Therapeutic selection for abnormal uterine bleeding with ovulatory dysfunction: a cross-sectional study in Chinese women

The uterus is the most important reproductive organ for females. It has two key functions that occur during different reproductive phases. It carries embryos and the fetus during pregnancy and sheds menstrual blood during the nonpregnancy period. Abnormal uterine bleeding (AUB) is one of the most common gynecologic conditions experienced by women of reproductive age [ 1 , 2 ]. According to the International Federation of Gynecology and Obstetrics (FIGO), AUB is a broad term that describes irregularities in the menstrual cycle involving frequency, regularity, duration, and volume of flow outside of pregnancy [ 3 , 4 ]. AUB leads to various complications, such as anemia and neurasthenia, which greatly affect the health and quality of life of patients and significantly increase the social and economic burden [ 5–7 ]. Studies have shown that structural causes such as endometrial polyps, adenomyosis, uterine leiomyoma, and endometrial malignancy, as well as nonstructural causes such as systemic coagulation disorders, ovulatory dysfunction, endometrial abnormalities, and iatrogenic factors, are major risk factors for AUB [ 8–11 ]. Ovulatory dysfunction is the most common reason for AUB and accounts for approximately 50% of all AUB patients [ 12 ]. In this study, 3527 abnormal uterine bleeding with ovulatory dysfunction (AUB-O) patients were investigated and analyzed by means of questionnaires related to the choice of treatment. The influencing factors of therapeutic choice have also been studied to provide scientific evidence for medical services and therapeutic drug development.

Here, a cross-sectional study of the questionnaires of 3556 AUB-O patients was conducted by “AUB Cloud Classroom Case Live Broadcast”. Among them, 2332 questionnaires were collected in 2021, and the other 1224 were collected in 2022. The subjects of the study were outpatients of 1874 gynecologists from 803 hospitals in 30 provinces across China except Hong Kong, Macao, Taiwan, and Tibet. All study subjects were AUB-O patients diagnosed by local doctors, and the diagnostic criteria were based on the Chinese AUB-O treatment guidelines [ 10 , 13 ], which is in accord with standards of FIGO. All the participating patients of AUB-O completed the survey form by themselves. Demographic information, such as age, educational level, and occupational status, was collected. Additionally, information related to AUB therapeutic options, including parity, disorders related to menstruation, therapeutic choice of solving problems, choice of departments, and drug preferences was obtained. All the participants were divided into three groups according to age and reproductive endocrine characteristics: the juvenile group (puberty: 14–18 years old), the reproductive group (reproductive age: 19–39 years old) and the senior group (perimenopausal period: 40–55 years old). The patient demographics were characterized. The mean and variance reported for continuous variables, the number and proportion reported for categorical variables. Univariate analyses were performed using chi-square tests to assess the impact of age, disorders related to menstruation, educational level, and occupational composition, respectively, on patients’ treatment choices. The multiple-choice questions were analyzed by statistical description. The primary statistical analysis was undertaken by the third-party Shanghai Bozheng Consulting Company, which was independent, and the research team conducted a review of the analytical protocols and codes to ensure reproducibility. Statistical analysis and visualization of the data were performed using Stata (Stata Corp LP, College Station, TX, USA) and GraphPad Prism 9.0 software (GraphPad Software, CA, USA).

