Comparative Study of 0.5 mg Dienogest Tablets (1 mg/Day) and Continuous Low-Dose Estrogen/Progestin for Dysmenorrhea: A Retrospective Analysis—Influence of Bleeding-Related Factors Such as Endometrial Polyps, Uterine Fibroids, and Adenomyosis

Abstract

Background/Objectives: Dienogest 0.5 mg tablets (DNG0.5) taken twice daily (1 mg/day) are more effective than cyclic low-dose estrogen/progestin/combined oral contraceptive (LEP/COC) in ameliorating dysmenorrhea pain and are recommended for dysmenorrhea treatment in Japan. However, their efficacy has not been directly compared with continuous LEP/COC regimens. Here, we evaluated the effectiveness of DNG0.5 compared to Yazflex^® (YZF), a continuous LEP, in treating dysmenorrhea. Methods: The efficacy of DNG0.5 in treating dysmenorrhea was compared retrospectively with that of Yazflex, the longest continuously administered LEP/COC available in Japan. Results: The improvement rates of dysmenorrhea scores at 3 and 6 months post-treatment were 59.1% and 66.4% in the LEP group (n = 113) and 88.1% and 96.4% in the DNG0.5 group (n = 125), respectively. The complete resolution rate of dysmenorrhea at 6 months was 88.0% in the DNG0.5 group and 23.9% in the LEP group. These findings indicate that DNG0.5 was significantly more effective than LEP (p < 0.01). DNG0.5 exerted an early pain-suppressing effect, which continued to increase thereafter. Furthermore, the presence of endometrial polyps, uterine fibroids, or adenomyosis, which are risk factors for irregular genital bleeding, was examined. Among these, endometrial polyps were particularly more likely to cause bleeding and potentially reduce the effect of DNG0.5; however, even with these three risk factors, DNG0.5 was more effective than LEP in reducing pain. Conclusions: Dienogest was more effective than LEP in managing dysmenorrhea, even at a dosage of 0.5 mg twice daily. However, factors affecting irregular vaginal bleeding should be considered when prescribing DNG0.5.

1. Introduction

Dienogest (DNG), used in the treatment of endometriosis, is now prescribed for dysmenorrhea in the form of 0.5 mg oral tablets (DNG0.5) twice daily (1 mg/day), and is covered by Japanese health insurance. DNG0.5 is exclusively available in Japan. In the August 2023 revision of the Japanese Guidelines for Outpatient Obstetrics and Gynecology Practice Guidelines, DNG was listed for the first time as a treatment option for dysmenorrhea, along with low-dose estrogen/progestin combination (LEP) [1].

Low-dose estrogen/progestin/combined oral contraceptives (LEP/COCs) are widely used in Japan for the treatment of dysmenorrhea. Yaz^® and Yazflex^® (YZF), two types of drospirenone/ethinylestradiol (DRSP/EE) combination tablets, are among the most prescribed LEPs due to their efficacy in managing premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD). Continuous administration of LEP/COC is more effective at alleviating pain than cyclical administration [2,3]. Additionally, continuous administration has been shown to be less likely associated with headaches and mood swings, which are common during the drug-free period [4]. For this reason, YZF, which can be administered continuously, has become the first-choice LEP/COC drug in our clinic. YZF allows the longest continuous prescription duration of up to 120 days.

To our knowledge, only one study on dose ranging of DNG in dysmenorrhea has evaluated the effect of both DNG0.5 and LEP combinations. Although the study showed the superiority of DNG0.5 over an LEP, the LEP evaluated was a cyclic formulation of DRSP/EE, Yaz^®. As mentioned above, continuous LEP/COCs are more effective than cyclic ones. This raises the question of which agent is most effective and suitable for the treatment of dysmenorrhea in clinical practice.

