Medical Treatment of Endometriosis PDF

Review Article Medical treatments of endometriosis: a review Bahi Elbasueny1,2, Maya Geerts1,...

Review Article Medical treatments of endometriosis: a review Bahi Elbasueny1,2, Maya Geerts1, Emily C. Yang1, Catherine Allaire1, Paul J. Yong1, Mohamed A. Bedaiwy1,* Downloaded from http://journals.lww.com/rdm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn Abstract Endometriosis is a chronic gynecological disorder that affects approximately 10% of women of reproductive age. Most medical YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/05/2024 treatments used today for endometriosis pain are hormonal therapies, which are not an option for those trying to conceive and are not tolerated by a subset of patients due to side effects. In this article, we offer a comprehensive review of current and investigational medical therapeutic options used to treat endometriosis pain, as well as a symptom-based systematic approach for patients with painful endometriosis. We have also included recommendations for research to enhance the evolution of novel therapeutic options. A thorough literature search was carried out, and the data were synthesized using a synthesis matrix that classifies and categorizes various arguments. Keywords: Endometriosis, Pelvic pain, Medical treatment, Medical therapy, Non-steroidal anti-inflammatory drugs, Combined oral contraceptives, Progesterone, GnRH agonist, GnRH antagonist, Aromatase inhibitors, Investigational endometriosis treatments Introduction invasion. A substantial delay in diagnosing endometriosis, which may last for several years, has been frequently reported. Endometriosis is a debilitating disease in which endometrial-like Patients with endometriosis may be asymptomatic but most tissue is present outside the uterine cavity, inducing a chronic commonly experience infertility/subfertility, CPP, dyspareunia, inflammatory response. It typically affects pelvic-dependent dysmenorrhea, dysuria, or dyschezia[14,15]. Transvaginal sonog- areas such as the anterior and posterior cul-de-sac; other sites raphy (TVS) and magnetic resonance imaging are good modal- include the ovaries, uterosacral ligaments, rectovaginal sep- ities for diagnosing and mapping endometriosis[16,17]. Visual tum, bladder, ureters, and in rare cases, pleura, pericardium, inspection by laparoscopy with histopathological confirmation and surgical scars[2,3]. Deep infiltrating endometriosis (DIE) is a is regarded as the gold standard for diagnosing endometriosis. severe phenotype of endometriosis where lesions exceed 5 mm However, symptom-based clinical diagnosis is now accepted by in depth. Endometriosis is a common condition that affects most international societies (NICE, SOGC) to prevent delay approximately 10% of women of reproductive age, nearly 50% in treatment initiation. Endometriosis treatment is a long- of infertile women, and 60% of patients with chronic pelvic pain term process that can extend to menopause and occasionally (CCP). It poses significant financial, physical, and mental bur- beyond. Endometriosis can be treated with medications, sur- dens on those affected[6,7]. The definitive cause of endometriosis gery, or both, and the treatment should be individualized for is uncertain, and various theories have been proposed, the most each patient. popular of which involves retrograde menstruation through the fallopian tubes. However, other explanations include hematog- enous or lymphatic spread, development from stem cells, coe- Medical treatment of endometriosis pain lomic metaplasia, and abnormal differentiation of Müllerian remnants[8–11]. Endometriosis is an estrogen-dependent systemic Most endometriosis pharmacotherapies available today manage inflammatory disease that is strongly associated with proges- symptoms by suppressing ovulation. There is no ideal medical terone resistance, neoangiogenesis, cellular proliferation, and therapy for endometriosis pain, as most therapies have limita- tions, including discontinuation due to unacceptable side effects, clinical ineffectiveness in certain endometriosis phenotypes, 1 Division of Reproductive Endocrinology and Infertility, Department of Obstetrics high costs, unavailability of drugs in certain locations, and the and Gynecology, Faculty of Medicine, University of British Columbia, Vancouver, contraceptive nature of nearly all available drugs that interfere BC, Canada; 2Department of Obstetrics and Gynecology, Faculty of Medicine, with fertility[20,21]. Despite these limitations, hormonal therapies Menoufia University, Menoufia, Egypt. remain the mainstay of endometriosis treatment and are benefi- *Corresponding to: Mohamed A. Bedaiwy, Department of Obstetrics and cial for many patients. As there are many drugs used in the treat- Gynaecology, BC Women’s Hospital and Health Centre, Faculty of Medicine, The University of British Columbia, D415-4500 Oak Street, Vancouver, BC V6H 3N1, ment of endometriosis pain, treatment should be approached in Canada. E-mail: [email protected] a systematic manner and customized to patient goals, such as Copyright © 2022 Reproductive and Developmental Medicine, Published by decreasing the disease burden, treating pelvic pain, improving Wolters Kluwer Health, Inc. quality of life, postponing, or reducing surgical interventions, This is an open-access article distributed under the terms of the Creative and enhancing postoperative outcomes. Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially Current therapeutic options without permission from the journal. Reproductive and Developmental Medicine (2023) 7:3 Non-steroidal anti-inflammatory drugs Received: 27 June 2022 Accepted: 4 September 2022 The most popular initial therapy for individuals with pelvic pain http://dx.doi.org/10.1097/RD9.0000000000000053 is non-steroidal anti-inflammatory drugs (NSAIDs) because of 166  Elbasueny et al., Reproductive and Developmental Medicine (2023) 7:3 https://journals.lww.com/RDM their over-the-counter availability, economic affordability, effec- In terms of postoperative CHC use, prolonged and continuous tiveness, tolerability, and acceptable adverse effects. Their use CHC use seems beneficial in reducing the rate of postoperative in endometriosis pain treatment is justified by their analgesic endometrioma and dysmenorrhea recurrence[42–44]. CHCs have and anti-inflammatory characteristics through the inhibition of many advantages, including easy accessibility, economic afford- the Cyclooxygenase (COX) enzyme, which is required to pro- ability, reversibility, long-term use safety which is also related to duce inflammatory mediators. Additionally, selective COX-2 risk reduction of both ovarian and endometrial cancers, fewer inhibitors can suppress the growth of ectopic endometrial tis- adverse effects, contraceptive action, convenience of use, and sue. NSAIDs are effective in managing primary dysmenor- ability to control the menstrual cycle. However, CHC use is Downloaded from http://journals.lww.com/rdm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn rhea. However, there is insufficient evidence to support their limited by an increased risk of thromboembolism, especially effectiveness for endometriosis pain, and there is no evidence with long-term use and high estrogen dose combinations, par- that one NSAID is more effective than the other. The most ticularly in smoking patients over 35 years old; intermenstrual frequently encountered adverse effects of NSAIDs are gastroin- bleeding, particularly when commencing treatment and with YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/05/2024 testinal upset and cardiovascular diseases. Moreover, selective lower estrogen dose combinations; and increased incidence of COX-2 inhibitors can interfere with ovulation[28,29]. disease recurrence upon discontinuation. Furthermore, past CHC use for severe primary dysmenorrhea has been associated with an increased risk of endometriosis development, especially Combined hormonal contraceptives DIE, supporting the theory that high estrogen doses may lead Despite being included in the management guidelines of multi- to the advancement of more invasive endometriosis. This does ple authoritative societies, the use of combined hormonal con- not imply that using CHC increases the likelihood of develop- traceptives (CHCs) for endometriosis-associated pain remains ing endometriosis, as it may be associated rather than causative, off-label[30,31]. They have the ability to suppress ovarian hor- as endometriosis patients have more severe dysmenorrhea and mone secretion via a negative feedback loop, inducing a state of are, therefore, more likely to be prescribed CHCs early. In hypoestrogenism, which leads to a decrease in estrogen-induced a non-randomized cohort study that followed over 17,000 prostaglandin production and suppresses inflammation related women for up to 23 years, it was concluded that endometriosis to endometriosis. Moreover, they promote decidualization of risk was low in women who were currently using CHCs but eutopic and ectopic endometrial tissues, which reduces with- higher in women who had previously used them compared to drawal bleeding, the volume of retrograde menses, and thus women who had never used them. pelvic oxidative stress. CHCs are available in low- and high- dose combinations according to their estrogen concentration; Progestins however, combinations with the lowest estrogen concentration are preferred because they are associated with a lower risk of Progestins are a variety of synthetic progestogen compounds thrombosis[22,33]. CHCs can be administered in a cyclic or con- with numerous actions on progesterone receptors, as well as tinuous manner. Continuous use has been demonstrated to estrogen, androgen, mineralocorticoid, and glucocorticoid offer lower recurrence rates for dysmenorrhea. However, there receptors. They are available as oral tablets, depot injec- were no significant differences between the two regimens in tions, implants, or intrauterine-releasing systems (IUS), with decreasing the recurrence of CPP, dyspareunia, or endometri- the active molecules being norethisterone acetate (NETA), dien- oma after conservative surgery. Moreover, the risk of unpre- ogest (DNG), desogestrel (DSG), medroxyprogesterone acetate dictable bleeding may increase with continuous use, and (MPA), levonorgestrel (LNG), etonogestrel, and cyproterone some women consider amenorrhea a non-physiological con- acetate (CPA). There is insufficient data showing the superiority dition. Therefore, cyclic use may increase compliance in these of one progestin over others. Progestins exert their actions by patients. Moreover, individual patient preferences should be inducing decidualization and atrophy of both eutopic and ecto- determined. Vaginal rings (VRs) and transdermal patches are pic endometria. They also decrease estrogen-induced mitosis, alternative methods of hormonal delivery. Both were effective suppress cell proliferation, inhibit inflammatory pathways, and in alleviating painful symptoms, with the ring being superior in inhibit angiogenesis and neurogenesis. However, in endometri- terms of efficiency, satisfaction, and compliance, especially in otic