A total of 3556 questionnaires were collected in this study, and 3527 AUB-O patients with complete data were used as the analysis sets. The survey qualification rate of all participants was 99.2%. Most subjects belonged to the reproductive group (2962 cases), accounting for 84.0% of all patients. Other patients were in the juvenile and senior groups, which were 84 cases (2.4%) and 481 cases (13.6%), respectively. A total of 2045 patients had a bachelor’s degree or above, accounting for 58.0% of all patients. A total of 80.3% of patients had stable full-time employment, and 60.9% had previously given birth ( Table 1 ). Demographic characteristics of AUB-O patients [n, (%)]. Irregular menstruation (37.6–46.3%), dysmenorrhea (29.9–44.4%), and heavy menstrual bleeding (16.7–32.2%) were the main symptoms of AUB-O patients ( Figure 1(A) ). Additionally, the symptoms of heavy menstrual bleeding became more severe with age, while dysmenorrhea and period-related acne were worst in the juvenile group, though the incidence decreased with age. The incidence of fatigue was similar in all age groups, at approximately 25%. Other symptoms, such as “hair loss”, “excessive body hair” and “weight gain”, are not shown in the figure due to their low incidence rates. Distribution of AUB-O patients according to (A) the symptoms during menstruation, (B) the different approaches to seeking help, (C) the department selection in the hospital, and (D) the therapeutic choice. The methods of AUB-O patients in different age groups seeking help for menstrual problems were generally similar ( Figure 1(B) ). More than 80% of patients went to the hospital for treatment or the pharmacy to buy medicine. Patients in the juvenile group (29.6% and 16.7%) and reproductive group (25.1% and 18.9%) were more likely to search for information or consultation online to obtain solutions than those in the senior group (16.8% and 13.9%). The proportion of patients in the different age groups who relied on consulting relatives or friends to solve problems was almost the same. According to the statistical results, more than 80% of patients chose to visit the Department of General Gynecology when they went to the hospital ( Figure 1(C) ). The proportion of patients who chose the Department of Gynecological Endocrinology was approximately 45% and was roughly equivalent among all age groups. The proportion of patients in the juvenile group (31.5%) who chose to visit the Department of Traditional Chinese Medicine (TCM) was slightly higher than that of the patients in the reproductive group (17.9%) and senior group (16.2%). In addition, the selection ratios of the Department of Endocrinology, Department of Infertility and other departments were relatively consistent among all age groups. The percentage of curettage therapy use increased with age (3.7% in the juvenile group, 11.9% in the reproductive group, and 28.1% in the senior group) ( Figure 1(D) ). Combined oral contraceptives (COCs), progestins and traditional Chinese medicine/Proprietary Chinese Medicine (PCM), and others were preferred over curettage therapy among AUB-O patients. Among the drugs, COCs, especially the new type contraceptives (drospirenone and ethinylestradiol tablets, Yasmin I/Yasmin II), accounted for a considerable proportion (37% in the juvenile group, 52.2% in the reproductive group, and 36.6% in the senior group). Interestingly, although the proportion of patients visiting the Department of TCM decreased with age, the proportion of patients with TCM/PCM treatment remained high in the reproductive and senior groups (34.6% and 34.7%, respectively). In the survey of patients’ willingness to try COCs, most patients (92.5%) expressed their willingness to try COCs (χ 2 =31.89 p < 0.0001) ( Table 2 ), but 7.5% of patients refused to try COCs. A series of concerns such as safety, hormone-level fluctuation, weight gain, fertility impacts and cancers, led to refusal ( Figure 2 ). Reasons why AUB-O patients refused to try COCs. Willingness to try COCs in AUB-O patients [n, (%)]. There were 1278 AUB-O patients who chose progestins or COCs in this study. The therapeutic selections of three kinds of patients, including irregular menstruation only, heavy menstrual bleeding only and irregular menstruation with heavy menstrual bleeding, were analyzed. The reproductive group (19–39 years old) showed a statistical preference for COCs (χ 2 =14.87, P = 0.0006). Due to the limited sample size, patients in the juvenile group (14–18 years old) had little difference in the choice between the two drugs (χ 2 =0.8816, P = 0.6435). Patients in the senior group (40–55 years old) also showed a significant tendency to select COCs (χ 2 =6.188, P = 0.0453) ( Table 3 ). Distribution of drug selection in AUB-O patients with different symptoms in different age groups [n (%)]. a IM: irregular menstruation; b HMB: heavy menstrual bleeding. Among all subjects, 1032 patients had irregular menstruation, 641 patients had heavy menstrual bleeding, 158 patients had irregular menstruation with acne, and 398 patients had irregular menstruation with dysmenorrhea. The therapeutic options of patients with different symptoms were analyzed and compared. The ways to seek help for menstrual problems were generally similar for patients with different symptoms ( Figure 3(A) ). Most patients chose to go to the hospital for treatment, and a considerable proportion of patients chose to go to the pharmacy to buy medicine. The proportion of patients who sought help on the internet was age-related. A relatively higher