INTRODUCTION:

The word ‘nutraceutical’ consists of two words, ‘Nutrient ‘and ‘Pharmaceuticals’. Nutrient supports the life of human beings or animals.¹Nutraceuticals are the food supplements that play a vital role to maintain healthy body and provide essential supplements required by the body in order to regulate body’s metabolic process as well as to prevent from diseases^.2.Nature provides us a vast diversified flora and fauna which are used tremendously from a long time by different civilizations for their health promoting effects.

Unlike modern day synthetic drugs, nutraceuticals have the ability to provide both preventive action as well as nutritive action without exerting any adverse effects. Hence, there is increase in the utilization of nutraceuticals in healthcare system. Nutraceuticals have gained interest worldwide ascribable to their nutritional and therapeutic effects without any toxic issues. They also does not require and regulatory criteria which makesthem easy for marketing.³Nowadays, nutraceuticals are indicated for different conditions including neurological disorders, cardiovascular disorders, atherosclerosis, cancer, diabetes and reproductive disorders.^4-7The market offers a wide variety of nutraceuticals that are also utilized in clinical settings, including polyunsaturated fatty acids (PUFAs), probiotics, prebiotics, selenium, antioxidants, vitamins, polyphenols, and various spices such as curcumin, fenugreek, garlic, capsaicin, ginger, and fennel.⁸

There is growing number of reproductive disorders especially endometriosis, polycystic ovary syndrome, irregular menstrual and uterine fibroids among women which have an impact on their social wellbeing and alsotheir longevity.⁹ The substances derived from foods and dietary supplements have shown different metabolic and biological actions on reproductivesystem in both human as well as animals.¹² The present review discusses the use of nutraceuticals in different reproductive health anomalies. We also focus regarding their mode of action and if any combinational therapy established. Our aim is to increase the confidence among physicians to prescribe nutraceuticals for different reproductive and urinary disorders. The mechanisms of action for various nutraceuticals are also reviewed. Articles were gathered using search engines such as Scopus, PubMed, Google Scholar, ResearchGate, and Science Direct.

Polycystic ovarian syndrome (PCOS):

Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition and a leading cause of infertility among women of reproductive age. PCOS includes variety of anomalies such as hormonal and metabolic disturbances, ovarian dysfunction, and irregular menstrual cycle.¹⁰PCOS is also allied with abnormal LH and FSH ratio, elevated androgen secretion and abnormal follicular development.¹¹

Nutraceuticals used for polycystic ovarian syndrome

Inositol:

Inositol is mainly found in fruits and beans. It is thought to be a member of vitamin B complex. In nature it exists in its nine isomeric forms. The most common isoform found in nature is myo-inositol (MI). In biological system MI has several functions like lipid synthesis, structure of cell membranes, cell growth, cell morphogenesis and cytogenesis.¹²Inositol is known for its diverse health benefits in conditions such as cancer, insomnia, high cholesterol, schizophrenia, Alzheimer’s disease, diabetic neuropathy, autism, attention-deficit/hyperactivity disorder, psoriasis, and elevated testosterone levels.¹³Myo-inositol and D-chiro-inositol are both stereoisomers of inositol used in the managementof PCOD.^14,15The proposed mechanism of inositol in PCOS involves its crucial role in the postsynaptic signal transduction of receptors like insulin, follicle-stimulating hormone (FSH), and thyroid-stimulating hormone (TSH).¹⁶ In PCOD women there are high levels of anti-mullerian hormone (AMH) than the healthy women.¹⁷MI shows its effects by decreasing high circulating AMH levels.¹⁸ Administering 2 grams of myo-inositol twice daily for eight weeks significantly reduced the LH/FSH ratio, FSH, prolactin, and rostenedione, testosterone, and insulin levels, thereby aiding the restoration of ovulatory function.¹⁹It was also reported that combined treatment of different isomers of inositol such as myo-inositol and D-chiro inositol showed better results than MI alone.²⁰Similarly, intake of MI with Alpha lipoic acid (ALA) produces greater effects than MI alone.²¹It was suggested that, MI supplementation at a dose of 2-4g is effective to decrease the symptoms associated with PCOS in women.²²Inositol may show some of the gastrointestinal symptoms such as nausea, diarrhea and flatulence but are rarely occur.²³

Alpha lipoic acid:

Alpha-lipoic acid (ALA) is a dithiol compound enzymatically synthesized in mitochondria from octanoic acid. ALA is aneffective antioxidant that can act as a scavenger of the reactive oxygen species. It has been used in cardiovascular, cognitive and neuromuscular disorders. It also acts as a modulator in inflammatory signalling pathways.²⁴Most of the researcher’s used ALA at 800mg as a normal dose in PCOS patients.²⁶Alpha lipoic acid when taken in a combination with D-chiro-inositol (DCI) showed significant efficacy inPCOS.²⁷

