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. 2025 Oct 9;25:480. doi: 10.1186/s12905-025-03985-9

Comparison of the short-term effects of dienogest and oral contraceptives on pain and quality of life in women with endometriosis: a systematic review and meta-analysis

Yanpin Gu 1,#, Yin Shi 1,#, Beilei Bi 1, Yi Jiang 1, Fan Ruan 1,✉
PMCID: PMC12509360  PMID: 41068815

Abstract

Objective

To compare the short-term effects of dienogest and oral contraceptives (OCPs) on pain and quality of life in women with endometriosis.

Method

The databases including PubMed, Cochrane Library, Embase, Web of Science, CNKI, and Wanfang Database were searched, and the date ranged from the establishment of the database to November 2024. The randomized controlled trials (RCTs) compared the efficacy of dienogest and oral contraceptives in the treatment of endometriosis were included. The indicators for evaluation mainly included pain score and quality of life. The secondary indicator was safety.

Results

Eight studies were included in this meta-analysis. Subgroup analysis was used to assess the endometriosis-related pain because patients received different types of OCPs. Dienogest was superior to mifepristone and Yasmin in improving VAS scores (P = 0.04, SMD=-1.19, 95%CI=-2.32 to -0.06; P = 0.03, SMD=-1.66, 95%CI=-3.16 to -0.15). However, Dienogest was not as effective as OCPs in improving pelvic pain and dyspareunia associated with endometriosis (P = 0.009, SMD = 0.42, 95%CI = 0.11 to 0.73; P = 0.006, SMD = 0.70, 95%CI = 0.20 to 1.19). For QoL score, compared to OCPs, dienogest significantly improved EHP-5, EHP-30, and SF-12 average PCS scores (P < 0.05), but there was no significant difference in SF-12 average MCS and WHO-QoL scores (P > 0.05). For side effects after treatment, there is no significant difference in the risk of vaginal bleeding, headache, hot flashes, back pain, skin dryness, and nausea between dienogest and OCPs. But, OCPs increase the risk of hand numbness and weight gain.

Conclusion

Dienogest is superior to OCPs in improving pain and QoL in patients with endometriosis, but not as effective as OCPs in pelvic pain and dyspareunia, and the safety was similar between the two types of drugs.

Keywords: Endometriosis, Dienogest, Oral contraceptives, Pain, Quality of life

Introduction

Endometriosis is characterized by the ectopic presence, proliferation, and infiltration of endometrial tissue (glands and stroma) outside the uterine cavity, predominantly invading sites including ovaries, uterosacral ligaments, peritoneum, and rectovaginal septum [1]. The cardinal clinical manifestation is chronic pelvic pain, with reproductive-age patients frequently presenting concomitant symptoms such as infertility, dyspareunia, menorrhagia, and prolonged menstrual cycles [2]. In addition, cyclic hemorrhage and chronic inflammatory stimulation at ectopic lesions contribute to mass formation and adhesive disease, imposing substantial physical and psychological burdens [3]. Current clinical guidelines universally recognize endometriosis as a chronic condition necessitating long-term therapeutic strategies to optimize pharmacological interventions and minimize repetitive surgical procedures [4]. For young patients prioritizing fertility preservation, surgical intervention with fertility-sparing techniques constitutes the primary therapeutic approach, given the limited efficacy of conventional medical management. Moreover, postoperative adjuvant pharmacotherapy proves critical for recurrence mitigation and fertility enhancement. Common therapeutic agents include non-steroidal anti-inflammatory drugs (NSAIDs), progestogens, oral contraceptives (OCPs), gonadotropin-releasing hormone agonists (GnRH-a), and traditional Chinese medicine [5].

