Background: The etiology of uterine leiomyoma (or fibroids) is poorly understood. Sex steroid hormones, genetic, and growth factors have been hypothesized to play a role in their development, and anthropometric characteristics may influence uterine leiomyoma risk through these sex steroid hormones.
Methods: We analyzed retrospectively-collected data from two hundred (200) patients diagnosed as having fibroids and two hundred (200) control subjects with similar age distribution as the patients. Anthropometric features of all participants were taken. Data on anthropometric were analyzed by unpaired t-test analysis and Logistic regression.
Results: There were significant differences between the patients and controls groups in terms of weight, waist circumference, hip circumference, BMI, and waist-to-hip ratio. When subjects’ BMI were classified as underweight (<18.5), normal (18.5 – 24.9), overweight (25.0 – 29.9) and obese (?30), analysis using Logistic regression revealed a strong association between the development of fibroid with an increase in the patients BMI; with the over weight patients having an almost two fold increased risk (OR= 1.91; exact 95% CI= 1.14 - 3.20) and the obese having far more than a two fold risk increased (OR= 2.25; exact CI= 1.21 - 4.17) of developing fibroid when compared to the patients with normal BMI. The under weight patients however had a decreased risk (OR= 0.70; exact 95% CI= 0.34 - 1.42) of developing fibroid when compared to the normal BMI patients. When subjects were categorized as normal or obese based on their waist-to-ratio and analyzed using Logistic regression, there was a strong association between obesity and the development of fibroid (OR= 3.60; exact 95% CI= 1.74 - 7.47) with the obese having close to a fourfold increased risk of developing fibroids.
Conclusion: High BMI and waist-to-hip ratio are may increase the risk of uterine leiomyoma possibly reflecting associated hormonal changes as well as alterations in metabolic controls that affect myometrial cell signaling through mediators such as insulin receptors, insulin-like growth factors, peroxisome proliferating activating receptors, and also influence uterine leiomyomata through changes in steroid hormone metabolism and bioavailability.
Uterine leiomyomas, also known as fibroids, are remarkably common benign smooth muscle tumors of the uterus . Symptoms vary in severity and include pelvic pain, abnormal menstrual bleeding, and pregnancy complications . The etiology of uterine leiomyoma is poorly understood. Studies indicate that hormonal, genetic, and growth factors may play various roles in their initiation and development . Since endogenous hormones influence growth during childhood and are associated with excess weight and body shape, anthropometric characteristics may be an outward reflection of the internal hormonal milieu.
Body composition is one of several possible factors that might be related to fibroid risk. Different epidemiologic studies have evaluated this possible relation but with inconclusive results [4, 5]. Observed associations between anthropometry and fibroids are often explained by an interaction with hormonal levels, but mechanisms through insulin or growth factors have also been proposed [4, 5]. A hormonal etiology for fibroids seems plausible because the normal growth and functioning of the uterus is influenced by steroid hormones. Thus progesterone and estrogen levels have been implicated in fibroid development , and body mass appears to influence serum concentrations of these hormones . In Ghana uterine fibroids are common and account for about 40% of all major gynecological operations . There exist some differences in serum levels of these hormones between blacks and whites populations of women . However most of the studies done on fibroids in relation to anthropometry have been carried out in developed countries where the environmental factors such as diet, exercise, culture, etc., that influence these anthropometric features are quite different from the ones that pertain in the developing countries such as Ghana. Hence the results of some studies from the developed countries do not always reflect what pertains in the developing countries. Separate studies need to be carried out in these developing countries and the results compared to the ones from the developed countries. The aim of this retrospective case-control study was therefore to evaluate associations of weight, body mass index (BMI), height, and waist-to-hip ratio with fibroid development.
