Endometriosis is disease with enigmatic etiology and an anticipated prevalence of 10%, and it can result considerable morbidity, and it is associated with risks for several major chronic diseases, psychological disorders and infertility [9, 10]. Our preliminary study evaluated the effects of BMI on IVF outcomes in non-obese endometriosis patients. To the best of our knowledge, this is the first study to address this issue in a very homogenous group of patients where the all other infertility causes were excluded, and where the diagnosis of endometriosis had been previously established solely during laparoscopy. Preliminary evaluation suggests that infertile women with endometriosis regarding BMI do not differ significantly in IVF outcomes. Nevertheless, a certain differences exist and although some did not reach statistical significance, ones deserve to be thoroughly annotated.
The prevalence of endometriosis as a single infertility factor among IVF couples was 5.61%. Apparently, the stringent selection study criteria led to the decrease of the number of evaluated endometriosis patients, thus explaining why this prevalence is lower than 9%, as described by other authors [11]. The only study that provided data on the prevalence of under, normal and overweight endometriosis patients who underwent IVF procedure [12], together with studies which revealed the prevalence of those BMI groups in general population of infertile women [13] or population undergoing IVF [11, 14] were published over 15 years ago. The prevalence of underweight infertile women irrespective to infertility causes was 3%, normal weight 17% and overweight 42% [13]. However, the same prevalence among infertility patients who underwent IVF in France were 21.8, 55.8, and 10.3% respectively [14], while in Australia were 12.3, 53.26, and 22.69% respectively [11]. Among non-obese endometriosis patients who underwent IVF in Portugal 21.22% were underweight, 59.4% normal weight and 19.54% were overweight women [12]. However, today’s lifestyle and behavior choices are often sedentary and unhealthy and consequently could lead to regrouping of women between populations of underweight, normal weight, overweight and obese women. We delivered up-to-date information on the specific prevalence of those groups among non-obese infertile women with endometriosis undergoing IVF: underweight, normal weight and overweight participants accounted for 10.26, 71.5 and 18.58% of study population, respectively. One of the aims of preliminary evaluation studies is to provide up-to-date data required for the future prospective trials [15]. The importance of such data lies in fact that an estimate of prevalence is needed for sample size calculation, especially under such circumstances where prevalences differ considerably [16]. Since the literature often delivers several different prevalences, up-to-date facts from the most recent preliminary studies with similar study design and population are most preferable [16]. Therefore, future investigators could calculate sample size according to planed primary study endpoint, estimation of pregnancy rates and on those grounds to appraise the time needed to enroll the target number of participants and the overall duration of the trial [15].
Analysis of characteristics of study participants demonstrated several significant dissimilarities between study groups. Underweight and normal weight patients more frequently reside in urban settlements, while overweight patients more often inhabit rural areas. This is in accordance with the study performed in the general population of women, which additionally noted that the rate of overweight increase is greater in rural areas than in urban areas [17]. Moreover, the mean age according to the study groups tends to increase as BMI increases (p < 0,001). Missmer et al. observed that the incidence rates of laparoscopically confirmed endometriosis are inversely associated with age [18]. This finding, together with our results which showed that the higher grades of endometriosis are more often present in patients with lower BMI, explains the highly significant differences in age among the study groups, with higher prevalence of moderate and severe forms of the disease among women with lower BMI and vice versa. Furthermore, BMI displayed an inverse gradient from less to more educated groups (p = 0,002) which is in line with the study of Lassale et al. [19].
Underweight participants more frequently have grades III and IV of the disease, while overweight patients more frequently have grade I endometriosis (p = 0,021). This is in the line with the findings of the majority of other authors [4, 12, 18]. Furthermore, Missmer et al. showed that BMI was associated with the incidence of endometriosis [18], while Moini et al. consider that BMI may be regarded as predictive factors not only for any type of endometriosis but also for severe ones [4]. In contrast, Hemmings et al. did not show any significant correlation between BMI and endometriosis [20]. However, they had different inclusion criteria in terms of a broad spectrum of preoperative indications (infertility, pelvic pain, pelvic mass, and others) and applied type of surgery (laparoscopy/laparotomy, tubal ligation/reanastomosis, hysterectomy). Besides, BMI showed a highly significant inverse correlation with endometriosis grade as infertile women with lower BMI tend to have the more severe form of the disease (p < 0.001). This finding was in agreement with studies by Calhaz-Jorge et al. [12], an Italian group [21] and Hediger et al. [22] study and could be explained with the fact that the severity of endometriosis is correlated with peripheral body fat distribution [5]. Underweight and normal weight patients had less frequently extensive surgical treatment (cystectomy of the endometriomas) comparing with overweight patients, due to fall in prevalence of moderate and severe endometriosis grades with increasing BMI.
The doses of used gonadotropins did not significantly differ between study groups. In contrast, most studies agree that the increase in BMI is related with the increased amount of gonadotropins used in the process of COS [1]. While some studies find the significant difference in the quantity of the used gonadotropins in both antagonists, as well as in agonist protocol [23], the other finds this significance only in antagonist protocol [14]. Unlike our study, the mentioned studies evaluated the impact of BMI on the applied amount of gonadotropins among women with different causes of infertility. This may indicate the different impact of BMI on ovarian response to COS in endometriosis patients, particularly if one takes into account that required gonadotropin doses per follicle is significantly higher in endometriosis compared to the women with tubal infertility [24]. The mean stimulation duration differed significantly according to the BMI groups, being highest in the overweight group, which is in line with study of Fedorcsák et al. [25] and Dokras et al. [26], but in contrast to other studies [14, 23]. Still, Wittemer et al. performed study in general population of women undergoing IVF [14], while Marci et al. had endometriosis and type 1 diabetes as exclusion criteria [23].
