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Therapeutic Potential of Pomegranate Extract for Women's Reproductive Health and Breast Cancer

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01 August 2024

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01 August 2024

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Abstract
Pomegranate extract has potential benefits for women's reproductive health, including fertility enhancement, menstrual cycle regulation, pregnancy support, and polycystic ovary syndrome (PCOS) treatment. It possesses antioxidant properties, reducing oxidative stress and improving fertility. Phytoestrogens in pomegranate extract may help regulate hormonal imbalances and promote regular menstrual cycles. The extract's rich nutrient profile supports placental development and fetal growth and may reduce the risk of preterm birth. Additionally, pomegranate extract shows promise in improving insulin sensitivity and reducing inflammation and oxidative damage in PCOS. Some studies suggest its potential anticancer properties, particularly against breast cancer. However, further research, including human clinical trials, is necessary to establish its effectiveness and safety. The current evidence is limited and primarily based on in vitro studies, animal studies, and clinical trials. This review provides a comprehensive summary of the benefits of pomegranate extract for women's reproductive health and breast cancer, serving as a reference for future research.
Keywords: 
pomegranate
;  
menopause-related issues
;  
polycystic ovary syndrome
;  
breast cancer
Subject: 
Medicine and Pharmacology  -   Medicine and Pharmacology

1. Introduction

The pomegranate plant (Punica granatum L.), is a deciduous shrub that produces fruits. It belongs to the family Lythraceae, specifically the subfamily Punicoideae. Typically, it reaches a height of 5–10 m, equivalent to 16–33 feet [1]. Pomegranate trees are extensively grown in various areas, including the Middle East, Iran, the Caucasus, northern and tropical Africa, the Indian subcontinent, arid parts of Southeast Asia, Central Asia, and the Mediterranean areas. They thrive in regions with hot, dry summers and mild winters, making them suitable for cultivation in semi-arid to arid climates. Additionally, pomegranate cultivation has expanded to other parts of the world with similar climatic conditions, such as parts of North and South America, Australia, and southern Europe [2].
The pomegranate fruit comes from the Punica granatum tree. Pomegranates typically ripen in the Southern Hemisphere between March and May and in the Northern Hemisphere from September to February [3]. Pomegranates are used in cooking, baking, and preparing smoothies; juice blends; alcoholic beverages, including cocktails and wine; and meal garnishes [4]. Scientifically classified as a berry, pomegranate has been recognized by humanity for < 5,000 years, with considerable cultural and historical significance [5]. Across various cultures, pomegranates bear symbolic importance, including prosperity, fertility, and abundance [6]. Pomegranates are approximately the size of an apple and have a rounded shape [7]. Encased in a robust, leathery outer skin, their color varies from deep red to yellow [8]. Internally, the fruit contains numerous small, edible seeds surrounded by juicy, ruby-red arils [9]. These arils are not only tasty but are also rich in essential nutrients [10]. Pomegranate have a distinctive combination of sweet and tart flavors, making them a favored option for juices, smoothies, and diverse culinary uses [11]. The taste and physical appearance of salads, yogurt, or desserts are enhanced when the arils of pomegranate are sprinkled on them [12]. In addition to their pleasing flavor, pomegranates are known for their health advantages. Pomegranates have abundant antioxidants, notably punicalagins, and anthocyanins, which protect against oxidative stress and inflammation within the body [13]. Consistent intake of pomegranate is linked to better heart health, a lowered risk of developing certain cancers, and improved immune function [14]. Overall, pomegranates are a delectable and nutritional addition to diet, providing both taste and health benefits [15].
The fruit comprises three components: the tough outer skin (exocarp), pulpy mesocarp, and arils containing seeds, known as kernels [1]. When the exocarp and mesocarp are combined, they form the pericarp, commonly considered part of the pomegranate peel (PP), accounting for nearly 50% of the fruit’s weight. The remaining 50% consists of the arils (40%) and seeds (10%) [16,17]. Singh et al. [18] discovered that PP contains remarkable phytochemicals with medicinal and nutritional significance. PP, along with other parts of the fruit, has been demonstrated to contain nearly 48 phenolic compounds, including polyphenols, flavonoids, ellagitannins, and proanthocyanidins [19,20]. The concentration of these active phytochemicals in pomegranates varies based on the cultivation method, maturity status, geographic region, and processing methods [21]. The juice and peel of pomegranates grown in the desert have a higher phenolic content than those grown in the Mediterranean [22].
Historically, pomegranate has been used as a traditional remedy for conditions such as dysentery, diarrhea, sore throat, hemorrhoids, diabetes, intestinal parasites, and vaginal itching, and a recent review paper on these has been published [4]. Moreover, pomegranate is believed to have tonic properties beneficial for the heart [23]. Furthermore, pomegranate has been recently used for the treatment of a variety of ailments, including Alzheimer’s disease [24], diabetes [25], cancer [17], arthritis [26], obesity [27], male infertility [28], and cardiovascular disorders [29]. In this review, we aimed to discuss the benefits of pomegranate extract on women’s reproductive health, including peri- and post-menopausal symptoms, polycystic ovary syndrome (PCOS), as well as its potential impact on breast cancer.

