Medical and surgical interventions to improve the quality of life for endometriosis patients: a systematic review

Endometriosis impairs the quality of life (QoL) of many women, including their social relationships, daily activity, productivity at work, and family planning. The aim of this review was to determine the instruments used to examine QoL in previous clinical studies of endometriosis and to evaluate the effect of medical and surgical interventions for endometriosis on QoL. We conducted a systematic search and review of studies published between January 2010 and December 2020 using MEDLINE. Search terms included “endometriosis” and “quality of life.” We only selected studies that used a standardized questionnaire to evaluate QoL before and after medical or surgical interventions. Only articles in the English language were examined. The initial search identified 720 results. After excluding duplicates and applying inclusion criteria, 37 studies were selected for analysis. We found that the two scales most frequently used to measure QoL were the Short Form-36 health survey questionnaire (SF-36) and the Endometriosis Health Profile-30 (EHP-30). Many medical and surgical treatments demonstrated comparable benefits in pain control and QoL improvement. There is no clear answer as to what is the best treatment for improving QoL because each therapy must be personalized for the patient and depends on the woman’s goals. In conclusion, women must be informed about endometriosis and given easily accessible information to improve treatment adherence and their QoL.


Introduction
Endometriosis is a benign chronic disease caused by the presence of ectopic endometrial tissue, which reacts to changes in ovarian steroids by differentiation, proliferation, and bleeding [1,2]. It occurs principally during one's reproductive age, most commonly between the ages of 25 and 35 [3,4]. Its prevalence of 7-10% makes endometriosis one of the most common gynecological chronic inflammatory diseases, and it often affects quality of life (QoL) and fertility [5][6][7][8][9]. Recent literature has shown that many factors contribute to the etiopathogenesis of endometriosis: genetic, hormonal, and immunological factors play a role, while even intestinal permeability may also be involved [10][11][12][13]. Symptomatic endometriosis can be extremely debilitating, leading to dysmenorrhea, chronic pain, dyspareunia, bleeding disorders, and infertility [14,15]. These painful symptoms can affect physical, mental, and social well-being to a remarkable degree. Infertility itself may also induce psychological stress, low self-esteem, and depression [16]. Endometriosis affects the QoL of many women, including social relationships, daily activity, productivity at work, and family planning [17]. According to the clinical context and the patient's needs, the treatment of this pathology can be medical or surgical [8,18]. In both blocking the progression of lesions and causing their regression, medical treatment has been demonstrated to be effective, resulting in improved symptoms. Moreover, pharmacotherapy has a major role in improving surgical treatment, either in the time preceding it or, more specifically, after surgery. Progestogens, combined oral contraceptives (COCs), gonadotrophin-releasing hormone analogs (GnRHa), and aromatase inhibitors are treatments available today [15,[19][20][21][22]. Furthermore, it is important to emphasize that an adequate lifestyle, a diet rich in vegetables and omega-3 polyunsaturated fatty acids, and a simultaneous reduction in red meat intake, coffee, and alcohol may effectively support and improve the benefits of medical therapy [23,24]. Surgical management may be necessary for patients who do not respond to medical therapy and have important severe symptoms (such as hydronephrosis caused by ureteral stenosis or intestinal obstruction) [8,25]. The aim is to completely remove the pathology, obtain good long-term results regarding pain relief and recurrence rates, and respect the functional anatomy of the organs involved [25][26][27].
The World Health Organization (WHO) has defined QoL as a "multi-dimensional construct of the individual perception of one's position in life in the context of culture and value systems in relation to goals, expectations, standards, and concerns" [28].
Many studies have underlined the damaging results of pelvic pain on women's mental health and QoL [29]. However, few studies have methodically analyzed whether the QoL of women with endometriosis is primarily affected by the disease itself, which is chronic and distinguished by unpredictable development (leading to uncertainty about the future in general and often triggering concerns about sexuality and infertility, among other vital moments of a woman's life), or only by the effect of pelvic pain [30][31][32]. However, in a randomized study, Facchin et al. demonstrated that pain is likely the main problem affecting the QoL of women with endometriosis, showing that patients with endometriosis, who reported overall pelvic pain among other symptoms, are more likely to report poor QoL than those with asymptomatic endometriosis [33].
Since endometriosis has been identified as a social scourge, many systematic reviews of clinical studies on QoL in women with endometriosis have been published [16,[34][35][36]. The aim of this review was, firstly, to identify the instruments used to examine QoL in previous clinical endometriosis studies, and, secondly, to evaluate the influence of medical and surgical interventions for endometriosis on QoL. We searched MEDLINE databases for relevant studies on QoL in patients with endometriosis, excluding case reports studies and review articles. Relevant, frequently cited articles in the English language published over the last 10 years were examined in more detail.

