Endometriosis is an estrogen-dependent chronic pelvic inflammatory disease characterized by the implantation and growth of endometrial tissue (glands and stroma) outside the uterus [1] [2] [3] . Endometriosis affects approximately 10% - 15% of women of childbearing age [4] [5] . The most common symptoms of the disease are pelvic pain, dysmenorrhea and infertility [1] [2] [3] [4] [5] . However, endometriosis can also be asymptomatic [5] [6] [7] .

The etiology of endometriosis is still poorly understood [8] - [14] . Several studies have shed light on the role of factors in the development of endometriosis such as familiar tendency, genetic predisposition, epigenetics, immune system dysfunction as well as oxidative stress [2] [8] [9] [10] [15] [16] [17] [18] [19] . It is now widely accepted that oxidative stress, defined as an imbalance between reactive oxygen species (ROS) and antioxidants, may be involved in the pathophysiology of endometriosis causing a general inflammatory response in the peritoneal cavity [17] [18] [19] . ROS are intermediates produced by normal oxygen metabolism and are inflammatory mediators known to modulate cell proliferation and have deleterious effects [20] . An excess of free radicals or an antioxidant deficit can cause oxidative stress and thus contribute to the development of certain inflammatory diseases including endometriosis [17] [18] [19] [20] . Indeed, oxidative stress and inflammation are closely linked processes: free radicals promote inflammation via inflammatory mediators (e.g. pro-inflammatory cytokines and prostaglandin 2), and inflammation causes the production of free radicals [10] [13] [21] [22] . Several studies have shown increased oxidative stress in the serum and peritoneal fluid of endometriotic women [14] [20] . An increase in oxidative stress has been shown in epithelial cells derived from ovarian endometriomas, secondary to an increase in the production of ROS and a lack of detoxification [23] . Moreover, this has been confirmed in vivo on mouse models of endometriosis treated with an antioxidant, N-acetyl-cysteine, which allows not only the reduction of endometriotic implants but also the decrease in local inflammatory phenomena [23] - [30] . Among the various antioxidant (enzymatic and non-enzyme), such as superoxide dismutase, catalase and glutathione peroxidase [24] [26] , vitamin E (neutralizing hydrogen peroxide) can play a crucial role by limiting the production of ROS, inactivating them and contributing to repair cell damage.

Vitamin E has received a lot of attention in recent years for its ability to improve reproductive health [31] [32] [33] . Moreover, vitamin E is involved in a wide range of physiological processes, from immune function and inflammation control to the regulation of gene expression and cognitive performance [33] . Vitamin E deficiency is a global public health concern [34] [35] . It is estimated that 2 billion people worldwide suffer from micronutrient deficiencies, especially pronounced in Africa [36] . Several epidemiological studies have shown that supplementation with a trace element, including vitamin E, considerably reduces the symptoms associated with endometriosis and improves the quality of life of endometriosis women [37] [38] [39] [40] .

Therefore, the aim of the present case-control study was to determine the frequency of hypovitaminosis E in sub-Saharan women with endometriosis in Kinshasa.

The present case-control study, with multivariable analysis, demonstrates the relation between hypovitaminosis E and lalaroscopic diagnosis of endometriosis in a sub-Saharan population with an OR: 4.538 (95% CI: 2.523 - 8.161, p < 0.001). Moreover, more than a quarter of case group had a severe hypovitaminosis E (inferior to 3 mg/L). Our findings are consistent with those of Murphy et al. [43] who, first, highlighted the role of oxidative stress in the pathogenesis and development of endometriosis. Subsequently, several studies have confirmed the relation between low level of vitamin E and endometriosis [44] [45] . Moreover, Darling et al. [46] reported among 1383 incident cases of laparoscopically-confirmed endometriosis that vitamin E level was inversely associated with endometriosis (OR = 0.70; 95% CI: 0.59 - 0.83; p < 0.001). However, data of the current study must be analyzed with caution particularly in the sub-Saharan population. First, vitamin E deficiency is a global public health concern especially in developing countries [34] [35] . It is estimated that 2 billion people worldwide struggle with micronutrient deficiencies, and this is most acute in Africa [36] [47] [48] [49] [50] [51] . Moreover, there is a lack on the true incidence and prevalence of endometriosis in Africa not permitting to draw definitive conclusion on vitamin E deficiency and endometriosis [52] . Indeed, inadequate micronutrient intake is also an issue in people of childbearing age [53] - [58] . Results from several studies reveal that poor nutritional status and higher prevalence of other oxidative stressors such as malaria and HIV infection predispose populations in developing countries to vitamin E deficiency [32] [33] [34] [56] . This deficiency is associated with increased prevalence of infections, anemia, stunted growth, and might be a factor of endometriosis development [34] [35] . Second, vitamin E is a collective term that refers to all tocol and tocotrienol derivatives including four tocopherols and four tocotrienols that share the chromanol ring structure [57] [58] . Among them, α-tocopherol is selectively enriched in human tissues inhibiting lipid peroxidation caused by oxidative stress [59] . Finally, the cut-off used to define vitamin E deficiency varies widely according to populations, from 2.8 to 24 μmol/L (0.1 to 1.0 mg/dL) for serum α-tocopherol [60] .