Studies indicate that OCPs and progestogens are widely used as first-line agents for dysmenorrhea and chronic pelvic pain management. OCPs, formulated as estrogen-progestogen combinations, exert therapeutic effects through hypothalamic-pituitary-ovarian (HPO) axis suppression, reducing gonadotropin secretion and consequent estrogen production, thereby inhibiting ectopic lesion progression [6]. Simultaneously, the high-potency progestogen component directly induces endometrial atrophy. Additionally, OCPs alleviate pain via prostaglandin synthesis inhibition and demonstrate prophylactic efficacy against postoperative dysmenorrhea recurrence and endometriosis relapse [7]. Extended-cycle or continuous OCPs administration surpasses cyclical regimens in therapeutic outcomes by inducing pseudopregnancy states through artificial amenorrhea. Nevertheless, OCPs carry thrombotic risks for patients over 40 or those with diabetes, hypertension, thrombotic history, smoking, or other high-risk factors [8]. Given the overexpression of estrogen receptors and low expression of progesterone receptors in ectopic endometrial lesions, OCPs use may paradoxically create estrogen dominance, increasing risks of irregular vaginal bleeding and disease progression, significantly impacting patients’ physical-mental health and quality of life [9]. Research also suggests long-term OCPs use may cause endometrial thinning and estrogen non-responsiveness, potentially affecting fertility outcomes [10]. Meanwhile, OCPs increase the incidence of blood clots and breast cancer, and decrease BMD levels, but their effect on BMD is still controversial.

Dienogest, a fourth-generation synthetic progestogen, demonstrates high progesterone receptor selectivity with antagonistic effects on androgen receptors, exhibiting potent progestogenic and significant anti-androgenic activities, and exerting anti-proliferative, anti-angiogenic, and anti-tumor effects, thus effectively inhibit endometrial-like tissue growth [11]. Previous studies have confirmed that dienogest is effective in relieving pain, and its improvement of pain symptoms in endometriosis is not different from GnRH-a [12]. Moreover, dienogest can shrink lesions and slow down disease progression, with a 5-year postoperative recurrence rate of 4% [13]. Dienogest belongs to the progesterone class of drugs and still has progesterone-related side effects, including decreased bone density, irregular vaginal bleeding, depression, breast discomfort, headache, acne, and weight gain, with an incidence of about 10%, which affects the quality of life of patients to a certain extent [14].

At present, multiple clinical trials have compared the safety and efficacy of dienogest with placebo, GnRH analogs, or oral contraceptives in the treatment of endometriosis, and some meta-analyses also comprehensively evaluate the effects of dienogest with placebo and GnRH analogs [15–17]. However, the difference in efficacy between dienogest and oral contraceptives in the treatment of endometriosis is still debatable. Therefore, this study conducted a meta-analysis to comprehensively evaluate the differences in pain and quality of life between dienogest and oral contraceptives in the treatment of endometriosis patients.

Methods

Search strategy

This meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, and registered in PROSPERO (CRD420251049817). We searched the databases including PubMed, Cochrane Library, Embase, Web of Science, CNKI, and Wanfang Database with no language limitations, and the date ranged from the establishment of the database to November 2024. The search terms include “endometriosis or endometrioma or endometriomas” and “dienogest” and “oral contraceptives or Yasmin or gestrinone or mifepristone”, and the types of studies were restricted to randomly controlled trials (RCTs).

Inclusion and exclusion criteria

Inclusion criteria: ① RCTs that have been published. ② all patients were diagnosed with endometriosis and treated with conservative medication or surgery combined with medication, the drugs were dienogest and oral contraceptives. ③ all included studies have complete raw data. Exclusion criteria: Non-RCTs; the basic information of patients and the raw data were incomplete; the studies about endometriosis combined with other gynecological diseases.

Data extraction

Two authors independently screened the literature and extracted data (YP Gu and F Ruan). When there is a disagreement among the authors, it can be discussed again or decided through joint consultation with a third author. The general information includes: the first author, publication year, type of literature, age of patients, sample size, interventions, types of drugs, dosage, and duration of medication. The outcome includes pain score, quality of life score, and safety.

Quality assessment

The Cochrane risk bias assessment tool was used to evaluate the quality of all included literature, and the items including the presence or absence of random allocation methods, allocation concealment, blinding of participants and implementers, blinding of outcome evaluation, completeness of outcome data, selective outcome reporting, and the presence of other types of bias. Each item could be evaluated based on the low risk, unknown risk, and high risk.

Statistical analysis

All the statistical analysis was conducted using RevMan 5.4 software. The standardized mean difference (SMD) is used as the effect analysis indicator for quantitative data, and 95% confidence intervals (CI) were calculated. The odds ratio (OR) is used as the effect analysis indicator for qualitative data. The statistical heterogeneity was evaluated using the heterogeneity variance (I2). When there is no significant heterogeneity (P > 0.05, I2 < 50%), a fixed effects model is used for analysis. When there is significant heterogeneity (P < 0.05, I2 > 50%), a random effects model is used for analysis. For significant clinical heterogeneity, subgroup analysis or sensitivity analysis were performed. The significant difference was observed if P value was < 0.05.

