Progestins

Progestins inhibit the hypothalamic-pituitary-ovarian axis, reducing serum estrogen levels and leading to anovulation and atrophy of the eutopic endometrium and endometrial lesions. They modulate the immune response involved in the pathogenesis of endometriosis, decreasing peritoneal inflammatory mediators, inhibiting angiogenesis and suppressing matrix metalloproteinases, factors that facilitate the growth and implantation of the ectopic endometrium [5] . Of this class, the main drugs and/or methods reported were: dienogest [5] , medroxyprogesterone acetate [7] and norethisterone acetate [6] [7] , as well as the levonorgestrel-releasing system (LGN-IUS) and the etonogestrel-releasing implant [25] .

It was found that dienogest, a 4th generation selective progesterone, composed of 19-nortestosterone and progesterone derivatives, has low androgenic, estrogenic, glucocorticoid and/or mineralocorticoid activities. In addition, it has anovulatory, antiproliferative effects and inhibits the secretion of cytokines in the stroma of endometrial cells [5] . Dienogest (2 mg/day) suppressed pain about 24 weeks after starting treatment, in addition to reducing bone mineral loss observed with the use of leuprolide acetate [7] .

Norethisterone acetate, a low-cost drug, improves chronic pelvic pain, dyspareunia and dyschezia, as well as symptoms referred to the gastrointestinal tract [7] . However, recurrence of pain was reported when associated with letrozole, as well as more side effects when associated with triptorelin and, consequent abandonment of therapy [7] . As for medroxyprogesterone acetate, an improvement of about 68% of pain in one year has been reported [7] .

The levonorgestrel-releasing system (LGN-IUS) has been reported as a comfortable use/maintenance intrauterine device, requiring replacement every 5 years; however, it can be displaced or expelled from the body in the condition of endometrial thickening, arising from endometriosis or adenomyosis. Subdermal etonogestrel-releasing implant (68 mg) lasting up to 3 years has been shown to reduce pelvic pain as well menstrual flow [25] . Furthermore, the most common side effects associated with these drugs were acne, bone mineral loss, weight gain, and mood change [5] , seborrhea, oily hair, pimples, headache, breast tenderness, and vaginal irritation [25] .

Gonadotropin-releasing hormone agonists (GnRH)

Regarding the class of GnRH agonists, the drugs (leuprolide, goserelin and nafarrelin) were reported as the main ones, which demonstrate efficacy in improving symptoms, especially pelvic pain. Side effects (vaginal bleeding, headache, weight gain, breast tenderness and loss of bone mineral density) associated with prolonged treatment with these drugs have also been reported, situations that limit their use [5] [7] .

Gonadotropin-releasing hormone antagonists (GnRH)

Regarding the class of GnRH antagonists, the drug (elagolix) was reported as a great innovation for the treatment of endometriosis, due to its mechanism of action. Elagolix acts on the binding site of an endogenous decapeptide in the anterior pituitary, but without activating. Unlike GnRH agonists, it does not induce the onset of gonadotropin release, a fact that leads to milder hypoestrogenism with consequent reduction in pain and side effects [26] .

The main side effects observed include hot flush, headache, nausea, loss of bone density and hyperlipidemia [27] . It is reported that this drug can be used in both low and high doses, the latter being more effective in the treatment of dysmenorrhea, pelvic pain and dyspareunia. There was also a reduction in the use of associated analgesics (non-steroidal anti-inflammatory drugs and opioids) after 3 months of elagolix use [27] .

Aromatase inhibitors

Regarding the class of aromatase inhibitors, the 3rd generation drugs (letrozole and anastrozole) were reported as the most used. They have a potent selective but reversible action on the aromatase enzyme [28] , which is responsible for converting cholesterol into estrogen, a hormone that exerts great activity on the growth and maintenance of endometriotic lesions and foci [29] . Excellent effects/results have been reported in the treatment of chronic pain, however, side effects such as, hot flashes, headache, arthralgia and significant bone mineral loss have been reported [28] . At dosages of 1 - 5 mg/day orally, these drugs were able to reduce estrogen levels by 97% - 99% [28] .

