Comparison of the Effect of Dienogest Alone and Dienogest Combined with Zinc on Pain and Quality of Life in Patients with Endometriosis

BRIEF TEXT

Background and Objective

Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, predominantly affecting women of reproductive age. This condition is associated with a wide range of symptoms, including chronic pelvic pain, refractory dysmenorrhea, dyspareunia, and pain [1]. … [2, 3]…. [3, 4] …. [5].

Treatment options for endometriosis vary depending on symptom severity, patient age, desire for fertility preservation, and response to previous therapies, and include a spectrum of medical and surgical approaches. Medical treatments are primarily based on hormone therapy using agents such as combined estrogen–progestin oral contraceptives, progestins, GnRH agonists, danazol, and non-steroidal anti-inflammatory drugs [6, 7]. … [7, 8].

These interventions are generally suppressive rather than curative; therefore, symptom recurrence is commonly reported upon discontinuation of therapy [9].

In recent years, dienogest, an oral progestin with high selectivity for the progesterone receptor, favorable bioavailability, and acceptable safety profile, has been widely used in the management of endometriosis. Its effectiveness in reducing pain and improving patients' quality of life has been demonstrated in various studies [10]. … [11-17].

In contrast, the role of micronutrients, particularly zinc, in modulating inflammatory responses and oxidative stress has gained attention. This raises the question of whether adding zinc supplementation to a dienogest regimen could lead to greater improvements in pain and quality of life among women with endometriosis [18]. … [19-22]. Based on this hypothesis, the present study was designed to evaluate the effects of concurrent administration of dienogest and zinc on pain intensity and quality of life in women with endometriosis.

Materials and Methods

This single-blind, randomized clinical trial enrolled 72 women with endometriosis who attended the Fatemieh Hospital outpatient clinic in Hamadan in 2025. Patients were evaluated according to standard diagnostic criteria for endometriosis, and after an initial gynecological assessment, they were screened based on the inclusion and exclusion criteria. Eligible participants who provided informed consent were enrolled. They were then randomly assigned to two groups, A and B.

In Group A, participants received oral dienogest at a dose of 2 mg daily for 4 months. In Group B, in addition to receiving the same dose and duration of dienogest, participants were administered 50 mg of oral zinc daily.

Pain intensity was assessed using the Visual Analog Scale (VAS), with participants rating their pelvic pain at baseline and after 4 months of treatment on a 10-cm VAS line. To evaluate endometriosis-related quality of life, the validated and disease-specific Endometriosis Health Profile-30 (EHP-30) questionnaire was used, which assesses multiple dimensions of quality of life, including functioning, control and empowerment, pain perception, social support, body image, and sexual function. The questionnaire was completed at baseline and after four months.

The collected data were coded and entered into SPSS (version 26) and analyzed using appropriate statistical tests.

Results

At baseline, there were no significant differences between the two groups in demographic characteristics or initial pain intensity, indicating homogeneous pre-treatment conditions. After four months of intervention, both groups exhibited a significant reduction in pain intensity; this decrease was highly significant in within-group analysis (P < 0.001) (Figure 1). However, pain reduction was greater in the dienogest plus zinc group than in the dienogest-only group, supporting the enhanced efficacy of the combined regimen.

Regarding quality of life based on the EHP-30 questionnaire, findings showed significant improvement across most quality-of-life domains in both groups after the intervention. However, the extent of improvement was significantly greater in all domains among participants receiving dienogest plus zinc (P < 0.05) (Table 1).

Quality of life scores improved across all domains before and after treatment, with the combination group showing greater improvement than the dienogestonly group. This difference was statistically significant in the pain, control, social support, and selfimage domains (P < 0.001). Only in the emotional domain was there no significant difference in improvement between the two groups (Table 2).

Regarding adverse effects, the frequency of side effects was 16.7% in the dienogest-only group and 11.1% in the combined group, with no statistically significant difference (P = 0.496), indicating that adding zinc did not significantly increase drug-related side effects (Figure 2).

Discussion

The findings of this randomized clinical trial demonstrate that dienogest alone is effective in reducing pain and improving quality of life in women with endometriosis; however, adding zinc supplementation at a daily dose of 50 mg to the dienogest regimen can lead to greater reductions in pain severity and broader improvements across multiple quality-of-life dimensions, without significantly increasing adverse effects.

… [23]… [24]… [25]… [26]. Given the chronic and recurrent nature of endometriosis, these results are clinically meaningful, as enhanced pain control and quality of life improvement are primary therapeutic goals. The potential role of zinc in modulating inflammatory responses, reducing oxidative stress, and regulating immune function [27, 28] may partially explain its additive effects alongside dienogest, although the precise mechanisms require further laboratory and clinical investigation.

Additionally, the lack of a significant increase in adverse events in the combination group suggests that this therapeutic combination may be a relatively safe option, particularly for patients requiring long-term symptom management, where treatment tolerability is essential [29, 30]. However, the results should be interpreted with limitations, such as the relatively small sample size, the four-month follow-up period, and the single-center design. Future studies with larger sample sizes, longer follow-up durations, multicenter settings, and assessments of additional outcomes—such as fertility parameters and inflammatory biomarkers—are recommended.

Conclusion

Based on the present findings, zinc supplementation alongside dienogest may be considered a promising adjunctive approach for managing pain and improving the quality of life in women with endometriosis.

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Figure 1. Mean and Standard Deviation of EndometriosisRelated Pain Scores (VAS) Before Initiation of Treatment and at the End of the Fourth Month After Treatment in the DienogestOnly Group and the DienogestPlusZinc Group

Figure 2. Frequency of Drug Adverse Effects in the Two Treatment Groups: Dienogest Alone versus Dienogest Plus Zinc

Table 1. Mean EHP Questionnaire Scores in Endometriosis Patients by Treatment Type and Assessment Time

Table 2. Differences in Mean EHP Questionnaire Scores between Baseline and the Fourth Month After Treatment Initiation in Endometriosis Patients by Treatment Type