Flaxseed:

Flaxseeds (Linum usitatissimum) are used in varieties of food products such as breads, muffins, juices, milk, dry pasta, dairy and meat products. Flaxseed contains several biological active compounds such as d-galacturonic acid, lignans, d-Xylose, L-Galactose, L-Rhamnose, and linolenic acid.²⁸There are reports of antimalarial, laxative, antidiabetic, cholesterol lowering, anti-inflammatory, hepatoprotective, anticancer, laxative and several other properties of flaxseed.²⁹It can reduce testosterone level which is assumed due to existence of lignan i.e., secoisolariciresinoldiglucoside (SDG). It does so by increasing the excretion of testosterone.³⁰15 grams of flax seed powder with milk every day for 3 months showed significant decline in mean ovarian volume, number of follicles and maintain regularity of menstrual cycle.³¹The common side effects associated with flaxseed are gastrointestinal effects like bloating, gas, abdominal pain, constipation, diarrhoea and nausea.³²

L- carnitine:

L-carnitine is a quaternary ammonium cation found endogenously in kidney, liver, brain as well as animal basedproducts such as milk, meat, fish and poultry.³³Daily oral intake of L-carnitine varies from 500mg to 3000mg.³⁴Itregulates metabolism, reduces harmful metabolites, improves insulin sensitivity.³⁵It also exhibits antioxidant and anti-inflammatory effects, reducing ovarian damage by lowering inflammatory cytokines such as IL-6 and TNF-alpha and oxidative stress markers like malondialdehyde (MDA). It also inhibits follicular apoptosis.Thus it increases the survival of follicular cells.^36,37It also helps in the maturation of oocytes by regulating transport of fatty acids and energy production.³⁸L-carnitine supplementation at a dose of 3 grams daily for 12 weeks improved ovulation, follicular quality, and menstrual regularity in women with PCOS.³⁹ However, doses exceeding 4 grams per day can lead to side effects such as nausea, vomiting, diarrhea, abdominal cramps, and a fish-like body odor.^40-46

Soy-isoflavones:

Soybeans contain approximately 35% oil, 24% carbohydrate and 50% proteins. It also contains isoflavones which is a phytoestrogen.⁴¹Genistein, glycitein and daidzein are the main isoflavonmes present in soybeans.⁴²Many studies suggested that dietary isoflavones can be used in coronary heart disease, cancer, hyperlipidaemia, osteoporosis, chronic renal disease and against menopausal symptoms.^43-45The presence of phenolic ring in isoflavones enablesthem to interact with estrogenic receptors (ERs) and mimick the osteogenic properties. Isoflavones also reported to down regulate the androgenic receptor. All these mechanisms make it useful in PCOS.⁴⁶Soy isoflavones at the dose of 50 mg per day for 12 weeks showed significant improvement in hormonal status, insulin resistance, triglyceride levels, hirsutism and oxidative stress in women suffering from PCOS.⁴⁷

Vitamin E:

Vitamin E is a lipophilic compound found naturally in many foods such as nut seeds, green leafy vegetables and fortified cereals. Naturally, it prevail in eight chemical forms, out of that alpha-tocopherol is used by human beings.⁴⁸Vitamin E offers multiple benefits, including anti-hypertensive, anti-hyperglycemic, anti-hypercholesterolemic, antioxidant, and anti-inflammatory properties..⁸¹It mimics a hormone called progesterone as well as helps to reduce the elevated levels of oestrogen and androgens like testosterone in body which makes it possible to be used in PCOS women.⁴⁹In a case study on 22 years old women with PCOS taking Vitamin E supplement at a dose of 400 IU/day as an addon therapy. Significant improvements were observed in follicle-stimulating hormone (FSH) levels, reductions in luteinizing hormone (LH), and decreases in total serum testosterone.⁵⁰ The recommended daily intake of vitamin E (alpha-tocopherol) is 22.4 IU.⁵¹A major side effect associated with high Vitamin E supplement is impaired blood clotting, which increases the risk of haemorrhage.⁸⁵Vitamin E is contraindicated in individuals taking anticoagulants like heparin, vitamin K antagonists (e.g., warfarin), antiplatelet medications (e.g., clopidogrel), and nonsteroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen).⁵²

Breast Cancer:

