Novel herbs and drugs for endometriosis management: A review on current and futuristic therapies

A disorder with estrogen dependency comprising of inflammatory lesions outside the uterus, causing pain and inflammation in pelvis and affecting women of reproductive age with infertility and post reproductive age is endometriosis. Endometriosis is viewed as public health issue with a major impact on quality of life of women. Medically advanced computational and chemical treatments are available to treat the progression of the disease by diagnostic imaging, clinical examinations, imaging and laparoscopy often leading to immediate surgery. A warrantable rethinking on the diagnosis and management of endometriosis is to be assessed and medical treatments should be considered as first-line option for therapeutic relief for endometriosis by suppressing the systemic estrogen levels providing desirable efficacy and safety, prior to performing endometriosis surgery. The aim of this review is to describe natural products, hormonal and non-hormonal compounds that suppress the progression of endometriosis. Various herbal, conventional and traditional therapies are investigated to treat gynecological disease, endometriosis. The information in this paper include various studies assessing the use of novel treatments in addition to the herbal and hormonal products in the endometriosis therapy. Most of the studies involved were in scrutinizing the pharmacological activity profiles of various sources of drugs in endometriosis treatment, hormonal drugs involved suppression and regulation of various hormones along with various factors like anti-inflammatory, anti-oxidant, anti-proliferative and apoptotic, anti-angiogenic, anti-invasive, immunomodulatory, and estrogen modulating activity. However, novel drugs and medicinal plants are also reviewed here to draw attention to the molecules of drugs that target at multiple points for rational therapeutic treatment of endometriosis.

Endometriosis, Fertility, Future Medical Therapy, Hormonal Drugs, Herbs A A disorder with estrogen dependency comprising of in lammatory lesions outside the uterus, causing pain and in lammation in pelvis and affecting women of reproductive age with infertility and post reproductive age is endometriosis. Endometriosis is viewed as public health issue with a major impact on quality of life of women. Medically advanced computational and chemical treatments are available to treat the progression of the disease by diagnostic imaging, clinical examinations, imaging and laparoscopy often leading to immediate surgery. A warrantable rethinking on the diagnosis and management of endometriosis is to be assessed and medical treatments should be considered as irst-line option for therapeutic relief for endometriosis by suppressing the systemic estrogen levels providing desirable ef icacy and safety, prior to performing endometriosis surgery. The aim of this review is to describe natural products, hormonal and non-hormonal compounds that suppress the progression of endometriosis. Various herbal, conventional and traditional therapies are investigated to treat gynecological disease, endometriosis. The information in this paper include various studies assessing the use of novel treatments in addition to the herbal and hormonal products in the endometriosis therapy. Most of the studies involved were in scrutinizing the pharmacological activity pro iles of various sources of drugs in endometriosis treatment, hormonal drugs involved suppression and regulation of various hormones along with various factors like anti-in lammatory, anti-oxidant, anti-proliferative and apoptotic, anti-angiogenic, anti-invasive, immunomodulatory, and estrogen modulating activity. However, novel drugs and medicinal plants are also reviewed here to draw attention to the molecules of drugs that target at multiple points for rational therapeutic treatment of endometriosis.

