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Dydrogesterone का नया अवतार (Part 1) Dr Sharda Jain
- 1. Dydrogesterone का नया अवतार PART - 1 DR. SHARDA JAIN DR JYOTI AGARWAL
- 3. Contents 1. Overview of Endometriosis 2. Diagnosis, Grading, And Classification Of Endometriosis 3. Endometriosis and Infertility 4. Rationale For Management Of Endometriosis 5. Dydrogesterone: The Right Choice For Treatment of Endometriosis 6. Key Messages PART - 1
- 5. Endometriosis: An Agonizing Condition 1. Parasar P, et al. Curr Obstet Gynecol Rep. 2017;6(1):34–41. 2. Schrager S, et al. Am Fam Physician. 2013;87(2):107–13. Endometriosis is a chronic and recurrent disease.1,2 DEBILITATING DISEASE ,PROGRESSIVE DISEASE ,NO CURE SO FAR The lesions can be peritoneal lesions, superficial implants or cysts on the ovary, or deep infiltrating lesions.1 It is characterized by functional endometrial glandular and/or stromal lesions outside the uterus.1
- 6. Prevalence of Endometriosis 10% Women of reproductive age suffer from endometriosis1 Global prevalence: 176 million women2 Prevalence in India: 25 million women3 1. Parasar P, et al. Curr Obstet Gynecol Rep. 2017;6(1):34–41. 2. Zondervan KT, et al. Nat Rev Dis Primers. 2018;4(1):9. 3. About Endometriosis – Endometriosis Society of India. Available from: http://endosocind.org/about-endometriosis/. Accessed on: 22 July 2020.
- 7. Pathogenic Theories of Endometriosis Retrograde menstruation Altered immunity Coelomic metaplasia Stem cells Genetics 1. Macer ML, et al. Obstet Gynecol Clin. 2012;39(4):535–49. 2. Rafique S, et al. Clin Obstet Gynecol. 2017;60(3):485.
- 8. Retrograde Menstruation: The Most Predominant Theory of Endometriosis Pathogenesis IL: interleukin; TNF: Tumour necrosis factor; RANTES: Regulated on activation, normal T expressed and secreted; VEGF: Vascular endothelial growth factor. Macer ML, et al. Obstet Gynecol Clin North Am. 2012;39(4):535–549. Endometrial fragments enter peritoneal cavity through fallopian tubes Attach to peritoneal cells Increased vascular supply Proliferation Endometrial implants Altered immunity IL-1, IL-6, IL-8, TNF RANTES, VEGF Increased leukocytes and macrophages in and around endometrial implants and in peritoneal fluid Cytokines and growth factors secretion Retrograde menstruation
- 9. at the Core of Endometriosis Pathogenesis 1. Broi MGD, et al. JBRA Assist Reprod. 2019;23(3):273–280. 2. Rafique S, et al. Clin Obstet Gynecol. 2017;60(3):485. IL: Interleukin; TNF: Tumor necrosis factor. Endometriosis pain and infertility1,2 Peritoneal endometrial lesions1,2 Activation of macrophages1,2 Increased generation of inflammatory factors, reactive oxygen and nitrogen species, proinflammatory cytokines (IL-1, IL-6, TNF-α), growth factors, and prostaglandins1,2 Chronic inflammation, proliferation of lesions, and local hormonal imbalance1,2 Adverse pelvic environment1,2 Chronic Inflammation
- 10. Endometriosis is a LEADER in causing Mental & Physical Pain
- 11. Signs and Symptoms of Endometriosis 1. Parasar P, et al. Curr Obstet Gynecol Rep. 2017;6(1):34–41. 2. Bulletti C, et al. J Assist Reprod Genet. 2010;27(8):441–447. Clinical presentations of endometriosis Intermenstrual bleeding1 Dysmenorrhea1 Painful intercourse1 Painful defecation1 Painful urination1 Pelvic pain1 Hemoptysis2 Menstrual cramps1 Infertility1
- 12. Risk Factors for Endometriosis Peterson CM, et al. Am J Obstet Gynecol. 2013;208(6):451. Increasing age Early menarche Shorter menstrual cycle interval Prolonged menstrual flow Family history of endometriosis Low body weight Intercourse during menses Caffeine intake
- 13. Comorbidities Associated With Endometriosis Adenomyosis Cancer (e.g. endometrioid ovarian cancer) Autoimmune diseases (e.g. systemic lupus erythematosus, Sjögren syndrome, multiple sclerosis, and rheumatoid arthritis) Cardiovascular conditions (e.g. myocardial infarction, angina, coronary angioplasty, or stent placement) Endometriosis- related comorbidities Zondervan KT, et al. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9.