Results

Description of search results and basic information

The results of the literature search and screening process are shown in Fig. 1. 226 articles were obtained through initial literature screening. After reading the titles, abstracts, and full texts, articles that did not meet the criteria were excluded. Finally, 8 articles were included in this study, all of which were RCTs [18–25]. The characteristics of all included studies are shown in Table 1. Among all the studies, 3 studies were double-blind controlled trials, and the other 5 studies did not report the method of blindness. 356 patients received 2 mg dienogest per day, and their average ages ranged from 27 to 38 years. The OCPs group included 358 patients with an average age between 26.92 and 38.2 years, who were orally administered 0.03 mg Ethynylestradiol and 3 mg drospirenone per day for a treatment period of 3–6 months. According to the Cochrane risk bias assessment tool, the quality and bias risk of the included studies were evaluated, and the results are shown in Figs. 2 and 3. All studies have low risk in random sequence generation and allocation concealment, 5 studies have unknown risks in the blinding of participants and personnel, and blinding of outcome assessment. 3 studies have a high risk of incomplete outcome data. For report bias and other biases, all studies were classified as low-risk and unknown risk.

Fig. 1.

Fig. 1

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Flow diagram for selected studies in this meta-analysis

Table 1.

Baseline characteristics of studies in this meta-analysis

Study Types of
Study		 Blind Sample sizes Ages Interventions and Dosages Duration Outcomes
DIG OCPs DIG OCPs DIG OCPs
Abolfazl, 2021 RCTs double-blind 30 30 34.22 ± 6.54 31.25 ± 6.18 2 mg dienogest orally, daily 30 µg ethinylestradiol and 0.3 mg levonorgestrel orally, daily 6 months ②③④⑤
Cheng, 2023 RCTs No report 61 63 38.0 ± 5.5 38.2 ± 5. 2 mg dienogest orally, daily 0.03 mg Ethynylestradiol + 3 mg drospirenone orally, daily 6 months ①
Fang, 2024 RCTs No report 56 56 32.13 ± 4.65 32.54 ± 4.81 2 mg dienogest orally, daily 12.5 mg mifepristone orally, daily 6 months ①
Gelareh, 2021 RCTs double-blind 30 30 34.22 ± 6.54 31.25 ± 6.18 2 mg dienogest orally, daily 30 µg ethinylestradiol and 0.3 mg levonorgestrel orally, daily 3 months ②③④⑤
Ilaria, 2021 RCTs No report 43 43 32.1 ± 1.1 30.7 ± 1.2 2 mg dienogest orally, daily 0.02 mg Ethynylestradiol + 0.1 mg levonorgestrel orally, daily 6 months ②③④⑤
Lina, 2021 RCTs double-blind 35 35 28.3 ± 6.5 29.8 ± 6.5 2 mg dienogest orally, daily 0.03 mg Ethynylestradiol + 3 mg drospirenone orally, daily 24 weeks ①④⑤
Yin, 2023 RCTs No report 51 51 28.82 ± 5.66 28.17 ± 5.13 2 mg dienogest orally, daily 12.5 mg mifepristone orally, daily 6 months ①④⑤
Zhou, 2022 RCTs No report 50 50 27.01 ± 10.83 26.92 ± 11.27 2 mg dienogest orally, daily 0.03 mg Ethynylestradiol + 3 mg drospirenone orally, daily 6 months ①⑤
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RCTs Randomized controlled trials, DIG Dienogest, OCPs Oral contraceptive pills

① visual analogue scale (VAS) score;② pelvic pain;③ dyspareunia;④QoL; ⑤safety

Fig. 2.

Fig. 2

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Risk of bias graph. Red (-), high risk of bias; green (+), low risk of bias; yellow(?), unclear risk of bias

Fig. 3.