INTRODUCTION
Endometriosis is a gynecological benign chronic in lammatory disorder that is described with the distinctive feature of dislodging of the endometriallike gland and stoma cells lining the uterus to outside the uterine cavity. It occurs more commonly in the pelvis and has an effect on a woman's reproductive organs contributing to infertility and dysmenorrhea (Guo, 2015;Edwards et al., 2013). It mainly affects women in reproductive years and may also affect menopausal women. The factors leading to the growth, development and relapse of the disease are proliferation of endometriostic cells, invasion, and neoangiogenesis. The shedding of endometrial tissue in the ectopic region leads to overproduction of mediators involved in in lammation like cytokines and prostaglandins causing chronic in lammatory reactions in the cells thereby resulting in adherence and scars, mediating pain and later infertility thereby affecting the quality of life (QoL) of woman. The symptoms of the disease depend on the location of endometriosis: intestinal symptoms can occur in case of bowel endometriosis, urinary symptoms in case of bladder or ureteral endometriosis. The etiology of endometriosis is found to be a complex intervention of genetic anatomic, immunologic, and environmental factors which has a major effect on women's vulnerability in the development of this disease.
Numerous medical therapies for treating endometriosis include the possibility to opt for the most acceptable treatment, based on pain intensity, age, fertility, route of administration, costs and QoL.
Developing novel targets to treat this disease is the target of medical science as the growth, prolongation and development of endometriosis depend on mechanisms like proliferation of cells, immunity, apoptosis, and angiogenesis (Vercellini et al., 2014).
Endometriosis-associated pain is treated successfully by suppressing the production of estrogen and amenorrheal induction thereby creating low estrogen content depressing the growth, development and progression of endometrial tissues in the ectopic region. Current medical therapy involves interpretation of the process of the disease to alleviate the disease symptoms and may require surgical and medical intervention.
The aim of this review is to consolidate the recent advancements in the hormonal, biological and herbal drugs to relieve from endometriosis.

Classi ication of Endometriosis
Endometriosis can be classi ied into 5 types and have been tabulated in Table 1.

Theories of Endometriosis
Various theories on endometriosis have been discussed in Table 2.

Diagnosis for Endometriosis
The various diagnostic methods for endometriosis are tabulated in Figure 1.

Therapies
All the currently available treatments are suppressive rather than being curative and the symptoms reoccur after cessation of treatment (Rivera et al., 1999). Present therapies for endometriosis target in treating the symptoms and lower the recurrence of disease by suppression of estrogen levels locally or systemically and its effects on lesions of endometriosis or targeting the lesions of endometriosis.

Hormonal action of progestins and oestrogenprogestin combinations
An effective way of treating endometriosis during the period in which the disease occurs which is reproductive age is by contraception to avoid pregnancies thereby treating the disease. The primary mechanism of the contraceptive action of combined hormonal contraceptives (CHCs) is considered to be the prevention of ovulation and not allowing the production of progesterone. They are considered to be the irst line medical therapies for endometriosis. According to Vercellini et al. study, the bene icial effects of hormonal drugs which causes suppression of ovulation and menstruation and pain which was found effective in estrogen-progestins and progestins. The ability to induce atrophy of eutopic and ectopic endometrium, possessing antiin lammatory and proapoptotic properties by these compounds by various novel routes was exclusively studied and proved (Vercellini et al., 2016).
Harada et al. investigated the effectiveness and safety of Ethinylestradiol/ drospirenone for management of endometriosis and it was found to have shown an increased ef icacy signi icantly when compared to placebo in endometriosis patients (Harada et al., 2017). Studies also have indicated that women with problems related to menstrual cycle may move from continuous administration to use of a combinational therapy during cyclic phase. Vercellini et al. investigated the comparative treatment of hormonal combination (desogestreladetinyloestradiol) and goserelin depot and observed that deep dyspareunia was signi icantly decreased in both groups, with goserelin proved to be a superior treatment when compared to the combinational therapy of hormonal drugs (Vercellini et al., 1993).  The visceral and abdominal peritoneum cells undergo metaplasia and form endometriosis

Combined Oral Contraceptives (COCs)
Combined Oral Contraceptives (COCs) is medical treatments given as irst line for endometriosis. The mechanism of action of COCs is the inhibition of GnRH, FSH and the LH surge in the mid cycle by estrogen and progestin.

Non-Steroidal Anti-in lammatory Drugs (NSAIDs)
NSAIDs is used in chronic in lammatory conditions, effectively reliving primary dysmenorrhea, hence proving to be the irst line of treatment.

Gonadotropin-Releasing Hormone Agonist
GnRH-agonist (goserelin, leuprolide, nafarelin, buserelin, triptorelin) decapeptides prove to be the second line therapies with their ability to decrease levels of LH and FSH by suppression of the production of ovarian estrogen by down regulation of GnRH receptors at pituitary level.

