In South Korea, National Health Insurance is mandatory for most Koreans (about 51 million people) [14]. Thus, the National Health Insurance Service (NHIS) can provide medical information for most diseases (including the income decile, operation code, drugs prescribed, medical insurance type, diagnosis code, region, and hospital grades), with the exception of a few cases, such as cosmetic surgery [14]. Furthermore, the Health Insurance Corporation regularly conducts adult health checkups for public health management purposes. Therefore, data on BMI, parity, menarcheal age, menopausal age, drinking, smoking, and physical exercise for health checkup recipients are also available. This study utilized NHIS-provided national health checkup and health insurance data from 2002 to 2019.

The participants and outcomes of this study were selected using the International Classification of Diseases, 10th revision. We chose women aged over 40 years who reported menopause from 2002 to 2011. The MHT group consisted of women who were prescribed menopausal hormones for more than 6 months between 2002 and 2011. The onset date of MHT was defined as the first day of menopausal hormone prescription, and the last drug used for at least 6 months served as the reference when multiple hormones were used. To ensure a sufficient follow-up period for patients included in the final year (2011), we excluded patients from 2012 to 2019 from this study.

The non-MHT group included women who did not use menopausal hormones from 2002 to 2019. Their non-MHT status began on the date of their first health checkup, where they reported having menopause.

Excluded cases included: 1) women reporting menopause in 2002 for washout. 2) Hysterectomy before the 180th days after participation. And 3) women with POP (N81) or any cancer before the 180th days after participation.

POP was defined as three or more visits to a medical institution with a POP diagnosis code (N81) for the first or second diagnosis. We tracked these results through December 31, 2019.

Menopausal hormones were classified into the following groups: tibolone; combined estrogen plus progestin by the manufacturer (CEPM; estradiol valerate [EV]/medroxyprogesterone acetate [MPA], estradiol hemihydrate [EH]/1 mg norethisterone acetate [NA], EH/drospirenone, EH/dydrogesterone, EV/cyproterone acetate, EH/NA, EV/NA); other oral MHT (estrogen [conjugated estrogen, EV, EH] plus progestogen [micronized progesterone, MPA, dydrogesterone]); and transdermal estrogen (except vaginal estrogen). Based on the inclusion date, the independent variables included age, Charlson comorbidity index (CCI), socioeconomic status (SES), BMI, region, parity, menarcheal age, menopausal age, physical exercise, alcohol consumption, smoking, and the period from menopause to inclusion. The CCI was computed using the diagnosis code obtained from medical institution visits 1 year prior to the start of the study. When medical aid health insurance was utilized, the SES was considered low. Age was stratified into 10-year intervals, and BMI categorization adhered to the standards outlined by the Asia-Pacific perspective [15]. If the medical institution was not located in a metropolitan area, the region was considered rural. Parity incorporated non-responses by combining them into the “0 or no response” category, along with “1”, “2”, and “over 3” levels. Smoking history was defined as “never”, “past”, or “current” while alcohol consumption was quantified by the weekly number of drinks. Physical exercise was considered for sessions lasting at least 30 minutes per week, categorized by their frequency.

SAS Enterprise Guide 6.1 (SAS Institute Inc., Cary, NC, USA) was used for all statistical analyses. Statistical significance was achieved when the P-value was less than 0.01. All statistical analyses were performed using two-sided tests. Continuous variables are expressed as median values (interquartile range) and categorical variables are defined as numbers (percentages). The study’s start date was defined as the date of the first MHT prescription or national health checkup, and follow-up was determined as the earliest of death, December 31, 2019, or the date of the last health insurance data record. The Cox proportional hazards model was used to adjust for confounding factors. For the sensitivity test to confirm the robustness of this study, women who received a prescription from a gynecologist were compared with the non-MHT group. Additionally, the pairwise deletion method was used to treat missing values in this study.