- 14. Endometriosis Has A Negative Impact on Quality of Life Marinho MCP, et al. J Womens Health (Larchmt). 2018;27(3):399–408. Impaired physical, mental, and social well-being Psychological stress, anxiety, or depression Low self-esteem and poor performance at work Poor quality of sleep How does endometriosis impact quality of life?
- 15. Diagnosis, Grading, and Classification of Endometriosis
- 16. Diagnosis of Endometriosis Based on clinical history of the patient • Uterine or adnexal tenderness • Retroverted fixture • Nodulating uterosacral ligament • Pelvic masses Laparoscopic inspection with histologic confirmation after biopsy is the gold standard for diagnosis. Parasar P, et al. Curr Obstet Gynecol Rep. 2017;6(1):34–41. Ultrasound (pelvic, transvaginal and transabdominal) MRI CT scans Tools to visualize pelvic masses CT: Computed tomography; MRI: Magnetic resonance imaging. Preliminary diagnosis Palpate Differential diagnosis • Urinalysis • Pap smear • Pregnancy test • Vaginal and endocervical swabs
- 17. Need of Early Diagnosis of Endometriosis An average delay in diagnosis of endometriosis in women between 18 and 45 years of age is 6.7 years. This leads to unnecessary suffering and reduced quality of life. Early referral, diagnosis, identification of disease, and treatment are needed to mitigate pain, prevent disease progression, and preserve fertility. Non-invasive tool to diagnose endometriosis could facilitate early diagnosis and intervention. Parasar P, et al. Curr Obstet Gynecol Rep. 2017;6(1):34–41.
- 18. ASRM classification Grading and Classification of Endometriosis (1/2) ASRM: American Society for Reproductive Medicine. 1. Capezzuoli T, et al. Gynecol Reprod Endocrinol Metab. 2020;1(1):14–22. 2. Zondervan KT, et al. Nat Rev Dis Primers. 2018;4(1):9. 01 02 04 Stage 1 (Minimal Endometriosis)1 1–5 points • Superficial lesions2 • Commonly on the pelvic walls or pouch of Douglas2 Stage 2 (Mild Endometriosis) 1 6–15 points • Superficial lesions or some deep lesions (>5 mm infiltration below the peritoneal surface2 Stage 3 (Moderate Endometriosis) 1 16–40 points • Includes endometrioma and minor adhesions between uterine and ovarian walls2 Stage 4 (Severe Endometriosis) 1 >40 points • Severe adhesions with bowel and/or bladder involvement2 • Severe damage to pouch of Douglas2 03
- 19. Grading and Classification of Endometriosis (2/2) ENZIAN classification Compartments of retroperitoneal structures • Compartment A: Vagina, recto-vaginal septum • Compartment B: Uterosacral ligaments to the pelvic wall • Compartment C: Rectum and sigmoid colon Classification of disease severity • Grade 1: Invasion <1 cm • Grade 2: Invasion 1–3 cm • Grade 3: Invasion >3 cm Deep endometriosis invasion and invasion of organs recorded • Far adenomyosis • Far bladder invasion • Far intrinsic ureteral endometriosis • Far bowel disease cranial to the sigmoid colon • Other locations Capezzuoli T, et al. Gynecol Reprod Endocrinol Metab. 2020;1(1):14–22.
- 21. Women with endometriosis have a lower monthly fecundity of about 0.02–0.1 per month. Endometriosis is associated with a lower live birth rate. Infertile women are 6 to 8 times more likely to have endometriosis than fertile women. Endometriosis and Infertility Bulletti C, et al. J Assist Reprod Genet. 2010;27(8):441–447.
- 22. Pathogenic Mechanisms in Endometriosis- Associated Infertility Underlying adhesions1 Ovarian cysts1 Change in tubal anatomy1 Abnormal folliculogenesi s2 Elevated oxidative stress2 Altered immune function2 Alteration of follicular and peritoneal hormones2 Reduced endometrial receptivity2 1. Rafique S, et al. Clin Obstet Gynaecol. 2017;60(3):485. 2. Gupta S, et al. Fertil Steril. 2008;90(2):247–57.