When analyzing the association of letrozole with some drugs from other classes, the reported results are interesting, for example: letrozole/norethisterone acetate increased the degree of relief of pelvic pain and deep dyspareunia compared to the use of progestin alone; as well as letrozole/GnRH agonist decreased the risk of lesion recurrence [30] .

Selective progesterone receptor modulators

Traditional progesterone-based drugs, widely used, can cause many side effects due to nonspecific binding to androgen and glucocorticoid receptors. Thus, new drugs with greater specificity to progesterone receptors have been developed, seeking to attenuate these undesirable results [5] . Regarding the class of selective progesterone receptor modulators, the drugs, mifepristone [31] and ulipristal acetate [32] have been addressed in the treatment of pain and endometriotic foci.

Women under mifepristone treatment [31] [33] obtained improvements in symptoms of chronic pelvic pain and dyspareunia, as well as reduction of endometriotic lesions [31] , however, side effects such as amenorrhea, hot flush and fatigue were observed [33] . On the other hand, use of mifepristone for abortion has been reported, mainly associated with misoprostol. Due to this abortifacient characteristic, there is strict control over its commercialization in much of the world; in addition, there is also a scarcity of studies proving its effectiveness [31] .

Ulipristal acetate attenuates pain and reduces endometriotic foci through regulation of prostaglandin and COX-2 synthesis and consequent pro-apoptotic, anti-proliferative and anti-inflammatory effects [32] . In contrast, studies have reported its relationship with pathological endometrial changes, which led physicians to discontinue its administration [34] [35] . Considering these effects, the fact that it is a more recent drug with abortifacient properties, the use of this drug needs further studies.

Combined contraceptives

Combined estrogen and progesterone contraceptives have been reported as first-line therapy for endometriosis-related pain because of their high tolerance and efficacy, few adverse effects, and low cost [6] [36] . These drugs block endogenous estradiol synthesis and ovulation, generating a hormonal environment with a predominance of progesterone; which deregulates the local estrogen receptors responsible for fueling the proliferation of lesions. In addition, this environment reduces the density of nerve fibers and inhibits angiogenesis in endometriotic foci. In this way, it is possible to delay the progression of the disease [37] .

The use of these drugs has been reported in a cyclical or continuous way; however, the continuous use has a better result in the attenuation of pain, due to the promotion of amenorrhea and extinction of dysmenorrhea [6] . However, mainly because they constitute long-term therapies, they have disadvantages such as risks of thromboembolism, impairment of fertility during use and high recurrence rate after discontinuation [29] . Regarding the risk of venous thromboembolism, low-dose hormonal contraceptives are more widely recommended and have lower risks [29] .

Improvement of chronic pelvic pain, dysmenorrhea and pain on defecation has been reported, mainly 12 months after starting treatment. However, side effects such as uterine bleeding, moderate weight gain, headache and decreased libido have been observed [7] . Furthermore, when comparing the use of combined contraceptives and other hormonal drugs, the progestogen dienogeste alone showed a greater decrease in pain scores [37] . In addition, women commonly opt for progesterone-only methods because of the side effects and their impact on life quality [6] .

Regarding the recommendation of anti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs) have been reported as first-line therapy for the control of pain and dysmenorrhea associated with endometriosis. NSAIDs can nonspecifically bind to the two isoforms of cyclooxygenase (COX-1 and COX-2) promoting its inhibition and/or blockade [38] .

Although both COX-1 and COX-2 receptors are present in the endometrium, a higher concentration of COX-2 receptors has been reported in ectopic endometrial tissue [29] . Both selective and non-selective COX-2 inhibitor NSAIDs have been reported, which should be administered a few days before the start of the menstrual cycle, aiming to reduce inflammatory mediators and consequently dysmenorrhea [38] .

