Prevalence of metabolic syndrome and its components in Chinese women with premature ovarian insufficiency

Abstract

Objectives

To assess the prevalence of metabolic syndrome (MetS) and its components in Chinese women with premature ovarian insufficiency (POI) and to explore the metabolic profile of Chinese women with POI.

Methods

118 POI women aged 20-38 years and 151 age-and-BMI-matched control women were recruited. Measurements included body height, weight, waist circumference (WC), hip circumference (HC), blood pressure, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG) and fasting insulin (FINS). Prevalence and components of MetS and metabolic indices were compared between the two groups.

Results

The prevalence of MetS in POI women and age-and-BMI-matched control women was 16.9% and 11.3%, respectively, which was not significantly different (p > .05). The prevalence of hypertriglyceridemia and high fasting glucose was significantly higher in POI than control (17.8% vs. 9.3%, p = .039; 16.9% vs. 6.6%, p = .008), without significant differences in the prevalence of other components of MetS (p > .05). The levels of TG, FINS, and HOMA-IR in POI were significantly higher than in control (p < .05) but without significant differences in WC, WHR, SBP, DBP, TC, HDL-C, LDL-C, and FPG (p > .05). HOMA-IR was positively correlated with WC, DBP, TG, and FPG and negatively correlated with HDL-C in both POI women and control (p < .05).

Conclusions

POI women presented with more unfavorable cardiovascular risk factors (higher prevalence of hypertriglyceridemia and high fasting glucose; higher TG, FINS, and HOMA-IR). So, women diagnosed with POI should always be covered with special care of metabolic profile.

Keywords:

• Premature ovarian insufficiency (POI)
• metabolic syndrome (MetS)
• metabolic profile
• insulin resistance

Introduction

Metabolic syndrome (MetS) lacks a universal definition, with different societies and workgroups publishing their definitions based on symptoms and laboratory parameters. Due to the difficulties in establishing a clear definition and exact pathogenesis, the Joint Interim Statement (2009) approved a consensus definition that includes central obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-C), hypertension, elevated fasting glucose or diabetes mellitus, respectively [1]. In our study, for the definition of MetS, at least three of these five components must be present, and thresholds are population- and country-specific, described in the ‘Methods’.

Premature ovarian insufficiency (POI) is defined as the loss of normal ovarian function before the age of 40, which affects approximately 1% of women under 40 years old and 0.1% of women under 30 years old [2]. POI is characterized by elevated levels of gonadotrophins and decreased levels of estradiol. It has been postulated that the loss of ovarian function and subsequent deficiency of endogenous estrogens in women with POI may contribute to a higher risk of cardiovascular diseases (CVD), which is the leading cause of death in women worldwide [3]. POI patients present several risk factors for developing CVD: endothelial dysfunction, abnormal lipid profile, insulin resistance, and insulin action disturbances. Therefore, patients present a higher risk of developing MetS [4], an endocrinopathy with increased mortality risk.

MetS is mainly associated with individual components, including central obesity, insulin resistance, dyslipidemia, and hypertension, and it is associated with an increased risk of CVD and type 2 diabetes mellitus (T2DM) [5]. It is reported that menopause nearly adversely affects all components of MetS [6]. We performed a previous study that showed that the prevalence of MetS in Chinese postmenopausal women was 33.7%, which is higher than that in women of reproductive age (23.3%) [7]. Other studies showed that specific metabolic parameters appeared to correlate with POI, and these correlations persisted after correction for BMI and age, but the results were controversial [4].

Although there are a few studies about MetS and POI in Western countries, studies on the prevalence of MetS in Chinese women with POI are scarce. Therefore, this study was designed to examine the prevalence of MetS and its components in Chinese women with POI and to compare the metabolic indices between POI women and age-and-BMI-matched controls. We aimed to explore the metabolic profile of Chinese women with POI and provide some advice for clinical work.

