- Email: [email protected]
Risks associated with premature ovarian failure in Han Chinese women
ARTICLE IN PRESS Reproductive BioMedicine Online (2015) ■■, ■■–■■
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Risks associated with premature ovarian failure in Han Chinese women
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Huidan Wang a,1, Haitao Chen b,1, Yingying Qin a, Zhuqing Shi b, Xiaoming Zhao c, Jianfeng Xu d,e, Bowen Ma f, Zi-Jiang Chen a,c,*
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Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, 324 Jingwu Road, Jinan 250021, China; b State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, 220 Handan Road, Shanghai 200433, China; c Center for Reproductive Medicine, Renji Hospital Affiliated to Shanghai Jiaotong University, 845 Lingshan Road, Shanghai 200120, China; d Fudan Institute of Urology and Department of Urology, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, 220 Handan Road, Shanghai 200433, China; e Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA; f Department of Biology, University of Connecticut, CT, USA
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* Corresponding author.
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E-mail address: [email protected] (Z-J Chen). 1 These authors have contributed equally to this paper. Dr Huidan Wang received her MD from Shandong University of Traditional Chinese Medicine, Shandong, China, in 2010. She is pursuing her PhD at the Center for Reproductive Medicine of Shandong University, which is one of the largest IVF centres in China and is a pioneer in IVF, oocyte cryopreservation and reproductive endocrinology and genetic diseases. Dr Wang has received both clinical and laboratory training. Her current academic focus is on the pathogenesis and mechanism of premature ovarian failure.
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In this retrospective study, the relationship between demographic characteristics, past medical history, general lifestyle habits and susceptibility of premature ovarian failure (POF) in Han Chinese population was investigated. Five hundred and fiftythree patients with POF and 400 women with normal ovarian function were recruited. A questionnaire was designed to gather information from responders. Logistic regression was carried out to calculate odds ratios (OR), 95% confidence intervals (95% CI) and P-values. History of pelvic surgery, mumps, having relatives with menstrual abnormalities and exposure to chemical agents were significantly associated with increased risk of POF (OR 5.53 [2.15 to 14.23]; 3.26 [2.38 to 4.47]; 28.12 [8.84 to 89.46]; 4.47 [2.09 to 9.58]). Vegetarian diet, tea and mineral water consumption reduced the risk of POF (OR 0.27 [0.19 to 0.37]; 0.04 [0.03 to 0.07]; 0.63 [0.47 to 0.85], respectively). Heredity, pelvic surgery, mumps and exposure to chemical agents were identified as risk factors for POF, whereas vegetarian diet, tea consumption and mineral water drinking were protective. Therefore, genetic consultation could help those women whose relatives manifested an early or premature menopause to avoid the consequences of possible premature ovarian function cessation. Avoidance of exposure to endocrine disrupters and flavonoids intake should be considered.
Abstract
© 2014 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
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http://dx.doi.org/10.1016/j.rbmo.2014.12.013 1472-6483/© 2014 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
ARTICLE IN PRESS 2
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KEYWORDS: lifestyle, medical history, premature ovarian failure, risk factors
Introduction Premature ovarian failure (POF), also known as premature menopause or primary ovarian insufficiency, affects 1–2% of women younger than 40 years of age (Coulam et al., 1986). It is characterized by primary or secondary amenorrhoea, infertility, oestrogen deficiency and elevated gonadotrophin (FSH > 40 IU/L) (Kalantaridou et al., 1998). Women with POF are now recognized to be at an increased risk for premature morbidity and mortality owing to experiencing oestrogen deficiency before the median age of natural menopause (Shuster et al., 2010). The physical consequences of premature hypooestrogen in women with POF include infertility, menopausal symptoms and higher risk of osteoporosis and cardiovascular disorders (Anasti, 1998; Sowers and La Pietra, 1995). In addition, POF also affects psychological health. The quality of life of women with POF as been evaluated with the World Health Organization Quality of Life-Brief (WHOQOLBREF), and results have shown that patients score poorly in physical health and psychological states (Benetti-Pinto et al., 2011). Multiple causes of POF have been defined, such as genetic, autoimmune, infectious, environmental factors and iatrogenic agents (e.g. pelvic surgery, chemotherapy and radiations) (Nelson, 2009; Shelling, 2010; Simpson and Rajkovic, 1999). The underlying causes, however, remain unexplained in most cases. The complexity and heterogeneity of POF make diagnosis difficult before irreversible damage to the ovarian reserve. Therefore, identification of risk factors for ovarian damage is of great importance. The prevalence of POF varies slightly among different populations. A cross-sectional survey of 15,605 women aged 40– 55 years was conducted at seven sites in the USA, and the overall prevalence of POF was 1.1%. By ethnicity, 1.0% of white, 1.4% of African–American, 1.4% of Hispanic, 0.5% of Chinese and 0.1% of Japanese women experienced POF (Luborsky et al., 2003). Also, healthy conditions, such as osteoporosis, female hormone use (excluding oral contraceptive), body mass index and current smoking in women with Q3 POF are different across ethnic groups (Luborsky et al., 2003). It has also been suggested that lifestyle and environmental Q4 factors may contribute to the development of POF. The aim of the present study was to analyse the relationship between POF and health, reproductive, demographic and lifestyle factors to determine possible risk factors for POF in Han Chinese.
Materials and methods In this case-control study, 553 patients with POF and 400 controls were recruited from the Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University between January 2008 and October 2013. The case Q5 and control selection followed a pre-established protocol. All the patients and controls were Han Chinese. Inclusion criteria of POF consisted of cessation of menstrual cycles before age 40 years and at least two serum FSH measurements exceeding 40 IU/L. Age-matched women requesting
treatment for infertility owing to their husbands’ azoospermia, who had normal menstrual cycles, serum levels of FSH, LH and oestradiol, were included as controls. All patients and controls provided written informed consent for personal data collection and analysis. The study was approved by the Institutional Review Board of Reproductive Medicine of Shandong University on 3 February 2014 (Institutional Review Board reference number 17). Information about participants was recorded on a predefined questionnaire. The questionnaire included demographic characteristics, gynaecological and obstetric data, past history, general lifestyle behaviour and environmental factors. Data were analysed using the Statistical Package for Social Sciences (SPSS) version 16.0 (SPSS Inc., USA). The continuous variables were compared by t-test, and the categorical variables were compared by chi-squared test. The binary and categorical logistic regression was used to calculate odds ratios (OR), 95% confidence intervals (95% CI), and P-values for each risk factor. P < 0.05 was considered statistically significant.
