Potential Health Benefits of Curcumin on Female Reproductive Disorders: A Review
Abstract
:1. Introduction
2. Methods of Review
3. Effect of Curcumin on Polycystic Ovary Syndrome (PCOS)
4. Effect of Curcumin on Ovarian Diseases
5. Effect of Curcumin on Endometriosis
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Type of Model | Treatment and Treatment Duration | Findings | References |
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A randomised, double-blind, placebo-controlled trial on 60 women with PCOS aged from 18 to 40 years old | 1. 500 mg/day curcumin 2. Placebo Orally 12 weeks | Curcumin significantly reduced the following parameters compared with the placebo: 1. weight and BMI; 2. fasting glucose; 3. serum insulin; 4. HOMA-IR (insulin resistance); 5. total cholesterol; 6. LDL-cholesterol; 7. total-/HDL cholesterol ratio Curcumin significantly increased the following parameter compared with the placebo: 1. HDL-cholesterol levels; 2. QUICKI (insulin sensitivity); 3. gene expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ); 4. gene expression of low-density lipoprotein receptor (LDLR) | [41] |
A randomised, double-blind, placebo-controlled clinical trial on 67 women with PCOS aged from 18 to 49 years old | 1. 500 mg curcumin powder in a capsule 2. Placebo (maltodextrin) capsules Orally 3 times daily for 12 weeks | -Decreased fasting plasma glucose (FPG) and dehydroepiandrosterone levels in the curcumin-treated group compared with the placebo -Statistically non-significant increase in oestradiol levels -No changes in fasting insulin, LH and FSH, homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), BMI and waist circumference among different groups | [42] |
A randomised, double-blind, placebo-controlled clinical trial on 60 overweight or obese women with PCOS | 1. 500 mg curcumin twice daily 2. Placebo Orally 6 weeks | -Intragroup analysis of serum insulin decreased, whereas QUICKI increases significantly in the curcumin-treated group -No significant changes were recorded in all parameters between the curcumin-treated and placebo groups, including FBS, insulin, HOMA-IR, QUICKI, total cholesterol, triglyceride, LDL and HDL and high-sensitivity C-reactive protein (hs-CRP) levels | [43] |
A randomised, double-blind, placebo-controlled clinical trial on 72 women with PCOS | 1. 1500 mg curcumin 3 times daily 2. Placebo Orally 3 months | Significantly increased gene expression of peroxisome proliferator-activated receptor γ coactivator 1α and the glutathione peroxidase enzyme activity -Non-significantly increased gene expression of sirtuin-1 and activity of the superoxide dismutase (SOD) enzyme | [44] |
Type of Model | Treatment and Treatment Duration | Findings | References |
---|---|---|---|
Adult female Wistar rats treated with oestradiol valerate to induce PCOS | 1. 100 mg/kg curcumin 2. 300 mg/kg curcumin Method of administration not specified 14 days | -Reduced number of insulin resistance index (HOMA-IR decreased, QUICKI increased) -Reduced interleukin-6 and C-reactive protein -Reduced necrotic liver cells | [45] |
Prepuberal BALB/c female mice treated with DHEA to induce PCOS | 5.4 mg/100 g curcumin in the form of curcumin-loaded super-paramagnetic iron oxide (Fe3O4) nanoparticles Intraperitoneally 20 days | -Reduced ovarian volume and total number of primary, secondary, antral and primordial follicles compared to the PCOS and vehicle groups -Significantly decreased Bcl-2-associated X protein (BAX) and levels of expression of Caspase3 (CASP3) protein; increased levels of B-cell lymphoma 2 (Bcl2) expression and moderated apoptosis in granulosa cells compared with PCOS group | [46] |
