Clinical perspectives for D-chiroinositol dose-dependent supplementation in estrogen-dependent hyperproliferative gynecological diseases

D-chiroinositol (D-CI) is an endogenous molecule that plays a key role in the insulin signaling cascade. Insulin promotes the release of inositolphosphoglycans, which contain D-CI so that D-CI deficiency in cells and tissues is directly related to insulin resistance. The mechanism of action of all insulin sensitizers is linked to increasing free D-CI concentration. However, the role of D-CI in vivo is not limited to mediating insulin signal transduction, as it is also involved in the dose-dependent regulation of various other essential physiological processes. This enables D-CI-level-based modulation of distinct physiological functions. D-CI dose-dependently modulates the activity of key steroidogenic enzymes, including 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and aromatase. It also exhibits anti-inflammatory and anti-tumor properties by downmodulating levels of tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB), as well as suppressing integrin β3 (protein that in humans is encoded by the ITGB3 gene) gene expression. These effects underpin potential D-CI therapeutic efficacy in managing a broad spectrum of reproductive system disorders. D-CI-related multifaceted effects on insulin resistance, steroidogenesis regulation, and inflammation position this molecule as a promising pharmaconutrient for correcting a wide range of conditions – spanning from insulin resistance syndrome with hyperandrogenism in polycystic ovary syndrome to hyperproliferative, estrogen-dependent diseases such as endometriosis, uterine fibroids, endometrial hyperplasia, and fibrocystic breast disease. The selection of appropriate D-CI daily dosage is a critical determinant underlying its full clinical efficacy.

1. Gambioli R., Forte G., Aragona C. et al. The use of D-chiro-Inositol in clinical practice. Eur Rev Med Pharmacol Sci. 2021;25(1):438–46. https://doi.org/10.26355/eurrev_202101_24412.

2. Bizzarri M., Fuso A., Dinicola S. et al. Pharmacodynamics and pharmacokinetics of inositol(s) in health and disease. Expert Opin Drug Metab Toxicol. 2016;12(10):1181–96. https://doi.org/10.1080/17425255.2016.1206887.

3. Gambioli R., Oliva M.М., Nordio M. et al. New insights into the activities of D-chiro-inositol: a narrative review. Biomedicines. 2021;9(10):1378. https://doi.org/10.3390/biomedicines9101378.

4. Adamyan L.V., Sonova M.M., Loginova O.N., Arslanyan K.N. The role of aromatase in the development of genital endometriosis. [Rol' aromatazy v razvitii genital'nogo endometrioza]. Obstetrics, Gynecology and Reproduction. 2016;10(4):39–48. (In Russ.). https://doi.org/10.17749/2313-7347.2016.10.4.039-048.

5. Madej P., Plewka A., Plewka D. et al. The aromatase expression in myomas and myometriums of women in reproduction and perimenopausal age. Folia Histochem Cytobiol. 2009;47(3):497–504. https://doi.org/10.2478/v10042-009-0105-0.

6. Zhao P.L., Zhang Q.F., Yan L.Y. et al. Functional investigation on aromatase in endometrial hyperplasia in polycystic ovary syndrome cases. Asian Pac J Cancer Prev. 2014;15(20):8975–9. https://doi.org/10.7314/apjcp.2014.15.20.8975.

7. Florova M.S., Yarmolinskaya M.I., Tkachenko N.N. et al. Role of insulin and insulin-like growth factor 1 receptor expression in the pathogenesis of genital endometriosis. [Rol' sistemy insulin/insulinopodobnyj faktor rosta v patogeneze genital'nogo endometrioza]. Zhurnal akusherstva i zhenskih boleznej. 2021;70(3):65–74. (In Russ.). https://doi.org/10.17816/JOWD58194.

8. Dobrokhotova Yu.E., Khachatryan A.S., Ibragimova D.M. Uterine leiomyoma: current insights into pathogenesis and use of medication tumor-reduction therapy. [Mioma matki. Sovremennye voprosy patogeneza i medikamentoznoj redukcionnoj terapii]. Doktor.Ru. 2013;(7– 1):29–32. (In Russ.).

9. Shtokh E.A., Tskhai V.B. Uterine myoma. Modern views of pathogenesis and risk factors. [Mioma matki. Sovremennoe predstavlenie o patogeneze i faktorah risk]. Sibirskoe medicinskoe obozrenie. 2015;(1):22–7. (In Russ.).

10. Rymashevsky A.N., Vorobyov S.V., Andryushchenko Yu.A. Hormonal and metabolic characteristics in patients with endometrial polyps and adiposity in postmenopausal period. [Gormonal'nye i metabolicheskie osobennosti u zhenshchin s polipami endometriya i ozhireniem v postmenopauze]. Fundamental'nye issledovaniya. 2011;(9–3):496–500. (In Russ.).

