Endometriosis – hormones and treatment

Endometriosis is a prevalent condition, affecting 10-15% of women of reproductive age and approxi - mately 70% of those with chronic pelvic pain. An estimated 176 million women worldwide are affected by this disease. The condition occurs predominantly between menarche and menopause, with peak in - cidence between the ages of 25 and 45. Endometriosis is characterized by the presence of endometrial - -like tissue outside the uterine cavity, leading to the formation of lesions most commonly in the ovaries but also in the fallopian tubes, gastrointestinal tract, and occasionally in distant locations like the pleura and central nervous system. Symptoms include chronic pelvic pain, heavy and painful menstrual pe - riods, dyspareunia, painful urination, and defecation. Diagnosis involves a combination of medical histo - ry, physical examination, imaging techniques, and the gold standard, diagnostic laparoscopy. There is an average delay of 6.7 years between symptom onset and diagnosis, often due to variable and confusing symptoms resembling other conditions. The pathogenesis of endometriosis involves genetic, hormonal, and environmental factors, with significant roles played by estrogens and progesterone. Treatment stra - tegies focus on managing symptoms through pain relief, hormonal therapy, and surgical interventions, although no permanent cure exists. Hormonal imbalances, particularly the interaction of progesterone and estrogens, play a crucial role in disease progression. Current research explores various treatment options, including hormonal therapy, nonsteroidal anti-inflammatory drugs, antioxidants, and surgical

to improve the quality of life for patients. Running title: Endometriosis review

endometriosis, hormones, treatment Patrycja Obrycka1, Julia Soczynska1, Wiktor Gawelczyk1, Paulina Tomecka1, Paul Edward Mozdziak2,3 Obrycka et al. Medical Journal of Cell Biology 2024 DOI: 10.2478/acb-2024-0008 Received: 22.05.2024 Accepted: 20.06.2024 1STN (Student Scientific Society) Anatomia-Klinika-Nauka, Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland 2Graduate Physiology Program, North Carolina State University, Raleigh, USA 3Prestage Department of Poultry Sciences, North Carolina State University, Raleigh, North Carolina, USA *Correspondence: [email protected] Full list of author information is available at the end of article Obrycka et al. Medical Journal of Cell Biology (2024) 55

Endometriosis affects 10-15% of women of re - productive age and about 70% of patients with chronic pelvic pain. [1,2]. It is estimated that this disease affects approximately 176 million women worldwide [3] . The vast majority of endometrio - sis cases occur in patients between menarche and menopause, with the peak incidence occurring be - tween the ages of 25 and 45 [4] . Endometriosis is a condition in which active endometrial foci (glan - dular cells and stroma) or endometrial-like tissue are found outside the uterine cavity [5]. Malignant transformation of endometriosis is considered ex - tremely rare, with an estimated incidence of less than 1% [6]. Endometrial tissue is most commonly found in the ovaries, causing the formation of choc - olate cysts, but it can also be found in the fallopian tubes, uterosacral ligaments, gastrointestinal tract, and less commonly in the pleura, pericardium, or central nervous system [5]. Lesions can be located within previous surgical incisions and even in dis - tant parts of the body, such as the cerebellum [7]. Rare subtypes of extrapelvic endometriosis include cutaneous endometriosis, which is characterized by the presence of non-neoplastic endometrial tissue on the skin [8]. Endometrial lesions develop near blood vessels, which supports their survival, and they become highly innervated, contributing to the chronic pelvic pain experienced by many patients [9]. In the case of endometriosis, approximately 30% of women are asymptomatic, while around 50% experience chronic pain associated with the disease. The remaining 20% experience sporadic pain related to endometriosis [10]. Heavy periods accompanied by intense pain, dyspareunia, painful urination or defecation can indicate endometriosis. Patients also complain of symptoms such as diar - rhea and bloating, abdominal discomfort, and occa - sionally recurrent pain in the lower limbs or bleed - ing from the rectum and urinary tract [11]. Clinical diagnosis should be a process combining medical history, physical examination including palpation for tenderness, presence of nodules or adhesions, and imaging diagnostics such as abdominal, trans - vaginal, or transrectal ultrasound, contrast X-ray of the large intestine, and urography [12]. The gold standard remains diagnostic laparoscopy, which in - volves surgically obtaining tissue samples for histo - pathological examination [11]. The average delay of 6.7 years between symptom onset and surgical diag- nosis of endometriosis, with longer waits in publicly funded healthcare systems (8.3 years compared to 5.5 years), highlights significant challenges in early diagnosis within primary healthcare settings [13]. These delays may result from variable and often confusing symptoms that can resemble other com - mon conditions such as irritable bowel syndrome [14]. There are several theories regarding the caus - es