The influence of ethanol consumption on a course of endometriosis

Approximately 10% of women in reproductive age (190 million women worldwide) suffer from atypical symptoms such as pain located in the region of the pelvis minor, diarrhea, constipation or fatigue [1]. The endometrium hails from intermediate mesoderm via mesenchymal to epithelial transition during the evolution of the urogenital system [2]. Endometriosis is a chronic, incurable and inflammatory gynecological disease, which is described as the implantation of ectopic endometrial tissue outside the uterine cavity [3]. The word “endometriosis” was introduced in 1927 by Sampson [4]. The basis was the description of endometrium-like tissue in myometrium made by Rokitansky, and in the rectovaginal septum by Cullen, who called it “adenomyoma”. The incidence of the disease is observed in every social and ethnic group [5]. Non-specific symptoms delay the diagnosis and worsen patient’s comfort of life which can be manifested as anxiety, depression, powerlessness, guilt, self-directed violence, and deterioration of interpersonal relations [6]. The successful diagnosis of endometriosis requires laparoscopy or surgical exploration with histological confirmation. Various hypotheses have been proposed to understand the pathology of endometriosis and tissue spreading inside the abdominal cavity. The classical hypothesis is that of transplantation where the retrograde menstruation very common phenomenon, other mechanisms include coelomic metaplasia, embryonic rest, lymphatic and vascular metastasis, iatrogenic direct implantation, mesenchymal cell differentiation or induction [7]. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. It is argued that 80% of our diet and lifestyle determine what we get sick with. The influence of genes is limited to only 20%. Does it also concern endometriosis [8]? Ethyl alcohol is one of the most used psychoactive substances in the world [9]. Occasional consumption may cause general improvement of the mood, cessation of feeling tired, relaxation. The effect of alcohol on brain cells is multidirectional. Alcohol interacts directly with GABA (Gamma-aminobutyric acid), NMDA (N-methyl-D-aspartate) receptors, as well as with acetylcholine and serotonin receptors. Long-term alcohol consumption may lead to abnormal reproductive hormone secretion and metabolism. Futhermore, alcohol has been shown to increase the body’s inflammatory response, insulin resistance and affects fertility [10]. The main aim of the study was to assess how alcohol consumption may affect the course of endometriosis and the scale of its symptoms.

The research issue was determined based on the latest literature. The publication includes articles from the Pubmed database. Two independent reviewers screened a database to identify potentially eligible studies. Focusing on the selected keywords: “endometriosis”, “alcohol”, “ethanol” research written only in English language were selected. Publications without full text access and duplicates were rejected. The discrepancies were discussed until consensus was reached among the authors (Fig. 1).

Many recent research show that endometriosis affects both body and mind. An interesting issue seems to be the influence of how we perceive the world and how it may affect disease manifestations. In line with this concept chronic stress exposure and related disorders of the autonomic nervous system at the hypothalamic-pituitary-adrenal level may cause the presence of central neurosensitization, increasing the perception of pain, damage to the peripheral nerves responsible for the innervation of the smaller pelvis and the presence of abnormal nerve fibers in the ectopic lesions and eutopic endometrium [11]. Endometriosis is characterized by the occurrence of ambiguous, diverse ailments, which in many cases is detected at an advanced stage. It is supposed that every one in ten women in reproductive age all over the world may develop endometriosis [12]. The final diagnosis may often be associated with stress, uncertainty and low self-esteem [13]. One of the most common symptoms is severe menstrual pain, which hinders daily functioning and requires the use of strong analgesics. Patients with endometriosis also report pain during sexual intercourse due to endometrial lesions in the genital area. Endometriosis can also cause bleeding between menstrual periods and chronic back/pelvic pain [14]. It can lead to social isolation, loneliness and a feeling of helplessness, which contributes to the development of depression. Due to above symptoms young women every day faces many limitations on the private, professional