Fig. 3

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Risk of bias summary. Red (-), high risk of bias; green (+), low risk of bias; yellow(?), unclear risk of bias

Evaluation of the pain outcome

Five studies involving 498 patients evaluated the effects of dienogest versus OCPs on the visual analog scale (VAS) score in women with endometriosis. Subgroup analysis was used to assess this outcome because patients received different types of OCPs (Fig. 4). Among these studies, two studies compared the effects of dienogest and mifepristone on VAS score, and three studies compared the effects of dienogest and Yasmin on VAS score. The random effect model was used because significant heterogeneity was observed (P < 0.00001, I2 = 94%). The results showed that dienogest was significantly better than mifepristone and Yasmin in improving VAS scores (P = 0.04, SMD=−1.19, 95%CI=−2.32 to −0.06; P = 0.03, SMD=−1.66, 95%CI=−3.16 to −0.15). Moreover, the overall effect results showed that dienogest significantly improved VAS score when compared with OCPs in women with endometriosis (P = 0.001, SMD=−1.46, 95%CI=−2.33 to −0.59). In addition, two studies compared the effects of dienogest and OCPs on pelvic pain in women with endometriosis. No obvious heterogeneity was observed, and a fixed effect model was used (P = 0.67, I2 = 0%). The results found that dienogest was inferior to OCPs in improving pelvic pain (P = 0.009, SMD = 0.42, 95%CI = 0.11 to 0.73) (Fig. 5). Three studies compared the effects of dienogest and OCPs on dyspareunia in women with endometriosis. Significant heterogeneity was observed (P = 0.05, I2 = 68%), and a random effect model was used. Moreover, dienogest was also no better than OCPs in improving dyspareunia (P = 0.006, SMD = 0.70, 95%CI = 0.20 to 1.19) (Fig. 6).

Fig. 4.

Fig. 4

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The effects of dienogest versus OCPs on VAS score

Fig. 5.

Fig. 5

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Comparison of the effects of dienogest and OCPs on pelvic pain in women with endometriosis

Fig. 6.

Fig. 6

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Comparison of the effects of dienogest and OCPs on endometriosis-related dyspareunia

QoL evaluation

In the included studies, 5 studies evaluated the quality of life (QoL) of patients, but the questionnaires used were different. One of the studies used the EHP-5 questionnaire, one study used the EHP-30 questionnaire, one study used the SF-12 questionnaire, and two studies used the WHO Quality of Life questionnaire (Table 2). The pooled analysis indicated that dienogest remarkably decreased the EHP-5 score compared to the OCPs group (P < 0.00001, SMD=−1.72, 95%CI=−2.24 to −1.20). Among the items of EHP-30 questionnaire, dienogest reduced the scores of lack of control and powerlessness (P = 0.01, SMD=−0.67, 95%CI=−1.19 to −0.14), emotional well-being (P = 0.02, SMD=−0.60, 95%CI=−1.12 to −0.08), social support (P = 0.002, SMD=−0.82, 95%CI=−1.34 to −0.29), self-image (P = 0.04, SMD=−0.53, 95%CI=−1.05 to −0.02), work (P = 0.01, SMD=−0.68, 95%CI=−1.20 to −0.16), sexual relationship (P = 0.003, SMD=−0.79, 95%CI=−1.32 to −0.26), possibility of infertility (P = 0.0004, SMD=−0.98, 95%CI=−1.52 to −0.44). However, there was no significant difference in the scores of pain (P = 0.15, SMD=−0.38, 95%CI=−0.89 to −0.14), relationship with child/children (P = 0.31, SMD=−0.26, 95%CI=−0.77 to −0.24), medical profession (P = 0.26, SMD=−0.29, 95%CI=−0.80 to 0.21) and treatment (P = 0.08, SMD=−0.46, 95%CI=−0.97 to 0.06) between the two groups.

Table 2.