Materials and Methods
A total of two hundred (200) patients diagnosed as having fibroids from clinical history, physical examination, ultrasound examination and also confirmed at surgery to have fibroids were consecutively enrolled at the obstetrics and gynaecology department of the Komfo Anokye Teaching Hospital for the study. Five to 6 patients were recruited per week from premenopausal women aged 20 years to 40 years with benign gynaecological pathology who had been proposed for surgery by gynaecologists at the department of obstetrics and gynaecology at the Komfo Anokye Teaching Hospital. Questionnaires were administered after diagnosis was explained to the women and physical examination done by a gynaecologist to determine their suitability or otherwise for the study. Women with obvious hormonal imbalance and chronic or malignant diseases such as diabetes, galactorrhoea, HIV/AIDS, tuberculosis, hepatitis, ovarian tumours and other gynaecological malignancies were excluded. Pregnant women, recently delivered women (delivered less than 6 months) and lactating mothers were also excluded. The questionnaires were also used to determine the socioeconomic background, clinical and gynaecological history. Ethical clearance was obtained from the Committee on Human Research, Publications and Ethics (CHRPE), School of Medical Sciences, Kwame Nkrumah University of Science & Technology (KNUST), Kumasi. Two hundred (200) control subjects with similar age distribution as the patients were also recruited for the study after obtaining their informed consent. The control subjects were examined by ultrasonography to exclude those with fibroids. controls were also carefully screened to exclude women with no past observable fibroids. The exclusion criteria for the control subjects were the same as for the patients and all controls were eligible as patients but for the fact that they had no fibroids. To make sure that the controls were subjected to the same conditions as the patients, only those who came to the obstetrics and gynaecology theatre for surgery and had all the other qualifications for the study as controls were used. Thus, they mostly were made up of women with vesico-vaginal fistulae (VVF), recto-vaginal fistulae, urethro-vaginal prolapses, old third and fourth degree perineal tears, and patients with hydrosalpinges. The consent of all women was sought before enrollment and those who declined to participate in the study did not differ in personal or clinical characteristics from those who participated. Both controls and subjects were given appointments by an obstetrician/gynaecologist for the surgery. They were admitted a day to the surgery at the obstetrics and gynaecology ward of the Komfo Anokye Teaching Hospital.
Anthropometric features of all participants were taken before they were operated upon. The weight of the subject was taken using bathroom weighing scale (Zhongshan Camry Electronics Co. Ltd., Guangdong,China) while barefooted and on light clothing to the nearest Kg. The height of the subject was also measured to nearest meter using a Gullick II Tape Measure (model 67020) which was mounted on a wall. The floor of the room where these measurements were done was flat and tiled. The waist circumference of the subject was taken using a measuring tape midway between the inferior angle of the rib cage and the suprailiac crest. The hip circumference of the subject was also taken using a tape measure at the outermost point of the greater trochanters. all parameters were taken twice a day, one in the morning and one in the evening and the average of the two computed. The body mass index (BMI) was then calculated by dividing the weight of the patient in kilograms by the square of her height in meters. The waist to hip ratio was computed by dividing the waist circumference by the hip circumference.
The surgical operations were undertaken by obstetrician/gynaecologists of the K. A.T. H. At laprotomy for myomectomy or hysterectomy, the uterine size was estimated in comparison to a gravid uterus. The number of myoma nodules removed were counted and recorded. The locations of the tumours within the uterus were also stated. The total weight of the tumour, that is the weight of all myomas removed at myomectomy or the uterus plus myomas in the case of hysterectomy were taken using a weighing scale.
Based on the WHO guidelines , subjects were categorized as underweight, normal, overweight, or obese based on their BMI. The subjects were also categorized as either normal or obese based on their WHR. The data on anthropometric features are presented as mean (± SEM). Data were analyzed by unpaired t-test anaysis. The data obtained from questionnaire were analysed using logistic regression and all odds ratios provided in this study were adjusted for the most potential confounders such as reproductive history, education and alcohol intake. All statistical analysis were done using GraphPad Prism version 5.00 for Windows, GraphPad Software, San Diego California USA and MedCalc for Windows, version 184.108.40.206 (MedCalc Software, Mariakerke, Belgium). In all statistical test, p values are two sided and a value of p<0.05 was considered significant.
Table 1.0 shows the general characteristics of the study population. The age of the patients and the controls are not significantly different from table 1.0.
The weight of patients differed significantly from those of the control subjects when the data was subjected to unpaired t-test analysis (t=2.244, p=0.0326). The mean weight of the patients was 92.50 ± 2.22 Kg while the mean weight of the control subjects was 83.55 ± 3.57 Kg as shown in Table 2.0. Spearman’s correlation analysis showed that the weight of the patient had a significant positive correlation with the height, waist circumference, hip circumference and BMI but had no significant correlation with the waist-to-hip ratio for both controls and patients; or weight of tumour developed in the case of patients; as shown in Table 3.0.
