INTRODUCTION:

Dysmenorrhea is defined as painful menstrual flow, often affect women starting at 6 to 12 months after menarche¹. The prevalence of dysmenorrhea varied greatly from the literature. World Health Organisation (WHO) conducted a systematic review and reported that the prevalence rate of dysmenorrhea ranged from lower than 2% to as high as 97%². China, Australia and the United States of America have lower prevalence rates of dysmenorrhea compared to Canada, India and most of the European countries. Northern Saudi Arabia, Iran, Ghana, Spain and Poland reported an overall prevalence rate of more than 60%^3–8. Cross-sectional studies among Chinese female college/university students reported varied prevalence rates from 31.5% to 79.4%^1,9,10.

There are two types of dysmenorrhea, primary and secondary. PD is common in teenagers who have no gynaecological disease¹¹. Secondary dysmenorrhea is associated with existing disorders which affect adult women¹¹. Endometriosis and adenomyosis are the most common causes of secondary dysmenorrhea^12,13. Differential diagnosis of dysmenorrhea can be performed based on the onset of dysmenorrhea, changes in menstrual follow, other gynaecological symptoms and presence of pelvic abnormality¹². Transvaginal ultrasonography and saline microscopy of vaginal fluid are used to evaluate the presence of endometriosis, adenomyosis and pelvic inflammatory disease, which provides valuable information for diagnosis primary or secondary dysmenorrhea¹⁴.

Risk of factors of PD is not conclusive as different studies employed different inclusion criteria for analysis of risks associated with PD. Age is reported to be significantly associated with the PD. One systematic review reported that women with age less than 30 years have a higher risk of PD¹⁵, whereas another stated that women less than 20 years old are associated with a higher risk of PD¹⁶. However, it can be concluded that younger age is one of the risk factors for PD¹⁷. Early age of menarche (with median age or 12.6 years old) is an important risk factor for PD, which may be due to longer exposure of uterine to prostaglandin^15,16,18. Nulliparous women^19–21, smoking^13,17,22, alcohol consumption^15,23, heavy menses^13,17 also predispose a woman to a higher risk of PD. Emotional and psychological are modifiable risk factors which play roles in PD, where depression and anxiety are positively associated with risk of PD ^16,17,24. Women with anxiety and depression have higher pain sensitivity, which renders them more sensitive towards the painful sensation of menstruation²⁵. One population study stated that stress predisposed a woman towards dysmenorrhea, suggested that stress may stimulate neuroendocrine response which impairs regular ovulation process^26,27.

Lower abdominal pain is the typical clinical manifestation of PD. The onset of pain can be 1 to 2 days before the start of menses and last for 4 days into menses²⁸. Headache, diarrhoea, fatigue, nausea and vomiting are common symptoms associated with pelvic pain²⁹. According to several survey studies, more than half of the women reported that they have moderate to severe pelvic pain which negatively affected the performance of women in school and workplace^30–32. International Association for Study of Pain reported that 5-14% of women have regular school absenteeism due to the symptoms of PD whereas 13-51% of women have been absent from school at least once in their lifetime³³. University female students agreed that PD affects their academic performance due to class and school absenteeism, loss of class concentration, impact on sports and social activity and inability to do homework^22,32,34. 40.9% of women reported that dysmenorrhea negatively affected their concentration and academic performance in the class whereas 29.6% of young women absented to school activities due to pain in a meta-analysis³⁵. Studies in Malaysia showed a positive correlation between the severity of pain due to PD with the number of days of school absences³⁶. The severity of pain is found to be significantly associated with the inability to work among young female³⁷. Treatment is warranted to relieve the symptoms and improve the quality of life of women. The underlying pathogenesis of PD must be fully explored to understand how the medication works to reduce menstrual pain.

