Practical aspects of endometriosis treatment in patients of reproductive age

Objective. To compare the effectiveness of various methods of combined treatment of patients with ovarian endometriosis.

and methods. The results of a retrospective study of clinical manifestations and effectiveness of various drugs for the treatment of patients with ovarian endometriosis in the postoperative period are presented in the article. All patients were divided into 4 groups: group I included patients who were treated for endometriosis with dienogest (n = 29), group II consisted of patients who received combined oral contraceptives with gestogen component represented by dienogest (n = 38), patients from group III were administered gonadotropin-releasing hormone agonists (GnRH a) "Buserelin-depot" 1 injection per month for a 6-month course (n = 15); 94 patients from group IV had a history of endometriosis, but did not receive hormone therapy for various reasons. Results. The study revealed more women with fertility disorders in group IV – up to 43.6 ± 10.0 % (p < 0.001), primary and secondary infertility lasting up to 4.7 ± 1.2 years was noted. Patients who received hormone therapy had a more realized reproductive history than those who refused treatment for various reasons. Dysmenorrhea incidence was higher in patients who did not receive hormone therapy - up to 24.5 ± 8.7 %, chronic pelvic pains were more frequent in women from group IV (patients who did not receive hormone therapy) as well - up to 83.0 ± 7.6 %. In patients treated for endometriosis with dienogest and GnRH agonists (Buserelin-depot) the longest relapse-free period was noted. Conclusions. The study showed that the results of the medication therapy, carried out for external endometriosis, ovarian endometriosis in particular, in the postoperative period, were different. The use of GnRH agonists and dianogest in postoperative treatment effectively reduced the frequency of endometriosis recurrence in women. Full Text

The relevance of the issue of endometriosis therapy is due to the significant increase in the proportion of women of fertile age with this pathology. Ovarian endometriosis can be considered the most common form of this disease in women of reproductive age. Ovarian damage in young women leads to the formation of adhesions, the development of infertility, and the appearance of chronic pelvic pain, which becomes a deep social and economic problem. Despite advances in the treatment of common forms of endometriosis, they are characterized by a high recurrence rate [1–3]. Although endometriosis was described more than 100 years ago as «endometrium-like tissue» outside the uterus, many questions regarding the diagnosis and treatment of this disease remain today. It is known that studying the pathogenesis of any disease provides opportunities to improve therapy, but the pathogenetic mechanisms of this pathology are still being discussed. According to modern scientific literature and clinical recommendations, therapy for ovarian endometriosis includes both surgical methods and medications, or a combination of both. Drug therapy is used to relieve pain, prevent new lesions or relapses, and can be prescribed as independent treatment or as the second stage after surgery. According to studies conducted in Russia, only up to 24 % of women receive hormone therapy for endometriosis among those for whom it is indicated [4]. It is possible that the patient's own wishes may be the reason for refusing this type of therapy. The aim of the study is to compare the effectiveness of various methods of combined treatment for patients with ovarian endometriosis.

A retrospective analysis was conducted of cases of the external form of endometriosis, particularly endometriomas, in 176 patients who underwent surgical treatment in the gynecology department of the Perm Regional Clinical Hospital between 2021 and 2023. The patients were hospitalized on a planned basis, and each woman had histologically verified ovarian endometriosis after surgery. According to the treatment for endometriosis provided at the outpatient stage (before hospitalization), all patients were divided into four groups: group I consisted of women who received dienogest for endometriosis therapy — 5 mg per day for 12 months (n = 29); patients in Group II took combined oral contraceptives (COCs) with dienogest as the gestagen component for 12 months (n = 38); Patients in Group III were prescribed gonadotropin-releasing hormone agonists (GnRH-a), «Buserelin-depot», one injection per month, the course lasted for six months (n = 15). The indication for hormone therapy in all groups was severe dysmenorrhea. Group IV consisted of 94 women with a history of endometriosis but who did not receive hormone therapy for various reasons. The analysis of medical records was carried out using a specially designed form. To determine the normality of the distribution, the Shapiro–Wilk test was used during the statistical processing of the material. To assess the statistical significance of differences (p) in independent samples for quantitative traits (with a normal distribution), a comparison of means (M) was used with the help of parametric criteria — the two-sample t-test. In the absence of a normal distribution, the Mann–Whitney U-test was applied. For multiple comparisons (three or more samples), the Kruskal–Wallis test was used [5]. Differences were considered significant at the significance level of p < 0.05. In the text and tables, the mean and relative values obtained from the samples were presented (for the purpose of generalizing the conclusions to the general population) in the form of confidence (95 %) intervals: mean values — M ± 2m, relative values — % ± 2m (per 100 ± 2m).