Gonadotropin-Releasing Hormone Antagonists
The usage of GnRH antagonists has been widely applied due to their suppression in the production of LH and FSH. Oral GnRH antagonists suppress gonadotropin production and produce a dose dependent environment of low estrogen levels. This causes the inhibition of proliferation and invasion of endometriotic cell thus maintaining the levels of estradiol suf iciently in circulation. Laboratory work resulted in proving GnRH-antagonists effects on endometriosis.

Selective Estrogen Receptor Modulators
The non-steroid ligands of Estrogen Receptors are Selective Estrogen Receptor Modulators (SERMs) possessing tissue-speci ic agonist, antagonist, or mixed agonist/antagonist activity. Raloxifene, a SERM used in postmenopausal osteoporosis and estrogen-responsive breast cancer (FDA approved). The SERM Bazedoxifene (BZA), antagonizes the endometrial stimulation induced by estrogen.

Herbal Remedies
The causative agent in progression of endometriosis in body is estrogen that needs to be deprived. Hence food supplements that reduce the levels of estrogen can be a supplemental therapy to deal with the disease. To deal with this progressive physical and metabolic alteration in an extraordinary way is to modify the diet that may help to alleviate the effects of disease. Certain foods create chemical reactions in the body and thereby have a promoting effect on endometriosis. A balanced and proper diet can help balance the estrogen levels. Another causative agent that was found to have both positive and negative effects on endometriosis was found to be prostaglandins. Medicinal plants and their active compounds have signi icant, antioxidant, anti-in lammatory, analgesic and proliferative properties which may help to treat the disease.
Management of endometriosis involve herbal medicines that target have pharmacological effects.

Medicinal plants for treatment against endometriosis
Investigational medicinal plants and phytochemicals for endometriosis treatment are listed below.

Achillea biebersteinii (Yarrow) from family Asteraceae
Demirel et al. investigated the role of various extracts of the aerial parts of Achillea biebersteinii in treatment of endometriosis and tested its effect of on animal endometriosis model and proved that after treatment, volumes of endometrial foci, TNFα, VEGF, and IL-6 were reduced in the ethyl acetate extract-treated group and no adhesion was detected in extract treated group. A promising alternative for treating endometriosis is ethyl acetate extract of A. biebersteinii due to the lavonoid aglycones found in the extract (Demirel et al., 2014).

Andrographis paniculata from family Acanthaceae
Zheng et al. isolated andrographolide, labdane diterpenoid from the plant aerial parts and proved that the plant has tumor depressing activity and inhibition of angiogenesis of tumor and endometriotic lesion volume reduction activity which is a promising alternative for treating endometriosis (Zheng et al., 2018).

Angelica sinensis from family Apiaceae
Wang et al. used the luid extract of the plant and used it to treat dysmenorrhea and severe bleeding. The extract was administered 7 days prior to menstruation and it inhibited PG synthesis and lessened the in lammation thereby reducing menstrual pain and chronic endometritis. Blood circulation was stimulated by inhibiting the in vitro synthesis of thromboxane A2 (Wang et al., 1993).

Alchemilla vulgaris from family Rosaceae
Stanilova et al. experimented on actions of in lammatory inhibition on the species and proved that the actions were because of high concentration of phenol. The effects of two Alchemilla species-Alchemillamollis (Buser) Rothm. and Alchemillapersica Rothm. on experimentally induced endometriosis in rat and showed signi icant inhibition of for-mation of cyst and endometrioma thereby proving the inhibitory activity on oxidation, in lammation and angiogenesis. Their phenolic constituents such as hyperoside and isoquercetin showed bene icial effects (Stanilova et al., 2012).

Allium sativum from family Liliaceae
Kim et al. showed cell proliferation reduction in TNF-α-activated human endometrial stromal cells by hexane extract of aged black garlic (Kim et al., 2013b).