Molecular Pathogenesis of Primary Dysmenorrhea:

Although different mechanisms and cascades were involved in the pathogenesis of PD, the ultimate painful sensation is either caused by abnormal contraction of the uterine muscle or uterine ischaemia (figure 1). Contraction of uterine is common in women during menstruation, with a basal tone of 3 to 4 every 10 minute and peak intrauterine pressure of 120mmHg.³⁸ However, elevated frequency of contraction (4 to 5 times every 10 minutes) and intrauterine pressure (often more than 150 – 180mmHg) were found in women with PD^38,39. Multiple inflammatory markers and hormones are associated with pelvic pain in women with PD. The roles of prostanoid and hormones will be discussed to summarise their inter-relationship in women with PD.

Figure 1: Molecular pathogenesis of primary dysmenorrhea

Hormones:

Hormones such as estrogen, progesterone, oxytocin, vasopressin, follicle-stimulating hormones (FSH) seems to be involved in the pathophysiology of PD. Significant increment of oxytocin, vasopressin, FSH was found in the plasma of women with PD⁴⁰. However, the mechanism of each hormones contributing to PD remains unclear. Several mechanisms were proposed by different studies, suggesting different roles of hormones in PD. A patient with PD has high oestrogen level and low progesterone level during menstruation. High oestrogen level increases the expression of oxytocin receptor (OTR), which leads to an influx of calcium ion and contraction of uterine smooth muscle⁴¹. Low progesterone level activates the arachidonic acid pathway and increases the synthesis of prostaglandins.

Vasopressin is a strong uterine stimulant in non-pregnant women, especially during menstruation⁴². Vasopressin may act both directly and indirectly to PD, either by direct stimulation of myometrium, reduction of blood flow to uterus as well as increasing endometrial synthesis of prostaglandin^43,44. In women with PD, vasopressin is elevated during the first day of menstruation compared to the control group⁴⁵. Women with intense pain have higher plasma level of vasopressin, suggested that the covariation between the intensity of pain and plasma level of vasopressin⁴⁶. Roles of vasopressin in PD is further supported by the successful treatment of PD with oral contraceptive pills. OCPs have been shown to significantly decrease plasma concentration vasopressin, therefore lower the uterine contractility⁴⁷.

Synthesis of prostaglandin and vasopressin is stimulated by oestrogen⁴⁸. An animal study demonstrated high PGF_2α level after injection of oestradiol⁴⁹. Involvement of oestrogen was furthered elucidated by a significant association between the polymorphism of human oestrogen receptor 1 (ESR1) gene PvuII with PD⁵⁰. Dual stimulation action of PGF_2α and vasopressin on uterine generates contraction, leading to pelvic pain in women with PD. Progesterone has been proposed to be involved in regulating oestrogen, prostaglandin and prostacyclin. It converts oestradiol into low active estrone, thereby reduces the prostaglandin and vasopressin synthesis, which consequently alleviates painful dysmenorrhea⁴⁸. Treatment of progesterone in rabbits successfully inhibited the stimulatory effect of oestrogen⁴¹. Thus, the plasma level of progesterone is shown to be inversely correlated with the severity of pain experienced. Phospholipase A2 is an enzyme which hydrolyses phospholipid into arachidonic acid and eicosatetraenoic acid (precursors of cyclooxygenase (COX) and lipoxygenase pathway). High progesterone level inhibits the activation of phospholipase A2, which reduces the biosynthesis of various inflammatory markers⁵¹. If pregnancy does not happen at the end of the luteal phase of the menstrual cycle, labilisation of lysosomes releases phospholipase A2, causing hydrolysis and release of the precursor of prostaglandin. However, an animal study reported that progesterone is not associated with the release of PGF_2α, proposed that the rate of PGF_2αsynthesis is governed by arachidonic acid⁴⁹. Although it has been proven that progesterone is required in the synthesis of prostaglandin, it may not directly affect the release of prostaglandin. More studies are needed to further study the association between progesterone and prostaglandin.