and Discussion The average age of patients receiving dienogest was 30.3 ± 1.3 years, COCs — 32.8 ± 2.4 years, GnRH-a — 48.1 ± 3.4 years. The average age of patients who did not receive hormone therapy was 32.5 ± 1.4 years (Table 1). Table 1 Clinically significant signs of patients with endometriosis (n), % ± 2m (M ± 2m) Sign | Group | p1–2 p1–3 | p2–3 p2–4 | p3–4 p4–1 | Pgen* | ||| I, n = 29 | II, n = 38 | III, n = 15 | IV, n = 94 | ||||| Average age of patients | 30.3 ± 1.3 | 32.8 ± 2.4 | 48.1 ± 3.4 | 32.5 ± 1.4 | 0.071 < 0.001 | < 0.001 0.852 | < 0.001 0.030 | < 0.001 | History of somatic pathology (obesity, chronic gastrointestinal diseases, cardiovascular diseases) | (15) 51.6 ± 17.3 | (18) 47.4 ± 15.9 | (9) 58.8 ± 22.7 | (31) 33.0 ± 9.5 | 0.761 0.656 | 0.477 0.196 | 0.094 0.128 | 0.182 | Note: statistically significant results are highlighted in bold font; * — comparison using the Kruskal–Wallis test. Thus, doctors at the outpatient level recommended GnRH-a («Buserelin-depot») mainly to older patients with endometriosis, although according to the instructions it does not have age restrictions for patients with this pathology. An analysis was made of clinically significant indicators of concomitant somatic pathology in the examined patients: no statistical differences were found between the groups. The most common concomitant pathologies were diseases of the stomach and intestines, and disorders of fat metabolism. However, it should be noted that there were no women with obesity of the 2nd and 3rd degree in the groups. Analysis of obstetric and gynecological history showed that in group IV there were more women with fertility disorders: in particular, 43.6 ± 10.0 % (p < 0.001) had primary and secondary infertility lasting up to 4.7 ± 1.2 years. Thus, those patients who received hormonal drugs had a more significant reproductive history than women who refused treatment for various reasons. Caesarean section in the groups did not have statistical significance. Operations on the pelvic organs and ovaries in the anamnesis occurred in 28–70 % of cases (Table 2). Table 2 Features of the obstetric and gynecological history of patients with endometriosis (n), % ± 2m (M ± 2m) Sign | Group | p1–2 p1–3 | p2–3 p2–4 | p3–4 p4–1 | Pgen* | ||| I, n = 29 | II, n = 38 | III, n = 15 | IV, n = 94 | ||||| Infertility (primary and secondary) | (1) 6.5 ± 6.5 | (2) 5.3 ± 5.3 | (1) 11.8 ± 11.8 | (41) 43.6 ± 10.0 | 0.899 0.862 | 0.937 0.001 | 0.022 0.001 | < 0.001 | No pregnancy in history | (7) 25.8 ± 15.2 | (1) 2.6 ± 2.6 | (3) 23.5 ± 19.6 | (43) 45.7 ± 10.1 | 0.034 0.400 | 0.396 < 0.001 | 0.010 0.013 | < 0.001 | No childbirth in history | (9) 32.3 ± 16.2 | (2) 5.3 ± 5.3 | (6) 41.2 ± 22.7 | (61) 64.9 ± 9.6 | 0.030 0.892 | 0.158 < 0.001 | 0.059 0.007 | < 0.001 | History of caesarean section | (4) 16.1 ± 12.7 | (5) 13.2 ± 10.7 | (3) 11.8 ± 11.8 | (13) 13.8 ± 7.0 | 0.869 0.701 | 0.601 0.835 | 0.657 0.998 | 0.963 | History of surgery on pelvic organs due to adhesions, ovarian cysts | (15) 51.6 ± 17.3 | (11) 28.9 ± 14.4 | (11) 70.6 ± 21.0 | (27) 28.7 ± 9.1 | 0.112 0.245 | 0.012 0.980 | 0.006 0.062 | 0.015 | History of endometriosis in combination with uterine fibroids | (3) 12.9 ± 11.6 | (11) 28.9 ± 14.4 | (10) 64.7 ± 22.1 | (4) 4.3 ± 4.1 | 0.195 0.001 | 0.034 0.027 | < 0.001 0.621 | 0.002 | No concomitant gynecological pathology | (8) 29.0 ± 15.7 | (10) 26.3 ± 14.0 | (3) 