Is Metabolic Syndrome a Fellow Traveler with Abnormal Uterine Bleeding in Women of Reproductive Age? A Case–Control Study

The menstrual cycle, a natural phenomenon, is the periodic shedding of endometrium because of hormonal changes occurring during the reproductive years of a woman. The menstrual cycle is divided into the proliferative or follicular phase and the secretory or luteal phase. The normal length of the menstrual cycle is the number of days between the 1st day of menstrual bleeding to the next and normally it ranges from 28 ± 7 days in women.[,] Abnormal uterine bleeding (AUB) is a frequent but serious presentation with variation in normal frequency and the regularity of the menstrual cycle, the duration, and the amount of blood loss during the menses. AUB is a major reason for gynecological consultations worldwide.[] One of the widely used classifications based on the cause for AUB is the PALM-COEIN classification which stands for AUB due to polyp is AUB-P, adenomyosis is AUB-A, leiomyoma is AUB-L, malignancy, and hyperplasia is AUB-M, coagulopathy is AUB-C, ovulatory dysfunction is AUB-O, endometrial is AUB-E, iatrogenic is AUB-I and not otherwise and is AUB-N.[] The prevalence of AUB differs with the different populations worldwide. The overall prevalence spans from 10% to 30% in women.[,,] The reported prevalence of AUB in Shimla, India, is 17.9%,[] and in Silchar, India it is 20.48%, representing the burden of the disease.[] Indian cultural trends of early menarche, early marriage, and frequent pregnancies in Indian women[] could be one of the risk factors of AUB, which has not been adequately explored. India is considered the diabetes capital of the world. Diabetes poses a significant health-care burden to the country in particular reaching almost epidemic proportions and also to the world at large.[,] Diabetes mellitus is a known and well-established risk factor for cardiovascular diseases. In addition to diabetes mellitus, hypertension, abdominal obesity, increased fasting blood sugar (FBS), and dyslipidemia are also considered major cardiometabolic risk factors.[,] These also form the core diagnostic parameters of metabolic syndrome and have shown to have a major influence on not only the initiation but also the progress and course of endometrial pathology in postmenopausal women of more than 50 years[] and there are very few studies in young women. Furthermore, metabolic syndrome is an already proven risk factor for endometrial cancer which is one of the causes of AUB.[] It is well-known that women in developing countries such as India often have limited autonomy in matters concerned with their health decisions,[] and hence, often leading to neglect of their overall health. Besides, AUB can also have a major social, psychological, and economic impact on women aged 18–45 years, in their most productive stage of life, and when the social and family responsibilities are the greatest. It is thus the direct cause of a significant health burden for women and their related stakeholders.[] Since, Indians have a high propensity for metabolic syndrome[] with a gap in the existing literature for the association of menstrual and obstetric patterns, cardiometabolic risk factors, and metabolic syndrome with AUB in women of reproductive age, we had planned to undertake this study among young women patients with AUB and compare them with age-matched controls.

