Continuous Dienogest vs Cyclical Dienogest with Ethinyl Estradiol in the Management of Pelvic Endometriosis- A Prospective Interventional Study

1. Senior Resident, Department of Obstetrics and Gynaecology, Medical College, Kolkata, West Bengal, India. 2. Associate Professor, Department of Obstetrics and Gynaecology, Medical College, Kolkata, West Bengal, India. 3. Resident Medical Officer Cum Clinical Tutor, Department of Obstetrics and Gynaecology, Medical College, Kolkata, West Bengal, India. 4. Assistant Professor, Department of Obstetrics and Gynaecology, Medical College, Kolkata, West Bengal, India. 5. Professor, Department of Obstetrics and Gynaecology, NRS College, Kolkata, West Bengal, India. 6. Junior Resident, Department of Obstetrics and Gynaecology, Medical College, Kolkata, West Bengal, India.

Abstract

Introduction: Endometriosis is a disease of adolescents and women of reproductive age group characterised by the presence of endometrial tissue outside the uterine cavity. It is a typical gynaecological condition that causes symptoms such as dysmenorrhoea, dyspareunia, dyschezia, chronic pelvic pain, irregular uterine bleeding, and infertility. Being a prevalent disease primarily affecting women of reproductive age, this condition significantly reduces the Quality of Life (QoL) with frequent recurrence of symptoms after discontinuation of conservative therapy.

Aim: The aim of this study was to investigate the alleviation of Endometriosis-associated Pelvic Pain (EAPP), effective cycle control, and to compare the side effects of continuous dienogest and cyclical dienogest with ethinylestradiol, as well as the improvement in QoL in the two study groups.

Materials and Methods: A prospective interventional study was conducted at the Department of Obstetrics and Gynaecology, Medical College Kolkata, West Bengal, India. The study duration was 12 months, from June 2020 to May 2021. Patients attending the Gynaecology Outpatient Department (GOPD) with clinical, sonological, and/or surgical diagnosis of endometriosis were enrolled in the study and divided into two groups of 30 patients each. Group 1 was treated with Dienogest (D) 2 mg, and group 2 received a combination of dienogest 2 mg and Ethinyl Estradiol 30 mcg (D+EE) combination. The Visual Analogue Scale (VAS) was used to define endometriosis-related symptoms. Patient satisfaction in terms of improvement in QoL was measured using a free online calculator based on the 12-item Short Form Health Survey (SF-12), which includes both physical and mental components. Follow-ups were conducted at one, three, and six months. Data were summarised as mean and Standard Deviation (SD) for numerical variables and count and percentages for categorical variables. A p-value <0.05 was considered statistically significant.

Results: A total of 60 patients were enrolled in the study and divided into two groups of 30 patients each. At three and six months, endometriosis-associated pelvic pain significantly decreased in patients receiving Dienogest+Ethinylestradiol (D+EE) compared to patients receiving dienogest alone (p<0.001). The effectiveness in cycle control at three and six months was also higher in the D+EE group (p=0.0098 and 0.0443, respectively). The safety profile was similar in both groups during follow-ups. QoL, as assessed by the Physical Component Score (PCS-12), showed a significant decrease at one, three, and six months with D+EE compared to Dienogest alone (p=0.0135, p=0.0058, and p<0.0001, respectively). The Mental Component Score (MCS-12) at three and six months significantly improved in patients on D+EE (p=0.0101, p<0.0001, respectively).

Conclusion: Cyclical D+EE was found to be more effective in the management of pelvic endometriosis compared to continuous dienogest alone, resulting in reduced EAPP, improved cycle control, and enhanced QoL.

Chronic pelvic pain, Dysmenorrhoea, Effective cycle control, Pain relief

Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity. It is a chronic estrogen-dependent and benign inflammatory disease that affects 10-30% of women in the reproductive age group (1). In India, around 26 million women are reported to have endometriosis, with 20-50% among infertile women (2),(3). Various studies in India have reported the incidence to be about 34-48% as diagnosed by laparoscopy (2),(4). Endometriosis represents one of the most challenging gynaecologic conditions to manage. Endometriotic lesions may be located in various areas, with more frequent findings on the pelvic peritoneum, ovaries, rectovaginal septum, uterosacral ligaments, vesicouterine fold, and more rarely in the bowel, diaphragm, umbilicus, pericardium, and pleura (5).

