Next Article in Journal
Effect of Dairy Matrix on the Postprandial Blood Metabolome
Next Article in Special Issue
Therapeutic Properties and Use of Extra Virgin Olive Oil in Clinical Nutrition: A Narrative Review and Literature Update
Previous Article in Journal
Glycaemic and Appetite Suppression Effect of a Vegetable-Enriched Bread
Previous Article in Special Issue
Oleanolic Acid-Enriched Olive Oil Alleviates the Interleukin-6 Overproduction Induced by Postprandial Triglyceride-Rich Lipoproteins in THP-1 Macrophages
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Nutrients
Volume 13
Issue 12
10.3390/nu13124279
nutrients-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Protective Effects and Benefits of Olive Oil and Its Extracts on Women’s Health

by
Thanh Truong Giang Ly
1,2,
Jisoo Yun
1,2,
Dong-Hyung Lee
3,
Joo-Seop Chung
4,* and
Sang-Mo Kwon
1,2,*
1
Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Korea
2
Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Korea
3
Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital, Yangsan 50612, Korea
4
Department of Hematology-Oncology, Medical Research Institute, Pusan National University Hospital, Busan 49241, Korea
*
Authors to whom correspondence should be addressed.
Nutrients 2021, 13(12), 4279; https://doi.org/10.3390/nu13124279
Submission received: 8 November 2021 / Revised: 26 November 2021 / Accepted: 26 November 2021 / Published: 27 November 2021
(This article belongs to the Special Issue Virgin Olive Oil and Health)
Browse Figure
Versions Notes

Abstract

:
Women and men share similar diseases; however, women have unique issues, including gynecologic diseases and diseases related to menstruation, menopause, and post menopause. In recent decades, scientists paid more attention to natural products and their derivatives because of their good tolerability and effectiveness in disease prevention and treatment. Olive oil is an essential component in the Mediterranean diet, a diet well known for its protective impact on human well-being. Investigation of the active components in olive oil, such as oleuropein and hydroxytyrosol, showed positive effects in various diseases. Their effects have been clarified in many suggested mechanisms and have shown promising results in animal and human studies, especially in breast cancer, ovarian cancer, postmenopausal osteoporosis, and other disorders. This review summarizes the current evidence of the role of olives and olive polyphenols in women’s health issues and their potential implications in the treatment and prevention of health problems in women.

1. Introduction

Olea europaea, (Oleaceae) which is commonly known as olive tree, is one of the oldest species of trees in the Mediterranean region. Olive oil (OO) is extracted from olives—the fruits of the olive tree. The crucial role of OO was investigated in the 7th century BC. Some ancient scientists have recommended using OO in several diseases related to the stomach and skin [1]. While Mediterranean countries produce about 70% of the OO in the world, Australia and USA also produce significant amounts of OO. However, the variety and quality of OO differ among these countries [2].
One of the most prominent parts of the Mediterranean diet (MD) is OO consumption, which is the principal source of fats. Other components of the MD include frequent consumption of various vegetables and fruits, cereals, fish and seafood, moderate alcohol intake, and relatively low meat intake. Current data on MD suggest that OO and its components have shown preventive effects in cancer [3,4], cardiovascular diseases [3,4], diabetes [3,4], and other diseases [4,5]. Monounsaturated fatty acid (oleic acid) and polyphenol constituents (such as oleuropein, hydroxytyrosol, and tyrosol) were important components that explain the protective role of OO in these diseases [6,7,8]. Among the phenolic components of OO, oleuropein (OLP) is considered the most effective biomolecule [9,10].
Even though there is similarity in diseases among men and women, women have specific issues related to reproductive characteristics, including menstruation, menopause, and post menopause, with a large range of disorders that manifest during this period, as well as gynecological diseases. This review focusses on these women-specific conditions.
Disease prevention and potential treatment therapy research are critical requirements in medical science. In the recent decades, scientists have paid more attention to natural products and their derivatives in order to investigate their effects on disease prevention and treatment. OO and its active components are potential agents with promising research results. Almost all human clinical trials have evaluated the beneficial effects of OO in the context of MD. Therefore, the role of OO requires further investigation.
Therefore, herein, we collected current data from cellular, animal, and human studies regarding the role of MD and OO and its components in various aspects of women’s health. The studies that were used in this review included in vitro studies, in vivo studies, meta-analyses, randomized controlled trials, and clinical trials. Therefore, this review suggests possible future research directions in this area.

2. Structure and Bioactivity

2.1. OO Subtypes

As described by the International Olive Council (IOC), virgin olive oils are the oils obtained from the fruit of the olive tree (Olea europaea L.) solely by mechanical or other physical means under conditions, particularly thermal conditions, that do not lead to alterations in the oil, and which have not undergone any treatment other than washing, decantation, centrifugation, and filtration. In addition, sensorial and chemical properties determine the classification: Extra virgin olive oil (EVOO) is a virgin olive oil which has a free acidity, expressed as oleic acid, of not more than 0.8 g per 100 g, and the other characteristics of which correspond to those fixed for this category in the IOC standard. Virgin olive oil (VOO) which has a free acidity, expressed as oleic acid, of not more than 2 g per 100 g and the other characteristics of which correspond to those fixed for this category in the IOC standard. Refined olive oil is the olive oil obtained from virgin olive oils by refining methods that do not lead to alterations in the initial glycerides’ structure. It has a free acidity, expressed as oleic acid, of not more than 0.3 g per 100 g and its other characteristics correspond to those fixed for this category in the IOC standard. When we talk about Olive oil in general (OO) we considered that is the oil consisting of a blend of refined olive oil and virgin olive oils fit for consumption as they are. It has a free acidity, expressed as oleic acid, of not more than 1 g per 100 g and its other characteristics correspond to those fixed for this category in the IOC standard [11]. EVOO has the best organoleptic characteristics [4]. EVOO and OO had nearly the same fatty acid component but very different phenolic content [12]. EVOO contains the highest concentration of polyphenols [13]. EVOO has a flying flavor and light color due to fatty acid removal [14]. Many factors that influenced the quality of OO include pre-harvest factors (the cultivar, growing area, environmental condition, soil, tree age, treatment, irrigation, fruit ripening, harvest time, fruit picking) and post-harvest factors (fruit storage, leaves removing and washing, fruit crushing, paste malaxation, oil extraction systems, oil storage, cooking) [15]. OO constituents can be divided into the saponifiable fraction (98.5–99.5%) and the unsaponifiable fraction (0.5–1.5%) [4]. Triglycerides are the most important part of the saponifiable fraction. Unsaponifiable fraction contains hydrocarbons, chlorophylls, tocopherols, aliphatic alcohols, sterols, phenolic compounds, volatile compounds [4]. Oleic acid is the major monounsaturated fatty acid in OO, accounting for approximately 83% [16]. In EVOO, the mean concentration of total phenolic content was 483 mg·kg−1 measured by qNMR, although the phenolic content registered a large variation among the various cultivars [17]. Triacylglycerol content depends on the cultivar and the ripening stage [18]. Microclimatic, agronomic, oil’s extraction conditions, the cultivar, and the harvest date influenced the sterols [19], fatty alcohols [20,21], and waxes [22,23]. Phenolic and fatty acid composition is influenced by harvest date [24] and growth environment [25].
OO polyphenols include tyrosol (4-hydroxyphenylethanol), hydroxytyrosol (3,4-dihydroxyphenylethanol), oleuropein, caffeic acid, vanillic acid, syringic acid, p-coumaric acid, o-coumaric acid, protocatechuic acid, 4-hydroxybenzoic acid, 4-hydroxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid [26]. The chemical structure of representative phenols was illustrated in Figure 1. Oleocanthal [27], tyrosol, HT [28], and OLP [29] have a wide variety of beneficial health effects [30].

2.2. Bioactivities

OO extracts have shown protective effects against several diseases, such as hypertension, diabetes, sepsis, obesity, osteoporosis, neurodegeneration, and chronic kidney diseases [31,32,33]. OO consumption decreases the risk of all-cause mortality [34]. OO and its active derivatives showed antioxidant and anti-inflammatory effects [35]. Moreover, OO has antibacterial properties [36].
MD is associated with a risk reduction in the incidence and mortality of many types of cancers [37,38,39]. Trichopoulou et al. crudely calculated that in the group eating a traditional healthy MD diet, there was a 25% lower incidence of colorectal cancer, 15% lower incidence of breast cancer, and 10% lower incidence of prostate, pancreas, and endometrial cancer compared to the Western diet group [38]. MD can reduce the inflammatory process that contributes to cancer pathogenesis [40,41]. MD maintains the gut microbiota balance, which reduces inflammation in the intestinal mucosa, resulting in cancer reduction [42,43]. Polyphenols also show anti-cancer effects through various mechanisms related to apoptosis, proliferation, inflammation, angiogenesis, and cell cycle arrest [44]. HT showed a protective effect in the aging process via AMP-activated protein kinase (AMPK) and autophagy [33]. OO consumption decreased the risk of stomach cancer, ovarian cancer, colon cancer, endometrium cancer, particularly breast cancer. These beneficial findings have been reported in several meta-analysis studies [45,46,47]. OO, most likely oleic acid, regulates the HER2 gene associated with cancer [48]. Bioactivities of OO were characterized by a high level of monounsaturated fatty acid and antioxidant effects of polyphenols. Although various studies showed the protective effects of OO in the prevalence of several types of cancers. However, the mechanism by which the effects of OO reduce the risk of cancer remains poorly understood. So, it requires more studies that focus on the mechanism of how OO and its bioactive components impact the development of cancer, such as the regulation of the expression of the oncogenes.

3. Cancer in Women

Cancer remains a major cause of death in humans. In 2020, the cancer statistics calculated by Ferlay et al. included 19.3 million new cases and almost 10 million cancer-related deaths. Breast cancer is the most common cancer worldwide, with 2.26 million cases [49]. Cancer negatively affects various aspects of life, such as the economy and society as well as health and wellbeing. Although there have been therapeutic advances, including the development of targeted therapies, cancer patients still face short-term and long-term side effects from current therapies and medication resistance. More studies are required to investigate potential low-risk therapies for cancer prevention and treatment to improve the outcome and quality of life of cancer patients. Natural products have recently attracted attention for their anticancer role as potential adjunctive therapies due to their effects and because they are well tolerated. OO extracts and their bioactive components are some of the agents that have been investigated.

3.1. Ovarian Cancer

Ovarian cancer is one of the most common gynecologic cancers in both developed and developing countries, negatively affecting women’s health and fertility. Primary epithelial ovarian cancer is the most common type of ovarian cancer. Risk factors for ovarian cancer include increasing age, infertility, and endometriosis. Approximately 20% of ovarian cancer cases have familial factors. Ovarian malignancy is diagnosed at an average age of 63. Major therapies for ovarian cancer include surgery and chemotherapy. Ovarian cancer patients with advanced stage disease face a high risk of relapse and poor outcomes [50,51].
In 2021, Benot-Dominguez et al. reported that olive leaf extract (OLE) reduces the cell proliferation cell cycle and increases apoptosis via mitochondrial impairment, which leads to a decrease in tumor growth [52]. Shabani suggested that OLP induces apoptosis, inhibits cell proliferation, and decreases cisplatin resistance by regulating miRNA expression [53]. Although older radiation therapy is rarely used in ovarian cancer, the improved radiotherapy techniques showed potential effects in ovarian cancer treatment [54]. OLP increases the sensitivity to radiotherapy in ovarian cancer patients [55]. Polyomavirus enhancer activator 3 (PEA3) a transcription factor of ETS family [56], PEA3 contributed to the organs forming include kidney [57], mammary gland [58], and limb buds [59]. PEA3 inhibits tumor formation that depends on HER-2/neu [60,61]. Menendez et al. suggested a protective mechanism of oleic acid in cancer via inhibition of the HER-2/neu gene promoter, which depends on PEA3 [62]. Tzonou et al. showed that there was a statistically significant inverse association between mono-unsaturated fat (mostly OO) consumption and ovarian cancer in a case-control study in Greece [63]. Bosetti et al. reported similar results [39,64]. However, a review of meta-analyses of observational studies and randomized trials showed that the association between ovarian cancer and the MD remains elusive [32].

