Int J Endocrinol. 2016; 2016: 1849162.
Published online 2016 Oct 23. doi: 10.1155/2016/1849162
PMCID: PMC5097808
Abstract
Polycystic
ovary syndrome (PCOS) is a common endocrine disorder, with complex
etiology and pathophysiology, which remains poorly understood. It
affects about 5–10% of women of reproductive age who typically suffer
from obesity, hyperandrogenism, ovarian dysfunction, and menstrual
irregularity. Indeed, PCOS is the most common cause of anovulatory
infertility in industrialized nations, and it is associated with insulin
resistance, type 2 diabetes mellitus, and increased cardiovascular
risk. Although insulin resistance is not included as a criterion for
diagnosis, it is a critical pathological condition of PCOS. The purpose
of this systematic review is the analysis of recent randomized clinical
trials of inositol(s) in PCOS, in particular myo- and D-chiro-inositol,
in order to better elucidate their physiological involvement in PCOS and
potential therapeutic use, alone and in conjunction with assisted
reproductive technologies, in the clinical treatment of women with PCOS.
1. Introduction
Polycystic
ovary syndrome (PCOS) is one of the most common endocrine disorders
affecting women of reproductive age. PCOS is associated with a wide
range of maladies, such as hormonal and metabolic impairments, ovarian
dysfunction, and menstrual irregularity. According to the Rotterdam
criteria developed in 2003, PCOS is diagnosed if two out of the three
following features are met: chronic oligo- or anovulation, anatomically
polycystic ovaries on ultrasonography, and clinical and/or biochemical
hyperandrogenism [1].
Although not included as criteria, insulin resistance and
hyperinsulinemia are important etiologic factors associated with the
typical clinical signs and hormonal disorders of PCOS. Indeed, insulin
resistance along with hyperinsulinemia affects approximately 40–50% of
PCOS patients, both lean and obese [2–6];
however, in obese women with PCOS the prevalence of insulin resistance
accompanied by compensatory hyperinsulinemia approaches 80% [7].
Treatment of PCOS with insulin-sensitizing drugs, such as metformin,
troglitazone, and pioglitazone, has been shown to improve ovulatory
function and reduce circulating androgens, corroborating the critical
link between insulin resistance and the pathogenesis of this syndrome.
Of these insulin-sensitizing agents, metformin is most commonly used in
the treatment of PCOS, although it has no official indication outside of
type 2 diabetes in many countries and therefore it is considered as an
off-label product when used in nondiabetic women with PCOS.
Nevertheless, nausea, diarrhea, and weight increase are side effects of
metformin, which reduce patients' compliance and the suitability of its
use [3, 8, 9].
In
the past two decades, several studies have reported the effectiveness
of inositol(s), mainly the two stereoisomers myo-inositol (Myo-Ins) and
D-chiro-inositol (D-chiro-Ins), in improving the pathological conditions
associated with PCOS [3, 8–14]. Indeed, Myo-Ins and D-chiro-Ins have been shown to play different roles in the physiology and treatment of PCOS [15]. In the ovary, D-chiro-Ins is involved in insulin-mediated androgen synthesis [16], whereas Myo-Ins mediates glucose uptake and follicle stimulating hormone (FSH) signaling [14, 15, 17, 18].
In human ovaries, 99% of the intracellular pool of inositol consists of
Myo-Ins and the remaining part consists of D-chiro-Ins [17];
imbalance of ovarian Myo-Ins and D-chiro-Ins concentrations, like a
putative Myo-Ins deficiency, might impair the FSH signaling, as observed
in PCOS patients [17–19]. D-chiro-Ins is synthetized from Myo-Ins through the epimerase enzyme, which in turn is stimulated by insulin [19]. The epimerase activity is increased in the theca cells, causing a deficit of Myo-Ins [19]
and this appears to be a critical factor in the pathogenesis of PCOS.
Indeed, reduced intraovarian Myo-Ins may adversely affect glucose uptake
and metabolism of both oocytes and follicular cells. Since oocytes are
characterized by high glucose consumption this would compromise oocyte
quality.
Several studies have emphasized the pivotal role of Myo-Ins in improving oocyte quality [10, 14, 25, 31, 32].
Myo-Ins and D-chiro-Ins are intracellularly incorporated into inositol
phosphoglycans (IPGs), which are second messengers of insulin, and some
actions of insulin are mediated by these IPG mediators. A number of
studies have suggested that insulin pathway impairment could be due to
dysregulation of the IPG second messenger system [33, 34].
This is consonant with the studies of Nestler et al. which suggest that
altered metabolism of inositol or IPG mediators contribute to the
insulin resistance of women with PCOS [13].
Indeed, they have demonstrated that D-chiro-Ins supplementation
replenished stores of the mediator and improved insulin sensitivity in
both lean and obese women with PCOS [12, 13].
Given
the physiologic role of inositol(s) in oocyte and spermatozoa
development, the 2013 Florence International Consensus Conference on
myo- and D-chiro-inositol in obstetrics and gynecology addressed the use
of inositol(s) in assisted reproductive technologies (ART) [35].