Selective COX-2 inhibitors, in addition to blocking the inflammatory process, also inhibit the growth of endometrial tissue [29] . These drugs should be used with caution, due to their side effects on the gastric system and the risk of kidney damage when in chronic use [38] . Factors such as genetic polymorphisms, bioavailability, and changes in cytochrome P450 have been reported to interfere with cyclooxygenase inhibition, which explains why some women experience significant symptom improvement and others do not [38] . However, further studies are needed to fully understand the molecular mechanisms that justify resistance to these drugs. Furthermore, thalidomide, a drug that acts on cell proliferation without interfering with ovarian function, has been shown to reduce the size of cysts in the retrocervical and ovarian regions, as well as decrease pelvic pain, in women with endometriosis [39] .

On the other hand, laparoscopy has been the gold standard surgical method performed in patients with endometriosis. It allows the definitive diagnosis, through evaluation of the lesions at a macro and microscopic level [40] , classifying them according to their severity [41] , in addition to being a quick, efficient and minimally invasive procedure, which generally does not involve major complications [40] . Its indication has been reported mainly for women with chronic pelvic pain and infertility, cases in which empirical treatment has not had an effect, cases of drug intolerance and for immediate diagnosis/resolution of the disease [6] . In addition, it has been reported as the first treatment option for symptomatic intestinal endometriosis, as improves quality of life, especially regarding intestinal functioning [24] .

Laparoscopy encompasses two distinct procedures, including conservative or definitive methods, involving hysterectomy with or without removal of the ovaries. Still, in the conservative method, two different techniques (ablation or excision) can be applied [6] . Ablation usually involves the application of an energy source (carbon dioxide laser), which destroys the lesions; or even performing mono or bipolar electrosurgery. In contrast, in excision the cysts are removed in the traditional way [40] . A greater reduction in pain scores has been reported in women with deep infiltrating disease undergoing laparoscopy compared with those with superficial endometriosis [40] [42] . In contrast, a higher incidence of recurrence of pain symptoms has been reported in women undergoing ablation compared to excision, particularly in women with deep endometriosis [40] . This finding is related to the fact that in deep endometriosis, only the most superficial lesions are treated, since in these cases deep penetration with ablation energy on the lesions is not recommended, due to the risk of damage to adjacent tissues [40] .

A reduction in the recurrence of dysmenorrhea, dyspareunia, non-menstrual pelvic pain and an increase in the possibility of spontaneous pregnancy, as well as improvement in ovarian changes were found in women undergoing excision [6] [40] . On the other hand, the risk of the excisive method has been reported for women who want a future pregnancy, as this procedure can lead to reductions in ovarian reserves. In more severe cases, in the presence of infiltrative ovarian lesions, there is a need for a thorough evaluation of the ureteric course, as well as infiltrations of the urinary tract, cul-de-sac or intestine. Surgical procedures are long and delicate, involve greater risk, in addition to demanding greater knowledge, experience and precision from the multidisciplinary team [40] .

Hysterectomy methods themselves have been reported to be effective in treating severe pain, however, in women under 40 years of age, ovary conservation is indicated in order to avoid surgical menopause. In these cases, the possibilities of recurrence of symptoms and need for further surgery are also more common [6] . However, it is important to pay attention to the recurrence of symptoms and endometriotic foci in the late postoperative period, since recurrences of about 10% and 40% - 50% of symptoms were reported after 1 or 5 - 7 years, respectively [6] . A study comparing cyclic or continuous contraceptive use or non-use by patients undergoing laparoscopy reported the following rates of recurrence of ovarian endometriomas (29%, 14.7% and 8.2%) when not in use, in cyclical use or continuous use, respectively [43] . Thus, it is obvious that pharmacological measures, including the use of contraceptives in order to avoid relapses or to prolong the patients return to the operating room, are important and necessary.