3.2. Breast Cancer

Breast cancer is the leading cause of cancer-related deaths in women. Genetic factors contribute to the risk of breast cancer [65]. Currently, breast cancer treatment therapies include surgery, radiation, endocrine therapy, neoadjuvant chemotherapy, and biological therapy. The five-year survival rate of breast cancer in women is approximately 90% in the United States [66]. The choice of treatment therapies depends on the types of breast cancer, including triple-negative breast cancer, HER2 (human epidermal growth factor receptor 2)-negative cancer, and hormone receptor (HR)-positive breast cancer, and HER1-positive diseases [67]. The application of adjuvant systemic therapy reduces mortality in breast cancer [68,69,70].
The anticancer role of OO extracts and their bioactive components in breast cancer has been evaluated in numerous in vitro, in vivo, and several clinical trials [71,72,73,74,75].
The OO extract contains several types of compounds. OLP has been shown to play the most important role in breast cancer cell toxicity [76,77]. In breast cancer, OLP inhibits cell proliferation, induces apoptosis, and induces cell cycle arrest [78,79,80,81,82]. Several mechanisms have been suggested, including miRNA dysregulation [79]. According to Bent-Dominguez, OLE, whose main compound is OLP, was found to increase reactive oxygen species (ROS) generation results in cell cycle delay, apoptosis, and mitochondria dysfunction [52]. Another study showed that phenolic extracts induced cell death and increased ROS production [80]. Hassan supported that OLP-induced apoptosis due to p53 pathway activation is regulated by the BAX and BCL2 genes [83]. Biosynthesized OLP aglycone (OLA) inhibited tamoxifen-resistant MCF-7 cell growth, whereas normal breast epithelial cells did not change. OLA also inhibits the cell cycle and induces apoptosis [84]. Messeha et al. showed that OLP altered the mRNA expression related to the apoptosis process of two kinds of triple-negative breast cancer cell lines, MDA-MB-468 and MDA-MB-231, and supported that OLP is more effective in MDA-MB-468 than in MDA-MB-231 [82]. The effect of OLP was higher in MDA-MB-231 cells than in MCF-7 cells. OLP reduces breast cancer cell growth by regulating the cell cycle by decreasing NF-κB and cyclin D1 expression and increasing p21 expression [85]. Epithelial-mesenchymal transition (EMT) is a fundamental step in the metastasis process [86,87]. In 2019, Choupani et al. showed that OLP inhibits EMT via downregulation of sirtuin1 leads to inhibition of breast cancer cells migration [88]. In addition, combination therapy with doxorubicin and OLP may be possible due to their synergistic effect on apoptosis of human breast cancer cells [88].
HT, the main phenolic compound of the olive oil, has also been shown to be effective in breast cancer. It inhibits cell growth and cell cycle arrest by reducing the expression of cyclinD1 by upregulating c-Jun and reducing pin-1 expression [89]. Moreover, OLP and HT decrease the migration and invasion of estrogen-positive breast cancer cell lines such as MCF7 [81,90] and T47D via autophagy activation [90] or histone deacetylase regulation [81,91]. Sirianni et al. showed that OLE and HT inhibit the ERK1/2 activation that is dependent on E2 [92].
Another bioactive phenolic compound from EVOO purification is S-(-) oleocanthal (OC). OC inhibited triple-negative breast cancer progression and metastasis to the lung in two heterogeneous triple-negative breast cancer animal models, and no considerable toxicity was observed. Additionally, using a microarray gene signature, this study showed that OC treatment protects almost all steps of cancer progression, including cell-to-cell adhesion signaling, interaction, invasion, and migration [93].
OO and its active components demonstrated effects in cancer formation, progression, metastasis, prognosis, and response to treatment therapy. MCF-7 breast cancer cell line proliferation requires the protein tyrosine phosphatase 1B (PTP1B) [94], an enzyme that plays a crucial anti-cancer role [95]. OLP reduces PTP1B activity, which is correlated with cell growth and cell cycle delay. This suggests that PTP1B phosphatase may be a target for OLP treatment in breast cancer [96]. HER-2 plays an important role in various aspects of cancer progression in breast cancer, including its etiology, progression, and response to therapies. Over-expression of HER2 leads to poor prognosis, decreased relapse time, and low survival [97,98,99]. This study showed that EVOO inhibits HER2 activity by increasing the proteasomal degradation of this protein [100]. Menendez et al. showed that EVOO polyphenols also inhibit fatty acid synthase (FASN) expression in HER-2-overexpression breast cancer [101]. FASN is strongly expressed in many human cancers and is positively correlated with poor prognosis and low survival; therefore, it is considered an oncoprotein [102]. This study also examined the role of EVOO, especially the role of OLP aglycone in the improvement of the effect and resistance of trastuzumab in vitro [77]. Therefore, OO may be synergistic with the current therapies. OLP also showed anti-metastatic effects by decreasing matrix metalloproteinase (MMP) expression and increasing the expression of tissue inhibitors of metalloproteinases [103]. HDCA plays an important role in cell proliferation and apoptosis [104,105]. OLP decreases HDCA expression, including HDAC2, HDAC3, and HDAC4 [81,91]. Plasminogen activator inhibitor-1 (PA-1) contributes to blood clotting, and increased PA-1 expression is associated with poor outcomes in breast cancer [106,107]. Tzekaki et al. supported OLP as a strong binder to PA-1. EVOO and OLP treatment inhibited PA-1 expression in ER-/PR- breast cancer cell lines. Moreover, this study showed that EVOO and OLP suppressed cell growth and caspase activation [108].
Cancer stem cells (CSC), characterized by self-renewal and differentiation, contribute to the pathogenesis of therapy resistance, tumor formation, and metastasis abilities [109,110,111]. Therefore, CSC are considered a target for investigating novel therapies. Corominas-Faja et al. showed EVOO-derived crude phenolic extract (EVOO-PE) inhibited CSC formation in the first step. Because of the most abundant compound in EVOO-PE, purified OLA and decarboxymethylated oleuropein aglycone (DOLA) were used for further experiments. They observed DOLA has greater inhibitory effects compared to OLA. DOLA significantly decreased the mammosphere-forming in four traditional breast cancer cell lines (DCIS.com, T47D, ZR-75-1, and SUM-159). For in vivo tumor formation ability, they used SM-159 cells pre-treated DOLA 20µg/L for 3 days with daily re-feeding and injected subcutaneously. DOLA reduced tumor formation compared to the control group. DOLA also suppressed the growth of tumors in the orthotopic implantation model. DOLA also regulated the gene expression related to stem cell fate. In silico computational studies determined DOLA as a dual mTOR/DNMT inhibitor [112].
In summary, underlying molecular mechanisms of OO function, especially OLP, it has been suggested that diverse signaling pathways related to apoptosis, cell growth, cell cycle, and ROS generation contribute to tumor growth and metastasis. In addition, it regulates many genes related to the prognosis and outcomes of breast cancer patients.
Regarding OO, MD, and its constituents in clinical trials, long-term MD+EVOO reduced breast cancer incidence in a study (n = 4152) performed from 2003 to 2009 [74]. In 1208 patients with early stage breast cancer, a MD combined with exercise decreased breast cancer recurrence [75]. Skouroliakou et al. evaluated the MD intervention in postmenopause breast cancer survivors for 6 months. There was a significant decrease in body weight, body fat mass, waist circumference, body mass index, and increase in the vitamin C, CoQ10 levels in the intervention group. In the comparison between the two groups at the end of the study, registered blood glucose concentration was significantly lower while the vitamin C, CoQ10 levels were considerably higher compared to the control group [113].
In 2018, in a clinical trial using HT in combination with omega-3 fatty acid and curcumin, Martinez et al. found reduced levels of C-reactive protein, a marker of inflammation and pain in early stage breast cancer patients treated with hormonal therapy [114].
OO intake can reduce breast cancer risk [45,46,47,115]. In 2021, a meta-analysis that assessed the OO consumption and breast cancer risk data from 10 observational studies (two prospective studies and 8 case-control studies) showed that OO intake may decrease breast cancer risk, the random effects summary OR for breast cancer was 0.48 (95% CI = 0.09–2.70) for prospective studies and 0.76 (95% CI = 0.54–1.06) in case-control studies, comparing women with the highest intake to those with the lowest intake category of olive oil. The relationship between breast cancer risk and dose-response olive oil was not significant; the OR (95% CI) for breast cancer in the dose-response meta-analysis with a 14 g/day increase in olive oil intake was 0.93 (0.83–1.04) [116].

3.3. Cervical Cancer

Cervical cancer is the fourth most common cancer in women and is one of the leading causes of death in developing countries [117]. In 2020, 604,000 new cases of cervical cancer and 342,000 deaths were reported worldwide [118]. Human papillomavirus (HPV) infection accounts for 99.7% of cervical cancers [119]. Treatment of cervical cancer includes surgery, chemotherapy, and radiation, which vary with disease stage.
Torics et al. (2020) assessed the effect of the phenolic compounds in EVOO on cervical cancer. They showed that EVOO phenolic extracts inhibit cell growth, although in combination with current cancer therapy such as irinotecan and 5-fluorouracil, the results were not statistical different [120]. OO polyphenols increased GSH levels, the most crucial intracellular antioxidant molecules measured by flow cytometry, but did not alter ROS levels. HT may have a higher antioxidant effect than tyrosol [121]. A cross-sectional study in Italy by Barchitta et al. suggested that MD might lower the risk of HPV infection and high-grade cervical intraepithelial neoplasia [122]. OLP increases apoptosis by upregulating the JNK/SPAK signaling pathway [123].
Another study showed that a high olive diet enhanced cervical cancer growth and metastasis in a mouse xenograft model. Oleic acid increases cell proliferation, migration, and invasion. Oleic acid induces CD36 via SRC/ERK activation, which contributes to cervical cancer formation and the progression of cervical cancer [124]. Zhang et al. reported that a high olive diet can enhance tumor growth in cervical cancer in vivo. Oleic acid increased the proliferation and migration of cervical cancer cells. This study also showed the different gene expression patterns altered by the olive oil diet and a set of hub genes for further investigation [125].

3.4. Endometrial Cancer

Endometrial cancer is one of the most common cancers in women. Estrogen is a major risk factor, obesity, low physical activity, and poor nutrition are also other risk factors for endometrial cancer. The major histopathological features of endometrial cancer originate from the epithelium. Its incidence peaks between the ages of 60 and 70 years. Treatment methods include surgery and adjuvant chemotherapy for high-risk endometrial cancer [126,127,128]. The study evaluating the role of OO and its extracts in endometrial cancer is not available.

3.5. Vaginal Cancer

The incidence of vaginal cancer is lower than that of ovarian and cervical cancers. Most vaginal tumors are squamous carcinomas, and other histologic types are less common. The majority of vaginal cancers are a result of metastasis from other organs such as the endometrium, cervix, vulva, ovary, breast, rectum, and kidney. The mean age of the patients tends to be around 60 years. Treatment therapy decisions depend on many factors, including the location, size, and clinical stage of the tumor, and these are also prognostic factors for vaginal cancer patients. Treatment therapies include surgery, radiation, and chemotherapy [66,126,129,130]. The evidence related to the association between OO, active phenolic constituents, and vaginal cancer is not available.

3.6. Vulvar Cancer

Primary vulvar cancer is a rare disease that is less common than vaginal cancer. The major histopathology is squamous cell carcinoma. Treatment therapy consists of surgery, radiation, and chemotherapy. HPV infection is a major type of vulvar cancer [131,132,133]. The effect or impact of MD or OO and its components in vulvar cancer is not available. A study assessed the risk of fat consumption in mice in relation to reproductive system tumor formation. They used four groups of fat, including corn oil, fish oil, OO, and lard. There were no significant differences among these groups [134].