Adult female Wistar rats treated with letrozole to induce PCOS | 1. Nanocurcumin (50, 100 and 200 mg/kg) 2. Clomiphene citrate (1 mg/kg) Orally 15 days | -Nanocurcumin (50 mg/kg) and clomiphene citrate attenuated the PCOS-induced reduction in oestradiol and progesterone levels -Nanocurcumin (50 and 100 mg/kg) and clomiphene citrate attenuated the PCOS-induced testosterone increment -Nanocurcumin (50 mg/kg) and clomiphene citrate improved triglyceride, total cholesterol, and LDL and HDL cholesterol levels -All doses of curcumin and clomiphene citrate reduced the PCOS-induced increment of fasting blood glucose and insulin -Clomiphene citrate and curcumin alleviated insulin resistance -Clomiphene citrate and curcumin decreased the MDA level and increase GSH and SOD activity -Clomiphene citrate and curcumin decreased TNF-α levels -Clomiphene citrate and curcumin increased the protein expression of PI3K/AKT/mTOR levels -Treatment with nanocurcumin showed thickened granulosa cells and the appearance of oocytes in a dose-dependent manner -Nano curcumin treatment and clomiphene retained the pancreatic tissue integrity and caused a gradual increase in the area of the islet and count of β-cells | [47] |
Adult female Wistar rats treated with oestradiol valerate to induce PCOS | Curcumin (100, 200, 300 and 400 mg/kg) Intraperitoneally 14 days | -Significant reduction in thickness of theca layer and increased corpus luteum diameter in the curcumin-treated group compared with the PCOS group -Curcumin decreased the IL-6 and CRP levels -Curcumin decreased TNF-α in the granulosa layer and follicular fluid | [48] |
Adult female Wistar rats treated with letrozole to induce PCOS | 1. Curcumin (100 and 200 mg/kg) 2. 1 mg/kg clomiphene citrate Orally 15 days | -Curcumin significantly inhibited the decrease in uterine weight -Clomiphene citrate and 100 and 200 mg/kg curcumin reversed the disturbance in testosterone and progesterone levels in PCOS-induced rats, whereas only clomiphene and 200 mg/kg curcumin effectively normalised the oestrogen level -Both doses of curcumin reduced fasting blood glucose and HbA1c levels -Clomiphene and 100 and 200 mg/kg curcumin decreased triglyceride, total cholesterol and LDL levels, whereas only 200 mg/kg curcumin increased HDL level -100 and 200 mg/kg curcumin increased SOD and CAT activity, and only 200 mg/kg curcumin decreased the TBARS level and increased GSH level -Clomiphene increased catalase activity, reduced TBARS and showed no effect on GSH and SOD -Clomiphene citrate and both curcumin doses resulted in the disappearance of cysts and the appearance of healthy follicles and corpora lutea | [49] |
Type of Model | Treatment and Treatment Duration | Findings | References |
---|---|---|---|
D-galactose-induced premature ovarian failure (POF) in mice | 100 mg/kg/day curcumin Intraperitoneally 42 days | -Increased progesterone and oestrogen levels while decreasing FSH and LH levels -Increased SOD and decreased the MDA and SOD2 levels and CAT mRNA expression -Increased primordial follicles -Decreased 8-OhdG, 4-HNE, NTY and senescence-associated protein P16 expression levels -Increased AMH expression levels -Reduced apoptosis in granulosa cells -Increased p-Akt, Nrf2 and HO-1 protein expression levels -Reduced cleaved caspase-3 and -9 protein expression levels | [65] |
Porcine ovarian granulosa cells | Curcumin medium at 0, 1, 10 and 100 μg/mL 2 days | -Reduced PCNA and its mRNA, increased Bax and its mRNA, reduced cell viability and stimulated progesterone and testosterone release | [67] |
