Gianfranco Carlomagno

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

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.

Results from the International Consensus Conference on Myo-inositol and d-chiro-inositol in Obstetrics and Gynecology: the link between metabolic syndrome and PCOS.

In recent years, interest has been focused to the study of the two major inositol stereoisomers: myo-inositol (MI) and d-chiro-inositol (DCI), because of their involvement, as second messengers of insulin, in several insulin-dependent processes, such as metabolic syndrome and polycystic ovary syndrome. Although these molecules have different functions, very often their roles have been confused, while the meaning of several observations still needs to be interpreted under a more rigorous physiological framework. With the aim of clarifying this issue, the 2013 International Consensus Conference on MI and DCI in Obstetrics and Gynecology identified opinion leaders in all fields related to this area of research. They examined seminal experimental papers and randomized clinical trials reporting the role and the use of inositol(s) in clinical practice. The main topics were the relation between inositol(s) and metabolic syndrome, polycystic ovary syndrome (with a focus on both metabolic and reproductive aspects), congenital anomalies, gestational diabetes. Clinical trials demonstrated that inositol(s) supplementation could fruitfully affect different pathophysiological aspects of disorders pertaining Obstetrics and Gynecology. The treatment of PCOS women as well as the prevention of GDM seem those clinical conditions which take more advantages from MI supplementation, when used at a dose of 2g twice/day. The clinical experience with MI is largely superior to the one with DCI. However, the existence of tissue-specific ratios, namely in the ovary, has prompted researchers to recently develop a treatment based on both molecules in the proportion of 40 (MI) to 1 (DCI).

Contribution of myo-inositol and melatonin to human reproduction

Diet is a critical factor for the development of both embryo and fetus, as well as maternal health. In particular, two natural molecules have been shown to exert beneficial effects on fertility, pregnancy wellness and embryo development: myo-inositol and melatonin, whose requirements increase during pregnancy. In the present review, we summarize the most important functions of melatonin and myo-inositol on male and female reproductive systems (oocyte quality and development, sperm quality), on the maintenance of a physiological pregnancy and on embryo development.

The rationale of the myo‐inositol and D‐chiro‐inositol combined treatment for polycystic ovary syndrome

PCOS is one of the most common endocrine disorders affecting women and it is characterized by a combination of hyper‐androgenism, chronic anovulation, and insulin resistance. While a significant progress has recently been made in the diagnosis for PCOS, the optimal infertility treatment remains to be determined. Two inositol isomers, myo‐inositol (MI) and D‐chiro‐inositol (DCI) have been proven to be effective in PCOS treatment, by improving insulin resistance, serum androgen levels and many features of the metabolic syndrome. However, DCI alone, mostly when it is administered at high dosage, negatively affects oocyte quality, whereas the association MI/DCI, in a combination reproducing the plasma physiological ratio (40:1), represents a promising alternative in achieving better clinical results, by counteracting PCOS at both systemic and ovary level.

Results from the International Consensus Conference on myo-inositol and D-chiro-inositol in Obstetrics and Gynecology – assisted reproduction technology

Abstract A substantial body of research on mammalian gametogenesis and human reproduction has recently investigated the effect of myo-inositol (MyoIns) on oocyte and sperm cell quality, due to its possible application to medically assisted reproduction. With a growing number of both clinical and basic research papers, the meaning of several observations now needs to be interpreted under a solid and rigorous physiological framework. The 2013 Florence International Consensus Conference on Myo- and D-chiro-inositol in obstetrics and gynecology has answered a number of research questions concerning the use of the two stereoisomers in assisted reproductive technologies. Available clinical trials and studies on the physiological and pharmacological effects of these molecules have been surveyed. Specifically, the physiological involvement of MyoIns in oocyte maturation and sperm cell functions has been discussed, providing an answer to the following questions: (1) Are inositols physiologically involved in oocyte maturation? (2) Are inositols involved in the physiology of spermatozoa function? (3) Is treatment with inositols helpful within assisted reproduction technology cycles? (4) Are there any differences in clinical efficacy between MyoIns and D-chiro-inositol? The conclusions of this Conference, drawn depending on expert panel opinions and shared with all the participants, are summarized in this review paper.

Ovulation induction with myo-inositol alone and in combination with clomiphene citrate in polycystic ovarian syndrome patients with insulin resistance

Abstract Background: Insulin resistance plays a key role in the pathogenesis of polycystic ovarian syndrome (PCOS). One of the methods for correcting insulin resistance is using myo-inositol. Aim: The aim of the present study is to evaluate the effectiveness of myo-inositol alone or in combination with clomiphene citrate for (1) induction of ovulation and (2) pregnancy rate in anovulatory women with PCOS and proven insulin resistance. Patients and methods: This study included 50 anovulatory PCOS patients with insulin resistance. All of them received myo-inositolduring three spontaneous cycles. If patients remained anovulatory and/or no pregnancy was achieved, combination of myo-inositol and clomiphene citrate was used in the next three cycles. Ovulation and pregnancy rate, changes in body mass index (BMI) and homeostatic model assessment (HOMA) index and the rate of adverse events were assessed. Results: After myo-inositol treatment, ovulation was present in 29 women (61.7%) and 18 (38.3%) were resistant. Of the ovulatory women, 11 became pregnant (37.9%). Of the 18 myo-inositol resistant patients after clomiphene treatment, 13 (72.2%) ovulated. Of the 13 ovulatory women, 6 (42.6%) became pregnant. During follow-up, a reduction of body mass index and HOMA index was also observed. Conclusion: Myo-inositol treatment ameliorates insulin resistance and body weight, and improves ovarian activity in PCOS patients.

