The Impact of Estrogen Deficiency Symptoms on Health-Related Quality of Life in Menopausal-Aged Women in China

1. Introduction

The adult female life is made up of three broad phases: reproductive, menopausal transition, and postmenopause [1]. According to the STRAW staging system [1], updated 10 years later as STRAW+10 [2], these three phases include a total of seven stages which are centred on the final menstrual period (Stage 0) [1, 2]. The reproductive phase is made up of early (Stage −5), peak (Stage −4), and late (Stage −3) stages and is followed by the menopausal transition phase, which consists of early (Stage −2) and late (Stage −1) stages [1]. Following Stage 0, the postmenopause phase includes early (Stage +1) and late (Stage +2) stages [1, 2]. The perimenopausal phase extends from early (Stage −2) through late (Stage −1) menopausal transition to early post menopause (Stage +1), lasting up to four years [2].

Vasomotor symptoms (VMS) such as hot flushes, sweating, sleep disturbances, irritability, anxiety, and depression [3, 4, 5] are often considered the cardinal symptoms of menopause and are “likely” and “most likely” during perimenopausal Stages −1 and + 1, respectively, according to the STRAW+10 criteria [2, 3, 6, 7, 8, 9]. The postmenopausal period is associated with genitourinary syndrome of menopause (GSM), with vaginal dryness, burning and irritation, sexual symptoms including lack of lubrication and dyspareunia and urinary issues including increased urgency, dysuria and recurrent urinary tract infections comprising the key symptoms [10]. Menopausal symptoms at all stages are a critical health issue as they can have a substantial detrimental effect on women’s physical and mental health and substantially impair health-related quality of life (HRQoL) [11, 12, 13, 14, 15, 16]. Figure 1 illustrates the effects of estrogen deficiency in the female body.

The frequency of VMS due to estrogen deficiency symptoms of menopause can vary based on ethnicity [17, 18, 19]. Women of Asian ethnicity often report fewer hot flushes and a shorter duration of VMS than those from other ethnic backgrounds, with reasons for these variations including lifestyle, genetics, body weight, and psychosocial and perceptual differences [17, 18, 20]. In China, there are currently almost 168 million women aged 45 to 59 years, highlighting the large number potentially experiencing menopausal symptoms and requiring healthcare services to alleviate their symptoms [3, 5, 8, 21, 22, 23, 24]. Furthermore, research has shown the symptom burden among Chinese women of menopausal age to be high, with hot flushes/sweating, sleep disorders, mood disorders, and fatigue reported to be prevalent [25], However, additional robust research into the prevalence and impact of menopausal symptoms or HRQoL among menopausal-aged women in China, particularly during the perimenopausal phase, is needed.

Patient-reported outcome (PRO) tools are increasingly being recognized by regulators and healthcare professionals as valuable in collecting unique, patient-centred information on the impact of health conditions and treatments [26], with PRO research using digital technology offering a promising alternative to time-consuming, resource intense paper-based research [27]. PROs are regularly used in clinical trials of menopausal women and can provide important insights into the patient journey and need for support and treatment. Popular tools include the 5-item European Quality of Life Dimension Five Level (EQ-5D-5L), the Menopause-Specific Quality of Life (MENQOL) questionnaire, a 29-item, 4-domain questionnaire assessing menopause-specific QoL, and the 11-item, 3-scale, Menopause Rating Scale (MRS), a self-administered questionnaire that measures the severity of a range of menopause-related symptoms in aging women with high reliability and validity [28, 29, 30].

2. Symptoms and health-related quality of life among pre-, peri- and post-menopausal women

Cost utility models are playing an increasingly important role in decision making in China, with health state utility values (HSUV) measured by the preferred, validated and widely used EQ-5D-5L being a key requirement [31]. With this in mind, a cross-sectional study by Rautenberg et al. measured symptoms and health-related quality of life in a cohort of menopausal-aged women in China, with the purpose of parameterising for a cost utility model to inform healthcare services in China [32]. As perimenopause has previously been associated with more somatic symptoms than other menopause stages [33], Rautenberg et al. also looked to explore utility by stage. In the cross-sectional study, around 30,000 females were invited to a survey link via SMS or WeChat, with the first 2000 females over 45 years included. Participants completed screening questions and the EQ-5D-5L, programmed in a personal digital assistant (PDA) format for smartphone. Utility tariffs were converted to EQ-5D-5L raw scores using Chinese value sets [34].

