MEDICINAL EFFECTS OF NIGELLA SATIVA IN GYNECOLOGICAL DISORDERS: A SYSTEMATIC REVIEW

MEDICINAL EFFECTS OF NIGELLA SATIVA IN GYNECOLOGICAL DISORDERS: A SYSTEMATIC REVIEW

H. K. Deepthika, K. P. K. R. Karunagoda and P. K. Perera *

Institute of Indigenous Medicine, University of Colombo, Colombo, Sri Lanka.

ABSTRACT: Comprehensive search of previously published research was conducted in PubMed, Science Direct, Scopus, and google scholar databases for studies published between 2012 and August 2021. The keywords used in combination to search for articles included Nigella sativa and “Gynecology”. In the first stage, the total articles obtained from searching the above databases using the above keywords were pooled together, and duplicate articles were removed. The remaining articles were primarily screened by reading the title and abstracts and selecting the most relevant articles. In the last stage, articles were reviewed again by reading the entire article, and those that did not meet the inclusion requirements were eliminated. A manual search was conducted using the reference list of the included research publications to collect additional data. In the various databases, the literature search found the following number of research articles: PubMed (n=11), Science Direct (n=35), Scopus (n=07), and Google Scholar (n=1070). After removing duplicates, there were 1062 articles. Those articles were further screened first by reading topics and abstracts and secondly, reading full text that did not match the inclusions was removed. After removing those articles, there were 40 articles, and after adding 05 manual search articles, finally, 45 articles were included in the systematic review. Nigella sativa has medicinal benefits for gynecological disorders such as PCOS, menopause-related issues, Hyperprolactinemia, Candidiasis, Trichomoniasis, Cervical cancer, Breast cancer, ovarian cancer, Premenstrual syndrome and Pre-eclampsia. Nigella sativa also improves endometrium, oocyte maturity and quality and reduces ovarian tissue damage without any adverse effects.

Keywords: Nigella sativa, Black cumin, Medicinal effects, Gynecological disorders

INTRODUCTION: Herbal drugs are used by nearly 80% of the world's population for health care, particularly in developing countries, according to the World Health Organization ¹. Nigella sativa, a species of the Ranunculaceae family, is a widely used plant in Ayurveda medical system. It is also known in English as "Black cumin" and "Black seed," in Sinhala as "Kaluduru" and in Sanskrit as "Krishna-jira." Almost seeds of the Nigella sativa have medicinal use ². This plant is cultivated in Panjab and Bihar in India ³. The seeds are considered bitter and pungent in taste.

Ayurveda mentions its properties as a stimulant, analgesic, appetizer, digestive, deodorant, aromatic, anthelmintic, emmenagogue, galactagogue, diuretic, thermogenic, febrifuge, carminative and it is widely used for a variety of diseases in the respiratory, digestive, reproductive, urinary and central nervous systems ^{4, 5}. In-vitro and in-vivo research had demonstrated and proven medicinal effects of Nigella sativa such as, antidiabetic activity, cardiovascular activity, gastroprotective activity, pulmonary activity, central nervous system activity, nephroprotective activity, hepatoprotective activity immuno-modulation activity, antioxidant activity, antimicrobial activity and reproductive activity, etc. This systematic review was aimed to analyze the most recent scientific research and provide a complete overview of the medical effects of Nigella sativa in gynecological problems that have been scientifically validated.

MATERIAL AND METHODS: A systematic review of published full research papers reporting the medicinal effects of Nigella sativa in gynecological disorders was designed based on the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement guidelines ⁶. Eligibility criteria are based on the PICO (Population, Intervention, Comparison, Outcomes) approach, study design, Language, and date.

1. Types of Studies: The therapeutic effects of Nigella sativa on gynecological illnesses were explored in this systematic study.

1.1. Inclusion Criteria: All the published full research papers within the period of 2012 to August 2021, written in English, studied the effect of Nigella sativa on gynecological problems were included.