Rat model of ovarian ischemia–reperfusion injury | Curcumin at 200 mg/kg Administered intraperitoneally with reperfusion Group 1: 2 h ischemia and 2 h reperfusion Group 2: 4 h ischemia and 4 h reperfusion Subgroup: (1) Sham: abdominal incision with no ischemia/perfusion (2) Control: abdominal incision with ischemia/perfusion (3) Curcumin: abdominal incision with ischemia/perfusion and curcumin at 200 mg/kg | Group 1: -No significant differences were observed between nitric oxide (NO), NO synthase (NOS), xanthine oxidase (XO), total antioxidant status (TAS) and total oxidant status (TOS) -Significantly higher ovary histological grade in the control and curcumin subgroups compared with the sham subgroup Group 2: -Significantly higher TOS and TAS in the control group than in the sham and curcumin groups -Significantly higher histological grade in the control and curcumin subgroups compared with the sham subgroup -No change in NO, NOS or XO levels | [68] |
Rat model of ovarian ischemia–reperfusion injury | 1. 100 mg/kg curcumin 2. 1 mg/kg nano curcumin Intraperitoneal Group SSG: laparotomy only Group I: 3 h ischemia only Group I/R: 3 h ischemia and 3 h reperfusion Group I/C: 3 h ischemia only and 100 mg/kg curcumin Group I/R/C: 3 h ischemia, 3 h reperfusion and 100 mg/kg curcumin Group I/NC: 3 h ischemia only and 1 mg/kg nano curcumin Group I/R/NC: 3 h ischemia, 3 h reperfusion and 1 mg/kg nano curcumin | -Nanocurcumin-treated animals showed significantly improved development of ischemia and reperfusion tissue injury compared with other groups -I/R/NC group showed significantly higher superoxide dismutase values, total glutathione, glutathione peroxidase, glutathione reductase and glutathione S-transferase than other groups (p < 0.05) -I/R/NC group showed a significantly lower value of nitric oxide synthase, malondialdehyde, myeloperoxidase and 8-hydroxy-2 deoxyguanine levels compared with other Groups -No difference in all biochemical parameters in other groups | [69] |
CBA female mice immunised with an extract from the ovaries of outbred albino mice to induce immune disease of the ovaries (model of autoimmune disease in women) | Curcumin at 100 μg/g (four times a week) Intragastric | -The percentage of oocytes in metaphases I and II: Immunised mice: the numbers of oocytes with dissolved germinal vesicle (metaphase I) and the formed polar body (metaphase II) decreased significantly Curcumin-treated mice: the level of oocytes in metaphases I and II increased significantly compared with the immunised group -The number of apoptotic and necrotic cells in the thymus, spleen and lymph node: No changes were recorded in apoptosis cell levels in all groups Immunised mice: significantly increased necrotic cell number in thymus, spleen and lymph node Curcumin-treated mice: Decreased necrotic cell number in thymus, spleen and lymph node compared with the immunised group -Percentage of blood stab neutrophils: Immunised group—increased Curcumin-treated group—decreased -Correlation between parameters of death of immunocompetent cells and number of oocytes resuming meiosis: Significantly negative correlation in immunocompetent cell necrosis and percentage of oocytes in metaphase I for spleen and lymph nodes only | [70] |
Female Kunming mice injected with 8 mg/kg sodium arsenite to induce ovarian oxidative stress | 0, 100, 150 or 200 mg/kg curcumin once a day Intragastric 21 days | -All doses of curcumin reduced the sodium arsenite-induced increment in ROS value -All doses of curcumin reduced the sodium arsenite-induced increment in MDA value -All doses of curcumin increased the sodium arsenite-induced decrease in SOD value -Decreased sodium arsenite treatment; no change in comparison with curcumin treatment -All doses of curcumin reduced the sodium arsenite-induced increment in the number of atretic follicles. No changes were recorded in primordial, primary and secondary follicles -Curcumin prevented the inhibition of proliferation of granular cells in the sodium arsenite group -p66Shc expression upregulated under oxidative stress was lowered by curcumin | [71] |