11.8 ± 1.8 | (31) 33.0 ± 9.5 | 0.737 0.379 | 0.183 0.194 | 0.012 0.147 | 0.060 | Thus, most patients with external endometriosis had one or another surgery on the pelvic organs before the current surgery (in all groups). Abnormal uterine bleeding (AUB) before surgery was detected with the same frequency in all groups. At the same time, scanty dark-colored bloody discharge before menstruation was noted in 6.5 ± 6.5 % of patients in group I (one patient), 13.2 ± 10.7 % in group II (five), 17.6 ± 17.1 % in group III (two), and 6.4 ± 4.9 % in group IV (six), which did not show the statistical significance of this symptom in patients with verified external endometriosis (p < 0.878). The incidence of dysmenorrhea was more pronounced in the group of patients who did not receive hormone therapy – 24.5 ± 8.7 % of cases (Table 3). Chronic pelvic pain (CPP) was detected mainly in patients in group IV (who did not receive hormone therapy) — 83.0 ± 7.6 % (figure). Table 3 Clinical manifestations of endometriosis in patients (n) % ± 2m Clinical tations | Group | p1–2 p1–3 | p2–3 p2–4 | p3–4 p4–1 | Pgen* | ||| I, n = 29 | II, n = 38 | III, n = 15 | IV, n = 94 | ||||| CPP | (4) 16.1 ± 12.7 | (11) 28.9 ± 14.4 | (5) 35.3 ± 22.1 | (78) 83.0 ± 7.6 | 0.291 0.293 | 0.805 < 0.001 | 0.002 < 0.001 | < 0.001 | AUB | (4) 16.1 ± 12.7 | (12) 31.6 ± 14.8 | (1) 11.8 ± 11.8 | (23) 24.5 ± 8.7 | 0.215 0.701 | 0.161 0.523 | 0.270 0.386 | 0.421 | Dysmenorrhea | (9) 32.3 ± 16.2 | (11) 28.9 ± 14.4 | (4) 29.4 ± 21.0 | (23) 24.5 ± 8.7 | 0.884 0.814 | 0.898 0.688 | 0.892 0.594 | 0.948 | Dyspareunia | (3) 12.9 ± 11.6 | (7) 18.4 ± 12.3 | (1) 11.8 ± 11.8 | (5) 5.3 ± 4.5 | 0.573 0.843 | 0.508 0.240 | 0.933 0.683 | 0.700 | Note: * — comparison using the Kruskal–Wallis test; CPP — chronic pelvic pain; AUB — abnormal uterine bleeding. Fig. The incidence of infertility and chronic pelvic pain (CPP) in the groups It was found that patients were referred for surgical treatment with ovarian masses averaging 4.0–5.6 cm in size, and pain syndrome was present in a statistically insignificant number of patients. Thus, in most cases, the indication for surgical treatment was the presence of an ovarian mass, rather than pain syndrome or fertility disorders. The duration of the recurrence-free period was assessed in patients with a history of hormone therapy for ovarian endometriosis and without it, taking into account the size of the formation and the duration of treatment (Table 4). Regardless of the chosen drug for treatment, the recurrence rate in the groups did not have a statistical difference. The nature of the endometriosis lesion of the ovaries — unilateral or bilateral — also did not have a significant impact on the recurrence rate. Table 4 Recurrence rate in groups of patients with ovarian endometriosis (n) % ± 2m (M ± 2m) Clinical sign | Group | p1–2 p1–3 | p2–3 p2–4 | p3–4 p4–1 | Pgen* | ||| I, n = 29 | II, n = 38 | III, n = 15 | IV, n = 94 | ||||| Recurrence | (2) 9.7 ± 9.7 | (5) 13.2 ± 10.7 | (1) 11.8 ± 11.8 | (27) 28.7 ± 9.1 | 0.662 0.990 | 0.715 0.162 | 0.171 0.076 | 0.176 | Size of endometrioma | 4.0 ± 0.5 | 5.3 ± 0.5 | 5.6 ± 0.9 | 4.7 ± 0.4 | 0.001 0.001 | 0.497 0.016 | 0.030 0.200 | 0.002 | Bilateral ovarian endometriosis | (6) 22.6 ± 14.5 | (7) 18.4 ± 12.3 | (1) 11.8 ± 11.8 | (9) 9.6 ± 5.9 | 0.874 0.450 | 0.508 0.427 | 0.857 0.367 | 0.717 | Duration of therapy, months | 9.6 ± 1.4 | 10.5 ± 