2. Pomegranate Extracts

Pomegranate extracts reportedly have various physiological benefits, such as antibacterial [30], anticancer [31], antidiabetic [32], antifungal [33], anti-inflammatory [34], antigenotoxic [35], anti-malarial [36], anti-obesity [37], antioxidant [38], antiviral [39], antihypertensive [40], cardioprotective [41], hepatoprotective [42], and neuroprotective [43] (Figure 1).
Pomegranate juice is extracted by removing the PP and using only the arils of the pomegranate. The process begins by harvesting fully ripe fruits and separating the peels from the arils. The arils containing the juice are meticulously gathered and the juice extracted. Subsequently, the juice undergoes straining to eliminate pulp and solid particles, followed by pasteurization for safety and prolonged shelf life [44]. Pomegranate juice comprises water (85.4%), polyphenols (0.2–1%), sugars (10.6%), and pectins (1.4%) [17]. The vivid color of pomegranate juice is impacted by anthocyanins, and it diminishes during the pressing process [45]. In addition to minerals, including moderately concentrated sodium, selenium, calcium, magnesium, cesium, zinc, and cobalt, the juice contains small amounts of fatty acids, organic acids, sterols, and triterpenoids [46]. Pomegranate juice has a high antioxidant capacity, surpassing other polyphenol-rich beverages and fruit juices, such as red wine, green tea, and various fruit juices [47].
Apart from pomegranate juice, pomegranate seed oil (PSO) can be obtained from different sections of the pomegranate seeds, such as the arils and kernels. Approximately 3% of the weight of a pomegranate is attributed to its seeds, and these seeds contain approximately 12–20% seed oil [29]. Pomegranate seeds are separated from the ripe fruit, air-dried to reduce moisture, and cold-pressed at low temperatures to maintain oil quality. Meticulous filtration enhances clarity, and the resulting pristine PSO is bottled in dark containers to protect it against light and air and preserve its longevity and quality [48]. Pomegranate seeds are rich in tannins, including ellagic acid, gallic acid, punicalagin, and punicalin, as well as anthocyanins, such as cyanidin, delphinidin, and pelargonidin [49,50]. PSO primarily consists of fatty acids, <95% of its composition [51]. Punic acid, an isomer of linoleic acid unique to pomegranate seeds, accounts for nearly 76% of PSO [52]. Moreover, PSO contains sterols, steroids, and cerebroside. The seed matrix contains varying amounts of isoflavones, lignins, and hydroxybenzoic acids. The seed coat contains organic acids, such as malic, citric, and ascorbic acids [50].

3. Phytochemicals Present in the Pomegranate Extract

Pomegranates contain various physiologically active compounds with potential health benefits [53]. Ellagic acid, present in pomegranate as ellagitannins, is a prevalent bioactive compound known for its antioxidant properties and has been investigated for its possible anticancer properties [54]. Punicalagins, potent antioxidants found in both pomegranate juice and peel, play a significant role in the fruit’s overall antioxidant activity, potentially offering anti-inflammatory and anticancer benefits [55]. Anthocyanins in pomegranate, responsible for its red color, possess antioxidant and anti-inflammatory properties, potentially supporting cardiovascular health [56]. Furthermore, pomegranate contains assorted flavonols, including kaempferol, quercetin, and myricetin, with antioxidant properties, contributing to its anti-inflammatory benefits [57]. Punicic acid, the primary fatty acid in PSO, belongs to the conjugated linolenic acid family and has potential anti-inflammatory and anticancer properties [58]. Pomegranate is rich in vitamins, including vitamins C and B [59]. Vitamin C, an antioxidant, safeguards cells from damage and supports the immune system [60]. The fruit contains essential minerals, including potassium and copper, crucial for bodily functions [59]. In addition to ellagic acid and punicalagin, pomegranate contains other polyphenols, such as catechins and epicatechins, contributing to its overall antioxidant capacity [13]. We have classified the major phytochemicals found in pomegranate, and the structures of the identified compounds are illustrated in Figure 2. Additionally, we have classified the phytochemicals present in pomegranate juice (Table 1) and seed (Table 2) extracts [17,61,62].

