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Meta-Analysis
. 2020 Aug 27;8(8):CD007807.
doi: 10.1002/14651858.CD007807.pub4.

Antioxidants for female subfertility

Marian G Showell  1 , Rebecca Mackenzie-Proctor  2 , Vanessa Jordan  1 , Roger J Hart  3
Affiliations
Meta-Analysis

Antioxidants for female subfertility

Marian G Showell et al. Cochrane Database Syst Rev. .

Abstract

Editorial note: M.G. Showell, R. Mackenzie‐Proctor, V. Jordan, and R.J. Hart, “Antioxidants for Female Subfertility,” Cochrane Database of Systematic Reviews, no. 8 (2020): CD007807, https://doi.org/10.1002/14651858.CD007807.pub4 This Editorial Note is for the above article, published online on August 27, 2020, in Cochrane Library (cochranelibrary.com), and has been issued by the Publisher, John Wiley & Sons Ltd, in agreement with Cochrane. The Editorial note has been agreed due to concerns discovered by the Cochrane managing editor regarding the retraction of six studies in the Review (Badawy et al. 2006, 10.1016/j.fertnstert.2006.02.097; El Refaeey et al. 2014, 10.1016/j.rbmo.2014.03.011; El Sharkwy & Abd El Aziz 2019a, https://doi.org/10.1002/ijgo.12902; Gerli et al. 2007, https://doi.org/10.26355/eurrev_202309_33752, full text: https://europepmc.org/article/MED/18074942; Ismail et al. 2014, http://dx.doi.org/10.1016/j.ejogrb.2014.06.008; Hashemi et al. 2017, https://doi.org/10.1080/14767058.2017.1372413). In addition, expressions of concern have been published for two studies (Jamilian et al. 2018, https://doi.org/10.1007/s12011-017-1236-3; Zadeh Modarres 2018, https://doi.org/10.1007/s12011-017-1148-2). The retracted studies will be moved to the Excluded Studies table, and their impact on the review findings will be investigated and acted on accordingly in a future update. Initial checks indicate that removal of the six retracted studies did not make an appreciable difference to the results. Likewise, the studies for which Expressions of Concern were issued will be moved to the Awaiting classification table; they did not report any review outcomes, so removal will have no impact on the review findings.

Background: A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility.

Objectives: To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women.

Search methods: We searched the following databases (from their inception to September 2019), with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial registers.

Selection criteria: We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events.

Main results: We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I2 = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I2 = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I2 = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I2 = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I2 = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I2 = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.

Authors' conclusions: In this review, there was low- to very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.

Trial registration: ClinicalTrials.gov NCT01019785 NCT01782911.

PubMed Disclaimer

Conflict of interest statement

Roger Hart is the Medical Director of Fertility Specialists of WA and a shareholder in Western IVF. He has received educational sponsorship from Merck Serono and Ferring pharmaceuticals, and is on the medical advisory board of MSD and Ferring Pharmaceuticals.