Breast cancer is a prevalent type of cancer occurring in women. It is a malignant proliferation of epithelial cell lining of the ducts or lobules of the breast.⁵³

Nutraceuticals used for breast Cancer:

Green tea:

Green tea is a very popular beverage in the world produced from the leaves of Camellia sinensis. Flavonoids are abundant, with catechins being the predominant type, including epicatechin (EC), epicatechin-3-gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG). Among them, EGCG is competent compound in green tea. Green tea possesses properties such as antioxidant, antibacterial, antiviral, chemo-protective effects, anti-proliferative and anti-mutagenic activity.⁵⁴The mechanism of its anticancer action is by preventing angiogenesis in tumor area by reducing plasma VEGF levels⁵⁵, interacting with different types of target proteins such as phosphoinositide 3 kinase (PI3K)⁵⁶, Ras-GTPase activating protein (GAP) SH3 domain-binding protein 1 (G3BP1)⁵⁷, Bcl-xL, Bcl-2⁵⁸,vimentin⁵⁹, Fyn⁶⁰, insulin like growth factor 1 receptor (IGF-1R)⁶¹ and others. EGCG has also been shown to inhibit enzymes such as cyclin-dependent kinases (CDK) 2 and 4, leading to cell cycle arrest in G0 and G1 phases and increased expression of CDK inhibitor p21 in human breast cancer cells.⁶² All these actions together inhibit the tumor growth and augmentation of the breast cancer. A study involving postmenopausal women preparing for breast cancer surgery showed that taking 940mg of green tea extract daily for 35 days reduced markers of cell proliferation, such as Ki-67.⁶³ The adverse effects of green tea are mild to moderate nausea, constipation, abdominal pain, and increased blood pressure.⁶⁴

Curcumin:

The constituents present in turmeric are protein (6.3%), carbohydrate (69.4%) and water (13.1%). Curcumin is a yellow colour ingredient presents in turmeric. Turmeric (Curcuma Longa) is an important part of different traditional systems of medcine like Indian Ayurveda and Chinese medicine. It is universally used as a food-colouring agent and spices.⁶⁵ Traditionally, it has been used as a home remedy for conditions including anorexia, cough, diabetic wounds, biliary disorders, liver conditions, rheumatism, and sinusitis.⁶⁶Evidence also suggests that it is useful against ischemia, inflammation, cancer, and aging.^67,68Curcumin is metabolized in liver and leads to generation of its by-products such as hexahydrocurcuminol, hexahydrocurcumin, tertrahydrocurcumin, dihyfrocurcumin as well as their glucuronide and sulfate conjugates which show anti-cancer properties.⁶⁹The anti-cancermechanism of curcumin is by inhibiting angiogenesis in breast cancer tissues causing nutrient deficiency and hypoxia thereby results in cell death.⁷⁰It induces apoptosis in cancer cells without affecting normal cells and different transcriptional factors like NF-_kB. Curcumin selectively arrests the cell cycle in G2/S phase in a dose dependent manner.⁷¹A daily intake value of curcumin is 0-3 mg/kg without showing any adverse effects.⁷²Generally, curcumin have adverse effects like diarrhea, headache, rash.⁷³

Urinary tract infection (UTIs):

Urinary tract infections are caused by a range of pathogens, but most commonly by Klebsiella pneumoniae, Escherichia coli, Enterococcusfaecalis, Proteusmirabilis and Staphylococcus saprophyticus etc.⁷⁴

Nutraceuticals used for Urinary tract infection:

Cranberry:

Cranberry (Vaccinium macrocarpon) is a shrub native to north America’s fruit. It is derived by the contraction of cranberry.It consists of several complex organic acids, vitamin C, flavonoids, anthocyanidins, catechins and triterpenoids.⁷⁵ The presence of proanthocyanidins in cranberry is linked with the bacterial antiadhesion activity. Cranberry is a strong antioxidant and has anti-inflammatory activity which makes it enable to use in many conditions such as cancer and cardiovascular diseases. It also improves lipid profile, urinary tract infection, endothelial functions and digestion.^76-78Cranberries help prevent the adherence of E. coli strains with type 1 and P-fimbriae to the urothelium, thereby preventing infection of the mucosal surface. This activity is attributed to fructose, which blocks type 1 fimbriae adhesion, and proanthocyanidins (PACs), which inhibit P-fimbriae attachment.⁷⁹It also decreases the expression of p-fimbriae in E. coli by doing conformational changes of the molecule’s surface.⁸⁰Cranberry capsules twice daily for a period of 12 months showed significant improvement in UTI symptoms in a randomised clinical trial.⁸¹Daily recommended doses of cranberry juice varies from 120 to 1,000ml, which may divided into many doses.⁸² The intake of cranberry juice with probiotics effectively reduce the recurrence of UTI. The possible adverse reactions associated with cranberry are excessive urination, stomach acidity and increased the risk of urate stones.⁸³