In addition, a previous systematic review by Unfer et al. provided an
overview of the clinical outcomes of Myo-Ins as a treatment to improve
ovarian function, as well as hormonal and metabolic parameters, in PCOS
women [14].
In the present systematic review, we present updated information about
inositol(s), in particular Myo-Ins and D-chiro-Ins, through an analysis
of recently published reports, in order to better outline the
physiological involvement and clinical use of inositol(s) in PCOS and
ART.
2. Methods
A
critical review of the literature was performed by searching core
databases to select pertinent scientific articles: Medline, Amed, and
the Cochrane Library. We conducted a search over the period from January
1999 to May 2016, and only randomized controlled trials (RCTs),
involving women with PCOS, were included in the present study. Search
terms included “inositol,” “myo-inositol,” “D-chiro-inositol,”
“polycystic ovary syndrome,” “oocyte quality,” “ovarian stimulation,”
“in vitro fertilization,” “ovarian function,” and “insulin resistance.”
No language restrictions were imposed. Data from treatments with Myo-Ins
or D-chiro-Ins in combination with other drugs, as well as animal and
in vitro investigations, were excluded. Full articles were obtained
through either our own library or interlibrary loan, for all published
studies that were considered eligible for inclusion in the review. As
described below, a total of 12 studies were finally included for review.
The main outcomes we aimed to focus on were the following: glucose and insulin sensitivity, 17β-estradiol
(E2), testosterone (T), androstenedione (A), the homeostatic model
assessment (HOMA) index, sex hormone binding globulin (SHGB), r-FSH,
stimulation days, oocyte quality, embryo quality, biochemical
pregnancies, and pregnancy rate.
3. Results of the Literature Search
The
systematic search yielded 102 papers for consideration. A total of 69
studies were excluded during the screening phase as not being pertinent.
Of the remaining 33 studies, 21 did not meet the selection criteria.
This left 12 studies that were included and analyzed in the final review
(Tables (Tables1,1, ,2,2, ,3,3, and and4).4). All the RCTs analyzed in this review studied patients with PCOS.
Eligible RCTs where myo-inositol and/or D-chiro-inositol have been evaluated for the treatment of PCOS patients.
Eligible RCTs where myo-inositol and/or D-chiro-inositol have been evaluated for the treatment of PCOS patients undergoing ART.
Biochemical and clinical findings related to hyperandrogenism and metabolism.
IVF parameters and fertilization outcomes.
Eight trials evaluated the effect of Myo-Ins administration on hormonal levels and oocyte quality [10, 11, 20, 21, 25–27, 29]. In one trial, the effects of different concentrations of D-chiro-Ins on the oocytes quality were assessed [28].
Three RCTs evaluated the effects of combined therapy with Myo-Ins and
D-chiro-Ins on oocyte quality and in vitro fertilization (IVF) outcomes [22, 23, 30].
Of note, two trials were randomized controlled Myo-Ins versus folic acid, as placebo [20, 25]; three were double-blind randomized controlled trial Myo-Ins versus folic acid [11, 21, 26]; one was a randomized controlled Myo-Ins versus metformin [27]. One study was a dose-response study of D-chiro-Ins on ovaries [28]. A single study, RCT, also compared the efficacy between Myo-Ins and D-chiro-Ins in improving oocyte quality [29]. In the last 3 RCTs, the combination of Myo-Ins/D-chiro-Ins (40 : 1) was examined in PCOS patients [22, 23, 30].
In the report of Genazzani et al. [20],
PCOS patients were recruited in the trial and treated with either
Myo-Ins plus folic acid (Inofolic®, LO.LI. Pharma, Rome, Italy) or folic
acid alone (Table 1). The endocrine profile was evaluated and main outcomes are shown in Table 3.
Consistent and significant changes were observed in the group receiving
Myo-Ins plus folic acid. Indeed, prolactin (PRL), plasma luteinizing
hormone (LH), and follicle stimulating hormone (FSH) ratio significantly
decreased. The index of insulin sensitivity, expressed as
glucose-to-insulin ratio, significantly increaed. The Ferriman-Gallwey
score decreased after 12 weeks of Myo-Ins administration although the
reduction was not statistically significant (22.7 ± 1.4 to 18.0 ± 0.8)
whereas the reduction of the ovaries volumes was significant (12.2 ±
0.6 mL to 8.7 ± 0.8 mL, p < 0.05).
The study design and the endocrine profile after treatment obtained in the RCT of Costantino et al. [21] are shown in Tables Tables11 and and3.3.