Results The clinical features of the 553 patients with POF are presented in Table 1. A total of 65 (11.95%) women presented with primary amenorrhoea, and 479 (88.05%) with secondary amenorrhoea. The menstrual cycle length before onset of premature ovarian failure in 328 (70.24%) patients was between 25 and 35 days, and longer than 35 days in 102 (21.84%) patients. The proportion of patients with secondary infertility was 113 (20.66%). Chromosomal abnormalities were present in 48 out of 553 (8.68%) POF cases, of which, 47 (97.92%) involved in the X chromosome and one (2.08%) was non-mosaic 46, XY. No autosome abnormalities were found. Associations betweeen demographic characteristics and environmental exposure with POF are presented in Table 2. Housing renovation, exposure to agricultural chemicals and chemical agents were associated with an increased risk of POF (OR 4.76 [2.98 to 7.61]; 11.56 [5.51 to 24.25]; 4.47 [2.09 to 9.58]). Living in a suburb was a protective factor for POF (OR 0.38 [0.27 to 0.55]). Occupation and education showed no significant difference between POF and controls. Medical history of the two cohorts were also compared (Table 3). A history of mumps and pelvic surgery, including ovarian cystectomy (e.g. endometrial, simple serous and teratoma cysts), unilateral oophorectomy and tubal ectopic pregnancy surgery (e.g. salpingectomy and salpingostomy) conferred a higher risk of POF (OR 3.26 [2.38 to 4.47]; OR 5.53 [2.15 to 14.23]). Ovarian surgery (e.g. ovarian cystectomy and unilateral oophorectomy) increased the risk of POF (OR 5.97 [1.78 to 20.02]). Women who had relatives with abnormal menstrual cycles had an increased risk for POF (OR 28.12 [8.84 to 89.46]). Compared with controls, allergy was a protec- Q6 tive factor for POF (OR 0.62 [0.44 to 0.89]). No significant association was found between POF and menarche age, intermenstrual bleeding and usage of diet pills (P > 0.05). Univariate associations between lifestyle habits and POF are presented in Table 4. Tea consumption, vegetarian diet
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
ARTICLE IN PRESS Risks for POF in Han Chinese 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
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Table 1
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The reproductive and menstrual features of 553 patients with premature ovarian failure.
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n (%)
Characteristics
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Menstrual status
Primary amenorrhoea Secondary amenorrhoea <25 days 25–35 days >35 days Pregnancy Delivery Termination Miscarriage Non-pregnancy X chromosome X-numerical abnormalities X-structural abnormalities X-autosomal translocatons 46, XY
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Menstrual cycle length before onset of premature ovarian failure
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Reproduction history
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Chromosomal abnormalities
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21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
65 479 37 328 102 113 66 68 25 434 47 14 26 7 1
(11.95) (88.05) (7.92) (70.24) (21.84) (20.66) (12.07) (12.43) (4.57) (79.34) (8.50) (2.53) (4.70) (1.27) (0.18)
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Table 2 The demographic characteristics and environmental exposure in patients with premature ovarian failure and controls (univariate regression analysis).
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Premature ovarian failure group, n (%)
Control group, n (%)
P-value
OR (95% CI)
110 (20.87) 310 (58.82) 107 (20.30)
73 (18.25) 259 (64.75) 68 (17.00)
NA NS NS
1.00 (reference) 0.79 (0.57 to 1.12) 1.04 (0.68 to 1.60)
49 (9.06) 347 (64.14) 145 (26.80)
33 (8.25) 287 (71.75) 80 (20.00)
NA NS NS
1.00 (reference) 0.81 (0.51 to 1.30) 1.22 (0.73 to 2.05)
108 110 182 23 10 8
NA <0.01 NS <0.01 <0.01 <0.01
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Occupation Unemployed Blue-collar worker White-collar worker Education Primary school Junior or senior secondary school University education Residence Urban Suburb Rural Housing renovation Exposure to agricultural chemicals Exposure to chemical agents
216 84 248 115/511a 32/140a 46/550a
(39.42) (15.33) (45.26) (22.50) (22.86) (8.36)
(27.00) (27.50) (45.50) (5.75) (2.50) (2.00)
1.00 0.38 0.68 4.76 11.56 4.47
(reference) (0.27 to 0.55) (0.51 to 0.92) (2.98 to 7.61) (5.51 to 24.25) (2.09 to 9.58)
Q12 NA, not applicable; NS, not statistically significant. a
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Total numbers of categories.
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and mineral water were associated with a decreased risk of POF (OR 0.04 [0.03 to 0.07]; OR 0.27 [0.19 to 0.37]; OR 0.63 [0.47 to 0.85]). No significant association was found between POF and use of plastic tableware. Multivariate logistic regression analysis was carried out to test the relationship between risk factors and POF for confounding variables. Odd ratios, confidence intervals and P-values obtained by multivariate logistic regression analysis are shown in Table 5. Housing renovation and exposure to chemical agents were strongly associated with POF compared with controls (OR 11.40 [5.71 to 22.76]; OR 6.34 [2.06 to 19.52]). Women who lived in suburbs and consumed more vegetable, mineral water and tea were less likely to have POF (OR 0.46 [0.28 to 0.77]; OR 0.19 [0.12 to 0.30]; OR 0.56 [0.36 to 0.87]; OR 0.03 [0.01 to 0.05]). Women who had relatives with menstrual abnormalities and history of pelvic surgery were
at a high risk of POF (OR 18.01 [5.03 to 64.48]; OR 13.41 [3.84 to 46.91]).
