Endometriosis is a chronic condition determined by the presence of ectopic endometrial glands and stroma. The disease affects approximately 10% of women of reproductive age and 35–50% of women with chronic pelvic pain and/or infertility (1-3). This condition is prevalent among the East Asian race, while African Americans are less frequently affected (4). Genetic, phenotypic, and lifestyle factors seem to influence the multifactorial etiology of endometriosis and endometriomas (5).
The ovaries are the most common implantation site of ectopic tissue and endometriotic cysts are one of the classic phenotype of the disorder (6). The cysts are more frequently unilateral, with a left-sided predisposition (7).
The etiopathogenesis of endometriosis is multifactorial and it cannot be supported by a single pathogenetic theory (8). Several hypotheses have been proposed, among which the in-situ theory and the transplantation theory: the first is based on endometriosis development by metaplasia of the germinal epithelium of the ovary or by embryological origin from mesonephric and Müllerian remnants (9-11). The transplantation theory, instead, is based on the concept that the endometriotic lesions may originate from ectopic endometrial tissue carried through the fallopian tubes during menstruation. In support of the theory of retrograde menstruation and the role of peritoneal fluid movements, the left predisposition of endometriomas may be explained by the anatomic barriers of the sigmoid colon that may delay the elimination of endometriotic tissue from the left hemipelvis and promote the ovarian implant (12-14).
Several mechanisms, both inherited and acquired, may influence in developing endometriosis. A large number of genes seem to have a combined action, coupled with epigenetic phenomena controlling the acquisition of immunologic, histological, and biological changes observed in patients affected by endometriosis (8). Some of these responsible genes regulate the expression of estrogen receptors and the cyclic estrogen and progesterone serum levels (15). A high estrogen concentration and an overexpression of estrogen receptor beta (ERβ), with an inversion of ERα to ERβ ratio in endometriotic tissue, seem to support estrogen-based ectopic cells survival; moreover, the progesterone resistance found in women affected plays a synergistic role in the maintenance of this dysregulated hormonal environment, considering the usual modulation in estrogen response by progesterone (16,17).
Transvaginal ultrasonography is a very sensitive and specific instrument for the endometrioma diagnosis. Unilocular cyst with a “ground glass” homogeneity, low levels of echogenicity, and poor vascularization are typical ultrasound characteristics of endometriomas (18,19).
Surgical and/or medical therapies for endometriomas aim to control symptoms (in particular, chronic pelvic pain and dysmenorrhea) and prevent cyst growth; medical therapy may be employed to reduce recurrence rate after surgery. Unfortunately, the reported postoperative recurrence rate of endometriomas is high, ranging from 30% to 40%, representing a source of frustration for the gynecologist in the management of this chronic condition (6,20-25).
There are no medical therapies that effectively treat existing endometriomas. Therefore, tertiary prevention, consisting in a pharmacological adjuvant treatment, takes place after surgical excision in order to prevent the disease recurrence and to minimize the risk of damage to the ovarian reserve, especially in women desiring to conceive in the future (26-29). Moreover, medical therapy should be started shortly after cystectomy, considering the speed of disease recurrence (30).
It is reported that long-term suppressive hormonal treatment has a crucial role in preventing the recurrence of ovarian endometriomas (31). Several hormonal alternatives have been proposed and are employed in the clinical practice, such as oral contraceptives (OC), progestins (PG), GnRH analogs (GnRHa), danazol, aromatase inhibitors (AI), GnRH antagonists, selective estrogen receptor modulators (SERMs) and selective progesterone receptor modulators (SPRMs) (32,33). In parallel or in addition to hormonal therapy, alternative phytotherapeutic options, such as medicinal plants, phytochemicals, and multi-component herbal preparations, have been investigated, obtaining promising results. In fact, some of these compounds appear to influence epigenetic factors, apoptosis, and cell survival as well as angiogenetic processes and oxidative stress. Moreover, specific agents have a role in the estrogen modulation (34-36).
However, hormonal treatment remains the most employed option for treating pain related to endometriosis and therefore the use of phototherapies should be limited to the scientific research setting. The suppression of ovulation and the reduction in retrograde menstruation, two factors that have a crucial role in the development of the disease, are potential mechanisms by which OC and PG act. These drugs represent the most common medical therapy for endometriomas due to the low cost and the favorable safety profile (37-39). These medications should be assumed regularly as long-term regimens in case of the patients have not desire of conception. If administrated continuously, these compounds can induce amenorrhea, totally resolving dysmenorrhea and avoiding retrograde menstruation (31,40).
