Effects of myo-inositol in women with PCOS: A systematic review of randomized controlled trials

Abstract

Polycystic ovary syndrome (PCOS) affects 5%-10% of women in reproductive age, and it is the most common cause of infertility due to ovarian dysfunction and menstrual irregularity. Several studies have reported that insulin resistance is common in PCOS women, regardless of the body mass index. The importance of insulin resistance in PCOS is also suggested by the fact that insulin-sensitizing compounds have been proposed as putative treatments to solve the hyperinsulinemia-induced dysfunction of ovarian response to endogenous gonadotropins. Rescuing the ovarian response to endogenous gonadotropins reduces hyperandrogenemia and re-establishes menstrual cyclicity and ovulation, increasing the chance of a spontaneous pregnancy. Among the insulin-sensitizing compounds, there is myo-inosiol (MYO). Previous studies have demonstrated that MYO is capable of restoring spontaneous ovarian activity, and consequently fertility, in most patients with PCOS. With the present review, we aim to provide an overview on the clinical outcomes of the MYO use as a treatment to improve ovarian function and metabolic and hormonal parameters in women with PCOS.

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Gynecological Endocrinology
2012
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© 2012 Informa UK, Ltd.
10.3109/09513590.2011.650660
0951-3590
1473-0766
Gynecological Endocrinology, 2012; 1–7, Early Online
Copyright © 2012 Informa UK, Ltd.
ISSN 0951-3590 print/ISSN 1473-0766 online
DOI: 10.3109/09513590.2011.650660
Polycystic ovary syndrome (PCOS) affects 5%–10% of women in
reproductive age, and it is the most common cause of infertility
due to ovarian dysfunction and menstrual irregularity. Several
studies have reported that insulin resistance is common in PCOS
women, regardless of the body mass index. The importance
of insulin resistance in PCOS is also suggested by the fact that
insulin-sensitizing compounds have been proposed as putative
treatments to solve the hyperinsulinemia-induced dysfunction
of ovarian response to endogenous gonadotropins. Rescuing
the ovarian response to endogenous gonadotropins reduces
hyperandrogenemia and re-establishes menstrual cyclicity and
ovulation, increasing the chance of a spontaneous pregnancy.
Among the insulin-sensitizing compounds, there is myo-inosiol
(MYO). Previous studies have demonstrated that MYO is capable
of restoring spontaneous ovarian activity, and consequently
fertility, in most patients with PCOS. With the present review, we
aim to provide an overview on the clinical outcomes of the MYO
use as a treatment to improve ovarian function and metabolic
and hormonal parameters in women with PCOS.
Keywords: Infertility, insulin resistance, IVF, myo-inositol, oocyte
quality, PCOS
Introduction
Polycystic ovary syndrome (PCOS) is the most common cause
of infertility, ovarian dysfunction and menstrual irregularity,
aecting 5%–10% of women in reproductive age [1]. Both the
aetiology and diagnosis of the syndrome are controversial. Indeed,
the European Society of Human Reproduction and Embryology
and the American Society for Reproductive Medicine sponsored
a Consensus Meeting in Rotterdam (2003) [2,3], in order to reach
a general agreement of the scientic community on diagnostic
criteria for this syndrome.
Although nowadays the criteria established in Rotterdam are
widely accepted, they leave out a crucial condition related to
PCOS: insulin resistance.
Several studies have reported that insulin resistance is common
in PCOS women, regardless of the body mass index (BMI).
Indeed, hyperinsulinaemia due to insulin resistance occurs in
approximately 80% of women with PCOS and central obesity, as
well as in 30%–40% of lean women diagnosed with PCOS [4,5].
e exact cause of the insulin resistance observed in PCOS
women is unknown, although a post-receptor defect, that
could aect glucose transport, has been proposed [6,7]. Insulin
resistance is signicantly exacerbated by obesity, and it is a
key factor in the pathogenesis of anovulation and hyperandro-
genism [5,8]. e importance of insulin resistance in PCOS is
also suggested by the fact that insulin-sensitizing compounds,
such as metformin, pioglitazone and troglitazone, have been
proposed as treatment to solve the hyperinsulinemia-induced
dysfunction of ovarian response to endogenous gonadotropins.
