Camran Nezhat, MD

Endometriosis - defined as the presence of endometrial-like glands and stroma in any extrauterine site - is a common disease occurring in 7-10% of all women, and is often associated with chronic pelvic pain and infertility. Apart from these significant individual problems women with endometriosis and their families may face, this disease has a significant impact our society due to its chronic nature 

The symptoms of endometrioses are variable and its course is often unpredictable. While some women may be asymptomatic, the most common manifestations are pelvic pain, particularly with periods, dispaureunia, pain associated with bowel movements, and dysuria or hematuria in cases of bladder involvement.  Despite significant improvements in understanding of this disease, the pathogenesis of endometriosis remains unclear. There are several theories that were suggested; most prominent includes theory of retrograde menstruation associated potentially with genetic susceptibility for the disease. Also theories of hematogeneous and/or lymphogenic spread, genetic link, or defects in immunocompetency have been suggested

The link between endometriosis and ovarian cancer is well recognized and has perplexed physicians for a long time 

. Epidemiological studies have suggested a specific link with endometrioid and clear-cell ovarian cancers, but no firm evidence established endometriosis as an ovarian cancer precursor lesion. Several lines of clinical evidence have supported the observation that non-serous ovarian carcinomas such as endometrioid and clear-cell carcinomas arising from atypical endometriotic foci have a higher likelihood of early diagnosis, as the associated endometriosis can cause pelvic pain or infertility requiring specialized gynecologic care including diagnostic laparoscopy. Deligdisch et al. reported a series of 76 cases of stage I ovarian carcinomas and documented that non-serous carcinomas (54/76) were diagnosed because of the associated symptoms including pelvic pain associated with endometriosis or vaginal bleeding associated with hyperestrogenism and endometrial pathology

. Interestingly they also found that serous carcinomas were frequently found in asymptomatic women with breast cancer diagnoses 

. These and similar observations support the emerging dual model of ovarian carcinogenesis. According to this model, Type I cancers are low grade, slowly developing ovarian carcinomas (including endometrioid, mucinous and low grade serous) associated with KRAS, BRAF, PTEN and B-catenin mutations and often associated with endometriosis. Type 2 is high-grade serous carcinomas associated with TP53 mutations that develop rapidly, are more aggressive and their origin is now thought to be tubal epithelium 

In the recent remarkable study reported in Lancet Oncology, the team of researchers from the Ovarian Cancer Association Consortium (OCAC) performed pooled analysis of 13 case-control studies and confirmed that women with self-reported history of endometriosis have significantly increased of clear cell carcinoma (odds ratio 3.05) and endometrioid ovarian cancer (odds ratio 2.04) 

. In addition the authors show, for the first time, that endometriosis is associated low-grade serous ovarian carcinomas, doubling its risk in women with endometriosis

.  However, there was no association between endometriosis and high-grade serous carcinomas or other subtypes of ovarian cancer in the study.

Taken together these findings will have considerable clinical implications and may affect the ways we think about strategies for ovarian cancer screening and prevention. In particular, the emerging knowledge of the link between ovarian cancer and endometriosis gives us an unprecedented opportunity to develop comprehensive screening plans to aid in the early detection and prevention of specific types of ovarian cancer in women with endometriosis. Such planning should include:

1) Identification of all women with endometriosis – either surgically documented or self-reported by symptoms;

2) Careful  follow up of ovarian presumed endometriomas by imaging studies, perhaps by MRI, for any characteristics changes such as mural formation;

3) Complete surgical resection of all endometriotic foci in women undergoing surgical treatment and tissue evaluation of ovarian endometriomas to rule out malignancy;

4) Hormonal treatment aimed at reducing the risk of cancer in high-risk women.

While it is well known that most women with endometriosis do not develop ovarian cancer, the women and their physicians should always discuss these new findings, carefully document and discuss any new symptoms and formulate plan for regular evaluations and treatment.


1. Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis-cost estimates and methotologic perspective. 