During the present study, a reduction in the systolic and diastolic
blood pressure (SBP and DBP) values was observed in patients treated
with Myo-Ins (131 ± 2 mmHg to 127 ± 2 mmHg and 88 ± 1 mmHg to 82 ±
3 mmHg, resp.), while these values increased in placebo group (128 ±
1 mmHg to 130 ± 1 mmHg, p = 0.002, and 86 ± 7 mmHg to 90 ± 1 mmHg, p
= 0.001, resp.). Furthermore, in Myo-Ins group, plasma triglycerides
decreased from 195 ± 20 mg/dL to 95 ± 17 mg/dL and total cholesterol
significantly decreased from 210 ± 10 mg/dL to 171 ± 11 mg/dL. In
Myo-Ins-treated group the composite whole body insulin sensitivity index
(ISI) increased significantly from 2.80 ± 0.35 mg/dL to 5.05 ±
0.59 mg/dL, while it did not change in placebo group. Ovulation was
restored in 69.5% of women in Myo-Ins group and 21% of placebo (p
= 0.001). After treatment, the peak level of progesterone (P) was
higher in Myo-Ins patients (15.1 ± 2.2 ng/mL) compared to placebo.
Furthermore, there was a significant reduction of more than 50% in the
serum dehydroepiandrosterone sulphate in Myo-Ins women (366 ± 47 μg/dL to 188 ± 24 μg/dL; p = 0.003), whereas it was not significant in placebo.
Gerli et al. [10, 11]
evaluated the effect of Myo-Ins on ovarian and metabolic factors in
PCOS subjects, in 2 different studies conducted in 2003 and 2007 (Tables
(Tables11 and and3);3); in the first trial [10], the ovulation frequency was significantly higher (p < 0.01) in Myo-Ins-treated group (23%) compared with placebo (13%). The main outcomes are defined in Table 3.
In addition, it was found that E2 concentration increased only in
Myo-Ins group during the first week of treatment inducing follicular
maturation. The body mass index (BMI) and leptin were significantly
reduced in treated patients, whereas body weight augmented in placebo. A
significant increase in circulating high-density lipoprotein (HDL) was
recorded in Myo-Ins women. In the second study [11], in addition to the main findings shown in Table 3,
a significant increment of the ovulation frequency in Myo-Ins group
compared to placebo was observed. All patients started treatment outside
the luteal phase, and the delay to the first ovulation after starting
the program was significantly shorter in the study group (24.5 versus
40.5, p = 0.02). The analysis on the first and eighth day of
treatment showed that the Myo-Ins-treated group had a significant
increase in E2 levels (p = 0.03), whereas controls showed no
change. Circulating levels of inhibin B remained unvaried. Circulating
leptin concentration declined in Myo-Ins patients, in contrast to
controls. The low-density lipoprotein (LDL) showed a trend toward
reduction, and the HDL increased significantly in Myo-Ins group.
In Nordio and Proietti study [22], the combination of Myo-Ins and D-chiro-Ins versus Myo-Ins alone was evaluated (Tables (Tables11 and and3).3).
Either treatment was efficacious in improving the ovulation function
and metabolic parameters. Besides the main findings displayed in Table 3,
a reduction of SBP and SDB was observed in both groups (Myo-Ins plus
D-chiro-Ins, 131.0 ± 1.6 mmHg to 128.0 ± 1.2 mmHg and 88.0 ± 3.3 to 80 ±
2 mmHg, resp., versus Myo-Ins, 129.0 ± 2.5 mmHg to 127 ± 2 mmHg and
87.0 ± 2.6 mmHg to 82 ± 1 mmHg, resp.). Also BMI and waist-to-hip ratio
(WHR) were reduced after treatment but not significantly.
In a very recent study [23],
an improvement of patients' insulin resistance and ovulatory function
was observed after Myo-Ins and D-chiro-Ins treatment, significantly
rebalancing their endocrine and metabolic profiles (Tables (Tables11 and and33).
Papaleo et al. [25]
broaden the clinical use of Myo-Ins by evaluating its effect on oocyte
quality and the ovarian stimulation protocol for PCOS women (Table 2). As can be seen in Table 4,
the number of oocytes retrieved did not differ between the two groups,
whereas in the group treated with Myo-Ins the number of immature oocytes
and degenerated oocytes was significantly reduced (1.0 ± 0.9 versus 1.6
± 1.0; p = 0.01), with a trend for increased percentage of metaphase II stage oocytes.
In the study of Ciotta et al. [26],
oocyte's quality was assessed after the oocyte pick-up during the
assisted reproductive technology (ART) procedure in women with PCOS (Table 2). Besides results shown in Table 4, the number of immature oocytes resulting significantly reduced in Myo-Ins group (degenerated oocytes 0.93% versus 14.37%, p < 0.02; germinal vesicles 1.4% versus 9.37%, p < 0.02) and the mean number of transferred embryos was significantly higher.
Raffone et al. [27]
compared the effects of metformin (Glucophage®, Merck Pharma) and
Myo-Ins (Inofolic, LO.LI. Pharma, Rome, Italy) on PCOS patients (Tables (Tables22 and and4).4).
In Myo-Ins group 65% of patients versus 50% of metformin group restored
spontaneous ovulation activity, after a mean of 14.8 (±1.8) days and
16.7 (±2.5) days from day 1 of the menstrual cycle, respectively.
Fifty-four women diagnosed with PCOS were selected in the study of Isabella and Raffone, 2012 [28] (Table 2).
