Trends in the estimated proportion of outpatients with menstrual disorders and the number of prescribed low-dose estrogen/progestin drugs in Japan: A descriptive study

Menstruation is a physiological phenomenon characterized by periodic bleeding through the vagina in reproductively mature women. It is an important health indicator for women, but many women experience abdominal pain and other symptoms of discomfort before and during menstruation [ 1 – 4 ]. Historically, women’s health, particularly in relation to menstruation, has been both neglected and stigmatized, leading to embarrassment and marginalization. Furthermore, until a few decades ago, menstruation was less frequent than it is today, and fewer women experienced menstrual disorders. Consequently, women with menstrual health concerns have remained largely invisible. These factors have contributed to the lack of extensive research on menstrual health until recent years [ 1 , 5 , 6 ]. However, the number of women with menstruation-associated symptoms is currently higher than in the past [ 1 , 7 , 8 ], presumably due to an increase in the lifetime number of menstrual cycles. In recent years, a global consensus that menstruation is important for improving many social aspects necessary for a healthy society, including physical and mental health and gender equality, has been increasingly established [ 9 ].Menstruation-associated symptoms have recently received renewed attention, as they have been reported to not only lower the quality of life and cause serious illnesses but also incur economic losses due to decreased labor productivity [ 4 , 5 , 10 – 12 ]. Dysmenorrhea is the primary condition responsible for menstruation-associated symptoms. When symptoms such as abdominal cramps and lower back pain occurs during or around menstrual period are so severe that they interfere with daily life, the condition is medically defined as dysmenorrhea. Dysmenorrhea can be classified into primary dysmenorrhea, which is not caused by a gynecological disease, and secondary dysmenorrhea, which is caused by a gynecological disease such as endometriosis [ 7 , 8 ]. In Japan, birth rate has been declining over the past several decades. The total fertility rate declined from 3.65 in 1950 to 1.26 in 2022 in Japan [ 10 ]. Women who do not become pregnant or breastfeed experience more menstrual periods than those who do, which may be a reason for the increased incidence of endometriosis which causes dysmenorrhea [ 11 ]. In addition, the decreased prevalence of endometriosis among women who have given birth suggests that the increased number of menstrual cycles among women who have not given birth may have increased the severity of menstruation-associated symptoms over the past decades [ 13 ]. In Japan, the treatment for dysmenorrhea at medical facilities mainly involves the prescription of low-dose estrogen/progestin combination (LEP) drugs [ 14 ]. LEP has been covered by public health insurance in Japan for the treatment of dysmenorrhea and endometriosis since 2010. However, most women with menstruation-associated symptoms self-manage and few visit a physician [ 15 , 16 ]. Those who do not see a doctor have stated that they do nothing in particular or take over-the-counter (OTC) medicines to cope with their symptoms [ 17 , 18 ]. A study comparing the effectiveness of LEPs prescribed by physicians to women with that of OTC nonsteroidal anti-inflammatory drugs (NSAIDs) purchased by women on their own reported a reduction in the impact of menstruation-associated symptoms on daily life only in women who were prescribed LEPs [ 17 ]. Thus, in women with menstruation-associated symptoms, a visit to a healthcare provider may improve menstruation-related absenteeism and presenteeism. However, no studies have provided reliable statistical information on the extent to which women with menstrual symptoms visit their doctors and are prescribed LEPs. The objectives of this descriptive study are twofold: first, to compare trends in the estimated proportion of outpatients with menstrual disorders (using medical facility-based data) and the proportion of persons reporting irregular menstruation or menstrual pain (using population-based self-report data); and second, to describe changes in LEP prescription patterns and their temporal relationship with outpatient visits for menstrual disorders. By integrating multiple national datasets, we aim to provide a comprehensive overview of menstrual health trends in Japan from both clinical and population perspectives.