of endometriosis that attempt to logically explain the relationship between symptom severity and disease progression. However, none of these models are sufficient to fully explain the clinical diversity of the disease manifestations [15,16]. It is undisputed that genetic factors and the impact of environmen - tal factors play a role in the development of endo - metriosis. However, researchers primarily attribute a significant role to hormones—steroid hormones, in particular. Besides the misplacement of cells in incorrect locations, the main essence of the disease lies in their reaction to these hormones. As a conse- quence of their action, the foci undergo alternating growth and shedding according to the menstrual cy - cle. This leads to uncontrolled bleeding and inflam - matory conditions [17] . Endometriosis can affect fertility by altering the peritoneal environment and causing anatomical distortions in the pelvis, which can lead to difficulties in conceiving for about 30% of patients [18]. Endometriosis is also associated with many other conditions, including gastrointes - tinal diseases, malignant tumors, cardiovascular diseases, depression, and autoimmune disorders [19]. In light of the above, endometriosis can be con- sidered a significant health issue that many women face, both during their reproductive years and post - menopause. This article aims to review the available literature on the pathogenesis, hormonal balance, and potential treatments for endometriosis. Description of stormal cells in endometriosis The stromal cells of disease foci exhibit dysfunc - tions in gene function unrelated to changes in DNA sequence, involving key transcription factors. They display insufficient expression of progesterone re - ceptor and overly effective production of GATA-6 factor, steroidogenic factor-1, and estrogen recep - tor-beta. These cells can transform cholesterol into estradiol and progesterone, and produce proteins and enzymes such as aromatase. [20]. Hormones Progesterone One of the steroid hormones included in the group of progestagens, playing a significant role in the discussed issue, is progesterone. Its target includes the uterus, where under the influence of this steroid, cyclic physiological changes occur. Through the hypothalamic-pituitary axis, gonado - tropin-releasing hormone influences the secretion of luteinizing hormone. This, in turn, stimulates ovulation and contributes to the transformation of the ovarian follicle remnants into the corpus lute - um, which produces progesterone in large quanti - ties [21]. Physiologically, the compound formed is a significant element involved in the implantation of the blastocyst by influencing the secretion of en - zymes that dissolve the zona pellucida and changes Obrycka et al. Medical Journal of Cell Biology (2024) 56 in the uterine lining. Through its action, it weakens the response of Th1, Tc, and NK cells and stimulates the production of anti-inflammatory factors such as IL-4 and IL-10. In feedback loops, it reduces gonad - otropin-releasing hormone secretion, thereby in - hibiting axis activity, while also stimulating its own production in corpus luteum cells. Progesterone causes a decrease in the number of receptors bind - ing to oxytocin and prostaglandins and can mimic GABA, thereby reducing uterine contractions [22]. In the event that fertilization does not occur and the corpus luteum, responsible for a high percentage of progesterone production, degenerates, a process of shedding ensues, which involves bleeding. This, in turn, leads to inflammatory processes in the affect - ed areas. [23]. Progesterone is a lipophilic molecule, a female steroid with 21 carbon atoms. Despite its name suggesting female origins, it occurs in both sexes [24]. Due to its chemical nature, progesterone can penetrate cell membranes and act intracellular - ly by binding to nuclear PR (progesterone receptor) receptors, which are transcription factors belonging to the NR3C subgroup of nuclear receptors [25]. Dis- ruptions in PR function are crucial in the develop - ment of endometriosis. In the endometrium, these receptors enable progesterone to act on stromal and epithelial cells, on smooth muscle cells in the myometrium, and on glandular epithelial cells and stromal fibroblasts in the cervix [26]. Progesterone can also influence human cells through non-genom - ic effects [27]. PR receptors are also found in ovari - an cells and the hypothalamus. They can be detect - ed as functional isoforms with distinct molecular masses: PR-A, located in the cell nucleus, and PR-B, observable in both the nucleus and cytoplasm. The resulting complex initiates a cascade of events lead - ing to specific effects through classical mechanisms, such as acting as a transcription factor. In terms of endometrial growth, PR-A plays a crucial role by interacting with estrogens [28]. PR receptors are most abundant in the mid-cycle, with their numbers lowest in the late secretory phase. In endometrio - sis, this cyclical pattern is disrupted. Sources indi - cate that conditions associated with inflammation, driven by cytokines, contribute to the methylation of the PRG promoter, which is involved in transcrip - tion and the formation of PR-B, while the promoter for PRA remains unmethylated. This phenomenon leads to an imbalance favoring PRA over PRB [29]. Foci