Rebecca Mackenzie‐Proctor: no conflict of interest to declare

Vanessa Jordan: no conflict of interest to declare

Marian Showell: no conflict of interest to declare

Figures

1
1
Study flow diagram.
2
2
Methodological risk of bias summary: review authors' judgements about each methodological bias item for each included study.
3
3
Methodological risk of bias graph: review authors' judgements about each methodological bias item presented as percentages across all included trials.
4
4
Funnel plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).
5
5
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.1 Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).
6
6
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).
7
7
Forest plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment, outcome: 1.9 Adverse events.
8
8
Forest plot of comparison: 2 Head‐to‐head antioxidants, outcome: 2.1 Live birth; type of antioxidant (natural conceptions and undergoing fertility treatments).
9
9
Forest plot of comparison: 2 Head‐to‐head antioxidants, outcome: 2.4 Clinical pregnancy; type of antioxidant (natural conceptions and undergoing fertility treatments).
10
10
Forest plot of comparison: 2 Head‐to‐head antioxidants, outcome: 2.7 Adverse events.
1.1
1.1. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 1: Live birth; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)
1.2
1.2. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 2: Live birth; type of antioxidant
1.3
1.3. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 3: Live birth; indications for subfertility
1.4
1.4. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 4: Live birth; IVF/ICSI
1.5
1.5. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 5: Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)
1.6
1.6. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 6: Clinical pregnancy; type of antioxidant
1.7
1.7. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 7: Clinical pregnancy; indications for subfertility
1.8
1.8. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 8: Clinical pregnancy; IVF/ICSI
1.9
1.9. Analysis
Comparison 1: Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 9: Adverse events
2.1
2.1. Analysis
Comparison 2: Head‐to‐head antioxidants, Outcome 1: Live birth; type of antioxidant (natural conceptions and undergoing fertility treatments)
2.2
2.2. Analysis
Comparison 2: Head‐to‐head antioxidants, Outcome 2: Live Birth; indications for subfertility
2.3
2.3. Analysis
Comparison 2: Head‐to‐head antioxidants, Outcome 3: Live Birth; IVF/ICSI
2.4
2.4. Analysis
Comparison 2: Head‐to‐head antioxidants, Outcome 4: Clinical pregnancy; type of antioxidant (natural conceptions and undergoing fertility treatments)
2.5
2.5. Analysis
Comparison 2: Head‐to‐head antioxidants, Outcome 5: Clinical pregnancy; indications for subfertility
2.6
2.6. Analysis
Comparison 2: Head‐to‐head antioxidants, Outcome 6: Clinical pregnancy; IVF/ICSI
2.7
2.7. Analysis
Comparison 2: Head‐to‐head antioxidants, Outcome 7: Adverse events
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References