lesions, progesterone receptor expression is reduced and cases of rectovaginal lesions. However, both were associated disrupted due to epigenetic abnormalities affecting receptor with abnormal uterine bleeding, especially with continuous gene transcription, which accounts for progesterone resistance use. CHCs reduce dysmenorrhea and endometrioma size and the ineffectiveness of therapy in some patients. compared to placebo, particularly for endometriomas larger NETA is an orally active synthetic progestin derived from than 3 cm. In a large, multicenter, randomized controlled trial 19-nor-testosterone and is a cost-effective option for endo- (RCT), the use of a flexible extended regimen of estrogen-pro- metriosis-related pain. The United States Food and Drug gestin contraceptives (ethinylestradiol 20 μg/drospirenone 3 mg) Administration (US FDA) approved the continuous administra- was reported to be superior to placebo in reducing severe endo- tion of NETA (5 mg/day) for endometriosis treatment. metriosis-associated pelvic pain. Additionally, it alleviated the It is safe and tolerable for long-term treatment, particularly cul-de-sac induration, uterine mobility limitations, and pelvic in patients with rectovaginal endometriosis. NETA is not tenderness. Furthermore, patient satisfaction and improvement inferior to extended-cycle oral contraception in controlling pain in daily functioning and sleep were noted. Economically, symptoms, maintaining patient satisfaction, or decreasing the CHCs yielded a greater degree of quality-adjusted life year at a volume of endometriomas, either alone or in combination with lower cost than “no hormonal treatment”. Conversely, there letrozole. Common adverse effects associated with NETA was unsatisfactory evidence to draw a conclusion about CHCs’ include breakthrough bleeding, decreased libido, weight gain, efficacy compared to placebo in a Cochrane database of system- and minor adverse changes in the serum lipid profile[20,53,55]. atic reviews. However, the outcomes of this review were based DNG is a selective progestin of the fourth generation, which on limited evidence from two trials at a high risk of bias. is supported by most evidence derived from RCTs and cohort 167  Elbasueny et al., Reproductive and Developmental Medicine (2023) 7:3 https://journals.lww.com/RDM studies. It is tolerable and beneficial in ameliorating painful Irregular breakthrough bleeding was reported to be the most endometriosis symptoms, as well as enhancing the quality of common side effect associated with LNG-IUS use. life, sexual functioning, psychiatric profile, and patient satisfac- DSG is a third-generation progestin that is available as hor- tion with tolerability in about 80% of its users. DNG can monal contraception in oral tablets, either alone or in combina- be considered a long-term maintenance treatment after initial tion with ethinylestradiol or subdermal implants. In affected GnRH agonist therapy in patients with recurrent endometri- patients, it was found to improve migraines without aura after 6 osis. Moreover, it decreases the size of endometriomas and months of treatment, alleviate symptoms of rectal DIE, and alleviates symptoms in patients with recurrent endometriosis. enhance quality of life[81,82]. Downloaded from http://journals.lww.com/rdm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn It is effective in the treatment of rectovaginal endometriosis. Etonogestrel is the active form of DSG that is available as A study protocol of The Visanne Post-approval Observational a subdermal implant. Etonogestrel implants effectively Study published in 2020 will be the largest real-world study alleviated pain and reduced menstrual flow after 2 years of assessing endometriosis medical management across six treatment. RCT evidence showed that they alleviated dysmen- YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/05/2024 European countries: Germany, Russia, Switzerland, Poland, orrhea and CPP and reduced serum levels of soluble CD23, sim- Ukraine, and Hungary. A total of 25,000 patients with endo- ilar to LNG-IUS. They also exclusively reduced CA-125 levels metriosis were planned for enrollment with a 7-year follow-up over 2 years of treatment. Additionally, they improved sexual period. The primary objective of this study was to compare the and social function in patients with a sonographic diagnosis of safety of oral DNG (2 mg/day) with that of other hormonal ther- endometrioma 1 year after insertion. Unfortunately, the endo- apies. The most common adverse effect associated with DNG metrioma size did not decrease with treatment. use is abnormal uterine bleeding. However, other known side CPA is a synthetic steroid with antiandrogenic and progesto- effects include breast discomfort, depressed mood, acne, weight genic properties that is primarily used as an oral contraceptive gain, headaches, and constipation[62,63]. The effect of DNG on pill (OCP) in combination with ethinylestradiol and has been bone mineral density (BMD) is debatable as some studies claim approved in some countries for severe hirsutism treatment[20,47]. BMD loss with DNG therapy[64,65], and other investigators con- CPA has been proven to be an efficacious, tolerable, and afford- cluded no or little BMD changes following DNG treatment[56,66]. able treatment for recurrent pelvic pain after conservative sur- DNG may represent a valid alternative in patients who experi- gery for recurrent painful endometriosis. In a preliminary ence androgenic side effects with NETA use. report, CPA alleviated dysmenorrhea, slightly reduced hirsut- MPA is a