{"paper_id":"57b86d76-bfe6-433d-9c9c-a08f0c771070","body_text":"Endometriosis – hormones and treatment\nAbstract\nEndometriosis is a prevalent condition, affecting 10-15% of women of reproductive age and approxi -\nmately 70% of those with chronic pelvic pain. An estimated 176 million women worldwide are affected \nby this disease. The condition occurs predominantly between menarche and menopause, with peak in -\ncidence between the ages of 25 and 45. Endometriosis is characterized by the presence of endometrial -\n-like tissue outside the uterine cavity, leading to the formation of lesions most commonly in the ovaries \nbut also in the fallopian tubes, gastrointestinal tract, and occasionally in distant locations like the pleura \nand central nervous system. Symptoms include chronic pelvic pain, heavy and painful menstrual pe -\nriods, dyspareunia, painful urination, and defecation. Diagnosis involves a combination of medical histo -\nry, physical examination, imaging techniques, and the gold standard, diagnostic laparoscopy. There is an \naverage delay of 6.7 years between symptom onset and diagnosis, often due to variable and confusing \nsymptoms resembling other conditions. The pathogenesis of endometriosis involves genetic, hormonal, \nand environmental factors, with significant roles played by estrogens and progesterone. Treatment stra -\ntegies focus on managing symptoms through pain relief, hormonal therapy, and surgical interventions, \nalthough no permanent cure exists. Hormonal imbalances, particularly the interaction of progesterone \nand estrogens, play a crucial role in disease progression. Current research explores various treatment \noptions, including hormonal therapy, nonsteroidal anti-inflammatory drugs, antioxidants, and surgical \nmethods to improve the quality of life for patients.\nRunning title: Endometriosis review\nKeywords: endometriosis, hormones, treatment\nPatrycja Obrycka1, Julia Soczynska1, Wiktor Gawelczyk1, Paulina Tomecka1, Paul Edward Mozdziak2,3\nObrycka et al. \nMedical Journal of Cell Biology 2024\nDOI: 10.2478/acb-2024-0008\nReceived: 22.05.2024\nAccepted: 20.06.2024\n1STN (Student Scientific Society) Anatomia-Klinika-Nauka, Division of Anatomy, Department of Human Morphology and Embryology, Faculty of \nMedicine, Wroclaw Medical University, Wroclaw, Poland\n2Graduate Physiology Program, North Carolina State University, Raleigh, USA\n3Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, North Carolina, USA\n*Correspondence: patrycja.obrycka@student.umw.edu.pl\nFull list of author information is available at the end of article\n\nObrycka et al. Medical Journal of Cell Biology (2024)\n55\nIntroduction\nEndometriosis affects 10-15% of women of re -\nproductive age and about 70% of patients with \nchronic pelvic pain.  [1,2]. It is estimated that this \ndisease affects approximately 176 million women \nworldwide [3] . The vast majority of endometrio -\nsis cases occur in patients between menarche and \nmenopause, with the peak incidence occurring be -\ntween the ages of 25 and 45  [4] . Endometriosis is \na condition in which active endometrial foci (glan -\ndular cells and stroma) or endometrial-like tissue \nare found outside the uterine cavity  [5].  Malignant \ntransformation of endometriosis is considered ex -\ntremely rare, with an estimated incidence of less \nthan 1%  [6]. Endometrial tissue is most commonly \nfound in the ovaries, causing the formation of choc -\nolate cysts, but it can also be found in the fallopian \ntubes, uterosacral ligaments, gastrointestinal tract, \nand less commonly in the pleura, pericardium, or \ncentral nervous system  [5]. Lesions can be located \nwithin previous surgical incisions and even in dis -\ntant parts of the body, such as the cerebellum  [7]. \nRare subtypes of extrapelvic endometriosis include \ncutaneous endometriosis, which is characterized by \nthe presence of non-neoplastic endometrial tissue \non the skin  [8]. Endometrial lesions develop near \nblood vessels, which supports their survival, and \nthey become highly innervated, contributing to the \nchronic pelvic pain experienced by many patients  \n[9]. In the case of endometriosis, approximately \n30% of women are asymptomatic, while around \n50% experience chronic pain associated with the \ndisease. The remaining 20% experience sporadic \npain related to endometriosis  [10]. Heavy periods \naccompanied by intense pain, dyspareunia, painful \nurination or defecation can indicate endometriosis. \nPatients also complain of symptoms such as diar -\nrhea and bloating, abdominal discomfort, and occa -\nsionally recurrent pain in the lower limbs or bleed -\ning from the rectum and urinary tract  [11]. Clinical \ndiagnosis should be a process combining medical \nhistory, physical examination including palpation \nfor tenderness, presence of nodules or adhesions, \nand imaging diagnostics such as abdominal, trans -\nvaginal, or transrectal ultrasound, contrast X-ray \nof the large intestine, and urography  [12]. The gold \nstandard remains diagnostic laparoscopy, which in -\nvolves surgically obtaining tissue samples for histo -\npathological examination  [11]. The average delay of \n6.7 years between symptom onset and surgical diag-\nnosis of endometriosis, with longer waits in publicly \nfunded healthcare systems (8.3 years compared to \n5.5 years), highlights significant challenges in early \ndiagnosis within primary healthcare settings  [13]. \nThese delays may result from variable and often \nconfusing symptoms that can resemble other com -\nmon conditions such as irritable bowel syndrome  \n[14]. There are several theories regarding the caus -\nes of endometriosis that attempt to logically explain \nthe relationship between symptom severity and \ndisease progression. However, none of these models \nare sufficient to fully explain the clinical diversity of \nthe disease manifestations  [15,16]. It is undisputed \nthat genetic factors and the impact of environmen -\ntal factors play a role in the development of endo -\nmetriosis. However, researchers primarily attribute \na significant role to hormones—steroid hormones, \nin particular. Besides the misplacement of cells in \nincorrect locations, the main essence of the disease \nlies in their reaction to these hormones. As a conse-\nquence of their action, the foci undergo alternating \ngrowth and shedding according to the menstrual cy -\ncle. This leads to uncontrolled bleeding and inflam -\nmatory conditions  [17] . Endometriosis can affect \nfertility by altering the peritoneal environment and \ncausing anatomical distortions in the pelvis, which \ncan lead to difficulties in conceiving for about 30% \nof patients  [18]. Endometriosis is also associated \nwith many other conditions, including gastrointes -\ntinal diseases, malignant tumors, cardiovascular \ndiseases, depression, and autoimmune disorders  \n[19]. In light of the above, endometriosis can be con-\nsidered a significant health issue that many women \nface, both during their reproductive years and post -\nmenopause. This article aims to review the available \nliterature on the pathogenesis, hormonal balance, \nand potential treatments for endometriosis.\nDescription of stormal cells in \nendometriosis\nThe stromal cells of disease foci exhibit dysfunc -\ntions in gene function unrelated to changes in DNA \nsequence, involving key transcription factors. They \ndisplay insufficient expression of progesterone re -\nceptor and overly effective production of GATA-6 \nfactor, steroidogenic factor-1, and estrogen recep -\ntor-beta. These cells can transform cholesterol into \nestradiol and progesterone, and produce proteins \nand enzymes such as aromatase.  [20].