Rescuing the ovarian response to endogenous gonadotropins
reduces hyperandrogenemia, re-establishes menstrual cyclicity
and ovulation, increasing the chance of a spontaneous pregnancy
[9–11].. In particular, metformin induces reduction of total and
free testosterone concentrations [12]. However, commonly used
insulin-sensitizing drugs, like metformin, can induce gastroin-
testinal side eects [13], possibly resulting in reduced patients’
compliance [13].
Further studies have suggested that impairment in the insulin
pathway could be due to a defect in the inositolphosphoglycans
(IPGs) second messenger [14,15]. IPGs are known to have a role
in activating enzymes that control glucose metabolism [16,17].
In PCOS women, a defect in tissue availability or altered metabo-
lism of inositol or IPGs mediators may contribute to insulin
resistance [18].
Inositol belongs to the vitamin B complex. Epimerization of
the six hydroxyl groups of inositol leads to the formation of up to
nine stereoisomers, including myo-inositol (MYO) and D-chiro-
inositol (DCI); both stereoisomers were used, as insulin sensitizer
drugs, in the treatment of PCOS treatments [19–23]. Human
adults consume approximately 1 g of inositol (mainly MYO) per
day in dierent biochemical forms [18]. Circulating free MYO
is taken up by most tissues by a membrane-associated sodium-
dependent inositol co-transporter; inositol uptake is inhibited by
glucose [24]. In particular, it was shown that MYO had 10 times
more anity for the transporter compared to DCI [25].
Data from other groups have shown that DCI is synthesized by
an epimerase that converts MYO into DCI, with each tissue having
its own particular conversion rate, likely due to the specic needs
for the two dierent molecules [26,27]. In particular, it was shown
that the DCI to mass index (MI) ratio was itself insulin depen-
dent. In fact, in subjects suering from type 2 diabetes, the DCI/
MI ratio was reduced [14,15,27,28], and less DCI was synthesized
due to a reduction in epimerase activity [14,15,27,28].
All of these studies were performed on insulin sensitive tissues,
such as muscle and liver. However, unlike tissues such as muscle
and liver, ovaries do not become insulin resistant [29–31].
REVIEW ARTICLE
Effects of myo-inositol in women with PCOS: a systematic review of
randomized controlled trials
V. Unfer1, G. Carlomagno1, G. Dante2 & F. Facchinetti2
1Gynecology Association Unfer Costabile (A.G.UN.CO.), Obstetrics and Gynecology Center, Rome, Italy and
2Mother-Infant Department, University of Modena and Reggio Emilia, Modena, Italy
Correspondence: Vittorio Unfer, Rome 00155, Italy. Tel: 3393690338. E-mail: vunfer@gmail.com
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2 V. Unfer et al
Gynecological Endocrinology
Furthermore, elevated concentrations of MYO in human folli-
cular uid play a role in follicular maturity and provide a marker
of good-quality oocytes [32,33].
Previous studies have demonstrated that MYO is capable of
restoring spontaneous ovarian activity, and consequently fertility,
in most patients with PCOS [21].
Here, we aim to provide an overview on the clinical outcomes
of MYO as a treatment to improve ovarian function and meta-
bolic and hormonal parameters in women with PCOS.
Methods
Systematic literature search was performed in December 2010
in the following electronic databases: Medline, Amed, and e
Cochrane Library. We performed a search over the period January
1999 to November 2010 and only randomized controlled clinical
trials (RCT) were included.
Search terms were as follows: “myo-inositol,” “inositol,” “poly-
cystic ovary syndrome,” “oocyte quality,” “ovarian stimulation,”
“in vitro fertilization,” “ovarian function,” “insulin resistance.”
No language restrictions were imposed. Further relevant
papers were located by hand-searching the reference lists of recent
systematic reviews. Only human studies were included. Data from
treatments with myo-inositol in combination with other drugs as
well as animal and in vitro investigations were excluded.