Probiotics:

The term “probiotics” this means ‘for life’is derived from Greek word “pro bios”. As per WHO definition, probiotics are the live microbes when administered in adequate amounts confer a health benefit on the host.⁸⁴Different microorganisms considered as a probiotic are Lactobacillus species (L. acidophilus, L. casei), Bifidobacterium species (B, bifidum, B. breve), and other nonlactic acid bacteria (Bacillus cereus, Escherichia coli strain nissle).⁸⁵Probiotics are mainly found in yogurt, cheese and other fermented dairy products.⁸⁶ Probiotics have shown benefits in managing several health issues, including kidney and urinary stones, atopic conditions, colic, Helicobacter pylori infections, UTIs, liver diseases, dental caries, halitosis, acute and antibiotic-associated diarrhea, Candida infections, constipation, viral upper respiratory tract infections, colon cancer, diabetes, obesity, and modulation of the gut-brain axis.⁸⁷ Its use in UTI by its ability to inhibit the growth of pathogens and biosurfactant secre tion in uroepithelial cells.⁸⁸In a randomized placebo-controlled trial among 100 young women with recurrent UTI, received Lactobacillus crispatus probiotic given intravaginally for 10 weeks, showed significantly reduced in recurrent UTI.⁸⁹The adverse effects associated with probiotics include bloating and flatulence.⁹⁰

Ascorbic acid:

Vitamin C (ascorbic acid), a water-soluble vitamin, is found abundantly in raw red and green peppers, oranges, grapefruits, kiwis, broccoli, strawberries, and Brussels sprouts.⁹¹ It is consumed in diseases such as common cold⁹², wound healing⁹³, atherosclerosis⁹⁴, cancer⁹⁵, and oxidative stress.⁹⁶The recommended daily intake of vitamin C is 90mg for men and 75 mg for women.⁹⁷ Its use in UTIs is due to its bacteriostatic properties, which are mediated by reducing urinary nitrates to reactive nitrogen oxides rather than lowering urinary pH⁹⁸Pregnant women receiving 100mg of ascorbic acid for 3 months significantly reduced the frequency of urinary infections.⁹⁹The major adverse effects associated with higher than recommended dose of vitamin C are dental erosion¹⁰⁰, increased risk of cancer¹⁰¹ and heart disease ¹⁰²

D- mannose:

D-mannose is a monosaccharide produced as an intermediate in the biosynthesis of secretory proteins and glycoproteins in the human body. It is mainly found in number of fruits like peaches, apples, cranberries, blueberries and oranges.¹⁰³ It has many beneficial effects in diabetes, intestinal diseases, urinary tract infection and immune disorders.^104-107 D-mannose prevents the adherence and incursion of E.coli to the uroepithelium cells by inhibiting FimH (fimbrial adhesins type I – Mannose). In a randomized cross over trial among the women with UTI, ingestion of 1 g of D-mannose thrice a day for 2 weeks, and then twice a week for 22 weeks, showed effective to elevate the symptoms and prevented recurrence of UTI. Several studies recommended 2 to 3 g per day of D-mannose for use in UTI. Combined treatment of D-mannose with other nutraceuticals such as cranberry showed good effects in reducing the symptoms of UTI.¹⁰⁸The adverse effect associated with D-mannose is diarrhoea.¹⁸³

Erectile dysfunction:

Erectile dysfunction (ED) is predominant sexual disorders affected by the men at the age range of 40 - 70 years. It is a condition in which there is persistent inability to maintain a sufficient penile erection during the sexual intercourse. The major risk factors related to ED are age, smoking, coronary artery or peripheral vascular disease, depression, hypertension, lower urinary tract infection, trauma or surgery to the pelvis, diabetes mellitus, and benign prostate hypertrophy. The current available treatments for ED include oral medications such as sildenafil and tadalafil, alprostadil self-injection, penile revascularization, penile implants and psychological counselling. ED greatly affects the lifestyle and self-esteem as well as increases depression among men which ultimately creates a problem in relationship.¹¹⁰

Nutraceuticals used for erectile dysfunction:

Ginseng (Panax ginseng):