Type of Model | Treatment and Treatment Duration | Findings | References |
---|---|---|---|
Hetero-transplantation of endometrium tissue of ovariectomised donor mice into the peritoneal cavity containing subcutaneous implant of oestradiol-17β of recipient BALB/c mice | Model: 12, 24 and 48 mg/kg/day via intraperitoneal injection Therapeutic: 48 mg/kg/day curcumin 5 mg/kg, twice/day celecoxib Intraperitoneal injection Mice model: Administered once daily for 1 day prior to the inoculation of the endometrium and continued for another 3 days Therapeutic model (no pre-treatment given prior to inoculation): Curcumin once daily and celecoxib twice daily for the next 5 days | -Pre-treatment with curcumin showed obliteration of glandular regions with sparse infiltration inflammatory cells in the intestinal mucosal layer Curcumin treatment: -Downregulated MMP-3 activity during early regression of endometriosis in a dose-dependent manner -Decreased activity of MMP-3 and increased IκB-α expression leads to reduced NF-κB translocation within the nucleus -Increased in TUNEL positive cells in pre-treated endometriotic tissues as compared with untreated tissue -Induced Cyt-c release and caspase-9 expression suggested the involvement of mitochondrial pathway in stimulating apoptosis -Increased the size of mitochondria, decreased the expression of Cyt-c and increased the expression of Bax within the mitochondria -Distinct lesion of endometriosis was significantly reduced in number and volume by curcumin and moderately by celecoxib -P53 protein expression was upregulated during curcumin treatment but not during celecoxib treatment -Both curcumin and celecoxib activated phosphorylated p38 MAP kinase -The apoptotic response was triggered by increased caspase-9 expression by curcumin and celecoxib compared with normal samples | [74] |
Autotransplantation of endometrium tissue of the left horn of the uterus to the abdominal wall and intestinal mesentery of Sprague-Dawley rats | 48 mg/kg/day of curcumin 7.2 mg/kg/day of danazol 0.3 mL of ethanol 50% (vehicle) Intraperitoneal injection 4 weeks | -Serum level of leptin in the curcumin treatment group was significantly higher than in all the study groups except the danazol-treated group -No significant difference in serum levels of resistin, homocysteine and CA 125 in the danazol and curcumin treatment groups -Significantly lower serum level TAC in the curcumin-treated group compared with control and danazol-treated group | [77] |
Endometriosis with varying severity developed in mice by peritoneal implantation of uterine fragments | (1) 16, 32 and 48 mg/kg/day curcumin (2) 48 mg/kg/day curcumin for therapeutic model (3) PBS (vehicle) Intraperitoneal injection Daily for 3 days Therapeutic model: -Daily for 10 days -Daily for 20 days from day 15 post-endometriosis | At doses of 16, 32 and 48 mg/kg: -Curcumin decreased the secreted matrix metalloproteinase (MMP)-9 activity by 50%, 70% and 80% and the synthesis of MMP-9 decrease significantly by 60%, 70% and 90%, respectively In the therapeutic model: -Curcumin decreased the secreted MMP-9 activity by 45% and 85%, inhibited TNF-α and elevated TIMP-1 -Curcumin decreased lipid peroxidation and protein carbonylation | [78] |
Autotransplantation of endometrium tissue during oestrus stage in Wistar rats | 50, 100 and 150 mg/kg/d curcumin 0.5% sodium carboxymethyl cellulose solution (vehicle) Intragastric injection Daily for 4 weeks | -Hyperplasia in ectopic tissue was halted -Disappearance of the ectopic gland tissue with the narrowed lumen and sparse cells -Microvessel density (MVD) was higher in ectopic endometrium -In eutopic endometrium, all treated groups showed no significant difference compared with the normal group -Eutopic and ectopic endometrium expression of VEGF protein in the model rat group was higher than in the normal group | [79] |