Dysmenorrhoea, deep dyspareunia, dyschezia, and dysuria are the most frequently reported symptoms (6). Together, dysmenorrhoea, pelvic pain, and infertility result in a significant reduction in the QoL during reproductive age in patients with endometriosis (7). Laparoscopy with histologic confirmation is the gold standard technique for diagnosing endometriosis (8). Medical therapies approved for the treatment of endometriosis include progesterone, danazol, Combined Oral Contraceptives (COCs), and Gonadotropin-Releasing Hormone (GnRH) agonists [9,10]. The use of danazol is limited due to many side effects such as acne, seborrhoea, muscle cramps, fluid retention, hot flashes, liver dysfunction, emotional lability, and androgenic side effects like hirsutism, deepening of the voice, and decreased breast size. Similarly, GnRH agonists, despite their benefits in alleviating endometriosis-related symptoms, are associated with abnormal lipid profiles, hot flashes, urogenital and vaginal atrophy, loss of libido, and loss of bone mineral density (9),(10).

Dienogest is a synthetic, fourth-generation progestin that has anti-proliferative, anti-androgenic, anti-inflammatory, and anti-angiogenic properties. It is a derivative of 19-nortestosterone with high selectivity for progesterone receptors (9). It significantly reduces endometriotic lesions and has effective pain relief with a favourable safety and tolerability profile (11),(12). COCs are widely used to treat the symptoms of endometriosis. The putative biological effects of COCs include both inhibition of endometrial cell implantation and a protective effect against endometrial lesion necrosis (13). Dienogest 2 mg+EthinylEstradiol 30 mcg is a novel COC with high contraceptive efficacy and minimal side effects. It reduces EAPP and improves sexual activity and QoL (12). The primary mechanisms include the inhibition of ovulation, atrophy of the endometrial lining, and changes in cervical secretion. Present study was conducted as a pilot study since no study comparing the safety and efficacy of these two drugs could be found. With this background, the present study was conducted to compare the efficacy of the above two drugs in the management of pelvic endometriosis.

Material and Methods

A prospective interventional study was conducted in the Department of Obstetrics and Gynaecology at Medical College Kolkata, West Bengal, India. The study duration was 12 months, from June 2020 to May 2021. The study was conducted after getting approval from the Institutional Ethical Committee (Ref. no. MC/KOL/IEC/NON-SPON/623/02/2020 dated 08/02/20). The sampling frame consisted of patients attending the outpatient department with clinical, sonological, and/or surgical diagnosis of endometriosis. A purposive sampling technique was used.

Inclusion criteria: Women in the age group of 20-40 years who were clinically, sonologically, or surgically diagnosed with endometriosis and had the willingness to participate in the study were included.

Exclusion criteria: Patients with a desire for pregnancy, associated pelvic diseases such as fibroids, pelvic inflammatory disease, suspected malignancy, and liver and circulatory diseases were excluded from the study.

Study Procedure

The sampling frame consisted of patients attending the GOPD with clinical, sonological, and/or surgical diagnosis of endometriosis. A purposive sampling technique was used. A total of 60 patients were included and randomly divided into two study groups of 30 each (Table/Fig 1). Randomisation was done using a computer-generated randomisation schedule. Group 1 was treated with dienogest 2 mg, and group 2 received a combination of dienogest and ethinylestradiol (D+EE). The drugs were given once a day for a period of six months. Follow-up of patients was conducted at one, three, and six months. The questionnaire for data collection was filled out by one of the authors by interviewing the participants in 15person during their routine follow-up visits. In each follow-up, patients were assessed for reduction in EAPP using the VAS scoring system (14), intensity and duration of menstrual bleeding, effectiveness in cycle control (cycle length 28±7 days), side effects and tolerability, and patient satisfaction in terms of QoL. Each participant was subjectively inquired at each follow-up visit. QoL in patients was measured using the online calculator based on the 12-item SF-12, which includes both physical and mental components (PCS-12 and MCS-12). The SF-12 is a general health questionnaire that was first published in 1995 as part of the Medical Outcomes Study (MOS) (15). The SF-12 was constructed using questions drawn from each of the eight dimensions of the MOS 36-item Short Form Survey (SF-36). It is designed to have similar performance to the SF-36 while taking less time to complete. Two summary scores are reported from the SF-12: the MCS-12 and the PCS-12 (16).

Statistical Analysis

For statistical analysis, the data were entered into a Microsoft Excel spreadsheet and then analysed using Statistical Package for Social Sciences (SPSS) version 27.0 and GraphPad Prism version 5. The data were summarised as mean and Standard Deviation (SD) for numerical variables and count and percentages for categorical variables. Unpaired t-test and Chi-square test were performed as applicable. The VAS score and QoL score between the groups were compared using an unpaired t-test. A p-value <0.05 was considered statistically significant.

Results

Both the dienogest group (group 1) and the dienogest+EE group (group 2) were comparable in terms of age distribution and parity (Table/Fig 2),(Table/Fig 3). The pretreatment distribution of symptoms like dysmenorrhoea, dyspareunia, and chronic pelvic pain in the two groups was not statistically significant (Table/Fig 4).