Prostanoid:

Multiple cytokines are also involved in the stimulation and inhibition of COX-2 in the arachidonic acid pathway. Pro-inflammatory cytokine genes (interleukin 1B, tumour necrosis factor, interleukin 6 and interleukin 8) were significantly expressed in the first day of menstruation, whereas anti-inflammatory cytokines (interleukin F5 and interleukin 11) were markedly reduced in the patient with PD⁵². Ultimately, prostaglandin synthesis increased due to increased expression of pro-inflammatory gene and decreased expression of anti-inflammatory gene.

Prostaglandinplays a major role in pelvic pain associated with PD. Symptoms of nausea, vomiting and diarrhoea which resembles the side effects of prostaglandin, are presented in 60% patient with PD³⁸. Out of several types of prostaglandin, prostaglandin F_2α (PGF_2α) is most commonly reported by studies that showed a statistically significant positive correlation with the severity of dysmenorrhea³⁸. Roles PGF_2αfor the contraction of uterine have been supported by the increased number of contractions of ewes’ uterine muscle after injection of PGF_2α. FP prostanoid receptors are highly expressed in myometrium and have been identified as the target of PGF_2α^53,54. An animal study showed that the mice lacking FP failed to delivered offspring due to persistent production of progesterone and lack of uterine contractility⁵⁵. During PD, there is an increase in the synthesis of PGF_2αin the myometrium. PGF_2α activates FP prostanoid receptors, which increases intracellular calcium and inositol triphosphate level, leading to a contraction of the uterine muscle⁵⁶. Release of PGF_2α into uterine spiral artery wall will stimulate vasoconstriction of the blood vessel, leading to uterine ischemia⁴⁸. Pelvic pain of PD can be induced by abnormal uterine contraction and uterine ischemia, which mediated by PGF_2α.

Prostaglandin E₂ (PGE₂) may involve in the pathogenesis of PD but it is controversy. Generally, the overproduction of PGE₂ was observed in women with dysmenorrhea⁵⁷. However, variability in uterine activity was observed with different doses of PGE₂exposed^54,58. One in-vivo study reported that the contraction of uterine was increased with a low dose of PGE₂but decreased with a higher dose of PGE₂⁵⁹. Since PGE₂may not be an effective marker for PD, PGF_2α/PGE₂ratio has been suggested as a potential indicator for the severity of PD. The statement has been supported by higher PGF_2α/PGE₂ratio in women with PD than normal women⁶⁰. Although the association between PGF_2α/PGE₂ratio and uterine contraction activity is established, more studies are warranted to study the mechanism of PGF_2α/PGE₂ratio in PD is warranted⁶¹. Central sensitisation of nociception (allodynia) has been discussed in several studies which may contribute to reduced pain threshold towards PD. Both PGF_2αand PGE₂increased sensitivity towards pain stimuli, mediated through changes in nociceptive specific neurons⁶². The mechanism of allodynia is fully understood, but the prolonged release of central excitatory neurotransmitters such as glutamate and aspartate may facilitate the PG induced allodynia⁶³.

Relationship between thromboxane B₂ (TXB₂), the metabolite of thromboxane A₂ (TXA₂) and 6-keto-prostaglandin F₂_α, metabolite of prostaglandin I₂(PGI₂) with PD were reported in some studies⁶⁴. TXB₂is a strong stimulant of vascular and uterine smooth muscle, whichshowed uterine contraction activity in vitro, suggesting its role in the pathogenesis of PD⁶⁴. Elevation of TXB₂in women with dysmenorrhea was observed but its mechanism of action has not been fully elucidated⁶⁵. It has been suggested that potent vasoconstriction property of TXB₂ may lead to uterine ischemia, resulting in pelvic pain⁵⁷. PGI₂ is a potent platelet aggregation inhibitor, which showed conflicting data on uterine contraction, either increasing or decreasing in uterine contractility^46,66.