Quality of life score of all included studies

Types of questionnaires Included studies Items SMD (95%CI) P value
EHP-5 Yin, 2023 - −1.72 (−2.24, −1.20) < 0.00001
EHP-30 Lin, 2021 Pain −0.38 (−0.89, 0.14) 0.15
Lack of control and powerlessness −0.67 (−1.19, −0.14) 0.01
Emotional well-being −0.60 (−1.12, −0.08) 0.02
Social support −0.82 (−1.34, −0.29) 0.002
Self-image −0.53 (−1.05, −0.02) 0.04
Work −0.68 (−1.20, −0.16) 0.01
Sexual relationship −0.79 (−1.32, −0.26) 0.003
Relationship with child/children −0.26 (−0.77, 0.24) 0.31
Medical profession −0.29 (−0.80, 0.21) 0.26
Treatment −0.46 (−0.97, 0.06) 0.08
Possibility of infertility −0.98 (−1.52, −0.44) 0.0004
SF-12 Ilaria, 2021 PCS 0.13 (−0.26, 0.52) 0.51
MCS 0.42 (0.03, 0.82) 0.04
WHO Quality of Life Questionnaire Abolfazl, 2021 Physical health −0.15 (−0.50, 0.21) 0.42
Gelareh, 2021 Psychological health −0.19 (−0.55, 0.17) 0.30
Social relationships −0.19 (−0.55, 0.17) 0.30
Environmental health −0.26 (−0.62, 0.10) 0.15
Total point −0.16 (−0.52, 0.20) 0.38
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For the SF-12 questionnaire, one study assessed the average physical component score (PCS) and mental component score (MCS) after treatment 6 months. Compared to the OCPs group, dienogest significantly increased the average MCS (P = 0.04, SMD = 0.42, 95%CI = 0.03 to 0.82), but there was no significant difference in average PCS (P = 0.51, SMD = 0.13, 95%CI=−0.26 to 0.52). For WHO Quality of Life questionnaire, there was no obvious effect on the scores of physical health (P = 0.42, SMD=−0.15, 95%CI=−0.50 to 0.21), psychological health (P = 0.30, SMD=−0.19, 95%CI=−0.55 to 0.17), social relationships (P = 0.30, SMD=−0.19, 95%CI=−0.55 to 0.17), environmental health (P = 0.15, SMD=−0.26, 95%CI=−0.62 to 0.10), and total point (P = 0.38, SMD=−0.16, 95%CI=−0.52 to 0.20) between the two groups. Based on the above data, it can be inferred that dienogest may be superior to OCPs in the improvement of quality of life.

Side effects

At present, research has found that the common complications of dienogest and OCPs include vaginal bleeding, hair loss, headache, hot flashes, weight gain, nausea, etc. Moreover, the risk of bleeding was higher in dienogests. In this study, we comprehensively evaluated the differences in the risk of side effects between two types of drugs, as shown in Table 3. Five studies compared the difference in the risk of vaginal bleeding between dienogest and OCPs. The results showed that there was no significant difference in the risk of vaginal bleeding by the use of dienogest and OCPs in the treatment of endometriosis (P = 0.32, OR = 0.76, 95%CI = 0.44 to 1.31). Four studies were included to evaluate the risk of headache, hot flashes, weight gain, and nausea. The results indicated that there was no significant difference in the risk of headache, hot flashes, and nausea between dienogest and OCPs (P = 0.83, OR = 0.91, 95%CI = 0.38 to 2.19; P = 0.1.00, OR = 1.00, 95%CI = 0.50 to 2.01; P = 0.33, OR = 0.57, 95%CI = 0.18 to 1.76), but OCPs significantly increased the risk of weight gain in patients with endometriosis (P = 0.003, OR = 0.36, 95%CI = 0.18 to 0.71). Three studies were included to evaluate the risk of back pain occurrence, and no significant difference was found between the two types of drugs (P = 0.05, OR = 2.77, 95%CI = 1.02 to 7.50). Two studies were included to evaluate the risk of hand numbness and dry skin occurrence. Compared with dienogest, OCPs significantly increased the risk of hand numbness (P = 0.003, OR = 0.36, 95%CI = 0.18 to 0.71), but there was no significant difference in the incidence of skin dryness between the two types of drugs (P = 1.00, OR = 1.00, 95%CI = 0.14 to 7.34).

Table 3.

Evaluation of the side effects after treatment

Classes of system organ Variables Analysis method OR (95%CI) P value
Analysis model I2 P value
Central nervous system Headache Random effect model 59% 0.06 0.91 (0.38, 2.19) 0.83
Backache Fixed effect model 0% 0.46 2.77 (1.02, 7.50) 0.05
Hand numbness Fixed effect model 0% 0.76 0.17 (0.04, 0.82) 0.03
Metabolic system Weight gain Fixed effect model 0% 0.59 0.36 (0.18, 0.71) 0.003
Reproductive system Bleeding Fixed effect model 43% 0.13 0.76 (0.44, 1.31) 0.32
Hot flashes Fixed effect model 0% 0.43 1.00 (0.50, 2.01) 1.00
Skin system Skin dryness Fixed effect model 0% 1.00 1.00 (0.14, 7.34) 1.00
Digestive system Nausea Random effect model 65% 0.04 0.57 (0.18, 1.76) 0.33
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Sensitivity analysis and publication bias

In the process of data analysis, we conducted sensitivity analysis by excluding medium to low-quality studies and using a one by one exclusion method, but the results did not show any qualitative changes. In addition, the Eggers test and Beggs test were used to evaluate publication bias. The results showed that PEggers=0.35 and PBeggers=0.24, with P values were more than 0.05, indicated that the publication bias in this study was low.