3.1. Flavonoids

Flavonoids constitute a significant category of natural compounds, are characterized by a polyphenolic structure, and are widely distributed in vegetables, fruits, and certain beverages as secondary plant metabolites [63]. They have crucial health-promoting benefits and find essential applications in medicine, pharmaceuticals, nutraceuticals, and cosmetics [64]. Flavonoids can be classified as anthocyanins, flavones, flavanones, flavonols, chalcones, and isoflavones [65]. These compounds have been found in various parts of the whole fruit, such as the peel, pericarps, leaves, flowers, barks, seeds, and juice [66]. Wang et al. [67] identified numerous prevalent flavonoids, such as prunin, chrysin, catechin, cyanidin, biochanin, apigenin, luteolin, glucoside, and taxifolin. Figure 2A–C depicts the commonly recognized flavonoids in pomegranate.

3.2. Anthocyanins

Anthocyanins, active compounds found in pomegranates, are accountable for the fruit’s color from when it begins to ripen until it fully matures [14]. They are made of one or two hexose sugars linked with cyanidin (cyanidin 3-glucoside, cyanidin 3,5-diglucoside, cyanidin 3-rutinoside, cyanidin–pentoside–hexoside, and cyanidin-pentoside), pelargonidin (pelargonidin 3-glucoside and pelargonidin 3,5-diglucoside), and delphinidin (delphinidin 3-glucoside and delphinidin 3,5-diglucoside) [68]. Figure 2D–F depicts the common anthocyanins present in pomegranate.

3.3. Tannins

Pomegranate, rich in polyphenols, contains tannins, which are present in the seeds and peel [69]. Tannins have various pharmacological properties, including antiviral [70] and antimicrobial [71] properties. Tannins in pomegranate include ellagitannins and gallotannins. Tannins that have been isolated from pomegranate include 3,3′,4′-tri-O-methylellagic acid; 2-O-galloylpunicalin; 1,2,3-tri-O-galloyl-β-4C1-glucose; 3,3′-Di-O-methylellagic acid; castalin; castalagin; casuarinin; epicatechin; corilagin; flavogallonic acid; gallagyldilacton; gallagic acid; lagerstannin C; granatin A/B; pedunculagin; punicacortein A, B, C, and D; punicalagin; punicafolin; punicalin α; and β punicatannin [53]. Figure 2G–I depicts the tannins commonly found in pomegranate.

3.4. Fatty and Organic Acids

Pomegranate contains 83.6% and 16.3% saturated and unsaturated fatty acids, respectively, with the unsaturated fatty acids being a major component of pomegranate seeds [53]. Essential oils, which contain both fatty and organic acids, are known for their various pharmacological benefits, such as anti-parasitic, antimicrobial, pain-relieving, antioxidant, and insect-repellent properties [72]. Volatile compounds and organic oils, such as heneicosanoic, punic, nonadecanoic, palmitic, stearic, oleic, linolenic, octoic, and linoleic acids, and coumestrol, have been identified in pomegranates [67,73]. Figure 2J–L depicts commonly recognized fatty and organic acids in pomegranate.

3.5. Sterols

Sterols, classified as natural steroids [74], are the least abundant bioactive compounds found in pomegranate [75]. Their primary role is to decrease cholesterol absorption and low-density lipoprotein cholesterol (LDL-C) in the plasma [74]. Puneeth et al. [76] identified asiatic acid as the main sterol compound, while Wong et al. [77] identified cholesterol, sitosterol, and stigmasterol. Sex steroids, including estrone, estriolm and testosterone are found in pomegranate seeds. Moreover, pomegranates are known to contain several sterol compounds, including campesterol, daucosterol, and sitosteryl-acetate [77]. Figure 2M–O depicts sterols commonly found in pomegranate.