Patients were randomized into 5 groups, including a placebo group and 4
groups that received 300, 600, 1200, and 2400 mg of D-chiro-Ins
(Interquim s.a., Barcelona, Spain) daily, respectively. In addition to
the main results reported in Table 4,
they found that high D-chiro-Ins concentrations progressively increase
the number of immature oocytes, in a significant manner (p < 0.04).
As shown in Tables Tables22 and and4,4, Unfer et al. [29]
compared the efficacy of Myo-Ins and D-chiro-Ins in patients diagnosed
with PCOS. The selected ones were randomly divided into two groups
receiving either Myo-Ins or D-chiro-Ins (Table 2). Along with the main findings presented in Table 4,
it was reported that the number of immature oocytes was significantly
lower in Myo-Ins group compared to D-chiro-Ins group (0.69 ± 0.64 versus
2.23 ± 0.85; p < 0.01).
The
combination 40 : 1 of Myo-Ins and D-chiro-Ins (Inofolic Combi, LO.LI.
Pharma, Rome, Italy; patented) was also evaluated by Colazingari et al. [30], in PCOS patients undergoing IVF (Table 2).
In this study, for evaluation of results, women age was also taken into
account, dividing them into 2 further categories: ≤35 or >35 years.
The combination of Myo-Ins and D-chiro-Ins gave a greater result in the
ovarian stimulation protocol compared to D-chiro-Ins alone (Table 4).
In Myo-Ins plus D-chiro-Ins patients, oocytes of high quality resulted
and the number of degenerated oocytes was lower. In particular results
showed that Myo-Ins plus D-chiro-Ins treatment reduced the number of
degenerated oocytes in both age groups (≤35 years old: 1.04 ± 1.15
versus 1.82 ± 1.55; >35 years old: 1.00 ± 0.91 versus 1.45 ± 0.89).
4. Discussion
A
critical review of the 12 RCTs included in this systematic review
highlights that oral administration of Myo-Ins, alone or in combination
with D-chiro-Ins, is capable of restoring spontaneous ovulation and
improving fertility in women with PCOS.
Myo-Ins and
D-chiro-Ins are 2 of the 9 different stereoisomers of inositol, polyol
found in many foods, in particular cereals, nuts, and fruits as well as
in human cells. They exert important actions in the control of glucose
homeostasis and, when incorporated into phosphoglycans, have been shown
to serve as second messengers involved in the signaling-transduction
cascade of insulin [36, 37]; Myo-Ins and D-chiro-Ins are also involved in a number of biochemical pathways within oocytes [38, 39]. PCOS women have lower serum D-chiro-Ins levels and elevated urinary loss of D-chiro-Ins-IPG [40].
As noted above, inositol phosphoglycans (IPGs) are potentially
important putative intracellular mediators of insulin action. It has
been demonstrated that, in patients affected by PCOS, the metabolism of
inositol is dysregulated, highlighting the subtle connection between
insulin resistance and inositol deficiency in PCOS patients [41].
Indeed, in women with PCOS, insulin resistance and compensatory
hyperinsulinemia due to dysregulation of inositol metabolism may
actually be the major underlying cause of the disorder. Various studies
have shown the role of D-chiro-Ins at low dosage in increasing insulin
sensitivity and ovulation frequency, as well as in decreasing levels of
lipid biomarkers and serum androgen [12, 13].
D-chiro-Ins is converted from Myo-Ins through insulin-stimulated
NAD-dependent epimerase. Myo-Ins is the most abundant inositol isomer
within the ovary, as suggested by the fact that approximately 99% of the
ovarian intracellular pool of inositol consists of Myo-Ins [17].
Indeed, it was shown that an increased activity of epimerase in theca
cells of ovaries of PCOS women is associated with a consistent reduction
in the intraovarian ratio of Myo-Ins to D-chiro-Ins [19]. These experimental data are in line with the so-called D-chiro-Ins ovarian paradox posited by Carlomagno et al. [18];
these investigators advanced the hypothesis that epimerase activity is
increased in the ovaries of PCOS subjects, resulting in a local Myo-Ins
deficiency responsible for the oligoovulation and poor oocyte quality of
the disorder. This hypothesis has drawn attention to the importance of
Myo-Ins and D-chiro-Ins supplementation in a physiological ratio in
order to restore normal ovary functionality. In fact, a correlation
between Myo-Ins concentration in the follicular fluid and high oocyte
quality was found and a number of studies have reported that Myo-Ins
supplementation is able to improve oocyte quality [25, 31].
In
this systematic review a number of recent articles were selected in
order to critically analyze the roles of Myo-Ins and D-chiro-Ins,
combined or alone, as a treatment of PCOS. Although there are a number
of published articles on the use of Myo-Ins as a treatment in women with
PCOS, only few of them were designed as RCT. These RCT studies,
reviewed here, support the hypothesis of a primary role of IPGs as
second messengers of insulin signaling and demonstrate that Myo-Ins
supplementation beneficially affects the hormonal milieu of PCOS
patients. Indeed, these trials provide evidence that Myo-Ins reduces
insulin levels, probably either by conversion to D-chiro-Ins (via the
epimerase enzyme) or by serving as substrate for the formation of
Myo-Ins-containing IPGs and D-chiro-Ins-containing IPGs, which would in
turn amplify insulin signaling. In particular, two studies [20, 25]
suggest that deficiency of Myo-Ins and/or D-chiro-Ins might be an
additional cofactor contributing to the pathophysiology of the insulin
resistance of PCOS patients [42]. In these studies, hormonal parameters improved significantly in all PCOS patients treated with Myo-Ins [10, 11, 20, 21, 25–27, 29].