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    1. Panti Abubakar A, Egondu Shehu C, Saidu Y, Nwobodo EI, Tunau Abubakar K, Jimoh A, et al. Oxidative stress and antioxidant supplementation in patients with polycystic ovarian syndrome (PCOS). International Journal of Gynecology and Obstetrics 2015;131 Suppl 5:E505.
Polak de Fried 2013 {published data only}
    1. Polak de Fried E, Bossi NM, Notrica JA, Vazquez Levin MH. Vitamin-d treatment does not improve pregnancy rates in patients undergoing art: a prospective, randomized, double-blind placebo-controlled trial. Fertility and Sterility 2013;100(Suppl):S493.
Rasekhjahromi 2018 {published data only}
    1. Rasekhjahromi A, Babaarabi ZZ, Ebrahimi M, Jahromi MN. Comparison of sufficient and insufficient vitamin e in treatment of infertile PCOS patients. International Journal of Gynecology and Obstetrics 2018;143(Supplement 3):343.
Rashidi 2009 {published data only}
    1. Rashidi B, Haghollahia F, Shariata M, Zayeriia F. The effects of calcium-vitamin D and metformin on polycystic ovary syndrome: a pilot study. Taiwanese Journal of Obstetrics and Gynecology 2009;48(2):142-7. - PubMed
Razavi 2015 {published data only}
    1. Razavi M, Jamilian M, Kashan ZF, Heidar Z, Mohseni M, Ghandi Y, et al. Selenium supplementation and the effects on reproductive outcomes, biomarkers of inflammation, and oxidative stress in women with polycystic ovary syndrome. Hormone and Metabolic Research 2015;48(3):185-90. - PubMed
Rizk 2005 {published data only}
    1. Rizk A, Bedaiwy M, Al-Inany H. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate–resistant patients with polycystic ovary syndrome. Fertility and Sterility 2005;83(2):367-70. - PubMed
    1. Rizk A, Bedaiwy M, El Enany H. N-acetyl-cysteine is a novel adjuvant to clomiphene citrate in clomiphene citrate–resistant patients with polycystic ovary syndrome. Human Reproduction; Abstracts of the 20th Annual Meeting of the ESHRE, June 27-30. 2004 2004;19:i53. - PubMed
Rizzo 2010 {published data only}
    1. Rizzo P, Raffone E, Benedetto V. Effect of the treatment with myo-inositol plus folic acid plus melatonin in comparison with a treatment with myo-inositol plus folic acid on oocyte quality and pregnancy outcome in IVF cycles: a prospective, clinical trial. European Review for Medical and Pharmacological Sciences 2010;14(6):555-61. - PubMed
Salehpour 2009 {published data only}
    1. Salehpour S, Tohidi M, Akhound M, Amirzargar N. N acetyl cysteine, a novel remedy for polycystic ovary syndrome. International Journal of Fertility and Sterility 2009;3(2):66-73.
Salehpour 2012 {published data only}
    1. Salehpour S, Akbari Sene A, Saharkhiz N, Sohrabi M, Moghimian F. N-acetyl-cysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. Iranian Journal of Reproductive Medicine 2012;10 Suppl 1:18 Abstract no: O-30. - PubMed
    1. Salehpour S, Akbari Sene A, Saharkhiz N, Sohrabi M, Moghimian F. N-acetyl-cysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. Iranian Journal of Reproductive Medicine 2012;10:9. - PubMed
    1. Salehpour S, Akbari Sene A, Saharkhiz N, Sohrabi MR, Moghimian F. N-acetylcysteine as an adjuvant to clomiphene citrate for successful induction of ovulation in infertile patients with polycystic ovary syndrome. Journal of Obstetrics & Gynaecology Research 2012;38:1182-6. - PubMed
Schachter 2007 {published data only}
    1. Schachter M, Raziel A, Strassburger D, Rotem C, Ron-El R, Friedler S. Prospective, randomized trial of metformin and vitamins for the reduction of plasma homocysteine in insulin-resistant polycystic ovary syndrome. Fertility and Sterility. 2007;88(1):227-30. - PubMed
Schillaci 2012 {published data only}