In addition to laparoscopy, nerve transection has also been reported as a method for the management of endometriosis, since presacral neurectomy helps to reduce pain and dysmenorrhea, however, changes such as constipation and bladder dysfunction have been related to this procedure [6] . Also, more recently, robotic laparoscopic surgery has emerged, a method that has aroused scientific and commercial interest. It is reported as a differential of this method, the possibility of increasing precision, depth perception and wrist articulation compared to traditional laparoscopy. However, in practice, significant differences in length of stay, blood loss and possible intraoperative and postoperative complications were not reported, in addition to being an expensive procedure [44] . In addition, it requires longer surgical time, a fact related both to the profile of patients who, in these cases, present more severe conditions with deep infiltrations in the urinary and/or intestinal tract, and to the profile of professionals due to the lack of extensive experience in this field [44] . In this sense, robotic surgery is a viable and promising possibility for the treatment of endometriosis, but at the moment it does not present significant advantages over traditional laparoscopy [44] .

There are several surgical procedures. However, it is noteworthy that, although these procedures do not involve major risks, they still exist; with emphasis on infections, hemorrhages and injuries in abdominal pelvic organs (intestine and bladder) [41] . Thus, a thorough clinical analysis is feasible to avoid performing undue procedures, which are relatively invasive and costly. In addition, it is also ideal that the choice of procedure is adapted to factors (age, infertility, sexual health, family planning, attempts at other treatments, among others) related to the patient, seeking to treat the whole.

Although pharmacological and/or surgical means are the most used to treat endometriosis, it is noteworthy that both have more unwanted side effects. Thus, alternative methods that can help to improve symptoms and promote better quality of life, in addition to presenting little or no side effects, are also reported.

Acupuncture methods

Regarding acupuncture, several methods (traditional Chinese or Japanese acupuncture, electroacupuncture and auriculoacupuncture) have been reported. They are relatively safe and widely indicated methods for pain relief in endometriosis, as they result in physiological and psychological benefits [45] [46] .

Briefly, traditional Chinese acupuncture advocates the existence of a natural pattern of vital energy (Qi) throughout the body, thus, interruption and/or imbalance of this energy flow indicates illness and/or pain. Therefore, this method aims to correct these endometriosis-related changes [46] . Japanese acupuncture is similar to the Chinese method. The main difference is in the application of needles, performed only in the superficial layers of the dermis. Therefore, it is a well-accepted and commonly associated method of treating endometriosis in adolescents [45] . Electroacupuncture has characteristics similar to the previous methods; with a difference, the stimuli are performed through electric current. Auriculoacupuncture involves stimulation of specific points in the ears, the points being: Ting Zhong (cymbian auricle center), Pi Zhi Xia (hypocortex), Nei Fen Mi (endocrine), Jiao Gan (sympathetic) and Nei Sheng Zhi Qi (internal genital organs), traditionally addressed in pain relief and improvement of the reproductive system [46] .

Studies report the ability of these methods to; increase the pain threshold by decreasing the expectation of symptoms and activating the brain’s analgesic mechanisms to release neural and humoral factors, including adenosine, alpha-aminobutyric acid, opioid peptides, acetylcholine, nitric oxide, noradrenaline and dopamine [45] [46] , as well as stimulating increased cytotoxicity of NK cells, promoting a cross-relationship between the neurotransmitter network and the immune system, mediated by nitric oxide, beta endorphins and cytokines [45] . Other positive effects were also reported: Acupuncture was able to decrease estrogen levels, with consequent reduction of endometriotic tissue and pain [45] , as well as, auriculoacupuncture significantly improved dyspareunia and severe dysmenorrhea compared to chinese herbal medicine [46] , in addition to promoting a decrease in menstrual flow and the size of endometriomas [47] . Furthermore, it has been hypothesized that acupuncture may play a role in ovulation induction and fertility treatment by normalizing the hypothalamic-pituitary-ovarian axis [46] , as well as reducing plasma levels of CA-125 [45] .

However, it should be noted that the appropriate moment for performing these methods must be considered individually. According to one study, an intervention was started in the week before the premenstrual period, including 3 weekly sessions, as during this period the regularization of Qi and blood flow would occur and the consequent achievement of pain relief [48] . Typically, 9 - 16 sessions are required, lasting about 15 - 25 minutes each [49] .

