Use of I3C in gynecology
1Erik Dosedla, 1Zuzana Turcsányiová
1 Gynecology and Obstetrics Clinic of the Faculty of Medicine UPJŠ, Hospital Košice-Šaca a.s. 1st private hospital, Slovak Republic
Corresponding author: MUDr. Erik Dosedla, PhD, MBA
Obstetrics and Gynecology Clinic of the Faculty of Medicine UPJŠ, Hospital Košice-Šaca a.s. 1st private hospital, Lúčna 57, 040 15 Košice
ABSTRACT
Indole-3-carbinol (I3C) is a phytochemical derived from cruciferous plants. Upon consumption, it forms several oligomeric components, including 3,3′-diindolylmethane, known for its anti-estrogenic and anti-proliferative activity. Studies demonstrate positive outcomes in various oncological diseases, highlighting beneficial changes in estrogen metabolism.
I3C finds application in preventing and treating papillomatous diseases caused by human papillomavirus, as well as in endometrial and early-stage breast cancer. Its influence on estrogen and glucose metabolism, coupled with insulin resistance reduction, positions it as a promising adjunctive treatment for polycystic ovary syndrome. Long-term use of I3C is considered safe.
INTRODUCTION
Epidemiological and prospective clinical studies reveal that populations consuming more cruciferous vegetables exhibit a lower incidence of cancer and improved biochemical indicators, such as reduced oxidative stress. Cruciferous vegetables like broccoli, Brussels sprouts, cabbage, and cauliflower owe their beneficial effects to compounds called glucosinolates, notably indole-3-carbinol (I3C).
Metabolism of I3C
Phytochemicals like I3C are obtained through the hydrolysis of glucobrazinin glucosinolate catalyzed by myrosinase. Following consumption, I3C undergoes a condensation reaction in the stomach, forming about 15 or more oligomeric components, with 3,3′-diindolylmethane (DIM) being the most studied. I3C acts as a precursor to DIM, with approximately 10% to 20% of I3C being metabolized to DIM.
Use in Gynecology
I3C’s application in gynecology is extensive. Its antiproliferative, antioxidant, and apoptotic effects make it valuable in chemoprevention. Positive outcomes are noted in breast diseases, diseases caused by human papillomavirus, and conditions like polycystic ovary syndrome. The compound’s influence on hormonal balance, alleviation of premenstrual syndrome symptoms, and positive effects on insulin resistance contribute to its potential in gynecological treatments.
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Indole-3-Carbinol in the Role of Chemoprevention
Since 1991, I3C has been investigated for use in various conditions, including patients with human papillomavirus-induced diseases like cervical cancer (8), respiratory papillomatosis (9), those at an increased risk of breast cancer (6.1, 14), and vulvar intraepithelial neoplasia (10). Studies have shown beneficial changes in estrogen metabolism, and I3C supplements have been used for up to 82 months (6.8 years) with no reported side effects, indicating long-term safety.
HPV
The clinical focus of I3C is primarily on diseases caused by human papillomavirus (HPV), including cervical cancer and respiratory papillomatosis. Studies in patients with biopsy-confirmed CIN II-III treated with oral I3C or DIM show a statistically significant regression of CIN compared to a placebo. Clinical success has been reported in the treatment of laryngeal lesions induced by HPV using I3C (9, 16). I3C is considered a suitable candidate for chemoprevention, especially in precancers and dysplastic lesions of the cervix (8, 16).
VIN
Oral I3C at doses of 200 or 400 mg/d in 12 women with vulvar intraepithelial neoplasia led to a significant reduction in symptoms and substantial improvement in estrogen metabolism (10).
Breast Cancer
Studies confirm the effect of I3C on up-regulating the expression of BRCA1 and BRCA2 genes in breast cancer, particularly hormone-dependent types. A meta-analysis shows an inverse association between cruciferous vegetable consumption and breast cancer risk, and experimental studies demonstrate I3C’s anti-proliferative and pro-apoptotic effects on inflammatory carcinoma of the mammary gland, considered the most aggressive type of breast cancer (19).
Mechanism of Action of Chemoprevention
I3C induces the liver enzyme P450 1A1/1A2, playing a role in estrogen metabolism and reducing the risk of hormone-dependent cancers. The primary mechanism involves altering the 2-hydroxyestrone/16 alpha-hydroxyestrone ratio. I3C suppresses the proliferation of various cancer cell lines and induces apoptosis in breast cancer cells. Other effects include cell cycle arrest, inhibition of tumor invasion and metastasis, modulation of angiogenic factors, and changes in gene expression, including BRCA expression. The complex of indole metabolites obtained from cruciferous plants exhibits a synergistic anticarcinogenic effect.
Indole-3-Carbinol and PCOS
Polycystic ovary syndrome (PCOS) is one of the most widespread metabolic and reproductive diseases in women of reproductive age. Women with PCOS suffer from symptoms related to menstrual cycle disorders and excess androgens, significantly impacting their quality of life. They face an increased risk of multiple diseases, including obesity, insulin resistance, type II diabetes mellitus, cardiovascular disease, infertility, oncological diseases, and psychological issues (26). The exact cause of PCOS is not fully understood, and current treatments aim to improve the clinical picture (27). However, due to the limitations of treatments directed against symptoms like hyperandrogenism and insulin resistance, there is a need to explore new therapies that act at a specific molecular level (26).
I3C is currently the subject of ongoing research for its possible anticarcinogenic, antioxidant, anti-inflammatory, anti-apoptotic, and anti-atherogenic properties. Recent studies have focused on assessing the possible effects of I3C on various endocrine diseases, confirming its antiandrogenic and growth inhibitory effects. These effects could potentially improve the pathological features of PCOS (28). I3C and its metabolite 3,3′-diindolylmethane have been reported to ameliorate hyperglycemia-mediated oxidative stress (12). Additionally, I3C has been shown to regulate estrogen levels, contributing to overall oxidative stress regulation. Recent studies attempt to establish a relationship between I3C and metabolic diseases, including PCOS (29). Abdelbaqi et al. reported the effective antiandrogenic and antiestrogenic effects of I3C and its metabolites, alleviating hormonal disturbances in PCOS (28). Gao et al. found that I3C reduces LH and FSH production, potentially preventing fluctuations in estrogen and progesterone levels in PCOS (30). I3C improves insulin resistance and lipid profile, probably through the suppression of pro-inflammatory factors and attenuation of hyperglycemia-mediated oxidative stress often present in PCOS (12).
Cable and Co. compared the effects of I3C and I3C in combination with linagliptin in rats. The combined therapy showed inhibitory effects on TGF-β1 expression and attenuation of pro-inflammatory cytokines. They observed improvements in BMI, plasma hormone levels, lipid profiles, and tissue TBARS. I3C in combination with linagliptin appears to have a synergistic effect, potentially improving PCOS manifestations (11,31).
Conclusion
While several positive effects of I3C and its metabolites have been demonstrated in epidemiological and clinical studies, its use is limited by the lack of large prospective, randomized clinical studies determining the appropriate dose and duration for specific diseases in humans. Most work has been done in vitro or in animal models. Despite its proven beneficial effects, I3C has great potential not only in oncology but also in regulating hormonal disorders and diseases associated with glucose metabolism. Despite the positive results of multiple studies, there is still a lack of large clinical trials to establish I3C as one of the therapeutic options for PCOS. These promising results could be the subject of further clinical trials, considering I3C’s great potential and its perceived safety for use.
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