The Role of medicinal herbs in treatment of insulin resistance in patients with Polycystic Ovary Syndrome: A literature review

Search Strategy

The present research reviews the studies that focus on PCOS, herb, medical herbs, antioxidant, and nutrition by searching international databases of PubMed, Google Scholar, ISI, Embase (Elsevier) from 1990 to 2019. The current research was performed using the terms of medical subject headings and combinations of the keywords using the following search strategy: “polycystic ovary syndrome” or “PCOS” and “medical herbs” or “herb” or “antioxidant” or “nutrition” or “ovarian cysts” or “hyperandrogenism” or “hirsutism” or “botanical medicine”, or “insulin resistance”. All articles collected in the electronic search process, as well as the references used in these articles, were reviewed. Irrelevant, non-English, and inappropriate articles were excluded from the review process. Studies that have quantitatively investigated the association between polycystic ovary syndrome and herb or medical herbs were included in our review.

Assessment of methodological rigor

At this stage, studies conducted to investigate the association between medicinal herbs, insulin resistance, and polycystic ovary syndrome were selected. The quality of the studies was independently assessed by 2 persons (SD and MGh), and if two assessors do not agree with each other, the assessment was completed as a discussion with a third person (SAMJ). The irrelevant articles were excluded from the intended articles. The full text of the articles known as appropriate in this study was investigated. Figure 1 reported the selection process of articles. In the initial search, 361 articles were collected. After investigating the title and abstract, 221 articles were excluded from the study. Additionally, 102 articles were excluded after studying the full text of the articles, and finally 38 eligible articles were identified and included in the review study. The main characteristics of the studies are presented in table 1.

Figure1

The number of records identified, included and excluded through the different phases of the review.

Aloe vera

Aloe vera is a medicinal plant with hypoglycemic effects [13, 15, 16]. Aloe vera is rich in fiber which accelerates gastrointestinal transit, absorption, and modulation of hemostasis [15, 16, 17]

Aloe vera contains many compounds with different potential biological activities. Phytosterols in the Aloe vera can alter the steroidogenic response and express estrogen receptor protein, reduce androgens, increase estrogens, and ultimately improve the conditions of the PCOS. Aloe vera phytosterols such as sitosterol reduce serum cholesterol levels and normalized (3β-Hydroxysteroid dehydrogenase) 3βHSD activity in PCOS rats [15, 17, 18].

One study by Radha et al. was conducted to investigate the effect of Aloe vera gel on rats with PCOS. In this study, Aloe vera was administered to rats of each group at different doses (5 mg/kg, 10 mg/kg, and 15 mg/kg) for 60 days, and it was found that Aloe vera can improve glucose tolerance in a dose-dependent manner. Although all dosages of Aloe vera may cause changes in the structure of the ovary, high dose treatment decreases atretic follicles and 3βHSD and 17β-. Hydroxysteroid dehydrogenase (17βHSD) activates. Serum insulin levels and insulin resistance were significantly decreased in all groups and the doses of 10 and 15 mg significantly decreased the testosterone levels [17].

A clinical trial examined the endocrine effects of 1 mL of Aloe vera gel for 45 days in rats; as a result, Aloe vera did not change the biomarker enzymes and weight but improved the insulin sensitivity and 3βHSD and 17βHSD activity [18]. Some studies reported that Aloe vera can reduce Triglyceride (TG) and low-density lipoprotein (LDL-C) levels, decrease atretic follicles, and improve glucose intolerance and lipid metabolizing enzyme activities [15, 18, 19].

Faisal [20] reported a significant reduction in plasma glucose, insulin, and TG to high-density lipoprotein (HDL) ratio after oral supplementation with Aloe vera in mice. Aloe vera is an insulin sensitizer and influence on pancreatic β-cells [21].

Cinnamon

Cinnamomum is an herbaceous plant belonging to the Lauraceae family. Cinnamomum grows in tropical Southern India and Sri Lanka. Many studies have reported that cinnamon acts as an insulin sensitizer [22]. Cinnamon includes different flavonoids and polyphenols that have free radical scavenging and antioxidant activities [23].