4. Role of Pomegranate Extracts in Alleviating Peri- and Post-menopausal Symptoms

4.1. Peri- and Post-Menopausal Symptoms

The onset of menopause signifies the conclusion of a woman’s reproductive phase, typically happening at approximately 50 years old, though the transition might commence in the late 40s or even earlier [78]. Peri-menopause refers to the period leading up to menopause, while post-menopause refers to the time following the last menstrual period [79]. Many women encounter challenging symptoms throughout peri- and post-menopause, which may involve vasomotor symptoms, such as night sweats and hot flashes (HFs), disruptions in sleep and mood, weight gain, and sexual dysfunction [80,81]. Over 80% of women undergo HFs during menopause, which are marked by sudden, sporadic feelings of warmth, sweating, reddening of the skin, anxiety, and cold sensations lasting from 1 to 5 minutes [82]. These episodes can be distressing, especially when severe and frequent [83]. Although hot flashes typically diminish with time, around 10%–15% of women continue to experience moderate to severe symptoms even a decade or more after reaching menopause [84]. Additionally, menopausal women may face complications, such as osteoporosis, resulting from the loss of post-menopausal bone density due to estrogen deficiency [85]. After menopause, there’s a notable increase in the risk of cardiovascular disease (CVD) due to declining estrogen levels. Estrogen and testosterone are pivotal in women’s CVD development, affecting cardiac function, endothelial function, vascular tone, and metabolic syndrome [86]. While menopausal symptoms may not pose a direct threat to life, they impose significant financial burdens on the healthcare system due to their widespread occurrence and adverse impact on quality of life, incurring costs amounting to billions of dollars [87].

4.2. Effect of Pomegranate Extract on Peri- and Post-Menopausal Symptoms

Research suggests that pomegranate extract may offer potential health advantages for women in the peri- and post-menopausal stages, positively impacting their overall health [88,89,90,91,92,93]. Research has shown that pomegranate extract is potentially beneficial in alleviating common menopausal symptoms, such as HFs and night sweats [85]. Compounds found in pomegranate that promote bone health may help reduce the heightened risk of osteoporosis and bone loss associated with menopause [89,90]. Pomegranate extract can be advantageous for cardiovascular well-being, particularly relevant during and after menopause. It elevates high-density lipoprotein cholesterol (HDL-C), lowers LDL-C, enhances overall blood cholesterol levels, and decreases the presence of homocysteine, a risk factor for cardiovascular issues [88]. Pomegranate extract might be beneficial for maintaining hormonal equilibrium by regulating estrogen levels during menopause-induced hormonal changes [92]. The plentiful antioxidants found in pomegranates have the ability to mitigate oxidative stress and inflammation linked to aging, rendering them particularly beneficial during the menopausal phase [93].

5. Role of Pomegranate Extracts in PCOS

5.1. PCOS

PCOS is the prevailing endocrine disorder in women, with a prevalence rate of 4%– 18% among women of reproductive age [94]. PCOS is characterized majorly by the development of enlarged ovaries and numerous small cysts in the external layer of the ovaries [95]. PCOS is associated with an imbalance in the levels of female hormones, namely estrogen and progesterone, leading to an elevation in male hormones (androgens). This imbalance results in symptoms such as irregular menstrual cycles, hair loss, acne, and fertility issues [96]. Many women diagnosed with PCOS encounter insulin resistance, a condition where the body’s cells respond poorly to insulin [97]. This resilience can lead to increased insulin levels, which can contribute to weight gain and a heightened vulnerability to type 2 diabetes [98]. Additionally, PCOS is linked to metabolic irregularities, including dyslipidemia (abnormal lipid levels) and obesity, heightening the likelihood of developing CVD [99]. The exact origin of PCOS remains partially unclear, but it’s believed to stem from a combination of genetic predisposition and environmental influences [100]. The diagnosis of PCOS commonly relies on a combination of clinical indications, symptoms, and particular criteria, such as the Rotterdam criteria [101]. The emphasis in treatment lies in managing the symptoms and minimizing correlated health risks through lifestyle adjustments, including engaging in regular physical activity, maintaining a balanced diet, and managing weight [97]. Hormonal birth control pills may be recommended to regulate menstrual patterns and androgen levels [95]. To effectively treat PCOS, a comprehensive approach that considers both hormonal and metabolic dimensions is necessary [102].

5.2. Effect of Pomegranate Extract on PCOS

Although there have not been numerous studies on the efficacy of pomegranate extract in PCOS, some in vivo research has reported its effectiveness [103,104]. Hossein et al. [103] reported a significant increase in the concentrations of estrogen, testosterone, and androstenedione in the estradiol valerate-induced PCOS model compared with the control group, and they also reported that the elevated hormone levels in the PCOS model treated with pomegranate juice extract exhibited a significant decrease. Therefore, they recommended the consumption of pomegranate juice extract to improve the complex symptoms associated with PCOS. Ibrahim et al. [104] observed a notable elevation in serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, testosterone, and tissue malondialdehyde (MDA) in the PCOS group and histological alterations in the endometrial tissues. There was a considerable increase in the amount of collagen fibers in the endometrium, a noticeable increase in the expression of Ki67 and androgen receptor through immunohistochemistry, and a significant reduction in the average count of pinopodes. Concurrent application of pomegranate juice extract successfully normalized the levels of the investigated histological, biochemical, and immunohistochemical parameters. The endometrial histological changes associated with PCOS were reversed by pomegranate juice extract. Moreover, this effect can be attributed to its polyphenolic content, which has anti-inflammatory, antioxidant, anti-proliferative, anti-fibrotic, and anti-androgenic effects.