Dimethyl sulfoxide (DMSO) autotransplantation of endometrium tissue from the right horn of the uterus and placed be-tween the peritoneum and muscle of ovariectomised albino Wistar rats | DMSO as vehicle 100 mg/kg of curcumin 100 mg/kg of deferoxamine + curcumin Intragastric Group A: Water for injection daily for 3 days and DMSO Group B: Curcumin Group C: Deferoxamine at 6 h interval for 3 days and curcumin Daily for 20 days | -Endometriotic-like implant sizes were significantly reduced in groups B and C compared with group A (control) -Stroma and glands with surrounding fibrous connective tissue were present and well vascularised in the ectopic endometrium -Cytokeratin-7 antibodies displayed an immunoreactivity in glandular epithelial cells of both eutopic and ectopic endometrium -Blood iron levels were not significantly different between the treatment groups according to atomic absorption spectrophotometry results | [80] |
Hetero-transplant of the endometrium of the uterine horn of donor mice into the peritoneal cavity containing subcutaneous implant of oestradiol-17β pellet of recipient BALB/c mice | 48 mg/kg/day of curcumin Intraperitoneal injection Daily for 3 days | -No changes were seen in MMP-2 activity for the first 24 h -Both synthesised and secreted proMMP-2 activity were increased after 48 h -Curcumin suppressed the pro-MMP-2 activity, and progression of endometriosis was delayed -Activation of pro-MMP-2 was inhibited; hence, MMP-2 activity was halted by curcumin during the early stage of endometriosis -Upregulation of TIMP-2 inhibited MMP-2 activity during regression of endometriosis by curcumin -MT1MMP regulated MMP-2 activity, as confirmed by immunoblotting. Curcumin downregulated MT1MMP expression by 40% compared with the normal sample -Complex formation between MMP-2 and TIMP-2 was significantly increased in the curcumin-treated group, which inhibited MMP-2 activity and endometriosis progression | [81] |
Type of Model | Treatment and Treatment Duration | Findings | References |
---|---|---|---|
Cell culture of human endometriotic stromal cells from women with stage III/IV endometriosis | (1) 1, 10, 30 and 50 μM of curcumin (2) 30 μM of curcumin + 15 ng/mL of TNF-α primary (1) 24 h (2) Curcumin for 1 h and stimulated with TNF-α for 15 h for ELISA | -Curcumin did not affect the viability of endometriotic stromal cells at doses up to 50 μM -Pre-treatment with curcumin significantly suppressed TNF-α-induced ICAM-1 and VCAM-1 mRNA expression in a dose-dependent manner -Curcumin significantly suppressed TNF-α-induced ICAM-1 VCAM-1 cell surface expression in a dose-dependent manner -Pre-treatment with curcumin (30 μM) markedly suppressed TNF-α-induced total cellular protein expression of ICAM-1 and VCAM-1 -Curcumin (30 μM) suppressed the TNF-α-induced IL-6, IL-8 and MCP-1 from endometriotic stromal cells -Pre-treatment with curcumin (30 μM) blocked the TNF-α-induced nuclear translocation of NF-κB p65 from the cytosol into the nucleus and strongly inhibited TNF-α-induced phosphorylation and degradation of IκB -Curcumin (30 μM) significantly reduced the density of the NF-κB shifted band that was induced by TNF-α | [82] |
