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Article

Efficacy of 0.5 mg Dienogest Tablets in Treating Premenstrual Syndrome-like Symptoms: A Comparative Study with a Low-Dose Estrogen–Progestin Combination

by
Haruko Yokosuka
Department of Gynecology, Yokosuka Internal Medicine and Pediatrics/Haruko Women’s Clinic, 6-47-21 Kaneda Higashi, Kisarazu 292-0009, Chiba, Japan
Endocrines 2024, 5(3), 354-365; https://doi.org/10.3390/endocrines5030026
Submission received: 12 June 2024 / Revised: 7 August 2024 / Accepted: 12 August 2024 / Published: 15 August 2024
(This article belongs to the Section Female Reproductive System and Pregnancy Endocrinology)
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Abstract

:
Dysmenorrhea treatment with 0.5 mg dienogest tablets twice daily (1 mg/day) has proven useful, but its effect on premenstrual disorders has not yet been evaluated. This study aimed to evaluate the efficacy of 0.5 mg dienogest tablets in relieving premenstrual syndrome (PMS)-like symptoms during the treatment of dysmenorrhea in comparison with that of continuous low-dose estrogen–progestin (LEP/COC) drospirenone/ethinylestradiol combination, which is considered effective in treating premenstrual dysphoric disorder. During the standard course of dysmenorrhea treatment with dienogest or LEP/COC, PMS-like symptoms were scored based on patients’ reports, and the treatment effects were compared. As a result, the dienogest group experienced a significant improvement in PMS-like symptoms compared with the LEP/COC group over the 6-month study period (p < 0.01). Furthermore, dienogest was more effective in providing relief from PMS-like symptoms, with 89.7% of patients reporting a complete resolution of PMS-like symptoms at 6 months, compared with 47.1% in the LEP/COC group (p < 0.01). These results indicate that dienogest is effective in relieving PMS-like symptoms, similar to LEP/COC. Further studies are needed to determine whether 0.5 mg dienogest tablets, which are only available in Japan, are effective in treating premenstrual disorders diagnosed via standard methods.

