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2013
http://informahealthcare.com/gye
ISSN: 0951-3590 (print), 1473-0766 (electronic)
Gynecol Endocrinol, 2013; 29(4): 375–379
!2013 Informa UK Ltd. DOI: 10.3109/09513590.2012.743020
POLYCYSTIC OVARY SYNDROME
Endocrine and clinical effects of myo-inositol administration in
polycystic ovary syndrome. A randomized study*
P. G. Artini
1
, O. M. Di Berardino
1
, F. Papini
1
, A. D. Genazzani
2
, G. Simi
1
, M. Ruggiero
1
, and V. Cela
1
1
Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy, and
2
Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Modena, Modena, Italy
Abstract
Objective: To evaluate the effects the administration of myo-inositol (MYO) on hormonal
parameters in a group of polycystic ovary syndrome (PCOS) patients.
Design: Controlled clinical study.
Setting: PCOS patients in a clinical research environment.
Patients: 50 overweight PCOS patients were enrolled after informed consent.
Interventions: All patients underwent hormonal evaluations and an oral glucose tolerance test
(OGTT) before and after 12 weeks of therapy (Group A (n¼10): MYO 2 g plus folic acid 200 mg
every day; Group B (n¼10): folic acid 200 mg every day). Ultrasound examinations and
Ferriman–Gallwey score were also performed.
Main outcome measures: Plasma LH, FSH, PRL, E2, 17OHP, A, T, glucose, insulin, C peptide
concentrations, BMI, HOMA index and glucose-to-insulin ratio.
Results: After 12 weeks of MYO administration plasma LH, PRL, T, insulin levels and LH/FSH
resulted significantly reduced. Insulin sensitivity, expressed as glucose-to-insulin ratio and
HOMA index resulted significantly improved after 12 weeks of treatment. Menstrual cyclicity
was restored in all amenorrheic and oligomenorrheic subjects. No changes occurred in the
patients treated with folic acid.
Conclusions: MYO administration improves reproductive axis functioning in PCOS patients
reducing the hyperinsulinemic state that affects LH secretion.
Keywords
Hyperinsulinemia, inositolphosphoglycan,
myo-inositol, policystic ovary syndrome
History
Received 16 October 2012
Accepted 16 October 2012
Published online 22 January 2013
Introduction
Polycystic ovary syndrome (PCOS) is a common disorder of
chronically abnormal ovarian function and hyperandrogenism,
affecting 5–10% of female population in reproductive age.
Typically PCOS is characterized by hyperandrogenism (extremely
variable in its occurrence), chronic anovulation, polycystic
ovaries at ultrasound evaluation and dermatological problems
such as acne, hirsutism and seborrhoea [1]. PCOS is indeed the
most common cause of female infertility [2].
In the last years, a great body of evidence has demonstrated the
important role of altered insulin sensitivity in many, though not
all, PCOS patients [3]. In addition to the abnormal hormonal
parameters, patients affected by PCOS have been demonstrated to
present insulin resistance, in the absence of diabetes [4], probably
due to (especially in lean/normal-weight PCOS subjects) a
genetic/familiar predisposition [5]. Many investigators have
focused both on impaired glucose tolerance, which affects 30–
40% of patients with PCOS [6], and on insulin resistance, which is
present in a significant proportion of women with PCOS.
Hyperinsulinaemia, a consequence of insulin resistance, may
alter the FSH (Follicle-stimulating hormone)-to-LH (Luteinizing
hormone) shift, preventing the selection of a dominant follicle.
Moreover, insulin seems to increase granulose cells sensitivity to
LH and increase the production of androgens from the ovary by
stimulating cytochrome P450c17a. Some studies suggest that
ovarian theca cells in PCOS-affected women are more capable to
convert androgenic precursors to testosterone than in normal
women [7]. Finally, and most importantly, hyperinsulinemia
impedes ovulation. Several studies suggest that some abnormal
action of insulin might be dependent from inositolphosphoglycan
(IPG) mediators of insulin action and suggest that a deficiency in
a specific D-chiro-inositol (DCI)-containing IPG may underlie
insulin resistance, similarly to type 2 diabetes. DCI administration
has been demonstrated to reduce insulin resistance both in lean
and obese PCOS patients improving ovarian function and
decreasing hyperandrogenism [8,9]. Another inositol, myo-
inositol (MYO), has been reported to be greatly correlated to
ovarian function and oocyte quality in patients undergoing in vitro
fertilization (IVF) procedures, independently from circulating
plasma levels [9,10].