6. Role of Pomegranate Extracts in Breast Cancer

6.1. Breast Cancer

Breast cancer ranks as the second highest cause of cancer-related fatalities among women and has recently become the most prevalent type of cancer in the United States [105]. The widely recognized risk factors for developing breast cancer include getting older, having a family history of the disease, starting menstruation early, experiencing menopause later, prolonged use of estrogen replacement therapy, and having children at a later age [62]. There is a consensus that steroid hormones, especially estrogen, exert a substantial influence on the development of breast cancer [106]. Breast cancer treatment depends on various factors, including tumor type, size, stage, and the overall health of the patient. Frequently employed approaches to treat breast cancer encompass surgery, hormone therapy, chemotherapy, radiation therapy, and immunotherapy [107]. The mortality rate associated with breast cancer mortality rate is steadily increasing, prompting researchers to emphasize prevention as a key management strategy for this disease recently [108]. For centuries, the significance of natural substances has been acknowledged, with various factions advocating for the use of plant-derived compounds to prevent or treat diseases like breast cancer [109]. These naturally occurring compounds, referred to as phytochemicals, have garnered attention for their beneficial effects, particularly in plant-derived foods containing polyphenolic compounds [110].

6.2. Effect of Pomegranate Extract on Breast Cancer

Pomegranate extract has potential anti-cancer properties, especially against breast cancer [17,111]. Abundant in polyphenols, such as ellagic acid and punicalagin, pomegranate has exhibited cell anti-proliferation, anti-estrogenic, anti-inflammatory, and anti-angiogenic properties, indicating its potential to hinder the development and metastasis of breast cancer cells [112]. Pomegranate extract is capable of causing cell cycle arrest, a vital mechanism for preventing the unchecked growth of cancer cells. Additionally, it may trigger apoptosis, a programmed cell death process, in breast cancer cells, thereby contributing to the removal of impaired or abnormal cells [113,114]. Furthermore, the array of compounds present in pomegranates can either inhibit aromatase and 17β-hydroxysteroid dehydrogenase enzymes or demonstrate anti-estrogenic effects [115]. Furthermore, its anti-estrogenic properties might be advantageous in the treatment of hormone-dependent breast cancer [62]. The polyphenols in pomegranates can inhibit pro-inflammatory cytokines (interleukins (IL)-2, IL-4, IL-6, IL-12, IL-17, interferon-gamma inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, and tissue necrosis factor-α) and suppress inflammation. Additionally, it may help prevent angiogenesis by reducing the levels of vascular endothelial growth factor, a cytokine involved in the growth and formation of blood vessels, and promoting the migration inhibitory factor, a protein associated with cell movement inhibition. Inhibiting angiogenesis can limit tumor growth [116,117]. Pomegranate extracts have potential synergistic effects with existing breast cancer treatments, such as chemotherapy and hormone therapy, thereby improving their effectiveness [118].

7. Clinical Effects of Pomegranate Extract on Women’s Health

Several clinical studies of the effects of pomegranate extract in peri- and post-menopausal symptoms, PCOS, and breast cancer have been reported, and they are summarized in Table 3.

7.1. Clinical Effects of Pomegranate Extract Against Peri- and Post-Menopausal Symptoms

Clinical trials of pomegranate extract for the treatment of peri- and post-menopausal symptoms have been reported. Kim et al. [119] investigated the effect of pomegranate extract in 58 menopausal women. The participants were randomly assigned to two groups: one group received pomegranate extracts at a dosage of 1.5 g per day, while the other group took a placebo orally for 8 weeks. The group that received pomegranate extract exhibited a significant reduction in HFs score, HFs visual analog scale (VAS), HFs duration, and sweating VAS, indicating a notable decrease in patients’ HFs and sweating. Furthermore, the menopausal rating scales and Kupperman index scores significantly decreased in the group that consumed pomegranate extract. This outcome indicates a potential benefit of pomegranate extracts for women experiencing menopause.
Huber et al. [120] investigated the safety and effectiveness of PSO in patients with menopausal symptoms. Over the course of 46 months, 78 patients experiencing menopausal symptoms consumed 1000 mg of PSO daily, taking 2 capsules per day. The individuals demonstrated notable improvements across all aspects of the menopausal rating scale, particularly urogenital symptoms (dry vagina).