Respondents were classified as either premenopausal, perimenopausal and postmenopausal using the STRAW+10 criteria [2] and based upon a reported four-year median duration of perimenopause [4]. Premenopausal was defined as respondents with a uterus, regular menstruation and reporting last menstrual period up to the study date [December 2020]; perimenopausal was defined as respondents reporting irregular menstruation at the time of the study and up to four years prior to the study; and postmenopausal was defined as women with a uterus reporting the date of last menstrual period ≥ four years prior to the study [2, 4].

Among the 2000 included women (mean age: 49 years, 732 (37%) were premenopausal (mean age: 47 years), 798 (40%) were perimenopausal (mean age: 49 years) and 470 (23%) were postmenopausal (mean age: 53 years). A higher proportion of women reported an effect on the mobility, self-care, pain/discomfort and anxiety/depression domains of the EQ-5D-5L in the perimenopausal group compared with the premenopausal and postmenopausal groups. The proportion reporting effects was 25, 9 and 22% for mobility, 14, 3 and 14% for self-care, 60, 40 and 57% for pain/discomfort and 71%, 50% and 59% for anxiety/depression in the perimenopausal, premenopausal and postmenopausal groups, respectively. Additionally, symptomatic perimenopausal women with intact uterus had significantly lower HRQoL (health state utility value: 0.864) than symptomatic premenopausal (0.919, p < 0.05) and postmenopausal (0.877, p < 0.05) women (assessed using ANOVA with adjustment by the Tukey method). HRQoL was also significantly lower among symptomatic versus asymptomatic women within each group (premenopausal: 0.919 vs. 0.977 [p < 0.05]; perimenopausal: 0.864 vs. 0.956 [p < 0.05]; postmenopausal: 0.877 vs. 0.966 [p < 0.05]).

Overall, 83% of respondents reported experiencing menopausal symptoms. A significantly higher proportion of perimenopausal women (in the menopausal transition phase) reported symptoms (91%) compared with premenopausal (77%, p < 0.05) and postmenopausal (81%, p < 0.05) women. Nine of the 11 symptoms assessed (sleep problems, irritability, exhaustion, anxiety, hot flushes, depression, heart discomfort, loss of interest in sexual activity and vaginal dryness) were reported in significantly more women in the perimenopausal group compared with the premenopausal group. Two symptoms (joint pain and bladder problems) were reported in numerically more perimenopausal women but the differences did not reach statistical significance. Compared with the postmenopausal group, five of the 11 symptoms were reported in significantly more perimenopausal women (sleep problems, irritability, anxiety, hot flushes, depression), with no significant between-group difference in the other six symptoms (exhaustion, joint pain, heart discomfort, loss of interest in sexual activity, bladder problems and vaginal dryness).

HRQoL was significantly lower in the perimenopausal group compared with the premenopausal (with uterus) group for several symptoms of varying impact on daily life; this included sleep problems and anxiety (ranging from little or no impact to large impact), exhaustion (ranging from little or no impact to moderate impact), irritability (ranging from moderate to large impact), hot flushes, heart discomfort and loss of interest in sexual activity (moderate impact) and depression (large impact) (Table 1). HRQoL was also significantly lower for one symptom having a large impact on daily life (loss of interest in sexual activity) in the perimenopausal group compared with the postmenopausal (with uterus) group.

Overall, the study demonstrated that symptom burden is high across the menopausal stages, with perimenopausal women experiencing significantly more symptoms and having significantly lower HRQoL compared with premenopausal and postmenopausal women. One of the key strengths of the study was timely, smartphone-based electronic data collection in a large cohort that was representative of the general population in China [34, 35, 36, 37, 38, 39]. Utilizing smartphones for data collection in this study also resulted in no missing values when completing the EQ-5D-5L survey, as there was a requirement for each question to be completed before a respondent could move onto the next question. Furthermore, the EQ-5D-5L used during the study is more sensitive to changes in HRQoL than the EQ-5D-3L, which was used in a prior study by Liu et al. that measured HSUV in premenopausal (0.810) and postmenopausal (0.800) women in China but did not report HSUV for perimenopausal women [24]. The authors did highlight that many of the symptoms assessed during the study may occur independently of menopause and that due to the nature of the study, causality and relationship with hormone levels could not be assessed. Moreover, detailed socio-demographic characteristics that may have confounded outcomes were not measured. Respondents were also restricted to women with digital literacy and access to a smartphone. Despite the limitations, the findings provide important insights into the symptom and HRQoL burden among menopausal-aged women in China.