4. Postmenopausal Disorders

Postmenopausal women suffer from several disorders due to the reduction in estrogen and other hormones, including emotional fluctuations, hot flashes, depression, anxiety, and vaginal dryness from perimenopause to post menopause [135]. The incidence of obesity, metabolic syndrome, cardiovascular diseases, and osteoporosis is associated with menopause [136]. In ovariectomized rats, EVOO reduced IL-6, malonyldialdehyde, and nitrate levels. Thus, OO has antioxidant and anti-inflammatory effects during menopause. This study also evaluated cancer markers, including carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), α-fetoprotein (AFP), and carbohydrate antigen 19-9 (CA19-9), in two groups of gynecologic cancer patients who had bilateral ovarian and bilateral fallopian excisions and were consuming either 0 or 50 mL of OO every morning. This study showed a significant decrease in the concentrations of CA125, CEA, and AFP in the OO consumption group [137]. OO in combination with vitamin D3, K1, and B6 also showed beneficial effects on platelet function and nitrosative stress prevention in healthy postmenopausal women [138]. Salvini et al. reported that high EVOO consumption, especially HT, prevented oxidative DNA damage in postmenopausal women [139]. Because of the limited number of patients, further studies are required.
Although the evidence is relatively limited, OO and its components have a positive impact on other aspects of women’s health, such as menstruation and sex. This study showed a similar effect of EVOO and ibuprofen in relieving the symptoms of primary dysmenorrhea, including pain scores and pain durations [140]. Sexual disorders are a common disorder in breast cancer survivors. Juraskova et al. showed that OO, during intercourse is one of the factors of OVERcome therapy, and like OO, vaginal exercise, and moisturizer, improved dyspareunia and sexual disorders in breast cancer patients [141].

5. Osteoporosis

Osteoporosis is a common chronic disease that affects most elderly persons, with women accounting for two-thirds of cases. The risk of osteoporosis increases dramatically in the postmenopausal period. Osteoporosis is a complication that leads to an increase in mortality in patients with osteoporosis [142]. Olive and olive polyphenols have been shown to increase bone mineral density and protect bone health [143]. Liu et al. reported that EVOO increased bone mineral density (BMD) in rats in an artificial menopause state due to ovariectomy [137]. Hagiwara et al. also reported the suppression of bone loss in ovariectomized mice when they used OLP and HT orally at 3-day intervals [144]. Puel et al. in several studies showed the effect of OO and its components in bone loss prevention in animal models [145,146,147,148]. Saleh et al. also showed similar results in osteoporosis models in rats [149]. Several studies have suggested that olive polyphenols protect bone health via oxidative stress reduction and anti-inflammatory effects. Olive polyphenols enhance the growth and differentiation of pre-osteoblasts and decrease osteoclast formation [143,144,150,151]. Gamma-linolenic acid originating from OO inhibits bone resorption and increases calcium levels in bone [152]. Filip et al. showed that polyphenol extract from OO increases osteocalcin concentration, a bone formation marker, and may help maintain lumbar BMD [153]. In contrast, Keiler et al. showed that using the total polyphenolic fraction of EVOO did not attenuate bone loss due to ovariectomy in rat models [154].

6. Cardiovascular Diseases and Type 2 Diabetes

OO positively impacts cardiovascular diseases. The available data demonstrated its protective role on vascular endothelial functions, lowering triglyceride levels, LDL-cholesterol reduction, pro-thrombotic reduction, and anti-atherogenic effects [155,156,157,158,159,160]. EVOO also improved dyslipidemia in postmenopausal women [161]. Jimenez-Morales showed that EVOO interacted with the NOS3 Glu298Asp polymorphism to reduce endothelial dysfunction in patients with metabolic syndrome [160]. The protective effect of OO was observed in a meta-analysis, and OO consumption can reduce the risk of coronary heart disease and stroke [162]. OO also has anti-inflammatory and antioxidant effects [163,164]. The beneficial effects of OO were observed in young women with mild hypertension. Additionally, OO enhanced endothelial function in this group [165]. Moreover, OO showed beneficial effects on anti-inflammatory markers related to cardiovascular diseases, such as C-reactive protein and interleukin-6 [166]. Lockyer et al. supported that OLE protects vascular function and that OLE also significantly decreases the concentration of the cytokine IL-8. This study used a digital volume pulse to measure vascular function in a randomized, double-blind, placebo-controlled, crossover, acute intervention trial in humans [167]. Filip et al. documented that polyphenol extract (Bonolive®) from olives decreased the total and LDL-cholesterol levels in postmenopausal women [153].
OO consumption also reduced the risk of type 2 diabetes in a meta-analysis study [168]. OLP also showed a potential effect in preventing hypoglycemia and oxidative stress-related complications in diabetic rabbits via a positive impact on enzymatic and non-enzymatic antioxidants [164].

7. Conclusions and Future Directions

The collected evidence showed the beneficial effects of OO on women’s health, especially in breast cancer, ovarian cancer, postmenopausal osteoporosis, cardiovascular disease, type 2 diabetes, and other disorders, along with the potential action mechanisms. Two groups of OO constituents were investigated: monounsaturated fatty acids (oleic acid) and the phenolic components. However, the bioactivities of the two groups might have contrasting effects, for instance, in cervical cancer. Almost all human studies have evaluated the effect of OO in the context of MD, so interpreting these studies might be challenging. However, evidence for gynecologic malignancy is limited, and the results remain inconsistent. Therefore, further studies are required to clarify the role of OO in this disease group, especially the active components, and to investigate the underlying mechanisms. The roles of OO in various aspects of women’s health are summarized in Table 1.

Author Contributions

T.T.G.L. conceptualized the review, performed literature survey, wrote the manuscript, and made the figure, table. S.-M.K. and J.-S.C. edited and supervised. J.Y. and D.-H.L. edited. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Research Foundation of Korea (grant nos. 2021R1I1A3055686, NRF-2020R1A2C2101297, and NRF-2015R1A5A2009656) and the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (grant nos. HI18C2459 and HI18C2458).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

PEA3Polyomavirus enhancer activator 3
DNMTDNA methyltransferase
EVOO-PEEVOO-derived crude phenolic extract
CSCcancer stem cell
DOLAdecarboxymethyl oleuropein aglycone
EMTEpithelial-mesenchymal transition
IOCInternational Olive Council
EVOOextra virgin olive oil
OLEolive leaf extract
OLPoleuropein
OCS-(-)-Oleocanthal
PA-1plasminogen activator inhibitor-1
MTMediterranean
MDMediterranean diet
HThydroxytyrosol
OOolive oil
ROSreactive oxygen species
HDCAhistone deacetylase
MMPmatrix metalloproteinase
PTP1Bprotein tyrosine phosphatase 1B
FASNfatty acid synthetase
HPVhuman papillomavirus
BMDbone mineral density