7.2. Clinical Effects of Pomegranate Extract on PCOS

Multiple clinical studies have documented the potential impacts of pomegranate extracts on PCOS. Esmaeilinezhad et al. [126] reported the effects of synbiotic pomegranate juice (SPJ) on glycemic indices, sex hormone profiles, and anthropometric indices in PCOS. Ninety-two patients with PCOS were administered 2 L per week of SPJ, pomegranate juice (PJ), and synbiotic beverage (SB) for 8 weeks. The control group received 2 L of a placebo beverage (PB) per week. SPJ contains pomegranate juice with inulin and lactobacillus, SB consists of water, inulin, lactobacillus, and pomegranate flavoring, and PB contains water and pomegranate flavoring. Substantial alterations were observed in insulin resistance within the SPJ and SB groups, with a notable increase in insulin sensitivity. Insulin levels changed significantly in both the SPJ and SB groups. In addition, body mass index (BMI), weight, and waist circumference were significantly reduced in the SPJ and SB groups. Furthermore, a significant decrease in testosterone levels was observed in both the SPJ and SB groups. Conversely, there were no significant changes in the levels of LH, fasting plasma glucose, and FSH across any of the groups. The findings indicate that the innovative beverage SPJ may have the potential to enhance insulin levels, reduce insulin resistance, regulate testosterone levels, aid in weight management, lower BMI, and decrease waist circumference among individuals diagnosed with PCOS.
Abedini et al. [128] studied the impact of concentrated pomegranate juice (CPJ), a different type of pomegranate extract, on CVD risk factors among women diagnosed with PCOS. In their trial, which included 44 women aged 18–40 with PCOS and a BMI of 25 kg/m2 or higher, the intervention group consumed 45 mL. CPJ daily with 180 mL of water. Compared with the control group, CPJ significantly reduced systolic and diastolic blood pressure, serum triglyceride (TG) levels, and TG/HDL-C ratio. These discoveries indicate that CPJ has positive effects on blood pressure, serum levels of TG and HDL-C, and the TG/HDL-C ratio among women with PCOS.

7.3. Clinical Effects of Pomegranate Extract on Breast Cancer

Pomegranate extract and polyphenols have been thoroughly investigated for their potential to combat cancer, particularly in studies focusing on breast cancer, conducted both in vitro and in vivo [130,131,132,133]. However, presently, there is only one reported clinical study [111]. This limited number of clinical studies may be attributed to the availability of various anticancer agents for breast cancer treatment. Kapoor et al. [111] examined the impact of drinking pomegranate juice on hormonal indicators linked to the risk of breast cancer. Sixty-four post-menopausal women, who were in good health, were randomly assigned to consume either 8 ounces (236.6 mL) of 100% commercial pomegranate juice (as the intervention group) or apple juice (as the control group) for a duration of 3 weeks. Overall, individuals consuming pomegranate juice did not experience significant reductions in serum sex hormone levels or sex hormone-binding globulin compared to those in the control group. Yet, upon examining a subset comprising 38 women of average weight, those who consumed pomegranate juice exhibited a notable reduction in estrogen and testosterone levels in contrast to the control group.

8. Conclusions

Pomegranate extract is an abundant reservoir of diverse compounds known for their advantageous physiological effects, especially antioxidant and anti-inflammatory properties. About women’s reproductive health, pomegranate extract contributes to bone health and prevents osteoporosis in women at peri- and post-menopause through the activities of certain compounds, such as antioxidants and ellagic acid. Additionally, in women at peri- and post-menopause, pomegranate extract causes improvements in cholesterol levels and blood pressure, reducing the risk of heart diseases, such as atherosclerosis. Its anti-inflammatory properties can be used in treating symptoms related to hormonal changes during menopause. Pomegranate extract is beneficial in women with PCOS as it improves insulin sensitivity. Its anti-inflammatory effects can assist in managing chronic inflammation associated with PCOS. Pomegranate extract reportedly influences hormonal balance, particularly by regulating reproductive hormones in women with PCOS. Pomegranate extract exhibits potent antioxidant and anti-inflammatory effects, with specific compounds like ellagic acid having anticancer properties. Pomegranate extract may influence hormonal receptors in breast cancer cells, particularly affecting hormone-sensitive breast cancer. Currently, the efficacy of pomegranate extract in women at peri- and post-menopause, patients with PCOS, and patients with breast cancer has been observed clinically. However, more clinical studies are needed to determine the appropriate formulations and dosages for using pomegranate extracts to prevent or treat these conditions.

