Hostname: page-component-848d4c4894-xfwgj Total loading time: 0 Render date: 2024-06-19T19:42:51.014Z Has data issue: false hasContentIssue false
  • English
  • Français

Effects of myo-inositol plus folic acid on ovarian morphology and oocyte quality in PCOS mouse model

Published online by Cambridge University Press:  09 January 2023

Maryam Haghighi ,
Mehdi Mehdizadeh Open the ORCID record for Mehdi Mehdizadeh [Opens in a new window] ,
Fatemehsadat Amjadi ,
Zahra Zandieh ,
Mohammad Najafi ,
Tayebe Artimani ,
Fatemeh Mohammadi  and
Rana Mehdizadeh
Maryam Haghighi
Affiliation:
Anatomy Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran Student Research Committee, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
Mehdi Mehdizadeh*
Affiliation:
Anatomy Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran Reproductive Sciences and Technology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
Fatemehsadat Amjadi
Affiliation:
Anatomy Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran Reproductive Sciences and Technology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
Zahra Zandieh
Affiliation:
Anatomy Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran Reproductive Sciences and Technology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran
Mohammad Najafi
Affiliation:
Biochemistry Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
Tayebe Artimani
Affiliation:
Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
Fatemeh Mohammadi
Affiliation:
Anatomy Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran
Rana Mehdizadeh
Affiliation:
School of Dentistry, Central Tehran Branch, Islamic Azad University, Tehran, Iran
*
Author for correspondence: Mehdi Mehdizadeh, Anatomy Department, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran. E-mail: Mehdizadeh.m@iums.ac.ir
Get access Rights & Permissions [Opens in a new window]

Summary

Although the role of myo-inositol (MYO) in promoting the oocyte quality of PCOS patients has been documented in human studies; the cellular effects of this supplement on oocytes have not been directly examined due to ethical limitations. In the first phase of this study, MYO dosimetry was carried out simultaneously with the PCOS model development. An effective dose was obtained following the assessment of fasting insulin and testosterone levels using ELISA and ovarian morphology appraisal by histopathology. In the second phase, following the continuous administration of the effective dose of MYO and dehydroepiandrosterone (DHEA), cellular evaluation was performed. The quality of oocytes from superovulation was analyzed by examining maturity and normal morphology percentage using a stereomicroscope, intracellular reactive oxygen species (ROS) and glutathione (GSH) levels using fluorometry, and ATP count evaluation using ELISA. The results revealed that, among the four different MYO concentrations, the 0.36 mg/g dose compared with the DHEA group reduced testosterone levels and large atretic antral follicles (LAtAnF) diameter. This dose also increased the corpus luteum count and the granulosa:theca (G/T)layer thickness ratio in antral follicles. Furthermore, this dose increased mature oocytes and normal morphology percentage, ATP count, and GSH levels; however, it decreased ROS levels in mature oocytes. Our findings provide the grounds for further cellular and molecular studies on the PCOS mouse model, suggesting that the improvement in mitochondrial function and its antioxidant properties is probably one of the mechanisms by which MYO increases oocyte quality.

Keywords

Polycystic ovary syndromeDehydroepiandrosterone (DHEA)Myo-inositolOocyte qualityOxidative stressATP countGlutathione
Type
Research Article
Information
Zygote , Volume 31 , Issue 2 , April 2023 , pp. 111 - 122
Check for updates