Artemisia princeps from family Asteraceae
Kim et al. investigated and proved that leaf extract produced apoptosis by modulation of NF-kB and p38 pathway (Kim et al., 2013a).

Coccinia cordifolia from Family Cucurbitaceae
Jha et al. proved that C. cordifolia fertility induction in experimentally induced endometriosis female rats was not possible but the weight of endometrial implants reduced due to inhibitory effect on endometrial cell proliferation (Jha et al., 2010).

Centella asiatica from Family Apiaceae
Centella asiatica has an effect on in lammation and microbial reduction. Ivanov et al. proved that centella asiatica in combination with other herbs can treat endometriosis or to help in recovery after the surgery (Ivanov et al., 2008).

Copaifera langsdorf ii trees (Leguminosae-Caesalpinoideae family)
Nogueira Neto et al. proved the effect of in lammatory, nociceptive, microbial, cytotoxic, tumor reduction activity, and ulcer healing activity of C. langsdorf ii oil in endometrial growth in rats with endometriosis (Neto et al., 2011b).

Curcuma longa from Family Zingiberaceae
According to Chen et al. and Zhang et al. Curcumin, a major polyphenolic chemical found in"Turmeric" Curcuma longa (Zingiberaceae) stimulates antioxidant, anti-in lammatory, and antiproliferative, endometriosis symptom relief and microcirculation (Chen et al., 2010).
Zhang et al. suggested that curcumin use reduced the number of microvessels and the protein expression of VEGF in the ectopic endometrium of rat endometriosis models; also, the mRNA expression of the TNF"-induced cell surface and total protein expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 reduced.
Zhang et al. reported that curcumin decreased the number of endometriotic stromal cells (Qinshu et al., 2012).

Echinacea sp. From family Asteraceae
Sharma et al. investigated Echinacea sp. and proved the antioxidant use of the species by stimulating the immune system, increase in phagocytes, cytokines, and immunoglobins production and antiin lammatory action (Sharma et al., 2009).

Euterpe oleracea from family Arecaceae
Machado et al. investigated E. oleracea extract and proved that the extract exhibited anti-angiogenic and anti-in lammatory effects and decreased implant size (Machado et al., 2016).

Gossypium sp. from family Malvaceae
Bensky et al. has proved that the active ingredient, gossypol, has been found to have antagonistic effects of estrogen and progesterone (Bensky et al., 2004).

Lithospermum erythrorhizon from family Boraginaceae
Hisa et al. investigated shikonin has wound healing, antimicrobial, antiin lammatory, antitumor, and antioxidant activities. It has been considered to have inhibitory effect on angiogenesis (Hisa et al., 1998).

Paeonia lacti lora from family Paeoniaceae
Tanaka et al. proved that Paeonia lacti lora can treat endometriosis due to the presence of abnormal monoterpene paeoni lorin that has cage structure in the peeled root of the plant and also displayed antispasmodic effects in ileum and uterus smooth muscle when given oral decoction to laboratory animals. A Paeonia formula from Eastern tradition decreased the antiendometrial immunoglobulin M antibody levels in patients. Paeonia may also balance the estrogen-progesterone to normal levels (Tanaka et al., 2000).

Pinus pinaster from family Pinaceae
According to Kohama et al., the compound Pycnogenol had no in luence on menstrual cycles and levels of estrogen in patients with endometriosis but symptom scores were reduced (Kohama et al., 2007).

Prunella vulgaris from family Lamiaceae
Flavonoids, ursolic acid, Triterpenoids, polysaccharide prunelline, tannins, oleanolic acid, betulinic acid, and rosmarinic acid are the major chemical constituents of Prunella vulgaris. Collins et al. isolated the extract and experimented on blocking the proliferation of ectopic endometrium and demonstrated that the antiestrogenic properties were signi icant (Collins et al., 2009).