Some studies reported that Type-A polymers and procyanidine polyphenols in the cinnamon extract enhance insulin signaling at the post-receptor level, increase the activity of Phosphoinositide 3 (PI3) kinase, increase the glucose uptake via enhancing the GLUT4 glucose transporter, inhibit the glycogen synthesis, and enhance glycogen synthesis and hypoglycemic effects [22, 23]. A study by Wang et al. investigated the effect of cinnamon extract on insulin resistance in patients with PCOS. In this study, the control group received 3 meals and 1 capsule of placebo for each meal and the intervention group received capsules containing 333 mg of cinnamon extract per serving 3 times a day. The intervention group had a significant decrease in fasting blood sugar (FBS) and insulin resistance. The cinnamon improved insulin sensitivity and reduced oral glucose tolerance test in this study [22].

In another study by Kort et al. the intervention group received the cinnamon supplement (1.5 g) for 6 months and the control group received a placebo. The regular menstrual cycle in the intervention group confirmed the progesterone secretion in the luteal phase of the menstrual cycle. But the androgen levels and the insulin resistance had no significant changes between the two groups [23].

Borzoei et al. reported that using 500 mg cinnamon 3 days for 8 weeks improved FBS, insulin, and total cholesterol in patients with PCOS [24]. Another study carried out on 66 women that were diagnosed as PCOS. Participants were randomly allocated to two groups. The intervention group was treated by cinnamon powder capsules 1.5 g/day in 3 divided doses for 3 months and the control group received a placebo. It was concluded that cinnamon significantly decreased insulin resistance and fasting insulin levels in women with PCOS [25]. Another study reported that the metformin group had a lower anti-Müllerian hormone level, which is related to PCOS and reduces follicle sensitivity to FSH, compared to the cinnamon group. [26]. However, more side effects were observed in the metformin group compared to the cinnamon group. The ginger and cinnamon supplementation increase catalase, glutathione peroxidase, and superoxide dismutase levels [27]. Dou et al. reported that Cinnamon supplementation decreased insulin resistance and improved the health status of patients with PCOS [28]. It is possible that cinnamon down-regulates serum testosterone and insulin level reduces insulin-like growth factor-1 and increases Insulin-like growth factor 1 (IGF) binding protein level in plasma as well as in the ovary in PCOS. Cinnamon is a potential therapeutic agent for the PCOS [28].

Camellia sinensis

The scientific name of green tea is Camellia sinesis. Green tea is one of the richest sources of flavonoids and is used as a medicinal plant. Studies have indicated that green tea consumption might decrease FBS levels in diabetic patients and reduces the risk of CVD, cancer, and metabolic syndrome. Catechin inhibits catechol-O-methyltransferase (COMT) which is responsible for reduction of norepinephrine. Norepinephrine has a long-term effect on lipid metabolism. In humans, green tea supplementation increases energy consumption, fat oxidation, and reduces weight up to 4.6% in obese subjects for 3 months. Green tea contains caffeine that increases metabolic rate even at small doses (such as 100 mg/day) [31, 32, 33, 34, 35, 36, 37, 38, 39].

The green tea extract enhanced lipolysis and reduced hypertrophy of the follicular theca layer and reduced the thickness of this layer in PCOS rats. Due to this reduction, the level of steroid hormones and androgens produced by the follicular theca layer will decrease. Green tea extract enhanced the follicles and corpus luteum, and reduced cystic follicles in the ovary [32]. A study by Chan et al. in 2006 in Hong Kong aimed to investigate the effects of Chinese green tea on weight and biochemical and hormonal profiles in obese patients with PCOS. In this study, 340 Chinese obese women with PCOS were randomly divided into the intervention and placebo groups. The intervention group received green tea capsules at a dose of 540 mg (6 capsules 3 a day times for 3 months) and the control group received a placebo. At the end of the study, it was concluded that there was no significant change in BMI, weight, waist-hip ratio, and skin folds between the intervention and placebo groups. However, the level of triglyceride in the intervention group increased significantly [29].