QoL instruments and measures for endometriosis
Many instruments for assessing the QoL of patients with endometriosis have been previously described. The Short Form-36 health survey questionnaire (SF-36) is the most common questionnaire that measures general QoL in patients with endometriosis; it may be useful during diagnosis, treatment, and follow-up [37,38]. It consists of 36 items organized into eight domains: physical functioning; role-physical; bodily pain; general health; vitality; social functioning; role-emotional; and mental health.
An even shorter version of this questionnaire is the Short Form-12 (SF-12), which more briefly investigates the same domains as the SF-36, focusing on two domains: the physical component summary (PCS) and the mental component summary (MCS) [39].
Another useful, specific, and validated questionnaire developed by clinicians for the study of QoL in women with endometriosis is the Endometriosis Health Profile-30 (EHP-30) [40] and its short version, the Endometriosis Health Profile-5 (EHP-5) [41]. It consists of two sections. The first section applies to all women with endometriosis and addresses five domains: pain, control and powerlessness, emotions, social support, and selfimage. The second section is not suitable for all women and addresses six domains: work life, relationship with children, sexual intercourse, the medical profession, treatment, and infertility.
Other instruments used to assess QoL include the WHO Quality of Life BREF (WHOQOL-BREF). This is a shorter form (26 items) of the original WHOQOL and it investigates QoL in terms of social relationships, as well as physical, psychological, and environmental health [42,43]. The European Quality of Life-5 Dimensions questionnaire (EQ-5D) is a descriptive instrument invented in Europe, which contains one item for five domains: mobility, self-care, daily activities, pain, and emotional well-being [44].

Search strategy
We performed a systematic literature search on the electronic database PubMed/Medline to identify all studies that evaluated the effect of medical and surgical interventions for endometriosis on QoL. The key search terms included "endometriosis" and "quality of life." The search was limited to full-text articles in the English language published between January 2010 and December 2020. A systematic review was conducted following PRIS MA guidelines [45]. Additional articles were manually identified, as we searched references from the retrieved eligible articles to avoid missing relevant publications. Two independent reviewers (MND and SS) screened the studies identified from the literature search based on the keywords described above.

Selection criteria
All studies that assessed the QOL of reproductive-aged women with a diagnosis of endometriosis, using standardized questionnaires administered before and after surgical or medical interventions have been included. Articles studying QoL in women with adenomyosis or in adolescents were excluded. No restrictions for geographic area were applied. We included prospective studies, controlled and randomized controlled trials, and multicenter studies. Retrospective studies, opinion articles, editorials, case reports, pilot studies, review articles, letters to the editor, and comments were excluded. Articles specifically analyzing sexual dysfunction, mental disorders, and work productivity were excluded.

Results
The initial search identified 720 articles. After excluding duplicates and applying inclusion criteria, 27 full-text studies were assessed for eligibility. We selected 10 additional articles from a systematic review of the references of retrieved eligible articles. Thus, 37 studies were included in our qualitative synthesis. The selection process is shown in Fig. 1.
The main characteristics of studies included in this review are summarized in Tables 1 and 2.

