Current status and problems in the diagnosis and treatment of premenstrual syndrome and premenstrual dysphoric disorder from the perspective of obstetricians and gynecologists in Japan

To investigate the current status and problems in the diagnosis and treatment of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) from the perspective of obstetricians and gynecologists (OB/GYNs) in Japan, the Japanese Society of Obstetrics and Gynecology (JSOG) conducted a national‐wide survey.


INTRODUCTION
Premenstrual symptoms are characterized by emotional, behavioral, and physical symptoms that occur during the late luteal phase of the menstrual cycle and terminate after menstruation onset. 1 Epidemiological surveys have estimated that the frequency of premenstrual symptoms is relatively high (80%-90%). 2 Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) is classified in gynecology and psychiatry, respectively, as a pathological condition of premenstrual symptoms. 3 The prevalence of PMS in menstruating women is 20%-30%. 1 Further, 1.2%-6.4% women of reproductive age exhibit severe psychotic premenstrual symptoms that interfere with daily life as PMDD. 1 Premenstrual disorders (PMDs) include both PMS and PMDD. The International Society for Premenstrual Disorders has proposed to group both PMS and PMDD together as a continuum within the framework of PMDs. 4 Since the definition of the disease concept has not been well established, there is a problem in Japan regarding which department should see the patient. For example, it is unclear whether obstetricians and gynecologists (OB/GYNs) should see the patient if the symptoms are mainly physical or psychiatrists should see the patient if the symptoms are mainly psychological. There are no biochemical disease markers; therefore, the diagnosis must rely on subjective symptoms. Because symptoms are confined to the premenstrual period, patients tend to overestimate their symptoms. 5,6 To prevent this, the cyclicity of symptoms (symptom-free periods during the follicular phase) and reproducibility (presence of symptoms in most menstrual cycles) need to be checked for accuracy. Therefore, the diagnostic criteria for PMS according to the American College of Obstetricians and Gynecologists (ACOG) and PMDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 require a prospective two-cycle diary. 7,8 As a prospective symptom diary, the Daily Record of Severity of Problems is a questionnaire comprising 24 symptoms answered in six stages and is often used for research purposes such as clinical trials worldwide. 9,10 Prospective evaluation is helpful for accurate evaluation, but it is burdensome for patients. Therefore, it is questionable whether this is practiced in daily clinical practice. A survey of gynecologists and family physicians in the United States (US) in 2012 found that only 11.5% routinely performed a prospective two-cycle menstrual cycle assessment, 11 showing that there is a gap between research and actual clinical practice.
To compensate for the inconvenience of a forwardlooking daily chart, the use of screening tools for PMS/PMDD is helpful for an efficient examination. In a survey of family physicians and gynecologists in the US, 23.0% physicians used screening tools. Among them, the Premenstrual Symptoms Screening Tool (PSST) is commonly used globally. 12 The PSST is a self-rated retrospective questionnaire that is completed during clinical consultation with the patient. The PMDD scale in Japanese is essentially the Japanese version of PSST. 13 In contrast, the Premenstrual Symptoms Questionairre (PSQ) is a screening tool developed in Japan independently of the PSST. 14 The PSQ has been confirmed to be as effective as the PMDD scale. 15 Standard pharmacological treatments for PMS/PMDD include the use of selective serotonin reuptake inhibitors (SSRIs) and oral contraceptive pills (OCPs). The treatment guidelines of the Japanese Society of Obstetrics and Gynecology (JSOG) state that treatment should include counseling, lifestyle guidance, exercise therapy, prescription of OCPs such as drospirenone-ethinylestradriol, and administration of diuretics and Kampo medicines (traditional Japanese herbal medicines). 16 If psychiatric symptoms are predominant, the patient should be treated with SSRIs. Despite these recommendations, OCPs and SSRIs are not indicated and not insured for PMS/PMDD in Japan. In addition to health care issues, there are several problems with both drugs. OCP use and awareness are low in Japan; approximately 5% women of reproductive age take OCPs, of which 0.9% take OCPs purely for contraceptive purposes. 17 In Japan, there is a strong negative image of mental illness, and it is assumed that due to this, there is also a strong negative image of SSRIs, antidepressants. 18,19 Moreover, it is difficult to administer SSRIs to minors as it increases the risk of suicide attempts in patients aged ≤24 years, according to its package insert. 20,21 Various issues are assumed to exist in PMS/PMDD diagnosis and treatment in Japan, but the actual status of these issues is unclear. Therefore, we surveyed the current status of PMS/PMDD diagnosis and treatment and the associated problems among JSOG members.

Ethics
This study was conducted as a Women's Health Care Academic Committee survey of the JSOG, targeting physicians who are members of the society. This study was conducted in accordance with the principles outlined in the Declaration of Helsinki. The survey was anonymous and did not include any personal information. Before completing the survey, all participants read the description of the study's purpose and agreed to participate in the study by providing online consent.

Participants
An email survey was sent to all JSOG members (16 732 people) and a web-based survey was conducted using a Google form between the end of September and the end of November in 2021. The questionnaire was completed by 1312 respondents, and those who engaged in routine PMS/PMDD treatment provided answers to questions about their routine PMS/PMDD diagnosis and treatment ( Figure 1).