Methods

Study population

From October 2020 to June 2022, 118 POI women aged 20–38 years (mean age 31.08 ± 3.99 years) were recruited by the Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. POI women in this study were diagnosed with POI for the first time at the time of the enrollment. Recruitment of 151 women who underwent health examinations with regular menstrual cycles but without hormonal contraception as the control group took place at the same time, aged 20–38 years (mean age 31.17 ± 3.83 years). All the participants were Chinese Han population.

Ethics approval

This study was approved by the Human Ethics Committee of Beijing Obstetrics & Gynecology Hospital, Capital Medical University (2020-KY-051-01). All study participants were provided with written informed consent prior to participation.

Inclusion and exclusion criteria

For the definition of POI, we used the criteria published by the European Society of Human Reproduction and Embryology (ESHRE) (2016) [8], which includes the presence of oligo/amenorrhea for at least four months in women below the age of 40, and with an increased follicle-stimulating hormone (FSH) serum concentration of > 25 IU/L detected on at least two separate occasions > 4 weeks apart.

Inclusion for the control group included: age-matched women with regular menstrual cycles. Exclusion criteria for POI women included: abnormal karyotype; iatrogenic POI (POI caused by oophorectomy, radiotherapy, or chemotherapy); having a history of hormone replacement therapy (HRT) use or hormonal contraception within three months before recruitment. Exclusion criteria for both POI women and the control group included: pregnancy, tumors, taking drugs (e.g. diuretics) that could influence blood lipids, blood pressure, and/or blood glucose (except medication for diabetes, dyslipidemia, or hypertension); having diseases of the thyroid gland or adrenal gland; or drinking and smoking.

General characteristics

Body weight, body height, waist circumference (WC), and hip circumference were measured, with the participants wearing light clothes and no shoes. Body mass index (BMI) and waist–hip ratio (WHR) were calculated. Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured after resting for at least 20 min in a sitting position.

Laboratory evaluation

After an 8–12 h overnight fasting, blood samples were collected from each via venipuncture. Serum was separated by a centrifuge and then stored at −20 °C until analysis. Reproductive hormones, including FSH, luteinizing hormone (LH) and estradiol (E2), and fasting insulin (FINS), were measured with Siemens ADVIA Centaur XP. Triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and fasting plasma glucose (FPG) were examined with Abbott Architect ci16200 by Clinical Laboratory at Beijing Obstetrics and Gynecology Hospital. Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated as follows: [fasting insulin (mIU/L) × fasting glucose (mmol/L)/22.5].

The diagnostic criteria of MetS

A Joint Interim Statement approves a consensus definition [1] by which any patient can be diagnosed with MetS when any three of the following criteria are present: ① Elevated WC, whose thresholds depend on population- and country-specific definitions (≥ 80 cm for Chinese women); ② Elevated TG level: greater than 150 mg/dL (1.7 mmol/L; or drug treatment for elevated triglycerides); ③ Reduced HDL-C level: less than 50 mg/dL (1.3 mmol/L; or drug treatment for reduced HDL-C); ④ Elevated blood pressure: SBP 130 mmHg or higher and DBP 85 mmHg or higher (or antihypertensive drug treatment in a patient with a history of hypertension); ⑤ Elevated FPG level: 100 mg/dL or greater (5.6 mmol/L; or anti-diabetic drug treatment in patients with a history of diabetes).

Statistical analysis

All Normal distribution data were expressed as mean ± standard deviation (SD), and Non-normal distribution data were expressed as Median (25 Percentile, 75 Percentile) (M (P25, P75)). Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS for Windows, version 26.0). The unpaired T-test was applied to compare the Normal distribution data of the two groups, and the Mann-Whitney U test was used to compare the Non-normal distribution data of the two groups. The chi-square test was applied to compare the prevalence of metabolic syndrome and its components between POI women and the control group. Spearman correlation was applied for the correlation analysis between the components of MetS and HOMA-IR in both POI women and the control group. The level of significance was set as p < .05.