Ginseng (Panax ginseng) is an herb belonging to family Araliaceae. It contains ginsenoside, polysaccharides, flavonoids, volatile oils and gintonin.¹¹¹Ginsenosides contribute to the efficacy in treating ED males. Ginsenosides induce the synthesis of NO in endothelial cells and perivascular nerves which leads to relaxation of smooth muscles, thus increase the blood flow to the corpus cavernosum and ultimately causing erection.¹¹² Ginseng enhances spermatogenesis by upregulating the expression of glial cell-derived neurotrophic factor (GDNF) in Sertoli cells and activating testicular cAMP-responsive element modulator (CREM).^113,114In a double-blind randomized placebo-controlled study among the men affected with erectile dysfunction, ingestion of 900mg of ginseng thrice a day for 8 weeksshowed significant increase in their mean International Index of Erectile Functions as compared to placebo.¹¹⁵Adverse effects associated with ginseng are morning diarrhoea, skin eruption, sleeplessness, hypertension, oedema, nervousness, hypotension and gynecomastia.^116,117It is found that use of ginseng with imatinib leads to hepatotoxicity mediated by inhibiting CYP3A4 isoenzyme involved in the breakdown of imatinib.¹¹⁸

Fenugreek:

Fenugreek (Trigonella foenum-graecum), an annual plant from the Leguminosae family, is widely cultivated in Asia and the Mediterranean. Its seeds and leaves are used as spices and functional food additives, including stabilizers, adhesives, emulsifiers, and gums. Fenugreek contains several bioactive compounds, including steroidal sapogenins, glycosides, alkaloids like trigocoumarin and trigonelline, volatile oils, carbohydrates, and dietary fibers. Different parts of fenugreek have wide beneficial effects including hypoglycaemic effect, antioxidant, immunomodulatory effect, digestive effect, hypercholesterolemic effect, reduction in blood pressure, anti-cancer, anti-ulcer, gastro and hepatoprotective actions, cardiovascular effect, antibacterial, antifungal anti-asthmatic effect and used in wounds and sore muscle treatment.¹¹⁹The main steroidal saponin compound, furostanol is having androgenic activity, causing for complexing cholesterol in the cell membrane. Studies also indicated that fenugreek boosts the body’s testosterone levels by acting as 5-alpha reductase and aromatase inhibitor. Thus, maintain the erectile function.¹²⁰ In a double-blind, randomized, placebo-controlled trial among the male patients with low testosterone levels, ingestion of combination of Trigonella foenum seeds and Lespedeza cuneate (TFGL) at a dose of 200mg twice a day for 8 weeks, showed significantly increase in their testosterone levels and scores of the International Index of Erectile Function.¹²¹Fenugreek is used at a dose level ranges from 200mg to 2.5gm twice daily for different indications.²⁰⁹ The side effects of fenugreek are diarrhoea, flatulence and allergic reactions.^210,211

Pomegranate:

Pomegranate (Punica granatum) is a fruit belonging to family Punicaceae. The fruit contains a variety of phytoconstituents, including phenolics, flavonoids, ellagitannins, proanthocyanidins, and minerals such as potassium, nitrogen, phosphorus, calcium, magnesium, and sodium, as well as diverse polysaccharides..This fruit is used in cancer, cardiovascular disorders, Alzheimer’s disease, diabetes, male infertility, aging and AIDS.^123,124It increases the bioavailability of NO and precipitate smooth muscle relaxation by its antioxidant property due to presence of polyphenolic flavonoids. So it can be used in ED.¹²⁵In a double-blind, randomized, placebo-controlled trial involving 53 individuals with mild to moderate erectile dysfunction, consuming 8 ounces of pomegranate juice daily for 28 days significantly improved erectile dysfunction scores The side effect of pomegranate juice are diarrhoea, flatulence, hyperlipidaemia, nasal congestion and hypertension.¹²⁶ Studies indicated that, pomegranate juice inhibits the intestinal CYP2C9 and CYP2A4 isoenzymes which may cause interactions with drugs which are metabolized by these enzymes.¹²⁷

CONCLUSION:

Nutraceuticals have a protective role in various reproductive and urinary tract disorders. They can be used for prophylactic purpose in disease conditions like PCOS, breast cancer, UTIs and Erectile dysfunction. The pharmacology, clinical safety and efficacy of the nutraceuticals were discussed along with the side effects. The collected data of clinical trials will give the new scope towards use of nutraceuticals.

CONFLICTS OF INTEREST:

The authors declare that they have no conflicts of interest.

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Received on 15.04.2021 Revised on 27.05.2024

Accepted on 16.01.2025 Published on 02.05.2025

Available online from May 07, 2025

Research J. Pharmacy and Technology. 2025;18(5):2407-2415.

DOI: 10.52711/0974-360X.2025.00344

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