Questionnaire
We asked questions on the number of years they have been licensed as a doctor, their sex, their specialty (OB/GYN, psychiatry, internal medicine, or others), their specialist qualification, and their type of work (university hospital, general hospital or clinic). These questionnaires allowed us to have multiple answers. In addition, we surveyed the knowledge about the disease name, diagnosis, treatment, and practice; which department (OB/GYN, psychiatry, internal medicine, others) should diagnose and treat PMS and PMDD; and frequency of engagement. Those engaged in PMS/PMDD practice only were asked about the generic diagnosis procedure for PMS/PMDD (only vague interviews such as pre-menstrual physical and mental health problems, interview based on the ACOG or DSM-5 diagnostic criteria, keeping a one-or two-cycle symptom diary, using screening questionnaire [such as the PSST, PMDD scale, and PSQ], measurement of basal body temperature, and other free entry fields), which pharmacotherapies were most commonly used to treat PMS/PMDD ( 22,23 In the American Academy of Family Physicians' guidelines for the treatment of PMS/PMDD, it is referred to as the second drug after SSRIs. 24 Therefore, in this survey, they were listed together as SSRI/ SNRI as therapeutic agents. Multiple answers were allowed for the question on which department should diagnose and treat PMS and PMDD and those on treatment and diagnosis.

Statistical analysis
Statistical analysis was performed using JMP 16.0.0 (SAS, Cary). Statistical significance was set at p < 0.05. Data on the proportion of those using a prospective twocycle diary or using a screening tool in their diagnosis were compared to the 2012 US data. 11 We used hypothesis testing for the difference in the population proportions and the χ 2 test. The effect size was measured using Cramer's V calculated with BellCurve for Excel (Social Survey Research Information Co., Ltd.). The effect sizes F I G U R E 1 Flow diagram of study participants. Those treating PMS/PMDD were asked about diagnosis and treatment. JSOG, Japanese Society of Obstetrics and Gynecology; PMDD, premenstrual dysphoric disorder; PMS, premenstrual syndrome. of 0.10, 0.30, and 0.50 were judged as small, medium, and large, respectively. 25

RESULTS
The questionnaire was completed by 1312 respondents (7.8% of all JSOG members [16 732]) ( Figure 1). The background characteristics of the participants are described in Table 1. The sex ratio was 50:50, and most respondents (99.6%) specialized in OB/GYN. Among them, 94.8% had OB/GYN specialist qualifications-63% worked in university and general hospital facilities and 31% worked in clinics. Table 2 shows the degree of involvement and awareness regarding PMS/PMDD care. A total of 1191 (90.8%) respondents were "knowledgeable and involved in diagnosis and treatment." In terms of diagnoses and treatment, OB/GYN was preferred over psychiatry for PMS (91.4% vs. 45%); however, no differences were noted for PMDD (76.1% vs. 73.7%). In total, 1267 (96.6%) participants were currently engaged in routine PMS/PMDD treatment; however, 45 (3.4%) participants were not engaged (Figure 1).
The results regarding the diagnosis and treatment of PMS/PMDD are shown in Table 3. Regarding the generic diagnostic procedures, 84.4% answered "only a vague medical interview," and a few respondents reported assessment with a symptom diary (7.1% for one cycle and 8.4% for two cycles). Only 8.4% respondents kept a two-cycle symptom diary, as indicated by the ACOG and DSM diagnostic criteria, which is not significantly different compared to the US data (11.5%) (p = 0.328, Cramer's V = 0.027, χ 2 test). Only 10.3% answered they used a screening questionnaire, significantly less than that in the US data (23.0%) (p < 0.001, Cramer's V = 0.100, χ 2 test). 11 OCPs ( Regarding the first-line drugs for PMS/PMDD treatment, OCPs were the most commonly prescribed (76.8%), followed by Kampo medicine (19.5%); SSRIs were less frequently prescribed (2.6%; 0.9% for continuous administration and 1.7% for luteal phase administration).