In a study by Gerli et al. body weight and circulating leptin decreased
significantly and HDL concentrations increased significantly in the
patients treated with Myo-Ins, compared with the placebo group,
providing the first indication that Myo-Ins treatment might possibly
reduce the risk of cardiovascular diseases in PCOS women. Moreover, in
an equivalency study, Raffone et al. [27]
stated that Myo-Ins improves the pregnancy rate in PCOS women. These
findings further support the hypothesis of a key role of IPG as second
messenger of insulin signaling. The oral supplementation of Myo-Ins
might reduce insulin levels, by providing a higher availability of IPG
precursors, in this way improving the activities of this second
messenger of insulin signal [27].
The
study by Ciotta et al. demonstrated that Myo-Ins treatment reduced the
number of germinal vesicles and degenerated oocytes and improved the
development of mature oocytes, as previously reported in experimental
data [43].
The authors concluded that Myo-Ins alone is useful in PCOS patients as
insulin-sensitizer and for induction of oocyte maturation [26],
confirming that Myo-Ins is likely an important constituent of the
follicular microenvironment for normal nuclear and cytoplasmic oocyte's
development.
As already noted, the role played by
D-chiro-Ins in ovarian physiology is controversial. In this regard, a
study in which different concentrations of D-chiro-Ins were
administrated to nonobese PCOS women with normal insulin sensitivity
undergoing IVF reported that as the dosage of D-chiro-Ins was
progressively increased, oocyte quality and ovarian response worsened [28].
A possible explanation for this observation may lie in the different
tissue-specific ratios of Myo-Ins/D-chiro-Ins in different organs (i.e.,
100 : 1 in the ovary) and the diverse physiological roles of inositol
stereoisomers, as Myo-Ins increases glucose cellular uptake and
D-chiro-Ins is involved in glycogen synthesis [33, 44].
In fact, cells responsible for glycogen storage (such as liver,
muscles, and fat cells) contain high levels of D-chiro-Ins, whereas
brain and heart cells contain high concentration of Myo-Ins, since they
require high consumption of glucose. These data are in line with the
D-chiro-Ins paradox hypothesis and with the data of Unfer et al. (2011)
that demonstrated that Myo-Ins rather than D-chiro-Ins improved oocyte
quality in intracytoplasmic sperm injection cycles [18, 29].
To wit, Unfer et al. demonstrated that Myo-Ins treatment significantly
reduced ovarian stimulation days and the IU of r-FSH administrated and
improved both oocyte and embryo quality in euglycemic PCOS patients when
compared with treatment with D-chiro-Ins. This was also shown in 2009
by Papaleo et al. and included in our previous systematic review [14, 25].
However, as demonstrated by Nordio and Proietti, the combination of
Myo-Ins and D-chiro-Ins, at a physiological ratio of 40 : 1, was able to
more quickly restore to normal the hormonal and metabolic parameters in
overweight PCOS women than Myo-Ins treatment alone [22].
Bearing in mind previous studies, the physiological ratio of these two
isomers (40 : 1) seems to be an optimal and promising approach for the
treatment of PCOS disorders [45, 46].
This
might be due to the synergistic action of Myo-Ins and D-chiro-Ins, as
they regulate different biological processes. In fact, the combination
of Myo-Ins and D-chiro-Ins may be particularly beneficial in overweight
PCOS women, considering that Myo-Ins improves the ovulatory function and
D-chiro-Ins rapidly reduces the peripheral hyperinsulinemia. Notably,
Colazingari et al. also reported that combined therapy of Myo-Ins and
D-chiro-Ins, rather than D-chiro-Ins alone, improved oocyte quality in
PCOS women undergoing ART [30].
This study further corroborates previous data, suggesting that
D-chiro-Ins supplementation alone might not be the optimal or
appropriate approach for improving IVF outcomes in PCOS patients.
Treatment
with the combination of Myo-Ins and D-chiro-Ins has been further
investigated by Benelli et al. who demonstrated that these two
molecules, together in a 40 : 1 ratio, improved the endocrine profile
and insulin resistance of obese women with PCOS [23].
An important aspect of this study was that no relevant side effects
were recorded during combined therapy with Myo-Ins and D-chiro-Ins,
providing further evidence of the safety of the usage of these two
stereoisomers in combination. There is also accumulating evidence on the
beneficial effects of Myo-Ins administration on reproductive function
and the efficacy of combined Myo-Ins/D-chiro-Ins administration, in the
physiological plasma ratio of 40 : 1, for amelioration of the metabolic
aberrations of PCOS and for restoring spontaneous ovulation [47].