We obtained hard copies of all the papers listed through our
own university library or interlibrary loans. All sources of infor-
mation obtained were read and evaluated by one of us (G.D.), and
successively checked independently by the other authors (V.U.).
Results of the literature search
Decision tree is reported in Figure 1. A total of 70 studies were
identied; 49 out of 70 were excluded because of not involving
MYO treatment in women with PCOS. e remaining 21 trials
were considered eligible for this review. Six of them [20,22,34–37]
were RCTs (level of evidence Ib) and met the selection criteria for
this review and are presented in Table I. Four trials [22,34–36]
evaluated the eect of MYO administration on hormonal levels.
In one trial, it evaluated the eects of MYO on oocyte quality [20],
and in another one [37] data on ovarian function improvement
aer MYO administration were reported.
All the subjects analysed in these studies were PCOS patients.
Among the six studies that were RCTs, one trial was a random-
ized controlled MYO vs. folic acid [34]; two were double-blind
randomized controlled trial MYO vs. folic acid [22,35]; one was a
prospective randomized controlled MYO vs. folic acid [20]; one
was a randomized controlled MYO vs. metformin [36] and in
four of these trials [20,22,35,36] the dosage of 4 g of MYO was
used; in one trial [34] 2 g of MYO were used.
e last paper [37] described in Table I is not considered in our
discussion because it was performed on patients who were treated
with a multivitamin complex.
In the study of Genazzani et al. [34], 20 PCOS patients were
recruited, ve patients were amenorrheic and 15 oligomenorrheic.
Ten of the 20 patients (Group A) were randomly assigned to be
treated with MYO 2 g plus folic acid 200 g every day (Inofolic®,
LO.LI. Pharma, Rome, Italy). e other patients (Group B, control
group) were administered only folic acid at the daily dosage of 200
g. No changes of life style or diet were required from the patients.
Endocrine prole was evaluated aer treatment, on day 7 of the
rst menstrual cycle occurring aer the 10–12th week of treat-
ment. Consistent and signicant changes were observed in Group
A. Indeed, plasma luteinizing hormone (LH), prolactin (PRL), LH/
follicle-stimulating hormone (FSH) ratio and insulin levels signi-
cantly decreased; furthermore, the homeostatic model assessment
(HOMA) index that measures insulin resistance was also reduced.
On the other hand, the index of insulin sensitivity glucose/insulin
ratio signicantly increased. Furthermore, aer oral glucose load,
both insulin response and the area under the curve (AUC) were
signicantly lower (p < 0.01 and p < 0.05, respectively).
Ferriman-Gallway score decreased aer 12 weeks of MYO
administration although the reduction was not statistically signif-
icant (22.7 + 1.4 to 18 + 0.8). Ovarian volumes were signicantly
reduced (12.2 + 0.6 to 8.7 + 0.8 ml, p < 0.05). No changes were
observed in Group B.
Furthermore, as long as the patients were treated with
MYO, the normal menstrual cycles was restored, while patients
assigned to the Group B remained oligomenorrheic throughout
the study.
Figure 1. Flow chart of studies
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Myo-inositol in women with PCOS 3
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Table I. Eligible RCTs where MYO have been evaluated for the treatment of PCOS patients.
Reference Study design Duration Intervention N° of subjects Inclusion criteria Exclusion criteria Assessment of the response Results
34 Randomized,
controlled vs.
folic acid
12 weeks MYO 2 g FA
200 mg/day
N°= 20
Treatment: 10
Placebo: 10
Presence of micropolycystic
ovaries at ultrasound; mild-
to-severe hirsutism and/
or acne; oligomenorrhea or
amenorrhoea; absence of
enzymatic adrenal deciency
and/or other endocrine disease;
normal PRL levels (range
5–25 ng/ml); no hormonal
treatment for at least 6 months
before the study.