of endometriosis exhibit, compared to the en - dometrium, not only reduced levels of PR but also increased production of progesterone. Therefore, despite extensive considerations, the role of pro - gesterone in this phenomenon is not entirely clear [30]. There is a theory that despite their presence, PR may be biologically inactive, which explains the lack of sensitivity to this hormone [31]. This phe - nomenon leads to the disruption of progesterone’s normal interaction with stromal cells, inhibiting the secretion of paracrine factors responsible for stim - ulating adjacent epithelial cells to produce type 2 17β-hydroxysteroid dehydrogenase (17β-HSD-2). The interruption of this normal process results in reduced metabolism of estradiol (E2) to estrone (E1) by this enzyme, leading to the accumulation of E2, which is responsible for inflammation in ec - topic endometriotic lesions [32,33]. There are re - ports that progesterone influences the expression of PTEN (phosphatase and tensin homolog deleted on chromosome 10), leading to increased autoph - agy through inhibition of the PI3K/AKT pathway. In patients with endometriosis, this process is dis - rupted, likely due to faulty responses to this crucial hormone. In these patients, PTEN expression is im - properly reduced, resulting in the persistence of ab - normal stromal cells [34]. Estrogens Estrogens are another group of steroid hormones that play a crucial role in the development of endo - metriosis. This group includes hormones such as 17β-estradiol (E2) and estrone. They perform sev - eral important functions, including influencing the development of female secondary sexual charac - teristics, maintaining bone density, regulating cho - lesterol levels, and also controlling the menstrual cycle by affecting the endometrium. This aspect is significant in terms of both endometriosis devel - opment and endometrial cancer [35] . Estrogen’s influence on the uterine mucosa includes stimulat - ing the proliferation of endometrial cells and main - taining its proper structure to prepare for embryo implantation. Additionally, estrogens stimulate the development of blood vessels in the endometrium, which is crucial for supplying nutrients to the de - veloping mucosa [36] . The extent of endometrial growth stimulation largely depends on the duration of interaction between bioavailable 17β-estradiol (E2) and its receptor. It has been determined that the minimal dose of E2 required to induce sensi - tivity in the endometrium ranges from 1.5 to 3 ng. However, findings suggest that the level of estradi - ol must exceed a certain threshold to initiate early growth events associated with it in the uterus [37]. Estrogens can induce the aforementioned cellular processes through mechanisms such as direct or indirect regulation of gene expression via nuclear estrogen receptors or by interacting with estrogen receptors present on the cell membrane, which are coupled with G-proteins [38] . The mentioned nu - clear estrogen receptor exists in two isoforms, ERα and ERβ, which estrogen acts upon, thereby influ - encing the endometrium. [39]. Evidence obtained from studies on mouse models and isolated cells from patients with endometriosis indicates the in - volvement of ERβ (estrogen receptor beta) in nearly all gynecological pathologies, including menstrual bleeding disorders, endometriosis, and endome - Obrycka et al. Medical Journal of Cell Biology (2024) 57 trial cancer [38]. It has also been observed that the expression of this receptor is significantly higher in women with endometriosis, which results in the inhibition of ERα expression [40]. Estrogen recep - tor beta (ERβ) plays a unique role in endometriosis tissue, where it interacts with cytoplasmic apop - totic mechanisms and the inflammasome complex, thereby increasing IL-1β expression. This action aims to prevent cell death induced by TNF-α and enhance the adhesive and proliferative activities of endometriosis tissues [41]. ERβ also contributes to epithelial-to-mesenchymal transition (EMT), which occurs during embryogenesis and in various patho - logical conditions such as cancer [42]. In the men - tioned process, epithelial cells lose their polarized cytoskeletal organization and intercellular con - nections, acquiring high mobility characteristic of mesenchymal cells. This transformation is consid - ered a preliminary condition for the development of primary endometrial changes [43]. ERβ also stimu - lates the expression of genes involved in unfolded protein response and inhibits the IL-6/JAK/STAT3 signaling pathway, as well as suppresses the TNFα/ NF-kB signaling pathway in eutopic endometrium. This contributes to the dysfunction of endometrium associated with endometriosis [44]. Other studies also demonstrate that ERβ directly modulates the expression of mitochondrial DNA (mtDNA) genes, which ensures the resistance of endometrial cells to apoptosis induced by oxidative stress through the induction of ROS-scavenging enzyme, superoxide dismutase, and anti-apoptotic Bcl-2 protein [45]. Menstrual cycle – dependence between estrogen and progesterone levels, essential for maintaining proper endometrial proliferation Before assessing specific relationships between estrogen and progesterone in women suffering from endometriosis, it is important to first recall how these relationships