 2007;13:395-404.
2. Burney RO, Giudice LC: The Pathogenesis of Endometriosis. In Nezhat C, Nezhat F, Nezhat C, (eds): Nezhat’s Operative Gynecologic Laparoscopy and Hysteroscopy. 

New York, New York: Cambridge University Press

, 2008:251-7.
3. Munksgaard PS, Blaakaer J. The association between endometriosis and ovarian cancer: a review of histological, genetic and molecular alterations. 

 2012;124:164-69.
4. Nezhat F, Datta MS, Hanson V, et al. The relationship of endometriosis and ovarian malignancy: a review. 

 2008;90:1559-70.
5. Deligdisch L, PÃ©nault-Llorca F, Schlosshauer P, et al. Stage I ovarian carcinoma: different clinical pathologic patterns. 

 2007;88:906-10. 6. Levanon K, Crum C, Drapkin R. New insights into the pathogenesis of serous ovarian cancer and its clinical impact. 

 2008;26:5284-93.
7. Pearce CL, Templeman C, Rossing MA, et al. on behalf of the Ovarian Cancer Association Consortium. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. 

Articles

Emerging information on the link between ovarian cancer and endometriosis gives us an unprecedented opportunity to develop comprehensive screening plans for early detection and prevention of specific types of ovarian cancer.

Endometriosis and Risk of Ovarian Cancer: An update


 A fibroid is a benign tumor of the uterus. Various terms are used to refer to the tumor, such as fibromyoma, myofibroma, leiomyofibroma, fibroleiomyoma, myoma, fibroma, and fibroid. Of these, fibroid is the most common term, although myoma is more accurate.


 The incidence of fibroids is uncertain, but they are the most common tumors of the uterus and female pelvis. It has been estimated that one out of every four to five women older than 35 years of age has a uterine fibroid. It is also well documented that patients of African descent have a higher incidence of fibroids than Caucasian women, although the reason for this is not known. Leiomyomas are responsible for about one-third of all hospital admissions for gynecological services.


 The exact cause of uterine fibroids is not known, but it has been suggested that they arise from persistent small embryonic germ cells. Most studies have shown that the hormones estrogen and progesterone are involved in myoma growth. Most of the tumors occur during the reproductive years and usually become smaller after menopause. Oral contraceptives may cause myomas to enlarge. Older women who have never had children may have an increased risk of developing myomas. Women who have given birth have a decreasing risk of developing these tumors. A woman who has had five term pregnancies has only one-fifth the risk of developing a fibroid when compared to a woman with no children. Interestingly, the risk is reduced in women who smoke but increased in obese women.


 Most fibroids, even large ones, do not cause any symptoms. Indeed, most are discovered incidentally during a routine gynecological exam. Distortion of the normal abdominal wall contour due to a large tumor may also be discovered during self-exam. Patients with symptomatic fibroids typically have excessive or prolonged menses. This may sometimes cause anemia due to the large amount of bleeding. After bleeding, pressure is the second most common symptom of myomas. Pressure on the bladder can produce urinary frequency and urgency and, occasionally, inability to urinate. Pressure on the rectum may cause constipation. In cases of extremely large fibroids, pressure on the pelvic vessels may cause edema or varicose veins in the legs. Kidney symptoms are also possible if the fibroid extends upwards.

, a feeling of heaviness in the pelvis, or pain upon intercourse are also common symptoms. The pain may be dull or sharp, but is usually intermittent. Occasionally, fibroids cause dysmenorrhea (pain during menses). Myomas may also be related with infertility, especially if the myoma distorts the cervix enough that it becomes occluded. Pregnancy causes growth in size of any preexisting myomas, potentially causing an otherwise asymptomatic myoma to become symptomatic.


 In many cases, treatment is not necessary, particularly if there are no associated symptoms, if the tumors are small, or if the patient is postmenopausal. However, any patient with a diagnosed myoma should be carefully examined every three to six months to check for any unusual growth. If the patient is symptomatic, the myoma should be treated. Medical treatment, such as GnRH analogues, are available. They are effective, causing most myomas to shrink after a few months. Unfortunately, the myomas regain their original size several months after treatment is discontinued. Thus, surgery is still the best treatment option Common surgeries consist of either
 myomectomy (removal of the myoma alone) or hysterectomy (removal of the uterus and any associated myomas).