Not described LH, FSH, PRL, E2, A, 17OHP, T, insulin,
cortisol, OGTT* for insulin, glucose,
C-peptide determinations, vaginal
ultrasound examination Feriman-Gallway
score, BMI, HOMA
LH, PRL, T, insulin levels, LH/FSH results
weresignicantly reduced. Insulin sensitivity
results were signicantly improved. Menstrual
cyclicity was restored in all amenorrheic and
oligomenorrheic subjects.
35 Double-blind,
randomized,
controlled vs.
folic acid
12–16
weeks
MYO 4 g FA
400 mg/day
N° = 42
Treatment: 23
Placebo: 19
Presence of oligomenorrhea,
high serum-free testosterone
level and/or hirsutism presence
of micropolycystic ovaries at
ultrasound
Not described Systolic/diastolic blood pressure,
triglycerides, cholesterol, BMI, waist-
to-hip ratio, plasma glucose and insulin
sensitivity, total/free T, DHEAS, SHBG, A,
progesterone peak value
MI increased insulin sensitivity, improved
glucose tolerance and decreased glucose-
stimulated insulin release. ere was a
decrement in serum total T and serum-free
T concentrations. In addition, there was a
decrement in systolic and diastolic blood
pressure. Plasma triglycerides and total
cholesterol concentration decreased.
21 Prospective,
randomized,
controlled vs.
folic acid
During
ovulation
induction
for ICSI
MYO 4 g FA
200 mg/day
N° = 60
Treatment: 30
Placebo: 30
Age: <40 years PCOS
women diagnosed byoiligo
amenorrhea,hyperandroge
nism orhyperandrogenemia
andtypical features of ovarieson
ultrasound scan
Other medical
conditions causing
ovulatory disorders:
hyperinsulinemia,
hyperprolactinemia,
hypothyroidism, or
androgen excess,
such as adrenal
hyperplasia or
Cushing syndrome
Number of morphologically mature
oocytes retrieved, embryo quality,
pregnancy and implantation rates. Total
number of days of FSH stimulation, total
dose of gonadotropin administered, E2
level on the day of hCG administration,
fertilization rate per number of retrieved
oocytes, embryo cleavage rate, live birth
and miscarriage rate, cancellation rate,
and incidence of moderate or severe
ovarian hyperstimulation syndrome
Total r-FSH units and number of days of
stimulation were signicantly reduced in the
myo-inositol group. Peak E2 levels at hCG
administration were signicantly lower in
patients receiving myo-inositol. e mean
number of oocytes retrieved did not dier in
the two groups, whereas in the group cotreated
with myo-inositol the mean number of
germinal vesicles and degenerated oocytes was
signicantly reduced, with a trend for increased
percentage of oocytes in metaphase II
22 Double-blind,
randomized,
controlled vs.
folic acid
16 weeks MYO 4 g FA
200 mg/day
N° = 92
Treatment: 45
Placebo: 47
Age: <35 years women with
oiligoamenorrhea, amenorrhea
and PCOS ovaries. Ovaries were
described as polycystic (PCOs)
about the criteria of Adams
et al.**
Patients with
signicant
hyperprolactinemia,
abnormal thyroid
function tests and
congenital adrenal
hyperplasia.
Ovarian activity was monitored using
serum E2, P and LH. Ovulation frequency
was calculated using the ratio of luteal
phase weeks to observation weeks.
Inibin-b, fasting glucose, fasting insulin,
or insulin AUC, VLDL, LDL, HDL, total
cholesterol, triglycerides, BMI.
Benecial eect of MYO treatment upon
ovarian function, anthropometric measures
and lipid proles
36 Randomized,
controlled vs.
metformin
Until the
end of the
study or
positive
pregnancy
test
MYO 4 g FA
400 mg/day
N° = 120
Treatment:
60Placebo: 60
Age: <35 years Women with
PCOS dened by Rotterdam
Criteria
Other medical
condition
causing ovulatory
dysfunction, tubal
defects, semen
parameters defects.