- 23. Role of Inflammation in Endometriosis-Associated Infertility Macrophage activation Lesions in peritoneal endometrium Increase in inflammatory factors, reactive oxygen and nitrogen species, cytokines, growth factors, and prostaglandins Pelvic environment becomes adverse Increased inflammation in peritoneal fluid, damaged oocyte, and impaired oocyte quality Increased rate of infertility in women with endometriosis Broi MGD, et al. JBRA Assist Reprod. 2019;23(3):273–280.
- 24. 03. 02. 01. Disrupts progesterone and estrogen signaling1 Suppresses cellular response to progesterone exposure2 Hormonal imbalance leads to heightened inflammation, increased pelvic pain, and decreased endometrial receptivity.1 PROGESTERONE RESISTANCE confers endometrial tissue the ability to remain viable at foreign locations through successive menstrual cycles, as attenuation of progesterone target genes allows for continued growth and cell survival.2 Impaired Progesterone Signaling Exacerbates Endometriosis Symptoms 1. Marquardt RM, et al. Int J Mol Sci. 2019;20(15):3822. 2. McKinnon B, et al. Trends Endocrinol Metab. 2018;29(8):535–48.
- 26. Medical Therapy Is Essential for Endometriosis Endometriosis is impossible to cure, but it is possible to arrest the development of the disease and alleviate the symptoms.1,2 up to 21% up to 47% up to 55% 0% 10% 20% 30% 40% 50% 60% In 1 to 2 years In 5 years In 5 to 7 years Recurrence rate after surgery for endometriosis3 Recurrence rate of endometriosis is high after surgery3 The new strategy favors conservative treatment/medical therapy, with surgery suggested as an option only for cases that remain non-responsive for 6 months or longer.2 1. The Ministry of Healthcare of the Russian Federation. Clinical Guidance. Endometriosis. 2016. ID: КР259. 2. Dunselman GA, et al. Hum Reprod. 2014;29(3):400–412. 3. Adamian L. Endometriosis: Diagnostics, Treatment, and Rehabilitation. A Clinical Guide. Moscow. 2013, page 86.
- 27. Which Therapy Should Be Preferred for Early Endometriosis? Endometriosis therapy should enhance quality of life and reproductive health 1,2 Relieve/reduce pain symptoms3 Shrink/slow endometrial growths3 Preserve ovarian reserve and treat endometriosis associated infertility3,4 Prevent/delay recurrence of the disease3 1. The Ministry of Healthcare of the Russian Federation. Clinical Guidance. Endometriosis. 2016. ID: КР259. In Russian only. 2. Dunselman GA, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod, 2014;29(3):400–412. 3. Treatments for Endometriosis. Available at: https://endometriosisassn.org/about-endometriosis/treatments. Accessed on 22 July 2020, Orazov MR, Radzinsky VY, Khamoshina MB, et al. The efficacy of combined management of endometriosis-associated infertility. Int J Pharm Res 2019;11(3):1001–1006
- 28. Recommended Hormonal Therapy for Endometriosis Treatment Progestogens, or antiprogestogens NSAIDS; analgesics Combined oral contraceptives First-line medications according to ESHRE: Dunselman GA, et al. Hum Reprod. 2014;29(3):400–12. ESHRE: European Society of Human Reproduction and Embryology; GnRH: Gonadotropin releasing hormone; NSAID: Non-steroidal anti-inflammatory drugs. GnRH agonists and antagonists Aromatase inhibitors
- 29. Endometriosis Therapy Should Focus on Fertility Preservation in Women Desiring Conception Fertility Preservation in women of reproductive age (18–40 years) should be the focus of endometriosis therapy Women with endometriosis are at risk of decreased ovarian reserve and ovarian tissue damage which can lead to:1,2 Infertility Premature ovarian failure Reduced response to ovarian stimulation 1. Carrillo L, et al. J Assist Reprod Genet. 2016;33(3):317–23. 2. Llarena NC, et al. Clin Med Insights Reprod Health. 2019;13:1–8. Although many drugs are available for endometriosis treatment, there is an unmet need for a therapy that can preserve fertility while mitigating the endometriosis-associated pain.
- 31. Dydrogesterone: The NEW / Right Choice For Treatment of Endometriosis
- 32. PROGESTERONE ACTION IS CRUCIAL TO DECREASING INFLAMMATION IN THE ENDOMETRIUM Causes for progesterone resistance in the endometrium Repetitive retrograde endometrial shedding exacerbates progesterone resistance Endometriotic lesions and surrounding peritoneal fluid are rich in reactive oxygen species.2 Chronic inflammation1 Oxidative stress2,3 Dydrogesterone increases progesterone receptor expression and decreases proinflammatory cytokines1 Dydrogesterone exerts endothelial anti- inflammatory actions via a decrease in expression of leukocyte adhesion molecules.3 1. Patel BG, et al. Acta Obstet Gynecol Scand. 2017;96(6):623–32. 2. Reis FM, et al. Hum Reprod Update. 2020;26(4):565–585. 3. Chen JT, et al. J Clin Med Res. 2018;10(2):146–53.