proportion of patients in the juvenile group chose to search for information online or consult a doctor on the internet. Consultations with relatives and friends were similar across the age groups. Distribution of AUB-O patients with different symptoms according to (A) the different approaches to seek help, (B) the department selection in the hospital, and (C) the therapeutic choices. HMB: heavy menstrual bleeding; IM: irregular menstruation. Most patients chose to visit the Department of General Gynecology, followed by going to the Department of Gynecology Endocrinology. The proportion of patients in the juvenile group who visited the Department of Traditional Chinese Medicine was significantly higher among the patients with heavy menstrual bleeding. The patients in the reproductive group were in the best reproductive period, and most of them may also have had infertility problems. Compared with that in the other two groups of patients, the proportion of patients in the reproductive group who chose the Department of Infertility was significantly higher ( Figure 3(B) ). Among all kinds of treatments, the choice of surgical treatment was related to age. Only a few patients in the juvenile group received curettage. Among all medications, COCs, especially Yasmin I and Yasmin II, were the first choice for most patients. Progestins and TCM/PCM were also alternative treatments for patients ( Figure 3(C) ). COCs could almost alleviate bleeding within 3 days and effectively regulate menstruation. It could also relieve dysmenorrhea and reduce acne. These effects met the treatment expectations of most patients. Subjects in different age groups and with different symptoms showed a good willingness to try COCs ( Table 4 ). Willingness to try COCs in patients with different symptoms [n (%)]. a HMB: heavy menstrual bleeding; b IM: irregular menstruation. Reproductive age is the period when ovarian reproductive function and endocrine function are most prosperous. The prevalence of AUB-O was frequent during this period. We analyzed and compared the factors that might influence the decision to choose progestins or COCs in the 14–39-year-old subjects. The results showed that neither educational level (χ 2 =3.687, P = 0.5953) nor occupational composition (χ 2 =6.338, P = 0.1753) had an effect on the selection. This indicated that the use of COCs was not affected by these three factors and was widely accepted among patients ( Table 5 ). Factors influencing the selection on progestins or COCs in the 14–39 years old AUB-O patients [n, (%)].

AUB is a severe and common disease or symptom affecting the woman’s quality of life in clinical practice, and ovulatory dysfunction is the primary cause of AUB [ 14 ]. According to the analysis of the demographic characteristics of the subjects, the numbers of patients in the adolescent and perimenopausal groups were far lower than that in the reproductive group. Possible reasons for this phenomenon may be related to the neglect or endurance of patients or their parents. However, theoretically, there should be a higher rate of ovulatory dysfunctional problems at these unstable ages because the hypothalamus-pituitary-ovary axis is either not fully developed or functionally degraded [ 15–17 ]. This result indicates that extensive and comprehensive education of AUB-O patients is necessary to improve their awareness and correct their conception in the adolescent and perimenopausal group. Patients should be aware that AUB-O is not an inevitable process and does not need to be endured. AUB-O can be treated by active intervention and to avoid or reduce unpleasant effects. When patients went to the hospital for treatment, the Department of General Gynecology was the first choice of most patients, followed by Department of Gynecological Endocrinology. This suggested that knowledge of gynaecological endocrinology should be strengthened to diagnose and treat AUB-O for general gynecologists. AUB-O is not only a disease affecting women’s health but also a crucial manifestation of infertility, closely related to anovulation, oligo-ovulation, and luteal phase insufficiency [ 18–20 ]. Therefore, it is necessary for reproductive patients to visit the Department of Infertility or Department of Gynaecological Endocrinology to receive reproductive-related assessments and treatments. In the management of patients with AUB-O, progestins demonstrate the ability to replicate the hormonal environment of the luteal phase. They transform the endometrium into the secretory phase and facilitate its normal shedding, making them a suitable choice for treating AUB-O resulting from progesterone insufficiency. [ 21 , 22 ] High-efficiency synthetic progesterone exhibits potent efficacy in transforming the endometrium, making them suitable for elderly patients with hemoglobin levels below 90 g/L. Progesterone injections (20 mg/day), also known as medical curettage, promote rapid and synchronous shedding of the endometrium to achieve hemostasis. Gonadotropin-releasing hormone agonist (GnRH-a) represents a non-conventional treatment option, reserved solely for cases of refractory AUB-O. Hemostatic agents, iron supplements, and blood transfusions are utilized exclusively for the management of acute bleeding in AUB-O. The levonorgestrel releasing intrauterine system (LNG-IUS) is indicated for patients with no fertility requirements or those in the perimenopausal transition phase [ 13 ]. Our survey showed that most of the patients who received curettage were elderly patients, related to the higher prevalence of