Medical interventions
The effect of various medical treatments on the QoL of women with endometriosis was assessed. Medical treatments for endometriosis include hormonal and nonhormonal therapies, which can improve general health, reduce pain, and improve vitality and physical and physiological function.
Zhao et al. showed that after 12 weeks of therapy with gonadotrophin-releasing hormone agonists (GnRHa), women with endometriosis experienced improvement in almost all QoL parameters. Only anxiety and depression worsened, but these parameters improved after treatment with progressive muscle relaxation [46]. Another study also reported increased anxiety and depression during the use of GnRHa (perhaps for hypoestrogenic and genitourinary syndrome) to treat endometriosis [47]. In that study, additional benefits occurred after add-back therapy with estradiol and testosterone, leading to an improvement in all QoL parameters [47]. Besides this, GnRHa with add-back therapy proved as useful as a dienogest or dienogest plus estradiol valerate for preventing the recurrence of pain after a laparoscopic intervention for endometriosis, improving all QoL parameters without differences between the two therapies [48,49].
The newest gonadotrophin-releasing hormone antagonists (GnRHant) (elagolix) in the US market have demonstrated excellent results after 6 months of treatment, improving all QoL variables. This treatment particularly improved the fatigue experienced by women with endometriosis. Women receiving this treatment reported significant improvement compared to the placebo control group [50].
Treatment with progestins has also been shown to significantly improve the QoL of women with endometriosis. In particular, dienogest has been shown to improve many domains of SF-36 and EHP-30 [51][52][53] more than GnRHa or other progestins, such as leuprolide acetate, when used to treat symptomatic endometriosis [54]. Dienogest has even been proposed as a conservative therapy for bladder endometriosis and deep infiltrating (DIE) endometriosis decreasing pain and improving QoL [55]. Dienogest is considered to be an option for long-term postoperative management. Seo et al., in a prospective cohort study, compared long-term use of dienogest with combined oral contraceptive (COC) after gonadotropinreleasing hormone (GnRH) agonist plus add-back therapy as medical treatments after surgery for ovarian endometrioma. No difference was found in values of the psychological, physical, environmental, and social components of QOL between the two groups. Both COC and dienogest have proven to be tolerable options for long-term maintenance [56].
Caruso et al. found that a continuous COC regimen is more effective than a cyclical one for improving all aspects of QoL measured with SF-36 [57]. Moreover, for patients with recurrent migraines without auras, progestogen-only contraceptive pills (POPs) are more effective than COCs [58]. Both etonogestrel-releasing contraceptive implant and levonorgestrel-releasing intrauterine system have proven to be effective in treating symptoms associated with endometriosis and improving all QoL domains measured by the SF-36 and EHP-30 [59][60][61]. Carvalho et al. compared the two systems in a noninferiority randomized clinical trial and found no significant differences between reductions in endometriosis-associated pain and improvement in QoL [62]. Even non-hormonal therapies such as palmitoylethanolamide (PEA) and α-lipoic acid (LA) have been shown to improve QoL in selected patients with endometriosis [63].

Surgical interventions
Surgical treatments for endometriosis have a positive postoperative effect on pelvic pain and dyspareunia, improving patients' physical and mental QoL (physical pain, social and physical functioning, and mental and general health) and providing patients with years of healthy functioning [64,65]. However, in cases of minimal endometriosis surgery is seldom a good treatment for improving QoL [66].
Many studies have investigated the outcomes of various surgical treatments for DIE. In a prospective cohort study, Mabrouk et al. demonstrated that the laparoscopic excision of DIE lesions improves all domains of the SF-36 within 6 months after surgery, regardless of the surgical procedure performed (segmental bowel resection or rectal shaving) or the medical therapy recommended after surgery [67]. The same results have been confirmed by many other authors, especially those who focus on intestinal surgery in patients with bowel endometriosis [68][69][70][71]. No authors have found any correlation between QoL improvements and the type of surgical technique (i.e., segmental bowel resection rather than laparoscopic shaving or discoid excision) [72][73][74].
Two studies compared QoL improvement after laparoscopically assisted or open surgery colorectal resection and no difference was observed between groups [75,76].
With regard to the role of a hysterectomy with bilateral salpingo-oophorectomy for QoL improvements, Kent et al. found that this procedure improved all domains of the SF-36 [77].  Other studies have evaluated the role of post-surgical medical treatment with GnRHa in patients with DIE who received complete or incomplete laparoscopic surgical excision. Administration of GnRHa was followed by a temporary improvement in pain and QoL in patients with incomplete surgical treatment. Therefore, this appears to play no role in post-surgical pain when the surgeon was able to completely excise the DIE implants [78]. Recent studies have also considered whether new technologies could improve surgical treatments for endometriosis; several have already found that the use of plasma or CO2 lasers may improve QoL in selected case [79]. Instead, laparoscopic treatment of mild-to-moderate endometriosis with a helium thermal coagulator was not found to be superior to treatment with electrodiathermy in improving QoL measures [80].
No difference in QoL improvement has been demonstrated even between laparoscopic and robotic surgical techniques [81]. Studies have also examined whether surgical treatment of bladder endometriosis can lead to QoL improvements. Pontis et al. found that the innovative combined transurethral and laparoscopic approaches improved QoL 12 months after surgery [82].