11. Kayali A.G., Eichhorn J., Haruta T. et al. Association of the insulin receptor with phospholipase C-γ (PLCγ) in 3T3-L1 adipocytes suggests a role for PLCγ in metabolic signaling by insulin. J Biol Chem. 1998;273(22):13808– 18. https://doi.org/10.1074/jbc.273.22.13808.

12. Eichhorn J., Kayali A.G., Austin D.A., Webster N.J. Insulin activates phospholipase C-gamma1 via a PI-3 kinase dependent mechanism in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2001;282(2):615–20. https://doi.org/10.1006/bbrc.2001.4616.

13. Larner J., Brautigan D.L., Thorner M.O. D-chiro-inositol glycans in insulin signaling and insulin resistance. Mol Med. 2010;16(11–12):543–52. https://doi.org/10.2119/molmed.2010.00107.

14. Nestler J.E., Jakubowicz D.J., Reamer P. et al. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med. 1999;340(17):1314–20. https://doi.org/10.1056/NEJM199904293401703.

15. Baillargeon J.-P., Iuorno M.J., Jakubowicz D.J. et al. Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89(1):242–9. https://doi.org/10.1210/jc.2003-030437.

16. Cheang K.I., Baillargeon J.-P., Essah P.A. et al. Insulin-stimulated release of d-chiro-inositol–containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metabolism. 2008;57(10):1390–7. https://doi.org/10.1016/j.metabol.2008.05.008.

17. Genazzani A.D., Santagni S., Rattighieri E. et al. Modulatory role of D-chiro-inositol (DCI) on LH and insulin secretion in obese PCOS patients. Gynecol Endocrinol. 2014;30(6):438–43. https://doi.org/10.3109/09513590.2014.897321.

18. Casarini L., Santi D., Brigante G., Simoni M. Two hormones for one receptor: evolution, biochemistry, actions, and pathophysiology of LH and hCG. Endocr Rev. 2018;39(5):549–92. https://doi.org/10.1210/er.2018-00065.

19. Stocco C. Aromatase expression in the ovary: hormonal and molecular regulation. Steroids. 2008;73(5):473–87. https://doi.org/10.1016/j.steroids.2008.01.017.

20. Fuhrmeister I.P., Branchini G., Pimentel A.M. et al. Human granulosa cells: insulin and insulin-like growth factor-1 receptors and aromatase expression modulation by metformin. Gynecol Obstet Invest. 2014;77(3):156–62. https://doi.org/10.1159/000358829.

21. Monastra G., Vazquez-Levin M., Espinola M.S.B. et al. D-chiro-inositol, an aromatase down-modulator, increases androgens and reduces estrogens in male volunteers: a pilot study. Basic Clin Androl. 2021;31(1):13. https://doi.org/10.1186/s12610-021-00131-x.

22. Sacchi S., Marinaro F., Tondelli D. et al. Modulation of gonadotrophin induced steroidogenic enzymes in granulosa cells by d-chiroinositol. Reprod Biol Endocrinol. 2016;14(1):52. https://doi.org/10.1186/s12958-016-0189-2.

23. Nestler J.E., Romero G., Huang L.C. et al. Insulin mediators are the signal transduction system responsible for insulin’s actions on human placental steroidogenesis. Endocrinology. 1991;129(6):2951–6. https://doi.org/10.1210/endo-129-6-2951.

24. Hoffmann R., Niiyama S., Huth A. et al. 17α-estradiol induces aromatase activity in intact human anagen hair follicles ex vivo. Exp Dermatol. 2002;11(4):376–80. https://doi.org/10.1034/j.1600-0625.2002.110413.x.

25. Cisternas C., Zapata L.E.C., Arevalo M.-A. et al. Regulation of aromatase expression in the anterior amygdala of the developing mouse brain depends on ERβ and sex chromosome complement. Sci Rep. 2017;7(1):5320. https://doi.org/10.1038/s41598-017-05658-6.

26. Cloix L., Reverchon M., Cornuau M. et al. Expression and regulation of INTELECTIN1 in human granulosa-lutein cells: role in IGF-1-induced steroidogenesis through NAMPT. Biol Reprod. 2014;91(2):50. https://doi.org/10.1095/biolreprod.114.120410.

27. Nordio M., Basciani S., Camajani E. The 40:1 myo-inositol/D-chiro-inositol plasma ratio is able to restore ovulation in PCOS patients: comparison with other ratios. Eur Rev Med Pharmacol Sci. 2019;23(12):5512–21. https://doi.org/10.26355/eurrev_201906_18223.