Traditionally, the surgeries were done by laparotomy (making a large abdominal incision) and excising the appropriate tissue. However, recent advances in surgical technology now allow most patients to be treated with new minimally invasive techniques, consisting of laparoscopic myomectomy or laparoscopic hysterectomy. Laparoscopic surgery

 is performed via three or four small incisions in the abdomen. The myomas are then removed through these incisions by first cutting them into small pieces inside the abdomen, then removing each small piece. This has many advantages, because it leads to shorter hospital stay (about 24 hours, compared to three days after laparotomy) and less postoperative pain (due to a smaller incision, which leads to less scar tissue). It is also a good choice for any women desiring children in the future, because it causes less pelvic adhesions.

For further information regarding laparoscopic removal of myomas, e-mail 

Endometriosis is a disorder in which abnormal growths of tissue, histologically resembling the endometrium, are present in locations other than the uterine cavity. Although endometriosis was described in detail more than 100 years ago, it continues to be one of the unsolved, enigmatic diseases affecting women. It is often called "the career woman's disease," because it occurs almost exclusively in women of reproductive age. Endometriosis is usually confined to the pelvis in the region of the ovaries, uterosacral ligaments, cul-de-sac, and uterovesical peritoneum.

The development and extension of endometrial tissue in the uterine muscles is termed adenomyosis. It can also affect the bowel, especially the rectum, colon and appendix. Endometriosis is one of the most common reasons for pelvic pain and infertility.


 There are three main theories as to the cause of this elusive disease, but the exact etiology remains a mystery. The most common and scientifically valid theory is a combination of immunological alteration and retrograde menstruation- direct transportation of viable endometrial cells through the fallopian tube into the pelvis which then implants in ectopic sites. Other suggestions are coelomic metaplasia, which proposes that peritoneal epithelial cells change to endometrial cells. The last theory is lymphatic spread/mechanical transport, where the cells are picked up by the lymphatic or circulatory system and ferried about the body.


 Endometriosis is a common and important health problem. Its exact prevalence is unknown because surgery is required for its diagnosis, but it is estimated to be present in 10% of all reproductive age women. It is seen in 1-2% of women undergoing sterilization, in 10% of hysterectomy surgeries, and in 16-31% of laparoscopies. Endometriosis has a higher incidence among Caucasians than among people of African descent. Some genetic influences in the development of endometriosis have been described. Studies have found that 7-9% of endometriosis patients' first-degree female relatives are diagnosed with the disease, significantly greater than the control rate of 1-2%.
 
 

Unfortunately, there is no current noninvasive test for diagnosing endometriosis. However, the typical symptoms include infertility, ovarian cysts, or chronic pelvic pain

 such as generalized vague and sometimes sharp pain; painful periods (dysmenorrhea); painful intercourse (dyspareunia); back pain; and painful ovulation. Pain with bowel movement and bladder pain can also exist. The symptoms are often related to the menstrual cycle, generally resulting from functioning endometrial tissue or scarring in the affected site. Pelvic examination may confirm suspicion. However, in mild to moderate stages of endometriosis, physical and pelvic examinations may be completely normal. Pain or bleeding from any site coinciding with menses should raise suspicions of endometriosis and lead to careful evaluation of specific anatomic areas involved such as lungs, umbilicus, previous incisions, bowel, bladder, ureters and diaphragm.


 Different hormonal therapies, such as birth control pills, progesterone, danazol, GnRH analogs, and recently RU486 have been used with some success to decrease the size of endometriotic lesions. This treatment can be used alone or in conjunction with surgery. Preoperative hormonal therapy has been shown to create a pelvic environment with much less blood flow and reduce inflammatory reaction, making surgical identification and removal of endometriotic lesions easier.