\nHormones\nProgesterone\nOne of the steroid hormones included in the \ngroup of progestagens, playing a significant role \nin the discussed issue, is progesterone. Its target \nincludes the uterus, where under the influence of \nthis steroid, cyclic physiological changes occur. \nThrough the hypothalamic-pituitary axis, gonado -\ntropin-releasing hormone influences the secretion \nof luteinizing hormone. This, in turn, stimulates \novulation and contributes to the transformation of \nthe ovarian follicle remnants into the corpus lute -\num, which produces progesterone in large quanti -\nties [21]. Physiologically, the compound formed is \na significant element involved in the implantation \nof the blastocyst by influencing the secretion of en -\nzymes that dissolve the zona pellucida and changes \n\nObrycka et al. Medical Journal of Cell Biology (2024)\n56\nin the uterine lining. Through its action, it weakens \nthe response of Th1, Tc, and NK cells and stimulates \nthe production of anti-inflammatory factors such as \nIL-4 and IL-10. In feedback loops, it reduces gonad -\notropin-releasing hormone secretion, thereby in -\nhibiting axis activity, while also stimulating its own \nproduction in corpus luteum cells. Progesterone \ncauses a decrease in the number of receptors bind -\ning to oxytocin and prostaglandins and can mimic \nGABA, thereby reducing uterine contractions [22]. \nIn the event that fertilization does not occur and the \ncorpus luteum, responsible for a high percentage of \nprogesterone production, degenerates, a process of \nshedding ensues, which involves bleeding. This, in \nturn, leads to inflammatory processes in the affect -\ned areas. [23]. Progesterone is a lipophilic molecule, \na female steroid with 21 carbon atoms. Despite its \nname suggesting female origins, it occurs in both \nsexes [24]. Due to its chemical nature, progesterone \ncan penetrate cell membranes and act intracellular -\nly by binding to nuclear PR (progesterone receptor) \nreceptors, which are transcription factors belonging \nto the NR3C subgroup of nuclear receptors [25]. Dis-\nruptions in PR function are crucial in the develop -\nment of endometriosis. In the endometrium, these \nreceptors enable progesterone to act on stromal \nand epithelial cells, on smooth muscle cells in the \nmyometrium, and on glandular epithelial cells and \nstromal fibroblasts in the cervix [26]. Progesterone \ncan also influence human cells through non-genom -\nic effects [27]. PR receptors are also found in ovari -\nan cells and the hypothalamus. They can be detect -\ned as functional isoforms with distinct molecular \nmasses: PR-A, located in the cell nucleus, and PR-B, \nobservable in both the nucleus and cytoplasm. The \nresulting complex initiates a cascade of events lead -\ning to specific effects through classical mechanisms, \nsuch as acting as a transcription factor. In terms of \nendometrial growth, PR-A plays a crucial role by \ninteracting with estrogens [28]. PR receptors are \nmost abundant in the mid-cycle, with their numbers \nlowest in the late secretory phase. In endometrio -\nsis, this cyclical pattern is disrupted. Sources indi -\ncate that conditions associated with inflammation, \ndriven by cytokines, contribute to the methylation \nof the PRG promoter, which is involved in transcrip -\ntion and the formation of PR-B, while the promoter \nfor PRA remains unmethylated. This phenomenon \nleads to an imbalance favoring PRA over PRB [29]. \nFoci of endometriosis exhibit, compared to the en -\ndometrium, not only reduced levels of PR but also \nincreased production of progesterone. Therefore, \ndespite extensive considerations, the role of pro -\ngesterone in this phenomenon is not entirely clear \n[30]. There is a theory that despite their presence, \nPR may be biologically inactive, which explains the \nlack of sensitivity to this hormone [31]. This phe -\nnomenon leads to the disruption of progesterone’s \nnormal interaction with stromal cells, inhibiting the \nsecretion of paracrine factors responsible for stim -\nulating adjacent epithelial cells to produce type 2 \n17β-hydroxysteroid dehydrogenase (17β-HSD-2). \nThe interruption of this normal process results in \nreduced metabolism of estradiol (E2) to estrone \n(E1) by this enzyme, leading to the accumulation \nof E2, which is responsible for inflammation in ec -\ntopic endometriotic lesions [32,33]. There are re -\nports that progesterone influences the expression \nof PTEN (phosphatase and tensin homolog deleted \non chromosome 10), leading to increased autoph -\nagy through inhibition of the PI3K/AKT pathway. \nIn patients with endometriosis, this process is dis -\nrupted, likely due to faulty responses to this crucial \nhormone. In these patients, PTEN expression is im -\nproperly reduced, resulting in the persistence of ab -\nnormal stromal cells [34].