    1. Schillaci R, Mangione D, Lo Monte G, Vassiliadis A. Inositol supplementation and IVF outcome: Preliminary data. Italian Journal of Gynaecology and Obstetrics 2012;24(1):38-44.
Sen Sharma 2017 {published data only}
    1. Sen Sharma D. Co-enzyme Q10-A mitochondrial antioxidant - a new hope for success in infertility in clomiphene-citrate-resistant polycystic ovary syndrome. BJOG 2017;124(Supplement 1):9.
Siavashani 2018 {published data only}
    1. Siavashani AM, Zadeh Modarres S, Mirhosseini N, Aghadavod E, Salehpour S, Asemi Z. The effects of chromium supplementation on gene expression of insulin, lipid, and inflammatory markers in infertile women with polycystic ovary syndrome candidate for in vitro fertilization: a randomized, double-blinded, placebo-controlled trial. Frontiers in Endocrinology 2018;9(101555782):726. - PMC - PubMed
Taylor 2018 {published data only}
    1. Taylor TH, Das D, Patrick JL, Katz S, Johnson LN, Crain J. Embryo euploidy rates from advanced maternal age (AMA) patients with and without coenzyme Q10 (COQ10) supplementation: a pilot study and randomized control trial. Fertility and Sterility. Conference: 74th Annual Congress of the American Society for Reproductive Medicine, ASRM 2018. Denver Colorado, USA 2018;110(4):e406.
Tunon 2017 {published data only}
    1. Tunon JM, Trilles PP, Molina MG, Duvison MH, Pastor BM, Martin PS, et al. A double-blind, randomized prospective study to evaluate the efficacy of previous therapy with melatonin, myo-inositol, folic acid, and selenium in improving the results of an assisted reproductive treatment. Clinical Medicine Insights: Therapeutics 2017;9:no pagination.
Valeri 2015 {published data only}
    1. Valeri C, Sbracia G, Selman H, Antonini G, Pacchiarotti A. Beneficial effects of melatonin on oocytes and embryo quality in aged IVF patients. Human Reproduction 2015;30:i48-9.
Westphal 2006 {published data only}
    1. Westphal LM, Polan ML, Trant AS. Double-blind, placebo-controlled study of Fertilityblend: a nutritional supplement for improving fertility in women. Clinical and Experimental Obstetrics & Gynecology 2006;33(4):205-8. - PubMed
Xu 2018 {published data only}
    1. Xu Y, Nisenblat V, Lu C, Li R, Qiao J, Zhen X, et al. Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis young women with decreased ovarian reserve: a randomized controlled trial. Reproductive Biology and Endocrinology 2018;16(1):Article Number: 29. - PMC - PubMed
    1. Xu Y, Zhen X. Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis young women with decreased ovarian reserve: a randomized controlled prospective study. Human Reproduction. Conference: 34th Annual Meeting of the European Society of Human Reproduction and Embryology. ESHRE. Barcelona, Spain 2018;33 Suppl 1(2018):i299-i300. - PMC - PubMed
Youssef 2015 {published data only}
    1. Aboulfoutouh I, Youssef M, Khattab S. Can antioxidants supplementation improve ICSI/IVF outcomes in women undergoing IVF/ICSI treatment cycles? Randomised controlled study. Fertility and Sterility 2011;96 Suppl 3:S242-9.
    1. Youssef MA, Abdelmoty HI, Elashmwi HA, Abduljawad EM, Elghamary N, Magdy A, et al. Oral antioxidants supplementation for women with unexplained infertility undergoing ICSI/IVF: randomized controlled trial. Human Fertility 2015;18(1):38-42. - PubMed
Zadeh Modarres 2018 {published data only}
    1. Zadeh Modarres S, Heidar Z, Foroozanfard F, Rahmati Z, Aghadavod E, Asemi Z. The Effects of selenium sSupplementation on gene expression related to insulin and lipid in infertile polycystic ovary syndrome women candidate for in vitro fertilization: a randomized, double-blind, placebo-controlled trial. Biological Trace Element Research 2018;183(2):218-25. - PubMed