Involvement of leukotriene in the pathogenesis of PD has been explained in previous studies. The severity of PD demonstrated close correlation with leukotriene C4 and D4⁶⁷. Endometrial leukotriene level was significantly high in women with PD compared to pain-free women⁶⁸. A randomised clinical trial found that montelukast (leukotriene receptor antagonist) offers better visual analogue scale (VAS) scores in women with dysmenorrhea as compared to placebo⁶⁹. This study provides an insight into new alternatives available for the treatment of PD.

Polyherbal Formulation used for Treatment of Primary Dysmenorrhea:

According to Ayurvedic Medicine, the polyherbal formulation has several advantages in the management of disease over a single herb. Combination of several herbs in one formulation produces synergistic action and minimise its toxic effect⁷⁰. Synergistic action of constituent herbs in PHF confers better therapeutic effects⁷⁰. The therapeutic window of PHF is wider than single herbs, which can be used safely in high dose⁷⁰. Globally, 8 polyherbal formulations (prasaplai, xuefu zhuyu decoction, guizhi fuling capsule, bak foong pill, jingqian zhitong fang, dang gui shao yao san, siwu tang and jia-wei-xiao-yao san) have been commonly used for management of PD. The pharmacological action and scientific evaluation of all the above-mentioned formulations have been summarised in table 1.

Prasaplai:

Prasaplai has is a Thai traditional preparation originated 100 years ago, which is used for the management of PD. It is a powdered mixture of 10 crude herbs which and two pure compounds as shown in table 3¹⁰². It has been approved for management of PD and included in Thai traditional common household drug list⁷¹. National Drug List of Herbal Medicinal Products proposed the administration of 1000mg Prasaplai three times daily before meal for analgesic and anti-inflammatory purpose¹⁰³.

Standardisation of Prasaplai was conducted through high-performance liquid chromatography to justify the quality of the preparation in the modern medicine system⁷¹. To explore the mechanism of Prasaplai on PD, in-silico and in vivo studies were conducted. Prasaplai has demonstrated excellent inhibition of COX-1 and COX-2 enzymes in silico, which results in decreased prostaglandin synthesis⁷³. Potent inhibitory action of Prasaplai on PGE₂ and oxytocin renders it effective in relaxing rats’ uterine smooth muscle⁷⁴. Although Prasaplai is acutely non-toxic in rats, its side effect on increasing menstrual flow has not yet studied since the relaxation of uterine muscle tends to increase volume to bleeding during menstruation⁷⁴.

Clinical trials have been conducted on Prasaplai to assess its safety and effectiveness to date. Effectiveness of Prasaplai has been proved by a phase II clinical trial, where patients receiving Prasaplai experienced lesser pain and side effects as compared to mefenamic acid in 3 months follow up⁷⁵. In phase III clinical trial, Prasaplai was reported to be as effective as mefenamic acid in relieving menstrual pain with no liver and renal complication in 6 months of study⁷². One short term randomised trial indicated that although Prasaplai is useful in relieving pain, no significant difference with placebo. Nevertheless, 2 components of Prasaplai (Zingiber officinale and Nigella sativa) have antiemetic property, which reduces nausea and vomiting associated with PD. Despite multiple beneficial effects reported by three clinical studies, the dose used by three studies is different from the standardised dose recommended by National Drug List of Herbal Medicinal Products. Future study can be formulated to compare the standard dose (1000mg three times daily) of Prasaplai and NSAIDs for more reliable results.

Xuefu Zhuyu Decoction (XZD):

Xuefu Zhuyu decoction, also known as Hyeolbuchukeo-tang is a traditional Chinese medicine formula recorded in Correction of Medical Errors, 1850 in Qing Dynasty¹⁰⁴. It is used traditionally for the improvement of microcirculation and dyslipidaemia, which is beneficial in the management of coronary heart disease¹⁰⁵. Its role in the reduction of neuroinflammation has been reported in animal study, which plays a role in the pathogenesis of Alzheimer disease⁷⁸.

