisation, cosmetological treatment of acne and hirsutism to management of obesity and insulin
resistance. This study evaluates the effects of the insulin sensitisers in improving the clinical and hormonal alterations
in cases of PCOS and improving the reproductive outcomes.
Methods: This 3-arm prospective randomized comparative study was done from August 2015 to July 2016 in the
Department of Obstetrics and Gynaecology at SCB MCH, Cuttack wherein patients of PCOS were studied based on
treatment with metformin, myoinositol or both.
Results: Myoinositol helped in the resumption of spontaneous menstrual cycles in 66.66% of women with PCOS with
menstrual complaints, whereas the same effect in patients who took metformin was only in 15.78%, which was not
significant. Use of myoinositol in Infertile women with PCOS resulted in a pregnancy in 57.14% of women, without
the need of any ovulation inducing agent while use of metformin gave a pregnancy in all the 9 patients, thought 5 out
of them required clomiphene citrate for ovulation induction. With myoinositol there was a reduction in weight, BMI,
LH/FSH ratio, acne and hirsutism. Metformin has resulted in a decrement of body weight, BMI and acne only.
Conclusions: This study conclusively proves that myoinositol has a definitive role in decreasing the ovarian
dysfunction of PCOS. There has been a significant improvement in the symptom profile, weight loss and a significant
change in the hormonal parameters.

Keywords: Insulin resistance, Metformin, Myoinositol

INTRODUCTION stabilised, there has been a resurgence of newer drugs

aimed at correcting the biochemical abnormalities and
PCOS is a common endocrine disturbance affecting thereby, restoring ovarian function; compared to the
woman of reproductive age.1 The recent concept supports traditional use of hormones for ovarian suppression and
lifestyle changes that promote weight loss which can cycle regulation.7
essentially ameliorate the disease process in PCOS.2-4
Insulin sensitizers (metformin, glitazones) and anti-obesity This study evaluates the effects of the insulin sensitisers in
drugs (sibutramine, orlistat etc) have been extensively improving the clinical and hormonal alterations in cases of
studied.5 PCOS and improving the reproductive outcomes.8-10 It
compares the effects of metformin and myoinositol alone,
Myoinositol and berberine are the new-comers in the with another group of patients taking a combination of
group of insulin sensitizers, supposedly safe due to their both the drugs.
natural origin.6 While the diagnostic criteria for PCOS has

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METHODS • Group C- Myoinositol 1g/day + Metformin

000mg/day
This prospective study was done from August 2015 to July
2016 in the Department of Obstetrics and Gynaecology at Since patients already on treatment with either myoinositol
SCB MCH, Cuttack. or metformin were also included in the study, the number
of patients in each group slightly differed with group A
Women presenting in the OBGYN OPD with irregular having 26 patients, group B with 28 and group C with 22
cycles or oligo/amenorrhea, infertility, hirsutism and patients. But the difference was not found to be statistically
excessive acne were evaluated. PCOS was diagnosed significant.
based on the rotterdam criteria. Both lean and obese PCOS
patients were included in the study. Patients who were The treatment duration was 4 months. The patients were
already diagnosed with PCOS and on treatment with the explained how to take the medicines, possible side effects
drugs compared in this study. and explained to come for follow-up.

It is a 3-arm prospective randomized comparative study Clinically, weight, height, waist/hip ratio and BP was
where patients were assigned into Group A, B and C based measured along with examination for Hirsutism.
on computer generated numbers. It was an equivalence
trial where the null hypothesis was that both myoinositol Ultrasound was done to diagnose PCOS, ovarian volume,
and metformin are equally effective in PCOS. endometrial thickness was noted. In the 3rd and 4th month,
a mid-cycle ultrasound was done to look for spontaneous
The sample size was calculated based on the formula, ovulation.