References to studies excluded from this review

Aflatoonian 2014 {published data only}
    1. Aflatoonian A, Arabjahvani F, Eftekhar M, Sayadi M. Effect of vitamin D insufficiency treatment on fertility outcomes in frozen-thawed embryo transfer cycles: a randomized clinical trial. Iranian Journal of Reproductive Medicine 2014;12(9):595-600. - PMC - PubMed
Aksoy 2010 {published data only}
    1. Aksoy AN, Kadanali S. Evaluating the effects of vitamin E addition to clomiphene citrate on endometrial receptivity: a prospective controlled study. Turkiye Klinikleri Jinekoloji Obstetrik 2010;20(2):71-6.
Alborzi 2007 {published data only}
    1. Alborzi S, Ghotbi S, Parsanezhad ME, Dehbashi S, Alborzi S, Alborzi M. Pentoxifylline therapy after laparoscopic surgery for different stages of endometriosis: a prospective, double-blind, randomized, placebo-controlled study. Journal of Minimally Invasive Gynecology 2007;14(1):54-8. - PubMed
    1. Ghotbi S, Parsanezhad ME, Dehbashi S, Alborzi S, Alborzi M. Pentoxifylline therapy after laparoscopic surgery for different stages of endometriosis: A prospective, double-blind, randomized, placebo-controlled study. Journal of Minimally Invasive Gynecology 2007;14(1):54-8. - PubMed
Aleyasin 2009 {published data only}
    1. Aleyasin A, Aghahosseini M, Mohseni M, Mahavi A. Effects of pentoxifylline and vitamin E on pregnancy rate in infertile women by ZIFT: a randomized clinical trial. Iranian Journal of Reproductive Medicine 2009;7:175-9.
Al‐Omari 2003 {published data only}
    1. Al-Omari W, Abdul-Qadder A, Sulaiman W, Taher M. Antioxidants improve metabolic and ovarian response in polycsytic ovary syndrome. In: ESHRE. Vol. xviii. 2003:84.
Ardabili 2012 {published data only}
    1. Ardabili HR, Gargari BP, Farzadi L. Vitamin D supplementation has no effect on insulin resistance assessment in women with polycystic ovary syndrome and vitamin D deficiency. Nutrition Research 2012;32(3):195-201. - PubMed
Asadi 2014 {published data only}
    1. Asadi M, Matin N, Frootan M, Mohamadpour J, Qorbani M, Tanha FD. Vitamin D improves endometrial thickness in PCOS women who need intrauterine insemination: A randomized double-blind placebo-controlled trial. Archives of Gynecology and Obstetrics 2014;289(4):865-870. - PubMed
Baillargeon 2004 {published data only}
    1. Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Apridonidze T, He N, Nestler JE. Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome. Journal of Clinical Endocrinology & Metabolism 2004;89(1):242-9. - PubMed
Balasch 1997 {published data only}
    1. Balasch J, Creus M, Fabregues F, Carmona F, Martinez-Roman S, Manau D, et al. Pentoxifylline versus placebo in the treatment of infertility associated with minimal or mild endometriosis. Human Reproduction 1997;12(9):2046-50. - PubMed
Benelli 2016 {published data only}
    1. 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;2016:3204083. - PMC - PubMed
Bonakdaran 2012 {published data only}
    1. Bonakdaran S, Khorasani ZM, Davachi B, Shakeri MT. Comparison of calcitriol and metformin effects on clinical and metabolic consequences of polycystic ovary syndrome. Iranian Journal of Obstetrics, Gynecology and Infertility 2012;14(8):16-24.
Cheang 2008 {published data only}
    1. Cheang KI, Baillargeon J-P, Essah PA, Ostlund RE Jr, Apridonize T, Islam L, et al. Insulin-stimulated release of d-chiro-inositol-containing inositol phosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism: Clinical and Experimental 2008;57(10):1390-7. - PMC - PubMed
Ciotta 2012 {published data only}
    1. Ciotta L, Stracquadanio M, Pagano I, Formuso C, Di Leo S, Cianci A. D-chiro-inositol treatment in patients with polycystic ovary syndrome. Giornale Italiano di Ostetricia e Ginecologia 2012;34(1):145-8.
Costantino 2009 {published data only}
    1. 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):105-10. - PubMed
Creus 2008 {published data only}
    1. Creus M, Fabregues F, Carmona F, Del Pino M, Manau D, Balasch J. Combined laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated infertility: a preliminary trial. Human Reproduction 2008;23:1910-6. - PubMed
Crha 2003 {published data only}
    1. Crha I, Hruba D, Ventruba P, Fiala J, Totusek J, Visnova H. Ascorbic acid and infertility treatment. Central European Journal of Public Health 2003;11(2):63-7. - PubMed
Dastorani 2018 {published data only}
    1. Dastorani M, Aghadavod E, Mirhosseini N, Foroozanfard F, Zadeh Modarres S, Amiri Siavashani M, et al. The effects of vitamin D supplementation on metabolic profiles and gene expression of insulin and lipid metabolism in infertile polycystic ovary syndrome candidates for in vitro fertilization. Reproductive Biology and Endocrinology 2018;16(1):Article number: 94. - PMC - PubMed
Elgindy 2010 {published data only}