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Discussion
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To date, POF in white, African–American and Japanese populations has been associated with the following factors: heredity (Cordts et al., 2011; Davison et al., 2000; Goswami and Conway, 2007; Prueitt et al., 2000; Qin et al., 2007; Rizzolio et al., 2006); ovarian surgery (Busacca et al., 2006; Coccia et al., 2011); pelvic surgery (Farquhar et al., 2005; Read et al., 2010; Sparic et al., 2012); chemotherapy and radiotherapy (Blumenfeld et al., 2000; Fisher et al., 1979; Jensen et al., 2011; Koyama et al., 1977; Mackie et al., 1996; Oktay et al., 2001; Sonmezer and Oktay, 2004; Viviani et al., 1985; Warne
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
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Table 3
Medical history in the two groups (univariate regression analysis).
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Characteristics
Premature ovarian failure cases
Controls
P-value
OR (95% CI)
Menarche age, mean (STD) Inter-menstrual bleeding, n (%) Pelvic surgeryb, n (%) Ovarian surgery, n (%) Ovarian cystectomy, n (%) Oophorectomy, n (%) Tubal ectopic pregnancies surgery, n (%) Mumps, n (%) Relativesc with menstrual abnormalities, n (%) Diet pill use, n (%) Allergy, n (%)
14.28 ± 1.63 19/529a (3.59) 36/534a (6.74) 23/534a (4.31) 19/534a (3.56) 4/534a (0.75) 15/534a (2.81) 172/294a (58.50) 95/542a (17.53) 18/545a (3.30) 69/541a (12.75)
14.41 ± 1.34 7 (1.75) 5 (1.25) 3 (0.75) 2 (0.50) 1 (0.25) 2 (0.50) 121 (30.25) 3 (0.75) 8 (2.00) 76 (19.00)
NS NS <0.01 <0.01 <0.01 NS 0.02 <0.01 <0.01 NS 0.01
0.95 2.09 5.53 5.97 7.36 3.02 5.75 3.26 28.12 1.67 0.62
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NS, not statistically significant. a Total numbers of characteristics. b Pelvic surgery included ovarian cystectomy (endometrial, simple serous and teratoma cysts), unilateral oophorectomy and surgery for tubal ectopic pregnancies (salpingectomy and salpingostomy). c Relatives included mother, sister, aunt and grandmother.
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(0.87 (0.87 (2.15 (1.78 (1.70 (0.34 (1.31 (2.38 (8.84 (0.72 (0.44
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1.03) 5.02) 14.23) 20.02) 1.77) 27.10) 25.28) 4.47) 89.46) 3.88) 0.89)
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Table 4
Comparison of lifestyle habits in the two groups (univariate regression analysis).
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Lifestyle habits
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Premature ovarian failure cases (n, %)
Controls (n, %)
P-value
OR (95% CI)
419 72 20 152/550a
(75.77) (13.02) (3.62) (27.64)
236 153 11 129
(59.00) (38.25) (2.75) (32.25)
NA <0.01 NS NS
1.00 0.27 1.02 0.80
(reference) (0.19 ti 0.37) (0.48 to 2.17) (0.61 to 1.06)
359 121 67 22/537a
(64.92) (21.88) (12.12) (4.10)
228 122 50 201
(57.00) (30.50) (12.50) (50.25)
NA 0.02 NS <0.01
1.00 0.63 0.85 0.04
(reference) (0.47 to 0.85) (0.57 to 1.27) (0.03 to 0.07)
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Dietary habits Balanced diet Vegetarian diet Diet rich in animal protein Use of plastic tableware Drinking habits Tap water Mineral water Pure water Tea consumption NS, not statistically significant. a Total numbers of the characteristics.
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Q7 et al., 1973); exposure to toxicity and smoking (Cooper et al., 1999; Cramer et al., 1995a; Harlow and Signorello, 2000; Luoto et al., 1994; Nilsson et al., 1997). In the present study, risk factors for POF in Chinese included relatives with irregular menstruation, pelvic surgery and exposure to chemical agents, which was consistent with previous studies in white, African– American and Japanese (Bentzen et al., 2013; Beranger et al., 2012; Busacca et al., 2006; Coccia et al., 2011; Cramer et al., 1995b; Farquhar et al., 2005; Nilsson et al., 2012; Takae et al., 2014; Torgerson et al., 1997a, 1997b). Only three women had a history of chemotherapy, five women had undergone an oophorectomy and only three women smoked; therefore, insufficient statistical power was available to detect an association with POF. In the present study, familial clustering of menstrual abnormalities was a significant finding. Premature ovarian failure is considered to be a complex genetic disease and characterized by familial aggregation (Manolio, 2009). Previous epidemiological studies have supported a familial association between menopausal age of a mother and her daughter (Cramer et al., 1995b; Torgerson et al., 1994, 1997a, 1997b).
From a clinical perspective, the results suggest that women whose relatives experienced an early or premature menopause should undergo genetic testing. In this cohort of Chinese women with POF, the prevalence of chromosomal abnormalities was 8.68% (48/553), and most cases involved X-structural abnormalities or X-aneuploidy. Given the low prevalence (0.5%) of premutation of FMR1 gene in Chinese patients with POF (Guo et al., 2014), FMR1 premutation in the present cohort was included. Genetic factors are generally considered to play an important role in the cause of POF and, according to our data, environmental factors may be of equal importance. In the present study, pelvic surgery for ovarian cystectomy (e.g. endometrial, simple serous and teratoma cysts), unilateral oophorectomy and tubal ectopic pregnancy (e.g. salpingectomy and salpingostomy) increased the risk of POF. Pelvic surgery might impair ovarian blood supply or cause local inflammation, resulting in oocyte depletion and POF (Amato and Roberts, 2001; Hardy and Kuh, 1999). Obstetricians and gynaecologists must be careful to protect the ovary during pelvic surgery. The mean period of onset of ovarian
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
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ARTICLE IN PRESS Risks for POF in Han Chinese 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
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Table 5
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Comparison of characteristics between the two groups by multiple regression analysis.