structural diseases in this senior group. It should be noted that pathological assessment to exclude structural diseases through curettage is important, but there must be clear indications [ 23 , 24 ]. The indications included age greater than or equal to 45 years old, long-term irregular uterine bleeding, high-risk factors for endometrial cancer (high blood pressure, obesity, diabetes, family history of Lynch syndrome, etc.), excessive endometrial thickening and uneven echo, and insignificant drug treatment effect. Repeated curettage without clear indications in the short term should be avoided. COCs are primarily composed of progesterone and estrogen [ 25 , 26 ]. The estrogen component in COCs aids in the repair of the endometrium, suppressing abnormal endometrial hyperplasia, alleviating abnormal uterine bleeding, and restoring menstrual regularity [ 27 ]. Furthermore, they effectively regulate menstruation, alleviate dysmenorrhea, and reduce acne. Hence, COCs can fulfill the therapeutic aspirations of a majority of patients. This survey demonstrated that most AUB-O patients were willing to try COC treatment, indicating that COCs had been widely accepted by patients and possessed promising development values. Yasmin I and Yasmin II were COCs composed of a new type of progesterone drospirenone (3 mg) and low-dose ethinyl-oestradiol (20 μg or 30 μg). The progesterone in the previous COCs was derived from testosterone, which has certain androgen activity [ 28 , 29 ]. Drospirone, a spironolactone derivative, possesses anti-mineralocorticoid and anti-androgen activity and is closer to natural progesterone [ 30–32 ]. Thus, Yasmin I and Yasmin II have become the first choice of COC treatment in AUB-O in patients without contraindications for COCs [ 33 , 34 ]. Although COC treatment has additional benefits in menorrhagia, irregular menstruation and dysmenorrhea, doctors should fully consider the contraindications in elderly patients to ensure their safety when prescribing COCs. The contraindications include cardiovascular disease, thrombogenic conditions, hyperkalaemia, hormonally sensitive malignancies, hepatic disease, diabetes and migraines [ 35 ]. According to the results of this study, there was still a high proportion of COC treatment in the senior groups. The usage of a large dosage of COC for haemostasis in the perimenopausal period should be noted, by discouraging and strictly limiting the scope. For example, if there is no contraindication, 1 tablet/d could be prescribed, while the use of 2–3 tablets/d to stop bleeding is not encouraged. Some patients expressed concerns about COCs in the survey. Further analysis found that the main concerns were focused on drug safety, fertility impacts, weight gain, hormone levels, and cancers [ 36 ]. The patients’ fears of gaining weight and hormones might stem mainly from an intuitive feeling after using glucocorticoid medications. These misunderstandings of hormone medications and COCs could be well addressed by comprehensive and objective introductions of related popular science. In the future, the research and development of COCs should be further strengthened, and the safety in terms of fertility, weight gain, and hormone levels should be clarified. Furthermore, detailed publicity and education of clinical COC treatment should be emphasized. While our study offers valuable insights into the correlations between demographic factors and therapeutic choices for AUB-O, it is crucial to acknowledge its limitations. The diagnostic accuracy of AUB-O relied on the expertise of the local doctors, and the self-reported questionnaire could potentially introduce recall bias and misclassification into the dataset, thereby impacting the reliability of our findings. To mitigate these issues, stringent criteria for patient inclusion were implemented in the study, adhering to the Chinese AUB-O treatment guidelines that are aligned with the international standards set by the FIGO. This approach aimed to ensure consistency in diagnosis among different physicians to the greatest extent possible. Furthermore, our study only explored a series of selected therapeutic options, without delving into other influencing factors such as cultural nuances, and it was confined to settings with similar healthcare systems. Additionally, the cross-sectional design of the study inherently limits the ability to infer causal relationships among the investigated variables. Data collection was conducted at a single time point, enabling only the observation of associations between demographic factors and treatment choice variables, without definitive determination of causality. To address these limitations, future research considerations include adopting a longitudinal design to follow subjects over an extended period, under varying conditions of therapeutic regimens, social backgrounds, and healthcare systems, in order to gain a more comprehensive understanding of therapeutic selection for AUB-O patients.

In conclusion, irregular menstruation, dysmenorrhea, and heavy menstrual bleeding were the main symptoms of AUB-O and significantly affected the patients’ quality of life. In view of the therapeutic choices of AUB-O patients in Chinese women, it is important to strengthen the endocrine diagnosis ability of doctors in Department of General Gynecology. AUB-O patients had positive treatment intentions, and most of them were willing to choose COCs as a therapeutic option. Strengthening the in-depth publicity of COCs could promote further drug development and clinical application.