Salvia miltiorrhiza from family Lamiaceae
According to Zhou et al., the extract markedly decreased Cancer antigen 125 (CA-125) serum level and pro-in lammatory cytokines level in the endometriotic rat peritoneal luid. The levels of IL-13 in the peritoneal luids were also increased due to anti-apoptotic tanshinone IIA (Zhou et al., 2012).

Tripterygium wilfordii from family Celastraceae
Xiao et al. investigated that on administration the volume of endometrial implants and serum FSH and LH levels decreased and anti-endometrial antibody level normalized (Xiao et al., 2002).

Viburnum opulus from family Caprifoliaceae
In a study by Wichtl et al. demonstrated the stimulated secretion of FSH and LH when hot water extracts of European Verbena were administered. Fruits of V. opulus contains chlorogenic acid which reduced endometriotic volumes and in lammatory and angiogenic levels in endometriosis in rats (Wichtl, 2004).

Vitex negundo from family Verbenaceae
Amuthan et al. reported the reduction in size of endometrial cyst and endometrial epithelial morphology rupture (Amuthan et al., 2016).

Zingiber of icinale from family Zingiberaceae
Zingiber Of icinale "ginger" root is used as symptomatic relief from in lammation and spasm caused due to dysmenorrhea affected by endometriosis.

Apigenin-a lavonoid
According to Park et al., the lavonoid phytoconstituent has inhibitory effect on proliferation, in lammation and angiogenic properties (Park et al., 2018).

Baicalein
Jin et al. investigated the signi icant baicalein activities on human endometrial stromal cells from 6 female patients in vitro.
The usage of baicalein decreased human endometrial stromal cells viable count by inhibiting the nuclear factor (NF)-κB signaling pathway (Jin et al., 2017).

Epigallocatechin-3-gallate
Epigallocatechin Gallate (EGCG) is a catechin, a major lavonoid of Camellia sinensis, common monomer from green tea. Xu et al. studied that EGCG inhibited microvessels in endometriotic implants and inhibited angiogenesis both in vitro and in vivo (Xu et al., 2011).

Genistein
Genistein is isolated from soy which is an iso lavone, a strong phytoestrogenic. Lin et al. experimented on Genistein, a derivative of iso lavone showing antiangiogenic activity. The administration of genistein signi icantly decreased the expression of estrogen receptor α, VEGF and HIF-1" in peritoneal tissues and the expression of estrogen receptor β in mice was increased (Lin et al., 2014).

Ginsenoside
Ginsenoside Rg3 is from Panax. It is a glycoside that is steroidal in nature and triterpene saponin that has antioxidant and anti-in lammation action. Long et al. concluded that this plant can be used for endometriosis (Long and Li, 2012).

Palmitoylethanolamide (PEA)
PEA has actions against in lammation and positive effects of neuroprotectivity. Di Paola et al. reported that palmitoylethanolamide/polydatin (PEA/PLD), when co-micronized, decreased endometriotic lesions due to its actions against angiogenesis and decreased the nerve growth factor levels, intercellular adhesion molecule, MMP-9, and lymphocyte accumulation (Paola et al., 2016).

Puerarin
An iso lavonoid obtained from Radix puerariae. According to Cheng et al., its weak estrogenic property is contributed by its binding to estrogen receptors (Cheng et al., 2012).