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Characteristics
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Premature ovarian failure cases (n, %)
Controls (n, %)
P-value
OR (95% CI)
Area under curve
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Intercept Residence Urban Q13 Suburb Rural Housing renovation Exposure to chemical agents Pelvic surgerya Relativesb with menstrual abnormalities Dietary habits Balanced diet Vegetarian diet Diet rich in animal protein Drinking habits Tap water Q14 Mineral water Pure water Tea consumption
<0.01 216 84 248 115 46 36 95
(39.06) (15.19) (44.85) (22.80) (8.32) (6.51) (17.18)
(27.00) (27.50) (45.50) (5.75) (2.00) (1.25) (0.75)
NA <0.01 NS <0.01 <0.01 <0.01 <0.01
419 (75.77) 72 (13.02) 20 (3.62)
236 (59.00) 153 (38.25) 11 (2.75)
NA <0.01 NS
1.00 (reference) 0.19 (0.12 to 0.30) 0.97 (0.30 to 3.15)
359 121 67 22
228 122 50 201
NA 0.01 NS <0.01
1.00 0.56 0.80 0.03
(64.92) (21.88) (12.12) (3.98)
108 110 182 23 8 5 3
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(57.00) (30.50) (12.50) (50.25)
1.00 0.46 0.77 11.40 6.34 13.41 18.01
(reference) (0.28 to 0.77)** (0.51 to 1.18) (5.71 to 22.76) (2.06 to 19.52) (3.84 to 46.91) (5.03 to 64.48)
(reference) (0.36 to 0.87)* (0.46 to 1.38) (0.01 to 0.05)
NS, not statistically significant. a Pelvic surgery included ovarian cystectomy (endometrial, simple serous and teratoma cysts), unilateral oophorectomy and surgery for tubal ectopic pregnancies (salpingectomy and salpingostomy). b Relatives included mother, sister, aunt and grandmother.
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insufficiency after cystectomy was 4–6 years. Some patients, however, experienced ovarian insufficiency within 1 year (Busacca et al., 2006; Takae et al., 2014). Therefore, it was important to monitor ovarian reserve long after pelvic surgery, particularly for patients who wish to conceive in the future. Chemical agents have been shown to increase apoptosis or atresia of the primary or primordial follicle, resulting in decreased ovarian reserve (Béranger et al., 2012). Polycyclic aromatic hydrocarbons (environmental toxicants found in cigarette smoke) (Jurisicova et al., 2007; Mikkelsen et al., 2007), 4-vinylcyclohexene (produced during the manufacture of rubber tires) (Hoyer et al., 2001; Mayer et al., 2004; Takai et al., 2003), 2-bromopropane (a solvent for cleaning electrical components) (Boekelheide et al., 2004; Koh et al., 1998), Perfluorooctanoate and perfluorooctanesulfonate (manmade chemicals used in numerous household products) (Knox et al., 2011) have been shown to be toxic for follicles, which were components involved in house renovation materials and agriculture chemicals. Mumps is a common childhood infection caused by the mumps virus. The mumps virus leads to local inflammation with infiltrates of lymphocytes and macrophages. The orchitis and oophoritis are common complications of mumps, which develop in 15–30% of boys and 5% of adults with mumps, respectively (Hviid et al., 2008). Inflammation is now recognized as a type of non-specific immune response, either acute or chronic (Fox, 1992). In the past 3 decades, autoimmune mechanism has been shown to be involved in the pathogenesis of POF in up to 30% of cases (Conway, 1996). Autoimmune disorders related to POF include thyroid diseases, mumps, hyperparathyroidism and Addison’s disease. The ovarian biopsy in these conditions showed infiltration of follicles with plasma cells and lymphocytes (Okeke et al., 2013).
It was speculated that mumps might be a result of virusinfected oophoritis and autoimmune response. Few data, however, have supported mumps as a cause of ovarian failure (Morrison et al., 1975; Prinz and Taubert, 1969). In the present study, vegetarian diet, mineral water and tea consumption were found to be protective for ovarian function, attributed to an antioxidant effect. Harvey et al. (2002) found that mammalian oocytes were sensitive to oxidative stress, and that high levels of oxidative stress impaired oocyte maturation. High levels of reactive oxygen species led to mi- Q8 tochondrial DNA alterations and mitochondria dysfunction followed by impaired oxidative phosphorylation, and thus exhausted oocytes. Fruits, vegetables, tea and other plantderived food are abundant in natural antioxidants and flavonoids. An association has been found between trace elements present in mineral water, such as zinc and copper, and immune response, inflammation and oxidative stress (Kebapcilar et al., 2013). It has been suggested that flavonoids might inhibit oxidation and DNA damage by decreasing free radical formation, scavenging free radicals, and enhancing antioxidant capacity (Lopez-Lazaro, 2002; Ross and Kasum, 2002). The protective effect of certain flavonoids is to be encouraged. The early diagnosis of POF before irreversible damage to the ovarian pool is unfeasible in most cases, and, therefore, identification of risk factors for prevention is urgent. In the present study, heredity, pelvic surgery, mumps and exposure to toxic were identified as risk factors for POF, whereas vegetarian diet and tea and mineral water consumption were found to be protective. Therefore, genetic consultation is recommended for women with POF. Avoidance of exposure to endocrine disrupters could be considered as a preventative Q9 strategy and intake of certain flavonoids is suggested.
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
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This work is supported by grants from the National Basic Research Program of China (973 program-2012CB944700), the National Natural Science Foundation of China (81270662, Q10 81370687, 81370692), Foundation for the Author of National Excellent Doctoral Dissertation of the People’s Republic of China (201078), and Independent Innovation Foundation of Shandong University (IIFSDU) (2012TS130).
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ARTICLE IN PRESS Risks for POF in Han Chinese 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
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Declaration: The authors report no financial or commercial conflicts of interest.
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Received 10 October 2014; refereed 17 December 2014; accepted 17 December 2014.