- 33. Dydrogesterone Effectively Tackles Chronic Inflammation Associated With Endometriosis Reduces TNF-α-induced NF-κ-activation and suppresses proliferation of endometriotic stroma cells. Suppresses IL-8 production in lymphocytes. Increases NO production that plays an anti-inflammatory role. DYD: Dydrogesterone; IL: Interleukin; NF: Nuclear factor; NO: Nitric oxide; TNF: Tumor necrosis factor.
- 34. Improves the HR - QOL
- 35. Dydrogesterone Enhances Quality of Life and Reproductive Health Endometriosis therapy should enhance quality of life and reproductive health: No inhibition of ovulation2 Reduction in pain symptoms/ size of endometriosis lesions1 Improvement in quality of life parameters1 Improved pregnancy outcomes3 In Infertility Patients 1. Patient Information Leaflet of Duphaston®, 06.07.2020. In Russian only. 2. . Schweppe KW. Maturitas. 2009;65:S23–7. 3. Griesinger G, et al. Reprod Biomed Online. 2019;38(2):249–59. BCZ Induces Atrophy in Ectopic Endometrial Tissue
- 36. Dydrogesterone in Endometriosis: Recommended Regimen 1. Report of the results of ORCHIDEA, a multicenter open-label observational study of dydrogesterone in the treatment of endometriosis in Russia. Data from Abbott. In Russian only. 2. Prof. A.V. Kozachenko, presentation at the 14th International Congress of Reproductive Medicine, Moscow, January 21, 2020. In Russian only. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 Prolonged cyclical regimen Continuous regimen Dydrogesterone is the only gestagen with a choice between two efficacious regimen for endometriosis. Dydrogesterone 20–30 mg per day for 6 months and longer is the recommended regimen in management of endometriosis
- 37. • Endometriosis is a CHRONIC and Recurrent disease. • DEBILITATING DISEASE ,PROGRESSIVE DISEASE NO CURE SO FAR • Induces atrophy in ectopic endometrial tissues • Inhibits the formation of De- Novo endometriotic tissues without affecting endometriosis • Does not inhibit ovulation improves Pregnancy Rate in Patients with infertility • Improve the endometriosis associated pelvic pain & quality of life (QOL) NEW AVTAAR IOF DYDROGESTERONE IN ENDOMETRIOSIS
Editor's Notes
- Welcome to today’s presentation titled, ‘Endometriosis and Infertility in Women of Reproductive Age.’
- This section gives an overview of the burden and the current concepts about endometriosis.
- Endometriosis, a major health problem in women during their reproductive age, is a chronic and recurrent disease.1,2 It is defined as the presence of functional endometrial glandular and/or stromal cells outside the uterine cavity. 1 The lesions can be peritoneal lesions, superficial implants or cysts on the ovary, or deep infiltrating disease.1 References 1. Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34–41. 2. Schrager S, Falleroni J, Edgoose J. Evaluation and treatment of endometriosis. Am Fam Physician. 2013;87(2):107–13.
- Globally, endometriosis is known to affect about 10% of women of reproductive age,1 which translates to approximately 176 million women. According to the Endometriosis Society of India, the number of women with endometriosis is estimated to be about 25 million.3 This high prevalence rate, both globally and nationally, indicates the alarming situation and needs to draw attention from both researchers as well as physicians. References Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34–41. Zondervan KT, Becker CM, Koga K, et al. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9. About Endometriosis – Endometriosis Society of India. Available from: http://endosocind.org/about-endometriosis/. Accessed on: 22 July 2020.
- The definite pathogenesis of endometriosis is still unknown but there are a number of leading theories including retrograde menstruation, coelomic metaplasia, altered immunity, stem cells, and genetics.1 The most predominant theory is of retrograde menstruation. It is proposed that with retrograde menstruation the endometrial glands and stroma are attached and implanted in peritoneal cavity.2 References Macer ML, Taylor HS. Endometriosis and infertility: A review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012;39(4):535–549. Rafique S, Decherney AH. Medical management of endometriosis. Clin Obstet Gynecol. 2017;60(3):485.
