Triptorelin for the treatment of adenomyosis: A multicenter observational study of 465 women in Russia

Abstract Objective To evaluate the effectiveness of triptorelin for the treatment of adenomyosis, the benign invasion of endometrial tissue into the myometrium, as a fertility‐preserving alternative to the gold standard hysterectomy. Methods In this multicenter, open‐label, observational study in Russia, performed from November 3, 2011, to August 24, 2015, we assessed the efficacy and safety of triptorelin 3.75 mg administered intramuscularly every 28 days in Russian women who were gonadotropin‐releasing hormone agonist treatment‐naïve, aged 25–40 years, and had a diagnosis of endometriosis or adenomyosis with heavy menstrual bleeding. We performed a medical record review, interviews to assess symptom severity, and pelvic assessments including transvaginal ultrasound. Data were obtained at first injection of triptorelin (visit 1), on the day of last injection (visit 2), 6 months after last injection (visit 3), and 9 months after last injection (visit 4). Significance was assessed by Wilcoxon signed rank test. Results A total of 465 women were included. There was a significant improvement from baseline in severity of heavy menstrual bleeding in 390/463 (84.2%) of women 6 months after last injection (P<0.0001). Severity of dysmenorrhea, abnormal uterine bleeding, and pelvic pain was decreased at visit 3 compared with baseline (P<0.0001). Endometriosis symptoms stopped in 253/262 (96.6%) of women at visit 2 and in 243/263 (92.4%) of women at visit 3. Pregnancy was reported in 116/465 (24.9%) women within 9 months following the end of treatment. Conclusion Triptorelin has a favorable safety profile, is highly efficacious in treating clinical symptoms of adenomyosis, and improves reproductive function. ClinicalTrials.gov registration number: A‐38‐52014‐191, registered October 2011.

endometrial glands and stroma surrounded by hypertrophic and hyperplastic myometrium. The prevalence of adenomyosis at hysterectomy ranges from 5% to 70% of women. 5 Symptoms of adenomyosis include menstrual disorders and persisting pain syndrome, which can reduce quality of life. 7 Adenomyosis can also impair reproductive function, resulting in infertility, by affecting uterotubal transport and altering endometrial function and receptivity. In 50% of cases, adenomyosis can reduce the likelihood of pregnancy occurring naturally. Women with adenomyosis have poor reproductive outcomes compared with those without adenomyosis. 8 Limited data are available concerning the efficacy of different treatment options in improving fertility. 9 The most common comorbidity of adenomyosis is uterine fibroids (80%-85% of cases), which may result from similar pathogenic mechanisms. 10 Hysterectomy is used worldwide to treat adenomyosis in premenopausal and perimenopausal women with severe clinical symptoms 4,6,9 ; however, this major surgery can cause complications, reduce quality of life, and incur high economic costs. 5 Adenomyosis is more prevalent among women of childbearing potential than previously thought, 5 and alternative treatment options are required to preserve reproductive function. 4 Gonadotropin-releasing hormone (GnRH) agonists are used in nonsurgical therapy for all forms of endometriosis, as both main and adjuvant therapy. This treatment reduces both the intensity of endometriosis symptoms and uterine volume. [10][11][12] Triptorelin acetate 3.75 mg, a 28-day, prolonged-release GnRH agonist approved for endometriosis treatment, 13 has been shown to decrease endometriosis symptom severity and improve reproductive function. 3,[14][15][16][17] However, no large-scale clinical trials of triptorelin have been performed in women with adenomyosis. We conducted a large, multicenter, observational study to evaluate the effectiveness of triptorelin to treat adenomyosis in routine clinical practice. examinations, performed within 2 months before the first study-drug injection. Endometriosis disease severity (stage I, II, or III) was categorized using criteria routinely employed in Russia for evaluation of adenomyosis (Table S1). 18 To avoid recruitment bias, investigators recruited all consecutive patients meeting the inclusion criteria to the study.

| MATERIALS AND METHODS
Study exclusion criteria included pregnancy, previous treatment with or hypersensitivity to GnRH analogs, and participation in another clinical study (at enrollment and within the last 30 days). The decision to prescribe triptorelin was at the investigator's discretion and was made before and independently of the decision to enroll a patient.
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. 19,20   Spontaneously occurring safety events were recorded according to the registered drug's safety procedure; investigators registered and reported to the manufacturer's pharmacovigilance department any drug-related adverse events or serious adverse events via a spontaneous adverse event report form. Adverse events considered by the investigator to be unrelated to the study drug were not collected.
Collected data were analyzed using software SAS version 9.2 (SAS Institute, Cary, NC, USA). Data were expressed using descriptive statistics (mean, standard deviation [SD], median, minimal and maximal value, range, and number of valid cases for quantitative variables; and number, percentage, and distribution for qualitative variables). A P value less than or equal to 0.05 was considered statistically significant. Two-sided 95% confidence intervals (CI, Clopper-Pearson for qualitative variables) were also presented where relevant. The evolution of severity of symptoms compared with baseline conditions was assessed using a Wilcoxon signed rank test. The sample size calculation was based on the assumption that 10% of patients scheduled to receive GnRH treatment had stage I disease. Inclusion of 400 patients would allow an estimate of the proportion of overall responders with a precision of 4.9%, and of stage I patients with a precision of 15.5% (assuming a two-sided 95% CI). Assuming that 20% of the patients would be non-evaluable, up to 500 patients were calculated as needing to be enrolled to give sufficient power to the statistical analyses.
Data from the following study populations were assessed: screened set-patients who had completed screening and had given written informed consent; enrolled set-screened patients who had given written informed consent and were included in the study; effectiveness population-all enrolled patients with HMB symptom-severity data at baseline, who received at least one triptorelin 3.75 mg injection and had at least one post-baseline assessment of menorrhagia symptom severity; and per protocol population-all patients included in the effectiveness population for whom no major protocol deviations occurred.