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w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
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Risks associated with premature ovarian failure in Han Chinese women
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Huidan Wang a,1, Haitao Chen b,1, Yingying Qin a, Zhuqing Shi b, Xiaoming Zhao c, Jianfeng Xu d,e, Bowen Ma f, Zi-Jiang Chen a,c,*
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Center for Reproductive Medicine, Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key laboratory for Reproductive Endocrinology of Ministry of Education, Shandong Provincial Key Laboratory of Reproductive Medicine, 324 Jingwu Road, Jinan 250021, China; b State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, 220 Handan Road, Shanghai 200433, China; c Center for Reproductive Medicine, Renji Hospital Affiliated to Shanghai Jiaotong University, 845 Lingshan Road, Shanghai 200120, China; d Fudan Institute of Urology and Department of Urology, Huashan Hospital, State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, 220 Handan Road, Shanghai 200433, China; e Center for Cancer Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA; f Department of Biology, University of Connecticut, CT, USA
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* Corresponding author.
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E-mail address: [email protected] (Z-J Chen). 1 These authors have contributed equally to this paper. Dr Huidan Wang received her MD from Shandong University of Traditional Chinese Medicine, Shandong, China, in 2010. She is pursuing her PhD at the Center for Reproductive Medicine of Shandong University, which is one of the largest IVF centres in China and is a pioneer in IVF, oocyte cryopreservation and reproductive endocrinology and genetic diseases. Dr Wang has received both clinical and laboratory training. Her current academic focus is on the pathogenesis and mechanism of premature ovarian failure.
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In this retrospective study, the relationship between demographic characteristics, past medical history, general lifestyle habits and susceptibility of premature ovarian failure (POF) in Han Chinese population was investigated. Five hundred and fiftythree patients with POF and 400 women with normal ovarian function were recruited. A questionnaire was designed to gather information from responders. Logistic regression was carried out to calculate odds ratios (OR), 95% confidence intervals (95% CI) and P-values. History of pelvic surgery, mumps, having relatives with menstrual abnormalities and exposure to chemical agents were significantly associated with increased risk of POF (OR 5.53 [2.15 to 14.23]; 3.26 [2.38 to 4.47]; 28.12 [8.84 to 89.46]; 4.47 [2.09 to 9.58]). Vegetarian diet, tea and mineral water consumption reduced the risk of POF (OR 0.27 [0.19 to 0.37]; 0.04 [0.03 to 0.07]; 0.63 [0.47 to 0.85], respectively). Heredity, pelvic surgery, mumps and exposure to chemical agents were identified as risk factors for POF, whereas vegetarian diet, tea consumption and mineral water drinking were protective. Therefore, genetic consultation could help those women whose relatives manifested an early or premature menopause to avoid the consequences of possible premature ovarian function cessation. Avoidance of exposure to endocrine disrupters and flavonoids intake should be considered.
Abstract
© 2014 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
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http://dx.doi.org/10.1016/j.rbmo.2014.12.013 1472-6483/© 2014 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
ARTICLE IN PRESS 2
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KEYWORDS: lifestyle, medical history, premature ovarian failure, risk factors
Introduction Premature ovarian failure (POF), also known as premature menopause or primary ovarian insufficiency, affects 1–2% of women younger than 40 years of age (Coulam et al., 1986). It is characterized by primary or secondary amenorrhoea, infertility, oestrogen deficiency and elevated gonadotrophin (FSH > 40 IU/L) (Kalantaridou et al., 1998). Women with POF are now recognized to be at an increased risk for premature morbidity and mortality owing to experiencing oestrogen deficiency before the median age of natural menopause (Shuster et al., 2010). The physical consequences of premature hypooestrogen in women with POF include infertility, menopausal symptoms and higher risk of osteoporosis and cardiovascular disorders (Anasti, 1998; Sowers and La Pietra, 1995). In addition, POF also affects psychological health. The quality of life of women with POF as been evaluated with the World Health Organization Quality of Life-Brief (WHOQOLBREF), and results have shown that patients score poorly in physical health and psychological states (Benetti-Pinto et al., 2011). Multiple causes of POF have been defined, such as genetic, autoimmune, infectious, environmental factors and iatrogenic agents (e.g. pelvic surgery, chemotherapy and radiations) (Nelson, 2009; Shelling, 2010; Simpson and Rajkovic, 1999). The underlying causes, however, remain unexplained in most cases. The complexity and heterogeneity of POF make diagnosis difficult before irreversible damage to the ovarian reserve. Therefore, identification of risk factors for ovarian damage is of great importance. The prevalence of POF varies slightly among different populations. A cross-sectional survey of 15,605 women aged 40– 55 years was conducted at seven sites in the USA, and the overall prevalence of POF was 1.1%. By ethnicity, 1.0% of white, 1.4% of African–American, 1.4% of Hispanic, 0.5% of Chinese and 0.1% of Japanese women experienced POF (Luborsky et al., 2003). Also, healthy conditions, such as osteoporosis, female hormone use (excluding oral contraceptive), body mass index and current smoking in women with Q3 POF are different across ethnic groups (Luborsky et al., 2003). It has also been suggested that lifestyle and environmental Q4 factors may contribute to the development of POF. The aim of the present study was to analyse the relationship between POF and health, reproductive, demographic and lifestyle factors to determine possible risk factors for POF in Han Chinese.
Materials and methods In this case-control study, 553 patients with POF and 400 controls were recruited from the Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University between January 2008 and October 2013. The case Q5 and control selection followed a pre-established protocol. All the patients and controls were Han Chinese. Inclusion criteria of POF consisted of cessation of menstrual cycles before age 40 years and at least two serum FSH measurements exceeding 40 IU/L. Age-matched women requesting
treatment for infertility owing to their husbands’ azoospermia, who had normal menstrual cycles, serum levels of FSH, LH and oestradiol, were included as controls. All patients and controls provided written informed consent for personal data collection and analysis. The study was approved by the Institutional Review Board of Reproductive Medicine of Shandong University on 3 February 2014 (Institutional Review Board reference number 17). Information about participants was recorded on a predefined questionnaire. The questionnaire included demographic characteristics, gynaecological and obstetric data, past history, general lifestyle behaviour and environmental factors. Data were analysed using the Statistical Package for Social Sciences (SPSS) version 16.0 (SPSS Inc., USA). The continuous variables were compared by t-test, and the categorical variables were compared by chi-squared test. The binary and categorical logistic regression was used to calculate odds ratios (OR), 95% confidence intervals (95% CI), and P-values for each risk factor. P < 0.05 was considered statistically significant.