synthetic derivative of progesterone. It is avail- ism, and improved endometriosis on second-look laparoscopy able as a depot formulation that can be administered subcuta- in patients with a laparoscopic diagnosis of endometriosis and neously (DMPA-SC) or intramuscularly (DMPA-M) as well as hirsutism. in an oral formulation. Oral MPA (100 mg daily) was found to be efficient in controlling painful symptoms compared to pla- GnRH agonists cebo for up to 1 year of follow-up. Its depot preparations outperform oral preparations in eliminating the need for daily GnRH agonists are available as short-acting injections, long-act- administration, effective contraception, absence of hepatic first- ing depot injections, injected pellets, injected implants, surgi- pass metabolism, continuous delivery, and maintaining steady cally implanted pellets, and nasal sprays[20,88]. plasma drug levels. Despite offering a cost-effective thera- The action of these drugs relies on downregulating GnRH peutic option for endometriosis pain, issues such as prolonged receptors at the pituitary level, inhibiting gonadotropin syn- breakthrough bleeding, which can be difficult to control, and thesis and secretion, and inhibiting the ovarian secretion of cause treatment discontinuation. Additionally, there was a estrogen, leading to amenorrhea, which causes endometriotic prolonged delay in the resumption of ovulation and menstru- implants to regress and prevent new lesion formation through ation after DMPA discontinuation. In 2004, the FDA pub- estrogen deprivation. Though GnRH agonists stimulate the lished a blackbox warning, noting that DMPA has a negative pituitary gland to release follicle-stimulating hormone (FSH) impact on bone density, especially with continuous use, particu- and luteinizing hormone (LH) within the first few days of treat- larly in adolescents. ment, which may flare-up symptoms and delay the therapeutic LNG is a second-generation synthetic progestin that is mar- response, downregulation of pituitary GnRH receptors occurs keted as an IUS, which is a T-shaped device with 52 mg of with continuous treatment. GnRH agonists are usually pre- LNG delivering 20 µg of hormone in the uterine cavity per scribed in patients who found CHCs and progestin therapy day over a 5-year period. LNG reduces the expression of ineffective or intolerable, had aggressive DIE and extrapelvic glandular and stromal estrogen and progesterone receptors endometriosis, were unfit for surgery, refused surgery, had in eutopic and ectopic endometrial tissues, causing glandu- post-surgical interventions to prolong pain-free duration or had lar atrophy and decidualization of the stroma with the estab- pain recurrence after surgical treatment. According to a net- lishment of amenorrhea in about 20% of its users within 12 work meta-analysis, GnRH agonists more effectively improved months[73,74]. dysmenorrhea, dyspareunia, and CPP scores at three months LNG-IUS has numerous benefits, including a lack of negative of treatment than elagolix (75, 150, and 250 mg), DMPA-SC, effects on lipid metabolism and BMD loss, as it delivers pro- danazol, and placebo. Moreover, they are as effective as LNG- gesterone locally. Additionally, it does not require daily intake, IUS and DNG and superior to placebo in terms of total pelvic which decreases the fluctuating serum levels and leads to poor pain alleviation at 6 months. GnRH agonists are superior to patient compliance. Many beneficial outcomes have been placebo and no-treatment with regard to endometriosis pain recorded following LNG-IUS insertion, including alleviation of alleviation and are comparable to LNG and danazol treat- dyspareunia and dysmenorrhea, enhancing the quality of life, ments. GnRH agonists, progesterone, and expectant man- and reducing serum CA-125 levels and DIE nodule size[76,77]. It agement were successful in reducing painful endometriosis also can be a good option for postoperative pain control and when compared to placebo in a recent network meta-analy- the prevention of pelvic endometriotic lesion recurrence[78,79]. sis. However, expectant management was recommended as it 168  Elbasueny et al., Reproductive and Developmental Medicine (2023) 7:3 https://journals.lww.com/RDM surprisingly ranked the highest on the surface under the cumu- were conducted to assess the effectiveness of two doses of elago- lative ranking curve (SUCRA), and there is a lack of compel- lix (150 mg once daily and 200 mg twice daily) for 6 months ling evidence in favor of drugs or surgery. Long-term GnRH against a placebo in surgically diagnosed endometriosis patients agonist treatment associated with menopausal estradiol (E2) with moderate to severe endometriosis pain. These studies had serum levels can cause multiple side effects, such as depres- similar designs with different study populations; Elaris EM-I sion, lipid profile changes, hot flushes, headaches, urogenital was conducted in the United States, whereas Elaris EM-II was atrophy, and loss of libido, which may cause treatment discon- a worldwide study. They concluded that two doses of elago- tinuation[88,92]. Furthermore, prolonged therapy can induce a lix (150 mg once daily and 200 mg twice daily) were effective Downloaded from http://journals.lww.com/rdm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn significant decrease in BMD, which may exceed 1% per month in alleviating dysmenorrhea and non-menstrual pelvic pain, in the early months of therapy. As a result, their clinical use while a higher elagolix dose significantly improved dyspareu- is limited to 6 months due to concerns about the