    1. Elgindy EA, El-Huseiny AM, Mostafa MI, Gaballah AM, Ahmed TA. N-acetyl cysteine: could be an effective adjuvant therapy in ICSI cycles. In: ASRM. Vol. 90. September 2008:suppl 1. - PubMed
    1. Elgindy EA, El-Huseiny AM, Mostafa MI, Gaballah AM, Ahmed TA. N-acetyl cysteine: could it be an effective adjuvant therapy in ICSI cycles? A preliminary study. Reproductive Biomedicine Online 2010;20(6):789-96. - PubMed
Elnashar 2007 {published data only}
    1. Elnashar A, Fahmy M, Mansour A, Ibrahim K. N-acetyl cysteine versus metformin in treatment of clomiphene citrate–resistant polycystic ovarysyndrome: a randomized study. In: 12th Annual Meeting of the Middle East Fertility Society. Vol. 10 Suppl 1. 2005.
    1. Elnashar A, Fahmy M, Mansour A, Ibrahim K. N-acetyl cysteine vs. metformin in treatment of clomiphene citrate–resistant polycystic ovary syndrome: a prospective randomized controlled study. Fertility and Sterility 2007;88(2):407-11. - PubMed
    1. Elnashar A Fahmy M Mansour A Ibrahim K. N-acetyl cysteine vs. metformin in treatment of clomiphene citrate-resistant polycystic ovary syndrome: a prospective randomized controlled study. Fertility and Sterility 2007;88(2):406-9. - PubMed
Farzadi 2006 {published data only}
    1. Farzadi L, Salman Zadeh S. Metformin-therapy effects in 50 clomiphene citrate resistant PCOS patients. Journal of Medical Sciences 2006;6(5):765-71.
Fatemi 2017 {published data only}
    1. Fatemi F, Mohammadzadeh A, Sadeghi MR, Akhondi MM, Kamali K, Jouhari S, et al. Do dietary supplements improve ICSI outcomes in polycystic ovarian syndrome in infertile women? Journal of Reproduction and Infertility. 2nd International Congress of the Iranian Society of Embryology and Reproductive Biology, ISERB 2016. Islamic Republic of Iran 2016;17 Suppl 2(2):31-2.
    1. Fatemi F, Mohammadzadeh A, Sadeghi MR, Akhondi MM, Mohammadmoradi S, Kamali K, et al. Role of vitamin E and D3 supplementation in Intra-Cytoplasmic Sperm Injection outcomes of women with polycystic ovarian syndrome: a double blinded randomized placebo-controlled trial. Clinical Nutrition ESPEN 2017;18:23-30. - PubMed
Firouzabadi 2012 {published data only}
    1. Firouzabadi RD, Aflatoonian A, Modarresi S, Sekhavat L, Mohammad Taheri S. Therapeutic effects of calcium & vitamin D supplementation in women with PCOS. Complementary Therapies in Clinical Practice 2012;18(2):85-8. - PubMed
Genazzani 2008 {published data only}
    1. Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecological Endocrinology 2008;24(3):139-44. - PubMed
Hashim 2010 {published data only}
    1. Hashim HA, Anwar K, El-Fatah RA. N-acetyl cysteine plus clomiphene citrate versus metformin and clomiphene citrate in treatment of clomiphene-resistant polycystic ovary syndrome: a randomized controlled trial. Journal of Women's Health 2010;19(11):2043-8. - PubMed
Hebisha 2016 {published data only}
    1. Hebisha SA, Abdelhaleem BA, Salaam HN. Follicular fluid homocysteine with acetyl cysteine supplemented ovarian stimulation: orrelation with oocyte yield and ICSI cycle outcome. Reproductive BioMedicine Online 2016;32:S5.
    1. Hebisha SA, Mahmoud HM. Follicular fluid homocysteine levels with acetyl cysteine supplemented ovarian stimulation: correlation with oocyte yield and ICSI outcome. International Journal of Advanced Research 2016;4(9):1906-9.
    1. Hebisha SA, Omran MS, Sallam HN, Ahmed AI. Follicular fluid homocysteine levels with N-acetyl cysteine supplemented controlled ovarian hyperstimulation, correlation with oocyte yield and ICSI cycle outcome. Fertility and Sterility 2015;104 Suppl(3):e324.
Henmi 2003 {published data only}
    1. Henmi H, Endo T, Kitajima Y, Manase K, Hata H, Kudo R. Effects of ascorbic acid supplementation on serum progesterone levels in patients with a luteal phase defect. Fertility and Sterility 2003;80(2):459-61. - PubMed
Hernández‐Yero 2012 {published data only}
    1. Hernández-Yero A, Santana Pérez F, Ovies Carballo G, Cabrera-Rode E. Diamel therapy in polycystic ovary syndrome reduces hyperinsulinaemia, insulin resistance, and hyperandrogenaemia. International Journal of Endocrinology 2012:382719. - PMC - PubMed
Immediata 2014 {published data only}
    1. Immediata V, Romualdi D, De Cicco S, Tagliaferri V, Di Florio C, Cirella E, et al. Metformin versus myoinositol: which one is better in obese PCOS patients - a crossover study on clinical, endocrine and metabolic effects. Human Reproduction 2014;29 Suppl 1:i334 Abstract no: P-522.
Iuorno 2002 {published data only}
    1. Iuorno MJ, Jakubowicz DJ, Baillargeon JP, Dillon P, Gunn RD, Allan G, et al. Effects of d-chiro-inositol in lean women with the polycystic ovary syndrome. Endocrine Practice 2002;8(6):417-23. - PubMed
Jamilian 2016a {published data only}
