1. The Rationale of Inositol Therapy in Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS)’s rate is about 6% to10% among the reproductive aged
women; it is characterized by menstrual cycle irregularity with oligo-anovulation,
hyperandrogenism, insulin resistance, and compensatory hyperinsulinemia. Despite the
fact that the last two elements are present in a large percentage of PCOS women, they
are not mandatory for the diagnosis; in order to explain the pathogenesis in these
patients, it was supposed that ovarian theca cells got higher insulin sensitivity
probably related to the mechanism of intracellular signalling transduction (1). Corroborating
this view, it was previously demonstrated that diazoxid, which has the well-known
effect of decreasing insulin levels, reduced hyperandrogenism in lean women affected
by PCOS, even in the cases of normal insulin level and insulin sensitivity (2). Based
on the detrimental role of insulin resistance, several insulin sensitizer drugs have
been used to ameliorate PCOS symptoms and signs. Although metformin has represented
the landmark of PCOS therapy in the recent past, to date several studies have tested
the efficacy of Inositols, a carbocyclic polyols. Two stereoisomers, in particular
Myo-inositol (MI) and D-Dhiro-inositol (DCI) showed a clinical efficacy and safety
during PCOS. MI is converted in DCI by epimerase, an enzyme regulated also by insulin
action. In the form of inositol-phosphoglycans (IPGs), they are involved in a non-classical
insulin signalling cascade: insulin receptor is coupled by G-protein which can activate
phospholipase, allowing the release of second messengers (DCI-glycan), which is able
to stimulate pyruvate dehydrogenase and glycogen synthase activities, the enzyme involved
in the oxidative and the non-oxidative glucose metabolism (3). On one hand, MI-IPG
is able to inhibit cyclic adenosine monophosphate (cAMP) kinase and adenylyl cyclase,
both involved in free fatty acid metabolism. On the other hand, DCI-IPG play a pivotal
role during the binding of insulin to its receptor on cell membrane where it stimulates
IPG release and starts signalling cascade. In addition, Inositols are incorporated
in membrane phospholipids as phosphoinositides. Phosphatidylinositol 4, 5 bisphosphate
(PtdIns-4, 5P) and phosphatidylinositol 4P (PtdIns-4P), in particular, are involved
in the regulation of the cytoskeleton structure and in the regulation of cellular
motility, which account also the beneficial effects of Inositol administration on
sperm parameters. PtdIns-4, 5P plays a key role in controlling calcium-mediated intracellular
signalling which is mandatory to address the oocytes maturation and fecundation (4).
2. Overview of Clinical Studies
In these last twenty years Inositols have been studied as a helpful alternative to
metformin. As stated before, the insulin-like actions of nutritional inositol are
due to the production of inositol glycan secondary messengers which contain MI or
DCI. Recently, our group have tested the effects of oral administration of 1 gr of
DCI + 400 mcg of folic acid per day in a large cohort of PCOS women (5). After 6 months
of treatment, we found a significant reduction of prolactin, ∆-4-Androstenedione,
Ferriman-Gallwey score, LH, systolic blood pressure, free Testosterone, LH/FSH ratio,
HOMA Index, and total testosterone; in addition, we found a significant increase of
Glycemia/IRI ratio and Sex hormone binding globulin. Finally, we found significant
post-treatment menstrual cycle regularization. Similar results were found in an accurate
systematic review of randomized controlled trials (6) which tested MI in PCOS population.
In addition, a recent randomized trial showed that both MI and DCI improved ovarian
function and metabolic profile in patients affected by PCOS, although DCI showed the
most marked effect on hyperandrogenism, MI reduced insulin resistance more effectively
(7). Considering the accumulating evidence on this topic, several studies investigated
the effects of combined DCI and MI, demonstrating a better and faster re-addressing
of hormonal and metabolic parameters in PCOS population, maintaining the widely known
safety profile (1). Although the last Cochrane systematic review about the topic does
not offer a robust recommendation about the best treatment for PCOS among metformin,
rosiglitazone, pioglitazone and DCI (8), a recent trial did not find any significant
difference between metformin and MI in lowering BMI, ameliorating insulin sensitivity,
and improving menstrual cycle (9). Nevertheless, in the evaluation of the available
evidence, we should consider that Inositol administration is more effective in obese
patients with high fasting insulin plasma levels (10).
Last but not least, both isoforms of Inositol proved to be effective, also, in combination
with other nutraceuticals which enhance their insulin sensitizing action; in particular,
considering the close connection between oxidative stress and impaired ovarian follicular
maturation, the combination of MI and Melatonin significantly improve the quality
of oocytes and the quality of embryos (3).
3. Conclusion
Since many studies showed that both MI and DCI treatment were effective to improve
PCOS symptoms and signs, these two insulin-sensitizers gained increasing popularity
among gynecologists and endocrinologists. Complicit of this boom of prescriptions,
it should be not underestimated that the favorable safety profile of the two stereoisomers
allows their administration even in pregnancy in order to prevent gestational diabetes
mellitus. In addition, MI and DCI showed to be effective both in obese and lean PCOS
women, suggesting that the typical insulin resistance of this kind of patients should
be considered pivotal not only in the case of high BMI. Indeed, in our opinion, PCOS
can be considered as the result of concurrent and inter-related endocrine alterations;
recent data suggest that hyperinsulinemia and insulin resistance have paramount importance
in the development of hyperandrogenism, which in turn causes anovulation. Furthermore,
LH works in combination with hyperinsulinemia to increase androgen production by adrenal
and theca cells. Based on these elements, it is not surprising that MI and DCI achieved
excellent results on metabolic and hormonal parameters in PCOS women. In addition,
re-addressing them to the homeostatic levels allows an improvement of ovulation, oocyte
quality, and pregnancy rate.
Despite the promising results, we take the opportunity to solicit additional studies
on larger cohorts and adequate statistical power in order to establish the most suitable
therapeutic strategies based on the patient’s clinical condition; in particular, future
research should be aimed to compare Inositols to the other insulin sensitizers (rosiglitazone,
pioglitazone) and to test new combinations of them on different PCOS phenotypes.