and social level [15]. Ethyl alcohol has been considered as a universal remedy for thousands of years. It is now believed that the therapeutic effect of alcohol is limited and that its habitual consumption has devastating biological, social and cultural effects [16]. Treatment of alcohol as a supportive agent may also occur in endometriosis. Drinking for many reasons can be associated with an emotional state; for a better sleep, calm down or decrease pain as a self-management therapy. Lack of support and understanding of the disease can also contribute to a worsening of the mental state [17]. Alcohol as a psychoactive substance has a multidirectional effect on the body. It is classified as a depressant on the nervous system. In small doses, it first suppresses the inhibitory pathways, acting as a stimulant: anti-anxiety and psychostimulant. In higher oral doses, it is anaesthetic and sleepy. In the initial period of use it shows the characteristics of antidepressants. In the long run, it exacerbates depression [18] (Fig. 2). Alcohol consumption may not only affect psychological health but also women’s reproductive health. In recent years, many scientific papers have highlighted the effects of ethanol on fertility, pain sensation, and menstrual cycle. Some studies indicate that ethanol may raise estrogen levels, which could lead to more painful endometrial symptoms [19]. Researchers’ interest prompted to carry biochemical analyses which have identified several phytoestrogens in the congeners of bourbon, beer, and wine. Isolated substances obtained from grains, hops, corn, and rice exhibited estrogen-like activity as nonsteroidal phytoestrogens [20]. Based on the structure of the molecules these hormones may play essential roles in the development and maintenance of endometriosis. According to this hypothesis, which was tested in biochemical analyses, animal models and human studies, prolonged exposure to the phytoestrogens affects the function of the endometrium, and endometriosis-related changes which are cyclically altered by hormones in the same way as eutopic endometrium [21]. An excess of the hormone can deregulate/stimulate the environment to become more pro-inflammatory. Elevated level of estrogen increases the activity of COX-2 (cyclo-oxygenase-2) which in consequence stimulates the secretion of inflammatory prostaglandins (PGE2) [22]. PGE2 can directly stimulate the endings of nerve fibers and affect the formation of pain signal. One of the mechanisms that has also been proposed as responsible for exacerbating inflammation and, consequently, pain, is related to the expression of aromatase (an enzyme that converts androgens into estrogens) in endometriotic lesions [23]. It is worth notifying that ectopic endometrium posses aromatase activity. Estradiol and inflammation also stimulate growth and proangiogenic factors, including VEGF (Vascular endothelial growth factor receptor), which affects the growth of blood vessels that vascularize nerve fibers [24]. An attachment to peritoneal epithelium, invasion of the epithelium, establishment of local neurovascularity, continued growth and survival are necessary if endometriosis is to develop. Mild-to-moderate alcohol use may have numerous negative consequences for female reproductive function. Women with endometriosis often report irregular menstrual cycles to complete cessation of menses, absence of ovulation and infertility. Endometriosis can influence fertility in several ways: distorted anatomy of the pelvis, adhesions, scarred fallopian tubes, inflammation of the pelvic structures and altered immune system functioning [25]. Chronic/prolonged alcohol intake may lead to elevated estradiol levels. Hormonal disorders may be associated with the direct effect of alcohol on the ethanol hepatic metabolism, decreasing in the liver NAD+/NADH ratio, inhibiting hepatic estradiol to estrone oxidation and determining estradiol accumulation. Furthermore, it also reduced rate of hepatic conversion of pregnenolone to progesterone and decreased LH/hCG receptors expression in granulosa cells resulting in luteal phase insufficiency. Indirect action of ethanol may result from suppression of the serum growth hormone (GH) levels and a paralel decreased IGF-1 levels which is responsible for anti-apoptosis effect [26]. It is widely believed that endometriosis is a disease only within the reproductive system. Rare symptoms of the disease that worsen the quality of patient’s life manifest also as constipations, memory issues, difficulty concentrating, brain fog. It is supposed that proper hydration can alleviate muscle cramping and bloating. Peristaltic bowel