Although the longest prescription duration of YZF is 120 days, the drug tends to cause irregular genital bleeding in an average of 2–3 months. When irregular bleeding does occur, the drug is withdrawn for 4 days to induce menstrual-like withdrawal bleeding, which is called flex dosing. When menstrual-like bleeding occurs during withdrawal, symptoms of pain are more likely to occur [5]. In contrast, DNG0.5 which is thought to have more side effects of irregular genital bleeding than LEP/OC, typically stabilizes bleeding within 3–6 months of oral administration. In approximately 90% of cases, menstrual-like bleeding does not occur [6], eliminating the need for withdrawal in the event of bleeding. In other words, compared to LEP/COCs, which cause menstrual-like bleeding and associated pain (albeit once every few months and to a lesser degree than normal menstrual cramps), DNG0.5, which does not cause menstrual-like bleeding, may be more effective than LEP/COCs in dysmenorrhea.

In a previous study, the author focused on PMS and evaluated the effect of DNG0.5 compared to YZF on PMS-like symptoms associated with dysmenorrhea. PMS-like symptoms were assessed by a simple questionnaire administered to the patients. The findings showed that DNG0.5 was more effective in improving PMS-like symptoms than YZF, a continuous LEP/OC, in clinical practice [7].

In the present study, we focused on the effect of DNG0.5 on dysmenorrhea, the primary indication for treatment, and compared it with that of YZF, a continuous LEP. We retrospectively examined whether DNG0.5 was more effective in treating dysmenorrhea than YZF. Additionally, we examined whether efficacy differed between patients with primary dysmenorrhea and those with secondary dysmenorrhea. Furthermore, we investigated the impact of irregular genital bleeding on pain relief of dysmenorrhea, as previous studies suggested that irregular genital bleeding may negatively influence the improvement of PMS-like symptoms. Finally, we examined the effect of the presence or absence of uterine fibroids, uterine adenomyosis, and endometrial polyps—factors associated with irregular genital bleeding—on treatment outcomes.

2. Materials and Methods

2.1. Institutional Review Board Statement

The study protocol was approved by the Ethics Committee/Institutional Review Board of Yokosuka Internal Medicine & Pediatrics/Haruko Women’s Clinic (protocol code 01; approved on 15 June 2023). This retrospective study was conducted according to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to inclusion in this study.

2.2. Participants

At our clinic, patients seeking treatment for dysmenorrhea undergo a gynecological examination, including a medical interview, imaging diagnosis (ultrasonography), and blood tests, and are then informed of the efficacy and side effects of all the drugs used in insurance-covered treatment of dysmenorrhea, including DNG 0.5 and YZF. Subsequently, the patient chooses the treatment drug and treatment is started. The approved method of using DNG0.5 in Japanese healthcare is oral administration, taken twice a day—in the morning and evening. From April 2021 to September 2023, all patients who visited our clinic for dysmenorrhea and continuously received DNG0.5 or YZF for at least 6 months were included in the study, with informed consent obtained from 238 patients. A total of 125 and 113 participants were in the DNG0.5 group (Group D) and the YZF group (Group Y), respectively. Patients with severe anemia, a significantly enlarged uterus, or those who had used hormones within 6 months before starting YZF or DNG0.5 were excluded from the study.

2.3. Data Collection

Data regarding the presence or absence of dysmenorrhea were obtained through interview before drug use, 3 months after treatment, 3–6 months after treatment, and 6 months after treatment. The measurement at 3–6 months was conducted at intervals of more than 30 days between the 3-month and 6-month measurements. During the interview, participants used a response sheet to rate and describe the severity of dysmenorrhea and irregular genital bleeding.

The dysmenorrhea score and a numeric rating scale (NRS) were used to assess dysmenorrhea pain. The dysmenorrhea score is commonly used in Japanese clinical trials for dysmenorrhea [8]. This verbal rating scale comprises two item scores, defining pain according to a limited ability to work and the need for analgesics. The first item relates to the degree of interference of menstrual pain with daily life (scored as 0 = none, 1 = mild [some loss of work or study efficiency], 2 = moderate [up to 1 day of bed rest, loss of work], 3 = severe [>1 day of bed rest]). The second item is scored according to the number of days of painkiller use per menstrual period (0 = none, 1 = take analgesics for 1 day, 2 = take analgesics for 2 days, 3 = take analgesics for >3 days). The two item scores are added to obtain a final score that expresses the degree of menstrual pain on a 7-point scale from 0 to 6. The NRS score is an 11-point verbal rating scale that focuses on the pain itself. Respondents are asked to select a number from 0 to 10 that best represents their pain intensity, with 0 = “no pain at all” and 10 = “pain as bad as it could be”. The visual analog scale (VAS) is the most commonly used pain score, but the NRS has also been evaluated in the literature and is less clinically burdensome for the patient to answer [9,10].