Several reasons necessitate assessment of BMI influence on IVF outcome among non-obese women with endometriosis. The largest number of women undergoing IVF falls into the category of non-obese women. Besides, endometriosis is inversely related with early adult BMI, unlike most other infertility causes, in which higher BMI decreases reproductive chances [5]. Finally, understanding the impact of BMI on the IVF outcomes in endometriosis women would allow counseling of patients regarding the achievement of ideal BMI prior to the procedure, as part of the individual approach in the infertility treatment.
The previous studies demonstrated negative correlation between BMI and the number of oocytes retrieved in general population of women undergoing IVF [14, 27, 28]. Furthermore, even when divided into underweight, normal weight, overweight group, the underweight women have more oocyte retrieved [28]. Still, our results aroused from the analysis of IVF treatment of women with endometriosis as sole infertility factor were unable to confirm this relationship. Paradoxically, underweight women, who were significantly younger then overweight and normal weight patients, had the lower mean number of retrieved oocytes, although this difference did not reach statistical significance. Possible explanation could be higher prevalence of stage III and IV endometriosis observed among underweight participants compared to other study groups. Women with stage III-IV of endometriosis have fewer oocytes retrieved compared to women with stage I-II of the disease [29].
Although significant differences were not found between the groups in the number of good quality oocytes, total number of embryos, number of GQ embryos and number of transferred embryos, these figures were higher with the increase of BMI. This is not in accordance with Wittemer et al. who observed significantly lower number of good quality oocytes in overweight and underweight patients comparing to normally weighted women [14]. Significantly lower number of our previously surgically treated participants with higher BMI, together with detrimental relationship between endometriosis with previous ovarian surgery and ovarian reserve reported by Matalliotakis et al. [30], could explain our results. Furthermore, inferior ovarian response is more likely present among the subjects with grade III and IV endometriosis [31, 32], which were significantly more prevalent among our participants with lower BMI. Nevertheless, additional explanation of our findings is necessary since Opøien et al. did not find differences in the fraction of mature cumulus-oocyte complexes between ASRM III-IV and ASRM I-II groups [29].
Significant differences in biochemical, clinical and ongoing pregnancy rates between BMI groups were not found, which is in line with the other studies [14, 33, 34], but in contrast to the study of Marci et al. who found higher clinical pregnancies rates in patients with normal BMI comparing to overweight women [23]. When examined as a main variable alone, BMI does not appear to have a significant effect on IVF outcomes, but BMI x age interaction analysis reveals a marked decrease in pregnancy rates with increasing BMI for patients younger than 27 years of age [35]. Surprisingly, although did not reach the statistical significance, our pregnancy rates were higher with increased BMI values, despite the fact that the average age was the lowest in underweight and the highest in overweight participants.
The strength of the current study is the cautiously chosen homogeneous group of patients, which lessens potential confounders. Furthermore, participants showed fertility difficulties before laparoscopic surgery, consequently fertility problems were not necessarily due to the possible effect of surgery. Besides, endometriosis patients undergoing IVF in tertiary referral centers (as our clinic) usually do not differ from endometriosis patients in non-referral centers and general practices and in this sense external validity of the study is fulfilled. Moreover, we initially addressed the topic where no study has ever been done before and delivered information for further definitive studies and provided up-to-date data, needed for the calculation of the sample size for the future main trials. Additionally, contemporary medicine is focused both on the ideal therapeutic approach and on counseling the patient towards behaviors that optimize the effect of applied treatment. The example is the advice to obese and overweight women for the reduction of BMI prior to IVF treatment to achieve the higher pregnancy rates. However, this recommendation stemmed from studies performed in general population of infertile women. We often advise patients according to known facts concerning the general population of women, regardless to characteristics of a patient or a disease. Simultaneously, modern medicine favors customized approach, both in relation to the patient and in accordance to the type or severity of a disease or condition (e.g. endometriosis and infertility). For that reason, it is important to test if facts established for general populations are proper for each type of patient or infertility cause. Future prospective studies could give answer whether it is appropriate to advice overweight women with endometriosis to lose weight prior to IVF, which we often routinely do? Today we are aware that weight related issues, food and nutrients influence pathogenesis and progression of endometriosis. Therefore, dietary practices and lifestyle behaviors are becoming alternative and adjuvant treatments to combat the disease and its consequences, such as infertility [36].
We are aware that the strict inclusion criteria applied lead to a relatively small number of underweight participants and we acknowledge this as limitation of our study. Nevertheless, the study sample is highly homogenous and almost all confound factors that could lead to bias are therefore eliminated. Limitation of the study could be retrospective design, with issues as different assessment of the pelvis and the stage of the disease, different surgical and IVF approach to endometriosis patients. Nevertheless, participants underwent all procedures in our clinic, where the stuff of the Laparoscopy and IVF departments was stable during the study period and where the procedures for endometriosis patients were not considerably changed over the analyzed period. Besides, disease was staged by the same classification system. Further limitation is related to the fact that BMI should not be the single indicator of weight related health and reproductive issues. It does not distinguish android and gynaecoid fat distribution or regional fat distribution. Still, BMI represents a simple and consistent measure that has been individually and steadily related with numerous clinical endpoints.