In the past, surgical treatment of endometriosis included laparotomy and hysterectomy. This was mainly due to the fact that surgeons were unfamiliar with endometriosis and how to treat it. A fairly recent improvement in technology, called operative videolaseroscopy, has revolutionized the way patients are treated for endometriosis. The advantages over laparotomy include a smaller incisional site (1/4-1/2 inch vs. 4-6 inches), shorter hospital stay (one day vs. 3-5 days) and a shorter recovery period (1 or 2 weeks vs. 4-6 weeks).

Through operative videolaseroscopy, endometrial implants can be coagulated, excised or ablated using a carbon dioxide laser or electrosurgery. Laparoscopic scissors and a laser can be used to cut lesions close to vital structures. Laparoscopic restoration of pelvic anatomy, especially at the area of the posterior cul-de-sac, is not simple and should only be undertaken by a surgeon who is familiar with performing surgery on genital, gastrointestinal, and urinary tract.

For further information on laparoscopic surgery for treatment of endometriosis, e-mail 

A fibroid is a benign tumor of the uterus. Various terms are used to refer to the tumor, such as fibromyoma, myofibroma, leiomyofibroma, fibroleiomyoma, myoma, fibroma, and fibroid. Of these, fibroid is the most common term, although myoma is more accurate.

Fibroids

 A Novel Device for Peritoneal Access in Laparoscopic Surgery

"Safe abdominal entry and prevention of retroperitoneal vascular  injuries during laparoscopic surgery are the ultimate goals of any  laparoscopic surgeon.  Dr. Linda Nicoll and colleagues very capably have  been able to describe a new technique and technology that prevent  almost all retroperitoneal vascular injuries during laparoscopic entry."

 -    Linda M. Nicoll MD, Madelein Lemyre MD, Dorian Bosev MD, Jian Qun Huang MD, Lisa Bhagan MD and Camran Nezhat MD

 email us with their comments and questions

 by using the comment links at the end of each article.


           Editor-in-Chief
 "New Frontiers in Reproductive Medicine"
           OBGYN.net

afe abdominal entry and prevention of retroperitoneal vascular injuries during laparoscopic surgery are the ultimate goals of any laparoscopic surgeon.  Dr. Linda Nicoll and colleagues very capably have been able to describe a new technique and technology that prevent almost all retroperitoneal vascular injuries during laparoscopic entry.

Frontiers in Reproductive Medicine

Because endometriosis is a common disease entity among infertile patients with a prevalence of up to 50%

,  one could argue that without laparoscopy clinical work-ups can not  completely rule out all of the causes of infertility. The decision to  perform laparoscopy on patients with infertility is very complex owing  to a number of factors, such as maternal age, semen parameters, tubal  patency, pelvic symptoms, insurance coverage, surgical risks, and  availability of surgical expertise. Presently, many clinicians would  advocate proceeding to IVF in patients with “unexplained” infertility  without laparoscopic evaluation. However, the etiology of infertility  cannot be totally unexplained unless the presence of endometriosis as a  cause has been ruled out. In women with undiagnosed endometriosis,  fertility treatments not only may be less effective but also may  contribute to progression of disease

.
   
   One of the advantages of laparoscopic evaluation of infertile patients  is that the surgical findings could change the handling of their  clinical cases. A study done by Tanahatoe et al. showed that  laparoscopic evaluation of patients undergoing infertility treatment  resulted in surgical treatment of endometriosis rather than further  assisted reproductive techniques in 25% of their patients

.  In addition, in infertile couples, laparoscopy reveals abnormal  findings in 21%–68% of cases with a normal hysterosalpingogram (HSG)

.  The additional value of laparoscopy over a normal HSG depends not only  on the prevalence of disclosed pathology but also on the contribution of  the diagnostic laparoscopy with regard to the decision of which  treatment should be applied. Although time is of the essence in many  clinical cases, the installation of laparoscopic treatment into the  management of infertility early on could alleviate the need to  continually expose patients to fertility medicines by altering the  treatment strategy. This approach may also improve the results of  assisted reproductive treatment.
   