Bleeding volume and bleeding duration (in days) were used as indicators of genital bleeding. The amount of bleeding was scored on a three-point scale and recorded as an irregular genital bleeding score: 0 = none, 1 = small amount, and 2 = moderate.

2.4. Data Analysis

To evaluate the improvement in pain, the dysmenorrhea score and average NRS for Group D and Group Y were calculated by subtracting the average score at 3 months, 3 to 6 months, and 6 months after treatment from the average score before drug administration, respectively. The result was then divided by the average score before drug administration and multiplied by 100 to obtain the percentage improvement in the dysmenorrhea score and NRS for both groups.

The rate of complete resolution of dysmenorrhea after 6 months of use was also calculated by dividing the number of participants with an NRS of 0 after 6 months of use by the number of subjects with an NRS of 1 to 10 before drug administration and then multiplying by 100. The effect of the drug on primary dysmenorrhea and secondary dysmenorrhea was also examined in the same way.

The presence or absence of endometrial polyps, uterine fibroids, or adenomyosis as risk factors for irregular genital bleeding, which may reduce the efficacy of the treatment, was examined alongside the degree of bleeding. Dysmenorrhea scores were compared before and 6 months after treatment in patients from Group D and Group Y with these conditions. Similarly, the bleeding volume score and bleeding duration (in days) were used to compare whether the degree of genital bleeding differed depending on the presence of these conditions. The statistical analysis add-in software Excel Statistics 2022 was used for statistical processing of the data. Significant differences between Groups D and Y were examined using the Chi Square Test and the Welch test based on the average values of the two groups.

3. Results

Table 1. Comparison of participants’ age, body mass index, and number of gynecological illnesses between participants in Groups D and Y.

Data Item		Group D n = 125	Group Y n = 113	Significant Differences
Age (years)	Average	28.4	25.0	NS
	range	11–49	15–38
BMI (kg/m2)	Average	21.3	20.5	NS
	range	13.6–30.1	15.6–27.0
Dysmenorrhea Score	Average	4.1	3.8	NS
	range	1–6	1–6
NRS	Average	6.1	5.8	NS
	range	1–10	1–10
Number of patients with gynecological disease (%)	Uterine fibroids	18 (14.4)	15 (13.3)	NS
	Adenomyosis	90 (72.0)	80 (72.6)	NS
	Endometriosis	107 (85.6)	83 (73.5)	NS
	Ovarian endometriosis	8 (6.4)	2 (1.8)	p < 0.01
	Deep endometriosis	72 (57.6)	20 (17.7)	p < 0.01
	Endometrial polyp	8 (6.4)	5 (4.4)	NS
Number of patients with primary dysmenorrhea (%)		17 (13.6)	22 (19.5)	NS
Number of patients with secondary dysmenorrhea (%)		108 (86.4)	91 (80.5)	NS
Number of patients with dysmenorrhea (%)	Mild–moderate	62 (49.6)	63 (55.8)	NS
	Severe	63 (50.4)	50 (44.2)	NS

Note 1: n indicates the number of participants. Note 2: The number in parentheses is the percentage of participants (%). Note 3: BMI represents the body mass index. Note 4: Patients with endometriosis include those with one or more of the following conditions: adenomyosis uteri, ovarian endometriosis, and deep endometriosis. Note 5: Patients with secondary dysmenorrhea include those with uterine fibroids and those with endometriosis. Note 6: The severity of dysmenorrhea was assessed using a dysmenorrhea score. A dysmenorrhea score 0–4 was classified as mild-to-moderate and as not significantly interfering with daily life, and a dysmenorrhea score of 5–6 was classified as severe and as significantly interfering with daily life. Note 7: NRS indicates the numeric rating scale. Data were analyzed by Student t test or Chi Square Test. Statistical significance was set at <1%. NS: not significant (p > 0.01).

shows the background characteristics of the patients in Groups D and Y. No significant differences were observed in the participants’ age, body mass index, dysmenorrhea score, or NRS. Similarly, the prevalence of uterine fibroids, adenomyosis, endometriosis, and endometrial polyps showed no significant differences; however, the prevalence of ovarian endometriosis and deep endometriosis was significantly higher among participants in Group D.