The aim of our study was to evaluate the effects of MYO
administration on hormonal and clinical parameters in a group of
PCOS patients undergoing IVF.
Address for correspondence: Paolo Giovanni Artini, Department of
Reproductive Medicine and Child Development, Division of
Obstetrics and Gynecology, University of Pisa, Via Roma 56, 56126
Pisa, Italy. Tel.: þ39.050.554104. Fax: þ39.050.551293. E-mail:
paolo.artini@med.unipi.it
*Capsule: Myo-inositol administration in PCOS patients modifies
reproductive axis function, reducing the hyperinsulinemic state that
affects LH secretion. It could also improve oocytes quality and pregnancy
rates.
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Materials and methods
Among the 240 patients attending the Department of
Reproductive Medicine and Child Development Division of
Obstetric and Gynaecology – University of Pisa, Italy, candidates
for ART (Assisted Reproduction Technology), fifty PCOS
patients have been randomized for this study that was performed
for 12 months (April 2008–April 2009). An informed consent has
been obtained before entering the study and the study was
approved by the local Ethics Committee. These patients were
selected according to the following criteria: (a) presence of
micropolycystic ovaries at ultrasound, (b) mild to severe hirsutism
and/or acne, (c) oligomenorrhea (menstrual cycle435 days) or
amenorrhea, (d) absence of enzymatic adrenal deficiency and/or
other endocrine disease, (e) normal PRL (Prolactin) levels (range
5–25 ng/ml), (f) no hormonal treatment for at least six months
before the study. Instead the others 190 patients were excluded
because they do not met the inclusion criteria. (Figure 1)
On the therapeutic program day, these 50 women were
randomized into two groups (treatment and control group)
according to a computer-generated randomization list prepared
by one of the authors (PG.A.). Sealed and numbered envelopes,
containing the allocation information, were given to ART center
nurse coordinator, who assigned patients to study arms following
the recruitment by the physician on the morning of therapeutic
program. Twenty-five of the fifty patients were randomly assigned
to the Group A or Study Group and treated with MYO 2 gþfolic
acid 200 mg daily (INOFERT; Italfarmaco, Milano, Italy)
dissolved in a glass of water and assumed in the morning, plus
folic acid 200 mg daily, for 12 weeks. The other twenty-five
patients (Group B) received only folic acid 400mg daily for 12
weeks and were considered as the Control Group. Even if also
Group B received a treatment, it was considered as ‘‘Control’’
because it is ethically correct to administer folic acid in women
trying to get a pregnancy. No changes of life style or diet was
required. Treatment was started the first day of spontaneous
menstrual cycle or, in women with amenorrhea, after excluding
pregnancy by a proper test. Clinical measurement included: LH,
FSH, PRL, estradiol (17b-E2), androstenedione (A), 17-hydroxy-
progesterone (17OHP) and insulin. Oral glucose tolerance test
(OGTT) was performed at the baseline and 30, 60, 90, 120 and
240 minutes after the oral assumption of 75 g of glucose. All the
parameters were performed at the baseline and after 12 weeks of
treatment. During this period the therapy was not interrupted.
After twelve weeks of treatment, an IVF cycle was performed for
each patient. All patients underwent a pituitary desensitization
with SC administration of 0.2 ml die of a GnRH agonist
(Enantone Die; TAKEDA Italia Farmaceutici Spa, Roma, Italy)
from mid-luteal phase until the day of the start and then this
GnRH agonist was reduce to the value of 0.1 ml/die until the
intramuscular (IM) administration of 6500 IU hCG (Ovitrelle;
Merck-Serono, Geneva, Switzerland). Controlled ovarian hyper-
stimulation was performed in all patients by administration of
recombinant FSH (Gonal-F; Merck-Serono, Geneva, Switzerland)
Assessed for eligibility (n=240)
Excluded (n=190)
(n=171)
Analysed (n=25)
Lost to follow-up (give reasons) (n=0)
Discontinued intervention (give reasons) (n=1)
- Suspected Ovarian Hyper-stimulation
Syndrome (n=1)
Allocated to intervention (n=25)
oocytes fertilization) (n=0 )
Allocated to intervention (n=25)
oocytes fertilization) (n=0 )
Analysed (n=25)
Allocation
Analysis
Randomized (n=50)
Enrollment
Group A
(Treatment Group)
Group B
(Control Group)
Lost to follow-up (give reasons) (n=0)
Discontinued intervention (give reasons) (n=4)
- Suspected Ovarian Hyper-stimulation
Syndrome (n=4)
Follow-Up
Figure 1. CONSORT Flowchart of the study.