manifest in healthy women during the menstrual cycle and how they influence changes in the endometrium. The ovarian cycle consists of the follicular phase, ovulation, and the luteal phase. In the uterine cycle, we distinguish menstruation (corresponding to the early follicular phase), the proliferative phase (corresponding to the mid to late follicular phase), and the secretory phase (corresponding to the luteal phase) [46]. In the follicular phase, estrogen is the dominant ste - FIGURE 1 Development of inflammation in endometriosis Obrycka et al. Medical Journal of Cell Biology (2024) 58 roid hormone. Ovulation is triggered by an increase in LH and FSH levels. In the luteal phase, progester - one predominates, although estrogen remains pres - ent [47]. However, in situations where the balance between these two hormones is disrupted, due to an increased ratio of estrogens to progesterone, it can lead to excessive and uncontrolled stimulation of endometrial cell growth [48]. It is widely known that progesterone and estrogen mainly act through related receptors, triggering cascades of signaling pathways, which in endometriosis can lead to hor - monal signaling disruptions, resulting consequent - ly in progesterone resistance and estrogen domi - nance. This hormonal imbalance leads to increased inflammation and can exacerbate pelvic pain associ - ated with the disease [49]. In figure 1, a diagram of the development of in - flammation in endometriosis is presented. Treatment Treatment of endometriosis depends on the se - verity of symptoms, age, and reproductive goals of each patient. It is worth emphasizing that endome - triosis is a multifactorial disease, with hormones being just one element influencing its development. Therefore, therapy for endometriosis often includes various strategies, which may involve the use of pain relievers such as ibuprofen, paracetamol, or naproxen to help alleviate pain symptoms caused by endometriosis [50]. According to the recom - mendations of the Polish Society of Gynecologists and Obstetricians, the therapy for endometriosis should be based on a long-term plan aimed at max - imizing pharmacological treatment and minimizing the number of surgical procedures. For the treat - ment of chronic pain, the first-line pharmacological therapy should include combined oral contracep - tives (COCs), preferably those containing dienogest [51]. In women experiencing pelvic pain and who do not plan immediate pregnancy, pharmacological agents are the preferred choice [52]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of medications used in the treatment of endometri - osis because they are quite safe, readily available, and help women manage painful menstrual periods [53]. Hormonal therapy also finds its application because it can help limit the growth of endometrial tissue. It may include oral contraceptives, proges - tins, and gonadotropin-releasing hormone analogs (GnRH analogs) [54]. Hormonal therapy, however, is associated with varying responses due to the ex - istence of genetic and epigenetic concepts [55]. It includes various groups of drugs. One of them is danazol, a derivative of 17α-ethynyltestosterone, which exhibits androgenic activity. It strongly inhib - its GnRH, affecting the pituitary gland by reducing LH and FSH secretion. Unfortunately, this drug has many side effects such as weight gain, acne, breast volume reduction, and hirsutism. [56-58]. Another group of drugs used are GnRH analogues, which are derivatives of GnRH. They induce a hypogonado- tropic effect, resulting in reduced estrogen levels. Many studies have shown that these analogues are as effective as danazol in inhibiting symptoms and reducing the growth of endometriosis. However, their use also comes with side effects such as weight gain, edema, hirsutism, muscle pain, osteoporosis, vaginal dryness, and headaches [57,59-61]. Pro - gestins are derivatives of progesterone that mimic its activity. They are responsible for inhibiting the implantation and development of dysfunctional en - dometrium, inhibiting angiogenesis, and exhibiting anti-inflammatory effects. The precise analgesic mechanism of progestins is not fully understood, as the exact mechanisms of pain in endometrio - sis are also poorly understood [62,63]. There are many other drugs such as oral contraceptives and aromatase inhibitors that show similar therapeu - tic effects but differ in terms of side effects [57]. Current research also analyzes the potential role of antioxidants in the treatment of endometriosis. Taking supplements of vitamins C and E has been found to effectively reduce the severity of painful menstruation and improve dyspareunia and pelvic pain among patients [64]. However, when curcum - in was used in treatment, despite its potential an - ti-inflammatory and antioxidant properties, it did not prove to be an effective therapeutic agent [65]. Surgical methods, on the other hand, are used to re - move endometrial lesions and proliferating foci of endometriosis. This procedure can be performed using laparoscopy, where a laparoscope is insert - ed through a small incision in the abdominal cavi - ty [66]. It should be noted, however, that currently there is no permanent cure for endometriosis, but appropriate therapy can alleviate symptoms and improve the patient’s quality of life.