Table 2. Dysmenorrhea scores and corresponding improvement rates in Groups D and Y before, 3 months after, 3 to 6 months after, and 6 months after using DNG0.5 and YZF.

Stage		Dysmenorrhea Score		Chi Square Test Welch Test	Improvement Rate (%)		Chi Square Test Welch Test
		Group D	Group Y		Group D	Group Y
Before drug use	①	4.1	3.8	NS	-	-	-
	②	1–6	1–6
	③	1.76	1.84
3 months after drug use	①	0.4	1.6	p < 0.01	88.1	59.1	p < 0.01
	②	0–5	0–5		0–100.0	0–100.0
	③	0.91	1.45		25.5	36.2
3–6 months after drug use	①	0.2	1.4	p < 0.01	95.0	63.5	p < 0.01
	②	0–4	0–5		20.0–100.0	0–100.0
	③	0.69	1.37		14.8	35.3
6 months after drug use	①	0.2	1.2	p < 0.01	96.4	66.4	p < 0.01
	②	0–6	0–5		0–100.0	0–100.0
	③	0.76	1.27		14.0	37.0

Note 1: ① indicates the average value. Note 2: ② indicates the range. Note 3: ③ indicates the standard deviation value.

presents the average dysmenorrhea scores and dysmenorrhea score improvement rates for Groups D and Y. The average dysmenorrhea scores for participants in Groups D and Y at 3 months, 3 to 6 months, and 6 months after administration were 0.4 and 1.6, 0.2 and 1.4, and 0.2 and 1.2, respectively, with participants in Group D showing significantly lower values at all periods. The improvement rates in dysmenorrhea score for Groups D and Y were 88.1% and 59.1%, 95.0% and 63.5%, and 96.4% and 66.4%, respectively, with Group D consistently showing significantly lower values at all administration periods.

Table 3. NRS and respective improvement rates in Groups D and Y before, 3 months after, 3 to 6 months after, and 6 months after using DNG0.5 and YZF.

Stage		NRS		Chi Square Test Welch Test	Improvement Rate (%)		Chi Square Test Welch Test
		Group D	Group Y		Group D	Group Y
Before drug use	①	6.1	5.8	NS	-	-	-
	②	1–10	1–10
	③	2.35	2.22
3 months after drug use	①	0.9	2.8	p < 0.01	83.2	53.6	p < 0.01
	②	0–6	0–8		0–100.0	0–100.0
	③	1.57	2.04		29.3	33.4
3–6 months after drug use	①	0.5	2.6	p < 0.01	91.5	56.2	p < 0.01
	②	0–5	0–10		0–100.0	0–100.0
	③	1.22	2.05		21.6	37.4
6 months after drug use	①	0.3	2.4	p < 0.01	94.8	59.0	p < 0.01
	②	0–5	0–8		0–100.0	0–100.0
	③	0.90	1.93		17.1	32.1

Note 1: ① indicates the average value. Note 2: ② indicates the range. Note 3: ③ indicates the standard deviation value.

shows the average NRS and NRS improvement rates for Groups D and Y. The average NRS scores for Groups D and Y at 3 months, 3 to 6 months, and 6 months after administration were 0.9 and 2.8, 0.5 and 2.6, and 0.3 and 2.4, respectively, with Group D showing significantly lower values at all periods. The NRS improvement rates for Groups D and Y were 83.2% and 53.6%, 91.5% and 56.2%, and 94.8% and 59.0%, respectively, with Group D showing significantly lower values at all periods.