376 P. G. Artini et al. Gynecol Endocrinol, 2013; 29(4): 375–379
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with a starting dose of 150 IU/die. Patients were monitored by
measuring 17b-E2 and Progesterone plasma concentration and the
size of follicles on day 5-7-9 and 10 of the stimulation. The
gonadotropin dose was adjusted according to the individual
response. Intramuscular hCG was injected when serum 17b-E2
concentration exceeded 200 pg per follicle and at least three
follicles with a minimum diameter of 18 mm were identified. 36
hours after hCG injection, all patients have been submitted to the
oocyte pick-up, with transvaginal guidance. For all patients
enrolled in our study, according to Italian IVF law (in force from
March 2004 to May 2009), a maximum of three oocyte per patient
were inseminated. Oocyte and sperm preparation for conventional
IVF (fertilization in vitro embryo-transfer)/ICSI (intracyto-
plasmic sperm injection) procedure have been thoroughly
described by Artini et al., and Papaleo et al., respectively
[11,12]. Laboratory determinations of insulin, glucose and DCI-
IPG insulin mediator bioactivity assay have been performed
according to previously described [13].
Only one embryologist evaluated oocytes and embryos quality,
and chose the technique used for each patient. Intramuscular
progesterone in- oil administration, 341 mg every three days, and
intravaginal progesterone gel administration, 90 mg daily, was
started on the day of embryo transfer, and treatment was
continued until either a serum pregnancy test was negative or
an embryonic heart beat was sonographically confirmed.
Statistical analysis
We tested data for significant differences between groups, after
analysis of variance (one-way ANOVA), using Student’s t-test for
paired (within the same group) and unpaired data (between the
two groups), as appropriate. The area under the curve of OGTT
(AUC, subtracted from the baseline value) was computed using
the trapezoid formula so that to evaluate the insulin response to
oral glucose load. Insulin sensitivity was computed as glucose-to
insulin ratio since this ratio has been shown to be a good index of
insulin sensitivity in women with PCOS [14,15]. HOMA index,
computed as [basal glucose]6[basal insulin]/22.5, was also
evaluated since it indicates the insulin resistance [16].
Apvalue 50.05 was considered statistically significant.
Results
All the 50 studied patients among the two Groups underwent
ovarian stimulation. 45 patients arrived until the day of oocytes
pick-up; five patients were cancelled because of a suspected
Ovarian Hyper-Stimulation Syndrome: 1 patient belonged to the
Group A and 4 women to the Group B. (Figure 1)
We observed the presence of eventual modifications in both
metabolism/hormones and reproduction in the two Groups.
(Group A: INOFERT plus folic acid 200 mg daily; Group B:
only folic acid at the daily dosage of 400mg).
As shown in Table 1, both groups were comparable for age
(34.9 2.1 versus 36.2 2.3), infertility duration (40 18 versus
42 10.1) and BMI (26.5 6.1 versus 26.3 7).
Significant changes were observed in the Study Group since
several hormonal parameters modified during the treatment.
Indeed LH, PRL, A and insulin concentration significantly
decreased, as well as LH/FSH ratio, insulin sensitivity glucose/
insulin ratio and the HOMA index. Insulin response was
significantly reduced in the mio-inosytol treated group as well as
the AUC of insulin with respect to baseline conditions. Contrary
no changes were observed in the Control Group. (Table 2;
Figures 2 and 3).
After 12 weeks of treatment significant changes were observed
between Group A and B when data were compared after the
treatment.
First of all, in the MYO treated group, the duration of
stimulation was lower then in control group (11.5 0.8 versus
12.6 1.1; p¼0.002) and also r-FSH units used were fewer in the
MYO treated group. Moreover in the Group A there was only one,
while four cancelled cycles were in the Group B. In both groups,
the cause of the cancellation was a high risk of ovarian
hyperstimulation syndrome (OHSS) development.