\nEstrogens\nEstrogens are another group of steroid hormones \nthat play a crucial role in the development of endo -\nmetriosis. This group includes hormones such as \n17β-estradiol (E2) and estrone. They perform sev -\neral important functions, including influencing the \ndevelopment of female secondary sexual charac -\nteristics, maintaining bone density, regulating cho -\nlesterol levels, and also controlling the menstrual \ncycle by affecting the endometrium. This aspect is \nsignificant in terms of both endometriosis devel -\nopment and endometrial cancer  [35] . Estrogen’s \ninfluence on the uterine mucosa includes stimulat -\ning the proliferation of endometrial cells and main -\ntaining its proper structure to prepare for embryo \nimplantation. Additionally, estrogens stimulate the \ndevelopment of blood vessels in the endometrium, \nwhich is crucial for supplying nutrients to the de -\nveloping mucosa  [36] . The extent of endometrial \ngrowth stimulation largely depends on the duration \nof interaction between bioavailable 17β-estradiol \n(E2) and its receptor. It has been determined that \nthe minimal dose of E2 required to induce sensi -\ntivity in the endometrium ranges from 1.5 to 3 ng. \nHowever, findings suggest that the level of estradi -\nol must exceed a certain threshold to initiate early \ngrowth events associated with it in the uterus [37]. \nEstrogens can induce the aforementioned cellular \nprocesses through mechanisms such as direct or \nindirect regulation of gene expression via nuclear \nestrogen receptors or by interacting with estrogen \nreceptors present on the cell membrane, which are \ncoupled with G-proteins  [38] . The mentioned nu -\nclear estrogen receptor exists in two isoforms, ERα \nand ERβ, which estrogen acts upon, thereby influ -\nencing the endometrium.  [39]. Evidence obtained \nfrom studies on mouse models and isolated cells \nfrom patients with endometriosis indicates the in -\nvolvement of ERβ (estrogen receptor beta) in nearly \nall gynecological pathologies, including menstrual \nbleeding disorders, endometriosis, and endome -\n\nObrycka et al. Medical Journal of Cell Biology (2024)\n57\ntrial cancer  [38]. It has also been observed that the \nexpression of this receptor is significantly higher \nin women with endometriosis, which results in the \ninhibition of ERα expression  [40]. Estrogen recep -\ntor beta (ERβ) plays a unique role in endometriosis \ntissue, where it interacts with cytoplasmic apop -\ntotic mechanisms and the inflammasome complex, \nthereby increasing IL-1β expression. This action \naims to prevent cell death induced by TNF-α and \nenhance the adhesive and proliferative activities of \nendometriosis tissues  [41]. ERβ also contributes to \nepithelial-to-mesenchymal transition (EMT), which \noccurs during embryogenesis and in various patho -\nlogical conditions such as cancer [42]. In the men -\ntioned process, epithelial cells lose their polarized \ncytoskeletal organization and intercellular con -\nnections, acquiring high mobility characteristic of \nmesenchymal cells. This transformation is consid -\nered a preliminary condition for the development of \nprimary endometrial changes  [43]. ERβ also stimu -\nlates the expression of genes involved in unfolded \nprotein response and inhibits the IL-6/JAK/STAT3 \nsignaling pathway, as well as suppresses the TNFα/\nNF-kB signaling pathway in eutopic endometrium. \nThis contributes to the dysfunction of endometrium \nassociated with endometriosis [44]. Other studies \nalso demonstrate that ERβ directly modulates the \nexpression of mitochondrial DNA (mtDNA) genes, \nwhich ensures the resistance of endometrial cells to \napoptosis induced by oxidative stress through the \ninduction of ROS-scavenging enzyme, superoxide \ndismutase, and anti-apoptotic Bcl-2 protein [45].