Table 4. Number and percentage of patients with an NRS score of 0, complete pain resolution rates, and average genital bleeding score in Groups D and Y after 6 months of administration.

Data Item	Pain Status at 6 Months	Number of Patients	Percentage	Genital Bleeding Score at 6 Months	Chi Square Test Welch Test
Group D	Complete resolution (NRS = 0)	110	88.0	0.2	p < 0.01
	Incomplete resolution (NRS > 0)	15		1.0
Group Y	Complete resolution (NRS = 0)	27	23.9	0.7	NS
	Incomplete resolution (NRS > 0)	86		0.8

presents the complete pain disappearance rate in Groups D and Y after 6 months of treatment, along with the average irregular vaginal bleeding score for patients who had complete pain resolution (NRS = 0) and patients who did not (NRS > 0). In Group D, 88.0% of the participants experienced complete pain disappearance, compared to 23.9% in Group Y, indicating a significant difference in resolution rate.

In Group D, the irregular genital bleeding scores for participants who had pain resolution (NRS = 0) and those who did not (NRS > 0) after 6 months of treatment were 0.2 and 1.0, respectively, meaning that the amount of irregular genital bleeding was significantly less in patients who had pain disappearance. In Group Y, the irregular genital bleeding scores for patients who had pain disappearance and those who did not were 0.7 and 0.8, respectively, showing no significant difference.

Table 5. Dysmenorrhea score and NRS (average) and pain improvement rate for primary and secondary dysmenorrhea in Groups D and Y before and 6 months after the use of DNG0.5 and Yazflex, respectively.

Data Item/Stage		Dysmenorrhea Score		Statistical Significance Chi Square Test Welch Test	NRS		Statistical Significance Chi Square Test Welch Test
		Group D	Group Y		Group D	Group Y
Primary dysmenorrhea	Before drug use	2.8 (1–6)	2.7 (1–6)	NS	4.4 (1–9)	5.0 (1–10)	NS
	6 months after drug use	0.1 (0–1)	0.8 (0–4)	p < 0.05	0.3 (0–2)	2.0 (0–6)	p < 0.01
	Percentage of improvement	96.1	66.1	p < 0.05	94.4	62.4	p < 0.01
Secondary dysmenorrhea	Before drug use	4.3 (1–6)	4.1 (1–6)	NS	6.3 (1–10)	6.0 (1–10)	NS
	6 months after drug use	0.2 (0–6)	1.3 (0–5)	p < 0.01	0.3 (0–5)	2.5 (0–8)	p < 0.01
	Percentage of improvement	96.4	66.5	p < 0.01	94.9	58.2	p < 0.01

Note: () indicates a range.

shows the dysmenorrhea score, NRS, and score improvement rate in patients with primary dysmenorrhea or secondary dysmenorrhea before and 6 months after treatment. Both patients with primary and secondary dysmenorrhea showed similar responses to both treatments in terms of dysmenorrhea score and NRS. Regarding the effects of drugs, Group D showed significantly greater pain relief than Group Y in both subsets in terms of dysmenorrhea score and NRS, showing scores of 0.1 and 0.8, 0.2 and 1.3, 0.3 and 2.0, and 0.3 and 2.5, respectively. Similarly, the dysmenorrhea score improvement rates and NRS improvement in Groups D and Y in both patient subsets showed significant differences, showing superiority of Group D, which were 96.1% and 66.1%, 94.4% and 62.4%, 96.4% and 66.5%, and 94.9% and 58.2%, respectively.

Table 6. Average dysmenorrhea score, genital bleeding volume score, and duration of genital bleeding (in days) before and 6 months after treatment, categorized by the presence or absence of endometrial polyps, uterine fibroids, or adenomyosis.

