Myo-inositol in patients with polycystic ovary syndrome: a novel method for ovulation induction

Gynecological Endocrinology, December 2007; 23(12): 700-703 Myo-inositol in patients with polycystic ovary syndrome: A novelmethod for ovulation induction ENRICO PAPALEO1, VITTORIO UNFER2, JEAN-PATRICE BAILLARGEON3,LUCIA DE SANTIS1, FRANCESCO FUSI1, CLAUDIO BRIGANTE1, GUIDO MARELLI1,ILARIA CINO1, ANNA REDAELLI1, & AUGUSTO FERRARI1 1IVF Unit, Gynaecological-Obstetric Department, IRCCS San Raffaele Hospital, Vita-Salute University, Milan, Italy,2AGUNCO Obstetrics and Gynecology Centre, Rome, Italy, and 3Department of Medicine, University of Sherbrooke,Sherbrooke, Quebec, Canada (Received 11 June 2007; revised 6 September 2007; accepted 10 September 2007) Polycystic ovary syndrome (PCOS) is often characterized by chronic oligo- or anovulation (usually manifested as oligo- or amenorrhea), and hyperandrogenism. In addition, 30-40% of PCOS women have impaired glucose tolerance,and a defect in the insulin signaling pathway (inositol-containing phosphoglycan mediators) seems to be implicated in thepathogenesis of insulin resistance. PCOS patients are subfertile as a consequence of such ovulatory disorders and often needdrugs, such as clomiphene citrate or follicle-stimulating hormone, for ovulation induction, which increases the risk ofmultiple pregnancy and ovarian hyperstimulation syndrome. We hypothesized that the administration of an isoform ofinositol (myo-inositol), belonging to the vitamin B complex, would improve the insulin-receptor activity, restoring normalovulatory function.
Materials and methods.
Twenty-five PCOS women of childbearing age with oligo- or amenorrhea were enrolled in the study.
Ovulatory disorder due to PCOS was apparently the only cause of infertility; no tubal defect or deficiency of male semenparameters was found. Myo-inositol combined with folic acid (Inofolic1) 2 g twice a day was administered continuously.
During an observation period of 6 months, ovulatory activity was monitored with ultrasound scan and hormonal profile, andthe numbers of spontaneous menstrual cycles and eventually pregnancies were assessed.
Results.
Twenty-two out of the 25 (88%) patients restored at least one spontaneous menstrual cycle during treatment, of whom 18 (72%) maintained normal ovulatory activity during the follow-up period. A total of 10 singleton pregnancies (40%of patients) were obtained. Nine clinical pregnancies were assessed with fetal heart beat at ultrasound scan. Two pregnanciesevolved in spontaneous abortion.
Conclusion.
Myo-inositol is a simple and safe treatment that is capable of restoring spontaneous ovarian activity and consequently fertility in most patients with PCOS. This therapy did not cause multiple pregnancy.
Keywords: Myo-inositol, polycystic ovary syndrome, ovulation induction Gynecol Endocrinol Downloaded from informahealthcare.com by University Library SZ 100 on 11/30/10 Recently, many investigators have focused on the impaired glucose tolerance that affects 30-40% of Polycystic ovary syndrome (PCOS) is a medical patients with PCOS [3]. Insulin plays a direct role in condition that causes irregular menstrual cycles, the pathogenesis of hyperandrogenemia in PCOS, chronic anovulation most often manifested as oligo- acting synergistically with luteinizing hormone to or amenorrhea, and androgen excess, with the typical enhance the androgen production of theca cells [4].
ovarian ultrasound features [1]. It is the most common cause of ovulatory disorders and female D-chiro-inositol (DCI) is known to have a role in infertility, and affects approximately 6-10% of women activating enzymes that control glucose metabolism in childbearing age [2]. However, its pathogenesis is altered metabolism of DCI or inositol phosphoglycan Correspondence: E. Papaleo, IVF Unit, Gynaecological-Obstetric Department, IRCCS San Raffaele, via Olgettina 60, I-20132 Milan, Italy.
Tel: 39 02 26432202. Fax: 39 02 26434311. E-mail: papaleo.enrico@hsr.it ISSN 0951-3590 print/ISSN 1473-0766 online ª 2007 Informa UK Ltd.
DOI: 10.1080/09513590701672405 Myo-inositol for ovulation induction in PCOS mediators has been found in PCOS women and may concentrations were statistically compared using the contribute to their insulin resistance [6,7].