Dadian et al. investigated the effect of green tea consumption on weight loss and hormonal changes in obese patients with PCOS. Weight loss decreased fasting insulin levels and testosterone concentrations were significantly higher in the intervention group than the control group after 12 weeks of the intervention [30]. Green tea inhibited testosterone production and stimulation, reduced LH level, diastolic blood pressure, body and ovarian weight. However, some other studies indicated that green tea increases testosterone levels and it cannot be recommended to all women with PCOS, only those who do not have elevated levels [29, 30, 31, 32, 33, 34].

Fenugreek (Trigonella foenum-graecum L)

Fenugreek (Trigonella foenum-graecum L) is an annual plant and a traditional spice crop which is cultivated in Asia. Its crust contains 10–20 yellow seeds with appetizing aroma. Fenugreek has anti-diabetic and cholesterol-lowering effects and decreases insulin resistance in women with PCOS [35]. Fenugreek extracts have soluble fibers which decrease blood sugar by reducing enzymatic digestion and absorption of carbohydrates, thus decreasing post-prandial glucose levels [35, 36]. Fenugreek has hypoglycemic effects through stimulating insulin synthesis, insulin secretion from beta-pancreatic cells, and inhibiting alpha-amylase and sucrose [35, 36].

Hassanzadeh et al. investigated the effect of fenugreek seed extract on insulin resistance in women with PCOS. The intervention group received 3 tablets of 500 mg metformin and 2 tablets of 500 mg foenum, and the control group received 3 tablets of 500 mg metformin and 2 tablets of placebo for 2 months. A significant reduction was seen in ovarian cysts after 2 months. There was no change in fasting glucose, insulin sensitivity, and hormonal concentrations between the two groups [35]. Another study on premenopausal women with a similar methodology reported 46% reduction in cyst size and 71% of women reported the return of regular menstrual cycle after completion of the treatment [36]. However, fenugreek should be recommended to women with irregular periods and polycystic ovarian ultrasound, but not necessarily to those with impaired glucose tolerance [35, 36].

Silymarin

The flavonoid silymarin is extracted from the milk thistle (Silybum marianum L. Gaernt.). Silymarin has been reported to possess various pharmacological properties with hepatoprotective, anti-oxidant, anti-inflammatory, anti-cancer, and cardioprotective activities.

It is a strong inhibitor of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kb) activation. It helps to eliminate free radicals in the body and prevents peroxidation of lipids by increasing cellular glutathione [37, 38].

Silymarin has anti-angiogenesis effects which reduce proliferation of follicular cells, thereby reducing the production of testosterone, and increases in corpus luteum due to increasing progesterone hormone [37]. Silymarin lowers testosterone level but also acts as a hepatoprotective factor and can increase SHBG protein synthesis, and inhibit cyclooxygenase (COX) and inflammation by reducing cysts [37, 38]. Silymarin influences glucose 6-phosphatase and inhibits gluconeogenesis, reduces blood glucose level, and thereby decreases the symptoms of the PCOS. Reduction of oxidative stress is a beneficial effect in reducing blood glucose levels by silymarin, and silymarin reduces inflammation in the PCOS by inhibiting cyclooxygenase-2 (COX-2) and lipoxygenase [37, 38].

A study by Nebuni et al. in 2014 investigated the effect of silymarin on PCOS induced by estradiol valerate in rats. In this study, silymarin was administered to rats at doses of 20 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, and 300 mg/kg for 14 days [38]. It was reported that in the group treated with silymarin, body weight, abdominal size, number, and size of cysts were decreased. They reported no cyst at high doses (300 mg/kg), which could be due to anti-inflammatory properties of silymarin. Different doses of silymarin had positive effects such as a decrease in estradiol, testosterone, and LH and a significant increase in FSH and progesterone hormones due to the appearance of corpus luteum cysts in the ovary. Silymarin reduced inflammation and collagen in the follicular sheath and eventually reduced the layer thickness [37, 38].