1. Introduction

In recent years, dienogest (DNG), which is used for treating endometriosis, became available in Japan at a daily dosage of 1 mg for treating dysmenorrhea, a condition covered by Japan’s health insurance. In the Japan Obstetrics and Gynecology Clinical Practice Guidelines: Outpatient Gynecology Edition 2023, revised in August 2023, DNG was listed as a treatment option for dysmenorrhea, together with low-dose estrogen–progestin combination (LEP) for the first time [1]. Although a wide use of LEP in gynecological disorders, such as dysmenorrhea, premenstrual syndrome (PMS), or abnormal uterine bleeding, has already been established and recommended in some guidelines, the use of progestins is limited. In other countries, Cerazette®, Cerelle®, and NOR-Q.D.® have been approved as progestin-only pills, which are birth control pills, thus enabling women to choose progestins as an alternative to LEP for various gynecological conditions; however, they have not yet been approved in Japan. In Japan, DNG is a regularly used progestin-only agent; however, it was only indicated for endometriosis before it was approved for dysmenorrhea.
There are two types of dysmenorrhea: primary dysmenorrhea and secondary dysmenorrhea. In secondary dysmenorrhea, dysmenorrhea appears as a secondary symptom of conditions such as leiomyomas and endometriosis.
Because leiomyomas and endometriosis, which develop often between 30 and 40 years of age, are estrogen-dependent conditions, drugs to maintain a low estradiol level are preferable when treating secondary dysmenorrhea but may not be optimal for long-term treatment. In addition, treatment of primary dysmenorrhea without leiomyomas or endometriosis, a condition also seen in adolescent women, with LEP/COC has been reported to lower endogenous estradiol and result in reduced bone density [2]. Because 0.5 mg DNG tablets are an effective drug for dysmenorrhea that does not lower estradiol [3], it may be of less concern with respect to acquired bone mineral density loss in adolescent girls because of its reported benefit of not affecting bone metabolism [4].
DNG tablets (0.5 mg) have become the most common alternative to LEP prescribed to women with dysmenorrhea in our clinic. This is because, with the spread of coronavirus disease in 2019, 0.5 mg DNG tablets were prescribed at our clinic as an alternative to LEP, which is associated with a risk of thrombosis [5], as they contain no estrogen and are unlikely to cause thrombosis. Because 0.5 mg DNG tablets, unlike LEP, are administered continuously and have been reported to exert higher pain relief effects [3], these tablets are preferentially prescribed at our clinic.
Dysmenorrhea and PMS are menstrual complications that negatively impact women’s well-being and quality of life [6] and are among the most common illnesses in women.
The discomfort associated with monthly menstruation can reduce the quality of life of women and sometimes substantially interfere with daily activities. As dysmenorrhea appears for approximately a week during menstruation and PMS may appear for approximately 2 weeks in the premenstrual luteal phase, women who suffer from both are considered free of unpleasant menstruation-related symptoms for as little as 1 week in a month. Thus, women who suffer from both dysmenorrhea and PMS may not be in an optimal state for 3 weeks in a month. PMS is a condition that afflicts many women to varying extents; in particular, premenstrual dysphoric disorder (PMDD), more severe than PMS, often prevents women from performing their daily activities, and this issue has been highlighted by the international community. In recent years, the general term suggested for premenstrual sickness, including PMS and PMDD, is premenstrual disorders (PMDs).
Only 5.3% of women with PMDs and PMSs receive treatment, with only a few women receiving the appropriate treatment [7]. Dysmenorrhea and PMS often coexist, and a correlation between the intensities of dysmenorrhea and PMDs has been reported [8]. Therefore, it is necessary to consider this aspect during drug selection for dysmenorrhea; however, this task is challenging even when referring to the guidelines.
LEP, particularly drospirenone/ethinylestradiol (DRSP/EE) combination tablets, has been reported to be effective in treating PMDD. The Royal College of Obstetricians and Gynaecologists guidelines state that DRSP/EE combination tablets should be considered the first-choice drug for PMS [9]. Furthermore, compared with cyclic administration, the continuous administration of DRSP/EE combination tablets has been reported to significantly improve PMS [10].
In Japan, DRSP/EE combination tablets are not indicated for PMS; however, after administering DRSP/EE combination tablets, patients with dysmenorrhea have experienced relief from PMS-like symptoms [11].
Similarly, patients with dysmenorrhea reported an alleviation of PMS-like symptoms after taking 0.5 mg DNG tablets. To date, the reports that have examined the effects of progestin alone on PMS have only been on norethisterone and dydrogesterone, etc. There have been no reports on 0.5 mg DNG tablets that are new to the market, and so far, there have only been reports of its effect on dysmenorrhea. Therefore, this retrospective study aimed to determine whether 0.5 mg DNG tablets are effective in providing relief from PMS-like symptoms compared with LEP, for which there is evidence of providing such relief from PMS.

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 02; 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

Participants were female patients aged between 12 and 49 years who visited our hospital for the treatment of dysmenorrhea and were receiving hormone therapy (Yaz Flex [YZF, LEP DRSP/EE combination tablet] or 0.5 mg DNG tablet) for at least 6 months.
There were 125 and 113 participants in the 0.5 mg DNG tablet group (Group D) and the YZF group (Group Y), respectively. Patients with severe anemia, a severely enlarged uterus, or recent hormonal agent use within 6 months before starting YZF or DNG were excluded.