With a mean height of 1.60 ± 0.01 m and 1.59 ± 0.01 m for the patients and controls respectively there was no significant difference between the two groups (t=0.3788, p= 7060) as Table 2.0 shows. When correlated with the other anthropometric variables using Spearman's analysis, the height of the patient only had a positive correlation with the weight. The waist circumference, hip circumference, BMI and waist-to-hip ratio all had no significant correlation with the height in both patients and control groups as Table 3.0 shows. For the patients, the weight of the tumour developed did not correlate significantly with the height.
Table 2.0 shows that the Mean values for waist circumference for controls and patients were 66.44 ± 3.31 cm and 87.44 ± 3.47 cm implying a significant difference between the two means (t=4.352, p=0.0001). Within the patients waist circumference had a significant positive correlation with the weight, hip circumference, BMI and the waist-to-hip ratio but not with the height and the weight of tumour developed. For the controls there was a significant correlation between the waist circumference and, weight, hip circumference and BMI, but there was no significant correlation for the height and the waist-to-hip ratio as shown in Table 3.0.
A significant difference(t=2.028, p= 0.0474) was revealed after unpaired t-test analysis of the data with a mean hip circumference of 76.79 ± 5.23 cm for the control group and a mean of 92.55 ± 3.91 cm for the patients. This difference the means between the two groups can be seen in Table 2.0. There was a significant correlation between the hip circumference and the weight, waist circumference and BMI for both groups but on significant correlation for waist-to-hip ratio and height of the subjects. The tumour developed did not also correlated significantly with the hip circumference of the patients as seen in Table 3.0.
Comparison of BMI values for the patients and controls using unpaired t-test analysis showed a significant difference between the two groups (t=6.020, p<0.0001) with a mean BMI of 22.40 ± 0.22 and 25.35 ± 0.49 for the controls and the patients respectively as shown in Table 2.0. The BMI also correlated significantly with weight, waist circumference and hip circumference of both patients and control groups but did not have a significant correlation with height and the waist-to-hip ratio. The tumour weight and the BMI had a significant correlation as shown in Table 3.0. When subjects were classified as underweight (<18.5), normal (18.5 – 24.9), overweight (25.0 – 29.9) and obese (?30), analysis using Logistic regression revealed a strong association between the development of fibroid and an increase in the patients BMI; with the over weight patients having an almost two fold increased risk (OR= 1.91; exact 95% CI= 1.14 - 3.20) and the obese having far more than a two fold risk increased (OR= 2.25; exact CI= 1.21 - 4.17) of developing fibroid when compared to the patients with normal BMI (Figure 1.0). The under weight patients however had a decreased risk (OR= 0.70; exact 95% CI= 0.34 - 1.42) of developing fibroid when compared to the normal BMI patients (Table 4.0).
WHR for controls and patients were significantly different (t=2.763, p= 0.0084) although both groups had high WHR with a mean WHR of 0.91 ± 0.01 for the patients and 0.87 ± 0.01 for the control group as shown in Table 2.0. Except for the waist circumference of the patients where there was a significant correlation, the WHR did not correlate significantly with any of the other anthropometric variables in both groups as seen in Table 3.0. When subjects were categorized as normal or obese and analyzed using Fisher’s exact test, there was a strong association between obesity and the development of fibroid (OR= 3.60; exact 95% CI= 1.74 - 7.47) with the obese having close to a fourfold increased risk of developing fibroids as shown in Table 4.0.
