Inositol effects on ovulation induction in patients with polycystic ovary syndrome.

To the Editor:

I read with interest the recent paper of Morgante et al (1) describing positive effects of Inositol in increasing insulin sensitivity in patients with polycystic ovary syndrome (2), confirming the concept that insulin-sensitizer molecules alone or in combination with clomiphene citrate or gonadotrophin, somehow ameliorates ovulation in such patients.

However some comments on both design and results of the study are necessary for a critical view of potential clinical application of inositol in ART.

The ovulation induction protocol (defined by authors chronic low-dose step-down gonadotrophin regimen) seems a little bit risky.
A starting dose of 150 UI per day for three days is somewhat in contrast with the ESHRE/ASRM criteria on treatment (3), suggesting that a “chronic low dose” step up regimen is safer in terms of monofollicular development (4). Moreover it is widely accepted that monitoring of a step down protocol may require more experience and skill (5).

Overall, low-dose regimens, using 37.5-50 IU r-FSH per day, result in monofollicular ovulation rate of 70%, pregnancy rate of 20% and multiple live birth rate of 5,7%, with a low risk of OHSS ( 15 mm diameter, as shown in Table 1) in the control group with an unjustified cancellation rate of 40% as consequence of excessive response to r-FSH, could be mainly due to high r-FSH dose than to a deficit of inositol treatment.

It certainly will be more interesting to read about benefits of combination of inositol and FSH in increasing mono-ovulation rate.
I like the authors’ suggestion of adding Inositol in order to increase ovarian sensitivity, but I would like more details on both lactoferrin and bromelain supplementation.

In the manuscript no information on potential effects of these molecules are reported (positive vs. detrimental on ovulation induction) nor whether necessary for the aim of the study.

Authors could clarify why they do not supplement only inositol (as declared in the title) but a multivitamin complex, diverging from papers already published (6-10).

Finally a pregnancy rate of 33% per cycle in treated group is more likely to be obtained in IVF procedure than in controlled ovulation induction for free intercourses and need carefully review of the number of patients enrolled before concluding any statement.

In conclusion, nutritional supplementation is the most commonly used form of alternative medicine, and it is going to become more and more popular in the clinical practice of many gynecologists. In particular, we have the same opinion of the authors that the use of myo-inositol represents a novel and valuable tool in the approach to PCOS patients
Nevertheless, if vitamin or nutraceutical molecules would be certified as helpful in ART practice (10,11), multicenter studies should be designed and more significant and detailed results reported.

Enrico Papaleo, M.D.
Centro Natalità
Obstetric-Gynecological Departement
Vita-Salute San Raffaele University
Milan, Italy

References
1. Morgante G, Orvieto R, Di Sabatino A, Musacchio MC, De Leo V. The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen. Fertil Steril. 2011 Feb 5.

2. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19–25.

3. ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008;89:505–22.

4. Christin-Maitre S, Hugues JN. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum Reprod 2003;18:1626–1631.

5. Van Santbrink EJ, Donderwinkel PF, van Dessel TJ, Fauser BC. Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients. Hum Reprod 1995;10:1048–1053.

6. Genazzani AD, Lanzoni C, Ricchieri F,vJasonni VM. Myo-inositol administration positively affects hyperinsulinemia and hormonalvparameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol 2008;24: 139–44.

7. Papaleo E, Unfer V, Baillargeon JP, De Santis L, Fusi F, Brigante C, et al. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecol Endocrinol 2007;23:700–3.

8. Papaleo E, Unfer V, Baillargeon JP, Chiu TT. Contribution of myo-inositol to reproduction. Eur J Obstet Gynecol Reprod Biol 2009;147:120–3.

9. Gerli S, Papaleo E, Ferrari A, Di Renzo GC. Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci 2007;11:347–54.

10. Raffone E, Rizzo P, Benedetto V. Insulin sensitiser agents alone and in co-treatment with r-FSH for ovulation induction in PCOS women. Gynecol Endocrinol 2010;26:275–80.

11. Cetin I, Berti C, Calabrese S. Role of micronutrients in the periconceptional period. Hum Reprod Update. 2010 Jan-Feb;16(1):80-95. Epub . Review.

12. Papaleo E., Potenza MT., Brigante C., DE Michele F., Pellegrino M., Candiani C. Nutrients and infertility: an alternative perspective. Eur Rev Med Pharmacol Sci 2011; 15 (in press)

Comments to: “The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen” 

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.086

To the Editor:

In recent years, the interest of the scientific community in the efficacy of inositol-based products for the treatment of polycystic ovary syndrome (PCOS) has enormously increased, as reflected by several articles recently published on this topic in high- profile journals, including Fertility and Sterility.

Recently, a paper by Morgante and coworkers (1) entitled “The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen” has been accepted for publication on Fertility and Sterility. In this paper, the authors studied 15 PCOS patients treated with Redestop and 15 untreated PCOS patients.