Copyright
© The Author(s), 2023. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Akbari Sene, A., Tabatabaie, A., Nikniaz, H., Alizadeh, A., Sheibani, K., Mortezapour Alisaraie, M., Tabatabaie, M., Ashrafi, M. and Amjadi, F. (2019). The myo-inositol effect on the oocyte quality and fertilization rate among women with polycystic ovary syndrome undergoing assisted reproductive technology cycles: A randomized clinical trial. Archives of Gynecology and Obstetrics, 299(6), 1701–1707. doi: 10.1007/s00404-019-05111-1 CrossRefGoogle ScholarPubMed
Amini, L., Tehranian, N., Movahedin, M., Ramezani Tehrani, F. R. and Soltanghoraee, H. (2016). Polycystic ovary morphology (PCOM) in estradiol valerate treated mouse model. International Journal of Women’s Health and Reproduction Sciences, 4(1), 13–17. doi: 10.15296/ijwhr.2016.04 CrossRefGoogle Scholar
Aragno, M., Brignardello, E., Tamagno, E., Gatto, V., Danni, O. and Boccuzzi, G. (1997). Dehydroepiandrosterone administration prevents the oxidative damage induced by acute hyperglycemia in rats. Journal of Endocrinology, 155(2), 233–240. doi: 10.1677/joe.0.1550233 CrossRefGoogle ScholarPubMed
Aragno, M., Mastrocola, R., Brignardello, E., Catalano, M., Robino, G., Manti, R., Parola, M., Danni, O. and Boccuzzi, G. (2002). Dehydroepiandrosterone modulates nuclear factor-κB activation in hippocampus of diabetic rats. Endocrinology, 143(9), 3250–3258. doi: 10.1210/en.2002-220182 CrossRefGoogle ScholarPubMed
Artini, P. G., Di Berardino, O. M., Papini, F., Genazzani, A. D., Simi, G., Ruggiero, M. and Cela, V. (2013). Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Gynecological Endocrinology, 29(4), 375–379. doi: 10.3109/09513590.2012.743020 CrossRefGoogle ScholarPubMed
Azhary, J. M. K., Harada, M., Takahashi, N., Nose, E., Kunitomi, C., Koike, H., Hirata, T., Hirota, Y., Koga, K., Wada-Hiraike, O., Fujii, T. and Osuga, Y. (2019). Endoplasmic reticulum stress activated by androgen enhances apoptosis of granulosa cells via induction of death receptor 5 in PCOS. Endocrinology, 160(1), 119–132. doi: 10.1210/en.2018-00675 CrossRefGoogle ScholarPubMed
Bizzarri, M., Cucina, A., Dinicola, S., Harrath, A. H., Alwasel, S. H., Unfer, V. and Bevilacqua, A. (2016). Does myo-inositol effect on PCOS follicles involve cytoskeleton regulation? Medical Hypotheses, 91, 1–5. doi: 10.1016/j.mehy.2016.03.014 CrossRefGoogle ScholarPubMed
Cardozo, E., Pavone, M. E. and Hirshfeld-Cytron, J. E. (2011). Metabolic syndrome and oocyte quality. Trends in Endocrinology and Metabolism, 22(3), 103–109. doi: 10.1016/j.tem.2010.12.002 CrossRefGoogle ScholarPubMed
Chiu, T. T., Rogers, M. S., Law, E. L., Briton-Jones, C. M., Cheung, L. P. and Haines, C. J. (2002). Follicular fluid and serum concentrations of myo-inositol in patients undergoing IVF: Relationship with oocyte quality. Human Reproduction, 17(6), 1591–1596. doi: 10.1093/humrep/17.6.1591 CrossRefGoogle ScholarPubMed
Ciotta, L., Stracquadanio, M., Pagano, I., Carbonaro, A., Palumbo, M. and Gulino, F. (2011). Effects of myo-inositol supplementation on oocyte’s quality in PCOS patients: A double blind trial. European Review for Medical and Pharmacological Sciences, 15(5), 509–514.Google ScholarPubMed
Croze, M. L., Vella, R. E., Pillon, N. J., Soula, H. A., Hadji, L., Guichardant, M. and Soulage, C. O. (2013). Chronic treatment with myo-inositol reduces white adipose tissue accretion and improves insulin sensitivity in female mice. Journal of Nutritional Biochemistry, 24(2), 457–466. doi: 10.1016/j.jnutbio.2012.01.008 CrossRefGoogle ScholarPubMed
Eini, F., Novin, M. G., Joharchi, K., Hosseini, A., Nazarian, H., Piryaei, A. and Bidadkosh, A. (2017). Intracytoplasmic oxidative stress reverses epigenetic modifications in polycystic ovary syndrome. Reproduction, Fertility, and Development, 29(12), 2313–2323. doi: 10.1071/RD16428 CrossRefGoogle ScholarPubMed