- The most well accepted theory, retrograde menstruation, states that endometrial tissue is transported in a retrograde fashion through patent fallopian tubes into the peritoneal cavity. The endometrial cells then attach to the peritoneal mesothelial cells, establish a blood supply, proliferate and produce endometrial implants. Women with endometriosis have higher volumes of refluxed menstrual blood and endometrial-tissue fragments than women without the disorder. However, the incidence of retrograde menstruation is similar in women with and without endometriosis so the pathogenesis appears to be a multi-factorial mechanism. Women with endometriosis have altered immunity; preventing them from clearing the refluxed endometrial cells/fragments that appear in retrograde menstruation. This would help explain why some women with retrograde menstruation develop endometriosis while others do not. Cell-mediated immunity is thought to be deficient in patients with the disease; leukocytes are unable to recognize that the endometrial tissue is not in its normal location. Once endometriosis develops, the immune system has also been to shown to potentiate the development and increase the severity of the disease. In women with endometriosis there are increased numbers of leukocytes and macrophages in and around endometrial implants and in the peritoneal fluid. These cells secrete cytokines and growth factors (interleukin (IL)- 1,6 and 8, tumor necrosis factor (TNF), regulated on activation, normal T expressed and secreted (RANTES), vascular endothelial growth factor (VEGF) into the peritoneal milieu, which then recruit surrounding capillaries and leukocytes. The ultimate effect is proliferation of endometriosis implants with increased vascular supply. Reference Macer ML, Taylor HS. Endometriosis and infertility: A review of the pathogenesis and treatment of endometriosis-associated infertility. Obstet Gynecol Clin North Am. 2012;39(4):535–549.
- Women with endometriosis have immunological dysfunction preventing the removal of endometrial implants and leading to tissue adhesion in the peritoneal cavity. These peritoneal endometrial lesions are responsible for the activation of macrophages, with consequent increase in the generation of inflammatory factors, reactive oxygen and nitrogen species, pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor, growth factors, and prostaglandins in the endometrial lesions. A marked inflammatory response, with exacerbation of reactive species and cytokines, makes the pelvic environment adverse that is reflected in the peritoneal fluid. These alterations may lead to chronic inflammation, proliferation of lesions, local hormonal imbalance, resulting in poor oocyte quality, poor sperm motility, embryo toxicity, and reduced endometrial receptivity. Increased production of prostaglandins along with chronic inflammation leads to pain.1,2 References Broi MGD, Ferriani RA, Navarro PA. Ethiopathogenic mechanisms of endometriosis-related infertility. JBRA Assist Reprod. 2019;23(3):273–280. Rafique S, Decherney AH. Medical management of endometriosis. Clin Obstet Gynecol. 2017;60(3):485.
- The clinical presentation of endometriosis varies. Although 20–25% of patients of endometriosis are asymptomatic, typically, endometriosis causes pain and infertility.1 Patients often present with symptoms such as intermenstrual bleeding, painful periods (dysmenorrhea), painful intercourse (dyspareunia), painful defecation (dyschezia), painful urination (dysuria), hemoptysis, and infertility in association with 1 or more of the above.1,2 Pelvic pain may present before menstruation begins. Other symptoms indicative of endometriosis include pain and a heavy feeling in the lumbo-sacral column and/or legs; nausea, lethargy, chronic fatigue; any cyclical pain affecting other organs; hemoptysis; scapular or thoracic pain; and acute abdomen.1 References 1. Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34–41. 2. Bulletti C, Coccia ME, Battistoni S, et al. Endometriosis and infertility. J Assist Reprod Genet. 2010;27(8):441–447.
- The factors increasing the risk of endometriosis include increasing age, early menarche, shorter menstrual cycle interval, prolonged menstrual flow, family history of endometriosis, low body weight, intercourse during menses, and caffeine intake. Reference Peterson CM, Johnstone EB, Hammoud AO, et al. Risk factors associated with endometriosis: Importance of study population for characterizing disease in the ENDO Study. Am J Obstet Gynecol. 2013;208(6):451.