Restoration of spontaneous ovarian
activity by weekly serum P dosage
and a transvaginal ultrasound scan
documenting the presence of follicular
growth or luteal cyst
Both metformin and MYO can be considered
as rst-line treatment for restoring normal
menstrual cycles in most patients with PCOS,
even if MI treatment seems to be more
37 Double-blind,
randomized,
controlled vs.
placebo
16 weeks Inositol
200 mg/day
N° = 283
Treatment: 136
Placebo: 147
Age: <35 years Women
with oligomenorrhea,
amenorrhea and PCOS ovaries.
Ovaries weredescribed as
polycystic(PCOs) about the
criteria ofAdams et al.**
Patients with
signicant
hyperprolactinemia,
abnormal thyroid
function tests and
congenital adrenal
hyperplasia.
Ovarian activity was monitored using
serum E2, P and LH. Ovulation frequency
was calculated using the ratio of luteal
phase weeks to observation weeks.
Inibin-b, fasting glucose, fasting insulin,
or insulin AUC, VLDL, LDL, HDL, total
cholesterol, triglycerides, BMI.
eective than metformin
FA, folic acid; PRL, prolactin; E2, oestradiol; A, androstenedione; 17OHP, 17-hydroxy-progesterone; T, testosterone; P, progesterone; OGTT, oral glucose tolerance; BMI, body mass index; LH, luteinizing hormone; FSH, follicle stimulating
hormone; DHEAS, dehydroepiandrosterone; SHBG, sex hormone binding globulin; AUC, area under the curve of OGTT; VLDL, very-low-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
aOGTT performed sampling 15 minutes before and 30, 60, 90, 120 and 240 minutes aer the oral assumption of 75 g of glucose.
bAdams J, Polson JW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J 1986;293:355–359.
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4 V. Unfer et al
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Costantino et al. [35] recruited 42 patients; aer randomiza-
tion, 23 received 2 g of MYO plus 200 g of folic acid (Inofolic®,
LO.LI. Pharma) twice a day and 19 received 400 g folic acid alone
as placebo. Among the 42 women, seven had impaired glucose
tolerance and were assigned as follows: four of them received
MYO and three received placebo.
e study started when patients were in the follicular phase of
the menstrual cycle; no changes in usual habits for food, sport and
lifestyle were required.
During the present study, patient treated with MYO showed a
reduction in both systolic and diastolic pressure values (131 ± 2
to 127 ± 2 mmHg and 88 ± 1 to 82 ± 3 mmHg, respectively),
while these values increased in the placebo group (128 ± 1 to
130 ± 1 mmHg; p = 0.002 and 86 ± 7 to 90 ± 1 mmHg; p = 0.001,
respectively).
Furthermore, in the MYO treatment group, plasma triglycer-
ides decreased from 195 ± 20 to 95 ± 17 mg/dl and total cholesterol
signicantly decreased from 210 ± 10 to 171 ± 11 mg/dl. Although
there was no change in the fasting plasma insulin and glucose
concentration in either group, AUC, for both insulin and glucose,
decreased during the oral glucose tolerance test (8.54 ± 1.149
to 5.535 ± 1.792 µU/ml/min; p = 0.03 and 12.409 ± 686 to
10.452 ± 414 mg/dl/min; p = 0.04, respectively) for MYO-treated
patients. No changes were observed in the placebo group.
Consequently, the composite whole body insulin sensi-
tivity index (ISI) signicantly increased from 2.80 ± 0.35 to
5.05 ± 0.59 mg/dl in the MYO group, while it did not change in
the placebo group. Ovulation was restored in 16 (69.5%) women
belonging to the MYO group and four(21%) belonging to the
placebo group (p = 0.001). Aer treatment, the progesterone (P)
peak was higher in the MYO group (15.1 ± 2.2 ng/ml) compared
to placebo. Furthermore, a signicant reduction in total serum T
(99.5 ± 7 to 34.8 ± 4.3 ng/dl, p = 0.003) and in free T (0.85 ± 0.11
to 0.24 ± 0.03 ng/dl, p = 0.01) was observed.