Endometriosis is a complex and multifactori - al disease affecting millions of women worldwide, predominantly during their reproductive years. De - spite its high prevalence, there remains a significant delay in diagnosis due to the nonspecific and var - ied symptoms that often resemble other conditions. The disease’s pathogenesis is intricately linked to genetic, hormonal, and environmental factors, with estrogens and progesterone playing pivotal roles. Hormonal imbalances and disruptions in hormonal receptor function contribute to the disease’s pro - gression and the associated chronic pain and infer - tility. Treatment strategies are multifaceted, aiming to manage symptoms and improve patients’ qual - ity of life. Pharmacological treatments, including NSAIDs and hormonal therapies such as combined oral contraceptives, progestins, and GnRH analogs, are commonly used. However, these treatments of - ten come with significant side effects and variable Obrycka et al. Medical Journal of Cell Biology (2024) 59 efficacy due to genetic and epigenetic factors. Surgi - cal interventions, although effective in removing le - sions, do not offer a permanent cure and carry their own risks. Recent research highlights the potential role of antioxidants and other novel therapeutic agents, but their effectiveness remains inconclusive. Despite advances in understanding and managing endometriosis, the disease remains a significant health issue, necessitating continued research into more effective and less invasive treatments. Com - prehensive, long-term management plans tailored to individual patients’ needs and reproductive goals are essential for improving outcomes and quality of life for those affected by endometriosis. Ethical approval This study is not related to either human or animal use. Acknowledgments Not applicable. Corresponding author Patrycja Obrycka, STN (Student Scientific Society) Anatomia-Klini- ka-Nauka, Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, Wroclaw, Poland, e-mail: [email protected]. Conflict of interest The authors declare no conflict of interest.

1. Parasar P , Ozcan P , Terry KL. Endometriosis: epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34-41; DOI:10.1007/s13669-017-0187-1. 2. Carter JE. Combined hysteroscopic and laparoscopic findings in patients with chronic pelvic pain. J Am Assoc Gynecol Laparosc. 1994;2(1):43-7; DOI:10.1016/s1074-3804(05)80830-8. 3. Adamson GD, Kennedy S, Hummelshoj L. Creating solutions in en - dometriosis: global collaboration through the World Endometriosis Research Foundation. J Endometr Pelvic Pain Disord. 2018;2(1):3-6; DOI:10.1177/228402651000200102. 4. Eskenazi B, Warner ML. Epidemiology of endometriosis. Ob - stet Gynecol Clin North Am. 1997;24(2):235-58; DOI:10.1016/ S0889-8545(05)70302-8. 5. Tsamantioti ES, Mahdy H. Endometriosis [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2024 May 05]. 10 p. Available from: https://www.ncbi.nlm.nih.gov/books/NBK567777/. 6. Takeuchi M, Matsuzaki K, Uehara H, Nishitani H. Malignant trans - formation of pelvic endometriosis: MR imaging findings and patho - logic correlation. Radiographics. 2006;26(2):407-17; DOI:10.1148/ rg.262055041. 7. Meggyesy M, Friese M, Gottschalk J, Kehler U. Case report of cerebellar endometriosis. J Neurol Surg A Cent Eur Neurosurg. 2020;81(4):372-6; DOI:10.1055/s-0040-1701622. 8. Sharma A, Apostol R. Cutaneous endometriosis [Internet]. Treasure Is - land (FL): StatPearls Publishing; 2024 [cited 2024 May 05]. 5 p. Avail - able from: https://www.ncbi.nlm.nih.gov/books/NBK560918/. 9. Cousins FL, McKinnon BD, Mortlock S, Fitzgerald HC, Zhang C, Mont - gomery GW, Gargett CE. New concepts on the etiology of endometriosis. J Obstet Gynaecol Res. 2023;49(4):1090-105; DOI:10.1111/jog.15549. 