| RESULTS
In total, 463 patients (99.6%) completed all study assessments (visits [1][2][3][4]. Two patients discontinued the study, one after visit 2 and one after visit 3 (Fig. S1). Baseline demographic and disease characteristics are summarized in Table 1  as having "missing data" because they had improvements that corresponded to "no signs of adenomyosis," which was not an option on the database (Fig. S2).
The changes from baseline in ultrasonic parameters at visit 2 are summarized in Table 3. At visit 2, reductions from baseline in uterine length, width, wall thickness, anteroposterior dimension, and volume were observed (Table 3). Bimanual pelvic examination findings are reported in Table S5, and indicate a beneficial effect of triptorelin treatment on uterine size, shape, mobility, and tenderness.
F I G U R E 1 Proportion of women with heavy menstrual bleeding (HMB) during triptorelin treatment, categorized by endometriosis stage (effectiveness set). A statistically significant effect of treatment at visit 3 vs baseline (***P<0.0001) was observed for the overall study group and for each endometriosis stage; significance was calculated using a Wilcoxon signed rank test. a One patient discontinued after visit 2.

| DISCUSSION
The results suggest that intramuscular triptorelin acetate 3.75 mg offers an effective treatment for women with adenomyosis and has an acceptable safety profile. The primary study outcome was met, patients were classified with stage III endometriosis. 18 Our results confirm other findings showing that triptorelin decreases HMB manifestations and pain in patients with endometriosis, adenomyosis, and uterine myoma. [14][15][16] This is noteworthy given the high proportion of patients with stage II or III endometriosis, concurrent gynecologic diseases, and different forms of endometriosis in our study population.
During triptorelin treatment, a decrease from baseline in uterine size and volume was observed, which confirms previous findings. 14,15 Similarly, bimanual pelvic examination revealed reduced uterine size and diminished tenderness at palpation in most patients after treatment. The uterus became softer and returned to a normal (nonspherical) shape, with improved mobility, suggesting reduced adhesive processes in the pelvic cavity.
Adenomyosis treatment options are hormonal therapy, conservative surgery, and hysterectomy. The first drugs licensed for this purpose were GnRH analogs. The pronounced effect of triptorelin (and other GnRH analogs) on the course of endometriosis may be attributed to its capacity to suppress estrogen synthesis, as well as to its ability to inhibit endometrioid foci growth by decreasing the synthesis of anti-inflammatory cytokines and stimulating apoptosis of ectopic endometrioid cells. 10 Additionally, GnRH analogs can suppress angiogenesis, decreasing vascular growth factor synthesis. 4,10,23 Given their multiple effects on the endometrium and myometrium, GnRH analogs F I G U R E 2 Proportion of women with dysmenorrhea during triptorelin treatment, categorized by endometriosis stage (effectiveness set). A statistically significant effect of treatment at visit 3 vs baseline (***P<0.0001) was observed for the overall study group and for each endometriosis stage; significance was calculated using a Wilcoxon signed rank test. a One patient discontinued after visit 2.  24,25 The potential of GnRH analogs to induce apoptosis in the endometrium and simultaneously reduce uterine volume, menstrual blood loss, and size of myomatous nodes has been shown in multiple studies. 26,27 The positive effect of triptorelin on reproductive function is also of interest. Difficulty in becoming pregnant was diagnosed at baseline in almost half of the enrolled patients, in keeping with previous studies 28 All data are presented as n (%) unless otherwise stated.
In conclusion, treatment with intramuscular triptorelin acetate 3.75 mg decreased the clinical symptoms of adenomyosis in almost all patients. Considering the favorable safety profile as well as the capacity to improve reproductive function, triptorelin may be considered as a treatment option for adenomyosis, particularly in young women who wish to preserve reproductive potential.

AUTHOR CONTRIBUTIONS
EA and YA contributed to the study design and implementation. Both authors analyzed and interpreted the study data. Both authors were contributors in writing the manuscript and both authors read and approved the final manuscript.

ACKNOWLEDGMENTS
The study was funded and sponsored by Ipsen

CONFLICTS OF INTEREST
The authors have no conflicts of interest.

SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of the article.  improvement from stage I endometriosis, but an option for "not applicable/no signs of endometriosis" was not available on the case report form; therefore, these data have not been included.