Numbers of clinical trials have been conducted to assess the effectiveness of XZD in relieving PD. However, all studies have been published in the Chinese language. A meta-analysis has been done to analyse the finding of the published studies. Out of the 8 studies analysed, majority of them favoured the combination of western medicine and XZD or solely XZD in relieving menstrual pain of PD¹⁰⁶. The underlying mechanism of XZD is not fully elucidated yet. XZD is shown to possess anti-inflammatory activity through reduction of the arachidonic acid level in the brain⁷⁷. Since arachidonic acid is a precursor of prostanoid, reduction of arachidonic acid release may result in pain-relieving for PD. However, no study has been conducted to evaluate the effect of XZD on key inflammatory mediators (PGE₂, PGF_2α etc) involved in PD.

Guizhi Fuling Capsule (GFC):

Guizhi Fuling capsule is a traditional herbal formula widely used in Japan, Korean and China. It is known as Gyejibongneyong-hwan in Korean and Keishibukuryogan in Japan. It has a long history of being prescribed by traditional Chinese practitioners to improve blood circulation and break blood stasis in China⁷⁹. Fingerprinting of GFC was performed and major components of GFC has been confirmed by HPLC technique⁸¹. Mechanism of GFC in relieving PD has been studied extensively in animal studies. Biomarkers involved in uterine contraction such as Ca²⁺, PGE₂, PGF_2α, TXB₂ level were shown to be reduced after administration of GFC to rats^80–82. Oxytocin induced contraction of the uterus was inhibited, which mediated through reduced expression of COX-II protein and increased NO level in the uterine muscle⁸¹. Phase II clinical trials on GFC demonstrated that participants received a high dose of GFC experienced lesser menstrual pain.¹⁰⁷ Majority of participants were completely satisfied with the treatment outcome of GFC without manifestation of serious adverse effects as compared to placebo¹⁰⁷. GFC may be a good alternative for the management of PD due to its superior effectiveness and rather safe profile. However, chronic side effects are yet fully investigated in the Phase III clinical trial.

Bak Foong Pills (BFP):

Bak Foong pill (BFP) is a traditional Chinese formulation which contains 20 herbal and mineral ingredients⁸⁵. It has an extensive history of been used for management of a variety of gynaecological disorder such as dysmenorrhea and menstrual bleeding⁸⁵. Many beneficial effects of BFP have been reported in previous, including cardiovascular, digestive and reproductive system. However, it has been marketed with an indication of improvement of general wellness, relieving menstrual pain and regulating menstrual ailment.

A mixture of inhibition and induction of platelet aggregation was observed with individual ingredients of BFP, but BFP preparation showed significant anticoagulation activity as a whole⁸⁵. Inhibition of thromboxane formation and calcium mobilisation were hypothesised as a possible mechanism of action of BFP, which may play a role in the inhibition of uterine contraction in PD⁸⁵. In another in vivo study, BFP was shown to relax the uterine contraction in a concentration-dependent manner⁸⁴.However, mechanism of action of BFP was not concluded due to no significant results on the decrease in oxytocin, prostaglandin, cyclic adenosine monophosphate (cAMP), nitric oxide, 6-keto PGF_1α and PGE₂^83,84. Increase in somatostatin level may play role in the analgesic effect of BFP, but the detailed mechanism is unknown⁸³. Further study was suggested to further elucidate the roles of somatostatin in relief of menstrual pain. Although the mechanism of action of BFP remains unclear, multiple actions may be involved in the relieving PD.