2.3. Data Collection

Data regarding the presence or absence of PMS-like symptoms at four stages (before drug use, 3 months after drug use, 3–6 months after drug use, and 6 months after drug use) were obtained by interviewing participants during visits to the hospital.
The diagnostic criteria for PMS, as proposed by the American College of Obstetricians and Gynecologists (ACOG), requires observation of at least 2–3 consecutive menstrual cycles [12]. Various indexes have been proposed and used to evaluate PMS, such as the Mood Disorder Questionnaire and visual analog scale scores [13]; however, these indexes have numerous questions and may be burdensome to patients. In outpatient settings, it is difficult to obtain consent to delay the start of treatment for the diagnosis of PMS in patients who visit the hospital with dysmenorrhea as their primary complaint [14].
Therefore, this study adopted a scoring system for PMS-like symptoms that can be responded to easily and subjectively by patients who have started DNG or YZF treatment for dysmenorrhea.
This study focused on three endpoints with respect to PMS symptoms. Two of the three endpoints were in the diagnostic criteria for PMS in the ACOG practice bulletin: (1) physical and (2) psychological symptoms. Specific physical symptoms included breast tenderness or swelling, headaches, edema, joint or muscle pain, nausea, abdominal pain, bloating sensation, and weight gain. Psychological symptoms included irritability, angry outbursts, depression, anxiety, confusion, and social withdrawal. These two symptoms have a stressful impact on daily life. The third endpoint was to ask patients how much PMS interferes with their daily activities: (3) degree of interference with daily life. Regardless of whether the causal factor is physical, psychological, or another symptom, this third endpoint was added as an independent factor because the difficulty in performing daily activities may limit patients’ lives and activities.
All three endpoints were scored as 0 (none), 1 (mild), or 2 (severe) according to severity, and a total of the three scores was used as an index for PMS score.
When there was more than one symptom per item, the patient was asked to subjectively assess the score. For example, fatigue and edema were classified as physical symptoms; however, when fatigue and edema were mild, the score was 1, and when only fatigue was present and was severe, even without multiple symptoms, the score was 2.
During the interview, the participants scored and described their PMS-like symptoms using a response sheet, which was then collected for analysis.

2.4. Data Analysis

To assess the effect of improved PMS scores in Groups D and Y, the PMS scores for each group were calculated by subtracting the average scores at 3, 3–6, and 6 months after starting YZF and DNG treatment from the average score before drug administration. These scores were divided by the average score before drug administration and multiplied by 100 to obtain the PMS score improvement rate.
In addition, the ideal situation in which PMS-like symptoms disappear completely was examined. The complete disappearance rate of PMS was calculated by dividing the number of participants with a PMS score of 0 after 6 months of drug administration by the total number of participants with a PMS score of 1–6 before drug administration and then multiplying the obtained value by 100.
Furthermore, patients with dysmenorrhea were classified into primary dysmenorrhea and secondary dysmenorrhea. It was examined whether there was a difference in the treatment effect for PMS and dysmenorrhea between Groups D and Y. Dysmenorrhea scores were used to evaluate the effectiveness of treatment of dysmenorrhea [15]. In patients with primary dysmenorrhea or secondary dysmenorrhea, the PMS and dysmenorrhea scores were averaged and compared between Groups D and Y 6 months after drug use. The improvement rate of dysmenorrhea scores for both Groups D and Y was calculated by subtracting the average score 6 months after from the average score before drug use and dividing this score by the average score before drug use, and then multiplying the obtained value by 100.
Statistical data processing was performed using the statistical add-in software Excel Statistics 2022 (BellCurve for Excel). Student’s t-test and chi-squared test were used to determine significant differences.
In cases of severe endometriosis or when treatment with 0.5 mg DNG tablets or YZF was not effective, the dose was increased to 1 mg DNG tablets or changed to other treatments, and these cases were not included in this study.