3. Untreated symptom burden remains high in post-menopausal women

Symptom burden during the postmenopausal phase remains substantial, as shown by the high proportions of postmenopausal women experiencing symptoms in the Rautenberg study [32]. Furthermore, a secondary analysis of data from the Women Health Needs Survey 2018 involving 3199 women aged 40–55 years in China found that high proportions of women suffered from insomnia (48.0%), fatigue (42.7%) and mood swing (39.8%), with 19.3% suffering from depressive symptoms [40]. Notably, postmenopause increased the risk of depressive symptoms [40]. The high symptom burden during postmenopause is also highlighted by baseline data from a pooled analysis of two phase 3, double-blind, randomized, placebo-controlled studies assessing the impact of low (E1mg/D5mg) and ultra-low (E0.5mg/D2.5mg) estradiol plus dydrogesterone versus placebo on treating vasomotor symptoms in postmenopausal women [41]. The first study was conducted in France, Poland, Romania and Russia and the second was conducted in China. Patients enrolled in the European study were randomized 2:1:2 to receive oral continuous E0.5mg/D2.5mg, E1mg/D5mg or placebo for 13 weeks. Women enrolled in the Chinese study were randomized 1:1 to receive continuous combined E0.5mg/D2.5mg or placebo once daily for 12 weeks [42]. At baseline, despite having a lower number of hot flushes, the Chinese population had similar average MRS total scores compared with the European population (Table 2). Among the 11 MRS domains, “hot flushes and sweating” was the most negatively impacted domain at baseline (as shown by the highest score), while “sleep problems”, “irritability”, “physical and mental exhaustion” and “joint and muscular discomfort” were also strongly impacted at baseline for both populations. The Chinese population presented a higher baseline score in the “sexual problems” and “dryness of vagina” domains. In the European population, the baseline “somato-vegetative” subscale was higher than in the Chinese population, while the “psychological” subscores were similar and the “urogenital” subscore was lower in the European population than in the Chinese population. These data highlight the need for effective treatment spanning all symptomatic stages of menopause.

4. Estradiol plus dydrogesterone improves symptom frequency and severity among postmenopausal women

Estrogen-based menopausal hormone therapy is the foundation of treatment for estrogen deficiency symptoms, including VMS, and has been shown to reduce symptom frequency and severity and improve HRQoL [43, 44, 45, 46]. Guidelines recommend tailoring menopausal hormone therapy to individual patients’ symptoms and circumstances using the most appropriate dose of estrogen and, in some cases, selecting the most suitable route of estrogen administration [43, 46, 47, 48, 49, 50, 51].

For non-hysterectomized women, estrogen is given in combination with progestogen in either a cyclic or continuous form [43, 47, 48]. Progestogens have different affinity to receptors including the glucocorticoid receptors, androgen receptors and mineralocorticoid receptors in addition to their affinity for the progesterone receptor [52]. Dydrogesterone, a progestogen from a natural source, has the most neutral metabolic and side-effect profile of the progestogens [40, 52].

Femoston Conti®, low-dose estradiol plus dydrogesterone (1 mg 17β-estradiol combined with 5 mg dydrogesterone [E1mg/D5mg]) was approved in Europe in 2000 for the treatment of estrogen deficiency symptoms and prevention of osteoporosis in postmenopausal women at least 12 months since last menses [53]. In 2010, an ultra-low estradiol plus dydrogesterone (Femoston-mini®; 0.5 mg 17β-estradiol continuously combined with 2.5 mg dydrogesterone [E0.5mg/D2.5mg]) was approved for the treatment of estrogen deficiency symptoms in postmenopausal women at least 12 months since last menses [53]. Femoston is the only single fixed dose menopause hormone therapy containing dydrogesterone. Dydrogesterone, like the micronized progesterone, comes from a natural source (e.g. yam and soy) [54, 55]. Its unique molecular features are obtained through a photochemical process [53], creating a bent molecular conformation, conferring a high selectivity for progesterone receptors [54, 55], with better oral bioavailability compared with oral micronized progesterone [56, 57, 58]. Dydrogesterone presents a biological progestogenic, anti-estrogenic, anti-androgenic and anti-mineralocorticoid activity with no anti-gonadotrophic, estrogenic, androgenic, or glucocorticoid actions [55]. Unlike other progestogens, dydrogesterone is non-thermogenetic, non-sedative, does not inhibit gonadotropin release or ovulation, does not influence central nervous system function and psyche, and does not antagonize various central effects of estrogens [59].

The ultra-low dose formulations have been shown in several randomized, placebo-controlled clinical studies to reduce VMS, including hot flushes and moderate-to-severe hot flushes, in postmenopausal women compared with placebo, with no safety concerns [42, 60, 61, 62]. Additionally, patient-reported improvements have been shown with ultra-low estradiol plus dydrogesterone based on improved scores on the MRS [42, 62].