long-term nia. Hot flushes and changes in BMD and lipid levels were also impacts on BMD. Various strategies have been suggested recorded[105,106]. Elaris EM-III and Elaris EM-IV were extension YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/05/2024 to counteract these hypoestrogenic side effects and improve studies of Elaris EM-I and Elaris EM-II to assess the long-term patient compliance while maintaining treatment efficacy, such outcomes after an additional 6 months of treatment (net 1 year as widening the duration between doses. Another option is of continuous treatment). The results demonstrated that long- a three-month treatment protocol that should alleviate painful term elagolix treatment alleviated dysmenorrhea, non-men- symptoms for about 6 months. A potentially more effective strual pelvic pain, and dyspareunia, whereas the safety profile option with fewer side effects is to reduce the dose of GnRH suggested the presence of hypoestrogenic effects with no newly agonist (drawback therapy) that allows the therapy to begin encountered safety concerns[105,107]. with the standard daily dose; once pituitary downregulation Relugolix was approved in the United States for the treat- has been achieved, the dose can be gradually reduced. Finally, ment of endometriosis in December 2020. SPIRIT-1 and 2 add-back therapy is the most common strategy that should be were phase III clinical trials that assessed the efficacy of relu- used for even short-term treatment due to the early onset of hot golix combination therapy (40 mg relugolix +1 mg E2 + 0.5 mg flushes and vaginal dryness. Add-back therapy can be started NETA) in endometriosis treatment. Their results showed that simultaneously with GnRH agonist treatment since it does not oral relugolix combination therapy once per day effectively alle- decrease the effectiveness of GnRH agonist. A number of viated dysmenorrhea and non-menstrual pelvic pain. This treat- protocols have been suggested, the most widely used of which ment was well tolerated, with comparable vasomotor symptom is NETA, which is FDA-approved but can be used only for 1 frequencies to placebo, and showed preserved BMD for two year since data beyond that time frame are not accessible for years[108–110]. Furthermore, in another RCT, oral relugolix was estrogen and progestin add-back therapy. The higher cost, found to be as effective and safe as leuprorelin and was well tol- limited accessibility, contraceptive effect, and delayed therapeu- erated in its ability to improve painful endometriosis at a dose tic response due to the flare-up effect may be other concerns for of 40 mg. Linzagolix is another oral GnRH antagonist that GnRH agonist use. However, this flare-up effect can be avoided yet to be approved as an endometriosis treatment. Linzagolix by starting treatment in the mid-luteal phase or using an oral effectively alleviated endometriosis pain and enhanced the qual- progestogen for the first 7 to 10 days after the first dose[99,100]. ity of life at doses ranging from 75 to 200 mg, but BMD was reduced in a dose-dependent manner. GnRH antagonists Danazol Recently, there has been a significant increase in the use of GnRH antagonists in reproductive medicine, with encouraging outcomes Danazol is a synthetic ethisterone derivative with antigonado- in endometriosis treatment. Available preparations include non- tropic, hypoestrogenic, and hyperandrogenic properties, which peptide oral forms such as elagolix, relugolix (TAK385), linza- are beneficial for relieving endometriosis symptoms. Danazol golix (OBE2109), ozarelix, and abarelix, and injectables such was popular in endometriosis treatment during the 1970s and as cetrorelix and ganirelix[5,101,102]. Their use in endometriosis 1980s, but its oral use decreased with time due to its poorly treatment is justified by their ability to suppress ovulation in a tolerated androgenic side effects, as well as the introduction of dose-dependent manner through competition with endogenous more accepted alternatives, such as GnRH agonists and antag- GnRH for its pituitary receptors, inducing a hypoestrogenic state. onists. When administered vaginally, danazol was assumed This inhibits endometriotic cell proliferation while maintaining to have little systemic absorption, with fewer reported adverse adequate circulating estradiol levels to prevent menopausal symp- effects. Additionally, it alleviates pain and decreases the volume toms. In addition to lower degrees of hypoestrogenism, GnRH of the endometrial implants[113,114]. In 35 infertile patients, a vag- antagonists do not cause symptom flares like those caused by inal danazol ring alleviated dysmenorrhea and decreased the GnRH agonists, and their action onset is faster and fully revers- pelvic endometriosis load. Danazol has been formulated as ible, and regularization of gonadal function is anticipated just a an IUS that has been tested and shown to be effective in treating few days after stopping administration. Importantly, there is local uterine inflammation in a mouse model of adenomyosis. a distinct dose-response effect on pain control and the incidence of adverse effects. Although the ability to control the degree Gestrinone of induced hypoestrogenism has the advantage of reducing met- abolic side effects, it also increases the risk of unintended preg- Gestrinone is a synthetic derivative of ethinyl nor-testoster- nancy, as it does not perfectly suppress ovulation. Furthermore, one, which is currently used in Europe but is not available the teratogenic hazard of these drugs is unclear; therefore, a bar- in the United States or Canada. It induces the atrophy of rier or progestin-based contraception is needed. eutopic and ectopic endometrial tissues through anti-gonad- Elagolix has been approved for the treatment of endometri- otrophic and androgenic criteria. However, its clinical use osis in the United States since July 2018. Elaris EM-I and is limited owing to the increased incidence of adverse andro- Elaris EM-II were two large, double-blind, phase III trials that genic effects. 