	Total		Chi Square Test Welch Test p Value	Endometrial Polyp		Chi Square Test Welch Test p Value	Uterine Fibroids		Chi Square Test WELCH Test p Value	Adenomyosis		Chi Square Test Welch Test p Value
	D	Y		D	Y		D	Y		D	Y
	125	113		8	5		18	15		90	82
Dysmenorrhea Score (before)	4.1	3.8	NS	4.5	3.6	NS	4.1	4.0	NS	4.3	4.1	NS
Dysmenorrhea Score (6 months)	0.2	1.2	p < 0.01	0.6	1.2	NS	0.2	1.1	p < 0.05	0.2	1.3	p < 0.01
Bleeding Score (6 months)	0.3	0.7	p < 0.01	1.0	1.0	NS	0.4	0.9	p < 0.01	0.3	0.7	p < 0.01
Bleeding days (6 months)	2.0	2.3	NS	5.5	3.0	NS	2.3	4.0	NS	2.3	2.0	NS

shows the average values for the dysmenorrhea score, the score of irregular genital bleeding, and the duration of genital bleeding (in days) before and 6 months after administration of the drug in patients with endometrial polyps, uterine fibroids, or adenomyosis. The number of patients with endometrial polyps was 13 (including 8 in Group D and 5 in Group Y), accounting for 5.5% of the total participants (238). The dysmenorrhea score after 6 months of drug use in patients with endometrial polyps in Groups D and Y was 0.6 and 1.2, respectively, showing no significant difference. The bleeding score in patients with endometrial polyps in Groups D and Y was 1.0 and 1.0, respectively, showing no difference, and the duration of genital bleeding was 5.5 days and 3.0 days, respectively, showing no significant difference. The number of patients with fibroids was 33 (including 18 in Group D and 15 in Group Y), accounting for 13.9% of the total participants (238). In the group with uterine fibroids, the scores were 0.2 and 1.1, respectively, and the dysmenorrhea score in Group D was significantly lower than that in Group Y (p < 0.05). The bleeding score in patients with uterine fibroids was 0.4 in Group D and 0.9 in Group Y, which was significantly lower in Group D (p < 0.01). The duration of genital bleeding in patients with uterine fibroids was 2.3 days in Group D and 4.0 days in Group Y, with no significant difference. A total of 172 patients with adenomyosis (90 in Group D and 82 in Group Y), accounted for 72.3% of the total number of patients (238). In the group with adenomyosis, the dysmenorrhea score was 0.2 in Group D and 1.3 in Group Y. Group D had a lower dysmenorrhea score than Group Y (p < 0.01), which indicates a significant difference. The bleeding score in patients with adenomyosis was 0.3 in Group D and 0.7 in Group Y, which was significantly lower in Group D (p < 0.01). The duration of genital bleeding in patients with adenomyosis was 2.3 days in Group D and 2.0 days in Group Y, with no significant difference between the groups.

4. Discussion

DNG is characterized by its strong suppressive effect against dysmenorrhea pain. Similar to LEP/COCs, progestin reduces prostaglandin levels in the endometrium by inhibiting ovulation and endometrial proliferation [11]. DNG also directly inhibits the expression of prostaglandin E2 synthesis enzyme and aromatase in endometrial cells [12]. Additionally, DNG suppresses nerve growth factor expression in adenomyosis cells, significantly reducing nerve fiber density and thereby inhibiting pain transmission [13].

The 0.5 mg DNG tablets, available only in Japan, offer approximately 80% of the pain-relieving effect of 1 mg DNG tablets; however, they have the advantage of maintaining blood E2 levels just below 100 pg/mL [14].

Furthermore, DNG0.5 has been suggested to have less of an effect on bone mineral density in young people, a concern with LEP/COCs. In other words, one study indicates that DNG0.5 does not significantly affect bone turnover, as it maintains blood E2 levels without excessive suppression [15]. Unlike adult women, the effect of LEP/COCs on bone mineral density in young adults may be a concern as decreased bone mineral density has been reported in adolescent women who were less than 3 years from menarche and used oral contraceptives for more than 2 years [16]. Additionally, DNG0.5 is less likely to cause nausea, a common side effect observed with the introduction of LEP/COCs. These characteristics make DNG0.5 a suitable option for treating dysmenorrhea in young women. In addition, estrogen deficiency-related symptoms, such as headache, fatigue, and depression, are less likely to occur with DNG0.5 [17]. In a previous study, we compared DNG0.5 with LEP/COCs and reported that DNG0.5 can improve PMS/PMDD [7]. Therefore, 0.5 mg DNG tablets, unlike 1 mg DNG tablets, can be used in young patients with dysmenorrhea, offering the same indications as LEP/COCs, and could contribute to improving their coexisting PMS-like symptoms without reducing bone metabolism.