Genazzani, A. D., Prati, A., Santagni, S., Ricchieri, F., Chierchia, E., Rattighieri, E., Campedelli, A., Simoncini, T. and Artini, P. G. (2012). Differential insulin response to myo-inositol administration in obese polycystic ovary syndrome patients. Gynecological Endocrinology, 28(12), 969–973. doi: 10.3109/09513590.2012.685205 CrossRefGoogle ScholarPubMed
Gerli, S., Papaleo, E., Ferrari, A. and Di Renzo, G. C. (2007). Randomized, double blind placebo-controlled trial: Effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. European Review for Medical and Pharmacological Sciences, 11(5), 347–354.Google ScholarPubMed
Gleicher, N., Weghofer, A. and Barad, D. H. (2011). The role of androgens in follicle maturation and ovulation induction: Friend or foe of infertility treatment? Reproductive Biology and Endocrinology: RBandE, 9(1), 116. doi: 10.1186/1477-7827-9-116 CrossRefGoogle ScholarPubMed
Goud, P. T., Goud, A. P., Van Oostveldt, P. and Dhont, M. (1999). Presence and dynamic redistribution of type I inositol 1, 4, 5-trisphosphate receptors in human oocytes and embryos during in-vitro maturation, fertilization and early cleavage divisions. Molecular Human Reproduction, 5(5), 441–451. doi: 10.1093/molehr/5.5.441 CrossRefGoogle ScholarPubMed
Hakimpour, S., Jelodar, G., Shabani, R., Pourheydar, B., Ajdary, M. and Mehdizadeh, M. (2022). Study of vitamin D3 formulation prepared by phytosolve technique and its effect on CTRP6 gene expression in PCOS model. Journal of Drug Delivery Science and Technology, 73, 103489. doi: 10.1016/j.jddst.2022.103489 CrossRefGoogle Scholar
Hayes, M. G., Urbanek, M., Ehrmann, D. A., Armstrong, L. L., Lee, J. Y., Sisk, R., et al. (2015). Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nature Communications, 6, 7502. doi: 10.1038/ncomms8502 CrossRefGoogle ScholarPubMed
Henmi, H., Endo, T., Nagasawa, K., Hayashi, T., Chida, M., Akutagawa, N., Iwasaki, M., Kitajima, Y., Kiya, T., Nishikawa, A., Manase, K. and Kudo, R. (2001). Lysyl oxidase and MMP-2 expression in dehydroepiandrosterone-induced polycystic ovary in rats. Biology of Reproduction, 64(1), 157–162. doi: 10.1095/biolreprod64.1.157 Google ScholarPubMed
Huang, Y., Yu, Y., Gao, J., Li, R., Zhang, C., Zhao, H., Zhao, Y. and Qiao, J. (2015). Impaired oocyte quality induced by dehydroepiandrosterone is partially rescued by metformin treatment. PLOS ONE, 10(3), e0122370. doi: 10.1371/journal.pone.0122370 CrossRefGoogle ScholarPubMed
Ikeda, K., Baba, T., Morishita, M., Honnma, H., Endo, T., Kiya, T. and Saito, T. (2014). Long-term treatment with dehydroepiandrosterone may lead to follicular atresia through interaction with anti-Müllerian hormone. Journal of Ovarian Research, 7(1), 46. doi: 10.1186/1757-2215-7-46 CrossRefGoogle ScholarPubMed
Kamenov, Z. and Gateva, A. (2020). Inositols in PCOS. Molecules, 25(23), 5566. doi: 10.3390/molecules25235566 CrossRefGoogle ScholarPubMed
Karuputhula, N. B., Chattopadhyay, R., Chakravarty, B. and Chaudhury, K. (2013). Oxidative status in granulosa cells of infertile women undergoing IVF. Systems Biology in Reproductive Medicine, 59(2), 91–98. doi: 10.3109/19396368.2012.743197 CrossRefGoogle ScholarPubMed
Kim, H. H., Shaipanich, M., Hasselblatt, K. and Yeh, J. (2003). Induction of apoptosis and ovarian cyst formation in the mouse ovary by dehydroepiandrosterone (DHEA). Journal of Medicine, 34(1–6), 101–112.Google ScholarPubMed
Kockskämper, J., Zima, A. V., Roderick, H. L., Pieske, B., Blatter, L. A. and Bootman, M. D. (2008). Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes. Journal of Molecular and Cellular Cardiology, 45(2), 128–147. doi: 10.1016/j.yjmcc.2008.05.014 CrossRefGoogle ScholarPubMed