Discussion

Endometriosis (EMS) is a chronic disease characterized by pain and infertility, has a high incidence rate, high recurrence rate and high intractability, and patients mainly present abnormal menstruation and dyspareunia [26]. At present, the treatment core is to alleviate symptoms, improve quality of life and reduce recurrence. Clinically, surgical treatment is mainly adopted for severe endometriosis, which can effectively improve symptoms but has a high recurrence rate [27]. In recent years, dienogest and oral contraceptive pills (OCPs) as the main choices for hormone therapy, but the differences in efficacy and safety have always been controversial. Clinical studies have found that women of childbearing age who have previously used OCPs are not associated with the occurrence of endometriosis [28]. The use of OCPs in populations with reproductive age < 25%, 25–50%, or 50–50% does not increase the risk of developing superficial endometriosis, endometriosis, or deep infiltrating endometriosis. This study systematically compared the effects of two drugs on pain and quality of life in EMS patients through meta-analysis, revealing their heterogeneity in pain management, quality of life improvement and safety, providing an important basis for clinical individualized treatment.

This study showed that dienogest was significantly superior to mifepristone and Yasmin in improving VAS scores (P = 0.04; P = 0.03), which may be related to its unique pharmacological mechanisms. Dienogest is a selective progesterone receptor agonist that can directly inhibit the proliferation of ectopic endometrial cells and relieve pain by down-downregulating prostaglandin synthase (such as COX-2) and reducing the release of local inflammatory mediators [29]. In addition, dienogest can also reduce estrogen receptor expression, inhibit lesion angiogenesis, and further reduce lesion volume [30]. This mechanism has been validated in multiple animal models and clinical trials [31, 32]. In contrast, although OCPs indirectly inhibit lesion activity by suppressing ovulation and reducing estrogen levels, their effects may be limited by individual differences in estrogen sensitivity in patients, resulting in weaker improvement of generalized pain [33]. However, OCPs were superior to dienogest in improving pelvic pain (P = 0.009) and dyspareunia (P = 0.006), which might be related to regulating the pelvic microenvironment and reducing the release of local inflammatory mediators (such as prostaglandins) through the combined action of estrogen and progesterone [34]. In addition, an RCT found that patients with endometriosis who took long-acting progesterone or combined oral contraceptives after surgery three years showed similar improvement in endometriosis related pain, with patients of both groups experienced an improvement of approximately 40% compared to the preoperative levels [35].

It is worth noting that pelvic pain and dyspareunia may involve more complex neural sensitization mechanisms, and the regulatory effect of estrogen on neurovascular systems may be its advantage. Pelvic pain is often accompanied by pelvic congestion and nerve fiber infiltration, while dyspareunia is mostly caused by the deeply infiltrating lesions mediated by mechanical stimulation or nerve sensitization [36]. The estrogen components (ethinylestradiol) in OCPs can reduce inflammatory cell infiltration and inhibit the expression of nerve growth factor (NGF) by regulating vascular permeability in the pelvic microenvironment, thereby reducing the degree of nerve sensitization [37]. In addition, the cyclical hormone withdrawal of OCPs may further alleviate mechanical pain by regularizing endometrial shedding and reducing the formation of pelvic adhesions [38]. However, due to its potent progestogen activity, dienogest may cause excessive local tissue atrophy and exacerbate the discomfort of sexual intercourse [39]. Therefore, the pain management of EMS requires the stratified selection of medication based on pain type. For patients with generalized pain (such as dysmenorrhea and non-periodic abdominal pain), dienogest can be used as a first-line option. For local pelvic pain or dyspareunia, OCPs may have more advantages.