1.2. Exclusion Criteria: Other than English, research articles were written in a variety of other languages, Research papers published before the year 2012, abstract-only papers, journals with no full text available, case reports, case series, and systematic review studies were all eliminated.

1.3. Types of Outcomes: The primary outcome was the medicinal effect and secondary outcome was safety or adverse effects of Nigella sativa.

1.4. Search Strategy: A comprehensive search of previously published research articles was conducted in PubMed, Science Direct, Scopus, and google scholar databases for studies published between January 2012 and August 2021. The keywords used in combination to search for articles included "Nigella sativa" and "Gynecology." Other filters were selected as the limit to medicine, dentistry and complementary medicine. All relevant articles were gathered from databases in the first stage. The total articles found by searching the above databases with the above keywords were pooled together in the second stage, and duplicate articles were excluded. The remaining papers were often screened by reading the titles and abstracts, with the most relevant articles chosen. In the last stage, included articles were reviewed again by reading the entire article and those that did not meet the inclusion criteria were eliminated. A manual search was conducted via the reference list of the included research publications to collect additional data.

1.5. Evaluation of Article Quality: Two authors independently assessed the quality and acceptance of the articles.

1.6. Data Extraction: Information related to the study was collected, including the year of publication, authors' name, Type of study, Population, Sample size, intervention, outcomes, and Reference.

RESULTS AND DISCUSSION:

2. Literature Search: Using the above-mentioned search parameters, the following number of research articles were found in the various databases; PubMed (n=11), Science Direct (n=35), Scopus (n=07) and Google scholar (n=1070). After removing duplicates, there were 1062 articles. Those articles were further screened first by reading topics and abstracts, and secondly, reading full text that did not match the inclusions was removed. After removing those articles, there were 40 articles, and after adding 05 additional articles, finally, 45 articles were included in the systematic review. Fig. 1 summarizes the search approach. Finally, 13 clinical trials, 19 in-vivo studies, and 17 in-vitro research were analyzed in Tables 1, 2, and 3.

FIG. 1: SUMMARIZED SEARCH STRATEGY

2.1 In-vivo Evidence to Relive Primary Dysmenorrhea and Premenstrual Syndrome: Using isolated uterine horns, Aqel and Shaheen investigated the effects of the volatile oil of Nigella sativa seeds on the uterine smooth muscle of rats and guinea pigs in-vitro. The volatile oil from Nigella seeds suppressed both spontaneous and oxytocin-induced contractions in the uterine smooth muscle of rats and guinea pigs ⁷. N. sativa's analgesic effect has also been clinically demonstrated ^{8, 9}. Except for depression and stomach bloating, Nigella sativa oil was found to diminish the intensity of all Premenstrual syndrome symptoms ¹⁰ and Huseini et al. verified the analgesic effects of Nigella sativa on patients with cyclic mastalgia ¹¹.

2.2 In-vivo Evidence to Improve Oocyte Maturity and Quality: In-vivo animal studies have also shown that supplementing mice with N. sativa improves oocyte quality and preimplantation embryo development, resulting in improved reproductive performance ^{12, 13}. To improve reproductive performance, a nutritional supply of N. sativa seeds could be utilized instead of hormonal therapies. Protein, fat, carbs, vitamins, minerals, and beta-carotene are all abundant in N. sativa seeds ^{14, 15}.

2.2 In-vivo Evidence to Improve Endometrium: Raith A. S. Al-Saffar and Mohammad K. M. Al-Wiswasy conducted an in-vivo study on the pharmacological effects of Nigella sativa on the reproductive system in experimental rats.

As a result, vaginal smears of rats treated with a crude aqueous extract of Nigella sativa seeds showed a shorter vaginal cycle with a prolongation of both the estrus and metestrus phases; the diestrus phase was undetectable and showed an increase in the uterine wet weight of all experimental subgroups, with a profound and persistent diffuse endometrial hypertrophy, and enhanced glandulogenesis.

This adds to the evidence that the administrated crude aqueous extract of N. sativa seeds has a postovulatory, progesterone-like effect, as seen in the vaginal smears of treated rats. As a result, this suggests that N. sativa may have elicited its effects by boosting the endogenous release of estrogen and/or progesterone ¹⁶.