Results

The levels of TG and FINS in POI patients were significantly higher than in the control group (p < .05), but there were no significant differences in age, BMI, WC, WHR, SBP, DBP, TC, HDL-C, LDL-C, and FPG between the two groups (p > .05). HOMA-IR in POI patients was significantly higher than in the control group (p < .05) (Table 1).

Table 1. The baseline of indices and comparison between POI women and the control group (Mean ± SD or M (P25, P75)).

	POI group (n = 118)	Control group (n = 151)	T or Z	p
Age, years	31.08 ± 3.99	31.17 ± 3.83	−0.182	.855
BMI, kg/m^2	22.85 ± 3.09	22.16 ± 3.10	1.817	.070
WC, cm	79.44 ± 9.40	77.73 ± 9.04	1.519	.130
WHR	0.816 ± 0.053	0.824 ± 0.052	−1.340	.181
SBP, mmHg	115.72 ± 13.19	114.57 ± 11.07	0.778	.437
DBP, mmHg	74.94 ± 9.00	74.28 ± 8.30	0.620	.536
TG, mmol/L	1.28 ± 1.03	1.01 ± 0.78	2.465	.014
TC, mmol/L	4.77 ± 0.73	4.68 ± 0.79	0.973	.331
HDL-C, mmol/L	1.58 ± 0.51	1.59 ± 0.37	−0.258	.796
LDL-C, mmol/L	2.56 ± 0.62	2.58 ± 0.71	−0.246	.806
FPG, mmol/L	5.13 ± 0.72	5.05 ± 0.49	1.079	.281
FINS, pmol/L	14.58 ± 9.65	10.88 ± 6.10	3.837	<.001
HOMA-IR	2.53 (1.65, 4.79)	2.22 (1.44, 3.14)	−2.633	.008

BMI, body mass index; WC, waist circumference; WHR, waist-hip ratio; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglycerides; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; FPG, fasting plasma glucose; FINS, fasting insulin; HOMA-IR, homeostasis model assessment for insulin resistance.

According to the definition above, 20 MetS out of 118 POI women and 17 MetS out of 151 control women could be identified, i.e. the prevalence of MetS in our POI women and the control group was 16.9% and 11.3%, respectively. However, the two groups had no significant difference in prevalence (p > .05).

The prevalence of hypertriglyceridemia and high fasting glucose was significantly higher in POI women than in the control group (17.8% vs. 9.3%, p = .039; 16.9% vs.6.6%, p = .008), while there were no significant differences in the prevalence of central obesity, low HDL-C, and hypertension between the two groups (p > .05) (Table 2).

Table 2. Comparison of prevalence of MetS and its components between POI women and the control group (n, %).

	POI group (n = 118)	Control group (n = 151)	χ2	p
MetS	20 (16.9)	17 (11.3)	1.808	.179
WC ≥ 80 cm	47 (39.8)	54 (35.8)	0.468	.494
TG > 1.7 mmol/L	21 (17.8)	14 (9.3)	4.253	.039
HDL-C < 1.3 mmol/L	28 (23.7)	26 (17.2)	1.750	.186
SBP ≥ 130 mmHg or DBP ≥ 85 mmHg	23 (19.5)	22 (14.6)	1.152	.283
FPG ≥ 5.6 mmol/L	20 (16.9)	10 (6.6)	7.129	.008

MetS: metabolic syndrome; WC: waist circumference; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure; FPG: fasting plasma glucose.

HOMA-IR had a positive correlation with WC, DBP, TG, and FPG, and had a negative correlation with HDL-C in both POI women and the control group. HOMA-IR positively correlated with SBP in the control group, while it did not correlate with SBP in POI women (Table 3).

Table 3. Correlation between HOMA-IR and the components of MetS in POI women and control group.

	POI group (n = 118)	Control group (n = 151)
WC, cm	0.449**	0.419**
SBP, mmHg	0.171	0.228**
DBP, mmHg	0.196*	0.262**
TG, mmol/L	0.191*	0.423**
HDL-C, mmol/L	−0.349**	−0.264**
FPG, mmol/L	0.426**	0.530**

*p < .05, **p < .01.