However, the effect of 0.5 mg DNG tablets is slightly weaker than that of 1 mg tablets, and there is also concern that they cause frequent genital bleeding. Regarding their effects on dysmenorrhea, one report on the dose-finding study mentioned above reported that DNG 0.5 mg showed greater effectiveness than cyclic administration of Yaz [14]; however, comparison with the continuous LEP/COC has not been performed.

YZF is an improved formulation of Yaz, which can be used as either a cyclic or a continuous regimen for up to 120 days. Continuous treatment of YZF is more effective for relieving dysmenorrhea pain [2,3]. The withdrawal period for Yaz and YZF is reduced to 4 days, making its ovulation suppression more effective among LEP/COCs. In addition, one previous study indicates that drospirenone, one of its active components, is effective in managing PMS and acne [18]. These benefits, including the ovulation suppression effect and anti-androgenic effects, may motivate young female patients who seek contraception and skin beautification to continue treatment for dysmenorrhea over the long term. Furthermore, the flex administration method has the advantage of controlling initial bleeding and minimal side effects, making it easier to introduce to patients. However, breakthrough bleeding may still occur even after long-term use, and it is necessary to take occasional breaks from the medication.

Given these considerations, we sought to evaluate the comparative effectiveness and side effect of DNG0.5 and YZF in clinical practice. This study retrospectively compared the effects of two drugs. The patient characteristics before taking the medication and the dysmenorrhea scores and NRS of the patients before administration of the drug were comparable between Groups D and Y. This similarity suggests that the severity of dysmenorrhea symptoms was consistent across the groups, providing a reliable basis for examining and comparing the effects of the two medications.

Many reasons underlie the decision to initiate treatment for dysmenorrhea despite a low menstrual pain score. First, patients often have estrogen-dependent diseases, such as endometriosis and uterine fibroids, which cause painful intercourse and bowel movements, necessitating hormonal treatment. Another reason is that Kampo medicine is often the first treatment initiated for dysmenorrhea. Many Japanese people prefer Kampo medicine, which has a more natural image than conventional medicine; furthermore, some of the population avoids analgesics due to concerns about potential dependence and gastrointestinal symptoms. While Kampo treatment initially provides some pain relief, patients often discontinue its use due to the taste and the need to take multiple doses throughout the day (2–3 times). Consequently, patients opt for hormone therapy instead. Finally, patients often prefer hormonal drugs that also treat pain, anticipating additional benefits such as cosmetic and contraceptive effects, relief from PMS, and less painful menstrual cycles.

At 3–6 months and 6 months of the administration, Group D showed better results in both dysmenorrhea score and NRS, and the improvement was faster with DNG0.5, as shown in the improvement rates. After 6 months of treatment, the complete disappearance rate of dysmenorrhea in Group D was 88.0%, which was 3–4 times higher than the rate of 23.9% in Group Y. Notably, the effect of LEP plateaued after 3 months, while that of DNG0.5 continued to increase.

These effects showed a similar tendency for both primary and secondary dysmenorrhea. Our findings revealed that continued administration of DNG0.5 for 6 months is highly effective. These findings are generally consistent with a meta-analysis report examining the effects of LEP and DNG0.5 on dysmenorrhea with 10 studies from 8 randomized controlled trials. From the report, DNG0.5 had a higher pain-relieving effect than LEP in all aspects of visual analog scale change, dysmenorrhea score change, and complete disappearance rate, in a comparison with cyclic administration of Yaz [19]. From these, DNG0.5 was effective enough against dysmenorrhea, as it was against PMS symptoms in the previous report, even when compared to continuous administration of LEP drugs.