In
conclusion, the analysis of these clinical trials highlights the
salutary effects of Myo-Ins supplementation in improving several of the
hormonal and reproductive disturbances of PCOS; furthermore, the
analysis lends prominence to the pivotal role of inositol(s), mainly
Myo-Ins and D-chiro-Ins, as a safe and effective therapy for PCOS,
including an enhanced oocyte follicular development and oocyte
maturation and in stimulation and pregnancy outcomes in IVF procedures.
Competing Interests
Vittorio
Unfer is employee at LO.LI. Pharma, Rome, Italy. The other authors
declare that they have no conflict of interests regarding the
publication of this paper.
References
1. The
Rotterdam ESHRE/ASRM Sponsored PCOS Consensus Workshop Group. Revised
2003 consensus on diagnostic criteria and long-term health risks related
to polycystic ovary syndrome (PCOS) Human Reproduction. 2004;19(1):41–47. [PubMed]
2. Ciampelli
M., Fulghesu A. M., Cucinelli F., et al. Impact of insulin and body
mass index on metabolic and endocrine variables in polycystic ovary
syndrome. Metabolism: Clinical and Experimental. 1999;48(2):167–172. doi: 10.1016/S0026-0495(99)90028-8. [PubMed] [Cross Ref]
3. Genazzani
A. D., Battaglia C., Malavasi B., Strucchi C., Tortolani F., Gamba O.
Metformin administration modulates and restores luteinizing hormone
spontaneous episodic secretion and ovarian function in nonobese patients
with polycystic ovary syndrome. Fertility and Sterility. 2004;81(1):114–119. doi: 10.1016/j.fertnstert.2003.05.020. [PubMed] [Cross Ref]
4. Bigos
A., Palkowska E., Rosolowska-Huszca D. Effect of artificial and natural
sweeteners on glucose and insulin in plasma of rats. Journal of Pre-Clinical and Clinical Research. 2012;6(2):93–97.
5. Dunaif
A., Segal K. R., Futterweit W., Dobrjansky A. Profound peripheral
insulin resistance, independent of obesity, in polycystic ovary
syndrome. Diabetes. 1989;38(9):1165–1174. doi: 10.2337/diab.38.9.1165. [PubMed] [Cross Ref]
6. Laven
J. S. E., Mulders A. G. M. G. J., van Santbrink E. J. P., Eijkemans M.
J. C., Fauser B. C. J. M. PCOS: backgrounds, evidence and problems in
diagnosing the syndrome. International Congress Series. 2005;1279:10–15. doi: 10.1016/j.ics.2005.01.002. [Cross Ref]
7. Nestler J. E. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Seminars in Reproductive Endocrinology. 1997;15(2):111–122. doi: 10.1055/s-2007-1016294. [PubMed] [Cross Ref]
8. Lord J. M., Flight I. H. K., Norman R. J. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. British Medical Journal. 2003;327(7421):951–953. [PMC free article] [PubMed]
9. Pasquali R., Gambineri A. Insulin-sensitizing agents in polycystic ovary syndrome. European Journal of Endocrinology. 2006;154(6):763–775. doi: 10.1530/eje.1.02156. [PubMed] [Cross Ref]
10. Gerli
S., Mignosa M., Di Renzo G. C. Effects of inositol on ovarian function
and metabolic factors in women with PCOS: a randomized double blind
placebo-controlled trial. European Review for Medical and Pharmacological Sciences. 2003;7(6):151–159. [PubMed]
11. Gerli
S., Papaleo E., Ferrari A., di Renzo G. C. Randomized, double blind
placebo-controlled trial: effects of myo-inositol on ovarian function
and metabolic factors in women with PCOS. European Review for Medical and Pharmacological Sciences. 2007;11(5):347–354. [PubMed]
12. Iuorno
M. J., Jakubowicz D. J., Baillargeon J.-P., et al. Effects of
D-chiro-inositol in lean women with the polycystic ovary syndrome. Endocrine Practice. 2002;8(6):417–423. doi: 10.4158/EP.8.6.417. [PubMed] [Cross Ref]
13. Nestler
J. E., Jakubowicz D. J., Reamer P., Gunn R. D., Allan G. Ovulatory and
metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. The New England Journal of Medicine. 1999;340(17):1314–1320. doi: 10.1056/nejm199904293401703. [PubMed] [Cross Ref]
14. Unfer
V., Carlomagno G., Dante G., Facchinetti F. Effects of myo-inositol in
women with PCOS: a systematic review of randomized controlled trials. Gynecological Endocrinology. 2012;28(7):509–515. doi: 10.3109/09513590.2011.650660. [PubMed] [Cross Ref]
15. Nestler J. E., Unfer V. Reflections on inositol(s) for PCOS therapy: steps toward success. Gynecological Endocrinology. 2015;31(7):501–505. doi: 10.3109/09513590.2015.1054802. [PubMed] [Cross Ref]
16. Nestler
J. E., Jakubowicz D. J., de Vargas A. F., Brik C., Quintero N., Medina