Unlike other hormones, tibolone contains synthetic steroids with an androgenic reaction, which may have a different mechanism from that of CEPM [5]. Androgen receptor expression levels were fourfold higher in POP women than in non-POP women [16]. However, it is not yet known whether the androgenic effects of tibolone affect POP. Only one Finnish study investigated whether tibolone influences the occurrence of POP. That study showed that tibolone reduced the POP risk, similar to the present study’s findings [13]. However, while the Finnish study included only 155 women in the tibolone group, the number of women in the present study was much higher at 184,878. The reduced incidence of POP in the CEPM and tibolone groups may be related to the effects of estrogen and progesterone. Further research is required to determine the androgenic effects of tibolone on POP.

In this study, transdermal estrogen levels were not associated with POP risk. These findings align with those of a previous Austrian study of 103 women, which found no beneficial effect of transdermal estrogen therapy on POP symptoms [17]. However, there have been no large-scale studies on the effects of transdermal estrogen on pelvic floor diseases. Although vaginal transdermal estrogen is not used to relieve vasomotor symptoms, it is frequently used to reduce complications associated with pelvic organ prolapse (e.g., vaginal discharge and vaginal erosion caused by pessaries), and further research in this area is needed [18].

The significant risk factors for POP include parity, vaginal delivery, old age, and high BMI [19,20]. This study showed a high POP occurrence in all women over 50 years of age. Those with a BMI <18.5 had a lower risk of POP, and those with a BMI of 23-29.9 had a higher risk. However, the risk was not significant for those with a BMI >30. This result is consistent with those of previous studies [20-23]. However, the present study showed different results from those of previous studies, in which a parity of 0 did not increase POP risk. The present study also showed a higher POP risk in the parity 0 or no-response group [20,24,25]. This result may be due to the combination of no response and a parity of 0.

Furthermore, in rural areas, individuals who were current smokers, consumed alcohol one-six times weekly, and engaged in physical exercise one-four times a week had a lower risk of POP. No significant associations were observed between daily alcohol intake or physical activity level and risk of POP in this analysis. Previous studies have suggested a reduced occurrence of POP with PFM training, which may partially explain the lower risk of POP associated with exercise, but the exact causal relationship requires further research on the type of exercise [11,26-29]. However, the relationship between POP risk, smoking, and drinking remains unclear, as previous studies have shown inconsistent results [19,30,31]. Additionally, the exact mechanisms through which female sex hormones and MHT impact POP are not well understood. Further research is needed to explore these relationships and determine optimal MHT regimens.

This study had several strengths. The study was a large-scale population study with approximately 800,000 participants, which is comparable to previous observational studies conducted in Asia. The MHT group was subdivided into different subgroups, allowing for a detailed analysis of the correlation between MHT and POP. Factors influencing POP occurrence were considered, including age, BMI, CCI, SES, parity, menarcheal age, menopausal age, time from menopause to inclusion, alcohol consumption, smoking, and physical exercise. The age range was also controlled to reduce the effect of age, a significant risk factor for POP. Furthermore, the study included multiple types of CEMP drugs. However, this study had some limitations. First, it was not possible to determine the most effective drug for preventing POP owing to unknown usage details in the CEPM group. Further research is needed in this area for clinical practice. Second, the inclusion of only women diagnosed with POP in medical institutions by diagnosis codes for prolapse without pelvic examination or questionnaire may have missed women who had symptoms but did not seek medical attention or did not mention prolapse, and the study did not consider the tendency to visit medical institutions. However, the study included many women diagnosed with POP (21,059). Third, the variables in this study were identified based on the study’s start date. For example, BMI was only measured at the start of the study. Therefore, even if there was a significant change in BMI after the start of the study, it could not be reflected in the outcome. This study has a limitation in that it cannot correct changes over time.

In conclusion, MHT using tibolone and CEPM were associated with a reduced risk of POP compared to non-MHT treatment after menopause. Other types of oral MHT and transdermal estrogen levels were not associated with the risk of POP.