\nMenstrual cycle – dependence between \nestrogen and progesterone levels, essential \nfor maintaining proper endometrial \nproliferation\nBefore assessing specific relationships between \nestrogen and progesterone in women suffering \nfrom endometriosis, it is important to first recall \nhow these relationships manifest in healthy women \nduring the menstrual cycle and how they influence \nchanges in the endometrium. The ovarian cycle \nconsists of the follicular phase, ovulation, and the \nluteal phase. In the uterine cycle, we distinguish \nmenstruation (corresponding to the early follicular \nphase), the proliferative phase (corresponding to \nthe mid to late follicular phase), and the secretory \nphase (corresponding to the luteal phase) [46]. In \nthe follicular phase, estrogen is the dominant ste -\nFIGURE 1 Development of inflammation in endometriosis\n\n\nObrycka et al. Medical Journal of Cell Biology (2024)\n58\nroid hormone. Ovulation is triggered by an increase \nin LH and FSH levels. In the luteal phase, progester -\none predominates, although estrogen remains pres -\nent [47]. However, in situations where the balance \nbetween these two hormones is disrupted, due to \nan increased ratio of estrogens to progesterone, it \ncan lead to excessive and uncontrolled stimulation \nof endometrial cell growth  [48]. It is widely known \nthat progesterone and estrogen mainly act through \nrelated receptors, triggering cascades of signaling \npathways, which in endometriosis can lead to hor -\nmonal signaling disruptions, resulting consequent -\nly in progesterone resistance and estrogen domi -\nnance. This hormonal imbalance leads to increased \ninflammation and can exacerbate pelvic pain associ -\nated with the disease [49].\nIn figure 1, a diagram of the development of in -\nflammation in endometriosis is presented.\nTreatment\nTreatment of endometriosis depends on the se -\nverity of symptoms, age, and reproductive goals of \neach patient. It is worth emphasizing that endome -\ntriosis is a multifactorial disease, with hormones \nbeing just one element influencing its development. \nTherefore, therapy for endometriosis often includes \nvarious strategies, which may involve the use of \npain relievers such as ibuprofen, paracetamol, or \nnaproxen to help alleviate pain symptoms caused \nby endometriosis [50]. According to the recom -\nmendations of the Polish Society of Gynecologists \nand Obstetricians, the therapy for endometriosis \nshould be based on a long-term plan aimed at max -\nimizing pharmacological treatment and minimizing \nthe number of surgical procedures. For the treat -\nment of chronic pain, the first-line pharmacological \ntherapy should include combined oral contracep -\ntives (COCs), preferably those containing dienogest \n[51]. In women experiencing pelvic pain and who \ndo not plan immediate pregnancy, pharmacological \nagents are the preferred choice [52]. Nonsteroidal \nanti-inflammatory drugs (NSAIDs) are a group of \nmedications used in the treatment of endometri -\nosis because they are quite safe, readily available, \nand help women manage painful menstrual periods  \n[53]. Hormonal therapy also finds its application \nbecause it can help limit the growth of endometrial \ntissue. It may include oral contraceptives, proges -\ntins, and gonadotropin-releasing hormone analogs \n(GnRH analogs) [54]. Hormonal therapy, however, \nis associated with varying responses due to the ex -\nistence of genetic and epigenetic concepts [55]. It \nincludes various groups of drugs. One of them is \ndanazol, a derivative of 17α-ethynyltestosterone, \nwhich exhibits androgenic activity. It strongly inhib -\nits GnRH, affecting the pituitary gland by reducing \nLH and FSH secretion. Unfortunately, this drug has \nmany side effects such as weight gain, acne, breast \nvolume reduction, and hirsutism. [56-58]. Another \ngroup of drugs used are GnRH analogues, which are \nderivatives of GnRH. They induce a hypogonado-\ntropic effect, resulting in reduced estrogen levels. \nMany studies have shown that these analogues are \nas effective as danazol in inhibiting symptoms and \nreducing the growth of endometriosis. However, \ntheir use also comes with side effects such as weight \ngain, edema, hirsutism, muscle pain, osteoporosis, \nvaginal