Beyond the relation between hypovitaminosis E and the diagnosis of endometriosis, we observed a relation with some symptoms suggestive of endometriosis. Using univariable analysis, a relation was observed between hypovitaminosis E and dysmenorrhea, dyspareunia, dyschesia, dysuria and chronic pelvic pain but on multivariable analysis the relation was only confirmed for dysmenorrhea (OR: 24.234, 95% CI: 12.141 - 50.026, p < 0.001). When considering the intensity of dysmenorrhea between patients with and without endometriosis, a difference was observed between the groups, but only a trend for severe dysmenorrhea over 7 on VAS? The identification of oxidative stress as a major factor in endometriosis has prompted several authors to investigate the potential therapeutic action of vitamin E supplementation to reduce oxidative stress. Several randomized trials have looked at the effects of vitamins E and C in women with endometriosis-related pain. Women supplemented with Vitamin E experienced a reduction in pain, even in the short term [38] . Santanam et al. attributed the effects of vitamin E supplementation to its antioxidant and anti-inflammatory properties, although they described no clear physiological mechanism underlying this effect [40] . However, the 2016 Cochrane review on dietary supplements for dysmenorrhea versus placebo or no treatment stated no evidence of effectiveness for vitamin E. In a randomized double-blind trial, Mier-Cabrera et al. evaluated the impact of vitamins C and E supplementation on malondialdehyde (MDA) and lipid hydroperoxides (LOOH) serum levels as biomarkers of oxidative stress. They found a significant decrease in MDA and LOOH levels after 4 and 6 months of supplementation [24] . Since the publication of the Cochrane review, recent randomized trials and literature review have demonstrated the therapeutic action of vitamin E supplementation [38] [61] [62] . Despite no significant decline in total antioxidant capacity, the effectiveness of vitamin E supplementation on severity of pelvic pain (p < 0.001), dysmenorrhea (p < 0.001), and dyspareunia (p < 0.001) was noted suggesting that additional unknown co-factors to vitamin E are probably implicated in the therapeutic action [61] .

From physiopathology point of view of endometriosis, vitamin E has proved its role as antioxidant and free radical scavenger, protecting the integrity of unsaturated lipids in the bio-membranes of cells [32] [56] . Van Langendonckt et al. described a positive correlation between preventing the onset of endometriosis in rabbits and the increase in antioxidant levels. They also found higher levels of release of reactive oxygen species from macrophages, higher peritoneal levels of oxidized low-density lipoproteins and their byproducts, altered expression of endometrial antioxidant enzymes and decrease in vitamin E in peritoneal fluid [27] . Retrograde menstruation appears to be associated with highly pro-oxidant factors i.e. heme and iron in the peritoneal cavity, in addition to apoptotic endometrial cells known to induce oxidative stress [27] [43] . Moreover, vitamin E is involved in a wide range of physiological processes, from immune function and control of inflammation to regulation of gene expression, cognitive performance, and oxidation sensitive nociception involved in endometriosis [32] [33] [44] [45] [56] . Patients with endometriosis appear to have higher lipid peroxidase levels and lower selenium, superoxide dismutase and vitamin E levels than healthy controls; therefore, the reduction of the antioxidant system may be one of the underlying mechanisms in the occurrence of endometriosis [63] .

Some limits of the present study deserve to be underlined. First, despite the use of a case control methodology, it is not possible to exclude biases related to the characteristics of the study population. Second, the sample size of patients with endometriosis remains relatively low representing a true limit. Third, we evaluated only the serum vitamin E level while other markers of oxidative stress (enzymatic and non-enzymatic) were not analyzed. Fourth, we do not evaluate the vitamin E-binding protein afamin that has been shown to be altered in women with endometriosis imposing further studies [64] .

In conclusion, the current study underlines the role of vitamin E deficiency as a potential factor of endometriosis in a sub-Saharan population. As previously claimed by Blaner [65] , the functions, metabolism, and role of vitamin E is not fully elucidated and need further studies especially in the context of endometriosis.

The authors would like to thank the heads of health institutions who allowed us to collect data.

The authors declare no conflicts of interest.

Sibo, M., Mboloko, E., Mputu, L., Monka, I., Mamoi, M., Amba, N., Kabuya, N., Ferrier, C., Fastrez, M., Emile, D., Mogwo, S. and Mulunda, J.-C. (2023) Hypovitaminosis E and Endometriosis in a Sub-Saharan Population. Open Access Library Journal, 10: e10485. https://doi.org/10.4236/oalib.1110485