Testosterone reduction was accompanied by an increase in
serum sex hormone binding globulin. Furthermore, there was
reduction of more than 50% in the serum dehydroepiandros-
terone sulphate in the MYO group (366 ± 47 to 188 ± 24 µg/dl;
p = 0.003), while it was not signicant in the placebo group.
Papaleo et al. [20] broaden the clinical use of MYO by evaluating
its eect on oocyte quality and the ovarian stimulation protocol
for PCOS women. Sixty women were enrolled in the study; aer
randomization, 30 were assigned to receive 2 g MYO and 200 g
folic acid (Inofolic®, LO.LI. Pharma) twice a day (Group A); 30
received 400 g folic acid only (Group B).
In the Group A (Inofolic®), the stimulation protocol was
milder and shorter. Indeed, both the total recombinant FSH
(r-FSH units) (1958 ± 695 vs. 2383 ± 578; p = 0.01) and
number of stimulation days (11.4 ± 0.9 vs. 12.4 ± 1.4; p < 0.01)
were signicantly reduced. Furthermore, oestradiol (E2) levels
(2232 ± 510 vs. 2713 ± 595 pg/ml; p < 0.02) aer human chori-
onic gonadotropin administration were signicantly lower in
the Group A. ese resulted in signicant lower number of
cancelled cycles because of hyperstimulation risk (E2 > 4000
pg/ml). e number of oocytes retrieved did not dier between
the two groups, whereas in the group treated with MYO the
number of immature oocytes and degenerated oocytes was
signicantly reduced (1.0 ± 0.9 vs. 1.6 ± 1.0; p = 0.01), with a
trend for increased percentage of metaphase II stage oocytes
(0.82 ± 0.11% vs. 0.75 ± 0.15%).
No dierences were reported in fertilization and cleavage
rates, the number of transferred embryos, and the number of top-
quality transferred embryos and pregnancy rate.
Gerli et al. [22] enrolled 92 patients to evaluate MYO eects
on ovarian and metabolic factors; 45 received 2 g MYO combined
with 200 g folic acid twice a day (Inofolic®, LO.LI. Pharma), 47
received 400 g folic acid as placebo.
ere were eight conceptions and one miscarried in the rst
trimester. However, only 42 of the patients declared before the
study that they wished to conceive. Among these, the distribution
of pregnancy was: placebo one out of 19 patients, while in the
MYO group it was four out of 23 patients.
An intention to treat analysis revealed that eight of 45 MYO
patients failed to ovulate during treatment, compared with 17 out
of 47 placebo-treated patients (p = 0.04); the MYO-treated group
had a signicantly increased frequency of ovulation compared
with the placebo group. According to these data, the concen-
trations of P recorded during monitoring of ovarian function
indicated that most of the ovulations showed normal endocrine
proles during both MYO and placebo treatment. All patients
started treatment outside the luteal phase, and the delay to the
rst ovulation aer starting the program was signicantly shorter
in the MYO-treated group (24.5 vs. 40.5, p = 0.02).
e analysis of E2, inhibin-B, and T concentrations on the
rst and eighth day of treatment showed that the MYO-treated
group had a signicant (p = 0.03) increase in E2 levels, whereas
the control group showed no change. ere was no change in
circulating levels of inhibin-B or T concentrations.
e BMI decreased signicantly in the MYO group (p = 0.04).
No change was observed in the waist-to-hip ratio in either group.
Circulating leptin concentration declined in the MYO group, in
contrast to the control group, but there was no change recorded
in the fasting glucose, fasting insulin or insulin AUC in response
to the glucose challenge in either group.
e very-low-density lipoprotein showed little change during
the treatment period, but the low-density lipoprotein (LDL)
showed a trend toward reduction, and the high-density lipopro-
tein (HDL) increased signicantly in the MYO group.
Raone et al. [36] performed a study aiming to compare the
eects of metformin and MYO on PCOS patients: 120 women
were recruited; 60 patients were treated with metformin 1500 mg/
day (Glucophage®, Merck Pharma, Rome, Italy), while 60
received 4 g MYO plus 400 g folic acid (Inofolic®).