3. Results

The background factors used in this study are listed in Table 1. There were no significant differences in participants’ age or body mass index between Group D and Group Y. Regarding gynecological diseases, there were no significant differences in the prevalence of leiomyoma, adenomyosis, and endometriosis; however, the prevalence of endometrial polyps and ovarian cysts was significantly higher in Group D than in Group Y. In contrast, the prevalence of polycystic ovary syndrome was significantly higher in Group Y. The prevalence of psychiatric disorders was significantly higher in Group D. Regarding dysmenorrhea, there was no bias between Groups D and Y according to the number of patients with primary or secondary dysmenorrhea or the severity of dysmenorrhea.
The PMS score was evaluated based on (1) physical symptoms, (2) psychological symptoms, and (3) degree of interference with daily life at all stages before drug use, 3 months after drug use, 3–6 months after drug use, and 6 months after drug use.
As shown in Table 2, the PMS score of each endpoint accounts for approximately 30% of the whole score, and it was to be an index that could comprehensively evaluate and verify the endpoints of the three in a well-balanced manner.
The numbers of participants for each PMS score in Groups D and Y before drug use is shown in Figure 1. The PMS scores of Groups D and Y before drug use were similar in terms of the number of participants, confirming that the PMS-like symptom status of participants before drug use was not significantly different between Groups D and Y. Scores of PMS-like symptoms in Groups D and Y were averaged and compared before, 3 months after, 3–6 months after, and 6 months after drug use. The average PMS scores of Groups D and Y at the abovementioned four stages are shown in Table 3.
Compared with before drug use (Group D: 4.1, Group Y: 3.9), the average PMS scores at 3 months after drug use (Group D: 0.6, Group Y: 1.4) decreased by 3.5 and 2.5 points in Groups D and Y, respectively, indicating an early 1-point difference between the two groups. The average PMS scores at 3–6 months and 6 months after drug use were similar, with the average PMS scores at 6 months after drug use for Group D being 0.2 vs. 1.2 for Group Y, indicating that Group D showed more significant improvement than Group Y (p < 0.01).
Next, the improvement rate of PMS scores was compared between Groups D and Y. Figure 2 shows the percentage improvement in PMS scores at three stages (3 months after, 3–6 months after, and 6 months after drug use) for Groups D and Y. In the abovementioned three stages, the improvement rates of PMS scores in Group Y were 63.5%, 69.4%, and 70.5%, respectively. Meanwhile, the improvement rates of PMS scores in Group D were 85.3%, 91.2%, and 93.9%, respectively, with the improvement rate in all three stages being >20%, significantly higher than in Group Y (p < 0.01).
Drugs that exert effects rapidly have the advantage of increased patient motivation to adhere to them, enhancing the likelihood of continuous drug administration by the patient. Therefore, this study also compared how rapidly Groups D and Y experienced improvements in PMS-like symptoms.
Figure 3 shows the number of participants with PMS scores (integer) in Groups D and Y. The proportion of participants with a score of 0 after 3 months of drug use was 72.8% and 46.0% in Groups D and Y, respectively. This number was significantly higher in Group D than in Group Y (p < 0.01), indicating early efficacy in Group D. Furthermore, the number of patients who continued to improve to a score of 0 for up to 6 months increased by only 7 in Group Y, while the number increased by 22 in Group D, indicating a 3.1-fold increase in the number of patients who became symptom-free (Table 4).
Furthermore, the complete disappearance rates of PMS-like symptoms were compared between the two groups. The complete disappearance rate was significantly higher in Group D than in Group Y (89.7% vs. 47.1%; p < 0.01) (Figure 4).
Table 5 shows the PMS scores and dysmenorrhea scores of patients with primary dysmenorrhea and secondary dysmenorrhea in Groups D and Y before and 6 months after drug use, and Table 6 shows the improvement rates.
The average PMS scores of patients with primary dysmenorrhea in Groups D and Y before drug use were 2.8 (0–6) and 3.8 (0–6); however, 6 months after the start of drug use, they were 0.1 (0–2) and 1.3 (0–5), with PMS score improvement rates of 96.4% and 65.8% for Groups D and Y, respectively. In contrast, for patients with secondary dysmenorrhea, the average PMS scores before drug use in Groups D and Y were 4.3 (0–6) and 3.9 (0–6), respectively. However, after 6 months of drug use, they were 0.3 (0–6) and 1.1 (0–5), and the PMS score improvement rates for Groups D and Y were 93.0% and 71.8%, respectively. Thus, the PMS improvement rates were significantly higher in Group D than in Group Y, nearly 30% for primary dysmenorrhea and slightly more than 20% for secondary dysmenorrhea (p < 0.01).
Furthermore, the dysmenorrhea score improvement rates after 6 months of drug use in Groups D and Y were 96.4% and 68.0%, respectively, for patients with primary dysmenorrhea and 95.3% and 68.3%, respectively, for patients with secondary dysmenorrhea. For the dysmenorrhea treatment, Group D showed a significantly higher improvement rate of dysmenorrhea, nearly 30%, than Group Y, regardless of the dysmenorrhea classification (p < 0.01).