References

  1. Nomikos, N.N.; Nomikos, G.N.; Kores, D.S. The use of deep friction massage with olive oil as a means of prevention and treatment of sports injuries in ancient times. Arch. Med. Sci. AMS 2010, 6, 642. [Google Scholar] [CrossRef]
  2. Vossen, P. Olive oil: History, production, and characteristics of the world’s classic oils. HortScience 2007, 42, 1093–1100. [Google Scholar] [CrossRef] [Green Version]
  3. Foscolou, A.; Critselis, E.; Panagiotakos, D. Olive oil consumption and human health: A narrative review. Maturitas 2018, 118, 60–66. [Google Scholar] [CrossRef]
  4. La Lastra, C.; Barranco, M.; Motilva, V.; Herrerias, J. Mediterrranean diet and health biological importance of olive oil. Curr. Pharm. Des. 2001, 7, 933–950. [Google Scholar] [CrossRef] [Green Version]
  5. Abenavoli, L.; Milanović, M.; Milić, N.; Luzza, F.; Giuffrè, A.M. Olive oil antioxidants and non-alcoholic fatty liver disease. Expert Rev. Gastroenterol. Hepatol. 2019, 13, 739–749. [Google Scholar] [CrossRef] [PubMed]
  6. Owen, R.; Haubner, R.; Würtele, G.; Hull, W.; Spiegelhalder, B.; Bartsch, H. Olives and olive oil in cancer prevention. Eur. J. Cancer Prev. 2004, 13, 319–326. [Google Scholar] [CrossRef]
  7. Nocella, C.; Cammisotto, V.; Fianchini, L.; D’Amico, A.; Novo, M.; Castellani, V.; Stefanini, L.; Violi, F.; Carnevale, R. Extra virgin olive oil and cardiovascular diseases: Benefits for human health. Endocr. Metab. Immune Disord.-Drug Targets (Former. Curr. Drug Targets-Immune Endocr. Metab. Disord.) 2018, 18, 4–13. [Google Scholar] [CrossRef] [PubMed]
  8. Ditano-Vázquez, P.; Torres-Peña, J.D.; Galeano-Valle, F.; Pérez-Caballero, A.I.; Demelo-Rodríguez, P.; Lopez-Miranda, J.; Katsiki, N.; Delgado-Lista, J.; Alvarez-Sala-Walther, L.A. The fluid aspect of the Mediterranean diet in the prevention and management of cardiovascular disease and diabetes: The role of polyphenol content in moderate consumption of wine and olive oil. Nutrients 2019, 11, 2833. [Google Scholar] [CrossRef] [Green Version]
  9. Hashim, Y.Z.; Eng, M.; Gill, C.I.; McGlynn, H.; Rowland, I.R. Components of olive oil and chemoprevention of colorectal cancer. Nutr. Rev. 2005, 63, 374–386. [Google Scholar] [CrossRef]
  10. Owen, R.W.; Giacosa, A.; Hull, W.E.; Haubner, R.; Würtele, G.; Spiegelhalder, B.; Bartsch, H. Olive-oil consumption and health: The possible role of antioxidants. Lancet Oncol. 2000, 1, 107–112. [Google Scholar] [CrossRef]
  11. International Olive Council Regulation. In Trade Standard Applying to Olive Oils and Olive Pomace Oils; COI/T.15/NC No 3/Rev. 12 June 2018; International Olive Council: Madrid, Spain, 2018.
  12. Montedoro, G.; Servili, M.; Baldioli, M.; Miniati, E. Simple and hydrolyzable phenolic compounds in virgin olive oil. 1. Their extraction, separation, and quantitative and semiquantitative evaluation by HPLC. J. Agric. Food Chem. 1992, 40, 1571–1576. [Google Scholar] [CrossRef]
  13. Kalogeropoulos, N.; Tsimidou, M.Z. Antioxidants in Greek virgin olive oils. Antioxidants 2014, 3, 387–413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Fernández, A.G.; Adams, M.R.; Fernández-Díez, M. Table Olives: Production and Processing; Springer Science & Business Media: Berlin/Heidelberg, Germany, 1997. [Google Scholar]
  15. Mele, M.A.; Islam, M.Z.; Kang, H.-M.; Giuffrè, A.M. Pre-and post-harvest factors and their impact on oil composition and quality of olive fruit. Emir. J. Food Agric. 2018, 30, 592–603. [Google Scholar]
  16. Ramirez-Tortosa, M.C.; Granados, S.; Quiles, J.L. Chemical Composition, Types and Characteristics of Olive Oil; CABI Publishing: Oxford, UK, 2006. [Google Scholar]
  17. Diamantakos, P.; Ioannidis, K.; Papanikolaou, C.; Tsolakou, A.; Rigakou, A.; Melliou, E.; Magiatis, P. A New Definition of the Term “High-Phenolic Olive Oil” Based on Large Scale Statistical Data of Greek Olive Oils Analyzed by qNMR. Molecules 2021, 26, 1115. [Google Scholar] [CrossRef]
  18. Giuffrè, A. Variation in triacylglycerols of olive oils produced in Calabria (Southern Italy) during olive ripening. Riv. Ital. Sostanze Grasse 2014, 91, 221–240. [Google Scholar]
  19. Giuffrè, A.M.; LouAdj, L. Influence of crop season and cultivar on sterol composition of monovarietal olive oils in Reggio Calabria (Italy). Czech J. Food Sci. 2013, 31, 256–263. [Google Scholar] [CrossRef] [Green Version]
  20. Giuffrè, A. The effects of cultivar and harvest year on the fatty alcohol composition of olive oils from Southwest Calabria (Italy). Grasas Aceites 2014, 65, e011. [Google Scholar] [CrossRef] [Green Version]
  21. Giuffrè, A.M. Evolution of fatty alcohols in olive oils produced in Calabria (Southern Italy) during fruit ripening. J. Oleo Sci. 2014, 63, 485–496. [Google Scholar] [CrossRef] [Green Version]
  22. Giuffrè, A.M. Influence of harvest year and cultivar on wax composition of olive oils. Eur. J. Lipid Sci. Technol. 2013, 115, 549–555. [Google Scholar] [CrossRef]
  23. Giuffrè, A. Wax ester variation in olive oils produced in Calabria (Southern Italy) during olive ripening. J. Am. Oil Chem. Soc. 2014, 91, 1355–1366. [Google Scholar] [CrossRef]
  24. Giuffrè, A.; Piscopo, A.; Sicari, V.; Poiana, M. The effects of harvesting on phenolic compounds and fatty acids content in virgin olive oil (cv Roggianella). Riv. Ital. Sostanze Grasse 2010, 87, 14–23. [Google Scholar]
  25. Di Vaio, C.; Nocerino, S.; Paduano, A.; Sacchi, R. Influence of some environmental factors on drupe maturation and olive oil composition. J. Sci. Food Agric. 2013, 93, 1134–1139. [Google Scholar] [CrossRef]
  26. El Riachy, M.; Priego-Capote, F.; León, L.; Rallo, L.; Luque de Castro, M.D. Hydrophilic antioxidants of virgin olive oil. Part 1: Hydrophilic phenols: A key factor for virgin olive oil quality. Eur. J. Lipid Sci. Technol. 2011, 113, 678–691. [Google Scholar] [CrossRef]
  27. Parkinson, L.; Keast, R. Oleocanthal, a phenolic derived from virgin olive oil: A review of the beneficial effects on inflammatory disease. Int. J. Mol. Sci. 2014, 15, 12323–12334. [Google Scholar] [CrossRef] [Green Version]
  28. Hu, T.; He, X.-W.; Jiang, J.-G.; Xu, X.-L. Hydroxytyrosol and its potential therapeutic effects. J. Agric. Food Chem. 2014, 62, 1449–1455. [Google Scholar] [CrossRef] [PubMed]
  29. Barbaro, B.; Toietta, G.; Maggio, R.; Arciello, M.; Tarocchi, M.; Galli, A.; Balsano, C. Effects of the olive-derived polyphenol oleuropein on human health. Int. J. Mol. Sci. 2014, 15, 18508–18524. [Google Scholar] [CrossRef]
  30. Khalatbary, A.R. Olive oil phenols and neuroprotection. Nutr. Neurosci. 2013, 16, 243–249. [Google Scholar] [CrossRef]
  31. Sofi, F.; Cesari, F.; Abbate, R.; Gensini, G.F.; Casini, A. Adherence to Mediterranean diet and health status: Meta-analysis. BMJ 2008, 337, a1344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Dinu, M.; Pagliai, G.; Casini, A.; Sofi, F. Mediterranean diet and multiple health outcomes: An umbrella review of meta-analyses of observational studies and randomised trials. Eur. J. Clin. Nutr. 2018, 72, 30–43. [Google Scholar] [CrossRef]
  33. de Pablos, R.M.; Espinosa-Oliva, A.M.; Hornedo-Ortega, R.; Cano, M.; Arguelles, S. Hydroxytyrosol protects from aging process via AMPK and autophagy; a review of its effects on cancer, metabolic syndrome, osteoporosis, immune-mediated and neurodegenerative diseases. Pharmacol. Res. 2019, 143, 58–72. [Google Scholar] [CrossRef] [PubMed]
  34. George, E.S.; Marshall, S.; Mayr, H.L.; Trakman, G.L.; Tatucu-Babet, O.A.; Lassemillante, A.-C.M.; Bramley, A.; Reddy, A.J.; Forsyth, A.; Tierney, A.C. The effect of high-polyphenol extra virgin olive oil on cardiovascular risk factors: A systematic review and meta-analysis. Crit. Rev. Food Sci. Nutr. 2019, 59, 2772–2795. [Google Scholar] [CrossRef]
  35. Servili, M.; Esposto, S.; Fabiani, R.; Urbani, S.; Taticchi, A.; Mariucci, F.; Selvaggini, R.; Montedoro, G. Phenolic compounds in olive oil: Antioxidant, health and organoleptic activities according to their chemical structure. Inflammopharmacology 2009, 17, 76–84. [Google Scholar] [CrossRef]
  36. Nazzaro, F.; Fratianni, F.; Cozzolino, R.; Martignetti, A.; Malorni, L.; De Feo, V.; Cruz, A.G.; d’Acierno, A. Antibacterial activity of three extra virgin olive oils of the Campania region, Southern Italy, related to their polyphenol content and composition. Microorganisms 2019, 7, 321. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Schwingshackl, L.; Hoffmann, G. Adherence to Mediterranean diet and risk of cancer: An updated systematic review and meta-analysis of observational studies. Cancer Med. 2015, 4, 1933–1947. [Google Scholar] [CrossRef] [PubMed]
  38. Trichopoulou, A.; Lagiou, P.; Kuper, H.; Trichopoulos, D. Cancer and Mediterranean dietary traditions. Cancer Epidemiol. Prev. Biomark. 2000, 9, 869–873. [Google Scholar]
  39. Bosetti, C.; Pelucchi, C.; La Vecchia, C. Diet and cancer in Mediterranean countries: Carbohydrates and fats. Public Health Nutr. 2009, 12, 1595–1600. [Google Scholar] [CrossRef]
  40. Mantovani, A.; Allavena, P.; Sica, A.; Balkwill, F. Cancer-related inflammation. Nature 2008, 454, 436–444. [Google Scholar] [CrossRef]
  41. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [Green Version]
  42. Ostan, R.; Lanzarini, C.; Pini, E.; Scurti, M.; Vianello, D.; Bertarelli, C.; Fabbri, C.; Izzi, M.; Palmas, G.; Biondi, F. Inflammaging and cancer: A challenge for the Mediterranean diet. Nutrients 2015, 7, 2589–2621. [Google Scholar] [CrossRef] [Green Version]
  43. Bifulco, M. Mediterranean diet: The missing link between gut microbiota and inflammatory diseases. Eur. J. Clin. Nutr. 2015, 69, 1078. [Google Scholar] [CrossRef] [Green Version]
  44. Gorzynik-Debicka, M.; Przychodzen, P.; Cappello, F.; Kuban-Jankowska, A.; Marino Gammazza, A.; Knap, N.; Wozniak, M.; Gorska-Ponikowska, M. Potential health benefits of olive oil and plant polyphenols. Int. J. Mol. Sci. 2018, 19, 686. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Psaltopoulou, T.; Kosti, R.I.; Haidopoulos, D.; Dimopoulos, M.; Panagiotakos, D.B. Olive oil intake is inversely related to cancer prevalence: A systematic review and a meta-analysis of 13,800 patients and 23,340 controls in 19 observational studies. Lipids Health Dis. 2011, 10, 1–16. [Google Scholar] [CrossRef] [Green Version]
  46. Pelucchi, C.; Bosetti, C.; Negri, E.; Lipworth, L.; La Vecchia, C. Olive oil and cancer risk: An update of epidemiological findings through 2010. Curr. Pharm. Des. 2011, 17, 805–812. [Google Scholar] [CrossRef]