Toch et al. in a meta-analysis reported the effects of a fixed combination of Berberis aristata and Silybum marianum on sugar and lipid profile. Silybum marianum decreased low-density lipoprotein, cholesterol, and plasma glucose levels [39]. Another study reported that expression levels of the insulin receptor in the Alzheimer’s group were significantly down-regulated compared with the healthy group, and silibinin (polyphenolic flavonoid extracted of Silybum marianum) supplementation decreased down-regulation the insulin receptor expression level. This result suggests that silibinin improves the brain’s insulin signaling pathways [40].

Chamomile

Chamomile is a medicinal herb which is native to Western Europe and North Africa. The main derivatives of chamomile are amino acids, polysaccharides, fatty acids, essential fatty acid, minerals, flavonoids, and phytoestrogens that have anti-inflammatory, antispasmodic, and antioxidant effects [41]. Antispasmodic effect of chamomile makes the menstrual cramps easier and reduce premature births [42, 43]. Apigenin is one of the major flavonoid chamomile components which inhibit the binding of flunitrazepam (benzodiazepine derivatives) [42]. Benzodiazepine joined to gamma aminobutyric acid (GABA) is a natural neurotransmitter amino acid in brain and reduces the secretion of LH [44]. Chamomile contains phytoestrogen which can decrease the menstrual disorder through changes in hormone positive estrogen feedback [45].

Rafraf et al. reported that chamomile significantly decreased hemoglobin A1c (HbA1c), the insulin levels, total cholesterol, TG, and LDL-C [41].

A study by Zanganeh et al. investigated the effects of chamomile extract on biochemical and clinical parameters in PCOS rats. The intervention group received chamomile extract in different doses of 25 mg/kg, 50 mg/kg, and 75 mg/kg. In rats treated with a dose of 50 mg/kg, cysts were disappeared, the number of follicles was increased, and the level of estradiol levels, gonadotropins, LH, and FSH was significantly decreased [43]. In another study, subjects received 370 mg of oral capsules of chamomile for 3 months; the level of testosterone decreased. In addition, phytoestrogens inhibit progesterone metabolizing enzyme, 20-alpha-hydroxysteroid dehydrogenase and increase progesterone hormone. Some phytoestrogen compounds that control this enzyme include 3- and 7-dihydroxyflavone and flavones. An increase in progesterone leads to an increase in basal metabolism rate and may be the cause of weight loss. Finally, the sterols found in chamomile can reduce cholesterol absorption. Phytosterols in chamomile extracts increase the dehydroepiandrosterone, which is produced in the liver. Hydroalcoholic extract of chamomile also contains ascorbic acid to prevent weight gain and reduce cholesterol levels [46].

Heracleum persicum (Persian Hogweed or Golpar)

Heracleum persicum is a perennial herb that commonly used in the preparation of food and medicine in Iran, Iraq, and Turkey [47]. Heracleum persicum contains alkaloids, terpenoids, terpene, and steroids. Hydroalcoholic extract of Heracleum persicum contain furocoumarins such as sphondin. Heracleum persicum inhibited cyclooxygenase- 2 and decreased inflammation [48].

Heracleum persicum is used as an anti-inflammatory, antiseptic, anti-diabetic, and anti-bacterial in traditional medicine [47]. Heracleum persicum extract probably decrease plasma testosterone, body and testis weight, and thus can help to treat sexual dysfunction in males [49].