Trends in the rate of estimated outpatients for the subcategories, menstrual disorder and endometriosis, were examined using data from the Patient Survey ( Fig 1 ). The estimated proportion of outpatients with all injuries and diseases increased slightly during the first visit, while that for follow-up visits remained unchanged with some fluctuations ( Fig 1A , dotted line). For menstrual disorder, the estimated proportion of outpatients visiting for follow-up remained almost unchanged until 2011, whereas the estimated proportion of outpatients in the 2014 survey was approximately double that in 2011 and has continued to increase since then ( Fig 1B , dotted line). Finally, the estimated proportion of outpatients visiting for follow-up in 2023 was 32 per 100,000 females, which was 5.3 times the proportion in 1999. For endometriosis, the estimated proportion of outpatients on their first visit remained almost unchanged over all surveys, and for follow-up has continued to increase slightly since 2005 ( Fig 1C , dotted line). After adjusting for changes in the age distribution of the female population, the age-standardized trends in the estimated proportion of outpatients with menstrual disorders and endometriosis were similar to the crude trends (see solid lines in Fig 1A – C ). The increase in follow-up visits for menstrual disorders and endometriosis since 2014 remained evident after age standardization. The estimated proportion of outpatients peaked in the younger and older age groups for first-time outpatients with all injuries and diseases, with broad peaks for patients in their middle ages ( Fig 1D ). For menstrual disorders, the age distribution of the outpatients on the first visit was peaked among those in their 20s in most cases ( Fig 1E ). The age distribution of the outpatients on the first visit for endometriosis varied widely depending on the year of the survey ( Fig 1F ). Although the estimated proportion of outpatients who visited for follow-up for all injuries and diseases was higher in the older age groups ( Fig 1G ). The estimated proportion of outpatients visiting for follow-up due to menstrual disorders often peaked among those in their late 20s ( Fig 1H ). The estimated proportion of outpatients visiting for follow-up due to endometriosis was higher among those in their 40s ( Fig 1I ). Trends in the estimated proportion of outpatients with symptoms including all injuries and diseases (A), menstrual disorder (B), and endometriosis (C) among women. Trends in the age distribution of outpatients on their first visit for all injuries and diseases (D), menstrual disorder (E), and endometriosis (F) among women and on their follow-up visit for all injuries and diseases (G), menstrual disorder (H), and endometriosis (I) among women.Note: In panels A–C, solid lines represent age-adjusted rates, and dotted lines represent crude rates. In panels D–I, lines corresponding to the year 2023 are shown as bold solid lines to highlight the most recent data. According to the Comprehensive Survey of Living Conditions, the proportion of persons who reported any symptom showed a slight upward trend until 2007, after which the proportion began to decline ( Fig 2A ). The proportion of persons who reported symptoms of irregular menstruation or menstrual pain was highest in 2007, and then decreased until the 2013 survey, after which the proportion remained flat or slightly decreased ( Fig 2B ). The age distribution of persons who reported any symptoms decreased annually but indicated a higher proportion of persons in the older age groups ( Fig 2C ). A bimodal age distribution was observed among persons who reported menstrual irregularities and menstrual pain, with peaks among persons in their early 20s and late 40s ( Fig 2D ). Trends in the proportion of persons who reported any symptoms (A) and irregular menstruation or menstrual pain (B). Trends in the age distribution of persons who reported any symptoms (C) and irregular menstruation or menstrual pain (D). * The 2001 survey lacked data on the proportion of individuals who reported irregular menstruation or menstrual pain. According to the NDB Open Data, the number of LEP prescriptions increased 5-fold from 2014 to 2023 ( Fig 3A ). In 2014, NET/EE (35 μg) was the most prescribed LEP, whereas from 2015 to the present, DRSP/EE is the most prescribed. NET/EE was predominantly prescribed at low doses (LD) with an estrogen content of 35 µg from 2014 to 2018, while prescriptions at very low doses (ULD) with an estrogen content of 20 µg became more common from 2019. The prescription volume of the LNG/EE also increased when treatments for dysmenorrhea and endometriosis began to be covered by health insurance from 2019 onwards. All LEPs launched to date, regardless of the type of drug formulation, have increased in number. Regarding age distribution, LEPs were most frequently prescribed to patients in their 20s from 2014, with the most apparent increase seen in 2023 ( Fig 3B ). By 2023, the generic low-dose estrogen/progestin (LEP) formulations available in Japan included norethisterone/ethinylestradiol (NET/EE) at both low-dose (LD) and ultra-low-dose (ULD) levels, with the LD and ULD generics launched in 2015 and 2018, respectively, as well as drospirenone/ethinylestradiol (DRSP/EE), for which the generic product became available in 2022. After the introduction of these generics, prescriptions for the original brand-name products of both NET/EE (LD and ULD) and DRSP/EE were progressively replaced by their generic counterparts, resulting in a marked decline in the number of prescriptions for brand-name drugs ( Fig 3C ).The prices of both original and generic drugs have been declining over the years, with generic drugs priced at approximately half the price of the original drugs ( Fig 3D ). Trends in the number of LEP prescriptions by constituent (A). Trends in the number of prescriptions for LEPs by age distribution (B). Trends in the number of original and generic LD and ULD NET/EE drug prescriptions (C). Trends in the price of LD and ULD NET/EE and DRSP/EE drugs (D). Note: In all panels, the lines representing data from 2023 are shown as bold solid lines to emphasize the most recent trends.