Discussion
This review shows that endometriosis can adversely influence patients' QoL; the two most common problems affecting QoL are chronic pain and infertility. The connection between inflammatory diseases and mood disorders has been confirmed by medical research [84]. Associations between immunopathogenetic factors (imbalanced production of pro-and anti-inflammatory cytokines) and severe shifts in mood and mental health have been established in patients with endometriosis. Peripheral immunological alterations may induce the central neural system to cause a response that includes behavioral changes (such as fatigue, anhedonia, or sadness), which may negatively affect social interactions and relationships [85]. Furthermore, women with chronic pelvic pain related to endometriosis have pain hypersensitivity due to central and peripheral sensitization. This has been demonstrated in animal models and it is also   present in other painful syndromes such as irritable bowel syndrome and painful bladder [86]. This state of chronic inflammation and hypersensitivity to pain overlap with other painful syndromes, which can thus lead to anxiety, depression, and chronic fatigue, affecting patients' social lives and leading to a deterioration in QoL [5,6]. This review considered a number of instruments used to measure QoL in women with endometriosis. The two most common scales are the SF-36 and the EHP-30. The SF-36 is an excellent questionnaire for evaluating QoL in the general population and for comparing the effect of various pathologies on its domains, but it is insufficient for the specific assessment of the pain and infertility associated with endometriosis. Instead, the EHP-30 validated questionnaire is recommended by the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology for measuring QoL in patients with endometriosis. This questionnaire investigates some more specific domains of the disease (e.g., infertility, sexual intercourse, trust in the doctor) and is considered more reliable and specific for assessing the QoL of women with endometriosis [87].
Many medical and surgical treatments for endometriosis demonstrate comparable benefits in pain control and improvement in QoL. Medical therapy can control the symptoms of endometriosis and stop the development of pathology. However, long-term treatment may come with various side effects and a risk of recurrence when treatment is suspended. Surgical treatment should be proposed only when it is strictly necessary. Whenever possible, a conservative approach performed by a multidisciplinary team should be preferred.
Trying to compare medical therapy with surgical therapy to understand which is more effective for improving the QoL parameters is impossible in several aspects: (1) the data cannot be meta-analyzed because the articles considered in this review used different questionnaires; (2) the localization and stage of endometriosis in many papers are not specified, especially those in which medical therapy is used; (3) the sample of women studied in the articles have different ages and socio-anthropological characteristics or are not reported.
In the articles that have studied the effects of medical therapy on QoL in our systematic review, the localization is not mentioned, except in 4 papers, of which two focused on DIE [55,58] and two on endometrioma treatment [56,61]. Instead, since 14 out of 19 articles investigated the effects of surgery on QoL focused on DIE treatment, it seems that the surgical treatment is the most used for treating the most insidious form of endometriosis improving QoL. Logically from these results, we cannot assume that surgical therapy is better than medical one in improving the QoL of women with DIE. However, we can certainly state that the literature has focused attention on the surgical treatment of this form of endometriosis, which may particularly affect the QoL of our patients for his insidious clinical history. Surgical treatment is recommended for patients who have severe endometriosis-associated symptoms, such as chronic pelvic pain, with a visual analog scale for pain symptoms (VAS) > 7, hydronephrosis caused by ureteral stenosis, or subocclusive bowel syndrome cause by intestinal obstruction [88]; women who decline or have contraindications to the use of hormones; those who experienced a failure of medical treatment; cases of two or more in vitro fertilization (IVF) failures [89].
Although medical therapy could improve DIEassociated symptoms, it never offers a definite treatment for symptomatic patients, who often require surgical treatment. Moreover, it is not fully clear whether medical treatment is effective in preventing the progression of the disease, as discontinuous treatment commonly entails symptoms recurrence [90]. For these reasons, a surgical approach for severe DIE may be, overall, more effective and decisive, despite the possible complications associated with it [90]. The rationale behind DIE surgical treatment is to achieve the complete removal of all lesions through a one-step surgical procedure; to obtain promising long-term results for pelvic pain, recurrence rate, and fertility; and to protect the functionality of the involved organs. Achieving these results depends on the total removal of the pathology from the pelvis, in an attempt to preserve, as much as possible, the healthy tissues surrounding the site of the disease [91].

Conclusions
Which treatment best improves QoL in patients with endometriosis? There is no clear answer because therapy must be personalized for each patient and depends on the woman's goals.
Particular attention must be paid to the management of the patient with DIE, trying to take into account the natural history of the disease and book the surgery at the right time that matches the needs and desires of the woman, always following the guidelines provided by scientific societies.
Therefore, women should be educated about endometriosis and given easily accessible information to improve treatment adherence and, consequently, the QoL of patients with endometriosis.