Resveratrol
A polyphenol with actions against in lammations by the release of cytokines and the production of  (Zhang et al., 2019) Gyejibokryeonghwan (GBH) and Bogolgongjin-dan (BGD) Treatment of a patient with endometrioma The combination therapy of proved effective in treatment for endometrioma (Park, 2019) Rosmarinus of icinalis leaves and Scutellaria baicalensis root Effect of carnosic acid, rosmarinic acid and wogonin in vitro and in vivo The rosemary (Rosmarinus of icinalis) leaves, a Chinese herbal medicine used for endometriosis treatment in relieving symptoms and improving fertility. Wagnoninis has effects on endometriosis inhibition is a lavonoid isolated from the root of the medicinal herb Huang Qin (Scutellaria baicalensis), (Ferella et al., 2018) Traditional Korean Medicine (TKM) Inhibitory effect on the recurrent endometriosis after laparoscopic excision and hormone therapy Positive effect on inhibition of recurrent endometriosis after laparoscopic excision and hormone therapy (Kim and Yoo, 2018) Chinese Herbal Medicine (CHM) Safety, ef icacy, consistency and target actions of CHM Fertility improvement (Jiang et al., 2017) Viburnum opulus L Treatment of a patient with endometrioma Chlorogenic acid, fruit extract of Viburnum opulus has positive effect on inhibition of endometriosis (Saltan et al., 2016) Cat's Claw (Uncaria tomentosa) Macroscopic and histological changes after the drug treatment Positive effect on inhibition of endometriosis (Neto et al., 2011a) reactive oxygen species in monocytes, macrophages, and lymphocytes. Its antioxidant properties are suggestive to treatment of endometriosis. Maia et al. showed that resveratrol shows potentiating effect in endometriosis-related dysmenorrhea when used in combination with oral contraceptives inhibited aromatase expression and COX-2 in the endometrium (Jr et al., 2012).

Home Remedies for Endometriosis
Heat is found to have soothing effect on abdominal muscles by causing relaxation of the muscles in the uterus. The food habits to be practiced to avoid or to get relief from dysmenorrheal are avoiding re ined carbohydrates, Eliminating sugary foods and processed sugar, Eliminating dairy and reducing red meat and egg yolk consumption to at most 2-3times a week. No scienti ic studies support the theory of essential oils increasing blood circulation, reduce spasms and consequently lead to pain reduc-tion. Other approaches, such as yoga or body therapies, may reduce pelvic pain by improving lexibility of spine and pelvis strengthening.

Novel Herbal Therapies
An estrogen-dependent disease with extra uterine in lammatory lesions, causing infertility and dysmenorrhea. The primary target of conventional therapies is to reduce systemic levels of estrogens but do not produce effective actions and produce side effects. Therefore, the interest in the Herbal medicine is growing. The various novel herbal therapies are tabulated in Table 3.

Elagolix
Elagolix is used for treatment for pain related to endometriosis, orally. This drug suppresses levels of estrogen and progesterone hormones through antagonistic effects on GnRH receptor. This helps in in lammatory reduction and the endometrial tissue proliferation (Fantasia, 2019).

Anastrazole
Anastrazole is currently used to treat hormone receptor-positive breast cancer in post-menopausal women (Amsterdam et al., 2005).

Shock Wave Therapy
When medication is not satisfactory, or not tolerated or surgery is unwanted, a less invasive treatment, a novel approach to endometriosis treatment (Melki, 2019).

Statins
L.Gibra et al. studied the systemic review to understand the statins mechanism apoptosis stimulation, endometrial cell proliferation inhibition, angiogenesis blockade, adherence and invasion by endometrial cells interference into the peritoneum and oxidative stress and in lammation decrease (Gibran et al., 2014).

Nicotinic Acetylcholine Receptor
The anti-in lammatory and anti-nociceptive functions of nicotinic acetyl choline receptors (nAChRs) are of current researcher's interest as nicotinic acetylcholine receptors may be a novel therapeutic target for Endometriosis (Wu et al., 2011).

CONCLUSION
Elimination of pain and/or infertility is the current medical and surgical treatment option for suppression of lesion proliferation. Further care and treatment should shift toward a centering patient rather than single symptom, approaching in multidisciplinary level. The biology of endometriosis and possible endometriosis subtypes has to be ventured deeply that may lead to novel therapeutic outcomes and broader plans in personalized treatment. Broader research on gene targeted and its associated treatments may provide relief from endometriosis. Development of analogue molecules of herbs can be of futuristic research. The present need is to alleviate pelvic associated pain and infertility by exploration of quality clinical trials or establishment of simpli ied special registration procedures for speci ic molecules of herbs with safe traditional use.

Funding Support
The authors declare that they have no funding support for this study.