Results The clinical features of the 553 patients with POF are presented in Table 1. A total of 65 (11.95%) women presented with primary amenorrhoea, and 479 (88.05%) with secondary amenorrhoea. The menstrual cycle length before onset of premature ovarian failure in 328 (70.24%) patients was between 25 and 35 days, and longer than 35 days in 102 (21.84%) patients. The proportion of patients with secondary infertility was 113 (20.66%). Chromosomal abnormalities were present in 48 out of 553 (8.68%) POF cases, of which, 47 (97.92%) involved in the X chromosome and one (2.08%) was non-mosaic 46, XY. No autosome abnormalities were found. Associations betweeen demographic characteristics and environmental exposure with POF are presented in Table 2. Housing renovation, exposure to agricultural chemicals and chemical agents were associated with an increased risk of POF (OR 4.76 [2.98 to 7.61]; 11.56 [5.51 to 24.25]; 4.47 [2.09 to 9.58]). Living in a suburb was a protective factor for POF (OR 0.38 [0.27 to 0.55]). Occupation and education showed no significant difference between POF and controls. Medical history of the two cohorts were also compared (Table 3). A history of mumps and pelvic surgery, including ovarian cystectomy (e.g. endometrial, simple serous and teratoma cysts), unilateral oophorectomy and tubal ectopic pregnancy surgery (e.g. salpingectomy and salpingostomy) conferred a higher risk of POF (OR 3.26 [2.38 to 4.47]; OR 5.53 [2.15 to 14.23]). Ovarian surgery (e.g. ovarian cystectomy and unilateral oophorectomy) increased the risk of POF (OR 5.97 [1.78 to 20.02]). Women who had relatives with abnormal menstrual cycles had an increased risk for POF (OR 28.12 [8.84 to 89.46]). Compared with controls, allergy was a protec- Q6 tive factor for POF (OR 0.62 [0.44 to 0.89]). No significant association was found between POF and menarche age, intermenstrual bleeding and usage of diet pills (P > 0.05). Univariate associations between lifestyle habits and POF are presented in Table 4. Tea consumption, vegetarian diet
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
ARTICLE IN PRESS Risks for POF in Han Chinese 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
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Table 1
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The reproductive and menstrual features of 553 patients with premature ovarian failure.
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n (%)
Characteristics
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Menstrual status
Primary amenorrhoea Secondary amenorrhoea <25 days 25–35 days >35 days Pregnancy Delivery Termination Miscarriage Non-pregnancy X chromosome X-numerical abnormalities X-structural abnormalities X-autosomal translocatons 46, XY
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Menstrual cycle length before onset of premature ovarian failure
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Reproduction history
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Chromosomal abnormalities
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21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
65 479 37 328 102 113 66 68 25 434 47 14 26 7 1
(11.95) (88.05) (7.92) (70.24) (21.84) (20.66) (12.07) (12.43) (4.57) (79.34) (8.50) (2.53) (4.70) (1.27) (0.18)
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Table 2 The demographic characteristics and environmental exposure in patients with premature ovarian failure and controls (univariate regression analysis).
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Category
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Premature ovarian failure group, n (%)
Control group, n (%)
P-value
OR (95% CI)
110 (20.87) 310 (58.82) 107 (20.30)
73 (18.25) 259 (64.75) 68 (17.00)
NA NS NS
1.00 (reference) 0.79 (0.57 to 1.12) 1.04 (0.68 to 1.60)
49 (9.06) 347 (64.14) 145 (26.80)
33 (8.25) 287 (71.75) 80 (20.00)
NA NS NS
1.00 (reference) 0.81 (0.51 to 1.30) 1.22 (0.73 to 2.05)
108 110 182 23 10 8
NA <0.01 NS <0.01 <0.01 <0.01
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Occupation Unemployed Blue-collar worker White-collar worker Education Primary school Junior or senior secondary school University education Residence Urban Suburb Rural Housing renovation Exposure to agricultural chemicals Exposure to chemical agents
216 84 248 115/511a 32/140a 46/550a
(39.42) (15.33) (45.26) (22.50) (22.86) (8.36)
(27.00) (27.50) (45.50) (5.75) (2.50) (2.00)
1.00 0.38 0.68 4.76 11.56 4.47
(reference) (0.27 to 0.55) (0.51 to 0.92) (2.98 to 7.61) (5.51 to 24.25) (2.09 to 9.58)
Q12 NA, not applicable; NS, not statistically significant. a
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Total numbers of categories.
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and mineral water were associated with a decreased risk of POF (OR 0.04 [0.03 to 0.07]; OR 0.27 [0.19 to 0.37]; OR 0.63 [0.47 to 0.85]). No significant association was found between POF and use of plastic tableware. Multivariate logistic regression analysis was carried out to test the relationship between risk factors and POF for confounding variables. Odd ratios, confidence intervals and P-values obtained by multivariate logistic regression analysis are shown in Table 5. Housing renovation and exposure to chemical agents were strongly associated with POF compared with controls (OR 11.40 [5.71 to 22.76]; OR 6.34 [2.06 to 19.52]). Women who lived in suburbs and consumed more vegetable, mineral water and tea were less likely to have POF (OR 0.46 [0.28 to 0.77]; OR 0.19 [0.12 to 0.30]; OR 0.56 [0.36 to 0.87]; OR 0.03 [0.01 to 0.05]). Women who had relatives with menstrual abnormalities and history of pelvic surgery were
at a high risk of POF (OR 18.01 [5.03 to 64.48]; OR 13.41 [3.84 to 46.91]).