    1. Jamilian M, Bahmani F, Siavashani MA, Mazloomi M, Asemi Z, Esmaillzadeh A. The effects of chromium supplementation on endocrine profiles, biomarkers of inflammation, and oxidative stress in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Biological Trace Element Research: 2016;172(1):72-8. - PubMed
    1. Siavashani MA, Jamilian M, Karamali M, Khassaf A, Hosseini A, Sharif R, et al. The effects of chromium supplementation on endocrine profiles, biomarkers of inflammation and oxidative stress in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Journal of Reproduction and Infertility. 2nd International Congress of the Iranian Society of Embryology and Reproductive Biology, ISERB 2016. Islamic Republic of Iran 2016;17 Suppl 2(2):189-90.
Jamilian 2016b {published data only}
    1. Jamilian M, Foroozanfard F, Bahmani F, Talaee R, Monavari M, Asemi Z. Effects of zinc supplementation on endocrine outcomes in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. Biological Trace Element Research 2016;170(2):271-8. - PubMed
Kamencic 2008 {published data only}
    1. Kamencic H, Thiel JA. Pentoxifylline after conservative surgery for endometriosis: a randomized, controlled trial. Journal of Minimally Invasive Gynecology 2008;15(1):62-6. - PubMed
    1. Thiel JA, Kamencic H. Pentoxifylline (trental) after conservative surgery for endometriosis: a randomized control trial [abstract]. Journal of Minimally Invasive Gynecology 2006;(13 Suppl 5):S10. - PubMed
Kermack 2017 {published data only}
    1. Kermack AJ, Lowen PK, Wellstead SJ, Fisk HL, Montag M, Houghton FD, et al. PREPARE trial: a randomised double blinded controlled trial of a preconception Omega 3 and vitamin D rich dietary supplement in couples undergoing assisted reproduction treatment. Human Reproduction 2017;32(Supplement 1):i290.
Kilicdag 2005 {published data only}
    1. Kilicdag EB, Bagis T, Tarim E, Aslan E, Erkanli S, Simsek E, et al. Administration of B-group vitamins reduces circulating homocysteine in polycystic ovarian syndrome patients treated with metformin: a randomized trial. Human Reproduction 2005;20(6):1521-8. - PubMed
Le Donne 2012 {published data only}
    1. Le Donne M, Alibrandi A, Giarrusso R, Lo Monaco I, Muraca U. Diet, metformin and inositol in overweight and obese women with polycystic ovary syndrome: effects on body composition. Minerva Ginecologica 2012;64(1):23-9. - PubMed
Li 2013 {published data only}
    1. Li Y, Ma H, Zhang Y, Kuang H, Ng EHY, Hou L, et al. Effect of berberine on insulin resistance in women with polycystic ovary syndrome: Study protocol for a randomized multicenter controlled trial. Trials 2013;14(1):226. - PMC - PubMed
Mokhtari 2016a {published data only}
    1. Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. Efficacy of n-acetyl cysteine on implantation by effect on HOXA9 gene expression: a double blinded randomized placebo controlled trial. International Journal of Fertility and Sterility 2016;10(Supplement 1):102.
    1. Salmani B, Teimoorbakhsh E, Shahhoseini M, Akhlaghi AA, Moeini A, Afsharian P. Effect of N-acetyl cysteine on expression of oxidation-reduction genes during implantation window in Recurrent Implantation Failure: a double blinded randomized placebo controlled trial, phase II. Human Reproduction 2018;33(Supplement 1):i358-i359.
Moosavifar 2010 {published data only}
    1. Moosavifar N, Mohammadpour AH, Jallali M, Karimiz G, Saberi H. Evaluation of effect of silymarin on granulosa cell apoptosis and follicular development in patients undergoing in vitro fertilization. Eastern Mediterranean Health Journal 2010;16(6):642-5. - PubMed
Nazzaro 2011 {published data only}
    1. Nazzaro A, Salerno A, Marino S, Granato C, Pastore E. The addition of melatonin to myo-inositol plus folic acid improves oocyte quality and pregnancy outcome in IVF cycle: a prospective clinical trial. Human Reproduction 2011;26:i227-8.
Nestler 1999 {published data only}
    1. Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. New England Journal of Medicine 1999;340(17):1314-20. - PubMed
Nestler 2001 {published data only}
    1. Nestler J, Gunn R, Bates S, Gregory J, Jacobson W, Rogol A. D-chiro-inositol (INS-1) enhances ovulatory rate in hyperandrogenemic, oligomenorrheic women with the polycystic ovary syndrome. Fertility and Sterility 2001;76(3 Suppl 1):S110-1.
Nichols 2010 {published data only}
    1. Nichols J. A randomised controlled trial to compare conception rates for preconceptional folic acid 400 mg daily versus Pregnacare Plus in assisted conception. World Health Organization International Clinical Trials Registry Platform 2010. [ISRCTN23488518]
Nordio 2012 {published data only}
    1. 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):575-81. - PubMed
Oner 2011 {published data only}