Primary cell culture of human endometriotic stromal cells from women with endometriosis (EESCs) and normal endometrial stromal cells (NESCs) | (1) 1, 5, 10, 20 and 40 μg/mL of curcumin (2) DMSO as vehicle 24, 48 and 72 h | -100% apoptotic cell deaths at 40 μg/mL of curcumin but < 20 μg/mL had no significant apoptotic effects on endometrial stromal cells (ESCs) -IL-6, IL-8, IP-10, G-CSF, MCP-1 and RANTES were highly expressed in EESCs -IL-10 and IL-12 expressions were not different in both EESCs and NESCs -Curcumin treatment significantly inhibited secretion of IL-6, IL-8, IP-10, G-CSF, MCP-1 and RANTES in EESCs after 48 h -Curcumin significantly promoted IL-10 and IL-12 secretion in EESCs after 48 h -IL-17 was completely absent in the media after treatment with curcumin for 24 and 48 h -Curcumin inhibited the phosphorylation of IKKα, IKKβ and NF-κB in EESCs -Curcumin treatment significantly inhibited the phosphorylation of JNK and STAT3 in EESCs -JNK expression significantly decreased after curcumin treatment | [83] |
Bovine cumulus–oocyte complex cultured in a TCM 199 plus peritoneal fluid of infertile women with endometriosis | (1) TCM199 (control) (2) TCM199 + peritoneal fluid (PF) (3) TCM199 + PF + 0.2 mL curcumin 24 h | -GDF-9 and Kit Ligand expressions were higher in the treated group than in the non-treated group but decreased compared with the control group -TNFα expression in bovine COC cultured in PF from infertile women with endometriosis was reduced compared with those in the non-treated group -TNF-α was absent in the control group | [84] |
Endometriotic stromal cells, normal endometrial stromal cells, endometriotic epithelial cells and normal endometrial epithelial cells | 10, 30 and 50 μM of curcumin (2) 10 μL of WST-8 0, 24, 48, 72 and 96 h of curcumin treatment Oestradiol (E2) assay: 24 h incubation period ELISA: WST-8 for 4 h | -E2 value of endometriotic epithelial cells was higher than the endometriotic stromal cells -Expression of E2 in normal endometrial stromal and epithelial cells was extremely low -WST-8 result showed that compared with endometrial stromal cells, ectopic endometriotic stromal cells had a higher growth rate -The number of endometriotic stromal cells was reduced, and cell growth slowed compared with the 0 μmol/L group after curcumin treatment -Compared with the 0 μmol/L group, E2 level was lower after treatment with curcumin, especially in the 30 and 50 μmol/L groups | [85] |
Primary cell culture of human endometriotic stromal cells from women with endometriosis and eutopic endometrial stromal cells with no endometriosis | 0, 20 and 50 μmol/l of curcumin 48 h 72 h (for immunostaining assay) | -Cell morphology between ectopic and eutopic stromal cells was similar (spindle-shaped, abundant cytoplasm and oval-shaped nucleus); positive vimentin biomarker -Altered morphology, reduced permeability and increased cell suspension at 20 μmol/l curcumin after 48 h -Adherent cell decreased; a significant increase in cell suspension and presence of cell debris at 50 μmol/l curcumin after 48 h -Curcumin decreased the eutopic and ectopic cell growth -At 20 and 50 μmol/l curcumin after 48 h, endometriotic and endometrial stromal cells demonstrated increased percentages of G1-phase cells and decreased percentages of S-phase cells -Treatment with 20 and 50 μmol/l curcumin decreased the proportion of VEGF positive expression compared with the 0 μmol/l group -More in late apoptosis than early apoptosis in both endometriotic and endometrial cells | [86] |
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Kamal, D.A.M.; Salamt, N.; Yusuf, A.N.M.; Kashim, M.I.A.M.; Mokhtar, M.H. Potential Health Benefits of Curcumin on Female Reproductive Disorders: A Review. Nutrients 2021, 13, 3126. https://doi.org/10.3390/nu13093126
Kamal DAM, Salamt N, Yusuf ANM, Kashim MIAM, Mokhtar MH. Potential Health Benefits of Curcumin on Female Reproductive Disorders: A Review. Nutrients. 2021; 13(9):3126. https://doi.org/10.3390/nu13093126
Chicago/Turabian StyleKamal, Datu Agasi Mohd, Norizam Salamt, Allia Najmie Muhammad Yusuf, Mohd Izhar Ariff Mohd Kashim, and Mohd Helmy Mokhtar. 2021. "Potential Health Benefits of Curcumin on Female Reproductive Disorders: A Review" Nutrients 13, no. 9: 3126. https://doi.org/10.3390/nu13093126