2.3 In-vivo Evidence to Relieve PCOS Symptoms: In a double-blind placebo-controlled clinical trial, researchers used two soft gel capsules of Nigella sativa oil (500 mg each capsule) or placebo at night for sixteen weeks to prove the effect of Nigella sativa oil on oligomenorrhea, amenorrhea, and laboratory characteristics in patients with the polycystic ovarian syndrome. Menstruation was assessed using the cycle length, the duration, the occurrence of menstruation, and the severity of bleeding. The intervention group's menstrual interval was considerably shorter than the control group's following the trial. The intervention group had a considerably higher menstrual cycle frequency than the placebo group. As a result, it had proven N. sativa is a potential alternative treatment for PCOS-related menstrual abnormalities ¹⁷.

The average duration of menstruation and the monthly cycle ratio increased significantly, according to a pilot study conducted by Seyedeh Atieh Naeimi et al. additionally, the significant reduction in metabolic variables such as triglycerides, cholesterol, AST, and especially FBS and fasting insulin improved insulin resistance. As a result, it had suggested that N. Sativa could treat PCOS patients with oligo-amenorrhea ¹⁸.

Another randomized clinical research had done to see if supplementing metformin with thymoquinone (bioactive component derived from Nigella sativa) could help with symptoms of the polycystic ovarian syndrome. Patients who received a combination of black cumin oil capsules and metformin had a significant reduction in the number of patients suffering from amenorrhea or oligomenorrhea, significant weight loss (reduced BMI), body fat redistribution (reduced W/H ratio), regaining oxidative balance with a significant increase in antioxidant enzymes such as superoxide dismutase activity and regaining oxidative balance. The large drop in body weight in patients treated with a combination of thymoquinone and metformin may have increased sex hormone binding globulin (SHBG), and a subsequent fall in free testosterone levels may have contributed to the return of regular menstrual periods ¹⁹. Phyto estrogenic effect of Nigella sativa is another reason for the reduced menstrual intervals ²⁰.

Thymoquinone’s anti-inflammatory and anti-oxidant properties have also been linked to the return of menstrual cyclicity ²¹. Recent research has linked oxidative stress to the etiology of PCOS and shown that taking antioxidants improved symptoms significantly ²². In an in-vivo study to determine the anti-androgenic and insulin-sensitizing effects of Nigella sativa oil on polycystic ovary and related dyslipidemia and redox abnormalities, it was discovered that Nigella sativa oil dramatically decreased the number of cystic follicles. The effects of N. sativa oil on serum levels of E2 (Estradiol) and LH were significantly decreased and lowered serum T (Testosterone), and FSH levels ²³.

2.4 In-vivo Evidence to Relieve Menopause-related Problems: Treatment with N. sativa has a therapeutic and protective effect on weight gain, lipid profile, blood glucose, and hormone levels in the perimenopausal period and is thought to play an important role in the development of metabolic syndrome following menopause ²⁴. Menopause is linked to an increase in oxidative stress as well as a drop in several antioxidant markers. The use of garlic extracts and Nigella sativa seeds may assist the better balance between blood oxidants and antioxidants in healthy postmenopausal women, according to a study conducted by Randa M Mostafa et al. Low amounts of plasma malondialdehyde were found, along with enhanced erythrocyte glutathione peroxidase and superoxide dismutase activity, in this investigation ²⁵.