    1. Oner G, Muderris II. Clinical, endocrine and metabolic effects of metformin vs N-acetyl-cysteine in women with polycystic ovary syndrome. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2011;159(1):127-31. - PubMed
Pal 2016 {published data only}
    1. Pal L, Zhang H, Williams J, Santoro NF, Diamond MP, Schlaff WD, et al. Vitamin D status relates to reproductive outcome in women with polycystic ovary syndrome: Secondary analysis of a multicenter randomized controlled trial. Journal of Clinical Endocrinology and Metabolism 2016;101(8):3027-35. - PMC - PubMed
Papaleo 2007 {published data only}
    1. 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. Gynecological Endocrinology 2007;23(12):700-3. - PubMed
Papaleo 2008 {published data only}
    1. Papaleo E, De Santis, Baillargeon JP, Zacchè M, Fusi FM, Brigante C, et al. Comparison of myo-inositol plus folic acid vs clomiphene citrate for first-line treatment in women with polycystic ovary syndrome. Human Reproduction: ESHRE 24th Annual Meeting, Barcelona, 6-9 July 2008 2008;23 Suppl 1:Abstract No: O-251 Oral.
Pasha 2011 {unpublished data only}
    1. Pasha NG. Assessment of the effect of Ca-vitamin D and metformin on PCOS. WHO International Clinical Trials Registry Platform Search Portal. [IRCT: IRCT201009131760N9]
Pizzo 2014 {published data only}
    1. Pizzo A, Lagana AS, Barbaro L. Comparison between effects of myo-inositol and D-chiro-inositol on ovarian function and metabolic factors in women with PCOS. Gynecological Endocrinology 2014;30(3):205-8. - PubMed
Raffone 2010 {published data only}
    1. 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):275-80. - PubMed
Ruder 2014 {published data only}
    1. Ruder EH, Hartman TJ, Reindollar RH, Goldman MB. Female dietary antioxidant intake and time to pregnancy among couples treated for unexplained infertility. Fertility and Sterility 2014;101(3):759-66. - PMC - PubMed
Salem 2012 {published data only}
    1. Salem HT, Ismail A. L-carnitin as a treatment in clomiphene resistant PCO for improving quality of ovulation and pregnancy outcome; a novel treatment. Human Reproduction. 28th Annual Meeting of the European Society of Human Reproduction and Embryology, ESHRE 2012. Istanbul Turkey 2012;27 Suppl 2(ii302-ii337):Abstract number: P-529.
Santanam 2003 {published data only}
    1. Santanam N, Kavtaradze N, Dominguez C, Rock J, Partasarathy S, Murphy A. Antioxidant supplementation reduces total chemokines and inflammatory cytokines in women with endometriosis. Fertility and Sterility 2003;80(Suppl 3):S32-3. Abstract no: O-85.
Taheri 2015 {published data only}
    1. Taheri M, Modarres M, Abdollahi A. The effect of vitamin d supplementation on anti-mullerian hormone levels in reproductive-age women. Reproduction, Fertility and Development 2015;27:185-6.
Tamura 2008 {published data only}
    1. Tamura H, Takasaki A, Miwa I, Taniguchi K, Maekawa R, Asada H, et al. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. Journal of Pineal Research 2008;44(3):280-7. - PubMed
Twigt 2011 {published data only}
    1. Twigt JM, Hammiche F, Sinclair KD, Beckers NG, Visser JA, Lindemans J, et al. Preconception folic acid use modulates estradiol and follicular responses to ovarian stimulation. Journal of Clinical Endocrinology and Metabolism 2011;96(2):E322-9. - PubMed
Vargas 2011 {published data only}
    1. Vargas ML, Almario RU, Buchan W, Kim K, Karakas SE. Metabolic and endocrine effects of long-chain versus essential omega-3 polyunsaturated fatty acids in polycystic ovary syndrome. Metabolism 2011;60(12):1711-8. - PMC - PubMed
Yoon 2010 {published and unpublished data}
    1. Yoon JW, Kim CH, Ahn JW, Kang HJ, Song BM. Effect of omega-3-polyunsaturated fatty acids and metformin on ovarian morphology and intraovarian blood flow in patients with polycystic ovary syndrome. Fertility and Sterility 2010;94/4(Abstract no. P-346):S194. [ISSN: 0015-0282]

References to ongoing studies

ChiCTR1800019772 {published data only}
    1. ChiCTR1800019772. Effect of omega-3 fatty acids on oocyte quality and early embryo development in elderly infertile women. www.chictr.org.cn/showproj.aspx?proj=33415 (first received 28 November 2018).
ChiCTR‐IPR‐15006369 {unpublished data only}
    1. ChiCTR-IPR-15006369. The improvement of endometrial receptivity in PCOS patients by Vitamin D3: a prospective randomized controlled clinical trial. www.chictr.org.cn/showproj.aspx?proj=10938 (first received 8 August 2015).
CTRI/2012/08/002943 {unpublished data only}
    1. CTRI/2012/08/002943. Nutritional supplement for women with polycystic ovary syndrome or subfertility. www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=5002 (first received 31 August 2012).
EUCTR2015‐004233‐27‐IT {unpublished data only}
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References to other published versions of this review

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Associated data