The levonorgestrel-releasing intrauterine system (LNG-IUS) has been employed in this context. This device does not suppress ovulation (except for a few months after insertion); however, it reduces or abolishes the menstrual flow (41,42).
GnRHa represent another widely used choice. They have a beneficial impact on reducing pain and recurrence of endometriosis after surgery. However, they are more expensive and poorly tolerated due to the side effects related to the profound hypoestrogenism, such as hot flushes, urogenital atrophy, loss of libido, deterioration in the lipid profile, depression, and bone loss. Therefore, GnRHa are commonly administrated in combination with “add-back” therapy (consisting of norethisterone acetate, low-dose estrogen-progestin replacement, OC, and bisphosphonates) (33,43).
The present review aims to evaluate the efficacy of adjuvant hormonal treatments after surgery for preventing endometrioma recurrence.
Materials and methods
For the current review, we systematically searched PubMed, Embase and Cochrane Library for relevant studies on hormonal treatments for preventing endometrioma recurrence after surgery, using the following key words: “endometrioma recurrence”, “hormonal treatments”, “adjuvant therapy”, “endometrioma excision”, “GnRH agonist”, “oral contraceptives”, “progestins”, “levonorgestrel-releasing intrauterine system”, “danazol”, “aromatase inhibitors”. The searches were conducted by two authors, first by reading the title and the abstract and then by reading the full articles.
We included studies that met the following criteria: randomized controlled trial (RCT) or cohort studies with control or placebo group, a study group undergoing a surgical procedure for endometrioma and an adjuvant hormonal therapy, studies reporting endometrioma recurrence rate among outcomes and studies published in English. We excluded case reports, review or meta-analysis, studies published as abstract, study groups consisting of patients with endometriosis without specifying if they had an ovarian endometrioma and studies reporting only pregnancy outcomes among results.
A validated scale (Newcastle-Ottawa scale) was used for quality assessment of the included studies (Table S1).
The systematic search of Medline and other sources identified 1,748 studies and 48 articles were assessed for eligibility. We excluded one study as it was a case report (45), 12 studies in which there was no control group (24,46-56), four studies in which the hormonal therapy was not administered postoperatively (22,57-59), three studies because patients did not undergo surgical treatment of endometrioma (44,60,61), two studies as they did not clarify if patients with endometriosis had an ovarian endometriotic cyst (62,63), one study which did not report the endometrioma relapse rate (focusing only on the pregnancy outcome) (64), eight review or meta-analysis (31,39,43,65-69) and one study because the hormonal treatment began after the endometrioma recurrence (70). Finally, data evaluating the impact of postoperative hormonal treatment on prevention of endometrioma were extracted from 16 articles, of which eight were RCT (71-78) and eight were cohort studies (6,25,79-84). The process for identifying the relevant studies is shown in Figure 1.
Description of the studies and summary of the outcomes
The main details and the design of the studies included in the review are summarized in Table 1. Six studies evaluated the effect of OC on the recurrence of endometrioma after laparoscopic excision of the cyst (25,71,76,80-82), four studies reported the effect of adjuvant GnRHa treatment (72-74,79), two others compared GnRHa administration to PG use (6,84), one compared GnRHa to OC (75) and another to AI (77), one investigated the efficacy of PG (83) and another one showed the effect of LNG-IUS (78). All studies included a control or placebo group.
Almost all the included studies considered the endometrioma recurrence by an ultrasonographic exam [the only one which did not clarify the method of endometrioma relapse assessment was the study by Zhu et al. (84)] and some of them considered also the symptomatology (6,71,74,78,83) or the increased in serum CA125 level (73,74,78) as a sign of disease recurrence. Few studies reported also a surgical and histological confirmation of the endometriotic recurrent cyst (25,72,73,75).
Concerning the recurrence rate (see Table 2), seven studies reported an advantage on the prevention of the endometrioma relapse by postoperative hormonal treatment (25,72,76,80-83). Among these studies, the RCT by Shaw et al. (72) was poorly comparable with the other studies (Table S1) because the therapy was administrated after surgical aspiration (instead of an excision) of the endometriotic cyst. The authors reported that the use of goserelin for only three months may reduce the endometrioma size offering a potential advantage for a second-line surgery. Seracchioli et al. (76) found that the mean cyst recurrent diameter increased every 6 months of follow-up especially in the control group (non-users OC) (0.48±0.3 cm) compared to cyclic OC users (0.31±0.18 cm) and continuous OC users (0.25±0.09 cm).