   Several epidemiologic and molecular investigations have supported a link between endometriosis and ovarian cancer

  and endometriosis has been found in significantly higher frequency in  women undergoing surgery for endometroid and clear-cell subtypes of  ovarian cancers

. According to the literature, the incidence of malignant transformation is approximately 1% in patients with endometriosis

.  Without laparoscopic evaluation, the diagnosis of these serious  pathologies may be delayed. Obviously when discussing the pros and cons  of endoscopic surgery with infertility patients, the possible detection  of neoplasms at the time of surgery should be addressed. In addition,  the long-term effect of hormonal fertility treatments on female cancers  is currently unknown. Although direct causal link between ovarian  stimulation and cancer has not been established, until the relationship  between ovulation induction and ovarian cancer risk is defined more  accurately, a high index of vigilance is indicated. This is especially  true in women with endometriosis.
   
   Given the complexity of this matter, and the lack of prospective  randomized trials to provide further clarification, a consensus on this  subject in our field is far from being reached; the outcome of our  retrospective study has raised some issues that deserve further  discussion. We reported the outcome of patients with unexplained  infertility, who have failed at least 1 cycle of IVF and who  subsequently underwent either laparoscopy, additional IVF cycles,  controlled ovarian hyperstimulation with intrauterine insemination, or  no treatment.
   
   Our study

 was meant to offer an  alternative to repeated IVF attempts or oocyte donation in women who had  failed IVF. We acknowledge that patients need an indivualized approach  to infertility treatment and that every woman may not need to undergo a  laparoscopic evaluation in order to achieve pregnancy. However, in  patients who have not been able to achieve success by other methods,  laparoscopy is a reasonable option. Our findings suggest that thorough  laparoscopic treatment of endometriosis can be quite effective at  improving pregnancy rates. In our study, 22 out of 29 patients (76%)  achieved pregnancy after laparoscopic treatment of endometriosis. We  concur that our study suffers from the handicaps of retrospective  trials, and owing to the confounding factors elaborated by Drs. Penzias,  Diamond, Adamson, and Hershlag, this study is limited in its ability to  generalize the effect of laparoscopic treatment of endometriosis in all  infertile patients. Further prospective randomized trials need to be  performed to clarify this issue. However, this report should encourage  practitioners to offer a thorough laparoscopic evaluation and treatment  of endometriosis to patients who have failed IVF. After all, even some  of the most advanced cases of endometriosis might result in pregnancy  following surgical intervention

.
   
   Deepening the understanding of the mechanisms involved in infertility  associated with endometriosis will allow further improvement of the  outcome of infertility treatments and better care for endometriosis  patients. Although it is still early to state the last words on this  topic, we believe that laparoscopic diagnosis and treatment of  endometriosis is a rational approach to increasing the probability of  conception either spontaneously or with assisted reproductive treatment,  especially in patients with multiple IVF failures. 
   
   

 We appreciate the comments of  Drs. Penzias, Diamond, Adamson, and Hershlag concerning our paper. The  correspondents further elucidated the long-standing controversial issue  of the management of endometriosis-related infertility. We gratefully  acknowledge the efforts of Drs. Farr Nezhat, Ceana Nezhat, and Rosa  Moghadam in preparation of this manuscript.

1. Missmer SA, Cramer DW. The epidemiology of endometriosis. Obstet Gynecol Clin North Am 2003;30:1â19.    

2. The Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril 2004;81:1441â 6.    

3. Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a metaanalysis. Hum Reprod 1997:12:1865â72.    

4. Barnhart K, Dunsmorr-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002:77:1148 â55.    

5. Tanahatoe SJ, Hompes PG, Lambalk CB. Investigation of the infertile couple: should diagnostic laparoscopy be performed in the infertility    work up program in patients undergoing intrauterine insemination? Hum Reprod 2003;18(1):8 â11.    

6. Kalir T, Nezhat FR. Endometriosis and clues to the pathogenesis of ovarian cancer. CME J Gynecol Oncol 2003:8:52â 6.    

7. Brinton LA, Gridley G, Persson I, Baron J, Bergqvist A. Cancer risk after a hospital discharge diagnosis of endometriosis. Am J Obstet Gynecol 1997:176:572â9.    