Jingqian Zhitong Fang (JQF):

Jingqian Zhitong Fang is a Chinese traditional formulation which is originated from Fo Sou San. It has a long history of being prescribed by traditional medicine practitioner to women with PD in China. Angelica sinensis (female ginseng) is the main ingredient of JQF, which was proven to possess excellent anti-inflammatory action through inhibition of calcium, NO and cytokines production in vitro and in vivo^87,108. Other ingredients such as Leonurus japonicus, Paeonia lactiflora and Ligusticum striatum work synergistically in regulating menstruation and alleviating menstrual pain⁸⁶. In a clinical study, women with JQF and ibuprofen have comparable effectiveness in relieving menstrual pain. sex hormones and inflammatory markers levels of women was significantly changed with the administration of JQF. The study indicated that pain relief action of JQF is mediated through elevation of progesterone with a decrease in oestrogen, PGF2_𝛼, and PGE₂⁸⁷. Another in vivo study reported similar finding with additional finding of a decrease in Ca²⁺ level⁸⁶. However, PGE₂and NO were reported to be increased in JQF treated mice⁸⁶. PGE₂ may inhibit or induce uterine contraction, thus its effect on the menstrual pain can be ambiguous. Nevertheless, the JQF may be an effective alternative for PD.

Dang Gui Shao Yao San (DGSYS):

Dang Gui Shao Yao San (DGSYS) is a traditional Chinese formulation widely used in treating various gynaecological disorders such as menopause and irregular menstruation in china. DGSYS has been reported as one of the top ten common formula prescribed for uterine bleeding disorder in a population-based study in Taiwan¹⁰⁹. It is composed of six different herbs which are believed to relieve stagnation of liver qi (liver blood deficiency), nourish the blood and relieve psychological symptoms^91,109. Excellent antioxidant, anti-inflammatory and antiplatelet effect were reported, possibly due to superoxide radical savaging activity⁹⁰. In vitro study of the mechanism of action of DGSYS demonstrated promising inhibition of uterine contraction which is induced by PGF2_𝛼, acetylcholine, ergonovine (adrenergic agonist), propranolol (b-adrenergic antagonist) and oxytocin⁸⁸. However, uterine contraction in PD involves complex multiple hormones and inflammatory pathways. Therefore, in vivo study is suggested to evaluate the mechanism of action of DGSYS.

Meta-analysis has been conducted assessing the effectiveness of DGSYS on the treatment of PD compared with NSAIDs. 4 clinical trials with sample sizes ranging from 40 to 203 have shown favourable effects towards DGSYS as compared to NSAIDs⁸⁹. However, the assessment of side effects of DGSYS is not extensively reported. Only one clinical trial has reported side effects of the NSAID group (nausea and abdominal pain) in the clinical trial. Although Chinese traditional medicine has been “safely” used in the community for hundreds and thousands of years, the association of the traditional formula with its side effect may not be fully elucidated as robust clinical trials have not been conducted.

Jia-Wei-Xiao-Yao-San (JWXYS):

Jia-Wei-Xiao-Yao-San is one of the most common herbal formulation prescribed for treating PD in Taiwan¹¹⁰. Although no analgesic properties were proven for JWXYS, it is prescribed to treat mood disorder associated with PD. In the concept of traditional and complementary medicine, a combination of analgesia with mood modifiers, such as NSAIDs and JWXYS may be possible for optimal treatment of PD¹¹⁰. JWXYS was clinically proven to improve the quality of life and reduce anxiety symptoms in the patient, possibly mediated through brain GABA_A/benzodiazepine receptor stimulations^99,100. Insomnia is one of the commonly associated symptoms for PD. JWXYS helps to improve the quality of sleep without any significant side effects¹⁰¹. Since JWXYS demonstrates its most effect on the brain, future study is recommended to determine its central analgesic action.