Physical activity

The practice of physical activity has been associated with the improvement of chronic pain; however, studies exclusively related to endometriosis are scarce. A study was found comparing patients who underwent only pharmacological treatment with those who associated drugs (danazol and GnRH analogues) to the practice of physical activity. In this, a lower rate of disease recurrence was reported after discontinuation of the drug, as well as reduced androgenic side effects and testosterone levels and less bone mineral loss [50] . In this case, the explanation for the improvement in pain is still unclear. It is believed that, in part, there is a relationship with blood pressure, since physical exercise increases blood pressure by sympathetic activation, which activates baroreceptors and, consequently, triggers the nucleus of the solitary tract, a situation that in the long term, increases the peripheral pain threshold [51] .

However, women with endometriosis, because they have a greater perception of pain, find physical exercise an extremely unpleasant situation, which makes it difficult for them to adhere to physical training programs for a long time, allowing them to experience the benefits of this practice, especially in the long term [51] . In this sense, the practice of physical activity should be encouraged, as promotes improvement of possible psychological changes (anxiety and depression) related to the disease, in addition to improving the life quality.

Cognitive Behavioral Therapy

Commonly, much is studied and search for means of treatment of the physical symptoms of pain and infertility, however, little is addressed about the psychological effects such as; anxiety, depression, social aversion and difficulties in socializing and/or socializing, which many women with endometriosis experience in everyday life [7] [13] [52] .

Cognitive Behavioral Therapy (CBT) was reported as a means to improve the recognition and treatment of both psychological and physical impacts with the same relevance, seeking to treat the whole. Recent studies show significant reductions in pain and depression scores, as well as an improvement in the quality of life of women undergoing pharmacological treatments associated with CBT, a fact due to a better understanding and ways of dealing with the disease [7] [13] [52] .

Anti-inflammatory nutritional therapy

It is known that the severity of endometriosis and its symptoms are closely related to an extensive degree of inflammation observed in patients. In addition, nutrient-deficient diets, diets based on red meat and industrialized products, trigger lipid changes, generation of free radicals and oxidative stress, intensifying inflammatory processes, as well as triggering epigenetic abnormalities, involved with the development and progression of the disease [53] . However, the adoption of a balanced diet, including foods with anti-inflammatory properties, has been gaining relevance, as well as the search for the identification and understanding of its mechanisms of action.

Foods rich in omega 3, supplementation of N-acetylcysteine, vitamin D and resveratrol, associated with greater consumption of preferably organic fruits and vegetables, as well as whole grains, turmeric and ginger, have been reported as protective foods and reduce the risks of development of endometriosis and related to possible regression of the disease [53] . The consumption of vegetables was reported as the highlight of the moment in relation to their benefits, due to their anti-inflammatory, detoxifying and antitumor properties [54] . Brassic vegetables (cauliflower, broccoli, cabbage, kale and arugula) were associated with a significant reduction in the chronic inflammatory process, a benefit that is due to the glucosinolates present in these foods. After ingestion, these substances are converted to bioactive degradation products, which associate with inflammatory receptors [54] .

In addition, there is great scientific interest in curcumin, a phenolic component derived from turmeric, which has activities; antioxidant, anti-inflammatory, hypoglycemic, antimicrobial, antitumor, antiangiogenic and antimetastatic [55] . Studies have reported its ability to reduce the growth and number of endometriotic stromal cells and the development of peritoneal endometrial glands, induce the expression of apoptotic mitochondrial factors such as cytochrome C, increase the expression of p53 protein and inhibit the secretion of interleukins (IL-6 and IL-8) and monocyte chemotactic protein 1 (MCP-1) [55] [56] . In this sense, the approach of nutritional measures that prevent and/or alleviate the inflammatory picture in endometriosis becomes essential.