  47. Xin, Y.; Li, X.-Y.; Sun, S.-R.; Wang, L.-X.; Huang, T. Vegetable oil intake and breast cancer risk: A meta-analysis. Asian Pac. J. Cancer Prev. 2015, 16, 5125–5135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Colomer, R.; Menéndez, J.A. Mediterranean diet, olive oil and cancer. Clin. Transl. Oncol. 2006, 8, 15–21. [Google Scholar] [CrossRef]
  49. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer statistics for the year 2020: An overview. Int. J. Cancer 2021. [Google Scholar] [CrossRef] [PubMed]
  50. Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin. 2015, 65, 87–108. [Google Scholar] [CrossRef] [Green Version]
  51. Stenzel, A.E.; Buas, M.F.; Moysich, K.B. Survival disparities among racial/ethnic groups of women with ovarian cancer: An update on data from the Surveillance, Epidemiology and End Results (SEER) registry. Cancer Epidemiol. 2019, 62, 101580. [Google Scholar] [CrossRef] [PubMed]
  52. Benot-Dominguez, R.; Tupone, M.G.; Castelli, V.; d’Angelo, M.; Benedetti, E.; Quintiliani, M.; Cinque, B.; Forte, I.M.; Cifone, M.G.; Ippoliti, R. Olive leaf extract impairs mitochondria by pro-oxidant activity in MDA-MB-231 and OVCAR-3 cancer cells. Biomed. Pharmacother. 2021, 134, 111139. [Google Scholar] [CrossRef]
  53. Shabani, S.H.S.; Amini-Farsani, Z.; Rahmati, S.; Jazaieri, A.; Mohammadi-Samani, M.; Asgharzade, S. Oleuropein reduces cisplatin resistance in ovarian cancer by targeting apoptotic pathway regulators. Life Sci. 2021, 278, 119525. [Google Scholar]
  54. Fields, E.C.; McGuire, W.P.; Lin, L.; Temkin, S.M. Radiation treatment in women with ovarian cancer: Past, present, and future. Front. Oncol. 2017, 7, 177. [Google Scholar] [CrossRef] [Green Version]
  55. Xing, Y.; Cui, D.; Wang, S.; Wang, P.; Xing, X.; Li, H. Oleuropein represses the radiation resistance of ovarian cancer by inhibiting hypoxia and microRNA-299-targetted heparanase expression. Food Funct. 2017, 8, 2857–2864. [Google Scholar] [CrossRef]
  56. Shindoh, M.; Higashino, F.; Kohgo, T. E1AF, an ets-oncogene family transcription factor. Cancer Lett. 2004, 216, 1–8. [Google Scholar] [CrossRef] [PubMed]
  57. Chotteau-Lelièvre, A.; Desbiens, X.; Pelczar, H.; Defossez, P.-A.; de Launoit, Y. Differential expression patterns of the PEA3 group transcription factors through murine embryonic development. Oncogene 1997, 15, 937–952. [Google Scholar] [CrossRef] [Green Version]
  58. Chotteau-Lelievre, A.; Montesano, R.; Soriano, J.; Soulie, P.; Desbiens, X.; De Launoit, Y. PEA3 transcription factors are expressed in tissues undergoing branching morphogenesis and promote formation of duct-like structures by mammary epithelial cells in vitro. Dev. Biol. 2003, 259, 241–257. [Google Scholar] [CrossRef]
  59. Zhang, Z.; Verheyden, J.M.; Hassell, J.A.; Sun, X. FGF-regulated Etv genes are essential for repressing Shh expression in mouse limb buds. Dev. Cell 2009, 16, 607–613. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Xing, X.; Wang, S.-C.; Xia, W.; Zou, Y.; Shao, R.; Kwong, K.Y.; Yu, Z.; Zhang, S.; Miller, S.; Huang, L. The ets protein PEA3 suppresses HER-2/neu overexpression and inhibits tumorigenesis. Nat. Med. 2000, 6, 189–195. [Google Scholar] [CrossRef] [PubMed]
  61. Wang, S.-C.; Hung, M.-C. Transcriptional targeting of the HER-2/neu oncogene. Drugs Today (Barc.) 2000, 36, 835–843. [Google Scholar]
  62. Menendez, J.A.; Papadimitropoulou, A.; Vellon, L.; Lupu, R. A genomic explanation connecting “Mediterranean diet”, olive oil and cancer: Oleic acid, the main monounsaturated fatty acid of olive oil, induces formation of inhibitory “PEA3 transcription factor-PEA3 DNA binding site” complexes at the Her-2/neu (erbB-2) oncogene promoter in breast, ovarian and stomach cancer cells. Eur. J. Cancer 2006, 42, 2425–2432. [Google Scholar] [PubMed]
  63. Tzonou, A.; Hsieh, C.C.; Polychronopoulou, A.; Trichopoulos, D.; Kaprinis, G.; Toupadaki, N.; Karakatsani, A.; Trichopoulou, A. Diet and ovarian cancer: A case-control study in Greece. Int. J. Cancer 1993, 55, 411–414. [Google Scholar] [CrossRef]
  64. Bosetti, C.; Negri, E.; Franceschi, S.; Talamini, R.; Montella, M.; Conti, E.; Lagiou, P.; Parazzini, F.; La Vecchia, C. Olive oil, seed oils and other added fats in relation to ovarian cancer (Italy). Cancer Causes Control 2002, 13, 465–470. [Google Scholar] [CrossRef] [PubMed]
  65. Hu, C.; Hart, S.N.; Gnanaolivu, R.; Huang, H.; Lee, K.Y.; Na, J.; Gao, C.; Lilyquist, J.; Yadav, S.; Boddicker, N.J. A population-based study of genes previously implicated in breast cancer. N. Engl. J. Med. 2021, 384, 440–451. [Google Scholar] [CrossRef] [PubMed]
  66. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin. 2021, 71, 7–33. [Google Scholar] [CrossRef] [PubMed]
  67. Korde, L.A.; Somerfield, M.R.; Carey, L.A.; Crews, J.R.; Denduluri, N.; Hwang, E.S.; Khan, S.A.; Loibl, S.; Morris, E.A.; Perez, A. Neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer: ASCO guideline. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2021, 39, 1485–1505. [Google Scholar] [CrossRef] [PubMed]
  68. Early Breast Cancer Trialists’ Collaborative Group; Peto, R.; Davies, C.; Godwin, J.; Gray, R.; Pan, H.C.; Clarke, M.; Cutter, D.; Darby, S.; McGale, P.; et al. Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012, 379, 432–444. [Google Scholar] [PubMed] [Green Version]
  69. Early Breast Cancer Trialists’ Collaborative Group; Darby, S.; McGale, P.; Correa, C.; Taylor, C.; Arriagada, R.; Clarke, M.; Cutter, D.; Davies, C.; Ewertz, M.; et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet 2011, 378, 1707–1716. [Google Scholar]
  70. Forouzanfar, M.H.; Foreman, K.J.; Delossantos, A.M.; Lozano, R.; Lopez, A.D.; Murray, C.J.; Naghavi, M. Breast and cervical cancer in 187 countries between 1980 and 2010: A systematic analysis. Lancet 2011, 378, 1461–1484. [Google Scholar] [CrossRef]
  71. Escrich, E.; Moral, R.; Solanas, M. Olive oil, an essential component of the Mediterranean diet, and breast cancer. Public Health Nutr. 2011, 14, 2323–2332. [Google Scholar] [CrossRef] [Green Version]
  72. Escrich, E.; Solanas, M.; Moral, R.; Escrich, R. Modulatory effects and molecular mechanisms of olive oil and other dietary lipids in breast cancer. Curr. Pharm. Des. 2011, 17, 813–830. [Google Scholar] [CrossRef] [PubMed]
  73. Casaburi, I.; Puoci, F.; Chimento, A.; Sirianni, R.; Ruggiero, C.; Avena, P.; Pezzi, V. Potential of olive oil phenols as chemopreventive and therapeutic agents against cancer: A review of in vitro studies. Mol. Nutr. Food Res. 2013, 57, 71–83. [Google Scholar] [CrossRef]
  74. Toledo, E.; Salas-Salvadó, J.; Donat-Vargas, C.; Buil-Cosiales, P.; Estruch, R.; Ros, E.; Corella, D.; Fitó, M.; Hu, F.B.; Arós, F. Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED trial: A randomized clinical trial. JAMA Int. Med. 2015, 175, 1752–1760. [Google Scholar] [CrossRef] [PubMed]
  75. Villarini, A.; Pasanisi, P.; Traina, A.; Mano, M.P.; Bonanni, B.; Panico, S.; Scipioni, C.; Galasso, R.; Paduos, A.; Simeoni, M. Lifestyle and breast cancer recurrences: The DIANA-5 trial. Tumori J. 2012, 98, 1–18. [Google Scholar] [CrossRef]
  76. Quirantes-Piné, R.; Zurek, G.; Barrajón-Catalán, E.; Bäßmann, C.; Micol, V.; Segura-Carretero, A.; Fernández-Gutiérrez, A. A metabolite-profiling approach to assess the uptake and metabolism of phenolic compounds from olive leaves in SKBR3 cells by HPLC–ESI-QTOF-MS. J. Pharm. Biomed. Anal. 2013, 72, 121–126. [Google Scholar] [CrossRef]
  77. Menendez, J.A.; Vazquez-Martin, A.; Colomer, R.; Brunet, J.; Carrasco-Pancorbo, A.; Garcia-Villalba, R.; Fernandez-Gutierrez, A.; Segura-Carretero, A. Olive oil’s bitter principle reverses acquired autoresistance to trastuzumab (Herceptin™) in HER2-overexpressing breast cancer cells. BMC Cancer 2007, 7, 80. [Google Scholar] [CrossRef] [Green Version]
  78. Han, J.; Talorete, T.P.; Yamada, P.; Isoda, H. Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells. Cytotechnology 2009, 59, 45–53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Asgharzade, S.; Sheikhshabani, S.H.; Ghasempour, E.; Heidari, R.; Rahmati, S.; Mohammadi, M.; Jazaeri, A.; Amini-Farsani, Z. The effect of oleuropein on apoptotic pathway regulators in breast cancer cells. Eur. J. Pharmacol. 2020, 886, 173509. [Google Scholar] [CrossRef]
  80. Reboredo-Rodríguez, P.; González-Barreiro, C.; Cancho-Grande, B.; Forbes-Hernández, T.Y.; Gasparrini, M.; Afrin, S.; Cianciosi, D.; Carrasco-Pancorbo, A.; Simal-Gándara, J.; Giampieri, F. Characterization of phenolic extracts from Brava extra virgin olive oils and their cytotoxic effects on MCF-7 breast cancer cells. Food Chem. Toxicol. 2018, 119, 73–85. [Google Scholar] [CrossRef]
  81. Bayat, S.; Mansoori Derakhshan, S.; Mansoori Derakhshan, N.; Shekari Khaniani, M.; Alivand, M.R. Downregulation of HDAC2 and HDAC3 via oleuropein as a potent prevention and therapeutic agent in MCF-7 breast cancer cells. J. Cell. Biochem. 2019, 120, 9172–9180. [Google Scholar] [CrossRef] [PubMed]
  82. Messeha, S.S.; Zarmouh, N.O.; Asiri, A.; Soliman, K.F. Gene Expression Alterations Associated with Oleuropein-Induced Antiproliferative Effects and S-Phase Cell Cycle Arrest in Triple-Negative Breast Cancer Cells. Nutrients 2020, 12, 3755. [Google Scholar] [CrossRef]
  83. Hassan, Z.K.; Elamin, M.H.; Omer, S.A.; Daghestani, M.H.; Al-Olayan, E.S.; Elobeid, M.A.; Virk, P. Oleuropein induces apoptosis via the p53 pathway in breast cancer cells. Asian Pac. J. Cancer Prev. 2013, 14, 6739–6742. [Google Scholar] [CrossRef] [Green Version]
  84. Mazzei, R.; Piacentini, E.; Nardi, M.; Poerio, T.; Bazzarelli, F.; Procopio, A.; Di Gioia, M.L.; Rizza, P.; Ceraldi, R.; Morelli, C. Production of plant-derived oleuropein aglycone by a combined membrane process and evaluation of its breast anticancer properties. Front. Bioeng. Biotechnol. 2020, 8, 908. [Google Scholar] [CrossRef]
  85. Elamin, M.H.; Daghestani, M.H.; Omer, S.A.; Elobeid, M.A.; Virk, P.; Al-Olayan, E.M.; Hassan, Z.K.; Mohammed, O.B.; Aboussekhra, A. Olive oil oleuropein has anti-breast cancer properties with higher efficiency on ER-negative cells. Food Chem. Toxicol. 2013, 53, 310–316. [Google Scholar] [CrossRef] [PubMed]