Kokosar, M., Benrick, A., Perfilyev, A., Fornes, R., Nilsson, E., Maliqueo, M., Behre, C. J., Sazonova, A., Ohlsson, C., Ling, C. and Stener-Victorin, E. (2016). Epigenetic and transcriptional alterations in human adipose tissue of polycystic ovary syndrome. Scientific Reports, 6, 22883. doi: 10.1038/srep22883 CrossRefGoogle ScholarPubMed
Laganà, A. S., Rossetti, P., Buscema, M., La Vignera, S., Condorelli, R. A., Gullo, G., Granese, R. and Triolo, O. (2016). Metabolism and ovarian function in PCOS women: A therapeutic approach with inositols. International Journal of Endocrinology, 2016, 6306410. doi: 10.1155/2016/6306410 CrossRefGoogle ScholarPubMed
Lewin, L. M., Szeinberg, A. and Lepkifker, E. (1973). Gas chromatographic measurement of myo-inositol in human blood, cerebrospinal fluid and seminal fluid. Clinica Chimica Acta, 45(4), 361–368. doi: 10.1016/0009-8981(73)90036-3 CrossRefGoogle Scholar
Maurya, V. K., Sangappa, C., Kumar, V., Mahfooz, S., Singh, A., Rajender, S. and Jha, R. K. (2014). Expression and activity of Rac1 is negatively affected in the dehydroepiandrosterone induced polycystic ovary of mouse. Journal of Ovarian Research, 7(1), 32. doi: 10.1186/1757-2215-7-32 CrossRefGoogle ScholarPubMed
Mehlmann, L. M. and Kline, D. (1994). Regulation of intracellular calcium in the mouse egg: Calcium release in response to sperm or inositol trisphosphate is enhanced after meiotic maturation. Biology of Reproduction, 51(6), 1088–1098. doi: 10.1095/biolreprod51.6.1088 CrossRefGoogle ScholarPubMed
Mikaeili, S., Rashidi, B. H., Safa, M., Najafi, A., Sobhani, A., Asadi, E. and Abbasi, M. (2016). Altered FoxO3 expression and apoptosis in granulosa cells of women with polycystic ovary syndrome. Archives of Gynecology and Obstetrics, 294(1), 185–192. doi: 10.1007/s00404-016-4068-z CrossRefGoogle ScholarPubMed
National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. (2011). Guide for the Care and Use of Laboratory Animals. 8th edition. Washington (DC): National Academies Press (US). Available from: https://www.ncbi.nlm.nih.gov/books/NBK54050/ doi: 10.17226/12910 Google Scholar
Nikmard, F., Hosseini, E., Bakhtiyari, M., Ashrafi, M., Amidi, F. and Aflatoonian, R. (2017). Effects of melatonin on oocyte maturation in PCOS mouse model. Animal Science Journal, 88(4), 586–592. doi: 10.1111/asj.12675 CrossRefGoogle ScholarPubMed
Papaleo, E., Molgora, M., Quaranta, L., Pellegrino, M. and De Michele, F. (2011). myo-inositol products in polycystic ovary syndrome (PCOS) treatment: Quality, labeling accuracy, and cost comparison. European Review for Medical and Pharmacological Sciences, 15(2), 165–174.Google ScholarPubMed
Patel, S. S. and Carr, B. R. (2008). Oocyte quality in adult polycystic ovary syndrome. Seminars in Reproductive Medicine, 26(2), 196–203. doi: 10.1055/s-2008-1042958 CrossRefGoogle ScholarPubMed
Qiao, J. and Feng, H. L. (2011). Extra- and intra-ovarian factors in polycystic ovary syndrome: Impact on oocyte maturation and embryo developmental competence. Human Reproduction Update, 17(1), 17–33. doi: 10.1093/humupd/dmq032 CrossRefGoogle ScholarPubMed
Ravanos, K., Monastra, G., Pavlidou, T., Goudakou, M. and Prapas, N. (2017). Can high levels of d-chiro-inositol in follicular fluid exert detrimental effects on blastocyst quality? European Review for Medical and Pharmacological Sciences, 21(23), 5491–5498. doi: 10.26355/eurrev_201712_13940 Google ScholarPubMed
Safiulina, D., Peet, N., Seppet, E., Zharkovsky, A. and Kaasik, A. (2006). Dehydroepiandrosterone inhibits complex I of the mitochondrial respiratory chain and is neurotoxic in vitro and in vivo at high concentrations. Toxicological Sciences, 93(2), 348–356. doi: 10.1093/toxsci/kfl064 CrossRefGoogle ScholarPubMed
Song, X., Shen, Q., Fan, L., Yu, Q., Jia, X., Sun, Y., Bai, W. and Kang, J. (2018). Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome. Oncotarget, 9(15), 11905–11921. doi: 10.18632/oncotarget.24190 CrossRefGoogle Scholar