Effect of myo-inositol and melatonin versus myo-inositol, in a randomized controlled trial, for improving in vitro fertilization of patients with polycystic ovarian syndrome

Abstract Polycystic ovarian syndrome (PCOS) induces anovulation in women of reproductive age, and is one of the pathological factors involved in the failure of in vitro fertilization (IVF). Indeed, PCOS women are characterized by poor quality oocytes. Therefore, a treatment for enhancing oocyte quality becomes crucial for these patients. Myo-Inositol and melatonin proved to be efficient predictors for positive IVF outcomes, correlating with high oocyte quality. We tested the synergistic effect of myo-inositol and melatonin in IVF protocols with PCOS patients in a randomized, controlled, double-blind trial. Five-hundred twenty-six PCOS women were divided into three groups: Controls (only folic acid: 400 mcg), Group A (Inofolic® plus, a daily dose of myo-inositol: 4000 mg, folic acid: 400 mcg, and melatonin: 3 mg), and Group B (Inofolic®, a daily dose of myo-inositol: 4000 mg, and folic acid: 400 mcg). The main outcome measures were oocyte and embryo quality, clinical pregnancy and implantation rates. The treatment lasted from the first day of the cycle until 14 days after embryo transfer. Myo-inositol and melatonin have shown to enhance, synergistically, oocyte and embryo quality. In consideration of the beneficial effect observed in our trial and on the bases of previous studies, we decided to integrate routinely MI and M supplementation in the IVF protocols. The same treatment should be taken carefully in consideration in all procedures of this kind.

Improvement of mouse embryo quality by myo-inositol supplementation of IVF media

ObjectiveMyo-inositol (myoIns) has a positive role in mammalian development and human reproduction. Since experiments on farming species suggest a similar role in preimplantation development, we evaluated the hypothesis that the inclusion of myoIns in human embryo culture media would produce an increase in embryo quality in IVF cycles, using the mouse embryo assay.MethodsTo determine the effect of myoIns on completion of preimplantation development in vitro, one-cell embryos of the inbred C57BL/6N mouse strain were produced by ICSI, cultured in human fertilization media in the presence of myoIns (myoIns+) or in its absence (myoIns–) and evaluated morphologically. Daily progression through cleavage stages, blastocyst production and expansion and blastomere number at 96 hours post fertilization were assessed.ResultsCompared to myoIns– embryos, myoIns+ embryos displayed a faster cleavage rate and by the end of preimplantation development, the majority of myoIns+ blastocysts was expanded and formed by a higher number of blastomeres.ConclusionThe presence of myoIns resulted in both an increase in proliferation activity and developmental rate of in vitro cultured early mouse embryos, representing a substantial improvement of culture conditions. These data may identify myoIns as an important supplement for human embryo preimplantation culture.

Soft gel capsules improve melatonin’s bioavailability in humans

Objective: Oral bioavailability is one of the most important properties in drug design and development. A poor oral bioavailability can result in low efficacy and unpredictable response to a drug. Several dosages of melatonin have been used for various investigations to clarify its bioavailability in humans. Aiming to search for a pharmaceutical form, which is better absorbed, the pharmacokinetic (PK) profile of the new manufactured melatonin soft gelatin (soft gel) capsule form has been evaluated and compared with the commercially available melatonin powder. Research design and methods: A total of 60 healthy volunteers received 1, 3 mg of melatonin powder and 1 mg of melatonin in soft gel capsules. PK profiles were obtained by analysis of melatonin plasma concentration, and the respective melatonin bioavailability was compared. Results: Melatonin soft gel capsule form showed similar PK parameters compared with the highest doses of melatonin in powder form, but its bioavailability was improved. Conclusions: Soft gel capsules improved the bioavailability of melatonin in humans even when administered dose was reduced. Considering the number of conditions in which melatonin supplementation is recommended, this evidence could support a broader use of melatonin in clinical practice.

Efficacy and tolerability of brodimoprim at two different dosage schedules in the treatment of acute uncomplicated bacterial cystitis: comparative study vs. pefloxacin

In an open study, 172 male and female adult patients with acute uncomplicated bacterial cystitis were randomly allocated to three treatment groups. Two groups received brodimoprim 200 mg tablets as follows: a single dose of two 200 mg tablets on day 1, followed by one tablet per day on days 2 and 3 (58 patients); or a single daily dose of two tablets, for 2 days (63 patients). The third group received a single dose of pefloxacin, as two 400 mg tablets, for 1 day (51 patients). Complete urinalysis, sediment and urine culture examinations were carried out before treatment and 10 days after the last dose. Evaluation also comprised, at the time of enrolment and 48 h after the last dose, measurement of corporal temperature and assessment of symptoms (dysuria, pollakiuria, strangury, suprapubic pain, burning sensation during urination and urgency) on a 4-point scale. The eradication rate for the pathogen concerned was 98.3% and 96.7% in the groups receiving brodimoprim for 3 and 2 days, respectively, and 92.8% in the pefloxacin group (between-group comparison n.s.). There was significant regression of symptoms (P < 0.001) in the three groups (between-groups comparison n.s.). Mainly gastrointestinal adverse events occurred in 3 patients receiving brodimoprim for 2 days and in 4 patients from each of the other two groups.