Author Contributions

Conceptualization, J.Y.J., D.K., E.I. and N.D.K.; investigation, J.Y.J. and D.K.; writing—original draft preparation, J.Y.J.; writing—review and editing, D.K., E.I. and N.D.K.; supervision, E.I. and N.D.K.; project administration, J.Y.J. and N.D.K.; funding acquisition, N.D.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2022R1A6A3A01085858) (J.Y.J.), a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2021R1F1A1051265), and the Basic Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1D1A1B07044648) (N.D.K.).

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Physiological benefits of pomegranate extract.
Figure 1. Physiological benefits of pomegranate extract.
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Figure 2. Major phytochemical compounds found in pomegranate extract. (A–C) Flavonoids (A) Catechin; (B) Kaempferol; (C) Quercetin; (D–F) Anthocyanins (D) Cyanidin-3-glucoside; (E) Delfinidin-3-glucoside; (F) Pelargonidin-3-glucoside; (G–I) Tannins (G) Punicalagin; (H) Punicalin; (I) Ellagic acid; (J–L) Fatty acids and organic acids (J) Oleic acid; (K) Linoleic acid; (L) Coumestrol; (M–O) Sterols (M) Asiatic acid; (N) Stigmasterol; (O) Cholesterol.
Figure 2. Major phytochemical compounds found in pomegranate extract. (A–C) Flavonoids (A) Catechin; (B) Kaempferol; (C) Quercetin; (D–F) Anthocyanins (D) Cyanidin-3-glucoside; (E) Delfinidin-3-glucoside; (F) Pelargonidin-3-glucoside; (G–I) Tannins (G) Punicalagin; (H) Punicalin; (I) Ellagic acid; (J–L) Fatty acids and organic acids (J) Oleic acid; (K) Linoleic acid; (L) Coumestrol; (M–O) Sterols (M) Asiatic acid; (N) Stigmasterol; (O) Cholesterol.
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Table 1. Phytochemicals in pomegranate juice.
Table 1. Phytochemicals in pomegranate juice.
Chemical class Phytochemicals
Amino acids Aspartic acid, Glutamic acid, Methionine, Proline, Valine
Anthocyanins Cyanidin-3-O-glucoside, Cyanidin-3,5-di-O-glucosdie, Delphinidin-3-O-glucoside, Delphinidin-3,5-di-O-glucoside, Pelargonidin-3-O-glucoside, Pelargonidin-3,5-di-O-glucoside
Ellagitannins Casuarinin, Corilagin, Gallagyldilacton, Punicalagin, Punicalin
Flavan-3-ols Catechin, Epicatechin, Epigallocatechin-3-gallate
Flavonols Quercetin, Isoquercetin, Rutin
Hydroxybenzoic acid/Hydroxycinnamic acid Caffeic acid, Chlorogenic acid, Ellagic acid, Gallic acid, Quinic acid
Indoleamines Melatonin, Serotonin, Tryptamine
Organic acids Ascorbic acid, Citric acid, Fumaric acid, Malic acid, Succinic acid, Tartaric acid
Sugars Glucose, Fructose, Sucrose
Table 2. Phytochemicals in pomegranate seed.
Table 2. Phytochemicals in pomegranate seed.
Chemical class Phytochemicals
Conjugated fatty acids Punicic acid
Non-conjugated fatty acids Linoleic acid, Oleic acid, Palmitic acid, Stearic acid
Hydroxybenzoic acid 3,3’-Di-O-methylellagic acid, Ellagic acid, 3,3’-4’-Tri-O-methylellagic acid
Isoflavones Daidzein, Genistein
Lignins Coniferyl-9-O-[β-dapiofuranosyl(1→6)-O-β-D-glucopyranoide, Icariside D1, Phenylethyl rutinoside, Sinapyl-9-O-[βD-apiofuranosyl(1→6)-O-β-D-glucopyranoide
Sterols and steroids Camesterol, Cholesterol, 17-α-Estradiol, Estriol, Estrone, β-Sitosterol, Stigmasterol, Testosterone
Tocopherols γ-Tocopherol
Triterpenes Oleanolic acid, Ursolic acid
Table 3. Clinical effects of pomegranate extract on women’s health conditions.
Table 3. Clinical effects of pomegranate extract on women’s health conditions.
Conditions Interventions Dosage/Duration Brief Summary Outcomes Refs.
Menopausal Symptoms
MSs women
(Experience of menstrual irregularities lasting for more than 3 months or amenorrhea persisting for over 1 year postmenopause)		 PE,
Placebo		 125 mg of PE per 500 mg tablet, 12 tablets per day (= 1.5 g of PE per day) / 8 weeks Effects of PE on the MSs women Decrease in HFs score, HFs VAS, sweating VAS, HFs duration, MRS, KI, MSs frequency, and MENQOL [119]
MSs women
(Mean duration of MSs of 46 months)		 PSO,