28. Lin T.-H., Tan T.-W., Tsai T.-H. et al. D-pinitol inhibits prostate cancer metastasis through inhibition of αVβ3 integrin by modulating FAK, c-Src and NF-κB pathways. Int J Mol Sci. 2013;14(5):9790–802. https://doi.org/10.3390/ijms14059790.

29. Cooper J., Giancotti F.G. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell. 2019;35(3):347–67. https://doi.org/10.1016/j.ccell.2019.01.007.

30. Shi L., Yu X.T., Li H. et al. D-chiro-inositol increases antioxidant capacity and longevity of Caenorhabditis elegans via activating Nrf-2/SKN-1 and FOXO/DAF-16. Exp Gerontol. 2023;175:112145. https://doi.org/10.1016/j.exger.2023.112145.

31. Miller P.G., Al-Shahrour F., Hartwell K.A. et al. In vivo RNAi screening identifies a leukemia-specific dependence on integrin beta 3 signaling. Cancer Cell. 2013;24(1):45–58. https://doi.org/10.1016/j.ccr.2013.05.004.

32. Özkan N.T., Tokmak A., Güzel A.İ. et al. The association between endometrial polyps and metabolic syndrome: a case-control study. Aust N Z J Obstet Gynaecol. 2015;55(3):274–8. https://doi.org/10.1111/ajo.12339.

33. Serhat E., Cogendez E., Selcuk S. et al. Is there a relationship between endometrial polyps and obesity, diabetes mellitus, hypertension? Arch Gynecol Obstet. 2014;290(5):937–41. https://doi.org/10.1007/s00404-014-3279-4.

34. Zhang B., Guo X., Li Y. et al. d-Chiro inositol ameliorates endothelial dysfunction via inhibition of oxidative stress and mitochondrial fission. Mol Nutr Food Res. 2017;61(8):1600710. https://doi.org/10.1002/mnfr.201600710.

35. Liu H., Radisky D.C., Yang D. et al. MYC suppresses cancer metastasis by direct transcriptional silencing of αv and β3 integrin subunits. Nat Cell Biol. 2012;14(6):567–74. https://doi.org/10.1038/ncb2491.

36. Wong C.L.H., So P.L. Prevalence and risk factors for malignancy in hysteroscopy-resected endometrial polyps. Int J Gynaecol Obstet. 2021;155(3):433–41. https://doi.org/10.1002/ijgo.13656.

37. Porcaro G., Bilotta G., Capoccia E. et al. D-chiro-inositol in endometrial hyperplasia: a pilot study. Int J Mol Sci. 2023;24(12):10080. https://doi.org/10.33029/ijms241210080.

38. Radzinsky V.E., Mikhaleva L.M., Khamoshina M.B. et al. Effectiveness and safety of D-chiro-inositol in combination therapy of endometrial hyperplasia without atypia: results of a randomized placebo-controlled study. [Effektivnost' i bezopasnost' D-hiro-inozitola v kompleksnoj terapii giperplazii endometriya bez atipii: rezul'taty randomizirovannogo placebokontroliruemogo issledovaniya]. Akusherstvo i ginekologiya: novosti, mneniya, obuchenie. 2026;14(suppl):83–96. (In Russ.). https://doi.org/10.33029/2303-9698-2026-14-suppl-83-96.

39. Prokhorova M.V., Manukhin I.B., Gevorkyan M.A., Manukhina E.I. Estrogen metabolites in patients with external genital endometriosis. [Metabolity estrogenov u pacientok s naruzhnym genital'nym endometriozom]. Problemy reprodukcii. 2013;(5):81–4. (In Russ.).

40. Wang M., Wu Y., He Y. et al. SIRT1 upregulation promotes epithelialmesenchymal transition by inducing senescence escape in endometriosis. Sci Rep. 2022;12(1):12302. https://doi.org/10.1038/s41598-022-16629-x.

41. Nisolle M., Casanas-Roux F., Anaf V. et al. Morphometric study of the stromal vascularization in peritoneal endometriosis. Fertil Steril. 1993;59(3):681–4.

42. McLaren J., Prentice A., Charnock-Jones D.S. et al. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest. 1996;98(2):482–9. https://doi.org/10.1172/JCI118815.

43. Shifren J.L., Tseng J.F., Zaloudek C.J. et al. Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol Metab. 1996;81(8):3112–8. https://doi.org/10.1210/jcem.81.8.8768883.

44. Placidi M., Casoli G., Vergara T. et al. D-chiro-inositol effectively counteracts endometriosis in a mouse model. Mol Med. 2025;31(1):134. https://doi.org/10.1186/s10020-025-01178-6.