Isoforms of inositol belong to the vitamin B Moreover, eventual pregnancies were confirmed complex. Epimerization of the six hydroxyl groups by a positive test for plasma b-human chorionic of inositol results in the formation of up to nine gonadotropin and ascertainment of a fetal heart beat stereoisomers, including myo-inositol (MI) and DCI.
MI is widely distributed in nature whereas DCI, theproduct of epimerization of the C1 hydroxyl group of Elevated concentration of MI in human follicular Baseline clinical and biochemical features of the fluid appears to play a role in follicular maturity PCOS patients are reported in Table I. The outcome and provides a marker of good-quality oocytes [9].
of treatment is shown in Tables I and II.
After a mean of 34.6 + 5.5 days of MI adminis- showed that supplementation of MI in the culture tration, 22 out of the 25 women (88%) had a first medium increased meiotic progression of germinal menstrual cycle. Eighteen of these 22 patients presented monthly menstruations during the follow- up period. All of them maintained spontaneous Thus we hypothesized that the administration of ovulation activity, documented by follicular growth MI, a precursor of DCI, would improve insulin and increased serum progesterone concentrations in activity and restore ovulatory function and fertility in the luteal phase (mean 10.5 + 1.8 ng/ml). Further- more, after treatment with MI, these women showedsignificantly total testosterone (95.6 + 8.5 vs. 45.2 + 6.7 ng/dl; p ¼ 0.003) and free testosterone (1.0 + 0.8 vs.
A total of 25 women, 28 to 38 age years of age, with 0.38 + 0.1 ng/dl; p ¼ 0.005). The length of succes- PCOS defined by oligo- or amenorrhea (six or fewer sive cycles was improved to 31.7 + 3.2 days.
Two out of the 22 women showed only a follicular hyperandrogenism (hirsutism, acne or alopecia) or development on ultrasound without progesterone hyperandogenemia (elevated levels of total or free elevation during weekly blood sampling, while two testosterone) and typical ovarian features on ultra- women did not have any further ovarian activity after sound scan, were enrolled in the study.
All patients attended our IVF Unit for infertility During the observational period of 6 months a that had lasted for more than 14-16 months. Other total of ten biochemical pregnancies occurred. Nine medical conditions causing ovulatory dysfunction, of the ten were singleton pregnancies documented at such as hyperprolactinemia or hypothyroidism, or ultrasound scan, while one of them was a biochem- androgen excess, such as adrenal hyperplasia or ical abortion. One out of the nine pregnancies Cushing's syndrome, were excluded by hormonaltests. All women underwent assessment of tubalpatency and all male partners were evaluated with Table I. Clinical and biochemical features of the patients.
two different semen sample analyses, without findingany defect. Anovulation was ascertained by weekly Gynecol Endocrinol Downloaded from informahealthcare.com by University Library SZ 100 on 11/30/10 Thus, at the end of diagnostic procedures, it was determined that the most likely cause of the couple's subfertility was ovulation dysfunction only.
PCOS women were treated orally with MI 2 g plus folic acid 200 mg (Inofolic1; Loli Pharma, Rome, Italy) as soluble powder, twice daily, continuously, until the end of the study or a positive pregnancy test.
Patients were instructed to register their menstrual bleeding throughout the follow-up period of 6 months. Furthermore, in order to evaluate the restoration of spontaneous ovarian activity, weekly determination of serum progesterone and test- osterone levels, as well as transvaginal ultrasound scan documenting the presence of follicular growth Significant difference compared with baseline: *p ¼ 0.003; menstrual cycle. Pre- and post-treatment hormone Table II. Outcome of treatment with myo-inositol.
luteal phase, in most infertile patients with PCOS.
The present results are in line with other studies evaluating insulin-sensitizing agents in monotherapy No. of patients with menstrual cycle after or in association with clomiphene citrate [7,13,14, No. of patients with restored monthly ovulation 16-18], suggesting the positive effect that MI plays on spontaneous ovarian activity. Furthermore, we found that MI therapy is able to reduce serum No. of pregnancies/no. of treated patients (%) testosterone, both total and free, as already demon- No. of pregnancies/no. patients with restored strated with DCI. All pregnancies obtained in the follow-up period were singleton, and there was no In conclusion, MI is a simple and safe treatment that is able to restore spontaneous fertility in mostpatients with PCOS.
evolved in a spontaneous abortion at 7 weeks ofgestation. No multiple pregnancy was noted.
1. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2. Franks S. Polycystic ovary syndrome. N Engl J Med 1995; disorders affecting women. Insulin resistance and hyperinsulinemia are strictly inherent to the pheno- 3. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, type of a high proportion of women with PCOS. A Imperial J. Prevalence of impaired glucose tolerance and defect in insulin action has been suspected, particu- diabetes in women with polycystic ovary syndrome. Diabetes larly as consequence of a deficiency of DCI, a 4. Baillargeon JP, Nestler JE. Polycystic ovary syndrome: a component of inositol phosphoglycan.
syndrome of ovarian hypersensitivity to insulin? J Clin Chronic anovulation is often the main cause of infertility in patients of reproductive age. It is well 5. Larner J. Multiple pathways in insulin signaling - fitting the known that ovulation induction is a complex issue covalent and allosteric puzzle pieces together. Endocr J 1994; owing to the increased risk of ovarian hyperstimula- 6. Baillargeon JP, Diamanti-Kandarakis E, Ostlund RE Jr, tion syndrome and multiple pregnancy [11,12].
Apridonidze T, Iuorno MJ, Nestler JE. Altered D-chiro- Clomiphene citrate, an antiestrogen, is the common inositol urinary clearance in women with polycystic ovary first-choice drug in women with newly diagnosed syndrome. Diabetes Care 2006;29:300-305.
PCOS, while insulin-lowering medications represent novel therapies for restoring spontaneous ovulation Gunn RD, Allan G, Nestler JE. Effect of D-chiro-inositol inlean women with the polycystic ovary syndrome. Endocr Pract [13,14]. The efficacy of metformin is still debated, both alone and in association with clomiphene citrate [15,16]. Metformin treatment is associated with a Kinehara M, Ashida H. Genetic modification of Bacillus higher incidence of side-effects such as nausea, subtilis for production of D-chiro-inositol, an investigation drug vomiting and other gastrointestinal disturbances candidate for treatment of type 2 diabetes and polycystic ovarysyndrome. Appl Environ Microbiol 2006;72:1310-1315.
DCI administration increases the action of insulin Cheung LP, Haines CJ. Follicular fluid and serum concentra- Gynecol Endocrinol Downloaded from informahealthcare.com by University Library SZ 100 on 11/30/10 in patients with PCOS, thereby improving ovulatory tions of myo-inositol in patients undergoing IVF: relationship function and decreasing serum testosterone concen- with oocyte quality. Human Reprod 2002;17:1591-1596.
tration [6,18,19]. MI, a precursor of DCI, is widely 10. Chiu TT, Rogers MS, Briton-Jones C, Haines C. Effect of myo-inositol on the in-vitro maturation and subsequent distributed in nature whereas DCI is relatively rare development of mouse oocytes. Human Reprod 2003;18: [7]. MI is present in human follicular fluid, where elevated concentrations appear to play a positive role 11. Tummon I, Gavrilova-Jordan L, Allemand MC, Session D.
in follicular maturity and provide a marker of good- Polycystic ovaries and ovarian hyperstimulation syndrome: a quality oocytes [9]. Supplementation of MI in systematic review. Acta Obstet Gynecol Scand 2005;84:611-616.
culture medium increased meiotic progression of 12. Battaglia C, Mancini F, Persico N, Zaccaria V, de Aloysio D.
germinal vesicles in mouse oocytes by enhancing the Ultrasound evaluation of PCO, PCOS and OHSS. Reprod intracellular Ca2þ oscillation [10]. However, no data exist on therapy with MI in anovulatory women of 13. Cheang KI, Nestler JE. Should insulin-sensitizing drugs be used in the treatment of polycystic ovary syndrome? ReprodBiomed Online 2004;8:440-447.
Our study demonstrated that MI oral supplemen- 14. Baillargeon JP. Use of insulin sensitizers in polycystic tation restores spontaneous ovulation and menstrual ovarian syndrome. Curr Opin Investig Drugs 2005;6:1012- cycles, and increases progesterone secretion in the Myo-inositol for ovulation induction in PCOS 18. Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G.
Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, Ovulatory and metabolic effects of D-chiro-inositol in the McGovern PG, Cataldo NA, et al.; Cooperative Multicenter polycystic ovary syndrome. N Engl J Med 1999;340:1314- Reproductive Medicine Network. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J 19. Gerli S, Mignosa M, Di Renzo GC. Effects of inositol on ovarian function and metabolic factors in women with PCOS: 16. Pesant MH, Baillargeon JP. Ovulation induction in polycystic a randomized double blind placebo-controlled trial. Eur Rev ovary syndrome - how do metformin and clomifene citrate compare? Nat Clin Pract Endocr Metab 2007;3:512-513.
17. Lord JM, Flight IH, Norman RJ. Metformin in polycystic This paper was first published online on iFirst on 10 October 2007 ovary syndrome: systematic review and meta-analysis. B Med J2003;327:951-957.
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