A case–control study was conducted in the department of physiology in collaboration with Department of Obstetrics and Gynecology of a Medical college hospital in Dakshina Kannada, Karnataka, India. All the women attending to gynecology department during the period from August 2018 to January 2019 were considered as the study population. Thirty (n1 = 30) women were selected for our study and were labeled as “cases” after adhering to the following inclusion and exclusion criteria: Those who had presented with complaints of AUB and those who had consented to share their records for the purpose of the study were included in the study. Women who had AUB due to pregnancy, IUCD, endometrial hyperplasia and malignancies, coagulopathies were excluded from the study. For comparison, 31 (n2 = 31) age-matched women without AUB were selected and were labeled as “controls.” The present study was conducted after obtaining approval from the University Ethics Committee (YEC2018/083). Written informed consent was obtained from each participant after describing in full detail the procedure and purpose of the study. The following cardiometabolic parameters were collected from the study participants: Menstrual and obstetric history A detailed menstrual history, including the age of menarche, age of marriage, parity, and type of contraceptive used including oral contraceptive pills and intrauterine devices, was elicited. History of the type of child delivery (cesarean delivery and normal delivery) the participant had during the delivery of her child was elicited. Cardiometabolic risk factors Anthropometric measurements Anthropometric parameters of the study participants were measured. The subject was instructed to stand erect. A wall-mounted stadiometer was used to record the height to the nearest 0.5 cm. Subjects removed their shoes and stood with their heels together, backs straight, and a relaxed abdomen for measuring height. The body weight of the subject was measured without shoes/chappals in kilograms using a weighing scale. Body mass index (BMI) was derived using the Quetelet formula: BMI = weight in kilograms/height in m2. Waist circumference was measured using a measuring tape in a horizontal plane, midway between the lowest rib and iliac crest after normal expiration to the nearest 0.1 cm. The hip circumference was taken at the level of maximum circumference of the hip to the nearest 0.1 cm. measured in centimeters at the widest girth of the hip. Then, the waist-to-hip ratio (WHR) and waist-height ratio (WHtR) were calculated. Central obesity was defined WHR above 0.85 for women.[] Basal cardiovascular parameters Blood pressure (BP) was recorded in the sitting position on the upper arm, with a suitable-sized cuff following a minimum of 10 min of rest using a sphygmomanometer of Diamond Company India. The average of the last two measurements was used for the analysis according to Joint National Committee 8 criteria.[] Biochemical parameters Blood was estimated for FBS (FBS, mg/dl) and fasting lipid profile which included total cholesterol (TC, mg/dl), triglycerides, high-density lipoprotein (HDL, mg/dl), low-density lipoprotein (LDL, mg/dl), and very LDL (VLDL, mg/dl) by an automated method using VITROS 5600 Integrated Chemistry System. Metabolic syndrome With the above-mentioned anthropometric and biochemical parameters, it was determined if the study participants have metabolic syndrome. Based on Harmonization of Metabolic Syndrome: Joint Interim Statement of the International Diabetes Federation Global consensus definition, and also a Consensus Statement for Diagnosis of Obesity, Abdominal Obesity, and the Metabolic Syndrome for Asian Indians the presence of any 3 of the following five criteria is necessary for a woman to have metabolic syndrome; (a) increased waist circumference: ≥80 cm, (b) Increased Triglyceride: ≥150 mg/dl or on pharmacological treatment, (c) HDL cholesterol: 130 mmHg systolic BP or >85 mmHg diastolic BP or on treatment for hypertension, and (e) FBS: ≥100 mg/dl, or on treatment for diabetes mellitus.[,] By this, we identified the participants who had metabolic syndrome. Statistical analysis Statistical analysis was done using the IBM SPSS Statistics for Windows Version 21.0, Armonk, NY, USA and MS Excel. Age, anthropometric parameters (BMI, WHR, and WHtR), FBS, and fasting lipid are expressed as mean ± standard deviation and an unpaired t-test was done to compare the cases with the control group. The age of marriage, type of contraceptive use, parity, number of delivery, and the number of abortions were analyzed using the Chi-square test. The odd’s ratio was applied to determine the occurrence of metabolic syndrome in participants. All tests are two-tailed and P < 0.05 was considered statistically significant.

Both the groups were age matched with the mean age of the cases 38.9 ± 7.4 years and controls 35.8 ± 10.7 years which was not statistically significant. Among the cases, 23 of them belonged to 36–45 years, 4 belonged to 26–35 years, and 3 belonged to 18–25 years of age. The age of menarche in the cases was 12.9 ± 1.2 years and the controls group was 13.2 ± 1.1 years (P = 0.3), and the difference was not significant. A statistically significant number of cases had married earlier 18–23 years when compared to controls [Figure 1]. A significant number of cases (73.3%) have parity ≥2 when compared to control [Table 1]. Even though the BMI, WHR, and WHtR were higher in cases, it did not attain statistical significance [Table 2]. There was a significant increase in FBS, TC triglycerides, LDL, and HDL in cases than controls [Table 3]. A 33.3% of cases had metabolic syndrome. Women with metabolic syndrome were 15 times more likely to develop AUB, as compared to normal women [Table 4].