  86. Akalay, I.; Janji, B.; Hasmim, M.; Noman, M.Z.; Thiery, J.P.; Mami-Chouaib, F.; Chouaib, S. EMT impairs breast carcinoma cell susceptibility to CTL-mediated lysis through autophagy induction. Autophagy 2013, 9, 1104–1106. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Chua, K.-N.; Sim, W.-J.; Racine, V.; Lee, S.-Y.; Goh, B.C.; Thiery, J.P. A cell-based small molecule screening method for identifying inhibitors of epithelial-mesenchymal transition in carcinoma. PLoS ONE 2012, 7, e33183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Choupani, J.; Alivand, M.R.; Derakhshan, S.M.; Zaeifizadeh, M.; Khaniani, M.S. Oleuropein inhibits migration ability through suppression of epithelial-mesenchymal transition and synergistically enhances doxorubicin-mediated apoptosis in MCF-7 cells. J. Cell. Physiol. 2019, 234, 9093–9104. [Google Scholar] [CrossRef] [PubMed]
  89. Bouallagui, Z.; Han, J.; Isoda, H.; Sayadi, S. Hydroxytyrosol rich extract from olive leaves modulates cell cycle progression in MCF-7 human breast cancer cells. Food Chem. Toxicol. 2011, 49, 179–184. [Google Scholar] [CrossRef]
  90. Lu, H.-Y.; Zhu, J.-S.; Xie, J.; Zhang, Z.; Zhu, J.; Jiang, S.; Shen, W.-J.; Wu, B.; Ding, T.; Wang, S.-L. Hydroxytyrosol and oleuropein inhibit migration and invasion via induction of autophagy in ER-positive breast cancer cell lines (MCF7 and T47D). Nutr. Cancer 2021, 73, 350–360. [Google Scholar] [CrossRef]
  91. Mansouri, N.; Alivand, M.R.; Bayat, S.; Khaniani, M.S.; Derakhshan, S.M. The hopeful anticancer role of oleuropein in breast cancer through histone deacetylase modulation. J. Cell. Biochem. 2019, 120, 17042–17049. [Google Scholar] [CrossRef]
  92. Sirianni, R.; Chimento, A.; De Luca, A.; Casaburi, I.; Rizza, P.; Onofrio, A.; Iacopetta, D.; Puoci, F.; Andò, S.; Maggiolini, M. Oleuropein and hydroxytyrosol inhibit MCF-7 breast cancer cell proliferation interfering with ERK1/2 activation. Mol. Nutr. Food Res. 2010, 54, 833–840. [Google Scholar] [CrossRef]
  93. Qusa, M.H.; Abdelwahed, K.S.; Siddique, A.B.; El Sayed, K.A. Comparative Gene Signature of (−)-Oleocanthal Formulation Treatments in Heterogeneous Triple Negative Breast Tumor Models: Oncological Therapeutic Target Insights. Nutrients 2021, 13, 1706. [Google Scholar] [CrossRef]
  94. Liao, S.-C.; Li, J.-X.; Yu, L.; Sun, S.-R. Protein tyrosine phosphatase 1B expression contributes to the development of breast cancer. J. Zhejiang Univ. -Sci. B 2017, 18, 334–342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  95. Liu, X.; Chen, Q.; Hu, X.-G.; Zhang, X.-C.; Fu, T.-W.; Liu, Q.; Liang, Y.; Zhao, X.-L.; Zhang, X.; Ping, Y.-F. PTP1B promotes aggressiveness of breast cancer cells by regulating PTEN but not EMT. Tumor Biol. 2016, 37, 13479–13487. [Google Scholar] [CrossRef] [PubMed]
  96. Przychodzen, P.; Kuban-Jankowska, A.; Wyszkowska, R.; Barone, G.; Bosco, G.L.; Celso, F.L.; Kamm, A.; Daca, A.; Kostrzewa, T.; Gorska-Ponikowska, M. PTP1B phosphatase as a novel target of oleuropein activity in MCF-7 breast cancer model. Toxicol. Vitr. 2019, 61, 104624. [Google Scholar] [CrossRef] [PubMed]
  97. Harari, D.; Yarden, Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene 2000, 19, 6102–6114. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Yarden, Y. Biology of HER2 and its importance in breast cancer. Oncology 2001, 61, 1–13. [Google Scholar] [CrossRef] [PubMed]
  99. Nahta, R.; Yu, D.; Hung, M.-C.; Hortobagyi, G.N.; Esteva, F.J. Mechanisms of disease: Understanding resistance to HER2-targeted therapy in human breast cancer. Nat. Clin. Pract. Oncol. 2006, 3, 269–280. [Google Scholar] [CrossRef]
  100. Menendez, J.A.; Vazquez-Martin, A.; Garcia-Villalba, R.; Carrasco-Pancorbo, A.; Oliveras-Ferraros, C.; Fernandez-Gutierrez, A.; Segura-Carretero, A. tabAnti-HER2 (erb B-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO). BMC Cancer 2008, 8, 377. [Google Scholar] [CrossRef] [Green Version]
  101. Menendez, J.A.; Vazquez-Martin, A.; Oliveras-Ferraros, C.; Garcia-Villalba, R.; Carrasco-Pancorbo, A.; Fernandez-Gutierrez, A.; Segura-Carretero, A. Analyzing effects of extra-virgin olive oil polyphenols on breast cancer-associated fatty acid synthase protein expression using reverse-phase protein microarrays. Int. J. Mol. Med. 2008, 22, 433–439. [Google Scholar] [CrossRef] [Green Version]
  102. Menendez, J.A.; Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer 2007, 7, 763–777. [Google Scholar] [CrossRef]
  103. Hassan, Z.K.; Elamin, M.H.; Daghestani, M.H.; Omer, S.A.; Al-Olayan, E.M.; Elobeid, M.A.; Virk, P.; Mohammed, O.B. Oleuropein induces anti-metastatic effects in breast cancer. Asian Pac. J. Cancer Prev. 2012, 13, 4555–4559. [Google Scholar] [CrossRef] [Green Version]
  104. Lapierre, M.; Linares, A.; Dalvai, M.; Duraffourd, C.; Bonnet, S.; Boulahtouf, A.; Rodriguez, C.; Jalaguier, S.; Assou, S.; Orsetti, B. Histone deacetylase 9 regulates breast cancer cell proliferation and the response to histone deacetylase inhibitors. Oncotarget 2016, 7, 19693. [Google Scholar] [CrossRef]
  105. Senese, S.; Zaragoza, K.; Minardi, S.; Muradore, I.; Ronzoni, S.; Passafaro, A.; Bernard, L.; Draetta, G.F.; Alcalay, M.; Seiser, C. Role for histone deacetylase 1 in human tumor cell proliferation. Mol. Cell. Biol. 2007, 27, 4784–4795. [Google Scholar] [CrossRef] [Green Version]
  106. Duffy, M.J.; McGowan, P.M.; Harbeck, N.; Thomssen, C.; Schmitt, M. uPA and PAI-1 as biomarkers in breast cancer: Validated for clinical use in level-of-evidence-1 studies. Breast Cancer Res. 2014, 16, 428. [Google Scholar] [CrossRef] [Green Version]
  107. Ferroni, P.; Roselli, M.; Portarena, I.; Formica, V.; Riondino, S.; La Farina, F.; Costarelli, L.; Melino, A.; Massimiani, G.; Cavaliere, F. Plasma plasminogen activator inhibitor-1 (PAI-1) levels in breast cancer–relationship with clinical outcome. Anticancer Res. 2014, 34, 1153–1161. [Google Scholar] [PubMed]
  108. Tzekaki, E.E.; Geromichalos, G.; Lavrentiadou, S.N.; Tsantarliotou, M.P.; Pantazaki, A.A.; Papaspyropoulos, A. Oleuropein is a natural inhibitor of PAI-1-mediated proliferation in human ER-/PR-breast cancer cells. Breast Cancer Res. Treat. 2021, 186, 305–316. [Google Scholar] [CrossRef]
  109. Chaffer, C.L.; Weinberg, R.A. How does multistep tumorigenesis really proceed? Cancer Discov. 2015, 5, 22–24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Magee, J.A.; Piskounova, E.; Morrison, S.J. Cancer stem cells: Impact, heterogeneity, and uncertainty. Cancer Cell 2012, 21, 283–296. [Google Scholar] [CrossRef] [Green Version]
  111. Kakarala, M.; Wicha, M.S. Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008, 26, 2813. [Google Scholar] [CrossRef] [Green Version]
  112. Corominas-Faja, B.; Cuyàs, E.; Lozano-Sánchez, J.; Cufí, S.; Verdura, S.; Fernández-Arroyo, S.; Borrás-Linares, I.; Martin-Castillo, B.; Martin, Á.G.; Lupu, R. Extra-virgin olive oil contains a metabolo-epigenetic inhibitor of cancer stem cells. Carcinogenesis 2018, 39, 601–613. [Google Scholar] [CrossRef] [Green Version]
  113. Skouroliakou, M.; Grosomanidis, D.; Massara, P.; Kostara, C.; Papandreou, P.; Ntountaniotis, D.; Xepapadakis, G. Serum antioxidant capacity, biochemical profile and body composition of breast cancer survivors in a randomized Mediterranean dietary intervention study. Eur. J. Nutr. 2018, 57, 2133–2145. [Google Scholar] [CrossRef]
  114. Martínez, N.; Herrera, M.; Frías, L.; Provencio, M.; Pérez-Carrión, R.; Díaz, V.; Morse, M.; Crespo, M. A combination of hydroxytyrosol, omega-3 fatty acids and curcumin improves pain and inflammation among early stage breast cancer patients receiving adjuvant hormonal therapy: Results of a pilot study. Clin. Transl. Oncol. 2019, 21, 489–498. [Google Scholar] [CrossRef]
  115. Lipworth, L.; Martínez, M.E.; Angell, J.; Hsieh, C.-C.; Trichopoulos, D. Olive oil and human cancer: An assessment of the evidence. Prev. Med. 1997, 26, 181–190. [Google Scholar] [CrossRef] [PubMed]
  116. Sealy, N.; Hankinson, S.E.; Houghton, S.C. Olive oil and risk of breast cancer: A systematic review and dose–response meta-analysis of observational studies. Br. J. Nutr. 2021, 125, 1148–1156. [Google Scholar] [CrossRef]
  117. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef] [Green Version]
  118. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  119. Walboomers, J.M.; Jacobs, M.V.; Manos, M.M.; Bosch, F.X.; Kummer, J.A.; Shah, K.V.; Snijders, P.J.; Peto, J.; Meijer, C.J.; Muñoz, N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol. 1999, 189, 12–19. [Google Scholar] [CrossRef]
  120. Torić, J.; Brozovic, A.; Baus Lončar, M.; Jakobušić Brala, C.; Karković Marković, A.; Benčić, Đ.; Barbarić, M. Biological activity of phenolic compounds in extra virgin olive oils through their phenolic profile and their combination with anticancer drugs observed in human cervical carcinoma and colon adenocarcinoma cells. Antioxidants 2020, 9, 453. [Google Scholar] [CrossRef]
  121. Kouka, P.; Tsakiri, G.; Tzortzi, D.; Dimopoulou, S.; Sarikaki, G.; Stathopoulos, P.; Veskoukis, A.S.; Halabalaki, M.; Skaltsounis, A.L.; Kouretas, D. The Polyphenolic Composition of Extracts Derived from Different Greek Extra Virgin Olive Oils Is Correlated with Their Antioxidant Potency. Oxid. Med. Cell. Longev. 2019, 2019, 1870965. [Google Scholar] [CrossRef] [PubMed]
  122. Barchitta, M.; Maugeri, A.; Quattrocchi, A.; Agrifoglio, O.; Scalisi, A.; Agodi, A. The association of dietary patterns with high-risk human papillomavirus infection and cervical cancer: A cross-sectional study in Italy. Nutrients 2018, 10, 469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Yao, J.; Wu, J.; Yang, X.; Yang, J.; Zhang, Y.; Du, L. Oleuropein induced apoptosis in HeLa cells via a mitochondrial apoptotic cascade associated with activation of the c-Jun NH2-terminal kinase. J. Pharmacol. Sci. 2014, 125, 300–311. [Google Scholar] [CrossRef] [Green Version]
  124. Yang, P.; Su, C.; Luo, X.; Zeng, H.; Zhao, L.; Wei, L.; Zhang, X.; Varghese, Z.; Moorhead, J.F.; Chen, Y. Dietary oleic acid-induced CD36 promotes cervical cancer cell growth and metastasis via up-regulation Src/ERK pathway. Cancer Lett. 2018, 438, 76–85. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Zhang, X.; Yang, P.; Luo, X.; Su, C.; Chen, Y.; Zhao, L.; Wei, L.; Zeng, H.; Varghese, Z.; Moorhead, J.F.; et al. High olive oil diets enhance cervical tumour growth in mice: Transcriptome analysis for potential candidate genes and pathways. Lipids Health Dis. 2019, 18, 76. [Google Scholar] [CrossRef] [Green Version]
  126. Way, S. Vaginal metastases of carcinoma of the body of the uterus. BJOG Int. J. Obstet. Gynaecol. 1951, 58, 558–572. [Google Scholar] [CrossRef] [PubMed]