- Patients with endometriosis may be at a high risk of developing several other chronic diseases: Adenomyosis: A study including 227 women with infertility showed that the prevalence of adenomyosis was reported as high as 79% among women with surgically confirmed endometriosis compared with 28% among women without endometriosis. Cancer: Endometriosis is known to be positively associated with cancer (e.g. endometrioid ovarian cancer). Autoimmune diseases: Patients with endometriosis show a higher risk of autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjögren syndrome, multiple sclerosis, and rheumatoid arthritis. Cardiovascular conditions: Patients with endometriosis are at a greater risk of myocardial infarction, angina, need for coronary artery bypass graft surgery, coronary angioplasty, or stent placement. Other cardiovascular disease risk factors such as hypertension and hypercholesterolemia are also associated with endometriosis. Reference Zondervan KT, Becker CM, Koga K, et al. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9.
- Endometriosis has a negative impact on the quality of life as well. The painful symptoms may significantly impair physical, mental, and social well-being; and infertility itself may cause psychological stress, low self-esteem, and depression. Improvement of quality of life should be considered an important point during the management of endometriosis. Reference Marinho MCP, Magalhaes TF, Fernandes LFC, et al. Quality of Life in Women with Endometriosis: An Integrative Review. J Womens Health (Larchmt). 2018;27(3):399–408.
- In this section, we will discuss the methods used for the diagnosis of endometriosis and the criteria for grading and classification.
- Preliminary diagnosis of endometriosis is usually based on the clinical history as the majority of women show normal results of physical examination. The clinicians palpate for uterine or adnexal tenderness, a retroverted fixture, nodulating uterosacral ligament, and any pelvic masses. A tenderness on palpation of posterior fornix is the most common finding. Differential diagnosis is important because pelvic pain is also a symptom of other diseases (such as pelvic adhesions, adenomyosis, and gastrointestinal or urologic disorders). Other causes of pelvic pain should be ruled out by carrying out appropriate diagnostic tests like urinalysis, Pap smear, pregnancy test, vaginal and endocervical swabs. Pelvic masses are visualized by the use of transvaginal and transabdominal ultrasound. Occasionally, a magnetic resonance imaging and computed tomography scans are conducted to characterize the pelvic masses. Laparoscopic inspection with histologic confirmation after biopsy is the gold standard for diagnosis. Reference Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34–41.
- The average delay in diagnosis of endometriosis is about 6.7 years resulting in unnecessary suffering and reduced quality of life. As the majority of women with endometriosis report the onset of symptoms during adolescence, early referral, diagnosis, identification of disease, and treatment may mitigate pain, prevent disease progression, and thus preserve fertility. Barriers to early diagnosis include high cost of diagnosis and treatment in adolescent patients and presentation of confounding symptoms, such as cyclic and acyclic pain. Thus, a non-invasive tool to diagnose endometriosis could facilitate earlier diagnosis and intervention that could ultimately improve quality of life and preserve fertility. Reference Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep. 2017;6(1):34–41.
- The American Society for Reproductive Medicine classification system is the most widely used classification worldwide. It considers the intraoperative disease findings, and takes into account peritoneal endometriosis, ovarian endometriosis, posterior cul-de–sac obliteration, ovarian adhesions, and tubal adhesions. Scores are assigned to endometriosis lesions in the peritoneum and ovaries using points that correspond to the size of the lesions. By analogy, points are also assigned for adhesions on the ovaries and fallopian tubes. Additional points are assigned for partial or complete posterior cul-de–sac obliteration. The assigned points are summed and a value is obtained to classify the disease based on its severity.1 Stage I (minimal, 1–5 points) usually comprises few superficial endometriotic spots or adhesions. Stage II (mild, 6–15 points) can be a few , deep peritoneal lesions solely or in combination with superficial lesions and filmy adhesions. Stage III (moderate, 16–40 points) often includes an endometrioma by itself or in combination with superficial or deep endometriosis and/or dense adhesions. Stage IV (severe, >40 points) is often characterized by all of the above as well as bilateral ovarian endometrioma and/or dense adhesions that can lead to a partial or complete obliteration of the lesser or true pelvis (the structure that contains all the pelvic organs).2 Reference 1. Capezzuoli T, Clemenza S, Sorbi F, et al. Classification/staging systems for endometriosis: The state of the art. Gynecol Reprod Endocrinol Metab. 2020;1(1):14–22. 2. Zondervan KT, Becker CM, Koga K, et al. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9.
- The ENZIAN classification was developed as a supplement to the American Society for Reproductive Medicine classification score, in order to provide a morphologically descriptive classification of DIE, taking into account retroperitoneal structures. The prefix ‘F’ stands for ‘far’ or ‘foreign,’ referring to distant retroperitoneal structures. The ENZIAN classification nomenclature is similar to the tumor, lymph nodes, metastasis (TLM) staging system used in cancer staging. Reference Capezzuoli T, Clemenza S, Sorbi F, et al. Classification/staging systems for endometriosis: The state of the art. Gynecol Reprod Endocrinol Metab. 2020;1(1):14–22.