F. Insulin stimulates testosterone biosynthesis by human thecal cells
from women with polycystic ovary syndrome by activating its own receptor
and using inositolglycan mediators as the signal transduction system. The Journal of Clinical Endocrinology & Metabolism. 1998;83(6):2001–2005. doi: 10.1210/jc.83.6.2001. [PubMed] [Cross Ref]
17. Unfer
V., Carlomagno G., Papaleo E., Vailati S., Candiani M., Baillargeon
J.-P. Hyperinsulinemia alters myoinositol to d-chiroinositol ratio in
the follicular fluid of patients with PCOS. Reproductive Sciences. 2014;21(7):854–858. doi: 10.1177/1933719113518985. [PubMed] [Cross Ref]
18. Carlomagno G., Unfer V., Roseff S. The D-chiro-inositol paradox in the ovary. Fertility and Sterility. 2011;95(8):2515–2516. doi: 10.1016/j.fertnstert.2011.05.027. [PubMed] [Cross Ref]
19. Heimark
D., McAllister J., Larner J. Decreased myo-inositol to chiro-inositol
(M/C) ratios and increased M/C epimerase activity in PCOS theca cells
demonstrate increased insulin sensitivity compared to controls. Endocrine Journal. 2014;61(2):111–117. doi: 10.1507/endocrj.EJ13-0423. [PubMed] [Cross Ref]
20. Genazzani
A. D., Lanzoni C., Ricchieri F., Jasonni V. M. Myo-inositol
administration positively affects hyperinsulinemia and hormonal
parameters in overweight patients with polycystic ovary syndrome. Gynecological Endocrinology. 2008;24(3):139–144. doi: 10.1080/09513590801893232. [PubMed] [Cross Ref]
21. Costantino
D., Minozzi G., Minozzi F., Guaraldi C. Metabolic and hormonal effects
of myo-inositol in women with polycystic ovary syndrome: a double-blind
trial. European Review for Medical and Pharmacological Sciences. 2009;13(2):105–110. [PubMed]
22. Nordio
M., Proietti E. The Combined therapy with myo-inositol and
D-Chiro-inositol reduces the risk of metabolic disease in PCOS
overweight patients compared to myo-inositol supplementation alone. European Review for Medical and Pharmacological Sciences. 2012;16(5):575–581. [PubMed]
23. Benelli
E., Del Ghianda S., Di Cosmo C., Tonacchera M. A combined therapy with
myo-inositol and D-chiro-inositol improves endocrine parameters and
insulin resistance in PCOS young overweight women. International Journal of Endocrinology. 2016;2016:5. doi: 10.1155/2016/3204083.3204083 [PMC free article] [PubMed] [Cross Ref]
24. Adams J., Polson J. W., Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. British Medical Journal. 1986;293:355–359. [PMC free article] [PubMed]
25. Papaleo
E., Unfer V., Baillargeon J.-P., Fusi F., Occhi F., De Santis L.
Myo-inositol may improve oocyte quality in intracytoplasmic sperm
injection cycles. A prospective, controlled, randomized trial. Fertility and Sterility. 2009;91(5):1750–1754. doi: 10.1016/j.fertnstert.2008.01.088. [PubMed] [Cross Ref]
26. Ciotta
L., Stracquadanio M., Pagano I., Carbonaro A., Palumbo M., Gulino F.
Effects of Myo-Inositol supplementation on oocyte's quality in PCOS
patients: a double blind trial. European Review for Medical and Pharmacological Sciences. 2011;15(5):509–514. [PubMed]
27. Raffone
E., Rizzo P., Benedetto V. Insulin sensitiser agents alone and in
co-treatment with r-FSH for ovulation induction in PCOS women. Gynecological Endocrinology. 2010;26(4):275–280. doi: 10.3109/09513590903366996. [PubMed] [Cross Ref]
28. Isabella R., Raffone E. Does ovary need D-chiro-inositol? Journal of Ovarian Research. 2012;5(1, article 14) doi: 10.1186/1757-2215-5-14. [PMC free article] [PubMed] [Cross Ref]
29. Unfer
V., Carlomagno G., Rizzo P., Raffone E., Roseff S. Myo-inositol rather
than D-chiro-inositol is able to improve oocyte quality in
intracytoplasmic sperm injection cycles. A prospective, controlled,
randomized trial. European Review for Medical and Pharmacological Sciences. 2011;15(4):452–457. [PubMed]
30. Colazingari
S., Treglia M., Najjar R., Bevilacqua A. The combined therapy
myo-inositol plus D-chiro-inositol, rather than D-chiro-inositol, is
able to improve IVF outcomes: results from a randomized controlled
trial. Archives of Gynecology and Obstetrics. 2013;288(6):1405–1411. doi: 10.1007/s00404-013-2855-3. [PubMed] [Cross Ref]
31. Chiu
T. T. Y., Rogers M. S., Law E. L. K., Briton-Jones C. M., Cheung L. P.,
Haines C. J. Follicular fluid and serum concentrations of myo-inositol
in patients undergoing IVF: relationship with oocyte quality. Human Reproduction. 2002;17(6):1591–1596. doi: 10.1093/humrep/17.6.1591. [PubMed] [Cross Ref]