4. Discussion

Counseling, herbal medicines, diuretics, selective serotonin reuptake inhibitors, and the hormonal agent LEP have all been effective in treating PMS [1,9,12]. LEP is considered effective against PMS by suppressing ovulation.
In contrast, the efficacy evaluation of progestin preparations remains unclear. PMS in the luteal phase is considered to be caused by progesterone, which is released after ovulation. In a previous systematic review, progesterone and progestin preparations were not recommended for treating PMS [16]. The author extensively analyzed numerous studies on progesterone. However, the number of reports on progestins analyzed in that review is small, with the results derived largely from reports on dydrogesterone, which does not adequately suppress ovulation. Thus, the evaluation of progestins in a condition with an ovulation-inhibiting effect might be useful.
In addition to LEP, GnRH analogs and danazol have been reported to improve PMS by suppressing ovulation. In other words, suppressing ovulation is effective in improving PMS. The ovulation-inhibitory effect of DNG is dose-dependent, with ovulation inhibition observed in >90% of patients taking DNG at a dose of ≥1 mg/day [17]. Therefore, if suppressing ovulation improves PMS, DNG may be effective against PMS-like symptoms.
Furthermore, this study examined the use of a 0.5 mg DNG tablet to prove its efficacy for PMS. There are two dosage forms of DNG available in Japan. The 0.5 mg DNG tablet was selected because using ≥1 mg DNG tablets (daily dose of ≥2 mg) may cause the endogenous estradiol concentration to drop below 40 pg/mg [18]. In such cases, estrogen deficiency symptoms (vasomotor symptoms, depression, and headache), a form of menopausal syndrome, may occur. In contrast, 0.5 mg DNG tablets, unlike 1 mg DNG tablets, are characterized by a lesser lowering of E2 concentration in the blood, maintaining it at slightly less than 100 pg/mL [3]. Because some estrogen deficiency symptoms may be perceived as PMS-like symptoms, the use of 0.5 mg DNG tablets may be appropriate to avoid PMS-like symptoms. Thus, this retrospective study compared PMS-like symptoms during the treatment of dysmenorrhea with 0.5 mg DNG tablets and YZF.
YZF is a continuous dosing regimen of DRSP/EE combination tablets and is the most recommended LEP for the treatment of PMS by various guidelines. Therefore, comparing YZF to 0.5 mg of DNG could be a useful way to demonstrate the efficacy of DNG against PMS.
The results showed that the average PMS score decreased in both groups after 6 months of drug use. Moreover, Group D was shown to be significantly more effective than Group Y (p < 0.01), as the score decreased to 0.2 points in Group D and 1.2 points in Group Y. Similarly, DNG was more effective than YZF in terms of improvement rate, complete disappearance rate, and speed of improvement. In addition, after 3 months of YZF use, it was not expected to improve PMS-like symptoms, even if it was continuously used for >3 months. In comparison, 0.5 mg DNG tablets were able to improve PMS-like symptoms more effectively if treatment was continued for another 3–6 months after 3 months of use. The result that the 0.5 mg DNG tablet was more effective than YZF, which has been proven effective for PMS/PMDD, might indicate the effectiveness of DNG for both PMS-like symptoms and PMS/PMDD.
The result that 0.5 mg DNG tablets are as effective as or more effective than YZF for PMS-like symptoms applied equally to patients with primary dysmenorrhea and those with secondary dysmenorrhea, including endometriosis. Furthermore, in the treatment of dysmenorrhea symptoms, the main treatment was also examined. DNG tablets (0.5 mg) improved dysmenorrhea scores significantly more than YZF. DNG tablets (0.5 mg) may be more effective than YZF for PMDs and dysmenorrhea, regardless of the classification of dysmenorrhea.
DNG, a progestational drug that could be the causative factor, showed considerable effect on PMS. It is not clear about whether this is because of the type of progestin or whether the dosage was optimal for PMS. Nevertheless, two assumptions that DNG would be effective on PMS were postulated.