n=Z2×(p)×(1-p)/∆2 Investigations done at baseline were FSH, LH, TSH, PRL,

fasting blood sugar, fasting insulin and serum lipid profile.
n is the sample size. The FSH, LH were done on the Day 2/Day 3 of a
spontaneous or an induced menses.
Z is confidence interval i.e., 1.96 for 95%
At the end of 4th month, FSH, LH, FBS, fasting insulin
∆ is confidence level i.e., 0.05 for ±5% were repeated. Changes in weight and waist/hip ratio were
noted clinically.
P is the proportion of the population with the disease under
study i.e, 5% which in decimal converts to 0.05. Ultrasound was done at the end of 4 months to look for any
improvement in the ovaries in terms of the number of
So, n= (1.96)2×(0.05)×(1-0.05)/(0.05)2 follicles and the ovarian volume. Transabdominal
ultrasound was done in unmarried young patients and
n = 72 transvaginal ultrasound done for patients who presented
with Infertility.
Inclusion criteria
RESULTS
The inclusion criteria for entry were
In the study 34.2% were in myoinositol group, 36.8% were
• Patient with oligomenorrhea/amenorrhea in metformin group and 28.9% were in
• With polycystic ovaries on USG as described in myoinositol+metformin group.
rotterdam criteria
• With or without hyperandrogenism and/or obesity. There was no significant difference in age between three
groups (p value: 0.154) thus ensuring age matching.
Exclusion criteria
On comparison of the symptoms at the initiation of
• Abnormal TSH, PRL, AMH treatment between the three groups, was no significant
• Any chronic illness in the past or present- TB, thyroid difference in symptom profile of subjects in all the three
disease, malabsorption groups, ensuring adequate matching with respect to
• History of chemotherapy or radiotherapy in symptoms (p value: 0.244)
childhood.
Comparison of hirsutism before treatment between three
After randomization, each group comprised of 24 patients groups was statistically significant with more number of
each recieving the following treatment. subjects in the myoinositol+metformin group. (p value:
0.038). Comparison of acne before treatment between
• Group A-Myoinositol 1g/day three groups showed a p value of 0.412 ensuring that the
• Group B-Metformin 1000mg/day patients were adequately matched in this respect.

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Table 1: Comparison of FSH, LH and LH/ FSH and comparison of Fasting insulin, FBS and FBS/insulin ratio
between the three groups.

Groups
Myoinositol Metformin Myoinositol+Metformin P value
Mean SD Mean SD Mean SD
FSH 5.63 0.97 5.14 1.55 5.83 1.31 0.160
LH 13.43 6.68 12.59 9.47 14.87 3.49 0.539
LH/FSH 2.33 0.98 2.44 1.68 2.64 0.77 0.682
F.Insulin 13.55 5.03 18.70 7.42 17.30 6.72 0.015*
FBS 90.69 9.51 86.51 25.03 93.82 12.77 0.342
FBS/Ins 7.48 2.36 11.82 22.47 6.39 3.25 0.332
p value for Fasting Insulin: 0.015

Table 2: Comparison of ovarian volume on the right and left side between the three groups.

Groups
Myoinositol Metformin Myoinositol + Metformin P value
Mean SD Mean SD Mean SD
Ovarian Volume Right 10.92 4.93 11.33 4.08 10.03 3.40 0.551
Ovarian Volume Left 12.45 3.72 10.78 3.47 12.48 2.93 0.124
p value: 0.551 and 0.124 for both ovaries

Table 3: Summary of patient profile and anthropometry.

Myoinositol, n=26 Metformin, n=28 Myoinositol+ Metformin, n=22 p value

Age (years) 23.92±3.70 23.68±4.23 21.9±3.45 0.154
Amenorrhea (%) 46.2 53.6 54.5
Infertility (%) 53.8 32.1 36.4
Irregular cycles (%) 0 14.3 9.1 0.244
Hirsutism (%) 46.2 57.1 81.8 0.038
Acne (%) 23.1 39.3 36.4 0.412
Weight (kg) 59.23±2.07 61.79±5.92 67.36±17.87 0.05
BMI (kg/m2) 24.63±3.32 25.44±2.68 25.02±9.14 0.865
W/H Ratio 0.81±0.04 0.82±0.04 0.03±0.559 0.559

Table 4: The laboratory features and ultrasound.

Myoinositol Metformin Myoinositol+Metformin

Parameter p value
(n=26) (n=28) (n=22)
FSH (U/L) 5.63± 0.97 5.14±1.55 5.83±1.31 0.160
LH (U/L) 13.43±0.68 12.59±9.47 14.87±3.49 0.539
LH/FSH Ratio 2.33±0.98 2.44±1.68 2.64±0.77 0.682
Fasting Insulin μU/ ml 13.55±5.03 18.7±7.42 17.3±6.72 0.015
FBS (mg%) 90.69±9.51 86.51±25.03 93.82±12.77 0.342
FBS/Insulin 7.48±2.36 11.82±22.47 6.39±3.25 0.332
Ovarian volume-Right side (ml) 10.92±4.93 11.33±4.08 10.03±3.40 0.551
Ovarian volume-Left side (ml) 12.45±3.72 10.78±3.47 12.48±2.93 0.124

Comparison of FSH, LH, LH/FSH showed a p value >0.05 matching in selection of subjects with respect to the same
in all the 3 parameters This ensures matching in selection (Table 1).
of subjects with respect to hormonal levels. The mean
fasting insulin was higher in metformin group (18.7±7.42) The comparison of ovarian volume on right and left side
than in other two groups. between three groups was not of any stastical significance
(Table 2). On comparison of the patient profile and
p value for FBS and FBS/insulin ratio were 0.342 and anthropometry in the three groups, only the p value for
0.332 respectively between three groups. This ensures hirsutism: 0.038 (statistically significant). For all other

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parameters, there is no difference of statistical significance In the metformin group, p value for relief from menstrual
Table 3. On evaluation of the laboratory features and complaints: >0.05 and p value for pregnancy rate <0.001
ultrasound amongst the three groups, only the p value for (Table 6). However, 5 patients out of 9 infertile patients in
fasting insulin 0.015 was statistically significant Table 4. the metformin group had received clomiphene citrate for
ovulation induction.
The primary outcome of relief from menstrual complaints
p value <0.001and that for pregnancy rate p value <0.001
was statistically significant (Table 5).