DISCUSSION
This study aimed to show the current status of diagnosis and treatment for PMS/PMDD in Japanese OB/GYNs. In the Ministry of Economy, Trade and Industry, the issue of labor losses due to women's health issues costs approximately 490 billion yen per year. 26 In particular, menstrual symptoms in mature women are an important issue. To address these problems, OB/GYNs are expected to play a significant role. Despite the fact that the majority of OB/GYNs who responded to this survey indicated that they were knowledgeable about PMS/PMDD and are engaged in their practice, their treatment and diagnostic options include several problems from an evidence-based medicine (EBM) perspective.
Regarding which department is responsible for treating PMS and PMDD, 91% think that OB/GYNs should treat PMS and 76% think that OB/GYNs should treat PMDD. Considering that JSOG guidelines recommend a psychiatry referral when psychiatric symptoms are strong, this value for PMDD was unexpectedly high. This result suggests that survey respondents are likely to be biased toward OB/GYNs who are dedicated to treating PMS/PMDD.  In response to the question on how to diagnose, only 8.4% respondents performed a two-cycle prospective menstrual cycle assessment according to the ACOG guidelines or DSM-V as a diagnosis method. This result is similar to the 2012 US study data (11.5%). 11 Diarizing with prospective assessment such as DRSP is essential for research purposes, but the diagnostic method of symptom diarizing is inconsistent with clinical practice. 9 Most participants (84.4%) were diagnosed based on a vague medical history taking of PMS/PMDD, whereas 18.7% and 7.0% were interviewed based on the ACOG and DSM-5 diagnostic criteria, respectively. Therefore, the accuracy of the PMS/PMDD diagnosis is questionable, and education for OB/GYNs regarding PMS/PMDD diagnosis is needed. Although the screening methods such as the PSST and PSQ do not allow for a rigorous diagnosis because they are not a prospective evaluation, they may prove useful as they can evaluate the severity of premenstrual symptoms at the first visit according to the DSM PMDD criteria. In the future, it will be necessary to establish clinically accurate and simple diagnostic methods and disease markers that can quantitatively measure the disease severity.
Although 98% of OB/GYNs choose to treat with OCPs, acceptance is poor in the general population due to fears of OCPs' side effects. 27 Regarding drospirenone-containing OCPs, literature on their therapeutic efficacy for PMDD exists. [28][29][30] With regard to PMS, solid evidence of efficacy is lacking, but Japanese and UK guidelines recommend dosing these drugs for PMS. 10,16 Therefore, it is correct that 65.1% of Japanese OB/GYNs choose this drug. In other words, the remaining 34.9% make treatment choices that are not based on the guidelines. 10,16 Additionally, there are limitations in addressing PMDD with OCPs alone, and the use of SSRIs is necessary. SSRIs are considered the first line of treatment. 10,31 However, relatively few OB/GYNs in this study opted for SSRIs for treatment (persistent 39.2%; luteal phase: 16.9%). Despite the recommendation in the JSOG guidelines, OB/GYNs in Japan seem to be unfamiliar with the use of SSRIs. Education for OB/GYNs on the use of SSRIs and collaboration with psychiatrists is considered necessary.
One notable treatment aspect is the high selection of Japanese herbal medicine (Kampo) use. Although Kampo are traditional drugs in Japan, the drugs used can be industrial products similar to Western medicines, and high quality is assured. Kampo is also used universally in non-obstetrics and gynecology departments and is well accepted by patients. 32,33 Due to the poor acceptance of OCPs and SSRIs among the general population in Japan, Kampo preparations are probably the preferred choice. Of these, Kamishoyosan is the most frequently selected, used by 73.6% OB/GYNs for treatment. In a study using a mouse menopausal depression model, Kamishoyosan showed anti-stress effects mediated by serotonin signaling. 34 It may be effective in PMS/PMDD considering that serotonin abnormalities are an etiologic factor of PMS/PMDD. Future studies with double-blind comparative trials are needed to verify its efficacy in PMS/PMDD.
It should be emphasized that this is the first study on PMS/PMDD diagnosis and treatment in Japan, but it also has some limitations. First, there may be a bias as only 7.8% of all JOGR members responded to this survey. The reasons for only some participants answering the survey may vary according to their clinical practice and interest in PMS/PMDD. The fact that 96.6% participants engaged in PMS/PMDD treatment is a very high percentage judging from the experience in the field of obstetric and gynecological treatment in Japan. It can be inferred that the respondents to this survey should be taken as data from those who are actively involved in PMS/PMDD treatment. Second, concerning the study population, we excluded other types of health professionals who might be involved in PMS/PMDD assessment, such as psychiatrists and family physicians. We plan to investigate psychiatry as a subset in the future as well. Further, as we only looked at Japan, it is important to conduct future surveys of clinical practice for PMS/PMDD in other countries to evaluate whether there are any reports of better practices in other regions. Finally, regarding the assessment method, this study only used self-reported data. There are no data to verify the frequency with which doctors in this study encountered women with PMDD or what assessment method they used. Doctors might have under-or over-reported this information. As the study relied on retrospective reports of typical practice, doctors' recollections might have been biased in their reporting of this information. Therefore, the ability to locate physicians' practices in a prospective method could increase the accuracy of their responses about PMS/PMDD diagnosis and treatment.
This study found that most OB/GYNs practicing PMS/PMDD in Japan do not regularly use a prospective monitoring method according to the diagnostic criteria for PMS/PMDD. In addition, the effectiveness of treatment based on vague medical interviews, without even using screening tools, was strongly suspected. Regarding treatment, some drug choices were not based on EBM, and the need to educate OB/GYNs about PMS/PMDD was considered necessary, including addressing the low selection of SSRIs for use.

AUTHOR CONTRIBUTIONS
Conception and design: All authors. Acquisition of data: All authors. Analysis and Interpretation of data: All authors. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Kana Yoshimi and Takashi Takeda. Administrative technical or material support: Kana Yoshimi, Fumi Inoue, and Takashi Takeda. Supervision: Tamami Odai, Nahoko Shirato, Zen Watanabe, Tempei Otsubo, Masakazu Terauchi, and Takashi Takeda.