Moreover, the hydroalcoholic extract of Heracleum persicum changes plasma sex hormone levels, inhibits folliculogenesis, and affects sexuality in women [50]. Furanocoumarins such as sphondin, xanthotoxin, and pimpinellin in the Heracleum persicum inhibits nitric oxide (NO) syntheses that reduced LH levels and estradiol release. The estradiol reduction helps the natural process of human reproduction [49, 50]. Haj Hosseini et al. investigated the effect of Heracleum persicum tea on hormone profile in PCOS women. The intervention group received 2 cups daily (containing 250 ml of herbal tea for 4 week) and the control group received a placebo. Heracleum persicum caused a significant decrease in fasting insulin, DHEA-S (dehydroepiandrosterone sulfate) levels, and a significant improvement in HOMA-IR index. Also, Heracleum persicum reduces androgens, especially adrenal androgens. Another study reported that Heracleum persicum reduced LH, estradiol, and testosterone, while increased FSH in PCOS rats [51]. Alkan et al, found that Heracleum persicum extract decreased plasma glucose and HbAlc in diabetic groups and increased insulin and c-peptide levels [52].

Mentha

Mentha (peppermint) is a medicinal plant of the Lamiaceae family. The mentha is native to East India and Asia. Essential oils of mentha are used in the food and beverage industries. Mentha has strong inhibitory effects which induce cytochrome P450 3A4 (CYP3A4) that leads to a change in the concentration of steroid hormones and androgen and reduce free testosterone levels due to increased SHBG. Peppermint tea can increase the level of LH, FSH, and estradiol due to physiological changes in the menstrual cycle. Peppermint tea can replace anti-androgenic treatments for hirsutism [53, 54, 55].

One study by Mehmet Akdogan et al. in Turkey investigated the effect of peppermint tea on the level of androgen in women with hirsutism. In this study, the intervention group received a cup of peppermint tea, containing 5 grams of dried mentha leaves in 250 ml of boiling water (5 days, twice a day) during the follicular phase of menstrual period. The intervention group had a significant decrease in the level of free testosterone, triglyceride, and significant increase in the levels of LH, FSH, and Prostaglandin E2 (PGE2). However, the level of DHEA and total testosterone did not decrease substantially [54]. In another clinical trial, the intervention group received peppermint tea or chamomile tea twice a day for 30 days and covered one complete menstrual cycle. The results of the studies showed that peppermint tea caused a significant decrease in testosterone levels and an increase in LH and FSH levels. Similarly, the degree of hirsutism is reduced [55]. Another study investigated the effect of herbal mixture supplements including menthe, zingiber, and Cinnamomum with and without CC in PCOS women. They found that these supplements have important effects on the antioxidants levels, glycemic control, menstrual regulation, and pregnancy rate [27].

Foeniculum vulgare (fennel)

Foeniculum vulgare (fennel) is used in traditional medicine to treat hormonal and metabolic disorders in women with PCOS. Fennel is regarded as phytoestrogenand have protective effects against oxidative stress and kidney disease. The essential oil of Foeniculum vulgar has antimicrobial and antioxidant effects [57, 58].

The chemical analysis of the extract of fennel showed that linoleic acid (54.9 %), palmitic acid (5.4 %) and oleic acid (5.4 %) were major components of fennel. The palmitic acid β-oxidation has anti-androgenic effects. This compound also exerts an anti-androgenic effect by inhibiting the formation of the dihydrotestosterone receptor complex and reducing testosterone levels. Foeniculum vulgare may increase the aromatase enzyme activity and reduce testosterone levels [57]. Long-term use of the Foeniculum vulgare has a negative feedback effect on LH and testosterone levels. Reducing the androgen levels lead to reducing LH which can be a natural menstrual cycle in women with PCOS. Foeniculum vulga extract does not change creatinine level but decreases urea. Kerempour et al. in Iran investigated the effect of hydro-alcoholic extract of Foeniculum vulgare seeds on the serum levels of sex hormones in rats with PCOS. In this study, Foeniculum vulgare was injected intraperitoneally in different doses of 250 mg/kg, 500 mg/kg, and 1000 mg/kg for 10 days. The intervention group received 500 mg/kg and 1000 mg/kg. FSH significantly increased, and testosterone and LH levels were decreased in the group treated with 1000 mg/kg dose [58]. In line with this study, Fozalaee reported that the rats received a low dose of Foeniculum vulgare had a lower progesterone level than the control group [59].