The first reason 0.5 mg DNG tablets are effective for PMS-like symptoms is that, like LEP, they suppress ovulation. In contrast, progesterone is considered the cause of PMS, and as mentioned above, DNG, a progestin, could act directly on the central nervous system and cause PMS symptoms. However, this was not evident from the present results. Although LEP also has a progestin component, it is considered to ameliorate PMS because, while maintaining its ovulation-inhibitory effect, the amount of progestin it contains is considerably lowered; thus, it has little effect on the central nervous system. DNG is effective as a single agent for treating endometriosis and dysmenorrhea; its properties include being highly active in the endometrium and not having strong central nervous system effects [19]. The doses used for treating dysmenorrhea are lower than those included in fixed-dose combinations used as COCs overseas. Therefore, the dose of 0.5 mg DNG tablets may not be sufficient to cause PMS symptoms in the central nervous system.
The second reason 0.5 mg DNG tablets are effective against PMS-like symptoms is that DNG has little effect on estrogen levels in the blood. With 0.5 mg DNG tablets at a daily dose of 1 mg, the amount of endogenous estrogen discharged was 84 ± 71 pg/mL, identical to that discharged during the normal menstrual cycle [17].
During LEP administration, the follicles hardly develop because of a negative feedback mechanism; therefore, the only estrogen present in the body is ethinylestradiol, the estrogenic component of LEP. The half-life of ethinylestradiol is 6.5 h, rapidly disappearing in the body [20]. Ethinylestradiol levels increase above 50 pg/mL immediately after administration but rapidly decline to <10 pg/mL 12 h after administration [21]. Ethinylestradiol does not bind to sex hormone-binding globulin (SHBG) and becomes inactive when metabolized; thus, the estrogen in the patient’s body markedly fluctuates throughout the day [22,23]. Therefore, PMS-like symptoms tend to appear in patients who are off LEP medications [24]. In addition, this fluctuation may cause PMS-like symptoms such as headaches [25].
Conversely, the endogenous estrogen estradiol, maintained at 0.5 mg of DNG, binds to SHBG, acting as a reservoir, and metabolites also maintain their estrogenic activity. Thus, relatively rapid changes and symptoms such as headaches are less likely to occur with DNG than with LEP.
Therefore, it is considered that 0.5 mg DNG tablets are suitable for alleviating PMS-like symptoms because of their ovulation-inhibitory effect and their stabilization of blood estrogen levels.
Finally, DNG was more effective than LEP at an earlier stage and was more effective when taken continuously for 6 months beyond 3 months.
As mentioned earlier, when menstrual-like bleeding occurs during the withdrawal period while taking LEP, PMS-like symptoms tend to appear during or before the bleeding period [24]. Clinically, it appeared that DNG, similar to LEP, was prone to causing PMS-like symptoms during or around the period of irregular genital bleeding.
DNG is more prone to causing irregular genital bleeding than LEP [26]. DNG causes the endometrium to become pseudodecidual, resulting in a thin, flaky endometrium that does not thicken, thus causing irregular genital bleeding to be more likely to occur. However, after ~6 months of DNG administration, irregular genital bleeding disappears or becomes extremely unlikely in >90% of cases [27]. After 3 to 6 months of taking DNG, the patient is often at a point where the drug is firmly acting on the endometrium and settling down. Therefore, in consultation with the patient, it is acceptable to wait for the effect on PMS-like symptoms to appear until 6 months have passed, when bleeding is expected to settle down.
These results indicate that PMS-like symptoms are improved when DNG is used for treating dysmenorrhea and that progestin alone is also useful. It is believed that further studies are warranted to determine whether DNG is effective for treating PMS and PMDD based on a standard diagnosis.

Funding

This research received no external funding.

Institutional Review Board Statement

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Yokosuka Internal Medicine & Pediatrics/Haruko Women’s Clinic (protocol code 02; approved on 15 June 2023).

Informed Consent Statement

Informed consent was obtained from all participants involved in this study.