Medicinal plants

Some plants with medicinal properties and/or their derivatives with great potential to treat pain have also been addressed in the treatment of endometriosis. Resveratrol, a polyphenol commonly found in the seeds and skin of grapes, is endowed with anti-angiogenic and anti-inflammatory properties. It is capable of inducing apoptosis of endometrial stromal cells by suppressing the expression of survivin, an apoptosis-inhibiting protein, as well as inhibiting the synthesis of prostaglandins, attenuating the peritoneal inflammatory response and decreasing the development of endometriosis [42] [56] . In another study, it is reported that cotton (Gossypium sp), commonly used as a tonic in the stimulation of uterine contractions, demonstrated efficacy in the treatment of endometriosis, in the short (90%) and long term (54% - 63%), after 1 and 3 years respectively. This effectiveness is due to the mechanism of action related to the active substance (gossypol), which antagonizes the effects of estrogen and progesterone [57] .

Another plant, Cannabis sativa, is also addressed in pain management, due to the direct and/or indirect effects of its active principles D9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on specific receptors in the endocannabinoid system. Although several different receptors are present in this system, cannabinoid receptors 1 (CB1) and 2 (CB2) present mostly in central and peripheral presynaptic neurons are the most explored, with anandamide being its main neurotransmitter [58] .

CB1 receptors are highly expressed in the uterus and other non-reproductive tissues, while CB2 receptors are expressed in the immune system, uterus, intestines, lungs, pancreas, and skin tissue. The presence of CB1 and CB2 receptors was reported in different regions of the oocytes, according to the stage of maturation, as well as the presence of anandamide in the reproductive tract fluids. In the secretory phase, an important increase in CB1, mRNA and endometrial proteins was observed, a fact associated with the ability of progesterone to regulate the expression of these receptors [58] . In addition, a significant increase in anandamide associated with a decrease in CB1 expression has been observed in women with endometriosis, a situation that can impair the control of pain symptoms, aggravating chronic pelvic pain, dysmenorrhea and dyspareunia [58] .

Other interesting aspects are the time of absorption and improvement of symptoms, since THC has an immediate noticeable effect a few minutes after administration, while CBD requires a longer period. However, when administered together, improvement in acute and/or severe conditions, as well as in chronic symptoms, has been reported [59] , a fact that may play a vital role in pain management. Regarding dose, one study reported less pain, as well as fewer gastrointestinal symptoms, psychological and mood changes in women who received high concentrations of THC (inhaled) and CBD (orally), respectively [58] . A significant improvement in symptoms in response to medications was also reported in older women; however, this reason was not exactly clear. It is believed to be associated with factors that change with age, such as: hormonal changes, increased drug sensitivity, possible decline in the endocannabinoid system, and/or changes in pain perception [58] . CBD, in addition to acting on the chronic inflammatory process in the reproductive tract, also exhibits anxiolytic and antidepressant activities, through modulation of the serotonin receptor (5HT1A) [59] . Most synthetic cannabinoid ligands are found to ensure beneficial effects by acting as CB1 cannabinoid receptor agonists [58] . Furthermore, side effects associated with the use of these drugs are rarely reported [58] .

It is also important to highlight the existence of other medicinal plants (Angelica sinesis, Achillea biebersteinii, Hypericum perforatum, Uncaria tomentosa, Verbena hastata and Alchemilla mollis) with therapeutic potential for treating pain and improving the quality of life of women with endometriosis [57] . However, their applications in clinical practice are limited due to the scarcity of studies that address them more comprehensively.

This review discusses more recent research data published between 2010 and 2021 and related to pain management in women with endometriosis. However, this study has limitations, due to the inclusion only of articles published in English and Portuguese, thus excluding, to a large extent, relevant studies published in other languages. Another limitation is the lack of studies comparing the different means and/or methods, which makes it difficult to present positive and negative points regarding the use of techniques/treatments in isolation and divides the opinion of professionals, interfering in the development of a conduct pattern. There were studies that used a small number of patients or still did not distinguish them particularities such as age, time of diagnosis of endometriosis and comorbidities. Most of the time, the distinction was just the endometriosis site and symptoms. In addition, there were few studies focused exclusively on endometriosis pain management, which is a drawback of the retrospective design.