32. Papaleo
E., Unfer V., Baillargeon J.-P., et al. Myo-inositol in patients with
polycystic ovary syndrome: a novel method for ovulation induction. Gynecological Endocrinology. 2007;23(12):700–703. doi: 10.1080/09513590701672405. [PubMed] [Cross Ref]
33. Asplin
I., Galasko G., Larner J. Chiro-inositol deficiency and insulin
resistance: a comparison of the chiro-inositol- and the
myo-inositol-containing insulin mediators isolated from urine,
hemodialysate, and muscle of control and type II diabetic subjects. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(13):5924–5928. doi: 10.1073/pnas.90.13.5924. [PMC free article] [PubMed] [Cross Ref]
34. Kennington
A. S., Hill C. R., Craig J., et al. Low urinary chiro-inositol
excretion in non-insulin-dependent diabetes mellitus. The New England Journal of Medicine. 1990;323(6):373–378. doi: 10.1056/nejm199008093230603. [PubMed] [Cross Ref]
35. Bevilacqua
A., Carlomagno G., Gerli S., et al. Results from the International
Consensus Conference on myo-inositol and D-chiro-inositol in Obstetrics
and Gynecology-assisted reproduction technology. Gynecological Endocrinology. 2015;31(6):441–446. doi: 10.3109/09513590.2015.1006616. [PubMed] [Cross Ref]
36. Larner
J., Huang L. C., Schwartz C. F. W., et al. Rat liver insulin mediator
which stimulates pyruvate dehydrogenase phosphatase contains
galactosamine and D-chiroinositol. Biochemical and Biophysical Research Communications. 1988;151(3):1416–1426. doi: 10.1016/s0006-291x(88)80520-5. [PubMed] [Cross Ref]
37. Huang
L. C., Fonteles M. C., Houston D. B., Zhang C., Larner J. Chiroinositol
deficiency and insulin resistance. III. Acute glycogenic and
hypoglycemic effects of two inositol phosphoglycan insulin mediators in
normal and streptozotocin-diabetic rats in vivo. Endocrinology. 1993;132(2):652–657. [PubMed]
38. Chiu
T. T. Y., Rogers M. S., Briton-Jones C., Haines C. Effects of
myo-inositol on the in-vitro maturation and subsequent development of
mouse oocytes. Human Reproduction. 2003;18(2):408–416. doi: 10.1093/humrep/deg113. [PubMed] [Cross Ref]
39. Matsuda
M., Tsutsumi K., Kanematsu T., et al. Involvement of phospholipase
C-related inactive protein in the mouse reproductive system through the
regulation of gonadotropin levels. Biology of Reproduction. 2009;81(4):681–689. doi: 10.1095/biolreprod.109.076760. [PubMed] [Cross Ref]
40. Baillargeon
J.-P., Nestler J. E., Ostlund R. E., Apridonidze T.,
Diamanti-Kandarakis E. Greek hyperinsulinemic women, with or without
polycystic ovary syndrome, display altered inositols metabolism. Human Reproduction. 2008;23(6):1439–1446. doi: 10.1093/humrep/den097. [PMC free article] [PubMed] [Cross Ref]
41. Baillargeon
J.-P., Iuorno M. J., Apridonidze T., Nestler J. E. Uncoupling between
insulin and release of a d-chiro-inositol-containing
inositolphosphoglycan mediator of insulin action in obese women with
polycystic ovary syndrome. Metabolic Syndrome and Related Disorders. 2010;8(2):127–135. doi: 10.1089/met.2009.0052. [PMC free article] [PubMed] [Cross Ref]
42. Baillargeon
J.-P., Diamanti-Kandarakis E., Ostlund R. E., Jr., Apridonidze T.,
Iuorno M. J., Nestler J. E. Altered D-chiro-inositol urinary clearance
in women with polycystic ovary syndrome. Diabetes Care. 2006;29(2):300–305. doi: 10.2337/diacare.29.02.06.dc05-1070. [PubMed] [Cross Ref]
43. Goud
P. T., Goud A. P., Van Oostveldt P., Dhont M. Presence and dynamic
redistribution of type I inositol 1,4,5- trisphosphate receptors in
human oocytes and embryos during in-vitro maturation, fertilization and
early cleavage divisions. Molecular Human Reproduction. 1999;5(5):441–451. doi: 10.1093/molehr/5.5.441. [PubMed] [Cross Ref]
44. Ortmeyer
H. K., Huang L. C., Zhang L., Hansen B. C., Larner J. Chiroinositol
deficiency and insulin resistance. II. Acute effects of D-chiroinositol
administration in streptozotocin-diabetic rats, normal rats given a
glucose load, and spontaneously insulin-resistant rhesus monkeys. Endocrinology. 1993;132(2):646–651. [PubMed]
45. Bizzarri M., Carlomagno G. Inositol: history of an effective therapy for polycystic ovary syndrome. European Review for Medical and Pharmacological Sciences. 2014;18(13):1896–1903. [PubMed]
Articles from International Journal of Endocrinology are provided here courtesy of Hindawi Publishing Corporation