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Discussion
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To date, POF in white, African–American and Japanese populations has been associated with the following factors: heredity (Cordts et al., 2011; Davison et al., 2000; Goswami and Conway, 2007; Prueitt et al., 2000; Qin et al., 2007; Rizzolio et al., 2006); ovarian surgery (Busacca et al., 2006; Coccia et al., 2011); pelvic surgery (Farquhar et al., 2005; Read et al., 2010; Sparic et al., 2012); chemotherapy and radiotherapy (Blumenfeld et al., 2000; Fisher et al., 1979; Jensen et al., 2011; Koyama et al., 1977; Mackie et al., 1996; Oktay et al., 2001; Sonmezer and Oktay, 2004; Viviani et al., 1985; Warne
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
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Table 3
Medical history in the two groups (univariate regression analysis).
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Characteristics
Premature ovarian failure cases
Controls
P-value
OR (95% CI)
Menarche age, mean (STD) Inter-menstrual bleeding, n (%) Pelvic surgeryb, n (%) Ovarian surgery, n (%) Ovarian cystectomy, n (%) Oophorectomy, n (%) Tubal ectopic pregnancies surgery, n (%) Mumps, n (%) Relativesc with menstrual abnormalities, n (%) Diet pill use, n (%) Allergy, n (%)
14.28 ± 1.63 19/529a (3.59) 36/534a (6.74) 23/534a (4.31) 19/534a (3.56) 4/534a (0.75) 15/534a (2.81) 172/294a (58.50) 95/542a (17.53) 18/545a (3.30) 69/541a (12.75)
14.41 ± 1.34 7 (1.75) 5 (1.25) 3 (0.75) 2 (0.50) 1 (0.25) 2 (0.50) 121 (30.25) 3 (0.75) 8 (2.00) 76 (19.00)
NS NS <0.01 <0.01 <0.01 NS 0.02 <0.01 <0.01 NS 0.01
0.95 2.09 5.53 5.97 7.36 3.02 5.75 3.26 28.12 1.67 0.62
18 19 20 21 22
NS, not statistically significant. a Total numbers of characteristics. b Pelvic surgery included ovarian cystectomy (endometrial, simple serous and teratoma cysts), unilateral oophorectomy and surgery for tubal ectopic pregnancies (salpingectomy and salpingostomy). c Relatives included mother, sister, aunt and grandmother.
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(0.87 (0.87 (2.15 (1.78 (1.70 (0.34 (1.31 (2.38 (8.84 (0.72 (0.44
to to to to to to to to to to to
1.03) 5.02) 14.23) 20.02) 1.77) 27.10) 25.28) 4.47) 89.46) 3.88) 0.89)
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Table 4
Comparison of lifestyle habits in the two groups (univariate regression analysis).
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Lifestyle habits
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Premature ovarian failure cases (n, %)
Controls (n, %)
P-value
OR (95% CI)
419 72 20 152/550a
(75.77) (13.02) (3.62) (27.64)
236 153 11 129
(59.00) (38.25) (2.75) (32.25)
NA <0.01 NS NS
1.00 0.27 1.02 0.80
(reference) (0.19 ti 0.37) (0.48 to 2.17) (0.61 to 1.06)
359 121 67 22/537a
(64.92) (21.88) (12.12) (4.10)
228 122 50 201
(57.00) (30.50) (12.50) (50.25)
NA 0.02 NS <0.01
1.00 0.63 0.85 0.04
(reference) (0.47 to 0.85) (0.57 to 1.27) (0.03 to 0.07)
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Dietary habits Balanced diet Vegetarian diet Diet rich in animal protein Use of plastic tableware Drinking habits Tap water Mineral water Pure water Tea consumption NS, not statistically significant. a Total numbers of the characteristics.
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Q7 et al., 1973); exposure to toxicity and smoking (Cooper et al., 1999; Cramer et al., 1995a; Harlow and Signorello, 2000; Luoto et al., 1994; Nilsson et al., 1997). In the present study, risk factors for POF in Chinese included relatives with irregular menstruation, pelvic surgery and exposure to chemical agents, which was consistent with previous studies in white, African– American and Japanese (Bentzen et al., 2013; Beranger et al., 2012; Busacca et al., 2006; Coccia et al., 2011; Cramer et al., 1995b; Farquhar et al., 2005; Nilsson et al., 2012; Takae et al., 2014; Torgerson et al., 1997a, 1997b). Only three women had a history of chemotherapy, five women had undergone an oophorectomy and only three women smoked; therefore, insufficient statistical power was available to detect an association with POF. In the present study, familial clustering of menstrual abnormalities was a significant finding. Premature ovarian failure is considered to be a complex genetic disease and characterized by familial aggregation (Manolio, 2009). Previous epidemiological studies have supported a familial association between menopausal age of a mother and her daughter (Cramer et al., 1995b; Torgerson et al., 1994, 1997a, 1997b).
From a clinical perspective, the results suggest that women whose relatives experienced an early or premature menopause should undergo genetic testing. In this cohort of Chinese women with POF, the prevalence of chromosomal abnormalities was 8.68% (48/553), and most cases involved X-structural abnormalities or X-aneuploidy. Given the low prevalence (0.5%) of premutation of FMR1 gene in Chinese patients with POF (Guo et al., 2014), FMR1 premutation in the present cohort was included. Genetic factors are generally considered to play an important role in the cause of POF and, according to our data, environmental factors may be of equal importance. In the present study, pelvic surgery for ovarian cystectomy (e.g. endometrial, simple serous and teratoma cysts), unilateral oophorectomy and tubal ectopic pregnancy (e.g. salpingectomy and salpingostomy) increased the risk of POF. Pelvic surgery might impair ovarian blood supply or cause local inflammation, resulting in oocyte depletion and POF (Amato and Roberts, 2001; Hardy and Kuh, 1999). Obstetricians and gynaecologists must be careful to protect the ovary during pelvic surgery. The mean period of onset of ovarian
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
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ARTICLE IN PRESS Risks for POF in Han Chinese 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
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Table 5
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Comparison of characteristics between the two groups by multiple regression analysis.