In conclusion , the estimated proportion of outpatients with menstrual disorder in the Patient Survey showed a remarkable increase in follow-up visits since the 2014 survey. This increase was attributable to LEPs being covered by public health insurance for treating dysmenorrhea in 2010, the subsequent increase in LEP options, and the reduction in the economic burden of LEPs owing to the launch of generic LEP drugs. The socially perceived importance of women’s health, particularly menstruation-related health problems and menopause, is expected to increase in the coming years. This study is expected to contribute as a preliminary survey for more detailed studies in the near future and provide fundamental data for the formulation of health care policies regarding menstruation-related diseases.

This study is descriptive study for describing trend of the estimated number of patients with menstrual disorders and endometriosis, and prescription of LEPs using the Patient Survey, Comprehensive Survey of Living Conditions, and National Database (NDB) Open Data. All these surveys represent government statistics in Japan and are publicly available. Direct links to the original public datasets used in this study are provided in S1 File. The Patient Survey is conducted once every three years in Japan under the Statistics Act to clarify the actual conditions of patients who use medical facilities such as hospitals and clinics and to obtain basic data for medical administration. The subjects were patients who used the medical facility selected by random stratified sampling except for the hospitals with more than 500 bed (such hospitals are subject to an exhaustive survey) [ 19 ]. While the subjects of the survey are the patients who used the medical facilities, the responses to the survey are made by the administrators of each medical facility based on their medical records. Survey items include inpatient and outpatient statuses, treatment details, payment methods, and so on [ 20 ]. The estimated proportion of patients is defined as the estimated number of patients per day per 100,000 population and is used as an indicator of the number of patients. Patients are defined as individuals treated in hospitals, clinics, and dental clinics on the day of the survey. Data from the Patient Surveys in 1999, 2002, 2005, 2008, 2011, 2014, 2017, 2020 and 2023 were used in this study. The classification of injuries and diseases in the patient survey is based on the International Classification of Diseases (ICD-10) by the World Health Organization (WHO) [ 21 ]. The subclass menstrual disorders includes the following disorders with ICD-10 codes N91: absent, scanty, and rare menstruation (N91.0: primary amenorrhea; N91.1: secondary amenorrhea; N91.2: amenorrhea, unspecified; N91.3: primary oligomenorrhoea; N91.4: secondary oligomenorrhoea; N91.5: oligomenorrhoea, unspecified); N92: hypermenorrhea, frequent menstruation, irregular menstruation excluding postmenopausal bleeding (N95.0) (N92.0: excessive and frequent menstruation with regular cycle; N92.1: excessive and frequent menstruation with irregular cycle; N92.2: excessive menstruation at puberty; N92.3: ovulation bleeding; N92.4: excessive bleeding in the premenopausal period; N92.6: irregular menstruation, unspecified); N94: pain and other conditions associated with female genital organs and menstrual cycle (N94.0: Mittelschmerz; N94.3: premenstrual tension syndrome; N94.4: primary dysmenorrhea; N94.5: secondary dysmenorrhea; N94.6: dysmenorrhea, unspecified; N94.8: other specified conditions associated with female genital organs and menstrual cycle; N94.9: unspecified condition associated with female genital organs and menstrual cycle). The subclass endometriosis includes the following conditions with ICD-10 code N80: endometriosis (N80.0: endometriosis of uterus; N80.1: endometriosis of ovary; N80.2: endometriosis of fallopian tube; N80.3: endometriosis of pelvic peritoneum; N80.5: endometriosis of intestine; N80.8: other endometriosis; N80.9: endometriosis, unspecified). The estimated proportion of patients was extracted for the sub-categories menstrual disorders and endometriosis in the injury and disease sub-categories of the Patient Survey. The Comprehensive Survey of Living Conditions is conducted in Japan under the Statistics Act to obtain the basic data necessary for planning and administering the nation’s health, medical care, welfare, pensions, income, and