Placebo		 1000 mg of PSO per day in 2 capsules / 8 weeks Investigating the safety and effectiveness of PSO for MSs Reduction in MRS symptoms (HFs); Improvement in urogenital tract symptoms (dry vagina) [120]
Post-MSs women
(12 months of amenorrhea)		 PSO,
Placebo		 Two doses of 30 mg PSO per day / 12 weeks Investigating the potential effects of PSO on MSs Decrease in the score of the menopause rating scale II, the number of HFs, and the sum score of vegetative somatic symptoms; Improvement in sleeping disorders [121]
MSs women Pomegranate supplement,
Placebo		 3 mL three times per day / 4 weeks Effects of pomegranate supplement on MSs and quality of life in menopausal women Decrease in modified-KI and MENQOL [122]
Post-MSs women with type 2 diabetes CW, PE, TW, TPE 150 mL of PE per day / 6 weeks Effects of aerobic exercise and PE on antioxidant markers in post-MSs women with type 2 diabetes Increase in GPX, SOD, GSH, and TAC; The highest levels of the antioxidants in TPE [123]
Osteopenic women 2 PE capsules,
2 placebo capsules		 2 PE capsules per day / 6 month Changes in biomarkers related to bone absorption and formation in post-MSs women Urinary NTX and serum P1NP in post-MSs women
(Completed, No study results posted) 		[124]
Pre-MSs women PE,
Placebo		 2 mL of PE three times per day / 10 days during the 3 menstrual cycles (from 7 days before to 3 days after the estimated onset of menstruation) Effect of pomegranate supplementation on symptom severity in pre-MSs women Pre-MSs scale (Recruiting) [125]
PCOS
PCOS patients SPJ, PJ, SB, PB 2 L of PJ, SB, SPJ, PB per week / 8 weeks Effect of SPJ on glycemic, sex hormone profile, and anthropometric indices in PCOS Decrease in insulin resistance, FBS, testosterone, BMI, waist, and hip circumference; Increase in insulin sensitivity [126]
PCOS patients SPJ, PJ, SB, PB 300 mL of PJ, SB, SPJ, PB per day / 8 weeks The effect of SPJ on cardiovascular risk factors in PCOS patients Decrease in TC, LDL-C, MDA, hs-CRP, and blood pressure; Increase in HDL-C and TAC [127]
Women with PCOS
(18–40 years and
BMI of ≥ 25 kg/m2 )		 CPJ,
Placebo		 45 mL of CPJ in combination with 180 mL water per day / 8 weeks The effect of CPJ consumption on risk factors of cardiovascular diseases in women with PCOS Decrease in systolic and diastolic blood pressure and TG levels, TG/HDL-C ratio; Increase in LDL-C and HDL-C [128]
Women with PCOS
(18–40 years and
BMI of ≥ 25 kg/m2)		 CPJ,
Placebo		 45 mL of CPJ in combination with 180 mL water per day / 8 weeks The effect of CPJ on biomarkers of inflammation, oxidative stress, and sex hormones in overweight and obese women with PCOS Decrease in serum testosterone levels [129]
Breast Cancer
Healthy post-MSs women 100% commercial PJ,
100% apple juice (control)		 8 ounces (4 ounces in the morning and 4 ounces in the early evening) per day / 3 weeks effects of PJ on hormonal biomarkers of breast cancer risk Decrease in estrone and testosterone levels
(normal weight women)		 [111]
BMI, body mass index; CPJ, concentrated pomegranate juice; CW, control water; FBS, fasting blood sugar; FSH, follicle-stimulating hormone; GPX, glutathione peroxidase; GSH, plasma glutathione; HDL-C, high-density lipoprotein cholesterol; HFs, hot flashes; hs-CRP, high sensitive C-reactive protein; KI, Kupperman Index; LDL-C, low-density lipoprotein cholesterol; LH, luteinizing hormone; MDA, malondialdehyde; MENQOL, menopause-specific quality of life; MRS, menopausal rating scale; MSs, menopausal symptoms; NTX, N-terminal telopeptide; PB, placebo beverage; PCOS, polycystic ovarian syndrome; PE, pomegranate extract; P1NP, procollagen type 1 amino-terminal propeptide; PJ, pomegranate juice; PSO, pomegranate seed oil; SB, synbiotic beverage; SOD, superoxide dismutase; SPJ, synbiotic pomegranate juice; TAC, total antioxidant capacity; TC, total cholesterol; TG, serum triglyceride; TPE, training-pomegranate extract; TW, training-water; VAS, visual analog scale.
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