WC, waist circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; FPG, fasting plasma glucose.

Discussion

Prevalence of MetS and its components in Chinese women with POI

The menopausal transition is associated with increased fat mass (predominantly in the truncal region), insulin resistance, dyslipidemia, and endothelial dysfunction [9]. Some previous studies have shown that MetS prevalence in postmenopausal women was significantly higher than that of premenopausal women [10]. By definition, women diagnosed with POI experience menopause before 40 years of age, which is associated with an increased risk of MetS, CVD, osteoporosis, and neurological disorders such as dementia and Parkinson’s disease, reducing the quality and quantity of life [11–14]. MetS forms a cluster of metabolic dysregulations, including insulin resistance, atherogenic dyslipidemia, central obesity, and hypertension [15]. Because of autonomic and endothelial dysfunction, abnormal lipid profile, and insulin dysfunction, women with POI are at higher risk of metabolic syndrome development and cardiovascular disease [16, 17].

A study including 123 women (age 49.0 ± 4.3 years) diagnosed with POI earlier and 123 population controls (age 49.4 ± 3.9 years) from the Netherlands showed that the prevalence of MetS in women with POI was 16%, which was significantly higher than in controls (3%) [18]. The National Cholesterol Education Program (NCEP) definition was used to confirm the diagnosis of MetS. Likewise, in Turkey, a study of 56 women with POI (FSH > 40 IU/L) and 59 healthy controls in the same age range showed that the prevalence of metabolic syndrome was significantly higher in women with POI (14.3% vs. 3.4%, respectively; p = .049) [19]. In our study, the prevalence of MetS in POI patients and the control group was 16.9% and 11.3%, respectively, although this difference was not significantly different. Our present study also shows that the prevalence of hypertriglyceridemia and high fasting glucose was significantly higher in POI women than in the control group, while there were no significant differences in the prevalence of the other components of MetS between the two groups. Our results about the prevalence of MetS compared with those in the studies above were not completely consistent, probably because of the differences in the age of the subjects and the diagnostic criteria of POI and MetS, which are partly different for Western and Chinese women.

Metabolic profile of Chinese patients with POI

Dyslipidemia is common and increases the risk of cardiovascular disease. The menopause transition is associated with an atherogenic lipid profile, with an increase in TC and LDL-C, TG concentrations and a decrease in HDL-C concentration [20]. Several studies have examined the metabolic profile affected by POI, but the results are conflicting [4, 21].

Abnormalities in lipid profiles have been found, but the results are conflicting regarding particular lipoproteins. A recent meta-analysis showed that serum total cholesterol, LDL-C, and triglyceride levels were significantly higher in patients with POI than healthy controls. Serum HDL-C levels did not vary significantly between controls and patients with POI [21]. Another Meta-analysis showed that early cessation of ovulatory function may be associated with high serum TC and HDL-C [19]. One study showed that after regression analysis with correction for BMI and age, the serum concentrations of TC, HDL-C, and LDL-C were found to be significantly higher in the POI group when compared to healthy subjects, while triglycerides did not differ significantly between both groups [4]. A recent study in China found that women with POI were more likely to exhibit increased serum TG levels and decreased HDL-C and LDL-C levels compared with controls after adjusting the age and BMI [22]. Our present study showed that the level of TG in POI patients was higher than in the control group, while there was no significant difference in TC, HDL-C, and LDL-C between the two groups.

Regarding the effect of POI on blood pressure, the studies are relatively limited, and the results are also conflicting. A meta-analysis found that women with early menopause (age at menopause < 45 years) have an increased risk for arterial hypertension compared with those of normal age at menopause [23]. A case-control study showed that the middle age women with POI presented a higher prevalence of hypertension compared to age and BMI-matched population controls [18]. Women with POI had significantly higher blood pressure despite lower BMI than controls [24]. However, another study showed that after regression analysis with correction for BMI and age, the systolic (SBP) and diastolic blood pressure (DBP) did not differ significantly between both POI women and the control group [4]. Our present study showed no significant differences in SBP and DBP between POI and the control group.