Parhizkar et al. studied the effect of methanol and hexane extract of N. sativa on vaginal epithelial cells in menopausal mice in an animal study. The findings revealed that N. sativa, particularly its methanol extract, had estrogenic properties that are lower than conjugated estrogens. This characteristic can be utilized to treat hormone replacement therapy in women who have reached menopause²⁶. Maryam Molaie et al. tested the efficacy of a phytotherapeutic intervention with N. Sativa and Vitex agnus-castus. According to their randomized, double-blind, placebo-controlled pilot trial, using a combination of N. sativa and Vitex agnus-castusto improves the outcome of citalopram in managing hot flashes is an effective supplementary therapy ²⁷. Nigella sativa, on the other hand, has been shown to be ineffectual in terms of vasomotor symptoms and sleep quality in menopausal women ²⁸. In ovariectomized rats, Nigella sativa extract did not improve memory performance. Despite this, Sahak's research shows that N. Sativa can increase spatial working memory in Sprague Dawley normal mice ²⁹. This could be attributed to several factors. The first determinant is the exposure time of N. sativa. The injection of N. sativa to hypo estrogen mice was done for three weeks (21 days) in this study, whereas the prior study had N. Sativa exposure for 20 weeks. Another aspect that may influence the effect of N. sativa in this study is the neuron's state at the moment N. sativa is administered. If the neurons that regulate the memory system have just diminished cell function and have not suffered structural damage because of the degeneration process, memory enhancements will be more obvious ³⁰.

2.5 In-vivo Evidence to Decrease Prolactin: After the third week of administration with a liquid solution of Nigella sativa, in-vivo studies showed a significant drop in prolactin hormone levels in newly parturition rabbits ³¹. Hence, Nigella sativa seeds can thus be used to treat infertility and menstrual cycle irregularities caused by excessive prolactin hormone production during and after lactation.

2.6 In-vivo Evidence to Relieve Candidiasis: Farzaneh Adiban Fard et al. tested the therapeutic effects of Nigella sativa Linn seed powder on Candida albicans Vaginitis in a randomized, triple-blind, placebo-controlled clinical experiment. They gave the study group Nigella sativa Linn capsules and clotrimazole vaginal cream for seven days and the control group placebo capsules and clotrimazole vaginal cream. After treatment, there was a statistically significant difference in vaginal itching, discharge, irritation, vulvovaginal redness, and inflammation between the two groups. The study group's culture and wet mount findings improved dramatically after therapy. In most frequent symptoms and indicators of vaginitis, a combination of Nigella sativa L. capsules and clotrimazole vaginal cream was more beneficial than clotrimazole vaginal cream alone³². In-vivo investigations have also shown that N. sativa's therapeutic impact is achieved by reducing the number of fungal colonies while boosting IgM levels ^{33, 34}.

Thymoquinone (TQ) is a major constitute of Nigella sativa oil and in some studies, directly used the TQ-containing cream and proved that the anti-candidiasis activity was increased according to the concentration of TQ and had no significant effects on the growth of normal cell lines ³⁵.

2.7 In-vitro Evidence to Relieve Trichomoniasis: Several in-vitro studies have investigated the impact of Nigella sativa on Trichomonas vaginalis. The parasite is highly toxic to Nigella sativa oil, which causes severe cell damage, including cytoplasmic and nuclear damage ³⁶. After 96 hours of additional, the inhibitory effect of N. sativa alcoholic extract on the number and activity of Trichomonas vaginalis parasites were shown, and doses of 650 and 750 mg/ml showed the strongest inhibitory action for parasite growth ³⁷. Also, the crude extract of N. sativa is an anti-trichomonas agent, particularly when combined with metronidazole, which has a high synergic effect ³⁸. Nigella sativa oil could be a viable, less expensive, and safer alternative to metronidazole in the treatment of trichomoniasis ³⁹.

2.8 In-vitro Evidence to Relieve Cervical Cancer: The volatile oil derived from the seeds of N. sativa has anticancer characteristics like cisplatin and could be used as adjuvant therapy. It lowers adhesion protein in cervical cancer cells and diminishes it in a dose-dependent way. Morphological research revealed shrinkage and apoptotic alterations in grown cells, confirming the anticancer activity ⁴⁰. Ethanol extract of N. sativaalso significantly inhibited proliferation and colony formation and induced apoptosis in cervical cancer cells ⁴¹. Further, thymoquinone (a key bioactive component derived from Nigella sativa) has been studied in vitro and found to be a potential chemotherapeutic agent for cervical cancer. It decreases cell viability in a dose- and time-dependent way ^{42, 43}.