10. Adamson D. Minimal to mild endometriosis: 4 treatment options. OBG Management. 2004;16(5):46-58. 11. Basta A, Brucka A, Gorski J, Kotarski J, Kulig B, Oszukowski P , Poreba R, Radowicki S, Radwan J, Sikora J, Skret A, Skrzypczak J, Szyllo K. Stanowisko Zespołu Ekspertów Polskiego Towarzystwa Ginekologicznego dotyczące diagnostyki i metod leczenia endometriozy. Ginekol Pol. 2012;83:871-6. 12. Szyłło K. Scenariusz wywiadu w kierunku endometriozy. Ginekol Peri - natol Prakt. 2016;1(1):34-7. 13. Nnoaham KE, Hummelshoj L, Webster P , D’Hooghe T , De Cicco Nardo- ne F, De Cicco Nardone C, Jenkinson C, Kennedy SH, Zondervan KT . Im - pact of endometriosis on quality of life and work productivity: a mul- ticenter study across ten countries. Fertil Steril. 2011;96(2):366-73; DOI:10.1016/j.fertnstert.2011.05.090. 14. Frayne J, Milroy T , Simonis M, Lam A. Challenges in diagnosing and managing endometriosis in general practice: a Western Australian qualitative study. Aust J Gen Pract. 2023;52(8):547-55; DOI:10.31128/ AJGP-10-22-6579. 15. Ye H, Tian Y, Yu X, Li L, Hou M. Association between pelvic inflammatory disease and risk of endometriosis: a systematic review and meta-anal - ysis. J Womens Health (Larchmt). 2024;33(1):73-9; DOI:10.1089/ jwh.2023.0300. 16. Ochoa Bernal MA, Fazleabas AT . The known, the unknown and the future of the pathophysiology of endometriosis. Int J Mol Sci. 2024;25(11):5815; DOI:10.3390/ijms25115815. 17. Wyderka MI, Zalewska D, Szeląg E. Endometrioza a jakos�c� z�ycia. Piel Pol. 2011;4(42):199-206. 18. Allaire C, Bedaiwy MA, Yong PJ. Diagnosis and management of endome- triosis. CMAJ. 2023;195(10):E363-71; DOI: 10.1503/cmaj.220637. 19. Kvaskoff M, Mu F, Terry KL, Harris HR, Poole EM, Farland L, Missmer SA. Endometriosis: a high-risk population for major chronic diseases? Hum Reprod Update. 2015;21(4):500-16; DOI:10.1093/humupd/dmv013. 20. Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmei - er A, Yin P , Milad M, JianJun, Wei J. Endometriosis. Endocrine Reviews. 2019;40(4):1048-79; DOI:10.1210/er .2018-00242. 21. Silberstein SD, Merriam GR. Physiology of the menstrual cycle. Cephalale- gia. 2000;20(3):148-54; DOI:10.1046/j.1468-2982.2000.00034.x. 22. Dobrzyn� K, Kowalik MK. Molekularny mechanizm działania progestero- nu w żeńskim układzie rozrodczym. Postepy Biochem. 2022;68(3):336- 43; DOI:10.18388/pb.2021_458. 23. Tomac J, Cekinowic� D, Arapowic� J. Biology of the corpus luteum. Period biol. 2011;113(1):43-9. 24. Azeez JM, Susmi R, Remadevi V, Ravindran V, Sujatha AS, Ayswarya RNS, Sreeja S. New insights into the functions of progesterone re - ceptor (PR) isoforms and progesterone signaling. Am J Cancer Res. 2021;11(11):5214-32. 25. Zielniok K, Gajewska M, Motyl T . Molekularne aspekty działania 17β-e- stradiolu i progesteronu w komórkowych szlakach sygnałowych. Postei- py Hig Med Dosw. 2014;68:777-792; DOI:10.5604/17322693.1108390. 26. Patel B, Elguero S, Thakore S, Dahoud W, Bedaiwy M, Mesiano S. Role of nuclear progesterone receptor isoforms in uterine pathophysiolo - gy. Hum Reprod Update. 2015;21(2):155-73; DOI:10.1093/humupd/ dmu056. 27. Peluso JJ. Multiplicity of progesterone’s actions and receptors in the mammalian ovary. Biol Reprod. 2006;75(1):2-8; DOI:10.1095/ biolreprod.105.049924. 28. Niezgoda M. Ocena ekspresji chromograniny A oraz receptor o� w estro- genowych i progesteronowych w endometrium pacjentek z nowotwo- rem trzonu macicy [dissertation]. Białystok: Uniwersytet Medyczny w Białymstoku; 2020. 29. Reis FM, Coutinho LM, Vannuccini S, Batteux F, Chapron C, Petraglia F. Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure. Hum Reprod Up - date. 2020;26(4):565-85; DOI:10.1093/humupd/dmaa009. 30. Kim JJ, Kurita T , Bulun SE. Progesterone action in endometrial cann - cer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev. 2013;34(1):130-62; DOI:10.1210/er.2012-1043. 