other basic matters of living conditions through the Health, Labor and Welfare Administration. It is conducted annually, with a larger survey conducted once every three years. The subjects for the Health Questionnaire Survey were households and their members, selected through stratified random sampling. For the 2022 survey, for example, approximately 300,000 households were selected from a total of 54.3 million households in Japan. Of these, 205,063 households responded. Ultimately, data from 203,819 households were included in the final analysis, excluding those deemed ineligible for tabulation [ 22 ]. Health-related surveys were included as the survey items only in large-scale surveys. The health questionnaire included information on subjective symptoms, hospital visits, health consciousness, mental health, and cancer-screening status [ 22 ]. In this study, the proportion of persons who reported any symptom was used as an indicator of the number of persons with self-reported symptoms. The estimated proportion of people who reported symptoms was calculated as the number of people who reported symptoms per 1,000 population. The number of persons who reported symptoms was the number of persons in the population, excluding hospitalized persons who were aware of their illnesses or injuries. This study used data from the Comprehensive Survey of Living Conditions for 1998, 2001, 2004, 2007, 2010, 2013, 2016, 2019, and 2022. From this survey, the proportion of persons who reported symptoms of irregular menstruation or menstrual pain per 1,000 persons was extracted. Respondents selected more than one applicable symptom for this question from a list of 41 symptoms and “others.” For the 2001 survey, data on the proportion of persons who reported irregular menstruation or menstrual pain, classified according to sex and age, were not available online. NDB is an abbreviation for the National Database of Health Insurance Claims and Specific Health Checkups of Japan, a highly complete database that includes health insurance claims information and the results of specified health examinations and specific health guidance collected from health insurers in Japan. The NDB Open Data refer to a tabulation of aggregated basic information extracted from the NDB that does not contain confidential information and is maintained by the Ministry of Health, Labour and Welfare [ 23 ]. The NDB Open Data include tables outlining medical practices and their medical remuneration points, dental disease results from specific health checkups, and drug prescriptions. Data on drugs were disclosed for outpatient and inpatient oral, topical, and injectable drugs, including the top 100 drugs with the highest prescription quantities for each three-digit drug classification based on the unit of the national health insurance drug price standard listing. This study used the number of prescriptions (2014–2023) of LEPs used only in the treatment of dysmenorrhea and endometriosis under insurance coverage as an indicator. The LEPs utilized in this study included norethisterone/ethinylestradiol (NET/EE), drospirenone/ethinylestradiol (DRSP/EE), and levonorgestrel/ethinylestradiol (LNG/EE) combinations. All of these LEPs are administered orally. To account for changes in the age distribution of the female population over time, age-standardized rates were calculated for both the estimated proportion of outpatients with menstrual disorders and endometriosis (from the Patient Survey) and the proportion of persons reporting irregular menstruation or menstrual pain (from the Comprehensive Survey of Living Conditions). Age-specific rates were calculated for each 5-year age group, and the 2015 model female population in Japan was used as the standard population. The age-standardized rate for each survey year was obtained by weighting the age-specific rates by the corresponding age group proportions in the standard population and summing these weighted rates [ 24 ]. All surveys comprised government statistics publicly available on the Internet, all data were aggregated, and no personal information was included. Therefore, this study is not subject to the current ethical guidelines and did not require an ethical review.

This file contains a list of direct hyperlinks to the publicly available original datasets used for this study, including the Patient Survey, the Comprehensive Survey of Living Conditions, and the National Database (NDB) Open Data. (DOCX)