function seems to be essential for managing endometriosis. Ethyl alcohol, besides many other properties, has a diuretic effect. It adversely affects the water management of the body, disrupting the secretion of vasopressin [27]. Excessive water loss may contribute to decreased potassium, magnesium, and impaired glucose tolerance. Regular drinking of alcohol, even low-percentage, may damage the bacterial flora of the intestines, contribute to estrogen-dependent conditions, consequently worsen symptoms of the disease. | Table 1. The summary analysis between alcohol intake and a course of endometriosis | ||| | Source | Analysed parameter | An influence of a course of the disease | | | 1. | de Angelis C, Nardone A, Garifalos F, et al. Smoke, alcohol and drug addiction and female fertility. Reprod Biol Endocrinol. 2020; 18(1): 21. | More than 140 g per week alcohol intake | Ovulatory dysfunction, irregular menstrual cycles, higher estrogens level, reduced oviductal smooth muscle cells contractility | | 1–90 g per week alcohol intake | Reduction of more than 50% in the conception rate | || | 0–1 g per week alcohol intake | Unrelated to female infertility | || | 2. | Hemmert R, Schliep KC, Willis S, et al. Modifiable life style factors and risk for incident endometriosis. Paediatr Perinat Epidemiol. 2019; 33(1): 19–25 | A 12-ounce bottle of beer, a 5-ounce glass of wine, or 1.5 ounces of distilled spirits weekly | No associations between a risk of endometriosis and alcohol consumption | | 3. | Missmer SA, Hankinson SE, Spiegelman D, et al. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol. 2004; 160(8): 784–796. | Current alcohol intake | Associated with the incidence of endometriosis | | 4. | Adams KE, Rans TS. Adverse reactions to alcohol and alcoholic beverages. Ann Allergy Asthma Immunol. 2013; 111(6): 439–445. | Alcohol in general vs no alcohol | High level of estrogen in a group with alcohol intake | | 5. | Li Piani L, Chiaffarino F, Cipriani S, et al. A systematic review and meta-analysis on alcohol consumption and risk of endometriosis: an update from 2012. Sci Rep. 2022; 12(1): 19122. | Moderate/regular alcohol intake ≤ 100 g/week | Positive feedback with inflammatory mediators and oxidative stress —proinflammatory effect, positive association between alcohol consumption and endometriosis risk — higher risk of endometriosis | | No consumption | borderline statistical significance | || | 6. | Gavaler JS. Alcoholic beverages as a source of estrogens. Alcohol Health Res World. 1998; 22(3): 220–227. | Moderate drinking up to one drink per day | High level of estrogen, prolactin, HDL cholesterol, and SHBG increased | | 7. | Rosenblum ER, Stauber RE, Van Thiel DH, et al. Assessment of the estrogenic activity of phytoestrogens isolated from bourbon and beer. Alcohol Clin Exp Res. 1993; 17(6): 1207–1209. | No alcohol intake vs alcohol in general | High level of estrogen in a group with alcohol intake | | 8. | Naji Om, Abolghasemi J, Chaichian S, et al. Evaluation of the factors influencing endometriosis in reproductive age women. Medical Sciences. 2016; 26: 188–194. | No alcohol intake vs alcohol in general | High level of estrogen in a group with alcohol intake | | 9. | Ricci E, Chiaffarino F, Cipriani S, et al. Wine, spirits, and beer intake and endometriosis risk among infertile women: results from a case control study. Clin Exp Obstet Gynecol. 2017; 44(4): 548–551. | Women reporting no alcohol intake vs alcohol in general | Associated with the incidence wof endometriosis | | 10. | Saha R, Kuja-Halkola R, Tornvall P, et al. Reproductive and Lifestyle Factors Associated with Endometriosis in a Large Cross-Sectional Population Sample. J Womens Health (Larchmt). 2017; 26(2): 152–158. | Alcohol in general | No significant association | | 11. | Tivis LJ, Gavaler JS. Alcohol, hormones, and health in postmenopausal women. Alcohol Health Res World. 1994; 18(3): 185–188. | Moderate alcohol consumption (no more than one drink per day) vs abstainers | Significantly higher level of estradiol, the androgen testosterone and the pituitary hormone prolactin, FSH and LH decreased in alcohol consumption group | | 12. | Muti P, Trevisan M, Micheli A, et al. Alcohol consumption and total estradiol in premenopausal women. Cancer Epidemiol Biomarkers Prev. 1998; 7(3): 189–193. | Higher alcohol intake (92.8 g/week) vs (31.6 g/week) | Significant positive association between alcohol intake and estradiol level |