Clinically, irregular genital bleeding during the administration of DNG or LEP/COC might exacerbate pain, and the effectiveness of the drug for dysmenorrhea can differ depending on the presence or absence of risk factors for irregular genital bleeding. Therefore, in this study, we investigated whether the effectiveness of the drug for dysmenorrhea differs depending on the risk factors for irregular genital bleeding, such as endometrial polyps, uterine fibroids, and adenomyosis. Organic diseases commonly observed in patients with dysmenorrhea that might cause bleeding include adenomyosis, uterine fibroids, and endometrial polyps.

In general, the presence of endometrial polyps increases both the amount and duration of irregular genital bleeding. While the overall improvement in dysmenorrhea was significantly higher in Group D than in Group Y, no significant difference was observed in patients with endometrial polyps. This outcome is presumably due to the high incidence of bleeding associated with DNG, which may offset its effectiveness in these cases.

The effect of improving dysmenorrhea in patients with uterine fibroids was significantly higher in Group D (dysmenorrhea score after 6 months: 0.2) than in Group Y (dysmenorrhea score after 6 months: 1.1). Group D had an irregular genital bleeding score of 0.4 and duration of genital bleeding (in days) of 2.3, while Group Y had an irregular genital bleeding score of 0.9 and duration of genital bleeding (in days) of 4.0. Therefore, the amount of irregular genital bleeding in Group D was significantly lower than that in Group Y. Generally, DNG is believed to likely cause irregular bleeding in patients with fibroids [6]; however, this verification proved that the minimum amount of 0.5 mg of the DNG tablet reduced irregular bleeding compared to LEP, even in the presence of fibroids, and was also found to be highly effective in reducing pain.

The improvement in dysmenorrhea among patients with adenomyosis was significantly higher in Group D (dysmenorrhea score after 6 months: 0.2) compared to Group Y (dysmenorrhea score after 6 months: 1.3). In terms of irregular genital bleeding, Group D reported an average bleeding score of 0.3 and a duration of 2.3 days, while Group Y had an irregular genital bleeding score of 0.7 and a duration of 2.0 days. These results indicate that the amount of irregular genital bleeding was significantly lower in Group D than in Group Y. These findings suggest that DNG0.5 is effective in managing patients with adenomyosis, showing similar efficacy to that observed in patients with fibroids.

As noted, endometrial polyps, which directly affect the endometrium, reduced the therapeutic effect against dysmenorrhea by increasing irregular bleeding. However, participants in Group D consistently demonstrated greater effectiveness against dysmenorrhea compared to those in Group Y across all the patients with organic conditions, such as endometrial polyps, uterine fibroids, and adenomyosis. In addition, even in the presence of endometrial polyps, uterine fibroids, or adenomyosis, the amount and duration of irregular bleeding did not increase when using DNG0.5 compared to when using LEP. Notably, the minimum dose of 0.5 mg tablets of DNG was more effective against dysmenorrhea than LEP/COC, while also minimizing irregular bleeding.

In summary, DNG0.5 reduced dysmenorrhea pain in patients with or without organic disease more effectively than YZF and continuous LEP. The extent of irregular bleeding with DNG0.5 was not more frequent than that with YZF. Considering that DNG0.5 also showed improvement in PMS-like symptoms in a previous report, we propose that DNG0.5 be considered as a first-line medication for dysmenorrhea, similar to continuous LEP/COC.

5. Conclusions

In this study, we retrospectively compared the therapeutic effects of 0.5 mg DNG tablets and continuous administration of LEP/COC on dysmenorrhea. The effect of 0.5 mg DNG tablets on pain was superior to that of continuous administration of LEP. Although 0.5 mg DNG tablets were associated with a higher incidence of irregular genital bleeding, the bleeding was mild even in cases with organic conditions such as endometrial polyps, uterine fibroids, and adenomyosis. In these cases, the effect of 0.5 mg DNG tablets on dysmenorrhea remained superior to that of LEP. Based on these findings, although careful attention must be paid to irregular bleeding, pain control with DNG 0.5 mg tablets is an excellent method that is not inferior to continuous LEP. We propose that 0.5 mg DNG tablets be considered as a first-line medication choice for dysmenorrhea, alongside continuous LEP/COC.