17b-E2 levels (1839 520 versus 2315 601; p50.002),
evaluated the day of hCG administration, were lower in the MYO-
treated group. Analyzing the follicular pattern at the oocyte pick-
up (PU) day, it’s important to notice that small dimension follicles
(diameter512 mm) in the study group are considerably fewer than
in the control group (1.2 2 versus 4.6 3.6; p¼0.002), and also
that inter mediate follicles amount (diameter 12–16 mm) are lower
in the Group B than in Group A (3.5 2.9 versus 7.2 3.6;
p¼0.003). On the other hand, there are more large dimension
follicles (416 mm) in the Group A (7.4 3.2 versus 5.3 3.5;
p¼0.05). (Table 1)
At the oocyte pick-up surgeons recovered a lower number of
oocytes in the MYO-treated group rather than in the control group
(6.5 3.1 versus 10.8 8.8; p¼0.04). However a higher number
of Group A oocytes were of top-quality than the control group
(82% versus 65%; p¼0.05). In compliance with Italian IVF law,
no more than three oocytes per patient were injected. Evaluating
each condition, in Group A 9 FIVET and 15 ICSI have been
performed, while in the Group B the number of FIVET was
similar to the number of ICSI performed (11 versus 10). Among
the transferred embryos, top quality ones were fewer in the treated
group as compared to the control group (54% versus 64%; NS).
Finally, pregnancy rate (bHCG positive) was considerably
higher in the treated group (60% versus 32%; p50.05). 10 clinical
pregnancies developed in Group A (40%) and 4 in Group B
(16%), while the delivery rate was 8 versus 3 (32% versys 12%;
p50.05), respectively (Table 3).
Discussion
Recently, the recognition that a metabolic dysfunction, peripheral
insulin resistance, might be one of the main trigger point of
PCOS, has induced clinicians to use compounds to improve
insulin sensitivity such as metformin [17] and troglitazone [18].
Since hyperinsulinemia stimulates ovarian androgens production
in PCOS patients [19] attention has been given to IPG mediators
as post-receptor mediators or second messenger of insulin
signalling [20].
The present study supports the hypothesis that MYO
supplementation, similarly to DCI administration, induces the
Table 1. Caracteristics and outcome of patients.
Variable
Group A
(n¼25)
Group B
(n¼25) pValue
Age (years) 34.9 2.1 36.2 2.3 NS
Duration of infertility (months) 40 18 42 10.1 NS
Body mass index (kg/m
2
) 26.5 6.1 26.3 6.8 NS
Duration of stimulation (days) 11.5 0.8 12.6 1.1 0.002
No. of 75-UI ampules
or vials of FSH
27 6.5 31.8 9 0.002
17b-E2 level on day of hCG
administration (pg/ml)
1839 520 2315 601 0.005
Nof cancelled cycles 1 4 0.005
Nof follicles 512 mm 1.2 2 4.6 3.6 0.002
Nfollicles 12516 mm 3.5 2.9 7.2 3.6 0.003
Nfollicles 16 mm 7.4 3.2 5.3 3.5 0.05
NS: no statistically significant.
Data are reported as means SD.
DOI: 10.3109/09513590.2012.743020 Myo-inositol in pcos women 377
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reduction of insulin levels. It could probably act on the high
availability of such precursors of IPG and, thus, ameliorate
performances of this second messenger of the insulin signal [10].
Our data support what recently reported by Papaleo et al. [21]
who demonstrated the efficacy of MYO in ameliorating the
response to ovulation induction by a group of PCOS patients, and
also they demonstrated that several hormonal changes took place
after MYO administration. So, also our data suggest that a
deficiency in the IPG precursors such as MYO and/ or DCI might
be an additional cofactor contributing to the pathophysiology of
the insulin resistance in PCOS patients. Indeed, recent data
demonstrated that PCOS patients have lower DCI-levels of
plasma and higher DCI urinary levels then healthy eumenorrheic
women [22]. Our study demonstrated that MYO administration,
besides DCI, has a modulatory role on insulin sensitivity,
gonadotropin and androgen secretion, though no significant
differences for plasma or urinary MYO concentrations have
been previously reported in PCOS patients. However, it cannot be
excluded that a minimal part of such positive effects observed
during MYO administration might be related also to a minimal
MYO-DCI conversion.
In the present study, we evaluated mostly the effects caused by
MYO administration in patients treated with FIVET/ICSI
protocol, and we noticed a positive effect both for gonadotropins
response and pregnancy rate concordantly with previous studies.
[12]. Another interesting aspect is about the follicular pattern
present in PCOS patients after 12-weeks MYO treatment. Even if
the number of follicles evaluated with transvaginal echography at
the PU day were fewer then the control group, follicles
dimensions were quite similar to the normal non-PCOS size. In
the study group was discovered a higher amount of large-size
follicles (diameter 416 mm) and a lower amount of intermediate
size follicles, mostly seen in PCOS patients and also in the control
group (Table 1). Moreover a 17b-E2-peak level at the PU day was
Table 2. Hormonal pattern of PCOS patients under study.