45. De La Cruz M.S., Buchanan E.M. Uterine fibroids: diagnosis and treatment. Am Fam Physician. 2017;95(2):100–7.

46. Zepiridis L.I., Grimbizis G.F., Tarlatzis B.C. Infertility and uterine fibroids. Best Pract Res Clin Obstet Gynaecol. 2016;34:66–73. https://doi.org/10.1016/j.bpobgyn.2015.12.001.

47. McWilliams M.M., Chennathukuzhi V.M. Recent advances in uterine fibroid etiology. Semin Reprod Med. 2017;35(2):181–9. https://doi.org/10.1055/s-0037-1599090.

48. Iashchuk A.G., Musin I.I., Gumerova I.A. Current aspects of the study of uterine myoma etiology. [Sovremennye aspekty v izuchenii etiologii miomy matki]. Rossijskij vestnik akushera-ginekologa. 2019;19(3):49–56. (In Russ.). https://doi.org/10.17116/rosakush20191903149.

49. Ren Y., Yin H., Tian R. et al. Different effects of epidermal growth factor on smooth muscle cells derived from human myometrium and from leiomyoma. Fertil Steril. 2011;96(4):1015–20. https://doi.org/10.1016/j.fertnstert.2011.07.004.

50. Wang C., Sun Y., Cong S., Zhang F. Insulin-like growth factor-1 promotes human uterine leiomyoma Ccell proliferation via PI3K/AKT/mTOR pathway. Cells Tissues Organs. 2023;212(2):194–202. https://doi.org/10.1159/000525186.

51. Ishikawa H., Reierstad S., Demura M. et al. High aromatase expression in uterine leiomyoma tissues of African-American women. J Clin Endocrinol Metab. 2009;94(5):1752–6. https://doi.org/10.1210/jc.2008-2327.

52. Montanino O.M. D-chiro-inositol, vitamin D, and epigallocatechin gallate avoid surgery in females with uterine fibroids: two case reports. EMJ Repro Health. 2021;7(1):95–101. https://doi.org/10.33590/emjreprohealth/20-00261.

53. Tinelli A., Panese G., Licchelli M. et al. The impact of epigallocatechin gallate, vitamin D, and D-chiro-inositol on early surgical outcomes of laparoscopic myomectomy: a pilot study. Archives of Gynecology and Obstetrics. 2024;309(4):1–6. https://doi.org/10.1007/s00404-023-07324-x.

54. Radzinsky V.E., Ordiyants I.M., Zubkin V.I. et al. Non-cancerous diseases of the mammary glands and gynecological diseases. [Nerakovye zabolevaniya molochnyh zhelez i ginekologicheskie zabolevaniya]. Zhurnal Rossijskogo obshchestva akusherov-ginekologov. 2006;(2):65–8. (In Russ.).

55. Clemons M., Goss P. Estrogen and the risk of breast cancer. N Engl J Med. 2001;344(4):276–85. https://doi.org/10.1056/NEJM200101253440407.

56. Jones J.I., Clemmons D.R. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995;16(1):3–34. https://doi.org/10.1210/edrv-16-1-3.

57. Subik K., Lee J.-F., Baxter L. et al. The Expression patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by immunohistochemical analysis in breast cancer cell lines. Breast Cancer (Auckl). 2010;4:35–41. Erratum in: Breast Cancer (Auckl). 2018;12:1178223418806626. https://doi.org/10.1177/1178223418806626.

58. Kim Y.-s., Park J.-s., Kim M. et al. Inhibitory effect of D-pinitol on both growth and recurrence of breast tumor from MDA-MB-231 cancer cells. Nat Prod Sci. 2017;23(1):35–9. https://doi.org/10.20307/nps.2017.23.1.35.

59. Inokirol. Instructions for use. RLS. [Inokirol. Instrukciya po primeneniyu. RLS]. (In Russ.). Available at: https://www.rlsnet.ru/baa/inokirol-90222?ysclid=mnuj06x7mz945777604. [Accessed: 12.01.2026].

60. Gromova O.A., Torshin I.Yu., Tapilskaya N.I., Uvarova E.V. A systemic biological analysis of the role of manganese in obstetrics and gynecology: women's reproductive health, menstrual cycle regulation and prevention of fetal malformations: methodological developments. [Sistemno-biologicheskij analiz rolej marganca v akusherstve i ginekologii: reproduktivnoe zdorov'e zhenshchiny, regulyaciya menstrual'nogo cikla i profilaktika porokov razvitiya ploda: metodicheskie razrabotki]. Moscow: Izdatel'stvo «Dinastiya», 2020. 26 p. (In Russ.).

61. Fonteles M.C., Almeida M.Q, Larner J. Antihyperglycemic effects of 3-O-methyl-D-chiro-inositol and D-chiro-inositol associated with manganese in streptozotocin diabetic rats. Horm Metab Res. 2000;32(4):129–32. https://doi.org/10.1055/s-2007-978606.