Data Availability Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Distribution of participants’ premenstrual syndrome (PMS) scores (integers) prior to dienogest and Yaz Flex administration in Groups D and Y, respectively.
Figure 1. Distribution of participants’ premenstrual syndrome (PMS) scores (integers) prior to dienogest and Yaz Flex administration in Groups D and Y, respectively.
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Figure 2. Percentage improvement in PMS scores (average) at 3 months, 3–6 months, and 6 months after using dienogest and Yaz Flex in Groups D and Y, respectively.
Figure 2. Percentage improvement in PMS scores (average) at 3 months, 3–6 months, and 6 months after using dienogest and Yaz Flex in Groups D and Y, respectively.
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Figure 3. Distribution of PMS scores (integer) among participants in Groups D and Y at 3 and 6 months after using dienogest and Yaz Flex, respectively.
Figure 3. Distribution of PMS scores (integer) among participants in Groups D and Y at 3 and 6 months after using dienogest and Yaz Flex, respectively.
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Figure 4. Complete disappearance rates of PMS-like symptoms in Groups D and Y 6 months after using dienogest and Yaz Flex, respectively.
Figure 4. Complete disappearance rates of PMS-like symptoms in Groups D and Y 6 months after using dienogest and Yaz Flex, respectively.
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Table 1. Comparison of participants’ age, body mass index, and number of gynecological and psychiatric illnesses between Groups D and Y.
Table 1. Comparison of participants’ age, body mass index, and number of gynecological and psychiatric illnesses between Groups D and Y.
Data ItemGroup D
(n = 125)		Group Y
(n = 113)		Significant Differences
Age (years)Highest4938(Average value)
No significant difference at p = 0.01
Average28.425
Lowest1115
BMI (kg/m2)Highest30.127.0(Average value)
No significant difference at p = 0.01
Average21.320.5
Lowest13.615.6
Number of patients with gynecological disease (persons)Leiomyoma18 (14.4)15 (13.3)No significant difference at p = 0.01
Adenomyosis90 (72.0)80 (72.6)No significant difference at p = 0.01
Endometriosis107 (85.6)83 (73.5)No significant difference at
p = 0.01
Endometrial polyp8 (6.4)5 (4.4)Significantly higher in Group D (p < 0.01)
Ovarian cyst10 (8.0)4 (3.5)Significantly higher in Group D (p < 0.01)
Polycystic ovary syndrome27 (21.6)36 (31.9)Significantly higher in Group Y (p < 0.01)
Number of patients with mental illness (persons)10 (8.0)4 (3.5)Significantly higher in Group D (p < 0.01)
Number of patients with primary dysmenorrhea (persons)17 (13.6)22 (19.5)No significant difference at
p = 0.01
Number of patients with secondary dysmenorrhea (persons)108 (86.4)91 (80.5)No significant difference at
p = 0.01
Number of patients with dysmenorrhea (persons)Mild–moderate62 (49.6)63 (55.8)No significant difference at
p = 0.01
Severe63 (50.4)50 (44.2)No significant difference at
p = 0.01
Note 1: n is the number of participants (persons). Note 2: The number in parentheses is the percentage of participants (%). Note 3: BMI represents body mass index. Note 4: Patients with endometriosis include those with one or more of the following conditions: adenomyosis uteri, ovarian endometrial cysts, and deep endometriosis. Note 5: Patients with secondary dysmenorrhea include those with leiomyomas 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 as significantly interfering with daily life.
Table 2. Evaluation result of every endpoint of the PMS score (average score).
Table 2. Evaluation result of every endpoint of the PMS score (average score).