Cucinella et al. (82) compared the control group (women who refused the adjuvant therapy) to the cyclic OC users divided into three subgroups according to different progestin types (monophasic desogestrel, monophasic gestodene, and biphasic dienogest). They observed 74.7% cumulative probability of cyst recurrence among non-users, while a very lower risk among the other three subgroups (respectively 26.5%, 31.8%, and 20.5%). The mean recurrent endometrioma diameter showed a better trend among users (respectively 1.9, 1.8, 1.3 cm) compared to non-users (3.1 cm; P=0.0001).
Other researchers (83) operated 126 patients with endometriotic cyst and deep infiltrating endometriosis testing the effect of dienogest (DNG) on recurrent pain and endometriomas. They observed a significant decrease of endometriosis-related pain and endometriomas after the therapy compared to the control group. However, among other endometriosis-related symptoms (dysmenorrhea, non-menstrual pelvic pain, dyspareunia, and dyschezia), they did not find any statistically significant difference between DNG users and non-users, except for dysmenorrhea (P<0.001).
Finally, five studies did not report any advantage on the prevention of the endometrioma relapse with postoperative hormonal treatment (71,73-75,77). The other studies included in the review showed inconsistent results or different conclusions. The study with the largest population (6) (710 women) was inconclusive concerning the beneficial effect of postoperative hormonal treatment (P value not statistically significant); whereas it reported other factors to be more associated with the recurrence (previous medication use, previous surgery, total Revised American Fertility Society score and younger age at surgery).
Jee et al. (79) reported different results. They compared three different durations of GnRHa treatment (3, 4 and 6 months) to a control group, observing a low recurrence rate only after 6 months of treatment, while shorter therapy or no therapy had not a beneficial impact on the recurrence rate after conservative laparoscopic surgery for ovarian endometriomas.
The five studies (71,73-75,77) reporting no beneficial use of adjuvant treatment in terms of recurrence rate for endometriomas were based on a short-term usage of hormonal therapy (maximum 6 months) and the ultrasound assessment of the cyst relapse was performed several months after the end of the treatment. Only one study (78) reported no beneficial effect despite an equivalent period of treatment and follow up (30 months); this study is the only one included in the present review evaluating LNG-IUS as adjuvant treatment. However, the results are inconsistent with other studies concerning the postoperative use of LNG-IUS (not included because of the absence of a control group). Taneja et al. (54) compared LNG-IUS and danazol reporting that the first one was more effective in relieving pain (65.2% vs. 38.0%, P<0.05) and preventing the recurrence. In contrast, Cho et al. (52) found no significant difference between postoperative LNG-IUS use and cyclic OC in preventing endometrioma recurrence (P=0.461). Other researchers (48) compared depot medroxyprogesterone acetate with LNG-IUS, not observing a significant difference in the recurrence rate of endometriomas between both groups. Moreover, these authors reported better compliance in the LNG-IUS group with a beneficial effect on symptoms control and prevention of recurrence.
The retrospective cohort study by Zhu et al. (84) is the only study that reported the endometrioma recurrence rate both after 12 months (at the end of the medical treatment) and after 24 months (12 months after the end of the medical treatment). After the first year, the control group showed more recurrence rate, whereas after the treatment suspension the medical beneficial effect seemed to be less relevant.
Several hormonal compounds, such as OC, PG, and GnRHa, have proven to be beneficial on endometrioma recurrence even if some studies reported conflicting results. It is unclear if one postoperative hormonal treatment is superior to the others in the prevention of endometrioma recurrence. However, the duration of adjuvant therapy seems to have a crucial role in this field. There are still few studies concerning the role of danazol, AI, SERMs, and SPRMS in the postoperative period and other evidences are needed to clarify which hormonal treatment may represent the best choice.
Provenance and Peer Review: This article was commissioned by the Guest Editors (Simone Ferrero and Fabio Barra) for the series “Medical Therapy in Endometriosis Treatment” published in Gynecology and Pelvic Medicine. The article was sent for external peer review organized by the Guest Editors and the editorial office.
Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gpm-20-23). The series “Medical Therapy in Endometriosis Treatment” was commissioned by the editorial office without any funding or sponsorship. FB served as an unpaid Guest Editor of the series. SF served as an unpaid Guest Editor of the series and serves as an editorial board member of Gynecology and Pelvic Medicine from Oct 2018 to Sept 2020. The authors have no other conflicts of interest to declare.
Ethical statement: The authors are accountable for all aspects of this work in ensuring that questions related to the accuracy or integrity of any part of this work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Cite this article as: D’Alessandro G, Barra F, Tantari M, Ferrero S. Hormonal treatments for preventing recurrence of endometriomas. Gynecol Pelvic Med 2020;3:20.