8. Brinton LA, Lamb EJ, Moghissi KS, Scoccia B, Althuis MD, Mabie JE, Westhoff CL. Ovarian cancer risk associated with varying causes of infertility. Fertil Steril 2004:82:405â14.    

9. Jian X, Hitchcock A, Bryan E, Watsob R, Englefield P, Thomas E, et al. Microsatelite analysis of endometriosis reveals loss of heterozygosity a candidate ovarian tumor suppressor gene loci. Cancer Res 1996:56:3534â9.    

10. Saio N, Tsunoda M, Nishida M, Morishiu Y, Takimoto Y, Kuho T, et al. Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res 000;60;7052â 6.    

11. Sato N, Nishida M, Noguchi M. An approach to early genetic alterations in precancerous cells. Hum Cell 2000;13:103â 8.    

12. Han AC, Hovenden S, Rosenblum NO, Salazar H. Adenocarcinoma arising in extragonadal endometriosis. An immunohistochemical study. Cancer 1998;83:1163â9.    

13. Nezhat F, Cohen C, Rahman J, Gretz H, Cole P, Kalir T. Comparative immunohistochemical studies of bel-2 and p53 proteins in benign and    malignant ovarian endometriotic cysts. Cancer 2002;94:2935â 40.    

14. Lavy Y, Lev-Sagie A, Holtzer H, Revel A, Hurwitz A. Should laparoscopy be a mandatory component of the infertility evaluation in infertile women with normal hysterosalpingogram or suspected unilateral distal tubal pathology? Eur J Obstet Gynecol Reprod Biol 2004;10:11464â8.    

15. Nishida M, Watanabe K, Sato N, Ichikawa Y. Transformation of ovarian endometriosis. Gynecol Obstet Invest 2000;50:18 â25.    

16. Tagashira Y, Shimada M, Kigawa J, Iba T, Terakawa N. Ovarian endometrioid adenocarcinoma arising from endometriosis in a young    woman. Gynecol Oncol 2003;91:643â7.    

17. Kelly MG, Pejovic T, Nezhat F. What is the relationship between endometriosis and epithelial ovarian cancer? CME J Gynecol Oncol    2003:8:41â7.    

18. Osias J, Nezhat FR, Nezhat CH, Nezhat C. Malignant transformation of extragenital endometriosis. CME J Gynecol Oncol 2003:8:48 â51.    

19. Ness RB. Ovarian Cancer, inflammation and endometriosis. CME J Gynecol Oncol 2003:8:33â 40.    

20. Littman E, Giudice L, Berker B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril 2005;84:1574â8.    

21. Mohr C, Nezhat FR, Nezhat CH, Siedman DS, Nezhat C. Fertility considerations in patients with bowel endometriosis. J Laparoendosc Surg 2005;9:16 â24.1588 Nezhat et al. Is consensus possible with an enigma? Vol. 84, No. 6, December 2005

Because endometriosis is a common disease entity among infertile patients with a prevalence of up to 50%, one could argue that without laparoscopy clinical work-ups can not completely rule out all of the causes of infertility. The decision to perform laparoscopy on patients with infertility is very complex owing to a number of factors, such as maternal age, semen parameters, tubal patency, pelvic symptoms, insurance coverage, surgical risks, and availability of surgical expertise.

The dilemma of endometriosis: is consensus possible with an enigma?

(Fertil Steril 2005;84:1574–8.©2005 by American Society for Reproductive Medicine.)
         Key Words: Laparoscopy, endometriosis, infertility, IVF

Endometriosis is one of the most common gynecologic  disorders and is significantly more prevalent in the setting of  infertility

. The prevalence of endometriosis in infertile women ranges from 25% to 50% compared to 5% in fertile women

. Successful laparoscopic management of all stages of endometriosis was reported as early as 1986

.  This has revolutionized the management of endometriosis. The benefits  of surgical therapy for infertility associated with endometriosis have  been well documented

. However,
   with the advent of assisted reproductive technologies (ART), the  number of patients undergoing laparoscopic evaluation as part of the  initial workup has decreased. Recently, there has been a growing  tendency to bypass diagnostic laparoscopy after a normal  hysterosalpingogram