dryness, and headaches [57,59-61]. Pro -\ngestins are derivatives of progesterone that mimic \nits activity. They are responsible for inhibiting the \nimplantation and development of dysfunctional en -\ndometrium, inhibiting angiogenesis, and exhibiting \nanti-inflammatory effects. The precise analgesic \nmechanism of progestins is not fully understood, \nas the exact mechanisms of pain in endometrio -\nsis are also poorly understood [62,63]. There are \nmany other drugs such as oral contraceptives and \naromatase inhibitors that show similar therapeu -\ntic effects but differ in terms of side effects [57]. \nCurrent research also analyzes the potential role \nof antioxidants in the treatment of endometriosis. \nTaking supplements of vitamins C and E has been \nfound to effectively reduce the severity of painful \nmenstruation and improve dyspareunia and pelvic \npain among patients [64]. However, when curcum -\nin was used in treatment, despite its potential an -\nti-inflammatory and antioxidant properties, it did \nnot prove to be an effective therapeutic agent [65]. \nSurgical methods, on the other hand, are used to re -\nmove endometrial lesions and proliferating foci of \nendometriosis. This procedure can be performed \nusing laparoscopy, where a laparoscope is insert -\ned through a small incision in the abdominal cavi -\nty [66]. It should be noted, however, that currently \nthere is no permanent cure for endometriosis, but \nappropriate therapy can alleviate symptoms and \nimprove the patient’s quality of life.\nConclusions\nEndometriosis is a complex and multifactori -\nal disease affecting millions of women worldwide, \npredominantly during their reproductive years. De -\nspite its high prevalence, there remains a significant \ndelay in diagnosis due to the nonspecific and var -\nied symptoms that often resemble other conditions. \nThe disease’s pathogenesis is intricately linked to \ngenetic, hormonal, and environmental factors, with \nestrogens and progesterone playing pivotal roles. \nHormonal imbalances and disruptions in hormonal \nreceptor function contribute to the disease’s pro -\ngression and the associated chronic pain and infer -\ntility. Treatment strategies are multifaceted, aiming \nto manage symptoms and improve patients’ qual -\nity of life. Pharmacological treatments, including \nNSAIDs and hormonal therapies such as combined \noral contraceptives, progestins, and GnRH analogs, \nare commonly used. However, these treatments of -\nten come with significant side effects and variable \n\nObrycka et al. Medical Journal of Cell Biology (2024)\n59\nefficacy due to genetic and epigenetic factors. Surgi -\ncal interventions, although effective in removing le -\nsions, do not offer a permanent cure and carry their \nown risks. Recent research highlights the potential \nrole of antioxidants and other novel therapeutic \nagents, but their effectiveness remains inconclusive. \nDespite advances in understanding and managing \nendometriosis, the disease remains a significant \nhealth issue, necessitating continued research into \nmore effective and less invasive treatments. Com -\nprehensive, long-term management plans tailored \nto individual patients’ needs and reproductive goals \nare essential for improving outcomes and quality of \nlife for those affected by endometriosis.\nEthical approval\nThis study is not related to either human or animal use.\nAcknowledgments\nNot applicable.\nCorresponding author\nPatrycja Obrycka, STN (Student Scientific Society) Anatomia-Klini-\nka-Nauka, Division of Anatomy, Department of Human Morphology \nand Embryology, Faculty of Medicine, Wroclaw Medical University, \nWroclaw, Poland, e-mail: patrycja.obrycka@student.umw.edu.pl.\nConflict of interest\nThe authors declare no conflict of interest.\nReferences\n1. Parasar P , Ozcan P , Terry KL. Endometriosis: epidemiology, diagnosis \nand clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34-41; \nDOI:10.1007/s13669-017-0187-1.\n2. Carter JE. Combined hysteroscopic and laparoscopic findings in patients \nwith chronic pelvic pain. 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