Among the patients treated with metformin, 50% restored
spontaneous ovulation activity; in these patients, ovulation
occurred aer 16.7 (+2.5) days from the day 1 of the menstrual
cycle. Pregnancy occurred spontaneously in 11 of these patients;
seven women dropped out. e remaining 42 patients were treated
with 1500 mg of metformin plus r-FSH for a maximum of three
cycles. Pregnancy occurred in 11 women, nine of these pregnan-
cies occurred in the metformin-resistant patients (n = 23), two in
the group which had ovulation restored with metformin alone.
e total pregnancy rate was 36.6%, ve of the 22 pregnancies
(22.7%) evolved in spontaneous abortion at 9 weeks of gestation.
Seven subjects in the metformin group dropped out because of
the development of side eects and loss of follow-up.
In the MYO group, 65% of patients restored spontaneous
ovulation activity, ovulation occurred aer a mean of 14.8 (+1.8)
days from the day 1 of the menstrual cycle. Pregnancy occurred
spontaneously in 18 of these patients and four women dropped
out. e remaining 38 patients were treated with 4 g/day MYO,
400 g/day folic acid and r-FSH in small doses (37.5 U/day for
three cycles). Pregnancy occurred in a total of 11 women, eight
of these pregnancies occurred in the MYO-resistant patients
(n = 17), three in the group which had ovulation restored with
MYO alone.
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Myo-inositol in women with PCOS 5
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e total pregnancy rate was 48.4%, six of the 29 pregnan-
cies (20.6%) evolved in spontaneous abortion. e ecacy in
restoring regular ovulation was evaluated by comparing both
the percentage of patients who responded to the treatment and
the median length of follicular phase in metformin and in MYO
group: ovulation occurred aer a mean 16.7 (+2.5) days from the
day 1 of the menstrual cycle in the metformin group and aer
a mean 14.8 (+1.8) in the MYO group. e median between
metformin and MYO diered signicantly (p < 0.003). Inclusion,
exclusion criteria and the main outcome measures for all studies
are described in Table I.
Conclusions
PCOS is one of the most common endocrine disorders aecting
women, it is the most common cause of female infertility and it
is characterized by a combination of hyperandrogenism, chronic
anovulation and irregular menstrual cycle [38,39]. Several
patients aected by PCOS are also aected by insulin resistance
although they do not show signs of diabetes [4,10]; furthermore,
insulin resistance is not linked to the BMI [7,40]. PCOS-induced
insulin resistance determines a higher risk for the development
of type 2 diabetes, hypertension and dyslipidemia, all elements of
the metabolic syndrome [41].
MYO is an important constituent of follicular microenviron-
ment, playing a determinant role in both nuclear and cytoplasmic
oocyte development. Indeed, inositol 1,4,5-triphosphate modu-
lates intracellular Ca2+ release.
Calcium signaling in oocytes has been extensively studied in
various species because of its putative role in oocyte maturation
and the early stages of fertilization [42,43]. It has been demon-
strated that fully grown mammalian germinal vesicles (GV), that
exhibit spontaneous intracellular calcium oscillations, are asso-
ciated with a higher incidence of GV breakdown. MYO supple-
mentation was suggested to promote meiotic progression of these
GV. Indeed, high concentration of MI in the uids of the human
follicles strongly associates with good-quality oocytes [44].
Despite the relatively high number of reports evaluating clin-
ical studies that used MYO as a treatment in women with PCOS,
only few of them were designed as RCTs (level of evidence Ib).
Four articles [22,34–36] evaluated the eects of MYO admin-
istration on hormonal and metabolic parameters in patients with
PCOS. e results of these studies support the hypothesis of a
primary role of IPG as second messenger of insulin signal and
demonstrate that MYO administration signicantly aects the
hormonal milieu in PCOS patients.
ere are specic positive eects of MYO treatment on insulin
plasma levels and on insulin response to oral glucose load.