The 2024 pooled analysis by Yu et al., included data from 574 women who had received either E0.5mg/D2.5mg (n = 285) or placebo (n = 289) [41]. Similar to previous studies [17, 18, 20], the mean number of hot flushes per day at baseline was higher in the European population than in the Chinese population (Figure 2). In both the European and Chinese populations, women receiving E0.5mg/D2.5mg experienced greater reductions from baseline in the mean daily number of hot flushes at Weeks 4, 8 and end of treatment compared with women who received placebo (Figure 2). The absolute mean (95% confidence interval [CI]) daily number of hot flushes, measured weekly, was lower in women treated with E0.5mg/D2.5mg compared with placebo at each time point in the Chinese population and from Week 2 onwards in the European population (Figure 2). The reduction in absolute mean daily number of hot flushes with E0.5mg/D2.5mg treatment occurred more rapidly in the European population than in the Chinese population, in which the reduction was more gradual (Figure 2). Nevertheless, by end of treatment the absolute mean number of hot flushes per day in the E0.5mg/D2.5mg treatment arms had reached a similar level in the European and Chinese populations (Figure 2).

The same pattern was evident in the daily number of moderate-to-severe hot flushes. At baseline, the mean number of moderate-to-severe hot flushes per day was higher in the European population than in the Chinese population. Women receiving E0.5mg/D2.5mg experienced greater reductions from baseline in mean number of moderate-to-severe hot flushes per day at Weeks 4, 8 and end of treatment compared with women who received placebo, both in the European and Chinese populations.

By end of treatment, European women treated with E0.5mg/D2.5mg reported significant improvement in the ‘Hot flushes, sweating’ item score versus placebo. In the Chinese population, women receiving E0.5mg/D2.5mg reported significant improvements at end of treatment in all item scores except ‘Sexual problems’ and in the three subscale scores and the total score versus placebo (Table 2).

The pooled analysis had several strengths including the placebo-controlled, double-blind, randomized nature of the included studies and the individual data analysis. However, the authors noted that it was a post hoc analysis, therefore definitive conclusions from the results require further confirmation. Despite the limitations, the data provide clinically valuable information on the benefits of E0.5mg/D2.5mg among postmenopausal women of different ethnicities, building upon the favorable impacts shown in previous studies of ultra-low-dose estradiol plus dydrogesterone in postmenopausal women [42, 60, 61, 62]. Overall, the study showed consistent improvements in VMS with ultra-low-dose estradiol plus dydrogesterone versus placebo, in both European and Chinese postmenopausal women.

5. Conclusions

Menopause symptoms are a consequence of estrogen deficiency and can have a substantial detrimental effect on Chinese women’s HRQoL, as shown by the Rautenberg et al. study which demonstrated impaired HRQoL across all phases of menopause, with perimenopausal women experiencing significantly more symptoms and significantly lower HRQoL compared with premenopausal and postmenopausal women [31]. As such, timely identification and management of menopausal symptoms in this cohort is paramount. Recognition of symptoms associated with the perimenopausal stage should be pursued to ensure timely intervention before HRQoL is substantially impaired. Global medical societies recommend estrogen treatment for the efficacious management of estrogen deficiency symptoms, with decisions about dose made on an individualized basis with no arbitrary limits placed on the duration of use [43, 50, 63]. It is reported that Asian women can be less likely than Caucasian women to use menopausal hormone therapy, in part due to a lack of awareness of the treatment and in part due to uncertainty about the risks and benefits of such a therapeutic strategy within specific ethnic groups [25, 64, 65]. The benefits shown in the Chinese population of the pooled analysis described above include improved VMS and a consistently positive impact on HRQoL. These benefits are of real clinical relevance and can be used to support patients in their decision-making surrounding the use of menopausal hormone therapy.

Acknowledgments

Editorial assistance was provided by Metamols Ltd., funded by Abbott Established Pharmaceuticals.

Conflict of interest

IS, KK, and MGC are employees of Abbott Products Operations AG, Allschwil, Switzerland and own shares in Abbott. MD works for Griffith University on projects funded by the Australian Government Department of Health and Aged Care, Queensland Health, Abbott Products Operations AG, and Illumina.

QY declares no conflicts of interest.

TS reports having received in the past three years consulting fees from Astellas, Gedeon Richter, Mitsubishi Tanabe, Sojournix, Estetra, Actavis, Abbott, Medtronic, Applied Medical, Johnson and Johnson and speaker’s honoraria from Shionogi, Gedeon Richter, Theramex, Abbott, Intuitive Surgical, and Applied Medical.