- In this section, we will discuss the relationship of endometriosis with infertility.
- Endometriosis is closely linked with infertility. In normal couples, fecundity is in the range of 0.15 to 0.20 per month and decreases with age. Women with endometriosis tend to have a lower monthly fecundity of about 0.02–0.1 per month. Also, endometriosis is associated with a lower live birth rate. Infertile women are six to eight times more likely to have endometriosis than fertile women. Reference Bulletti C, Coccia ME, Battistoni S, et al. Endometriosis and infertility. J Assist Reprod Genet. 2010;27(8):441–447.
- The pathogenic mechanisms associated with infertility in endometriosis include underlying adhesions, ovarian cyst, change in tubal anatomy,1 abnormal folliculogenesis, elevated oxidative stress, altered immune function, altered hormonal milieu in the follicular and peritoneal environment, and reduced endometrial receptivity.2 References Rafique S, Decherney AH. Medical management of endometriosis. Clin Obstet Gynaecol. 2017;60(3):485. Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A. Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril. 2008;90(2):247-257.
- The immune function is known to be dysregulated in endometriosis patients. Peritoneal endometrial lesions are responsible for the activation of macrophages, with consequent increase in the generation of inflammatory factors, reactive oxygen and nitrogen species, cytokines, growth factors, and prostaglandins. This makes the pelvic environment adverse, which is reflected in the peritoneal fluid of these women. These changes in the microenvironment cause oocyte damage and lead to impairment of oocyte quality in endometriosis patients. Reference Broi MGD, Ferriani RA, Navarro PA. Ethiopathogenic mechanisms of endometriosis-related infertility. JBRA Assist Reprod. 2019;23(3):273–280.
- In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance.1 Progesterone resistance describes the suppressed cellular response to progesterone exposure.2 This hormone imbalance leads to heightened inflammation and may also increase pelvic pain and decrease endometrial receptivity to embryo implantation.1 In endometriosis, it confers endometrial tissue the ability to remain viable at foreign locations through successive menstrual cycles, as attenuation of progesterone target genes allows for continued growth and cell survival.2 References Marquardt RM, Kim TH, Shin JH, et al. Progesterone and estrogen signaling in the endometrium: What goes wrong in endometriosis? Int J Mol Sci. 2019;20(15):3822. McKinnon B, Mueller M, Montgomery G. Progesterone resistance in endometriosis: An acquired property? Trends Endocrinol Metab. 2018;29(8):535–48.
- In this section, we will discuss the rationale behind endometriosis treatment and the new for a new therapy for fertility preservation.
- Endometriosis is impossible to cure, but it is possible to arrest the development of the disease and alleviate the symptoms.1,2 Adamian et al. showed that the recurrence rate after endometriosis surgery is high, gradually increasing from 21% in 1-2 years to 55% in 5-7 years.3 Thus, a new strategy was devised that favors conservative treatment/medical therapy, with surgery suggested as an option only for cases that remain non-responsive for 6 months or longer.2 References The Ministry of Healthcare of the Russian Federation. Clinical Guidance. Endometriosis. 2016. ID: КР259. In Russian only. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: Management of women with endometriosis. Hum Reprod. 2014;29(3):400–412. Adamian L. Endometriosis: Diagnostics, Treatment, and Rehabilitation. A Clinical Guide. Moscow. 2013, page 86. In Russian only.
- Medical treatment for endometriosis should prevent loss of reproductive health and enhance quality of life.1,2 Endometriosis treatment goals should include:3 Relieve/reduce pain symptoms Shrink/slow endometrial growths Preserve ovarian reserve and restore fertility in long-term use Prevent/delay the recurrence of the disease References The Ministry of Healthcare of the Russian Federation. Clinical Guidance. Endometriosis. 2016. ID: КР259. In Russian only. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: Management of women with endometriosis. Hum Reprod. 2014;29(3):400–12. Treatments for Endometriosis. Available at: https://endometriosisassn.org/about-endometriosis/treatments. Accessed on: 22 July 2020.
- Currently, progestagens and anti-progestagens, non-steroidal anti-inflammatory drugs, analgesics, combined oral contraceptives, GnRH agonists and antagonists, and aromatase inhibitors are in clinical use. With no overwhelming evidence to support particular treatments over others, it is important that the decisions involved in any treatment plan are individual, and that a woman is able to make these based on an informed choice and a good understanding of what is happening to her body. Reference Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: Management of women with endometriosis. Hum Reprod. 2014;29(3):400–12.