Another study indicated that Foeniculum vulgare, as well as metformin, decreased the days between two menstrual cycles and pain of dysmenorrhea in PCOS patients [60].

Potentilla

Potentilla is used to treat menstrual irregularities, regulate sex hormones and improve fertility. Recent studies reported the non-estrogenic effects of Potentilla [61]. Different phytochemicals derivatives including tannins, phenolic acid, and triterpenoids have hypoglycemic, hypolipidemic, and anti-inflammatory activities. These compounds can decrease fasting blood glucose level, glycated serum protein, malondialdehyde, and NO through inhibition of glycogen phosphorylase activity [62, 63].

Potentillas increases the number of follicles and reduces the number of ovarian cysts. Phytoestrogens that have anti estrogenic effects are found in this plant. Vitex and lactone in Potentilla extract bind to the Dopamine receptor D2 (D2 R) of dopamine in the hypothalamus and glandular pituitary, thereby inhibiting prolactin secretion and reducing fibrocystic mastopathy [61, 64].

Jaldar et al. investigated the effects of the ethanolic root extract of Potentilla on ovarian tissue changes in rats with PCOS. The intervention group received 365 mg/kg dose for 30 days. Potentilla treatment did not significantly change the number of offspring [64].

Wang et al. investigated network pharmacology-based analysis on Potentilla derivates and found that Potentilla compounds may have important effects on glucose uptake [65].

Licorice

Licorice is a member of the Leguminosae family, a native plant that is growing in Spain, Italy, Turkey, Iran, Iraq, Central Asia, and Northeast China. Licorice may have estrogen-like activity and mild inhibitory effects on the metabolism of endogenous hormones [66]. Licorice inhibits the activity of 17-hydroxyl esterase dehydrogenase and 17,20-lyase activity, stimulates aromatase activity, affects α5 and β5 reductase, and is used for the treatment of menopause due to estrogen-like effects. Licorice reduces excess hair growth due to enzymatic effects on the melatonin production cycle and possibly inhibits tyrosinase activity [66, 67]. Also, licorice reduces serum hormones level by damaging the activity of 11β- hydroxysteroids dehydrogenase and increasing the aromatase activity or by progesterone-like activity [66, 67, 68]. Faghihi et al. reported that combination therapy of licorice gel and laser are much more effective than laser alone [67]. Another study concluded that treatment with licorice and spironolactone reduced the activity of the renin-angiotensin system but did not affect the blood pressure in the treatment group [68]. Yang et al. found that licorice extract inhibits the symptoms of PCOS by regulating controlling levels of serum FSH, LH/FSH ratio, and irregular ovarian follicles [69]

Marrubium vulgare (White Horehound)

Marrubium vulgare is a flowering plant in the mint family, a native plant that is growing in Europe, northern Africa, and Asia [44]. Marrubium vulgare contains polyphenols and flavonoids that produced hypoglycemic effects, reduced cholesterol, triglyceride, and oxidative stress. Some flavonoids, such as apigenin, competitively inhibit the binding of flunitrazpam, thereby reduce the secretion of LH [44, 70, 71]. Also, the β-testosterone in the extract of Marrubium vulgare reduces LH. β-sitosterol reduces testosterone synthesis by lowering cholesterol. β-sitosterol reduces estradiol levels by decreasing aromatase enzyme activity, thereby preventing conversion testosterone to estrogen. Also, apigenin and ursolic acid of white horehound extract, inhibit cytochrome P450 and inhibit the conversion of cholesterol to pregnenolone, and thus reduce the synthesis of steroid hormones such as progesterone [70, 71].

A study by Mokhtari et al. was conducted to investigate the effect of bleach extract on hormonal parameters in rats with PCOS. In this study, the experimental group orally received doses of 500 mg/kg and 1000 mg/kg for 21 days. LH hormone was significantly decreased in 1000 mg/kg dose [70].