Patients are commonly in their mid-30s or older when they  seek infertility therapy. This, combined with the risks of undergoing a  surgical procedure, often leads patients with failed controlled ovarian  hyperstimulation (COH) and IUI to the IVF path, without thorough  evaluation or therapy of potential endometriosis. Furthermore, when  initial IVF cycles fail, patients and physicians tend to choose  additional IVF treatment and some may even elect oocyte donation after  multiple failures. Many couples and physicians believe
   that because the ultimate therapy, IVF, failed to result in a  pregnancy, further infertility investigation and treatment are likely to  be futile.

In this study, we report our experience with patients who  have failed IVF treatment and underwent laparoscopic evaluation and  management.


   A retrospective analysis of infertility patients, with failed IVF  treatment, was conducted. Typically, multiple cycles of COH/IUI had  failed and these patients elected to proceed to IVF without undergoing  laparoscopic evaluation. The patients were offered laparoscopy for  further evaluation of infertility as an alternative to repeating IVF,  oocyte donation, or adoption. Of this group, those patients who chose  not to undergo a laparoscopic procedure were assigned as a control  group. Patient characteristics including age, parity, FSH, number of  failed IVF cycles, duration of infertility, stage of endometriosis, and  modes of conception were recorded. The duration of infertility before  seeking treatment varied largely, dependent on the presenting age of the  patient.
   Patients >37 years old tended to seek infertility treatment earlier  than patients <37 years of age. These patients were followed for a  minimum of 9 months and were closely matched for age, FSH, duration of  infertility, and number of
   failed IVF cycles. Patients with severe male factor infertility  requiring intracytoplasmic sperm injection (ICSI) or tubal factor  infertility with bilateral tubal obstruction were not included.

Surgical treatment consisted of thorough CO

  laser ablation or excision of all peritoneal and nonperitoneal  endometriotic lesions, lysis of adhesions, and appropriate management of  ovarian endometriomas

. The  surgical approach was based on intraoperative assessment of the  pathophysiology or the type of endometrioma, which is found to be quite  varied

. For example, reassurance was made that type I endometriomas are totally removed. In type
   II endometriomas, only the endometriotic plaque, not the luteal cyst wall is removed

. No medical treatment of endometriosis was administered after surgery. All surgeries were performed by the senior surgeon (CN).

Statistical calculations were performed using Student’s 

 test as appropriate, and statistical significance was defined as 

< .01. Institutional review board approval was obtained before chart review.


   Twenty-nine patients with multiple IVF failures underwent laparoscopic  treatment. Eighteen of these patients were nulliparous. Three patients  had a known history of endometriosis before IVF treatment, whereas the  remaining 26 had no previous laparoscopy. At least one IVF cycle had  failed in all
   patients, with an average of 2.2 ( ±0.7)  failed cycles. Twenty-two of 29 (76%) of the patients who had  laparoscopic treatment of endometriosis conceived. The mean age of this  group was 34.3 ± 3.6 years with a range of 28 – 40 years. The characteristics of these patients are shown in 

.  Of the patients in the study who were diagnosed with stage I disease,  4/4 (100%) conceived. Five of 6 (83%) of patients with stage II disease  conceived. Five of 6 (83%) of patients with stage III disease conceived  and 8/13 (62%) of those with stage IV disease conceived.

Twelve patients conceived spontaneously and two patients  conceived with clomid/IUI. Time to conception, in these 14 patients,  ranged from 1 to 8 months after surgery. Seven patients conceived with  additional IVF treatment after surgery. An additional patient conceived  by IVF and also had a subsequent spontaneous conception. Twenty-four  percent of the patients in the laparoscopy group did not conceive  (7/29). The mean age of these patients was 36.4 ±  5.7 years, with a range of 31–40 years. The majority of these patients  had stage IV endometriosis (5/7). For further analysis, the outcome
   of patients who decided not to undergo laparoscopy was compared with  those of patients who elected laparoscopic evaluation. The mean age of  this group was 35.1 years and the average number of cycles was 2.4,  which was not
   significantly different from the laparoscopy group. In this  nonlaparoscopy group 13 of 35 conceived. Of those who conceived, two of  the pregnancies were spontaneous and the rest were from repeat IVF  cycles.