This study found significant difference in weights but not the heights between the subjects in the two groups. The heights of subjects in both groups were similar and did not correlate significantly with the weight of the tumour obtained from the patients. Overall, it was observed that body mass index (BMI), weight, and waist-to-hip ratio were each associated with an increase in uterine leiomyoma risk. However, it was observed that there was no association with height. This pattern suggests that body mass and weight gain increases uterine leiomyoma risk, while height does not. Although height is associated with higher follicular-phase plasma oestradiol levels in premenopausal women  this study found no evidence of an association between height and uterine leiomyomata, consistent with findings from other studies . A significant difference in weight between the two groups and an insignificant difference in height between them resulted in the patients recording higher BMI compared to the controls. This observation suggests an association between high BMI and leiomyomata development and/ or growth. Though other studies have come out with similar findings, it is unclear whether BMI actually plays a role in development leiomyomata or it aids their growth; or both. Several epidemiologic studies [5, 12, 13] have found that the risk of uterine leiomyomata increases monotonically with increasing BMI. The results of this study also showed an association between increase in BMI and the risk of developing fibroid. This finding is also consistent with the findings of some other studies. In two of these studies the heaviest women were at 2- to 3-fold greater risk than the leanest women [5, 13]. Data from other studies, however, do not agree with the findings of this study as they show little or no increased risk associated with elevated BMI [14-16]. In one study where uterine leiomyomata confirmed by ultrasound were included, the associations tended to be weaker than when analyses were restricted to uterine leiomyomata confirmed by hysterectomy . This finding suggests that if obesity is related to uterine leiomyomata, it may be involved in enhancing the growth of uterine leiomyomata and/or promoting the development or severity of symptoms. There is some evidence from one cohort study that women who experience an increase in weight during the reproductive years are at increased risk, whereas weight at 18 years of age is not related to risk . The mean BMI for the patients was 25.35 ± 0.49 which suggest that the patients were generally slightly overweight in this study whereas the control subjects were generally of normal BMI as shown by a mean BMI of 22.4 ± 0.22. The results of this study also showed a higher mean serum progesterone concentration among the patients compared to the controls. Thus, the possible association between obesity and uterine leiomyomata may reflect associated hormonal changes as well as alterations in metabolic controls that affect myometrial cell signaling through mediators such as insulin receptors, insulin-like growth factors, and peroxisome proliferating activating receptors. Since ovarian hormones are believed to play a key role in the aetiology of uterine leiomyomata , body mass index which is a measure of absolute body fat  may influence the risk of uterine leiomyomata through changes in steroid hormone metabolism and bioavailability . Studies in premenopausal women have consistently documented an inverse association between BMI and circulating levels of sex hormone-binding globulin [11, 20]. Decreases in sex hormone-binding globulin may increase the proportion of free oestrogen or the fraction available for biologic activity . Obesity is associated with diminished 2-hydroxylation of estrone to catechol oestrogens and increased 16-alpha-hydroxylation of estrone to estriol, thereby producing oestrogens with greater uterotropic activity . The relation of uterine leiomyomata to body fat distribution, as measured by waist circumference or waist-to-hip ratio , has been evaluated only to a limited extent. Several studies have documented that central obesity is greater for black women than white women and is positively associated with age and parity which are all increased risk factors for fibroids. There is also evidence that women with greater upper body obesity have decreased sex hormone-binding globulin levels, altered oestrogen metabolism, and hyperinsulinaemia, factors that may promote tumour development.
In this study, evaluation of waist-to-hip-ratio showed a significant difference between the patients and the control group as the figures was generally higher for the patients. Again there was a positive significant correlation between the waist-to-hip ratio and the weight of the tumour obtained at surgery which implied that the waist-to-hip ratio could have an influence in the development and/or growth of the tumour. Independent of BMI, central obesity (excess fat in the upper trunk region) is associated with hormonal and metabolic changes in premenopausal women, including altered oestrogen metabolism, insulin resistance and hyperinsulinemia, and decreases in sex hormone-binding globulin levels [21-24]. Insulin, which is itself a mitogenic agent , is associated with down-regulation of sex hormone-binding globulin  and up-regulation of insulin-like growth factor-1 and epidermal growth factor. These agents could influence tumour development through direct promotion of myometrial smooth muscle cell proliferation or enhanced ovarian hormone secretion [18, 19]. The underweight subjects showed a rather reduced risk of developing fibroids according to the results of this study. Therefore this study suggests that being underweight is protective for fibroid. This finding of a reduced risk among the leanest women (BMI <20 kg/m2) supports the hypothesis that uterine leiomyomata are hormone-dependent tumours . It has been proposed that a variety of hormones may be involved in this modification of risk, given that thin or anorexic women are found to have higher levels of sex hormone-binding globulin [24, 25], decreased prolactin secretion , and increased hydroxylation of estrone to catechol oestrogens  —all of which may create an endogenous hormonal milieu with lower susceptibility to uterine leiomyomata.
BMI was found to be positively associated with leiomyomata development and/or growth. This possible association between obesity and uterine leiomyomata may reflect associated hormonal changes as well as alterations in metabolic controls that affect myometrial cell signaling through mediators such as insulin receptors, insulin-like growth factors, and peroxisome proliferating activating receptors. BMI may also influence uterine leiomyomata through changes in steroid hormone metabolism and bioavailabilty.
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