Indeed, MYO decreased insulin plasma levels, glucose/insulin,
HOMA index as well as other hormonal parameters such as LH,
LH/FSH, testosterone and PRL. Furthermore, MYO inositol is
able to induce normal menstrual cycles. ese trials supported
the hypothesis that MYO supplementation induces the reduction
of insulin levels probably by inducing an increase of IPG levels;
therefore, higher IPG levels could be able to amplify insulin
signal.
In particular, in two studies [20,34] the authors suggest that
a deciency in the precursors of IPG such as MYO and/or DCI
might be an additional cofactor contributing to the pathophysi-
ology of the insulin resistance of PCOS patients [18].
All the PCOS patients showed a signicant improvement of
typical hormonal parameters: indeed, aer MYO treatment
LH levels, LH/FSH ratio, T and HOMA index were decreased.
Furthermore, the insulin AUC aer glucose load was reduced,
being a clear signal of the improved peripheral sensitivity.
Interestingly, PRL plasma levels also resulted signicantly lower
under MYO administration.
In addition to this, Gerli et al. demonstrated a signicant
reduction in weight in the patients treated with MYO, in contrast
to the placebo group where the BMI increased. Associated with
the weight loss, it was possible to observe a signicant reduction
in circulating leptin and an increase in HDL concentrations, while
LDL showed a trend toward reduction.
ese data on HDL cholesterol were the rst evidence showing
that MYO treatment could be useful in reducing the risk of
cardiovascular diseases in PCOS women.
Several trials showed that insulin sensitizer agents, such as
metformin and MYO, are the rst-line treatment to restore
normal menstrual cycles in women suering from PCOS [9–13],
suggesting that an endocellular defect of the precursor of IPG
such as MYO and/or DCI might trigger the compensatory hyper-
insulinemia in most PCOS subjects.
Moreover, Raone et al. showed that MYO slightly improves
pregnancy rate compared to metformin.
ese ndings further support the hypothesis that the reduc-
tion of insulin levels induced by MYO oral supplementation
depends on the increased availability of the main precursor of
IPG insulin second messenger.
Furthermore, in one trial [20] it has been shown that MYO is
eective in ovarian stimulation protocols in women with PCOS.
PCOS women have an increased risk of hyperstimulation
syndrome [45]. Indeed, high levels of serum ovarian androgens
are implicated in production of elevated serum E2 levels aer
gonadotropin ovarian stimulation. PCOS patients treated with
MYO + gonadotropin showed a signicant reduction in E2 levels
aer hGC administration. is was reected on the lower number
of in vitro fertilization (IVF) cycles cancelled because of high E2
levels (sign of hyperstimulation syndrome [20]).
Literature studies already suggested that MYO has positive
eect on developmental competence of maturing oocytes [46].
In line with this evidence, a recent clinical trial aiming to
compare the eect of MYO or DCI supplementation on oocyte
quality of PCOS patients showed that only MYO rather than DCI
is able to improve oocyte quality [47]. Based on these data, we
developed a theory that identied a “DCI paradox [48],” where we
suggest that ovaries in PCOS patients likely present an enhanced
MI to DCI epimerization that leads to a MI tissue depletion;
this, in turn, could eventually be responsible for the poor oocyte
quality characteristic of these patients [49].
Remarkably, in all the studies analysed, no side eects were
reported at the doses of both 2 and 4 g/day, thus resulting in a
high patient compliance. e 4 g/day treatment regimen is useful
to treat all the symptom spectrum, resulting in a more complete
and eective treatment.
In conclusion, by analyzing dierent studies focused on MYO
supplementation to improve several of the hormonal distur-
bances of PCOS, we provide a level Ia evidence of MYO eective-
ness. MYO mechanism of action appears to be mainly based on
improving insulin sensitivity of target tissues, resulting in a posi-
tive eect on the reproductive axis (MYO restores ovulation and
improves oocyte quality) and hormonal functions (MYO reduces
clinical and biochemical hyperandrogenism and dyslipidemia)
through the reduction of insulin plasma levels.
Declaration of Interest: e authors report no conict of
interest.
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6 V. Unfer et al
Gynecological Endocrinology
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