Tamura, H., Takasaki, A., Miwa, I., Taniguchi, K., Maekawa, R., Asada, H., Taketani, T., Matsuoka, A., Yamagata, Y., Shimamura, K., Morioka, H., Ishikawa, H., Reiter, R. J. and Sugino, N. (2008). Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate. Journal of Pineal Research, 44(3), 280–287. doi: 10.1111/j.1600-079X.2007.00524.x CrossRefGoogle ScholarPubMed
Ubaldi, F. and Rienzi, L. (2008). Morphological selection of gametes. Placenta, 29, Suppl. B, 115–120. doi: 10.1016/j.placenta.2008.08.009 CrossRefGoogle ScholarPubMed
Unfer, V., Carlomagno, G., Papaleo, E., Vailati, S., Candiani, M. and Baillargeon, J. P. (2014). Hyperinsulinemia alters myoinositol to d-chiroinositol ratio in the follicular fluid of patients with PCOS. Reproductive Sciences, 21(7), 854–858. doi: 10.1177/1933719113518985 CrossRefGoogle ScholarPubMed
Unfer, V., Dinicola, S., Laganà, A. S. and Bizzarri, M. (2020). Altered ovarian inositol ratios may account for pathological steroidogenesis in PCOS. International Journal of Molecular Sciences, 21(19), 7157. doi: 10.3390/ijms21197157 CrossRefGoogle ScholarPubMed
Unfer, V., Facchinetti, F., Orrù, B., Giordani, B. and Nestler, J. (2017). myo-inositol effects in women with PCOS: A meta-analysis of randomized controlled trials. Endocrine Connections, 6(8), 647–658. doi: 10.1530/EC-17-0243 CrossRefGoogle ScholarPubMed
US Food and Drug Administration. (2005). Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Center for Drug Evaluation and Research (CDER), Rockville, MD. Available from: http://www.fda.gov/downloads/drugs/guidances/ucm078932.pdf.Google Scholar
Vitale, S. G., Rossetti, P., Corrado, F., Rapisarda, A. M. C., La Vignera, S., Condorelli, R. A., Valenti, G., Sapia, F., Laganà, A. S. and Buscema, M. (2016). How to achieve high-quality oocytes? The key role of myo-inositol and melatonin. International Journal of Endocrinology, 2016, 4987436. doi: 10.1155/2016/4987436 CrossRefGoogle ScholarPubMed
Wang, F., Tian, X., Zhang, L., He, C., Ji, P., Li, Y., Tan, D. and Liu, G. (2014). Beneficial effect of resveratrol on bovine oocyte maturation and subsequent embryonic development after in vitro fertilization. Fertility and Sterility, 101(2), 577–586. e571. doi: 10.1016/j.fertnstert.2013.10.041 CrossRefGoogle ScholarPubMed
Wesson, D. E. and Elliott, S. J. (1995). The H2O2-generating enzyme, xanthine oxidase, decreases luminal Ca2+ content of the IP3-sensitive Ca2+ store in vascular endothelial cells. Microcirculation 2(2), 195–203.CrossRefGoogle ScholarPubMed
Zacchè, M. M., Caputo, L., Filippis, S., Zacchè, G., Dindelli, M. and Ferrari, A. (2009). Efficacy of myo-inositol in the treatment of cutaneous disorders in young women with polycystic ovary syndrome. Gynecological Endocrinology, 25(8), 508–513. doi: 10.1080/09513590903015544 CrossRefGoogle ScholarPubMed
Zeng, L. and Yang, K. (2018). Effectiveness of myoinositol for polycystic ovary syndrome: A systematic review and meta-analysis. Endocrine, 59(1), 30–38. doi: 10.1007/s12020-017-1442-y CrossRefGoogle ScholarPubMed
Zhang, J., Bao, Y., Zhou, X. and Zheng, L. (2019). Polycystic ovary syndrome and mitochondrial dysfunction. Reproductive Biology and Endocrinology: RBandE, 17(1), 67. doi: 10.1186/s12958-019-0509-4 CrossRefGoogle ScholarPubMed
Zhu, J. Q., Zhu, L., Liang, X. W., Xing, F. Q., Schatten, H. and Sun, Q. Y. (2010). Demethylation of LHR in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome. Molecular Human Reproduction, 16(4), 260–266. doi: 10.1093/molehr/gap089 CrossRefGoogle ScholarPubMed
Zimmermann, M. (1983). Ethical guidelines for investigations of experimental pain in conscious animals. Pain, 16(2), 109–110. doi: 10.1016/0304-3959(83)90201-4 CrossRefGoogle ScholarPubMed