Regarding the effect of POI on glucose and insulin metabolism, data are also conflicting [11]. Some studies found that despite having a lower BMI, women with POI had significantly higher glucose levels [24, 25]. A systemic review and meta-analysis reported that patients with POI have a higher risk of developing T2DM than women with normal menopause [26]. However, some other studies did not detect differences in glucose metabolism [3]. A study found that glucose, insulin serum concentrations, and HOMA-IR did not differ significantly between POI patients and control groups [4]. A pilot study showed that the basal and 60 min insulin levels were significantly higher in women with POI than those in the control group, but there were no significant differences between the POI patients and controls for median values of the QUICKI, and the HOMA, Matsuda, McA, and FGIR indexes [27]. Our study showed that FINS and HOMA-IR in POI patients were higher than in the control group, but there was no significant difference in FPG between the two groups.

The correlation between IR and components of MetS

MetS begins with insulin resistance and proceeds to interlaced systemic disorders such as abdominal obesity, glucose intolerance, diabetes mellitus, dyslipidemia, hypertension, and coronary artery disease [28]. One of the significant drivers of MetS is weight gain and the evolution of insulin resistance [29]. Our study found that HOMA-IR had a positive correlation with WC, DBP, TG, and FPG and had a negative correlation with HDL-C in both POI women and the control group. However, HOMA-IR positively correlated with SBP in the control group, while it did not correlate with SBP in POI women. In conclusion, HOMA-IR highly correlated with the components of MetS in both POI and control group. It could be postulated that IR played an important role in the pathogenesis of MetS in both POI and controls.

Patients with POI will need HRT

ESHRE 2016 guidelines for POI and other guidelines recommend the use of HRT from POI diagnosis until the age of at least 50 years [8, 30]. Even though evidence is scarce about the metabolic benefits of HRT in women with POI, studies have shown the metabolic benefits of HRT use in women facing menopause in their 50s. Thus, our study population can have a massive benefit in getting long-term treatment with HRT. Patients who had used HRT in the past three months were excluded according to our study protocol to exclude this effect which would have interfered with our investigations. Indeed, because all patients enrolled in our study were diagnosed for the first time, they had not used HRT before. However, in the follow-up after our study, all patients with no contraindications for HRT are getting adequate hormonal treatment.

Strength and limitations

It is important to investigate the metabolic effects of POI in different populations. Although there are a few studies about MetS and POI in Western countries, studies on the prevalence of MetS in Chinese women with POI are scarce. Our study showed the prevalence of MetS and its components in Chinese women with POI. However, this cross-sectional and hospital-based study cannot determine whether POI causes metabolic abnormalities. Besides, the sample size of our study is limited. Prospective studies with a larger sample size should be performed further to elucidate the effect of POI on metabolic profiles.

Conclusions

Although the prevalence of MetS in POI women was not significantly higher than in age-and-BMI-matched controls, POI women still presented with more unfavorable cardiovascular risk factors (higher prevalence of hypertriglyceridemia and high fasting glucose). So, women diagnosed with POI should always be covered with special care, consisting of strict and regular control and monitoring of all existing risk factors for CVD.

Acknowledgments

We thank all our colleagues in the Department of Gynecological Endocrinology at Beijing Obstetrics and Gynecology Hospital, Capital Medical University, for their valuable assistance in coordinating this study and all the study participants. Additionally, we would like to acknowledge the editing and proofreading contributions of Pooja Dhungel, an English native speaker.

Disclosure statement

All authors declare that they have no conflict of interest.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.

Additional information

Funding

This study was supported by National Menopause Health Care Specialist Construction Unit of China [(2020)30]; Beijing Municipal Administration of Hospitals’ Ascent Plan (No. DFL20181401).