This study showed that dienogest was significantly superior to OCPs in EHP-5, EHP-30, and SF-12 average PCS (P < 0.05). The EHP-5 and EHP-30 scales focus on the impact of pain on daily activities and work abilities, while the SF-12 PCS covers dimensions such as physical function and role limitations [40]. The advantages of dienogest may stem from its more lasting pain relief effect, especially in reducing abnormal uterine bleeding and dysmenorrhea, thereby directly improving patients’ physical activity and social participation. Although dienogest showed excellent physiological function indicators, there was no significant difference in SF-12 average MCS and WHO-QOL score between the two groups (P > 0.05). This result may reflect the complexity of the impact of two types of drugs on psychosocial function. Firstly, the symptoms of depression and anxiety in patients with chronic pain are often related to the duration of the disease and social support, rather than the efficacy of a single medication. Secondly, OCPs may indirectly improve mood by regulating menstrual cycles and reducing premenstrual syndrome (PMS), while amenorrhea caused by dienogest may lead to some psychological burden for patients [41, 42]. Thus, when formulating treatment plans in clinical practice, it is necessary to comprehensively evaluate the physiological and psychological needs of patients. For young patients who focus on restoring workability or motor function, dienogest may be more suitable. For patients with high psychological pressure or emphasis on menstrual regularity, periodic treatment of OCPs may be more easily accepted.

In addition, there was no significant difference in the incidence of common side effects such as vaginal bleeding, headache, and hot flashes between the two drugs, which was consistent with previous studies [21, 22]. Dienogest could inhibit estrogen activity, lead to a low estrogen state, and then increase the risk of hot flashes and bone loss [13]. The risk of hand numbness and weight gain was significantly higher in the OCPs group (P < 0.05), which might be related to the following mechanisms. Estrogen can activate the renin-angiotensin system, leading to water and sodium retention and subcutaneous tissue edema, which in turn compresses nerves or increases body sensation [43]. Besides, OCPs may lead to weight gain by promoting appetite or altering fat distribution, which is particularly unfavorable for obesity or metabolic syndrome [44]. Therefore, we inferred that dienogest may be safer for patients with insulin resistance, a family history of obesity, or sensitivity to hand numbness. For patients with a low risk of thrombosis and the need for contraception, OCPs may be a reasonable choice.

Strengths and limitations

This study confirms that dienogest has more advantages in improving generalized pain and physiological function, while OCPs has better relief effects on pelvic pain and dyspareunia (Table 4). The overall safety of the two types of medication is similar, but the metabolic risk profile is different. Therefore, the pain types, quality of life priorities, and individualized risk tolerance of patients with EMS were needed for comprehensive consideration before clinical decision-making. In the future, it is necessary to deepen the understanding of therapeutic heterogeneity through mechanism research, and verify the feasibility of stratified treatment strategies through real-world data, ultimately achieving precise management of EMS.

Table 4.

Summary of the effects and side effects after treatment

Outcomes Subitems Favorability (Dienogest vs. OCPs)
Pain Generalized pain dienogest
Pelvic pain OCPs
Dyspareunia OCPs
QoL domains EHP-5 dienogest
EHP-30 dienogest
SF-12 dienogest
WHO QoL dienogest
Side effects both
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What’s more, this study has certain limitations: Firstly, the number of RCTs included is relatively small, and the pharmacological differences in OCPs types (such as mifepristone and yasmin) may affect the comparability of the results. Secondly, most of the included studies have a small sample size and are single-center studies, which may lead to limitations in the results. Third, the follow-up time of most studies was short and lacked long-term efficacy data, such as recurrence rate and bone changes. Fourth, the scales of pain assessment were different and susceptible to reporting bias. Finally, among all included studies, 7 of the eight studies reported the randomization method, only one prospective cohort study was not reported the randomization method, which might affect the risk of bias.

Acknowledgements

Not applicable.

Abbreviations

OCPs

Oral contraceptives

RCTs

Randomized controlled trials

NSAIDs

Non-steroidal anti-inflammatory drugs

GnRH-a

Gonadotropin-releasing hormone agonists

SMD

Standardized mean difference

QoL

Quality of life

Authors’ contributions

This article was put forward by F Ruan. YP Gu, Y Shi, BL Bi and Y Jiang designed this study and collected the data. Y Shi and BL Bi performed the initial analysis and wrote the manuscript. All authors reviewed the analysis and critically reviewed the manuscript.

Funding

This work was supported by the Traditional Chinese Medicine Science and Technology Program of Zhejiang Province (NO. 2021ZB051, 2024ZR004), the Integrated Traditional Chinese and Western Medicine Clinical (Obstetrics and Gynecology) Project of Zhejiang Province(2024-XK-07) and Zhejiang Clinovation Pride.

Data availability

All the data (used and analyzed) in this study are available from the corresponding author on request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yanpin Gu and Yin Shi are co-first author.

Yanpin Gu and Yin Shi contributed equally to this work.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All the data (used and analyzed) in this study are available from the corresponding author on request.

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