  127. Benedet, J.; Pecorelli, S.; Ngan, H.; Hacker, N.F.; Denny, L.; Jones, H.W., III; Kavanagh, J.; Kitchener, H.; Kohorn, E.; Thomas, G. Staging classifications and clinical practice guidelines for gynaecological cancers. Int. J. Gynecol. Obstet. 2000, 70, 207–312. [Google Scholar] [CrossRef]
  128. Bokhman, J.V. Two pathogenetic types of endometrial carcinoma. Gynecol. Oncol. 1983, 15, 10–17. [Google Scholar] [CrossRef]
  129. Lian, J.; Dundas, G.; Carlone, M.; Ghosh, S.; Pearcey, R. Twenty-year review of radiotherapy for vaginal cancer: An institutional experience. Gynecol. Oncol. 2008, 111, 298–306. [Google Scholar] [CrossRef] [PubMed]
  130. Dunn, L.J.; Napier, J.G. Primary carcinoma of the vagina. Am. J. Obstet. Gynecol. 1966, 96, 1112–1116. [Google Scholar] [CrossRef]
  131. Berek, J.S.; Karam, A.; Dizon, D.S. Vulvar Cancer: Epidemiology, Diagnosis, Histopathology, and Treatment; Goff, B., Dizon, D.S., Eds.; UpToDate: Waltham, MA, USA, 2020. [Google Scholar]
  132. Saraiya, M.; Watson, M.; Wu, X.; King, J.B.; Chen, V.W.; Smith, J.S.; Giuliano, A.R. Incidence of in situ and invasive vulvar cancer in the US, 1998–2003. Cancer 2008, 113, 2865–2872. [Google Scholar] [CrossRef]
  133. Schuurman, M.; Van Den Einden, L.; Massuger, L.F.; Kiemeney, L.; van der Aa, M.A.; de Hullu, J.A. Trends in incidence and survival of Dutch women with vulvar squamous cell carcinoma. Eur. J. Cancer 2013, 49, 3872–3880. [Google Scholar] [CrossRef]
  134. Walker, B.E.; Edwards, S.N. Reproductive system tumors in mice exposed to various types of fat perinatally. Anticancer Res. 2003, 23, 4689–4691. [Google Scholar]
  135. Nelson, H.D. Menopause. Lancet 2008, 371, 760–770. [Google Scholar] [CrossRef]
  136. Nappi, R.E.; Simoncini, T. Menopause transition: A golden age to prevent cardiovascular disease. Lancet Diabetes Endocrinol. 2021, 9, 135–137. [Google Scholar] [CrossRef]
  137. Liu, H.; Huang, H.; Li, B.; Wu, D.; Wang, F.; Zheng, X.h.; Chen, Q.; Wu, B.; Fan, X. Olive oil in the prevention and treatment of osteoporosis after artificial menopause. Clin. Interv. Aging 2014, 9, 2087. [Google Scholar] [CrossRef] [Green Version]
  138. Vignini, A.; Nanetti, L.; Raffaelli, F.; Sabbatinelli, J.; Salvolini, E.; Quagliarini, V.; Cester, N.; Mazzanti, L. Effect of 1-y oral supplementation with vitaminized olive oil on platelets from healthy postmenopausal women. Nutrition 2017, 42, 92–98. [Google Scholar] [CrossRef] [PubMed]
  139. Salvini, S.; Sera, F.; Caruso, D.; Giovannelli, L.; Visioli, F.; Saieva, C.; Masala, G.; Ceroti, M.; Giovacchini, V.; Pitozzi, V. Daily consumption of a high-phenol extra-virgin olive oil reduces oxidative DNA damage in postmenopausal women. Br. J. Nutr. 2006, 95, 742–751. [Google Scholar] [CrossRef] [PubMed]
  140. Rezaeyan, M.; Khedri, P.; Direkvand-Moghadam, A. The Impact of Nutritional Supplement on Reducing the Symptoms of Primary Dysmenorrhea in Comparison to the Classical Anti-Inflammatory Treatment; A Sequential Self Case-Controlled Study. Women’s Health Gynecol. 2017, 5, 2. [Google Scholar]
  141. Juraskova, I.; Jarvis, S.; Mok, K.; Peate, M.; Meiser, B.; Cheah, B.C.; Mireskandari, S.; Friedlander, M. The Acceptability, Feasibility, and Efficacy (P hase I/II Study) of the OVER come (O live Oil, V aginal E xercise, and Moisturize R) Intervention to Improve Dyspareunia and Alleviate Sexual Problems in Women with Breast Cancer. J. Sex. Med. 2013, 10, 2549–2558. [Google Scholar] [CrossRef] [Green Version]
  142. Lorentzon, M.; Johansson, H.; Harvey, N.; Liu, E.; Vandenput, L.; McCloskey, E.; Kanis, J. Osteoporosis and fractures in women: The burden of disease. Climacteric 2021, 1–7. [Google Scholar] [CrossRef]
  143. Chin, K.-Y.; Ima-Nirwana, S. Olives and bone: A green osteoporosis prevention option. Int. J. Environ. Res. Public Health 2016, 13, 755. [Google Scholar] [CrossRef]
  144. Hagiwara, K.; Goto, T.; Araki, M.; Miyazaki, H.; Hagiwara, H. Olive polyphenol hydroxytyrosol prevents bone loss. Eur. J. Pharmacol. 2011, 662, 78–84. [Google Scholar] [CrossRef]
  145. Puel, C.; Mardon, J.; Agalias, A.; Davicco, M.-J.; Lebecque, P.; Mazur, A.; Horcajada, M.-N.; Skaltsounis, A.-L.; Coxam, V. Major phenolic compounds in olive oil modulate bone loss in an ovariectomy/inflammation experimental model. J. Agric. Food Chem. 2008, 56, 9417–9422. [Google Scholar] [CrossRef]
  146. Puel, C.; Mardon, J.; Kati-Coulibaly, S.; Davicco, M.-J.; Lebecque, P.; Obled, C.; Rock, E.; Horcajada, M.-N.; Agalias, A.; Skaltsounis, L.A. Black Lucques olives prevented bone loss caused by ovariectomy and talc granulomatosis in rats. Br. J. Nutr. 2007, 97, 1012–1020. [Google Scholar] [CrossRef] [Green Version]
  147. Puel, C.; Quintin, A.; Agalias, A.; Mathey, J.; Obled, C.; Mazur, A.; Davicco, M.; Lebecque, P.; Skaltsounis, A.; Coxam, V. Olive oil and its main phenolic micronutrient (oleuropein) prevent inflammation-induced bone loss in the ovariectomised rat. Br. J. Nutr. 2004, 92, 119–127. [Google Scholar] [CrossRef]
  148. Puel, C.; Mathey, J.; Agalias, A.; Kati-Coulibaly, S.; Mardon, J.; Obled, C.; Davicco, M.-J.; Lebecque, P.; Horcajada, M.-N.; Skaltsounis, A.L. Dose–response study of effect of oleuropein, an olive oil polyphenol, in an ovariectomy/inflammation experimental model of bone loss in the rat. Clin. Nutr. 2006, 25, 859–868. [Google Scholar] [CrossRef]
  149. Saleh, N.K.; Saleh, H.A. Olive oil effectively mitigates ovariectomy-induced osteoporosis in rats. BMC Complement. Altern. Med. 2011, 11, 10. [Google Scholar] [CrossRef] [Green Version]
  150. Santiago-Mora, R.; Casado-Díaz, A.; De Castro, M.; Quesada-Gómez, J. Oleuropein enhances osteoblastogenesis and inhibits adipogenesis: The effect on differentiation in stem cells derived from bone marrow. Osteoporos. Int. 2011, 22, 675–684. [Google Scholar] [CrossRef]
  151. García-Martínez, O.; De Luna-Bertos, E.; Ramos-Torrecillas, J.; Ruiz, C.; Milia, E.; Lorenzo, M.L.; Jimenez, B.; Sánchez-Ortiz, A.; Rivas, A. Phenolic compounds in extra virgin olive oil stimulate human osteoblastic cell proliferation. PLoS ONE 2016, 11, e0150045. [Google Scholar] [CrossRef] [Green Version]
  152. Claassen, N.; Potgieter, H.; Seppa, M.; Vermaak, W.; Coetzer, H.; Van Papendorp, D.; Kruger, M. Supplemented gamma-linolenic acid and eicosapentaenoic acid influence bone status in young male rats: Effects on free urinary collagen crosslinks, total urinary hydroxyproline, and bone calcium content. Bone 1995, 16, S385–S392. [Google Scholar] [CrossRef]
  153. Filip, R.; Possemiers, S.; Heyerick, A.; Pinheiro, I.; Raszewski, G.; Davicco, M.-J.; Coxam, V. Twelve-month consumption of a polyphenol extract from olive (Olea europaea) in a double blind, randomized trial increases serum total osteocalcin levels and improves serum lipid profiles in postmenopausal women with osteopenia. J. Nutr. Health Aging 2015, 19, 77–86. [Google Scholar] [CrossRef]
  154. Keiler, A.M.; Zierau, O.; Bernhardt, R.; Scharnweber, D.; Lemonakis, N.; Termetzi, A.; Skaltsounis, L.; Vollmer, G.; Halabalaki, M. Impact of a functionalized olive oil extract on the uterus and the bone in a model of postmenopausal osteoporosis. Eur. J. Nutr. 2014, 53, 1073–1081. [Google Scholar] [CrossRef]
  155. Gryszczyńska, A.; Gryszczyńska, B.; Opala, B. The leaves of european olive (Olea europaea L.)–chemistry and application in medicine. Postępy Fitoter. 2010, 11, 30–37. [Google Scholar]
  156. Susalit, E.; Agus, N.; Effendi, I.; Tjandrawinata, R.R.; Nofiarny, D.; Perrinjaquet-Moccetti, T.; Verbruggen, M. Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: Comparison with Captopril. Phytomedicine 2011, 18, 251–258. [Google Scholar] [CrossRef] [PubMed]
  157. Perrinjaquet-Moccetti, T.; Busjahn, A.; Schmidlin, C.; Schmidt, A.; Bradl, B.; Aydogan, C. Food supplementation with an olive (Olea europaea L.) leaf extract reduces blood pressure in borderline hypertensive monozygotic twins. Phytother. Res. 2008, 22, 1239–1242. [Google Scholar] [CrossRef] [PubMed]
  158. Covas, M.-I. Olive oil and the cardiovascular system. Pharmacol. Res. 2007, 55, 175–186. [Google Scholar] [CrossRef] [PubMed]
  159. Ruano, J.; Lopez-Miranda, J.; Fuentes, F.; Moreno, J.A.; Bellido, C.; Perez-Martinez, P.; Lozano, A.; Gómez, P.; Jiménez, Y.; Pérez Jiménez, F. Phenolic content of virgin olive oil improves ischemic reactive hyperemia in hypercholesterolemic patients. J. Am. Coll. Cardiol. 2005, 46, 1864–1868. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  160. Jimenez-Morales, A.I.; Ruano, J.; Delgado-Lista, J.; Fernandez, J.M.; Camargo, A.; Lopez-Segura, F.; Villarraso, J.C.; Fuentes-Jimenez, F.; Lopez-Miranda, J.; Perez-Jimenez, F. NOS3 Glu298Asp polymorphism interacts with virgin olive oil phenols to determine the postprandial endothelial function in patients with the metabolic syndrome. J. Clin. Endocrinol. Metab. 2011, 96, E1694–E1702. [Google Scholar] [CrossRef]
  161. Anderson-Vasquez, H.E.; Pérez-Martínez, P.; Fernández, P.O.; Wanden-Berghe, C. Impact of the consumption of a rich diet in butter and it replacement for a rich diet in extra virgin olive oil on anthropometric, metabolic and lipid profile in postmenopausal women. Nutr. Hosp. 2015, 31, 2561–2570. [Google Scholar] [PubMed]
  162. Martinez-Gonzalez, M.A.; Dominguez, L.J.; Delgado-Rodriguez, M. Olive oil consumption and risk of CHD and/or stroke: A meta-analysis of case–control, cohort and intervention studies. Br. J. Nutr. 2014, 112, 248–259. [Google Scholar] [CrossRef] [Green Version]
  163. Medeiros-de-Moraes, I.M.; Gonçalves-de-Albuquerque, C.F.; Kurz, A.R.; Oliveira, F.M.d.J.; Abreu, V.H.P.d.; Torres, R.C.; Carvalho, V.F.; Estato, V.; Bozza, P.T.; Sperandio, M. Omega-9 oleic acid, the main compound of olive oil, mitigates inflammation during experimental sepsis. Oxidative Med. Cell. Longev. 2018, 2018, 6053492. [Google Scholar] [CrossRef] [Green Version]
  164. Al-Azzawie, H.F.; Alhamdani, M.-S.S. Hypoglycemic and antioxidant effect of oleuropein in alloxan-diabetic rabbits. Life Sci. 2006, 78, 1371–1377. [Google Scholar] [CrossRef]
  165. Moreno-Luna, R.; Muñoz-Hernandez, R.; Miranda, M.L.; Costa, A.F.; Jimenez-Jimenez, L.; Vallejo-Vaz, A.J.; Muriana, F.J.; Villar, J.; Stiefel, P. Olive oil polyphenols decrease blood pressure and improve endothelial function in young women with mild hypertension. Am. J. Hypertens. 2012, 25, 1299–1304. [Google Scholar] [CrossRef] [Green Version]
  166. Schwingshackl, L.; Christoph, M.; Hoffmann, G. Effects of olive oil on markers of inflammation and endothelial function—A systematic review and meta-analysis. Nutrients 2015, 7, 7651–7675. [Google Scholar] [CrossRef] [Green Version]