2.9 In-vitro and In-vivo Evidence to Relive Ovarian Cancer: As mentioned above, thymoquinone (TQ) is a powerful anti-ovarian cancer treatment that works by modifying apoptotic activity. Several in-vitro and in-vivo investigations have been conducted to demonstrate its anticancer properties in the ovary. TQ inhibited ovarian cancer cell multiplication while increasing apoptosis and autophagy. However, the ethnicity of cells had a significant impact on the chemotherapy's effectiveness. TQ primarily affects the autophagy mechanism to suppress tumor proliferation in ovarian cancer of the Chinese population ^{44, 45}. Thymoquinone and cisplatin (a chemotherapy medication used in allopathic medicine) both demonstrated comparable anticancer effects. Cisplatin lowered tumor cell growth while increasing apoptosis, resulting in a lower total tumor burden. Combining TQ with cisplatin reduced these markers further, demonstrating that the medications work together ^{46, 47}.

2.10 In-vitro and In-vivo Evidence to Relieve Breast Cancer: Overexpression of the chemokine receptor type 4 (CXCR4) has been linked to enhanced cell proliferation and metastasis, as well as serving as a predictor of poor prognosis in breast cancer patients. The effect of thymoquinone generated from Nigella sativa seeds on the expression and regulation of CXCR4 in breast cancer cells and the influence of bone metastases in a breast cancer mice model have been investigated. Thymoquinone has suppressed tumor growth and significantly reduced tumor vascular volume in a dose-dependent manner. TQ at dosages of 2 or 4 mg/kg b.w. administered intraperitoneally for four weeks can inhibit the growth and spread of breast cancer tumors ⁴⁸. Another two in-vitro studies were conducted to examine TQ's anti-angiogenic properties and the cytotoxic effects of thymoquinone-loaded nanostructured lipid carrier (TQ-NLC) on breast and cervical cancer cells lines. Thymoquinone was shown to have a dose-dependent effect on the viability of human breast MDA-MB-231 cells. TQ-NLC exhibited antiproliferative action in all cell lines in a dose-dependent manner, which was most cytotoxic towards breast cancer (MDA-MB-231) cells ^{49, 50}.

2.11 In-vivo Evidence to Reduce Tissue Damage of the Ovary: Two animal experiments had done to highlight Nigella sativa's ovarian tissue-protective properties. The effects of Nigella sativa in experimental ischemia and ischemia/reperfusion (I/R) injury in rat ovaries were evaluated biochemically and histopathologically, and it was proven that Nigella sativa administration is effective in reversing tissue damage caused by ischemia and/or ischemia/reperfusion in ovaries ⁵¹. Another study had used a rat model of ovarian torsion to assess the effects of Nigella sativa oil on ovarian oxidative damage following ischemia-reperfusion injury and found that Nigella sativa oil is ineffective in reducing oxidative stress-related biochemical damage in ovarian ischemia-reperfusion injury. However, antioxidant effects were observed ⁵².

2.12 In-vivo Evidence to Relive and Prevent Post-partum Infections: To determine infection prevention management during post-partum with administering Nigella sativa, an in-vivo study was done and found that provision of Nigella sativa did not affect the average number of leukocytes, lymphocytes, and monocytes in adult female mice after childbirth ⁵³.