StagePhysical SymptomsPsychological SymptomsDegree of Interference with Daily LifePMS
Total Score
Before drug use1.4 (35)1.2 (30)1.4 (35)4.0 (100)
3 months after drug use0.3 (30)0.3 (30)0.4 (40)1.0 (100)
3–6 months after drug use0.3 (37.5)0.2 (25)0.3 (37.5)0.8 (100)
6 months after drug use0.2 (28.6)0.2 (28.6)0.3 (42.8)0.7 (100)
Note: The values in parentheses represent the percentage contribution to the total score.
Table 3. Premenstrual syndrome scores for Groups D and Y before, 3 months after, 3–6 months after, and 6 months after using dienogest and Yaz Flex, respectively.
Table 3. Premenstrual syndrome scores for Groups D and Y before, 3 months after, 3–6 months after, and 6 months after using dienogest and Yaz Flex, respectively.
PMS/PMDD Score
Average Values		Group DGroup Y
Before drug use4.1 (0–6)3.9 (0–6)
3 months after drug use0.6 (0–5)1.4 (0–5)
3–6 months after drug use0.4 (0–6)1.2 (0–5)
6 months after drug use0.2 (0–6)1.2 (0–5)
Note: Numerals in parentheses indicate the minimum and maximum scores (integers). PMS, premenstrual syndrome; PMDD, premenstrual dysphoric disorder.
Table 4. Number of participants in Groups D and Y with PMS score of 0 at 3 and 6 months after using dienogest and Yaz Flex, respectively.
Table 4. Number of participants in Groups D and Y with PMS score of 0 at 3 and 6 months after using dienogest and Yaz Flex, respectively.
StageGroup D (Persons)Group Y (Persons)
Total number of participants125113
3 months after drug use9152
6 months after drug use11359
Table 5. PMS/PMDD and dysmenorrhea scores (average score) in primary dysmenorrhea and secondary dysmenorrhea for Groups D and Y before and 6 months after using dienogest and Yaz Flex, respectively.
Table 5. PMS/PMDD and dysmenorrhea scores (average score) in primary dysmenorrhea and secondary dysmenorrhea for Groups D and Y before and 6 months after using dienogest and Yaz Flex, respectively.
Data Item/StagePMS/PMDD ScoreDysmenorrhea Score
Group DGroup YGroup DGroup Y
Primary
dysmenorrhea		Before drug use2.8 (0–6)3.8 (0–6)2.8 (1–6)2.5 (0–6)
6 months after drug use0.1(0–2)1.3 (0–5)0.1(0–1)0.8(0–4)
Secondary
dysmenorrhea		Before drug use4.3 (0–6)3.9 (0–6)4.3 (1–6)4.1 (1–6)
6 months after drug use0.3 (0–6)1.1 (0–5)0.2 (0–6)1.3 (0–5)
Table 6. Percentage improvement in PMS/PMDD and dysmenorrhea scores (average score) in primary dysmenorrhea and secondary dysmenorrhea for Groups D and Y before and 6 months after using dienogest and Yaz Flex, respectively.
Table 6. Percentage improvement in PMS/PMDD and dysmenorrhea scores (average score) in primary dysmenorrhea and secondary dysmenorrhea for Groups D and Y before and 6 months after using dienogest and Yaz Flex, respectively.
Data ItemPMS/PMDD Score (%)Dysmenorrhea Score (%)
Group DGroup YGroup DGroup Y
Primary dysmenorrhea96.465.896.468.0
Secondary dysmenorrhea93.071.895.368.3
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Yokosuka, H. Efficacy of 0.5 mg Dienogest Tablets in Treating Premenstrual Syndrome-like Symptoms: A Comparative Study with a Low-Dose Estrogen–Progestin Combination. Endocrines 2024, 5, 354-365. https://doi.org/10.3390/endocrines5030026

AMA Style

Yokosuka H. Efficacy of 0.5 mg Dienogest Tablets in Treating Premenstrual Syndrome-like Symptoms: A Comparative Study with a Low-Dose Estrogen–Progestin Combination. Endocrines. 2024; 5(3):354-365. https://doi.org/10.3390/endocrines5030026

Chicago/Turabian Style

Yokosuka, Haruko. 2024. "Efficacy of 0.5 mg Dienogest Tablets in Treating Premenstrual Syndrome-like Symptoms: A Comparative Study with a Low-Dose Estrogen–Progestin Combination" Endocrines 5, no. 3: 354-365. https://doi.org/10.3390/endocrines5030026

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