  167. Lockyer, S.; Corona, G.; Yaqoob, P.; Spencer, J.P.; Rowland, I. Secoiridoids delivered as olive leaf extract induce acute improvements in human vascular function and reduction of an inflammatory cytokine: A randomised, double-blind, placebo-controlled, cross-over trial. Br. J. Nutr. 2015, 114, 75–83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Schwingshackl, L.; Lampousi, A.; Portillo, M.; Romaguera, D.; Hoffmann, G.; Boeing, H. Olive oil in the prevention and management of type 2 diabetes mellitus: A systematic review and meta-analysis of cohort studies and intervention trials. Nutr. Diabetes 2017, 7, e262. [Google Scholar] [CrossRef] [Green Version]
  169. Casado-Díaz, A.; Túnez-Fiñana, I.; Mata-Granados, J.M.; Ruiz-Méndez, M.V.; Dorado, G.; Romero-Sánchez, M.C.; Navarro-Valverde, C.; Quesada-Gómez, J.M. Serum from postmenopausal women treated with a by-product of olive-oil extraction process stimulates osteoblastogenesis and inhibits adipogenesis in human mesenchymal stem-cells (MSC). Exp. Gerontol. 2017, 90, 71–78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  170. Chimento, A.; Casaburi, I.; Rosano, C.; Avena, P.; De Luca, A.; Campana, C.; Martire, E.; Santolla, M.F.; Maggiolini, M.; Pezzi, V. Oleuropein and hydroxytyrosol activate GPER/GPR 30-dependent pathways leading to apoptosis of ER-negative SKBR 3 breast cancer cells. Mol. Nutr. Food Res. 2014, 58, 478–489. [Google Scholar] [CrossRef]
  171. Odiatou, E.M.; Skaltsounis, A.L.; Constantinou, A.I. Identification of the factors responsible for the in vitro pro-oxidant and cytotoxic activities of the olive polyphenols oleuropein and hydroxytyrosol. Cancer Lett. 2013, 330, 113–121. [Google Scholar] [CrossRef] [PubMed]
  172. Hassan, Z.K.; Daghestani, M.H. Curcumin effect on MMPs and TIMPs genes in a breast cancer cell line. Asian Pac. J. Cancer Prev. 2012, 13, 3259–3264. [Google Scholar] [CrossRef] [Green Version]
  173. Fu, S.; Arráez-Roman, D.; Segura-Carretero, A.; Menéndez, J.A.; Menéndez-Gutiérrez, M.P.; Micol, V.; Fernández-Gutiérrez, A. Qualitative screening of phenolic compounds in olive leaf extracts by hyphenated liquid chromatography and preliminary evaluation of cytotoxic activity against human breast cancer cells. Anal. Bioanal. Chem. 2010, 397, 643–654. [Google Scholar] [CrossRef] [PubMed]
  174. Goulas, V.; Exarchou, V.; Troganis, A.N.; Psomiadou, E.; Fotsis, T.; Briasoulis, E.; Gerothanassis, I.P. Phytochemicals in olive-leaf extracts and their antiproliferative activity against cancer and endothelial cells. Mol. Nutr. Food Res. 2009, 53, 600–608. [Google Scholar] [CrossRef] [PubMed]
  175. Tzonou, A.; Lipworth, L.; Kalandidi, A.; Trichopoulou, A.; Gamatsi, I.; Hsieh, C.; Notara, V.; Trichopoulos, D. Dietary factors and the risk of endometrial cancer: A case-control study in Greece. Br. J. Cancer 1996, 73, 1284–1290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Nutrients 13 04279 g001 550
Figure 1. Chemical structure of (a) oleuropein, (b) hydroxytyrosol, and (c) tyrosol.
Figure 1. Chemical structure of (a) oleuropein, (b) hydroxytyrosol, and (c) tyrosol.
Nutrients 13 04279 g001
Table
Table 1. The role of OO in various aspects of women’s health.
Table 1. The role of OO in various aspects of women’s health.
DiseasesProductsAuthorStudy DesignResults
OsteoporosisOOECasado-Diaz et al. 2017 [169]Human mesenchymal stem cell and serum from postmenopausal womenIncreased osteoblastogenesis
Polyphenol extract from OO (Bonolive®)Filip et al. 2015 [153]A double blind, placebo-controlled study in 64 postmenopausal womenIncreased osteocalcin levels
Lumbar BMD maintenance compared to BMD reduction in the control group
Total phenolic extract from EVOOKeiler et al. 2013 [154]Ovariectomized ratsNo attenuation of bone loss
OLP and HTHagiwara et al. 2011 [144]MC3T3-E1 cell line, ovariectomized miceDecreased bone loss in ovariectomized mice
OOSaleh et al. 2011 [149]Ovariectomy-induced osteoporosis ratsDecline in bone loss
Black lucques olives 2007Puel et al. 2004, 2006, 2007, 2008, [145,146,147,148]Ovariectomy/inflammation modelIncrease in bone mineral density
EVOO and OLP 2004
OLP 2006
HT and tyrosol 2008
Gamma-linolenic acidClaassen et al. 1995 [152]RatsInhibition of bone resorption
Increase in calcium level
Postmenopausal disorders
OO plus Vitamin D3, K, B6Vigini et al. 2017 [138]Human, single-center, randomized placebo-controlled trialReduction in nitric oxide levels
Maintenance of platelet function
EVOOAnderson-Vasquez et al. 2015 [161]A prospective, longitudinal and comparative study, 18 healthy postmenopausal womenDyslipidemia improvement
Polyphenol extract from OO (Bonolive®)Filip et al. 2015 [153]A double blind, placebo-controlled study, 64 postmenopausal womenDecreased the total and LDL-cholesterol
High-phenol EVOOSalvini et al. 2006 [139]Randomized cross-over intervention trial, postmenopausal womenPrevented oxidative DNA damage
Ovarian cancerOLPSheikhshabani et al. 2021 [53]A2780S and A2780/CP cell linesIncreased apoptosis
inhibition of cell proliferation
Decreases in cisplatin resistance
OLEBennot-Dominguez et al. 2021 [52]MDA-MB-231 and OVCAR-3Viability inhibition, increased apoptosis, increased ROS production, mitochondria dysfunction was induced
OLPXing et al. 2017 [55]In vitro in the Caov3 and Skov3 cell line and in a xenograft mouse modelUpregulated miR-299 expression and inhibited HPSE1 expression
Oleic acidMenendez et al. [62]SK-OV3Repressed HER2-neu expression via PEA3 protein action
Tzonou et al. 1993 [63]Case-control Risk reduction
OOBosetti et al. 2002 [64]Case-control Risk reduction
OOBosetti et al. 2009 [39]Case-controlRisk reduction
Breast cancerS-(−)-Oleocanthal (OC)Qusa et al. 2021 [93]MDA-MB-231 in vivo using two kinds of animal models: breast cancer patient-derived xenograft model and transgenic MMTV-PyVTInhibited cancer progression and metastasis. Investigated the mechanism at the gene level.
Controlled the gene related to progression and metastasis
OLPAsgharzade et al. 2020 [79]MCF-7 and MDA-MB-231Inhibited cell proliferation
Increased apoptosis
Dysregulated miRNA
OLPMesseha et al. 2020 [82]MDA-MB-468 and MDA-MB-231MDA-MB-468 is more susceptible to OLP than MDA-MB-231
OLP and HTLu et al. 2020 [90]MCF7 and T47DDecreased migration and invasion via autophagy activation
OLAMazzei et al. 2020 [84]MDA-MB-231, tamoxifen-resistant MCF-7
OLEBenot-Dominguez et al. 2020 [52]MDA-MB-231Inhibited cell proliferation
Induced apoptotic activity
Increased ROS generation
OLPReboredo-Rodríguez et al. 2018MCF-7Induced cell death and increased ROS production
EVOO Corominas-Faja et al. 2018 [112]In vivo and in vitro HMLER, MCF10DCIS.com, SUM-159, MCF-7Inhibited mammosphere formation, decreased tumor formation, regulated the expression of stem cell fates, inhibited self-renewal capacities via DNMT regulation and mTOR inhibition.
OLPBayat et al. 2018 [81]MCF-7Induced apoptosis, decreased migration and invasion
Decreased HDAC2 and HDAC3 expression
OLPMansouri et al. 2018 [91]MCF-7Inhibited cell growth and invasion Induced apoptosis via HDAC regulation
OLPChoupani et al. 2018 [88]MCF-7Inhibited the migration via EMT repression by decreasing sirtuin1 expression
OLP and HTChimento et al. 2014 [170]ER-negative SKBR3
OLPHassan et al. 2013 [83]MCF-7P53 pathway activation
OLPElamin et al. 2012 [85]MDA-MB-231, MCF-7, MCF-10ADelayed the cell cycle
Decreased NF-kB and cyclin D-1 expression, p21 activation.
OLP and HTOdiatou et al. 2012 [171]MDA-MB-231Produced H2O2 led to DNA damage
Decreased cell viability
OLPHassan et al. 2012 [172]MDADecreased MMP-2 and MMP-9 expression and increased TIMP1 and TIMP4 expression
OLEFu et al. 2010 [173]SKBR3, MCF-7, JIMT-1Inhibit the cell proliferation
HTBouallagui et al. 2010 [89]MCF-7Inhibited cell growth
Cell cycle arrest (reduced expression of pin-1 resulted in decreased cyclinD1 expression)
OLP and HTSirianni et al. 2010 [92]MCF-7Inhibited the activation of extracellular regulated kinase 1/2 that is dependent on E2
OLP and HydrotrosolHan et al. 2009 [78]MCF-7Inhibited cell proliferation
Induce cell apoptosis and G1 cell cycle arrest
OLEGoulas et al. 2008 [174]MCF-7Inhibited cell proliferation
EVOOMenendez et al. 2008 [100]MCF-7 and SKBR3Inhibited HER2 protein kinase activity
EVOOMenendez et al. 2008 [101]MCF-7 and SKBR3Inhibited the lipogenic enzyme expression in HER2-overexpression
EVOOMenendez et al. 2007 [77]MCF-7 and SKBR3Inhibited HER2
Increases the effect of trastuzumab in SKBR3 and reversed the resistance to trastuzumab
OOMenendez et al. 2006 [62]SK-Br3 and MDA_MB-231Repressed HER2-neu expression via PEA3 protein action
OOSealy et al. 2021 [116]Meta-analysisMay reduce the risk but there was no significant relationship between the dose of OO and risk
HT+omega-3 fatty acid+curcuminMartinez et al. 2019 [114]Clinical trial in early stage breast cancer patients using hormoneReduced CRP
Ameliorated pain
OOXin et al. 2015 [47]Meta-analysisReduced the risk
OOPelucchi et al. 2011 [46]Meta-analysisReduced the risk
OOPsaltopoulou et al. 2011 [45]Systemic review and meta-analysisReduced the risk
OOLipworth et al. 1997 [115]Meta-analysisReduced the risk
Cervical cancerEVOOToric et al. 2020 [120]HeLaInhibited cell growth
EVOOKouka et al. 2019 [121]HeLaIncreased antioxidants
Oleic acidZhang et al. 2019 [125]HeLaIncreased cell proliferation, migration, and tumor growth
Showed the different gene expression patterns altered by OO diet
Oleic acidYang et al. 2018 [124]HeLaEnhanced tumor growth via CD31 induction by Scr?/ RK upregulation
OLPYao et al. 2014 [123]HeLaInduced apoptosis via JNK/SPAK upregulation
Endometrial cancer
OOTzonou et al. 1996 [175]Case control study Reduced the risk
Vaginal and vulvar cancer Not available
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ly, T.T.G.; Yun, J.; Lee, D.-H.; Chung, J.-S.; Kwon, S.-M. Protective Effects and Benefits of Olive Oil and Its Extracts on Women’s Health. Nutrients 2021, 13, 4279. https://doi.org/10.3390/nu13124279

AMA Style

Ly TTG, Yun J, Lee D-H, Chung J-S, Kwon S-M. Protective Effects and Benefits of Olive Oil and Its Extracts on Women’s Health. Nutrients. 2021; 13(12):4279. https://doi.org/10.3390/nu13124279

Chicago/Turabian Style

Ly, Thanh Truong Giang, Jisoo Yun, Dong-Hyung Lee, Joo-Seop Chung, and Sang-Mo Kwon. 2021. "Protective Effects and Benefits of Olive Oil and Its Extracts on Women’s Health" Nutrients 13, no. 12: 4279. https://doi.org/10.3390/nu13124279

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop