Letrozole in Endometriosis

Dr Sujoy Dasgupta was invited to deliver a lecture at the Conference of IMA (Indian Medical Association), held at July 2019 in Kolkata. This session was sponsored by Meyer Organic.

1. Letrozole in Endometriosis Dr Sujoy Dasgupta MBBS (Gold Medalist, Hons ) MS (OBGY- Gold Medalist) DNB (New Delhi) MRCOG (London) Advanced ART Course for Clinicians (NUHS, Singapore) Consultant: Reproductive Medicine, Genome Fertility Centre, Kolkata Managing Committee Member, Bengal Obstetric & Gynaecological Society (BOGS)- 2019-20 Secretary, Subfertility and Reproductive Endocrinology Committee , BOGS- 2019-20 Winner, Prof Geoffrey Chamberlain Award , RCOG World Congress, London, 2019

2. ENDOMETRIOSIS is a chronic, estrogen-dependent , inflammatory, painful disorder in which endometrial tissue grows outside the uterus. Most commonly involves ovaries, fallopian tubes and tissue lining the pelvis as well as bladder, bowel, vagina or rectum. This endometrial tissue thickens and bleeds , just as normal endometrium does during menstrual cycle.

3. Occurs in 6–10% of women of reproductive age, with a prevalence of 38% in infertile women , and in 71–87% of women with chronic pelvic pain Improved recognition of endometriotic lesions may have led to an increase in detection rate CONFIDENTIAL; for internal use only

4. Prevalence of endometriosis in India The Endometriosis Society of India estimates that  25 million i.e about 35%  Indian women suffer from this condition. India : Most affected country Urban India : stress and lifestyle choices The Endometriosis Society : five schools in Kolkata : 5% of the girls below 18 who complained of dysmenorrhea

5. COMMON ENDOMETRIOSIS SYMPTOMS With many women, progression is slow, developing over many years

6. Endometriosis may be a diagnosis of exclusion A significant number of women with endometriosis remain asymptomatic Therefore, DIAGNOSIS of endometriosis in a woman with pelvic pain is often delayed & stretches over several years!

7. Differential Diagnosis Dysmenorrhea Primary Secondary (e.g., adenomyosis, myomas, infection, cervical stenosis) Dyspareunia Diminished lubrication or vaginal expansion because of insufficient arousal Infection (PID) Vaginigmus Generalized pelvic pain Endometritis Neoplasms, benign or malignant Non- gynecologic causes Ovarian torsion Pelvic adhesions Pelvic inflammatory disease Sexual or physical abuse Gastrointestinal causes (e.g., constipation, irritable bowel syndrome) Infection Musculoskeletal causes (e.g., pelvic relaxation, levator spasm) Pelvic vascular congestion Urinary causes (e.g., urethral syndrome, interstitial cystitis)

8. DIAGNOSIS OF ENDOMETRIOSIS Clinicians should consider the diagnosis of endometriosis in the presence of gynecological symptoms- Dysmenorrhea non-cyclical pelvic pain deep dyspareunia Infertility fatigue in women of reproductive age with non- gynecological cyclical symptoms Dyschezia rectal bleeding Dysuria Hematuria shoulder pain

9. Impact of endometriosis in different patients

10. Quality of Life Work Education Relationships Social functioning Reduced work effectiveness Depressive symptoms Anxiety As symptoms become more severe, quality of life is reduced further. Endometriosis places a considerable economic burden on families and on society. Delays in diagnosis, high rates of hospital admission, surgical procedures, and incidences of comorbid conditions contribute to make endometriosis a more costly public health problem than other chronic conditions such as migraine and Crohn’s disease.

11. There is NO permanent cure for endometriosis As stated by ASRM, “Endometriosis should be viewed as a chronic disease that requires a life-long management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures” No single treatment is ideal for all patients, management chosen should be directed to individual needs of each patient Combination therapy may be ideal; as it is a chronic disease, we should consider not only efficacy but also long-term safety and tolerability of treatment options. Long-term treatment / repeated courses owing to frequent recurrence of pain within 6-12 months of completing treatment course (within 5 years in about half of women)

12. ETIOLOGY Risks factors: Family history of endometriosis Early age of menarche Short menstrual cycles (< 27 d) Long duration of menstrual flow (>7 d) Heavy bleeding during menses Delayed childbearing Defects in the uterus or fallopian tubes

13. Visceral Hypersensitivity Thresholds for pain in endometriosis groups were found to be similar to those in the IBS group

14. Types of endometriosis Peritoneal endometriosis They are endometriotic implants on the surface of the surface of pelvic peritoneum and ovaries . Endometriomas They are ovarian cysts lined by endometrioid mucosa . Rectovaginal endometriotic nodules It is a complex solid mass comprised of endometriotic tissue blended with adipose and fibromuscular tissue , residing between the rectum and the vagina. Adenomyosis (Endometriosis Interna ) Endometriosis in the myometrium (Musculature of the uterus) Extragenital endometriosis Scar tissue, pleura, omentum , lungs, limbs

15. The NEW ENGLAND JOURNAL of MEDICINE REVIEW ARTICLE Endometriosis MECHANISMS OF DISEASE Sedar E. Bulun , M.D. Endometriosis is an estrogen-dependent inflammatory disease

16. Estrogen hormone

17. Follicular physiology – Ovary - Estrogen Theca cells LH FSH Granulosa cells Aromatase E strogen Aromatase Inhibitors Aromatase Ovary Adipose tissue Brain androsterone

18. Normal endometrium & endometriosis Estrogen is not produced locally, owing to the absence of aromatase. Normal endometrium COX-2 - Cyclooxygenase-2 PGE2 Detectable aromatase activity Endometriosis COX-2 PGE2 H igh aromatase activity endometrial and endometriotic tissues S evere menstrual cramps and chronic pelvic pain. Ectopic endometriosis full-blown molecular abnormalities COX-2 PGE2

19. Complex interaction between aberrant endometrial GENES expression & altered HORMONAL response Overproduction of PROSTAGLANDINS by an increased COX-2 activity Overproduction of ESTROGEN by increased aromatase activity ENDOMETRIAL LESIONS proliferate  release macrophages and proinflammatory cytokines in peritoneal fluid  inflammation, adhesions, fibrosis, scarring, anatomical distortions  Pain & Infertility 1 2

20. Estradiol also specifically fuels these types of pain through its effects on the endometriotic tissue Estradiol induces COX-2, which increases production of prostaglandin E 2  (PGE 2 ) PGE 2  directly causes pain and inflammation PGE 2  in turn leads to increased aromatase, resulting in increased local estradiol production Positive feedback loop is created.

21. Diagnosis of Endometriosis Clinical examination CA-125 TVS MRI Laparoscopy

22. NICE, 2017 Do not exclude the possibility of endometriosis if the abdominal or pelvic examination, ultrasound or MRI are normal. If clinical suspicion remains or symptoms persist, consider referral for further assessment and investigation.

23. Gold Standard The combination of laparoscopy and the histological verification of endometrial glands and/or stroma In many cases the typical appearances of endometriotic implants in the abdominal cavity are regarded as proof that endometriosis is present. Consider laparoscopy to diagnose endometriosis in women with suspected endometriosis, even if the ultrasound was normal. (NICE, 2017) A negative diagnostic laparoscopy (i.e. a laparoscopy during which no endometriosis is identified) seems to be highly accurate for excluding endometriosis and is therefore of use to the clinician in aiding decision-making. (ESHRE, 2013)

24. Standard procedure A good quality laparoscopy should include systematic checking of 1) the uterus and adnexa, 2) the peritoneum of ovarian fossae, vesico -uterine fold, Douglas and pararectal spaces, 3) the rectum and sigmoid (isolated sigmoid nodules), 4) the appendix and caecum and 5) the diaphragm. 6) speculum examination and palpation of the vagina and cervix under laparoscopic control, to check for 'buried' nodules. A good quality laparoscopy can only be performed by using at least one secondary port for a suitable grasper to clear the pelvis of obstruction from bowel loops, or fluid suction to ensure the whole pouch of Douglas is inspected. By a gynaecologist with training and skills in laparoscopic surgery for endometriosis

25. Biopsy to confirm the diagnosis of endometriosis (be aware that a negative histological result does not exclude endometriosis) to exclude malignancy if an endometrioma is treated but not excised deep infiltrating disease

26. Stage 1 : Lesions are minimal & isolated Stage 2 : Lesions are mild - may be several; adhesions are possible. Stage 3 : Lesions are moderate, deep or superficial with clear adhesions Stage 4 : Lesions are multiple & severe, both superficial & deep, with prominent adhesions. ASRM classification of endometriosis

27. Stage is based on location, amount, depth & size of endometrial tissue Criteria - Extent of spread of tissue; Involvement of pelvic structures in disease; Extent of pelvic adhesions; Blockage of fallopian tubes Limitations - not a good predictor of pregnancy, does not correlate well with the symptoms of pain and dyspareunia or infertility. E.g. Woman in stage 1  tremendous pain, while Woman in stage 4  asymptomatic.

28. NICE, 2017 Offer endometriosis treatment according to the woman's symptoms, preferences and priorities, rather than the stage of the endometriosis.

29. Is Laparoscopy is a MUST? Empirical treatment can be started without a definitive diagnosis- if signs of deep endometriosis or ovarian endometriosis are not present in physical examination and imaging. young adolescents or in women that decide not to have a laparoscopy solely to know if the disease is there. Even if peritoneal disease is found it might not be the cause of pain Treatment of peritoneal disease does NOT influence the natural course of the disease. If medical pain treatment relieves pain, many women will not be interested whether or not their pain symptoms were due to peritoneal endometriosis .

30. Management of endometriosis Surgical management Conservative surgery (preferably laproscopy ) Hysterectomy (laparoscopy/ laparotomy ) Medical management NSAIDS GnRh analogs Continuous combined oral contraceptives (COC) Progestins - oral, injectable , Mirena (IUD) Antiprogestins - Danazol

31. CHOICE OF TREATMENT

32. Empirical treatment of pain Counsel women with symptoms presumed to be due to endometriosis thoroughly, and to empirically treat them with adequate analgesia, COC or progestagens . Before starting empirical treatment, other causes of pelvic pain symptoms should be ruled out, as far as possible. Response to hormonal therapy does NOT always predict the presence or absence of endometriosis .

33. Analgesics Consider a short trial (for example, 3 months ) of paracetamol or a NSAID alone or in combination for first-line management of endometriosis-related pain If a trial of paracetamol or an NSAID (alone or in combination) does not provide adequate pain relief, consider other forms of pain management and referral for further assessment.

34. Hormonal therapies Clinicians are recommended to prescribe hormonal treatment [hormonal contraceptives, progestagens , antiprogestagens , or GnRH agonists] as one of the options, as it reduces endometriosis-associated pain  Explain to women that hormonal treatment for endometriosis can reduce pain and has no permanent negative effect on subsequent fertility. No overwhelming evidence to support particular treatments over other . Medical treatments listed above, do not eliminate the extra-uterine tissue growth, they just reduce the symptoms.

35. Combined hormonal contraceptives COC, vaginal contraceptive ring or a transdermal ( estrogen /progestin) patch- -Reduce endometriosis-associated Dyspareunia dysmenorrhea ( continuous use of a CHC ) non-menstrual pain The vaginal ring reduced dysmenorrhea significantly more in patients with RV endometriosis compared to women in the patch group.

36. Progesterone, Antiprogesterone progestagens [medroxyprogesterone acetate (oral or depot), norethisterone acetate, dienogest , cyproterone acetate] anti- progestagens ( gestrinone , danazol ) Danazol should not be used if any other medical therapy is available. Recent studies indicate that vaginal danazol may be better tolerated. LNG-IUS is particularly suited for deep RV endometriosis

37. GnRH Agnosists Evidence is limited regarding dosage or duration of treatment Acts by downregulating the pituitary Clinicians are recommended to prescribe hormonal add-back therapy to coincide with the start of GnRH agonist therapy, to prevent bone loss and hypoestrogenic symptoms during treatment. This is NOT known to reduce the effect of treatment on pain relief careful consideration to the use of GnRH agonists in young women and adolescents, since these women may not have reached maximum bone density. GnRHa is more effective than placebo but inferior to the LNG-IUS or oral danazol . No difference in effectiveness exists when GnRHa is administered IM/ SC/ intranasally .

38. Drawbacks Of Conventional Medical Management Medical treatments usually are directed at : Inhibiting estrogen production from the ovaries Do not address local estrogen biosynthesis by the aromatase enzyme in endometriotic lesions. Half of the patients : Refractory. hypoestrogenic state Potential side effects.

39. Surgery as a mode of treatment When endometriosis is identified at laparoscopy, clinicians are recommended to surgically treat endometriosis, as this is effective for reducing endometriosis-associated pain i.e. ‘see and treat’ Operative laparoscopy (excision/ablation) is more effective for the treatment of pelvic pain associated with all stages of endometriosis, compared to diagnostic laparoscopy only

40. Surgery for Peritoneal Endometriosis Ablation and excision of peritoneal disease are thought to be equally effective for treatment of endometriosis-associated pain. Excision of lesions could be preferred with regard to the possibility of retrieving samples for histology. ablative techniques are unlikely to be suitable for advanced forms of endometriosis with deep endometriosis component.

41. Surgery for ovarian endometrioma When performing surgery in women with ovarian endometrioma (≥3 cm) perform cystectomy instead of drainage and coagulation/ CO2 laser vaporization - as cystectomy reduces endometriosis-associated pain increases spontaneous pregnancy rates a lower recurrence rate of the endometrioma

42. Surgery for deep endometriosis surgical removal of deep endometriosis, reduces endometriosis-associated pain and improves quality of life- in a MDT context associated with significant complication rates, particularly when rectal surgery is required. Colorectal involvement – Laparoscopy was as effective as laparotomy superficial shaving, discoid resection and segmental resection of the bowel to remove the deep endometriosis nodules. It was impossible to make comparisons between different surgical techniques. Bladder endometriosis excision of the lesion and primary closure of the bladder wall Ureteral lesions may be excised after stenting the ureter segmental excision with end-to-end anastomosis reimplantation

43. Surgical interruption of pelvic nerve pathways Clinicians should not perform LUNA as an additional procedure to conservative surgery to reduce endometriosis-associated pain Clinicians should be aware that presacral neurectomy (PSN) is effective as an additional procedure to conservative surgery to reduce endometriosis-associated midline pain , but it requires a high degree of skill and is a potentially hazardous procedure - bleeding, constipation, urinary urgency and painless first stage of labour.

44. Hysterectomy consider hysterectomy with removal of the ovaries and all visible endometriosis lesions, in women who have completed their family and failed to respond to more conservative treatments. Women should be informed that hysterectomy will not necessarily cure the symptoms or the disease. five studies on the effect of hysterectomy on chronic pelvic pain : 3%–17% of women reported recurrence of pain 1 year after surgery. Hysterectomy with ovarian conservation was reported to have a risk for development of recurrent pain and a greater risk of reoperation .

45. Preoperative hormonal therapies Clinicians should not prescribe preoperative hormonal treatment to improve the outcome of surgery for pain in women with endometriosis In clinical practice, surgeons prescribe preoperative medical treatment with GnRH analogues as this can facilitate surgery due to reduced inflammation, vascularisation of endometriosis lesions and adhesions. However, there are no controlled studies supporting this (ESHRE, 2013) Consider GnRH agonist x 3 cycles before surgery for deep infiltrating endometriosis (NICE, 2017) From a patient perspective, medical treatment should be offered before surgery to women with painful symptoms in the waiting period before the surgery can be performed, with the purpose of reducing pain before, not after, surgery.

46. Postoperative hormonal therapies Short Term (<6 months) Do not prescribe adjunctive hormonal treatment after surgery, as it does not improve the outcome of surgery for pain Long term (>6 months)- Sec Prevention role for prevention of recurrence of disease and painful symptoms in women surgically treated for endometriosis. there are limited data After cystectomy for ovarian endometrioma in women not immediately seeking conception, prescribe hormonal contraceptives Deep endometriosis- prescribe postoperative use of a LNG-IUS or a COC (continuous/ cyclic) for at least 18–24 months, as one of the options for the secondary prevention of endometriosis-associated dysmenorrhea, but not for non-menstrual pelvic pain or dyspareunia postoperative pain recurrence is not different in women receiving GnRH agonists, danazol or MPA or pentoxifylline , when compared to placebo

47. Risks associated with surgical treatment Complete excision of endometriotic tissue not possible Invasive procedure and chances of damaging the surrounding organs increases. Chances of damage to the reproductive organs thus leading to infertility. Needs skill

48. Pain due to extragenital endometriosis surgical removal is the treatment of choice for symptomatic extragenital endometriosis Diagnosis is usually made by histological confirmation, which is important to exclude other pathology, particularly malignancy . When surgical treatment is difficult or impossible, clinicians may consider medical treatment of extragenital endometriosis to relieve symptoms

49. Causes of Infertility

50. Subfertility About 1/3rd of women with endometriosis also suffer from  subfertility . Endometriosis does not equal infertility . It just implies that some women may have a harder time becoming pregnant. Endometriosis causes adhesions and scar tissue which cause the internal organs to get stuck to each other. Once the endometriosis is treated then women can usually conceive naturally without any assisted reproductive techniques.

51. Endometriosis and Infertility Distorted Pelvic Anatomy. Altered Peritoneal Function. Hormonal and Ovulatory Abnormalities. Impaired Implantation (challenged based on b-3 integrin research) Oocyte and Embryo Quality. Abnormal Uterotubal Transport.

52. Unexplained Infertility 10-20 % of infertile couples Reflects an incomplete fertility evaluation Many cases represent undiagnosed endometriosis Can lead to empiric and costly therapies that may costly therapies that may be effective

53. French Study 63% Endometriosis Eur J Obstet Gynecol Reprod Biol. 2012 Time to Treat Undiagnosed Endometriosis In Unexplained Infertility Leads to Recurrent Implantation Failures Belgium Study 47% endometriosis Fertility & Sterility Vol. 92, 1, July 2009

54. Endometriosis and IVF Failure Repeated , unexplained IVF failure patients exist in most practices IVF centers may not the inclination or skills to diagnose endometriosis Studies have suggested endometrial receptivity defects Meta-analyses suggest IVF is affected by endometriosis ( Barnhart et al., F&S 2002) Brosens suggested aromatase expression is a marker of poor IVF performance ( Brosens et al., HR, 2004 )

55. Molecular expression - Implantation Aromatase present in Endometrium of women with endometriosis. ( Noble et al 1995) B-3 integrin expression is aberrant in endometrium of women with endometriosis ( Lessey et al 1996 ) Implantation Requires Synchrony Delayed implantation - leads to miscarriage Miscarriage goes up with each day of delay Clinical evidence for the window of implantation

56. Implantation window The reception-ready phase of the endometrium of the uterus is usually termed the "implantation window" and lasts about 4 days.  The implantation window occurs around 6 days after the peak in luteinizing hormone levels . days 6-10 postovulation 20th to the 23rd day after the last menstrual period

57. Implantation window

58. Analgesics NSAIDs must be avoided around the time of ovulation

59. NICE, 2017 Do not offer hormonal treatment to women with endometriosis who are trying to conceive, because it does not improve spontaneous pregnancy rates. 85

60. Hormonal therapies Pregnancy is not possible/contraindicated during hormonal therapy hormonal treatment for suppression of ovarian function does not improve the chance of natural conception Only indicated- if wants to delay Laparoscopy/ IVF and the pain is severe

61. Surgery for Peritoneal Endometriosis Both ablation and excision improve the chance of spontaneous conception in ASRM stage I/II endometriosis ( CO2 laser vaporization > monopolar electrocoagulation ) Complete surgical removal before ART- ?

62. Surgery for ovarian endometrioma Cystectomy improves the chance of spontaneous conception, but NOT the success of ART clinicians counsel regarding the risks of reduced ovarian function after surgery and the possible loss of the ovary. The decision to proceed with surgery should be considered carefully if the woman has had previous ovarian surgery.

63. Surgery for deep endometriosis In women with infertility and severe pelvic pain who are resistant to medical treatment or severe bowel stenosis , radical excision of endometriosis combined with bowel segmental resection and anastomosis was associated with a higher postoperative spontaneous pregnancy rate Role before ART- ?

64. Postoperative hormonal therapies Do not prescribe adjunctive hormonal treatment after surgery , in women trying for pregnancy

65. Surgical therapies as an adjunct to ART In infertile women with endometrioma > 3 cm there is no evidence that cystectomy prior to treatment with ART improves pregnancy rates. only to consider cystectomy prior to ART to improve endometriosis-associated pain the accessibility of follicles.

66. Aromatase Inhibitor Letrozole A Game Changer Failure of current medical and surgical treatments to relieve pain leads to target the aromatase molecule in endometriosis by using Aromatase Inhibitor . The rationale is that continued local estrogen production in endometriotic implants during other medical treatments (e.g., GnRH analogues) was , in part, responsible for resistance to these treatments .

67. Aromatase Inhibitors (ESHRE 2015) In women with pain from RV endometriosis refractory to other medical or surgical treatment consider prescribing aromatase inhibitors in combination with COC, progestagens , or GnRH analogues, as they reduce endometriosis-associated pain The side effects are mostly hypoestrogenic in nature The evidence on the long-term effects is lacking.

68. 1. Pain Management & lesion size: Letrozole have successfully treated pelvic pain and significantly reduced the lesion size . 2. In premenopausal women: In premenopausal women , an Aromatase Inhibitor alone may induce ovarian folliculogenesis , and thus Aromatase Inhibitor are combined with a progestin, a combination oral contraceptive, or a GnRH analogue. 3. Side-effect profile: The side-effect profile of Aromatase Inhibitor administered in combination with an oral contraceptive or a progestin is remarkably benign . : mild headache, nausea, and diarrhea. Compared with the case of GnRH analogues, hot flashes are milder and infrequent. Aromatase Inhibitor Letrozole A Game Changer

69. Aromatase inhibitors with Progestins resistant to existing medical and surgical treatments of endometriosis Premenopausal patients (10) resistant to existing medical and surgical treatments of endometriosis Dosage : AI ( letrozole ; 2.5 mg ) + Progestin ( norethindrone acetate; 2.5 mg ) daily for 6 months . Outcome : Pelvic pain scores & American Society for Reproductive Medicine laparoscopic scores decreased significantly . 9 of 10 patients responded to this regimen with decreased pelvic pain. No significant bone loss was detected, and no evidence of ovarian enlargement was found. These results were suggestive that the addition of a progestin ( norethindrone acetate) in moderate doses to an AI suppresses gonadotropins sufficiently in the majority of premenopausal patients with endometriosis.

70. Aromatase inhibitors with Progestins

71. Before treatment with inhibitors of aromatase Maria Yarmolinskaya After treatment with inhibitors of aromatase

72. Endometrial receptivity defects during IVF cycles with and without letrozole Paul B. Miller Brent A. Parnell Greta Bushnell Nicholas Tallman David A. ForsteinH . Lee Higdon, III Jo Kitawaki  Bruce A. Lessey A im was to study ways to improve IVF success rates in women with suspected endometrial receptivity defects . Effect of letrozole - 5 mg on Days 5–9 of stimulation ( aromatase inhibitor) on integrin expression as a marker of endometrial receptivity.  IVF outcomes in 97 infertile women who had undergone ανβ3 integrin assessment  Unexplained IVF failure in a subset of women with endometriosis may be avoidable using a simple 5-day treatment of the aromatase inhibitor, letrozole .

73. Ongoing pregnancy rate Ongoing pregnancy rate in women undergoing IVF with positive (black) or negative integrins (white). In standard IVF protocols women with a negative integrin test had a significantly worse outcome than those who tested positive (P , 0.02). In integrin-negative women who underwent IVF with letrozole (2.5–5 mg/day on Days 2–6 ), outcomes were similar to integrin-positive women in non- letrozole cycles .

74. Are we delivering the embryo at the wrong time? Dr Samir Hamamah Endometrial Receptivity Is it possible to prolong the Endometrial Receptive Window to improve Implantation rate ?

75. Ovarian hyperstimulation by gonadotropins causes very high estrogen levels E2 during the pre-implantation period (days 0–6) Dr. Carlos Simone ESHRE 1997 Fertility & Sterility Vol. 70, No. 2, Aug. 1998 Window of uterine receptivity remains open for an extended period at lower estrogen levels but rapidly closes at higher levels High estrogen levels provoke uterine non receptivity

76. Human Reproduction, Volume 27, Issue 3, 1 March 2012 Systems Biology in Reproductive Medicine, Volume 60, 2014 Letrozole improves the marker of Endometrial Receptivity Letrozole improves Integrin expression in IVF Letrozole improves Integrin, LIF & L- Selectin expression in natural cycle Window of uterine receptivity remains open for an extended period at lower estrogen levels but rapidly closes at higher levels PNAS March 4, 2003 100 (5) 2963-296

77. Letrozole use with gonadotropins in IVF cycles may increase endometrial receptivity by increasing integrin expression in the endometrium and by lowering estrogen concentrations to more physiologic levels Dr. Robert F Casper MD, FRCS(C) Editorial Editor of fertility & Sterility Restoring the physiological Symphony between the blastocyst and the endometrium Fertility-Promoting Endometriosis Therapy

78. Reduction in Endometrioma Size Breaking away from the treatment paradigm (The lancet 2010) Fertility-Promoting Endometriosis Therapy