169  Elbasueny et al., Reproductive and Developmental Medicine (2023) 7:3 https://journals.lww.com/RDM Investigational therapeutic options contraceptive in the United States. Different doses of mifepris- Investigational hormonal therapies tone effectively improved endometriosis symptoms and American Fertility Society scores. The efficacy of Ulipristal acetate (UPA) Aromatase inhibitors in the treatment of endometriosis is still under investigation. In rat Aromatase inhibitors (AIs) are currently considered the first-line models, it demonstrated endometriotic lesion regression, anti-in- treatment for estrogen receptor positive breast cancer. Third- flammatory action, and reduction of cellular proliferation. generation AIs are available as oral tablets, including anastro- UPA is being studied as a 3-month VR delivery system for con- traception, which could be a promising option for endometriosis Downloaded from http://journals.lww.com/rdm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn zole, letrozole, vorozole, and exemestane. Their action is based on the reduction of local estrogen and prostaglandins treatment. Moreover, it has been formulated as an IUS that is in endometriotic implants by inhibiting aromatase P450, the capable of suppressing the endometrium, leading to endometrial key enzyme in the conversion of testosterone and androstene- atrophy and amenorrhea in rhesus macaques. An important dione to estradiol and estrone, respectively, which are usually safety concern that limits UPA use in practice is the possibility YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/05/2024 overexpressed in endometriotic tissues. AIs also inhibit of severe liver injury, potentially requiring liver transplantation, estrogen production in peripheral tissues, which is beneficial in which led to its withdrawal from the market. post-menopausal women with endometriosis, where peripheral Asoprisnil (J867) was the first SPRM to reach an advanced adipose tissue is the primary estrogen contributor. AIs effi- clinical development stage in humans for endometriosis treat- ciently decrease the severity of endometriosis pain and could ment and was shown to be efficient, safe, and tolerable in be a good option for patients with severe pain due to resistant alleviating painful endometriosis symptoms during the three- endometriosis. Although they are not FDA-approved for month treatment period with no clinical signs or laboratory treating endometriosis pain, the European Society of Human data of hypoestrogenism. Despite three phase II clinical trials Reproduction and Embryology recommended their use in having been conducted to assess the safety and efficacy of vari- combination with CHCs, progestogens, or GnRH agonists in ous doses of asoprisnil, the full report of this industry-sponsored patients with painful, treatment-resistant rectovaginal endome- trial does not seem to have been published in a peer-reviewed triosis. Anastrazole 1 mg daily for 6 months, starting 1 month journal, and no further trials have been registered in clinical before conservative endometriosis surgery, effectively alleviated trials. Thus, the use of asoprisnil for endometriosis seems to painful symptoms for 1–2 years. However, it offers no other have been halted, mostly due to endometrial proliferation and significant benefits over LNG-IUS insertion with regard to the hyperplasia in some patients. A long-term use of SPRMs may reduction in endometrioma size and CA-125 serum levels. induce endometrial changes described as progesterone receptor Letrozole, in combination with NETA, effectively reduced rec- modulator-associated endometrial changes. Therefore, long- tovaginal endometriotic nodules after 1 year of treatment. term studies are needed to confirm the safety of SPRMs, and Anastrazole, combined with goserelin (a GnRH agonist), has until this is available, there may be an obvious reluctance to use been reported to decrease the risk of endometriosis recurrence these drugs for longer durations. and increase the pain-free interval. However, a significant reduc- tion in BMD was observed at the end of therapy. Letrozole, Investigational non-hormonal therapies in combination with NETA, significantly reduced the endome- trioma size[54,127]. However, Letrozole has been linked to a higher Emerging therapies that selectively target cell survival and pro- rate of side effects, more costs, and less satisfaction than NETA liferation pathways are currently under investigation for treat- alone. Long-term therapy with AIs in patients with breast ing endometriosis. cancer has been associated with negative effects on bone quality and BMD. Other menopausal symptoms, such as hot flushes, Anti-angiogenic drugs decreased libido, joint pain, and urogenital atrophy, have been recorded with AI use. AI use can also be associated with pos- Endometriosis progression relies heavily on angiogenesis. sible ovarian cyst development due to an initial FSH increase Bevacizumab, a recombinant humanized monoclonal antibody in the absence of ovulation but can be prevented by adding against vascular endothelial growth factor (VEGF), resulted in larger drugs that downregulate ovarian activity (such as progestogens, regression of endometriotic implants than DNG when injected along CHCs, or GnRH agonists)[130,131]. Add-back therapy in combina- with oral rosuvastatin in mice. Preclinical studies have shown tion with AIs can suppress follicle development, alleviate meno- the effects of various tyrosine kinase inhibitors. Sorafenib effectively pausal symptoms, and preserve BMD. decreased endometriotic lesion size in a mouse model of surgically induced endometriosis. Similarly, sunitinib also reduced adhe- sion formation compared to danazol treatment. Rapamycin, a Selective progesterone receptor modulators bacterial macrolide that inhibits the mammalian target of the rapa- Progesterone resistance is a major contributor to endometri- mycin (mTOR) pathway, also decreases the size of endometriotic osis pathogenesis. Selective progesterone receptor modula- implants. Furthermore, dopamine agonists, including cabergo- tors (SPRMs) could help with this component of the disease as line, have been shown to enhance pain relief similar to or greater they interact with progesterone receptors in different ways: they than NETA, in addition to reducing VEGF receptor 1 and being can act as pure agonists, pure antagonists, or partial agonists/ well tolerated with no major side effects. Quinagolide, another antagonists. SPRMs can potentially be applied in endome- dopamine agonist, reduces endometriotic lesion size in patients with triosis treatment, as they selectively inhibit endometrial growth hyperprolactinemia and endometriosis. without profound hypoestrogenism, reduce COX-2 expression in the endometrium, or directly suppress endometrial blood Immunomodulatory drugs supply[133,134]. Mifepristone (RU486), the most commonly stud- ied SPRM, is predominantly a progesterone antagonist and has Immunomodulators have the potential to suppress endometri- been used as an abortifacient. Ulipristal acetate is approved as otic activity by controlling inflammatory cytokines such as tumor a fibroid treatment in Europe and Canada and as an emergency necrosis factor α (TNF-α), nuclear factor kappa B (NF-KB), 170  Elbasueny et al., Reproductive and Developmental Medicine (2023) 7:3 https://journals.lww.com/RDM and interleukins. Infliximab is a monoclonal antibody targeting survival. The histone deacetylase trichostatin A (TSA) demon- TNFα. Infliximab decreased the size of endometriotic implants strated a significant reduction in endometriotic lesion size and in rats. However, it failed to do the same in 21 patients with notable improvement in response to painful stimuli in a mouse rectovaginal nodules greater than 1 cm. Moreover, it had no model of endometriosis. effect on pain symptoms in DIE patients. Etanercept, a fusion protein consisting of human recombinant soluble TNF receptor Gene therapy 2 conjugated to a human Fc antibody subunit, reduced the size and histopathological scores of rat endometrial implants[150,151]. In a mouse model, the efficiency of two novel gene therapies Downloaded from http://journals.lww.com/rdm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn Thalidomide and human chorionic gonadotropin A are NF-KB that target VEGF-mediated angiogenesis was demonstrated by inhibitors that reduce the expression of genes that regulate the a notable reduction in local angiogenesis and a clear decrease in release of inflammatory cytokines in animal and in vitro mod- endometriotic lesions[173,174]. els[152,153]. Imiquimod, an immunomodulatory drug, showed a YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/05/2024 regressing effect on glandular and stromal tissues of endome- Novel drug delivery methods in endometriosis pain triotic implants when administered intraperitoneally twice a treatment week for eight weeks in a rat model of endometriosis. Icon, The principle of innovative drug delivery systems depends on an immunoconjugate compound, also reduced the size of endo- their ability to deliver medications locally at lower systemic con- metriotic lesions in endometriosis mouse models. Although centrations, which can improve efficacy and decrease adverse the role of small ribonucleic acid (RNA) molecules/microRNAs effects. There are various drug delivery options, including in endometriosis pathogenesis remains unclear, they have been IUSs, VRs, implants, and nanotechnology. IUSs are considered investigated in many in vitro studies, with encouraging results one of the most efficient drug delivery methods. The use of that they inhibited the proliferation and invasiveness of endo- LNG-IUS enables intrauterine delivery of LNG, resulting in high metriotic cells[156,157]. local concentrations and low systemic levels that lessen adverse events and improve compliance. Danazol-loaded IUS effi- Antioxidants ciently relieved pelvic pain, dysmenorrhea, and dyspareunia in Oxidative stress plays a key role in stimulating the synthesis of patients with endometriosis. VRs allow effective drug deliv- inflammatory mediators in endometriotic implants. Metabolites ery for various medications, commonly hormones, for contra- from the lipoxygenase pathway and omega-3 polyunsaturated ception and hormone replacement therapy. The use of VRs to fatty acids suppress the growth of new endometriotic implants treat endometriosis can be justified by local drug delivery, which and significantly reduce the size of endometriotic lesions[158,159]. may have a direct impact on DIE and decrease side effects caused N-acetylcysteine (NAC), a common antioxidant, somewhat by systemic drug concentrations. However, evidence supporting reduced the mean