As indicated by the manufacturer, Redestop is a dietary supplement containing: Inositol 1500mg, lattoferrin 150mg, magnesium 200mg, zinc 6mg, selenium 25mcg, β-Carotene 4,5mg, Vitamin C 30mg, Vitamin E 5mg, Vitamin B6 0,6mg, bromelian 20mg, glutathione 25mg.

We strongly believe that the study by Morgante and co-workers was poorly designed and analyzed, for the following reasons:

1) In the study, the length of Redstop treatment varied from patient to patient, “up to 4weeks” before starting gonadotropin ovulation induction.

2) According to the composition provided by the manufacturer , Redestop is a multivitamin complex that, when taken twice a day, ensures the intake of 100% or more of the RDA of several components; therefore, since the control group received no treatment, it is not possible to conclude that the results observed where inositol-related.

3) After stimulation, the authors state that the number of follicles obtained was 3.5±1.2 for the untreated and 1.1±0.5 for the “inositol” treated group, resulting in a pregnancy rate of 13.33% and 33.33%, respectively. It has been shown by Nestler et al (2) that, after 4 weeks of inositol treatment, 50% of PCOS women spontaneously ovulate. Additional data from Papaleo et al. (3) showed that the treatment of 25 PCOS women (comparable for age and BMI, to the subjects treated by Morgante et al.) with Myo-inositol restored monthly ovulation in 88% (22 women) of the patients. The study reported also 10 pregnancies, 2 of which resulted in spontaneous abortions. Therefore, the clinical pregnancy rate in the study by Papaleo et al was 8/22 (36%) without any hormonal stimulation.

4) We were surprised by the extremely low percentage of clinical pregnancy obtained in the control group; indeed, these patients showed a clinical pregnancy rate about 50% lower than what should be expected in non-obese PCOS subjects under 35. This could be due to the fact that authors calculated the pregnancy rate taking into account also the cycles that were cancelled (6 out of 15) due to increased risk of ovarian hyperstimulation syndrome (OHSS). The authors reported two clinical pregnancies; therefore, the correct pregnancy rate, calculated only on the cycles that were actually performed, is 2/9 (22.22%); that it is in fact closer to what is expected. Furthermore, the authors did not mention which procedure(s) was performed in order to achieve the pregnancy.

5) The paper reports an erroneous Redestop composition.
Therefore, we believe that the authors should address the points we have raised in order to assure that only correct information is provided to the scientific community.

Pietro Rizzo, M.D.
Emanuele Raffone, M.D.
Obstetrics and Gynecology Department
G. Martino Hospital
Messina, Italy

References
1. Morgante G, Orvieto R, Di Sabatino A, Musacchio MC, De Leo V. The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen. Fertil Steril. February 5, 2011.

2. Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 1999;340:1314-20.

3. Papaleo E, Unfer V, Baillargeon JP, De Santis L, Fusi F, Brigante C et al. Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction. Gynecol Endocrinol 2007;23:700-3.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.088

The Authors Respond:

We would like to thank Drs. Papaleo and Rizzo for their interest in our study (1).

The chronic low-dose step-down gonadotrophin regimen is our protocol of choice in PCOS patients. Due to the known need for more experience and skills, it is always conducted by senior expert physicians, with good results (2,3). Our high pregnancy rates are comparable to previously published data (4), and are actually the reason for adopting this protocol.

We would like to thank Dr. Rizzo for providing the complete list of ingredients in the Redestop nutritional preparation. As mentioned, our preliminary study showed that Inositol nutritional supplementation reduces cancellation rate and improves pregnancy rate in insulin resistant PCOS patients, undergoing the low-dose gonadotropin step-down ovulation induction regimen, as compared to a matched historical cohort. Regarding cancellation and pregnancy rates, all figures were clearly presented in the Table.

We agree with Drs. Papaleo and Rizzo, that further large randomized prospective controlled studies are needed to elucidate the role of the different inositol containing nutritional supplementations, in insulin resistant PCOS patients, undergoing either the step-up or step-down regimen or any other ART practice.

Giuseppe Morgante, M.D.
Department of Obstetrics and Gynecology
University of Siena
Policlinico Santa Maria Le Scotte,
Siena, Italy

References
1. Morgante G, Orvieto R, Di Sabatino A, Musacchio MC, De Leo V. The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen. Fertil Steril. 2011 Feb.

2. ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008;89:505–22.

3. Van Santbrink EJ, Donderwinkel PF, van Dessel TJ, Fauser BC. Gonadotrophin induction of ovulation using a step-down dose regimen: single-centre clinical experience in 82 patients. Hum Reprod 1995;10:1048–1053.

4. Christin-Maitre S, Hugues JN. A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum Reprod 2003;18:1626–1631.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2011.03.087