2.0 | 6.4 ± 0.9 | – | 0.761 0.001 | 0.027 < 0.001 | < 0.001 | < 0.001 | Duration of relapse-free period, years | 7.0 ± 1.4 | 5.7 ± 1.9 | 15.0 ± 0.0 | 3.0 ± 1.4 | | | | | Note: * — comparison using the Kruskal–Wallis test. Thus, the patients who received dienogest for the treatment of ovarian endometriosis (5 mg, course lasted for more than six months) less frequently had a history of chronic pelvic pain. In addition, they had a lower recurrence rate compared to the group of those examined who received combined oral contraceptives. However, women who took GnRH-a (“Buserelin-depot”) showed the longest relapse-free period: even when compared with dienogest, the duration of the pain-free period averaged 15 years.

The study showed that the success of drug therapy for external endometriosis, in particular ovarian endometriosis, differs in the postoperative period. The use of GnRH agonists, in particular “Buserelin-depot”, in postoperative treatment effectively reduced the recurrence rate of endometriosis in women. An important result is the absolute reduction in the risk of repeated cystectomies for several years on average after surgery. This means that the loss of ovarian reserve in this cohort of patients was minimized. There is experience in the literature on studying the long-term safety and tolerability of the drug. The postoperative use of Buserelin-depot for endometrioid cysts is described in works [5–7]. Data on reducing the risk of relapse are also provided in studies [8–10], which is consistent with our results. Dienogest demonstrated a long anti-relapse effect compared to combined oral contraceptives (COCs). It is worth noting that the recommendation of drugs in this group (COCs) is justified only if patients with endometriosis have indications for contraception (according to the instructions for the drug). About the authors E. G. Kobaidze Ye.A. Vagner Perm State Medical University Author for correspondence. Email: [email protected] ORCID iD: 0000-0001-5042-1549 SPIN-code: 1585-3296 Scopus Author ID: 57219650638 DSc (Medicine), Professor of the Department of Obstetrics and Gynecology no. 1 Russian Federation, PermV. S. Sheludko Ye.A. Vagner Perm State Medical University Email: [email protected] ORCID iD: 0000-0002-7080-9142 SPIN-code: 1728-7269 PhD (Medicine), Specialist of the Department of Organization of Scientific Activity Support Russian Federation, PermN. V. Statnykh Ye.A. Vagner Perm State Medical University Email: [email protected] ORCID iD: 0000-0001-7760-226X SPIN-code: 5989-1635 PhD (Medicine), Associate Professor of the Department of Obstetrics and Gynecology no. 1 Russian Federation, PermD. A. Stepanova Ye.A. Vagner Perm State Medical University Email: [email protected] ORCID iD: 0009-0008-2585-0251 6th-year Student of the Medical Faculty Russian Federation, PermM. R. Fairushina Ye.A. Vagner Perm State Medical University Email: [email protected] ORCID iD: 0009-0009-0649-5634 6th-year Student of the Medical Faculty Russian Federation, PermReferences - Zhang K., Huang S., Xu H., Zhang J. et al. Effectiveness of gonadotrophin-releasing hormone agonist therapy to improve the outcomes of intrauterine insemination in patients suffering from stage I-II endometriosis. Ann. Med. 2022; 54 (1): 1330–8. doi: 10.1080/07853890.2022.2071458 - Chiu C.C., Hsu T.F., Jiang L.Y., Chan I.S., et al. 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