cyst diameter after three months of treatment VRs delivering CHCs in endometriosis treatment is still insuffi- in patients with ovarian endometriosis (1.5 mm), as opposed to cient, with a limited number of studies. The vaginal danazol a significantly increased cyst diameter (+6.6 mm) in untreated ring significantly alters the effectiveness and safety profile of the patients. When administered in high doses, statins have drug. Studies showed that vaginal danazol decreases pain anti-proliferative and anti-angiogenic effects in addition to and the size of endometriotic lesions in patients with DIE, with their antioxidant activity. Simvastatin reduced the number nearly no systemic androgenic side effects. However, no effect and volume of endometriotic implants in mice in a dose-depen- on the volume of endometriomas was observed, and concur- dent manner. Metformin, an insulin sensitizer, reduces the rent contraception was required, as it did not inhibit ovula- size and number of endometriotic implants in rats through the tion[114,115,177–179]. The effectiveness and tolerability of anastrozole regulation of ovarian steroidogenesis and its anti-inflammatory administered through a VR in patients with endometriosis are properties. Retinoic acid and Elocalcitol reduced the size currently under investigation in a randomized, double-blind and weight of endometriotic lesions in a mouse model[143,164]. phase IIb clinical trial (NCT02203331). The outcomes will The administration of the natural antioxidant resveratrol allow us to determine whether the use of a VR may constitute a reduced the size and number of endometrial lesions in endo- breakthrough in the use of AIs for endometriosis treatment. metriosis-prone animals and in vitro models. Resveratrol Implants that release etonogestrel improve dysmenorrhea and significantly improved pain scores when used in combination pelvic pain symptoms and enhance sexual and social function with oral contraceptives (COCs) in patients with endometriosis in patients with endometriosis[83–85]. Transdermal patches have pain who failed to respond to COCs alone. However, this study been used to deliver CHCs, and they improve pain in patients was limited by its small sample size (n = 12). Furthermore, with rectovaginal endometriosis. However, they are not as effi- it was not found to be more effective than a placebo when used cient as the VR and are associated with abnormal uterine bleed- as a single agent. Xanthohumol is a prenylated flavonoid. ing, especially with continuous use. Nanotechnologies have In a BALB/c mouse model, it safely suppressed endometriotic been evaluated as novel drug delivery systems for both inno- implant growth. Epigallocatechin-3-gallate (EGCG) is an vative and well-established drugs for endometriosis treatment. antioxidant compound found in green tea that has been shown They are composed of bioconjugates that deliver anti-angio- to decrease the size of both in vitro and animal endometriotic genic, antioxidant, anti-inflammatory, and immunomodulatory lesions[169–171]. A RCT of green tea extract to evaluate its effec- compounds at the level of endometriotic lesions. For com- tiveness and tolerability against placebo in endometriosis treat- pounds with low bioavailability, nanotechnologies are primar- ment is currently underway (NCT02832271). ily intended to improve the delivery effectiveness and targeted release duration. Nanotechnologies include the following nanoparticles: poly (lactic-co-glycolic) acid (PLGA) nanopar- Epigenetic inhibitors ticles, aminopropyl mesoporous silica nanoparticles (AMNPs), Epigenetic agents are emerging as endometriosis therapies that lipid nanoparticles, nanoparticles-based photothermal ablation, primarily act on histone deacetylases, which are essential for cell and nanofibers. Although this new technology has primarily 171  Elbasueny et al., Reproductive and Developmental Medicine (2023) 7:3 https://journals.lww.com/RDM been used for cancer treatment, endometriosis can theoretically considered in patients who fail COCs therapy. The debate be treated using the same drug delivery concept. The use becomes now, in the case of NETA ineffectiveness or intoler- of nanotechnology in endometriosis remains in the very early ance, what is the best next step? Is it reasonable to step up to stages of preclinical research. There is still little data, which is DNG despite the fact that one-third of patients not responding mostly tested in animal models. due to progesterone resistance, and some authors have failed to demonstrate any superiority of DNG over NETA with regard to efficacy in painful endometriosis treatment? Should the A stepwise approach for endometriosis pain next step up be GnRH agonists, which, despite their proven Downloaded from http://journals.lww.com/rdm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWn treatment efficacy, remain costly, have profound hypoestrogenic adverse Alleviation of pain should always be the target of endometriosis effects, and are approved only for 1 year with add-back ther- treatment, which typically necessitates long-term management apy. Alternatively, should we step up to GnRH antagonists, strategies aimed at optimizing the use of medical therapy while which are known for their ability to suppress ovulation in a YQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 09/05/2024 reducing the need for recurring surgeries[184,185]. Therefore, it dose-dependent manner that may control symptoms while lim- is important to use available therapies effectively in regard to iting adverse effects. However, they are still not widely accessi-