A lifestyle can serve as a significant predictor of endometriosis. Based on biological mechanisms, it is supposed that long-term alcohol consumption is not completely indifferent and may affect the course and symptoms of the disease. Alcohol has historically, and continues to, hold an important role in social life. In 2016, 0.88 billion of females aged 15 and older worldwide consumed alcohol [28]. Despite the monumental problems caused by alcohol abuse and dependence, its intake reflects in adverse health, reproductive and social consequences. According to the literature it is hard to assess the ‘’safe’’dosage of alcohol consumption. The problem may result from different definitions adopted in many scientific publications. Ricci et al. [29] classified moderate/regular intake of ethanol as ≤ 7 drinks/week, Saha et al. [30] ≤ 4.5 drinks/week, Ek et al. [31] ≤ 4 drink/week and Hemmert et al. [32] as 1–2 drinks/week. < 0.5 drinks/week was assumed as: 125 mL wine = 333 mL beer = 30 mL spirits. It is also worth highlighting that an alcohol metabolism is an individual matter. None of the papers released after 2017 reported a positive correlation between endometriosis and ethanol in consumption attributable to the “infrequent” category (1–2 drinks/week). In line with the studies conducted by Gao et al. [33] and Ek et al. [34] there has been a connection between endometriosis and mental state disorders (stress-related syndromes, anxiety or depression) which in response to disease, tend to turn to alcohol as a temporary treatment. Multiple studies show that women with endometriosis are twice as likely to suffer from a mental health condition [35]. Mood swings, anger, irritability, and frustration make everyday life depend on gynecological condition. According to the results of the study conducted by Lorençatto et al. [36] depression was diagnosed in 86% of the women with cyclic pelvic pain and in 38% patients without pain. A vicious circle between worsening of psychological condition and chronic pain increases perception both emotionally and cognitively, determining less tolerance to pain, treating alcohol as a temporary escape from unpleasant experiences. The association between fertility disorders and alcohol intake described Gavaler et al. [37] who analyzed biologically active estrogenic substances and their impact on hypothalamic-pituitary axis. In the literature it is assessed that from 30 to 50% of women with endometriosis are infertile. It is speculated that both moderate and acute alcohol administration may affect the endocrine profile in women of reproductive age, by elevating, and suppressing, estrogens and progesterone levels. Muti et al. [38] indicated that women who consumed alcohol had significantly higher serum levels of total estradiol, compared with abstainers. In further studies the researchers described that a consumption of 1–90 g alcohol per week contributed to a reduction of more than 50% in the conception rate which, in women with endometriosis, is already significantly reduced. In women with moderate (1–3 drinks per day) alcohol consumption, it took two or more years to conceive. Moderate (0–1 drinks per day) and high (more than 1 drink per day) alcohol consumption significantly increased the risk of ovulatory infertility (Fig. 3). A woman with endometriosis has often left alone to face many problems such as pain, low mood, reduced fertility. Despite no definitive treatment for endometriosis, awareness, knowledge of pathogenesis and etiological factors could proide the patients with tools to reduce the incidence and burden of disease.

- Women with endometriosis who are exposed to psychological stress, chronic pain and face the difficulty in a daily functioning are more prone to use an alcohol as a self-management therapy. - An alcohol may contribute to hormonal imbalance, stimulate the environment to become more pro-inflammatory and disturbs the oxidoreductive balance in the body. The above phenomena may lead to lower fertility, increase pain and deteriorate the quality of life. - Nowadays it is still hard to assess whether alcohol consumption is a cause or effect of the disease. The impact of different substances on the body is an individual issue and requires many research in the future. - In the long period of time as the cosequence of alcohol consuptiom is detrioration of endometriosis concomitant symptoms and the quality of life in many aspects. Article information and declarations Author contributions Conceptualization: M.K, M.G; Literature search: M.K, P.SZ.; Manuscript writing: M.K, P.SZ.; Manuscript editing: M.K, P.SZ, J.K, M.G; Visualization: M.K; Supervision: M.G., J.K. Funding This article has no funding. Acknowledgments All authors have read and agreed to the published version of the manuscript. Conflict of interest The authors declare no conflict of interest.