Siwu Tang (ST):

Siwu Tang is a traditional Chinese formula composed of 4 herbal ingredients. Taohong Siwu Tang (TST) and Xiang Fu Si Wu Decoction (XFSW) are two types of Siwu Tang (ST) with the addition of different substances into Siwu Tang. TST is commonly known as Siwu Tang with safflower (hong hua) and peach pit (tao ren) whereas XFSW consisted of 7 ingredients (addition of Cyperus rotundus, Saussurea costus and Corydalis yanhusuo in ST). Similar to other traditional Chinese medicine, ST is used to nourish the blood and improve blood circulation⁹⁷. It demonstrated potential effectiveness in relieving fatigue and improving cardiac function^93,96. Metabolomics study has been conducted to assess the underlying mechanism of TST on the treatment of menstrual pain and uterine bleeding. TST regulates lipid metabolism, which may exert anti-inflammatory activity through down-regulation of linoleic acid synthesis (precursor of prostaglandin and thromboxane)⁹⁷. Mechanism of action of TST may be possibly mediated through inhibition of COX-II⁹⁸. XFSW was reported to reduce intracellular Ca²⁺ level and decrease oxytocin-induced uterine contraction in vivo⁹².

Conflicting results were obtained from several clinical studies investigating the effect of TST. Although one of the clinical studies reported no significant effect on menstrual pain, another study suggested that longer period treatment with TST (at least 5 menstrual cycles) results in effective pain relief for PD^94,98. Doses of TST used in the clinical trial were not standardised, which makes an ambiguous conclusion on the clinical effects of TST. However, promising results were reported for XFSW. 3 clinical studies reported that XFSW exhibits significant pain relief effect as compared to NSAIDs⁹⁵. Contrasting results of TST and XFSW from clinical trials may be attributed to the additional ingredients added ST. Further investigation on roles of additional herbal ingredient in complementing the effect of ST may be useful to study the difference of their effects.

CONCLUSION:

Detailed pathophysiology of PD has been discussed in the first part of the review. PGF_2α, thromboxane B₂ and 6-keto-prostaglandin F_2α are the prostanoids which play significant roles in the contraction of the uterine muscle. Effect of PGE₂ on PD remains controversial, as variability in uterine contraction was observed with different concentration of PGE₂. PGF_2α/PGE₂ratio was suggested to be a reliable marker for the pathogenesis of PD, but limited studies are available to assess this marker. Oestrogen, progesterone, oxytocin, vasopressin are hormones involved in menstrual pain associated with PD. Progesterone regulates oestrogen negatively and inhibits the biosynthesis of various prostaglandin. Stopping the biosynthesis of prostaglandin may inhibit the further inflammatory cascade which ultimately leads to the contraction of uterine smooth muscle. Management of PD remains unchanged over decades, with NSAIDs and low dose OCPs are the mainstay of treatment for PD. However, long term NSAIDs increases the risk of gastrointestinal and cardiovascular diseases. Irregular uterine bleeding, nausea and water retention associated with low dose OCPs are unfavourable by most women. Therefore, traditional and complementary medicines are possible alternatives for the management of PD.

Multiple polyherbal formulations have reviewed in this article. Mechanism of action of most polyherbal formulations have been studied in vivo and in vitro. Most of the commercially available traditional medicines are polyherbal formulation instead of a single herb. In ayurvedic medicine, a combination of several herbs may achieve synergism in the treatment of diseases. Synergism of multiple herbs permits a lower dose of each constituent which may reduce their side effects. Most of the preparations demonstrated their action through regulation of inflammatory markers and hormones. Inconsistency in sample size, doses of herbal preparation and primary outcomes of clinical trials create controversial findings on the effectiveness of the polyherbal preparation. Further study was recommended to be carried out at a dose similar to the commonly prescribed dose by traditional and complementary medicine practice. Therefore, the effectiveness of the traditional polyherbal formulation can be elucidated around the safety dosing amount in practice.

ACKNOWLEDGEMENT:

The authors would like to express their gratitude to UCSI University for general support and provision of access to the database. The authors would like to support of fundamental research grant scheme which is provided by Ministry of Education, Malaysia (FRGS/1/2019/WAB07/UCSI/02/1).

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 21.01.2021 Modified on 10.09.2021

Research J. Pharm.and Tech 2022; 15(4):1891-1900.