Table 5: Primary outcome measures in the myoinositol group (n=26).

Before After Improvement (%) p value

Menstrual complaints 12 4 66.66 <0.001
Infertility 14 6 57.14 <0.001

Table 6: Primary outcome measures in the metformin group (n=28).

Before treatment After treatment Improvement (%) p value

Menstrual complaints 19 16 15.78 >0.05
Infertility 9 0 100 <0.001

Table 7: Primary outcome measures with myoinositol+metformin group (n=22).

Before treatment After treatment Improvement (%) p value

Menstrual complaints 14 6 57.14 <0.001
Infertility 8 0 100 <0.001

Table 8: Secondary outcome measures in myoinositol group.

Before After
P value
Mean SD Mean SD
Weight 59.23 9.070 58.00 8.65 <0.001*
BMI 24.63 3.31 24.06 3.43 <0.001*
LH/FSH 2.32 0.98 2.17 0.92 0.011*
F.Insulin 13.55 5.02 13.55 5.02 -
Ovarian volume right 10.92 4.93 10.92 4.93 -
Ovarian volume left 12.44 3.71 11.91 3.62 0.095

Table 9: Secondary outcome measures in metformin group.

Before After
P value
Mean SD Mean SD
Weight 61.79 5.92 61.04 6.11 0.003*
BMI 25.44 2.67 25.14 2.67 0.004*
LH/FSH 2.43 1.67 2.43 1.67 -
F.Insulin 18.69 7.41 18.69 7.41 -
Ovarian volume right 11.33 4.08 11.33 4.08 -
Ovarian volume left 10.77 3.46 10.77 3.46 -

Table 10: Secondary outcome measures in Myoinositol+Metformin group.

Before After
P value
Mean SD Mean SD
Weight 67.36 17.87 63.64 13.11 0.005*
BMI 25.01 9.13 25.62 4.02 0.686
LH/FSH 2.63 0.77 2.63 0.77 0.088
F.Insulin 17.29 6.71 15.78 5.69 0.019*
Ovarian volume right 10.02 3.39 10.02 3.39 -
Ovarian volume left 12.48 2.92 12.48 2.92 -

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In the group on both drugs, the p value for relief of hirsutism and acne in the treated patients. No change was
menstrual complaints was <0.001 and the p value for demonstrated in fasting insulin levels and ovarian volume.
pregnancy rate: <0.001 (statistically significant in both)
Table 7. In Group B (n= 28) in which patients received 1g
metformin per day, only 15.78% (p>0.05) patients with
Secondary outcome measures in myoinositol group menstrual complaints had improvement, whereas all
showed significant p values for weight, BMI and LH/FSH. patients with Infertility reported a pregnancy (p<0.001).
No significant effect was seen on fasting insulin and But 5 out of the 9 patients of infertility had taken
ovarian volume (Table 8). clomiphene citrate for ovulation induction. This factor is a
confounding factor in the interpretation of this result.
Secondary outcome measures in metformin group p value
for weight and BMI was statistically significant. No A significant decrement was demonstrated only in body
change was seen on LH/FSH, fasting insulin and ovarian weight, BMI and acne. There was no change in hirsutism,
volume on either sides (Table 9). LH/FSH ratio, fasting insulin and ovarian volume.

Secondary outcome measures in myoinositol+metformin In Group C (n= 22), patients received both myoinositol and
group showed statistically significant difference in weight metformin 1g each per day. 57.14% (p<0.001) patients
and fasting insulin. No significant effect was seen on BMI, with menstrual complaints resumed spontaneous regular
LH/FSH ratio and ovarian volume on both sides (Table cycles and all patients with infertility reported a pregnancy
10). (p<0.001).