- Fertility Preservation in women of reproductive age (18–40 years) should be the focus of endometriosis therapy. Women with endometriosis are at risk of decreased ovarian reserve and ovarian tissue damage that can lead to infertility, reduced response to ovarian stimulation, and premature ovarian failure.1,2 Although many drugs are available for endometriosis treatment, there is an unmet need for a therapy that can preserve fertility while mitigating the endometriosis-associated pain. References Carrillo L, Seidman DS, Cittadini E, et al. The role of fertility preservation in patients with endometriosis. J Assist Reprod Genet. 2016;33(3):317–23. Llarena NC, Falcone T, Flyckt RL. Fertility preservation in women with endometriosis. Clin Med Insights Reprod Health. 2019;13:1–8.
- Now let us discuss why dydrogesterone is the right choice for the treatment of endometriosis.
- Now let us discuss why dydrogesterone is the right choice for the treatment of endometriosis.
- Progesterone action is crucial to decreasing inflammation in the endometrium, and deviant progesterone signaling results in a proinflammatory phenotype. Conversely, chronic inflammation can induce a progesterone-resistant state. Repetitive retrograde endometrial shedding begets chronic peritoneal inflammation, which further exacerbates progesterone resistance.1 Dydrogesterone may overcome this phenomenon by increasing progesterone receptor expression and decreasing proinflammatory cytokines.1 Oxidative stress is another mechanism involved in progesterone resistance in endometriosis.2,3 The endometriotic lesions and the surrounding peritoneal fluid are rich in reactive oxygen species.2 Dydrogesterone exerts endothelial anti-inflammatory actions (i.e. via a decrease in expression of leukocyte adhesion molecules), thereby attenuating oxidative stress.3 References Patel BG, Rudnicki M, Yu J, et al. Progesterone resistance in endometriosis: Origins, consequences and interventions. Acta Obstet Gynecol Scand. 2017;96(6):623–32. Reis FM, Coutinho LM, Vannuccini S, et al. Progesterone receptor ligands for the treatment of endometriosis: The mechanisms behind therapeutic success and failure. Hum Reprod Update. 2020;26(4):565–585. Chen JT, Kotani K. Different effects of oral contraceptive and dydrogesterone treatment on oxidative stress levels in premenopausal women. J Clin Med Res. 2018;10(2):146–53.
- Dydrogesterone controls the growth of endometriosis by an anti-inflammatory mechanism. Tumor necrosis factor (TNF)-α and estradiol induce the proliferation of endometriotic stroma cells via nuclear factor (NF)-kappa-β, whereas dydrogesterone reduces TNF-α-induced NF-kappa-β activation. Interleukin (IL)-8 is one of the most potent angiogenic factors. Dydrogesterone also modulates immune responses via suppression of IL-8 production in lymphocytes. The increase in nitric oxide production seen with dydrogesterone also plays an important anti-inflammatory role. Reference Schweppe KW. The place of dydrogesterone in the treatment of endometriosis and adenomyosis. Maturitas. 2009;65:S23–7.
- Dydrogesterone enhances the quality of life and reproductive health as it leads to improvement of various endometriosis-related problems. It helps in: Reduction in pain symptoms/ size of endometriosis lesions1 Improvement in quality of life parameters1 No inhibition of ovulation2 Improved pregnancy outcomes3 References Patient Information Leaflet of Duphaston®, 06.07.2020. In Russian only. Schweppe KW. The place of dydrogesterone in the treatment of endometriosis and adenomyosis. Maturitas. 2009;65:S23–7. Griesinger G, Tournaye H, Macklon N, et al. Dydrogesterone: Pharmacological profile and mechanism of action as luteal phase support in assisted reproduction. Reprod Biomed Online. 2019;38(2):249–59.
- The study showed that dydrogesterone 20-30 mg per day, either cyclical or continuous regimen for 6 months and longer is the only gestagen for a doctor to have a choice between two efficacious regimens for endometriosis. References 1. Report of the results of ORCHIDEA, a multicenter open-label observational study of dydrogesterone in the treatment of endometriosis in Russia. Data from Abbott. In Russian only. 2. Prof. A.V. Kozachenko, presentation at the 14th International Congress of Reproductive Medicine, Moscow, January 21, 2020. In Russian only.