31. Donnez J, Dolmans MM. Endometriosis and medical therapy: from pro - gestogens to progesterone resistance to GNRH antagonists: a review. J. Clin. Med. 2021;10(5):1085; DOI:10.3390/jcm10051085. 32. Vannuccini S, Clemenza S, Rossi M, Petraglia F. Hormonal treatments for endometriosis: the endocrine background. Rev Endocr Metab Disord. 2022;23(3):333-55; DOI:10.1007/s11154-021-09666-w. 33. Tariverdian N, Theoharides TC, Siedentopf F, Gutie �rrez G, Jeschke U, Rabinovich GA, Blois SM, Arck PC. Neuroendocrine-immune disequilib - rium and endometriosis: An interdisciplinary approach. Semin Immu - nopathol. 2007;29:193-210; DOI:10.1007/s00281-007-0077-0. 34. Choi JY, Jo MW, Lee EY, Hwang SS, Choi DS. Aberrant PTEN expression in response to progesterone reduces endometriotic stromal cell apoptosis. Reproduction. 2017;153(1):11-21; DOI:10.1530/REP-16-0322. 35. Yu K, Huang ZY, Xu XL, Li J, Fu XW, Deng SL. Estrogen receptor function: impact on the human endometrium. Front Endocrinol. 2022;13:827724; DOI:10.3389/fendo.2022.827724. 36. Maciuszek M. Byc� kobietą, byc� kobietą – wpływ estrogeno� w na funkcjo- nowanie układu odpornos�ciowego. Wszechs�wiat. 2016;117:10-12. 37. Groothuis PG, Dassen HHNM, Romano A, Punyadeera C. Estrogen and the endometrium: Lessons learned from gene expression profil - ing in rodents and human. Hum Reprod Update. 2007;13(4):405-17; DOI:10.1093/humupd/dmm009. Obrycka et al. Medical Journal of Cell Biology (2024) 60 38. Hapangama DK, Kamal AM, Bulmer JN. Estrogen receptor b: the guard - ian of the endometrium. Hum Reprod Update. 2015;21(2):174-93; DOI:10.1093/humupd/dmu053. 39. Drabarek A. Kliniczne znaczenie ekspresji receptor o �w estrogenowych, progesteronowych i androgenowych u chorych poddanych leczniczemu zabiegowi operacyjnemu z powodu raka kory nadnercza [dissertation]. Gdańsk: Gdański Uniwersytet Medyczny; 2020. 40. Xiang D, Zhao M, Cai X, Wang Y, Zhang L, Yao H, et al. Betulinic acid inhibits endometriosis through suppression of estrogen receptor β signaling pathway. Front Endocrinol. 2020;11:604648; DOI:10.3389/ fendo.2020.604648. 41. Han SJ, Jung SY, Wu SP , Hawkins SM, Park MJ, Kyo S, Qin J, Lydon JP , Tsai SY, Tsai MJ, DeMayo FJ, O’Malley BW. Estrogen receptor β modu - lates apoptosis complexes and the inflammasome to drive the patho - genesis of endometriosis. Cell. 2015;163(4):960-74; DOI:10.1016/j. cell.2015.10.034. 42. Chantalat E, Valera MC, Vaysse C, Noirrit E, Rusidze M, Weyl A, Vergriete K, Buscail E, Lluel P , Fontaine C, Arnal JF, Lenfant F. Estrogen receptors and endometriosis. Int. J. Mol. Sci. 2020;21(8):2815; DOI:10.3390/ ijms21082815. 43. Yang YM, Yang WX. Epithelial-to-mesenchymal transition in the de - velopment of endometriosis. Oncotarget. 2017;8(25):41679-89; DOI:10.18632/oncotarget.16472. 44. Han SJ, Lee JE, Cho YJ, Park MJ, O’Malley BW. Genomic function of es - trogen receptor β in endometriosis. endocrinology. Endocrinology. 2019;160(11):2495-516; DOI:10.1210/en.2019-00442. 45. Liao TL, Lee YC, Tzeng CR, Wang YP , Chang HY, Lin YF, Kao SH. Mito - chondrial translocation of estrogen receptor β affords resistance to ox- idative insult-induced apoptosis and contributes to the pathogenesis of endometriosis. Free Radic Biol Med. 2019;134:359-73; DOI:10.1016/J. FREERADBIOMED.2019.01.022. . 46 Śliwerski A. Rola negatywnych stylów poznawczych w zespole napięcia przedmiesiączkowego. Łódź: Wydawnictwo Uniwersytetu Łódzkiego; 149 .2017 p. 47. Podsiadło-Urban G, Kiernicka M, Wysokin� ska-Miszczuk J. Wpływ estro- genów i progesteronu na stan przyzębia w poszczególnych okresach życia kobiety – przegląd piśmiennictwa. Dent Med Probl. 2010;47:89-6. 