DOI: 10.52711/0974-360X.2022.00316

Commercial Name	Formulation with scientific names	Country	Pharmacological Activity	Scientific Evaluation	Ref.
Prasaplai	Acorus calamus, Allium sativum, Citrus hystrix, Curcuma zedoaria, Eleutherine palmifolia, Nigella sativa, Piper retrofractum, Piper nigrum, Zingiber cassumunar, Zingiber officinale, sodium chloride, camphor	Thailand	Inhibition of COX-1 and COX-2	In silico, In vivo, Phase II and Phase III clinical trials	71–75
			Reduction of PGE2, oxytocin and acetylcholine release
Xuefu Zhuyu Decoction (XZD)	Prunus persica, Angelicae sinensis, Ligusticum striatum, Carthamus tinctorius, Paeoniae lactiflora, Rehmanniae glutinosa, Citrus aurantium, Bupleuri chinese, Platycodon grandiflorus, Achyranthes bidentatae, Glycyrrhizae uralensis.	China	Reduction of arachidonic acid level	Clinical trials	76–78
Guizhi Fuling Capsule (GFC)	Ramulus Cinnamomi, Poria cocos, Semen Persicae, Paeoniae Rubra or Paeoniae Alba, and Cortex Moutan	Korea, China	Reduction of expression of COX-2	In vivo, Phase II clinical trials, Spontaneous reporting system (SRS) on adverse effect	79–82
			Reduction of Ca²⁺, PGE₂, PGF_2α level
			Elevation of NO level
Bak Foong Pill (BFP)	Attractylodes macrocephala, Ligusticum striatum, Lycopus lucidus, Ophiopogon japonicus, Curcuma aeruginosa, Polygala tenuifolia, Poria cocos, Artemisia argyi, Cyperus rotundus, Amomum villosum, Leonurus japonicus, Atractylodes lancea, Angelica sinensis, Paeonia lactiflora, Ligustrum lucidum, Scutellaria baicalensis, Astragalus membranaceus, Eucommia ulmoides, Panax ginseng, Cervi pantotrichum, Linum usitatissimum, Cinnamomum cassia, Mel.	China	Elevation in somatostatin level (proposed)	In vivo	83–85
Jingqian Zhitong Fang (JQF)	Angelica sinensis, Leonurus japonicus, Paeonia lactiflora, Ligusticum striatum	China	Reduction of estrogen, PGF2_𝛼and calcium level	In vivo and clinical trials	86,87
			Elevation of progesterone level
			Reduction/Elevation of PGE₂level
			Elevation of NO level
Dang Gui Shao Yao San (DGSYS)	Poria cocos, Paeonia lactiflora, Atractylodes macrocephala, Ligusticum striatum, Alisma orientale, Angelica sinensis	China	Inhibition of PGF2_𝛼, acetylcholine, oxytocin medicated uterine contraction	In vitro and clinical trials	88–91
Siwu Tang (TST)	Taohong Siwu Tang (TST) Rehmannia glutinosa, Paeonia lactiflora, Angelica sinensis, Ligusticum striatum, Prunus persica and Carthamus tinctorius Xiang Fu Si Wu Decoction (XFSW) Rehmannia glutinosa, Paeonia lactiflora, Angelica sinensis, Ligusticum striatum, Cyperus rotundus, Aucklandia lappa and Cordalis yanhusuo	China	Down-regulation of linoleic acid synthesis	In vitro, in vivo and clinical trials	92–98
			Inhibition of COX-II
			Reduction of intracellular Ca²⁺ level
			Inhibition of oxytocin-induced uterine contraction in vivo
Jia-Wei-Xiao-Yao-San (JWXYS)	Angelica polymorpha, Paeonia lactiflora, Atractylodes ovata, Poria cocos, Bupleurum falcatum, Glycyrrhiza glabra, Paeonia suffruticosa, Gardenia florida, Zingiber officinale, Mentha arvensis	China	Stimulation of GABA_A/benzodiazepine receptor for anxiolytic effect	In vivo and clinical study	99–101