The prevalence of AUB is on the rise among the reproductive age group women of the Indian population with an Indian doctors’ survey reporting that 32.72% of women patients consult a physician because of AUB.[] Our study represents the influence of menstrual patterns on AUB and the odds that metabolic syndrome may coexist with AUB among young women of the reproductive age group. In our study, AUB had a peak incidence in 36–45 years with the mean age being 38.9 ± 7.4 years. Ali etal., in Gauhati, India found that majority were between 31 and 40 years of age.[] Mahapatra et al., in a study done in Bhubaneswar, India reported that 52 cases out of 140 cases were between 41 and 45 years of age.[] In contrast, Kotagasti, in Bangalore, India reported out of 1362 patients with AUB majority of patients belonged to 25–34 years cohort.[] This further proves that the incidence of AUB is increasing in the young women population. Menstrual history and obstetric history The menarcheal age of cases was less (12.9 ± 1.2 years) than the controls (13.2 ± 1.1 years), even though it did not reach a significant level. The analysis done by Pathak etal., on the menarcheal age of women in India showed a fall of nearly 1 month/decade.[] This could be one of the reasons for the increasing incidence of AUB as women are exposed to a longer duration of ovarian hormones. Both our cases and controls had lower age of menarche when compared to a study done by Omidvar et al., (13.36 ± 1.25 years) in Mysore, Karnataka.[] This difference could be because of regional, racial, socioeconomic, nutritional, health, and environmental factors influencing menarcheal age.[,] In the present study, women who married at an early age (18–23 years) were significantly associated with AUB when compared to the controls. In contrast, Alenezi etal. reported that most of the AUB cases married at 20–30 years.[] This disparity could be explained by the Indian cultural trend of early marriage and early childbirth contributing to early exposure to hormonal changes. In line with Ali etal., the majority of our study cases were ≥2 parity.[] Cardiometabolic parameters and metabolic syndrome In line with an earlier study, our study also had significant dyslipidemia with abnormally elevated blood sugar levels among cases as compared to that of controls.[] Obesity with high BMI is a known risk factor for AUB.[] Even though in the present study, the BMI, WHR, and WHtR were higher in cases, it was not statistically significant. However, Szhang Y et al., found a significant association of increased WHR with AUB.[] Our study did not document an abnormally elevated WHR and we attribute it to the racial difference in the study cohort. The occurrence of metabolic syndrome (According to the International Diabetic Federation 2005) was very high (33.3%) with an odds ratio of women having metabolic syndrome developing AUB being 15 times. Anupamasuresh etal. also found the prevalence of diabetes and hypertension in AUB patients.[] Similarly, Sowjanya etal. conducted a hospital-based study in Guntur, Andhra Pradesh, India on fifty patients and concluded that AUB is associated with a high prevalence of metabolic syndrome.[] Angiogenesis, a repeated process normally occurring in the uterus, supports the periodic growth, sloughing, and restoration of the endometrial layer and is a tightly regulated process by the ovarian hormones.[] Angiogenesis also requires nitric oxide (NO), platelets, and other growth factors. Insulin resistance, a feature of metabolic syndrome is documented to reduce NO and thus enhance shear stress on the endometrial cells.[] Reduced NO could thus be the contributing factor in AUB pathology. Further, patients with metabolic syndrome had an excess release of inflammatory cytokines and free radicals leading to endothelial damage, tissue hypoxia, and apoptosis. All of these pathological processes aggravate and precipitate AUB. Metabolic syndrome has a strong association with the severity of coronary artery disease as reported by Mahalle et al.[] Hence, it becomes imperative to reduce the incidence of metabolic syndrome not only because it is associated with AUB but also because of its strong association with coronary artery disease, especially in young women. A small sample size of this study is the limitation, similar such studies on a larger population form its future scope.

We conclude that age of menarche and type of contraceptive use did not influence but lower age of marriage and number of pregnancies had a profound effect on the occurrence of AUB in reproductive age group women. The presence of comorbid conditions such as diabetes and hypertension with increased FBS and TC, triglycerides, LDL, and decreased HDL increases the risk of AUB. Metabolic syndrome is significantly associated and could be a potential fellow traveler with AUB in women of reproductive age. The need of the hour is health education, to implement simple lifestyle changes which could go a long way in decreasing metabolic syndrome and eventually the occurrence of AUB in young women. Financial support and sponsorship This project was funded by Indian Council of Medical Research, under the Short Term Studentship Program (Reference ID: 2018-01143). Conflicts of interest There are no conflicts of interest. Acknowledgment We would like to acknowledge the contribution of the faculty of the Department of Obstetrics and Gynecology, Yenepoya Medical College, Mangalore for their constant support and Dr. Shobith Bangera, Associate Professor, Department of Physiology, Yenepoya (Deemed to be University) for his support during the statistical analysis.

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