48. Januszyk P . Profil ekspresji geno � w i kodowanych przez nie białek związanych ze zjawiskiem utraty adekwatnej odpowiedzi na leczenie w raku endometrium [dissertation]. Rzeszów: Uniwersytet Rzeszowski; 2021. 49. Marquardt RM, Kim TH, Shin JH, Jeong JW. Progesterone and estrogen signaling in the endometrium: what goes wrong in endometriosis? Int J Mol Sci. 2019;20(15):3822; DOI:10.3390/ijms20153822. 50. Maksym RB, Ruta H. Os �rodek kompleksowego leczenia endometriozy jako odpowiedz� na problemy zdrowotne szczego � lnej grupy pacjentek. Fides Ratio. 2020;43(3):353-63; DOI:10.34766/fetr.v43i3.317. 51. Kędzia M, Basta P , Czajkowski K, Gogacz M, Spaczyn� ski R, Mroczkowska B, Stojko R, Szaflik T , Szubert M, Szyłło K, Zaborowski M, Sieroszewski P . Rekomendacje Polskiego Towarzystwa Ginekologów i Położników do- tyczące postępowania w przypadku kobiet z endometriozą [Internet]. Warszawa: Via Medica; 2023 [cited 2024 May 5]. 62 p. Available from: https://www.ptgin.pl/artykul/rekomendacje-polskiego-towarzyst - wa-ginekologow-i-poloznikow-dotyczace-postepowania-w/. 52. Chapron C, Marcellin L, Borghese B, Santulli P . Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. 2019;15(11):666-82; DOI:10.1038/S41574-019-0245-Z. 53. Schrager S, Falleroni J, Edgoose J. Evaluation and treatment of endome- triosis. Am Fam Physician. 2013;87(2):107-13. 54. Wielgos� Mirosław, editor. Biblioteka ginekologa praktyka tom 3 – endo- metrioza. Gdan� sk: Via Medica; 2010. 39 p. 55. Amro B, Ramirez Aristondo ME, Alsuwaidi S, Almaamari B, Hakim Z, Ta- hlak M, Wattiez A, Koninckx PR. New understanding of diagnosis, treatn- ment and prevention of endometriosis. Int J Environ Res Public Health. 2022;19(11):6725; DOI:10.3390/ijerph19116725. 56. Wentz AC, Sapp KC. Danazol as a luteolytic agent. Fertil Steril. 1978;29(1):23-5; DOI:10.1016/S0015-0282(16)43030-X. 57. Smolarz B, Szyłło K, Romanowicz H. Endometriosis: epidemiology, clas- sification, pathogenesis, treatment and genetics (review of literature). Int J Mol Sci. 2021;22(19):10554; DOI:10.3390/ijms221910554. 58. Kalaitzopoulos DR, Samartzis N, Kolovos GN, Mareti E, Samartzis E, Eberhard M, Dinas K, Daniilidis A. Treatment of endometriosis: a review with comparison of 8 guidelines. BMC Womens Health. 2021;21(1):1-9; DOI:10.1186/S12905-021-01545-5/TABLES/2. 59. Waller KG, Shaw RW. Gonadotropin-releasing hormone analogues for the treatment of endometriosis: long-term follow-up. Fertil Steril. 1993;59(3):511-5; DOI:10.1016/s0015-0282(16)55791-4. 60. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Go - nadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev. 2000;(2):CD000346; DOI:10.1002/14651858.CD000346. 61. Gilliam ML. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Obstet Gynecol. 2011;117(3):727-8; DOI:10.1097/AOG.0b013e31820cb0fd. 62. Gezer A, Oral E. Progestin therapy in endometriosis. Womens Health (Lond). 2015;11(5):643-52; DOI:10.2217/whe.15.42. 63. Vercellini P , Fedele L, Pietropaolo G, Frontino G, Somigliana E, Crosig - nani PG. Progestogens for endometriosis: forward to the past. Hum Re - prod Update. 2003;9(4):387-96; DOI:10.1093/humupd/dmg030. 64. Amini L, Chekini R, Nateghi MR, Haghani H, Jamialahmadi T , Sathyapalan T , Sahebkar A. The effect of combined vitamin C and vitamin E supple - mentation on oxidative stress markers in women with endometriosis: a randomized, triple-blind placebo-controlled clinical trial. Pain Res Manag. 2021;2021:5529741; DOI:10.1155/2021/5529741. 65. Gudarzi R, Shabani F, Mohammad-Alizadeh-Charandabi S, Naghshineh E, Shaseb E, Mirghafourvand M. Effect of curcumin on painful symptoms of endometriosis: a triple-blind randomized controlled trial. Phytother Res. 2024;38(1):147-55; DOI:10.1002/PTR.8030. 66. Gawlik B. Hydrodysekcja w laparoskopowym usunięciu endometriozy jajnika [dissertation]. Rzeszów: Uniwersytet Rzeszowski; 2020.