DISCUSSION There was a statistically significant reduction in body

weight, fasting insulin and acne. There was no change in
The primary outcome measures focussed in this study were hirsutism and ovarian volume. None of the patients in any
i) resumption of spontaneous regular cycles in patients of the 3 groups reported any major side effects.
with oligo/amenorrhea and ii) pregnancy rate in infertile
patients None of the patients required discontinuation of the drug
due to any intolerable side effects. The expense of
The secondary outcome measures that were compared at treatment was a concern for some patients in Group A
enrolment and after treatment were: (myoinositol) and Group C (myoinositol+metformin).
Complaints of 4 patients in the metformin group was
• Clinical parameters-weight, BMI, acne and hirsutism nausea which got relieved after advising to take the drug
• Laboratory parameters-LH/FSH ratio, fasting insulin with meals. 5 patients in myoinositol reported an
• Ultrasound appearance of ovaries. unpleasant taste of the powder form of the drug when
dissolved in water and taken. They were advised the tablet
Patients in the 3 groups were adequately matched with form.
respect to the age at presentation, symptoms, and
complaints of acne. The patients were also matched in Use of both of the insulin sensitizers myoinositol and
regard to anthropometric assessments like weight, height, metformin has resulted in significant changes in the
BMI and W/H ratio. There was also good matching in symptoms of PCOS in this study, which reflects that a
baseline FSH, LH, LH/FSH ratio, fasting blood sugar and change in the pathogenesis has been caused by these drugs.
ovarian volumes. The use of either drug or in combination in this study has
shown a significant weight loss. And since the time that
The only clinical parameter where there was a disparity lifestyle factors have been implicated in PCOS, weight
was Hirsutism which was higher in the Group C. And the loss has been greatly emphasised in its management.11, 12
laboratory parameter where there was disparity in
matching was in the fasting insulin levels between the 3 The regular use of myoinositol helped in the resumption of
groups. The mean fasting insulin level was higher in the spontaneous menstrual cycles in 66.66% of women with
Group B compared to the other 2 groups. This did not PCOS with menstrual complaints, whereas the same effect
make a difference in the final comparison since this was in patients who took metformin was only in 15.78%, which
not one among the primary outcome. was not significant. Use of myoinositol in Infertile women
with PCOS resulted in a pregnancy in 57.14% of women,
In Group A (n=26) who were treated with myoinositol without the need of any ovulation inducing agent.13 The
1g/day, 66.66% (p <0.001) patients got relieved from role of myoinositol in improving the oocyte quality cannot
menstrual complaints and 57.14% (p<0.001) of patients be overlooked, the fact that has been proven in studies.14,15
with Infertility reported a pregnancy.
Also, the not so rare risks of ovarian hyperstimulation
Further, in Group A, there was a statistically significant syndrome (OHSS) and multiple pregnancy are also absent
reduction in the body weight and BMI, LH/FSH Ratio, when an ovulation inducing agent is not used in PCOS.16,17

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Metformin use in women with PCOS with Infertility in my 2. Liang SJ, Liou TH, Lin HW, Hsu CS, Tzeng CR, Hsu
study gave a pregnancy in all the 9 patients, but 5 out of MI. Obesity is the predictor of impaired glucose
them required clomiphene citrate for ovulation induction. tolerance and metabolic disturbance in polycystic
Hence, the actual pregnancy rate in the group for ovary syndrome. Acta Obstet Gynecol Scand.
metformin alone could not be assessed since clomiphene 2012;91(10):1167-72.
was the confounding factor. 3. Fritz MA, Speroff L. Clinical Gynecologic
Endocrinology and Infertility, 8th edition (Lippincott
With regard to the secondary outcome measures, Williams and Wilkins; 2010:505.
myoinositol has resulted in a significant reduction of more 4. Ravn P, Haugen AG, Glintborg D. Overweight in
parameters than metformin. With myoinositol there was a polycystic ovary syndrome. An update on evidence
reduction in weight, BMI, LH/FSH ratio, acne and based advice on diet, exercise and metformin use for
hirsutism. Metformin has resulted in a decrement of body weight loss. Minerva Endocrinol. 2013;38(1):59-76.
weight, BMI and acne only. This finding perhaps supports 5. Palomba S, Falbo A, La Sala GB. Metformin and
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quality.17 Biol Endocrinol. 2014(3);12:3.
6. Nordio M, Proietti E. The combined therapy with
The above-mentioned findings show a more favourable myo-inositol and D-chiro-inositol reduces the risk of
response of PCOS women to myoinositol compared to metabolic disease in PCOS overweight patients
metformin. But more studies with a bigger sample size and compared to myo-inositol supplementation alone. Eur
longer follow-up are required to establish the accurate Rev Med Pharmacol Sci. 2012;16(5):575-81.
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This study conclusively proves that myoinositol has a Capper F, Crowley RK et al. Hyperandrogenemia
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symptom profile, weight loss and a significant change in Endocrinol Metab. 2014;99(3):1027-36.
the hormonal parameters. 10. Vittorio U, Giuseppina P. Updates on the myo-inositol
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