Pain relief, as assessed by the VAS, was significant in the dienogest+EE group (p<0.001) after three and six months of therapy (Table/Fig 5). There was a statistically significant reduction in the mean duration of menstrual bleeding in the dienogest group at three and six months of therapy. Additionally, 23.33% of patients in this group were found to have amenorrhoea after six months of initiation (Table/Fig 6). Statistically significant effective cycle control was seen with the dienogest+EE group at three and six months after therapy (Table/Fig 6).

The most common side effects reported were headache, breast pain, nausea/vomiting, and weight gain. There was no statistically significant difference between the two groups in terms of side effects (Table/Fig 7). The mean PCS-12 score of patients significantly improved in the dienogest+EE group during all follow-up visits. The mean MCS-12 score was higher for the same group during the assessment at three and six months, and it was statistically significant (Table/Fig 8).

Discussion

In the present study, the EAPP as assessed by the VAS at baseline (mean±SD) in the dienogest group was 8.4000±0.6215. After three months of treatment, the score improved to 6.1333±1.1059, and further improvement to 4.7000±0.8367 was seen after six months of therapy with dienogest. In the dienogest+EE group, the mean VAS score at baseline was 8.6333±0.4901. After three months of treatment, the mean VAS score reduced to 4.9333±0.9444, and further reduction to 2.9333±0.7849 was observed after six months of treatment. The reduction in mean VAS score in the dienogest+EE group was statistically significant (p<0.001) after three and six months of therapy.

The findings of the present study were compared to a study by Strowitzki T et al., (2010), which showed statistically significant mean reductions in VAS score from baseline to week 12, with a reduction of 27.4 mm in the dienogest group and 15.1 mm in the placebo group (p<0.001). Dienogest at a dose of 2 mg daily for 12 weeks was significantly more effective than placebo in reducing EAPP (17).

In terms of the duration of menstrual bleeding, the present study showed that in the dienogest group, the mean duration after six months of therapy further reduced to 1.3333±0.9589, and in the dienogest+EE group, it was 3.4667±1.0080, which was statistically significant (p<0.001). Dmitrovic R et al., (2012) found that the continuous regimen was superior to the cyclic regimen after one month (mean difference: -27.3; 95% Confidence Interval (CI): (-40.5,-14.2); p<0.001) and three months (mean difference: -17.8; 95% CI: (-33.4,-2.1); p=0.03). Continuous Oral Contraceptive Pill (OCP) outperforms cyclic OCP in the short term, but this difference is lost after six months. The primary outcome in their study was the difference in the subjective perception of pain as measured by the VAS over a period of six months (18). Swailum MB et al., (2017) found that continuous use of low-dose OCPs is an effective treatment for pain associated with endometriosis with few adverse effects in women who do not wish to get pregnant in the near future (19). Moore C et al., showed that the dienogest+EE combination led to a reduction in the incidence of dysmenorrhoea from 28.8% before treatment to 12.9% in the 1st treatment cycle and near zero in the 6th cycle in over 2000 women (20).

There were no reported adverse effects that led to discontinuation of therapy in the present study. Only minor side effects were observed, and the drugs were well tolerated. This is comparable to the study by Strowitzki T et al., who found that dienogest had good tolerability and a favorable safety profile for up to 65 weeks when administered daily at a dose of 2 mg in women with endometriosis. Headache, breast discomfort, depressed mood, and acne were some of the most common adverse side effects, each occurring in <10% of women in their pooled analysis of 332 women with endometriosis (21). Vercellini P et al., (2016) showed a degree of satisfaction with treatment after six months of progestin therapy. The overall proportion of satisfied and very satisfied women was 71% and 72% in the “before” period (norethindrone acetate) and the “after” period (dienogest), respectively, after six months of treatment. Tolerability was significantly higher in dienogest users (80%) compared to norethindrone acetate users (58%) (22). No exactly similar study was found in the existing literature, so it was not possible to corroborate the findings of the present study in the same way as the existing literature.

Limitation(s)

The study group was small. Further studies with a larger number of study participants will provide better information regarding the two treatment options.

Conclusion

Cyclical dienogest with ethinylestradiol was found to be better in the management of pelvic endometriosis compared to continuous dienogest alone in terms of reducing the EAPP, improving cycle control effectiveness, providing better tolerability, and enhancing QoL. Future trials are needed to establish the use of cyclical dienogest and ethinylestradiol for managing EAPP.

Acknowledgement

The authors would like to express their gratitude to the Chairperson of the Institutional Ethics Committee, the Principal and MSVP of Medical College, Kolkata, West Bengal, India, for granting permission to conduct the study. They would also like to thank the Head of the Department (G&O) for his support, as well as all others who contributed to making this study possible.

DOI and Others

DOI: 10.7860/JCDR/2023/63284.18316

Date of Submission: Feb 09, 2023
Date of Peer Review: Apr 14, 2023
Date of Acceptance: May 26, 2023
Date of Publishing: Aug 01, 2023

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? Yes
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. NA

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ETYMOLOGY: Author Origin

EMENDATIONS: 6