2.13 In-vivo Evidence of Favorable Effects for Pre-eclampsia: Pre-eclampsia is characterized by high blood pressure and proteinuria at 20 weeks or more of pregnancy ⁵⁴. An ischemic placenta fills the bloodstream with soluble chemicals and cell debris, causing systemic inflammation and maternal oxidative stress. This causes endothelial dysfunction and the severe symptoms that lead to pre-eclampsia ⁵⁵. To keep the circulatory system running smoothly, healthy endothelial cells produce a balanced amount of endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors. Nitric oxide (NO) is an EDRF that induces smooth muscle relaxation in blood vessels. Even in arterioles, smooth muscle relaxation causes blood vessel dilatation, lowering vascular resistance and enhancing tissue perfusion ⁵⁶. In-vitro studies of the effect of Nigella sativa ethanol extract on nitric oxide (NO) levels and renal arteriole diameter in a pre-eclampsia mouse model revealed that treatment with N. sativa ethanol extract increases NO (nitric oxide) levels and enlarges renal arteriole diameter in a dose-dependent manner ⁵⁷. Another study looked at the effects of a black cumin seed ethanol extract on angiotensin II type 1-receptor autoantibody (AT1-AA- A is a factor known to be involved in pre-eclampsia.) serum levels and endothelin-1 (ET-1, which causes changes in renal function, increased Total Peripheral Resistance (TPR), and eventually hypertension) expression in the placenta in a pre-eclampsia patient. In a pre-eclampsia mouse model, ethanol extract of black cumin seeds decreases AT1-AA serum levels and represses ET-1 expression in the placenta ⁵⁸.

TABLE 1: CLINICAL STUDIES OF NIGELLA SATIVA

TABLE 2: IN-VIVO ANIMAL STUDIES OF NIGELLA SATIVA

TABLE 3: IN-VITRO RESEARCH STUDIES OF NIGELLA SATIVA

Nigella sativa was proven its medicinal benefits for gynecological problems such as PCOS, menopause-related issues, Hyperprolactinemia, candidiasis, Trichomoniasis, Cervical cancer, Breast cancer, ovarian cancer, Premenstrual syndrome and Pre-eclampsia, according to available in-vitro and in-vivo evidence. These effects were given to several forms of Nigella sativa seeds, including crude powder, ethanol extract, methanol extract, hexane extract, aqueous extracts, and oil. N. sativa's estrogen and progesterone-boosting properties could help with follicular maturity, follicular quality, endometrial enhancement, and menopause-related symptoms. Its anti-inflammatory and antioxidant effects also have a favorable impact on ovarian function.

Further, its anti-inflammatory and anti-oxytocic potential effects relieve primary dysmenorrhea and premenstrual syndrome. The action of thymoquinone (TQ), a key bioactive component derived from Nigella sativa, was used in most research. Ten research papers used thymoquinone directly, while others used Nigella sativa as a source of thymoquinone. It reduces tumor growth by regulating apoptotic activity while not affecting normal cell lines' proliferation. Thymoquinone also prevents organ damage by free radicals by preventing the formation of Reactive Oxygen Species. As a result, Nigella sativa can help with various cancer treatments and has favorable effects on pre-eclampsia. Nigella sativa was found to be extremely poisonous to the parasite. It produces severe cell damage, including cytoplasmic and nuclear death, and can be utilized in antifungal and trichomonas vaginalis treatments safely and efficiently. The review's limitation was that most of the research papers were identified on Google Scholar, with only a few publications found in other well-known databases.

CONCLUSION: Nigella sativa has medicinal benefits for gynecological disorders such as PCOS, menopause-related issues, Hyperprolactinemia, Candidiasis, Trichomoniasis, Cervical cancer, Breast cancer, Ovarian cancer, Premenstrual syndrome and Pre-eclampsia, according to the available in-vitro and in-vivo evidence. Nigella sativa also increases endometrium, oocyte maturity, and quality and reduces ovarian tissue damage without any adverse effects; to further evaluate whether these impacts have public health implications, randomized controlled clinical trials will be required.

Declarations:

Availability of Data and Materials: All data generated or analyzed during this study are included in this published article.

ACKNOWLEDGEMENT: We wish to express our sincere graduate to all the authors of the research articles we have utilized for the systematic review.

COMPETING INTERESTS: There were no conflicts of interest declared by the authors.

Funding: This study did not receive specific financing from the government, commercial, or non-profit organizations.

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    How to cite this article:

    Deepthika SHK, Karunagoda KPKR and Perera PK: Medicinal effects of Nigella sativa in gynecological disorders: a systematic review. Int J Pharm Sci & Res 2022; 13(8): 2977-87. doi: 10.13040/IJPSR.0975-8232.13(8).2977-87.

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