79. “Excision of endometriomas negatively impact ovarian reserve & number of oocytes retrieved for IVF” 3 months of Letrozole therapy 75% reduction in Endometrioma volume BioMed Research International Volume 2015 50% decrease in Endometrioma diameter Fertility-Promoting Endometriosis Therapy

80. Medical shrinkage of endometriomas with Letrozole appears to be a viable option for: Women interested in avoiding surgery for endometriomas . Women wishing to preserve fertility for future conception Wednesday, October 16, 2013 IFFS/ASRM -2013 Refractory endometriosis Chronic pain associated with endometriosis Indication

81. Aromatase inhibitor with GnRh -a (clinical study 2) McGill university C omparison of 2 months pretreatment with GnRH agonists with or without an aromatase inhibitor in women with ultrasound-diagnosed ovarian endometriomas undergoing IVF. 126 women aged 21–39 years who failed a previous IVF cycle and all subsequent embryo transfers and had sonographic evidence of endometriomas. Women were non-randomly assigned to either 3.75 mg intramuscular depo-leuprolide treatment alone or in combination with 5 mg of oral letrozole daily for 60 days prior to undergoing a fresh IVF cycle. Main outcome measures included clinical pregnancy rate and ongoing pregnancy rate after 24 weeks’ gestation. The combination of depo-leuprolide acetate monthly for 60 days combined with daily letrozole has better clinical outcomes at IVF in women with endometriomas than depo-leuprolide acetate treatment alone.

82. A comparison of pre-treatment with and without GNRH-agonist or Letrozole in women with 2 failed embryo transfers undergoing a frozen cycle & no evidence of endometriosis. A prospective cohort study was performed on subjects who failed two embryo transfers of blastocysts. 204 subjects were selected, 143 received 2-months of luprolide -acetate only and the rest received luprolide acetate 3.75 mg monthly IM and letrozole 5 mg daily orally for 60 days. The study found that c linical p regnancy rates and third-trimester pregnancies were highest among the GnRH- ag -Letrozole group as compared to GnRH- ag only group.

83. New Treatment Protocol A comparison of pre treatment with & without GnRH -agonist or Letrozole in women with 2 failed embryo transfers undergoing a frozen cycle & no evidence of endometriosis New Treatment Protocol Patient with 2 failed embryo transfers perform better if pretreated with GnRH-ag - Letrozole , due to treatment of undiagnosed Endometriosis

84. Addition of an aromatase inhibitor improves IVF outcomes when pre-treating women with 2 months of GnRH Agonist with Endometriomas . 60 days of treatment along with GnRH agonist in Recurrent Implantation Failure

85. Letrozole Vs Dienogest According to a study conducted by the Ott‘s Scientific Research Institute of Obstetrics , Russia : Endometriosis induced rats were treated with different medications like Letrozole, D ienogest, C abergoline, Melatonin and Metformin . I t was found that the efficacy of treatment was same in both the Letrozole and dienogest treatment group. This proves that dienogest as well as Letrozole provides the same efficacy of treatment

86. It was also worth noticing that…. After the end of treatment with aromatase inhibitors , 31% of patients with infertility, genital endometriosis and repeated courses of ineffective hormone therapy became pregnant A mong them in 18.2% of women pregnancy occurred spontaneously I n 31.8% - after ovulation induction with gonadotropins in 50% - in IVF protocol with the use of own (16,7 %) or donor (33.3 %) oocytes . The study showed that aromatase inhibitors can be used for treatment of patients of reproductive age with endometriosis. Application of aromatase inhibitors is an effective, safe and well tolerated method of endometriosis treatment, especially for patients with recurrence of endometriosis after GnRH agonist treatment and /or with reduced ovarian reserve. Maria Yarmolinskaya

87. Indications Refractory endometriosis Endometriosis confirmed during surgery in combination with history of ineffective treatment with GnRH and / or reduced ovarian reserve. Empirical treatment in unexplained infertility/ Recurrent Implantation failure

88. Take home message Aromatase inhibitors appear to be the first breakthrough in the medical treatment of endometriosis since the introduction of GnRH -agonists. Patients with endometriosis who do not respond to existing treatments appear to obtain significant pain relief from AIs . T he side-effect profiles of the AI regimens (including a progestin or OC add-back ) are more favorable compared with treatments using GnRH -a or danazol . Thus these regimens can potentially be administered over prolonged periods of time .

89. Thank you