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Characteristics
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Premature ovarian failure cases (n, %)
Controls (n, %)
P-value
OR (95% CI)
Area under curve
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Intercept Residence Urban Q13 Suburb Rural Housing renovation Exposure to chemical agents Pelvic surgerya Relativesb with menstrual abnormalities Dietary habits Balanced diet Vegetarian diet Diet rich in animal protein Drinking habits Tap water Q14 Mineral water Pure water Tea consumption
<0.01 216 84 248 115 46 36 95
(39.06) (15.19) (44.85) (22.80) (8.32) (6.51) (17.18)
(27.00) (27.50) (45.50) (5.75) (2.00) (1.25) (0.75)
NA <0.01 NS <0.01 <0.01 <0.01 <0.01
419 (75.77) 72 (13.02) 20 (3.62)
236 (59.00) 153 (38.25) 11 (2.75)
NA <0.01 NS
1.00 (reference) 0.19 (0.12 to 0.30) 0.97 (0.30 to 3.15)
359 121 67 22
228 122 50 201
NA 0.01 NS <0.01
1.00 0.56 0.80 0.03
(64.92) (21.88) (12.12) (3.98)
108 110 182 23 8 5 3
0.889
(57.00) (30.50) (12.50) (50.25)
1.00 0.46 0.77 11.40 6.34 13.41 18.01
(reference) (0.28 to 0.77)** (0.51 to 1.18) (5.71 to 22.76) (2.06 to 19.52) (3.84 to 46.91) (5.03 to 64.48)
(reference) (0.36 to 0.87)* (0.46 to 1.38) (0.01 to 0.05)
NS, not statistically significant. a Pelvic surgery included ovarian cystectomy (endometrial, simple serous and teratoma cysts), unilateral oophorectomy and surgery for tubal ectopic pregnancies (salpingectomy and salpingostomy). b Relatives included mother, sister, aunt and grandmother.
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insufficiency after cystectomy was 4–6 years. Some patients, however, experienced ovarian insufficiency within 1 year (Busacca et al., 2006; Takae et al., 2014). Therefore, it was important to monitor ovarian reserve long after pelvic surgery, particularly for patients who wish to conceive in the future. Chemical agents have been shown to increase apoptosis or atresia of the primary or primordial follicle, resulting in decreased ovarian reserve (Béranger et al., 2012). Polycyclic aromatic hydrocarbons (environmental toxicants found in cigarette smoke) (Jurisicova et al., 2007; Mikkelsen et al., 2007), 4-vinylcyclohexene (produced during the manufacture of rubber tires) (Hoyer et al., 2001; Mayer et al., 2004; Takai et al., 2003), 2-bromopropane (a solvent for cleaning electrical components) (Boekelheide et al., 2004; Koh et al., 1998), Perfluorooctanoate and perfluorooctanesulfonate (manmade chemicals used in numerous household products) (Knox et al., 2011) have been shown to be toxic for follicles, which were components involved in house renovation materials and agriculture chemicals. Mumps is a common childhood infection caused by the mumps virus. The mumps virus leads to local inflammation with infiltrates of lymphocytes and macrophages. The orchitis and oophoritis are common complications of mumps, which develop in 15–30% of boys and 5% of adults with mumps, respectively (Hviid et al., 2008). Inflammation is now recognized as a type of non-specific immune response, either acute or chronic (Fox, 1992). In the past 3 decades, autoimmune mechanism has been shown to be involved in the pathogenesis of POF in up to 30% of cases (Conway, 1996). Autoimmune disorders related to POF include thyroid diseases, mumps, hyperparathyroidism and Addison’s disease. The ovarian biopsy in these conditions showed infiltration of follicles with plasma cells and lymphocytes (Okeke et al., 2013).
It was speculated that mumps might be a result of virusinfected oophoritis and autoimmune response. Few data, however, have supported mumps as a cause of ovarian failure (Morrison et al., 1975; Prinz and Taubert, 1969). In the present study, vegetarian diet, mineral water and tea consumption were found to be protective for ovarian function, attributed to an antioxidant effect. Harvey et al. (2002) found that mammalian oocytes were sensitive to oxidative stress, and that high levels of oxidative stress impaired oocyte maturation. High levels of reactive oxygen species led to mi- Q8 tochondrial DNA alterations and mitochondria dysfunction followed by impaired oxidative phosphorylation, and thus exhausted oocytes. Fruits, vegetables, tea and other plantderived food are abundant in natural antioxidants and flavonoids. An association has been found between trace elements present in mineral water, such as zinc and copper, and immune response, inflammation and oxidative stress (Kebapcilar et al., 2013). It has been suggested that flavonoids might inhibit oxidation and DNA damage by decreasing free radical formation, scavenging free radicals, and enhancing antioxidant capacity (Lopez-Lazaro, 2002; Ross and Kasum, 2002). The protective effect of certain flavonoids is to be encouraged. The early diagnosis of POF before irreversible damage to the ovarian pool is unfeasible in most cases, and, therefore, identification of risk factors for prevention is urgent. In the present study, heredity, pelvic surgery, mumps and exposure to toxic were identified as risk factors for POF, whereas vegetarian diet and tea and mineral water consumption were found to be protective. Therefore, genetic consultation is recommended for women with POF. Avoidance of exposure to endocrine disrupters could be considered as a preventative Q9 strategy and intake of certain flavonoids is suggested.
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
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Acknowledgements
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This work is supported by grants from the National Basic Research Program of China (973 program-2012CB944700), the National Natural Science Foundation of China (81270662, Q10 81370687, 81370692), Foundation for the Author of National Excellent Doctoral Dissertation of the People’s Republic of China (201078), and Independent Innovation Foundation of Shandong University (IIFSDU) (2012TS130).
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ARTICLE IN PRESS Risks for POF in Han Chinese 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
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Declaration: The authors report no financial or commercial conflicts of interest.
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Received 10 October 2014; refereed 17 December 2014; accepted 17 December 2014.
Please cite this article in press as: Huidan Wang, et al., Risks associated with premature ovarian failure in Han Chinese women, Reproductive BioMedicine Online (2015), doi: 10.1016/j.rbmo.2014.12.013
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