Group A (n¼25) Group B (n¼25)
Baseline Under treatment Baseline Under treatment
LH mlU/ml 13.5 2.2 8.6 1.6*** 14.1 2.1 12.1 3.2***
FSH mlU/ml 5.5 0.5 3 0.3 3.9 0.4 4.4 0.5
PRL ng/ml 16 4 11.2 2.2* 17.1 2.3 15.7 1.9*
E2 pg/ml 84.6 17 89.1 16.4 87.5 14.7 77.4 17
T ng/100ml 52.4 5.6 53.8 6.2 60.3 7.2 54.2 9.1
17OHP ng/ml 1.3 0.2 1.4 0.3 1.3 0.3 1.2 0.4
A ng/100ml 168 19.6 167.5 29 180.3 23.1 18924
Insulin mU/ml 11.4 2.2 5.5 1.1*** 11.4 1.3 10.1 1.1***
LH/FSH 2.5 0.4 2.1 0.4*** 2.8 0.5 2.5 0.6**
BMI 28 1.6 27.3 1.3 26.6 2.1 27.5 1.7
Glucose/insulin 8.9 1.8 16.5 2.9** 8.2 3.2 8.4 2.6**
HOMA INDEX 2.5 0.6 1.1 0.3** 2.5 0.4 2.4 0.7**
*50.05; **50.01; ***50.005
versus baseline
*50.05; **50.01; ***50.005
versus Group A
Data are reported as means SD.
Figure 3. AUC of insulin after oral glucose load (OGTT). MYO
administration significantly reduced the AUC of insulin after 12 weeks
of treatment (Group A). Control subjects (Group B) did not show
changes. (mean þSEM) *p50.05.
Figure 2. Patients under MYO administration presented a reduction of
both insulin plasma levels before and 30 minutes after oral glucose load.
(mean þSEM) *p50.05, **p50.01.
Table 3. Pregnancy outcome, oocyte and embryo quality in patients
A-group and B-group.
Characteristic Group A Group B pValue
N of retrieved oocytes 6.5 3.1 10.8 8.8 50.05
Top-quality oocytes (%) 82 36 50.05
Fertilization rate (%) 66 60 NS
N embryos transferred 2.5 0.8 2.1 0.5 NS
Top-quality embrios (%) 54 64 NS
NofbhCG positive (%) 15 (60) 8 (32) 50.05
N of clinical pregnancies (%) 10 (40) 4 (16) 50.05
Delivery rate (%) 32 12 50.05
NS: no statistically significant.
Data are reported as means SD.
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less relevant in MYO treated patients compared to control ones,
with a lower risk of OHSS.
The lower amount of intermediate size follicles led to a lower
amount of oocytes retrieval at the PU day, but the large diameter
of recovered follicles determined top-quality oocytes that were in
significantly higher quantity compared to control group. This
means that MYO treatment is relevant for oocytes development.
MYO is an important constituent of follicular microenviron-
ment, playing a determinant role in both nuclear and cytoplas-
matic oocyte development [23]. Therefore higher MYO level in
the follicular fluid can be well indicative of oocytes quality [24].
In Group A, top quality embryos were fewer than in the Group
B, but in the MYO treated group, we performed a higher number
of ICSI (62.5% versus 47.6%). Since we could inseminate a
maximum number of three embryos, there could have been a
higher chance to use spermatozoons with DNA alterations [25].
Pregnancy rate was evaluated by dosing b-HCG 15 days after
PU and then by performing ultrasound echography in order to
individuate for the ovular chamber and heart beat (6–7 weeks).
Values obtained in treated group are significantly relevant
compared to controls.
In conclusion though the number of patients is too small, our
data support the hypothesis that a defect of insulin signal
transduction has to be considered as part of the physiopatholo-
gical factors that participate to the triggering of the PCO
‘‘syndrome’’. In fact MYO supplementation is efficient in
changing many of the hormonal disturbances of PCOS, improving
insulin sensitivity of target tissues and positively affecting the
hormonal functions. It is possible through the reduction of insulin
levels. It is then possible that it could modify the reproductive
axis, improving oocytes quality and pregnancy rates.
Declaration of interest
The authors declare to have no Conflict of Interest.
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Notice of Correction
This paper published online on 22 January 2013 contained an error in the title. The word ‘‘polycystic’’ was misspelled
as ‘‘policystyc’’. The error has been corrected for this version.
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