The group who underwent laparoscopy after failed IVF cycles is compared to the control group in 

.  There was no significant difference in the mean age or FSH level in  either of the patient groups. A significantly higher pregnancy rate (PR)  was demonstrated in the laparoscopy group vs. the
   nonlaparoscopy group. Also, the number of patients who were able to  conceive spontaneously was significantly higher in the group that had  undergone laparoscopic treatment of endometriosis. Statistical  significance was defined as 


   Fecundity rates in women with endometriosis tend to be lower than  normal in both natural and ART cycles, and despite extensive research,  no agreement has been reached concerning the mechanism of infertility

. A reduction in
   PR may be due to decreased fertilization secondary to the effect of  endometriosis on oocyte quality, decreased embryo quality, and a  decrease in implantation. Several studies have examined the association  of endometriosis and implantation failure on a molecular level. These  basic science studies
   suggest that endometriosis may be involved in the deregulation of  select genes that play critical roles in the process of implantation

.  Therefore, in addition to decreasing inflammation in the pelvis and  associated toxicity to embryos and gametes, surgical treatment of  disease may result in enhanced uterine receptivity.

In our study, 22 of 29 patients (76%) achieved pregnancy after  laparoscopic treatment for endometriosis. Other studies have quoted a  range of 20%–65% PR after laparoscopic treatment.

  We believe that the remarkably high PR achieved in the patients who  underwent laparoscopic evaluation is a reflection of the thorough  surgical technique. A recent study by Alborzi et al.

  concurred with this theory. This suggests that, even in the setting of  multiple IVF failures, laparoscopic management of endometriosis remains
   a viable option. A large number of patients, especially when age is a  factor, opt to proceed with IVF, without undergoing surgical evaluation  and treatment of endometriosis. It is likely that in many of these  women, IVF can still be successful despite the presence of untreated  endometriosis. However, bypassing the pelvic factor may not always be  sufficient to achieve optimal success. A meta-analysis conducted by  Barnhart et al.

, including 22 published studies pertaining to the effect of endometriosis on IVF success
   rates, concluded that patients with endometriosis-associated  infertility undergoing IVF respond with significantly decreased levels  of all markers of reproductive outcome and have 50% of the chance of  achieving pregnancy compared with tubal factor controls. It is our  stance that complete and
   thorough microsurgical eradication of endometriosis allows many  patients to conceive without further IVF therapy and may help optimize  success for those who require subsequent IVF cycles. Our findings are in  concordance with several published studies on the effect of ablation of  endometriosis lesions on fertility in patients with minimal-to-mild  endometriosis

, although there are some contradictory reports present in the literature

. The fact that almost 50% of the patients in our study (14/29) conceived without further IVF
   therapy is very encouraging.

Several studies have assessed the impact of the stage of endometriosis on ART outcomes

.  Those investigators found that patients with stage III–IV endometriosis  had significantly reduced fertilization rates as compared with
   patients with milder endometriosis. Thus, it may be that increasing  stages of endometriosis correlate inversely with fertilization  potential. Although there is still a lack of randomized controlled  trials that evaluate the effectiveness of
   laparoscopic surgery for severe endometriosis-associated infertility,  many observational studies suggest that in women with stage III–IV  endometriosis, without other identifiable infertility factors,  conservative surgical treatment with laparoscopy may increase fertility

.  Parallel to these findings, in our study, 13 of 19 patients (68.4%)  with stage III–IV endometriosis conceived spontaneously or with the aid  of IVF. Although there are concerns that surgical treatment may result  in diminished ovarian reserve

, in experienced
   hands, laparoscopic resection or ablation of endometriosis may enhance  fecundity in infertile women, regardless of the severity of the  disease. In fact, it has been our personal experience that more than 90%  of the infertile couples with unexplained infertility have  endometriosis or other pelvic pathology, like adhesions, at the time of  laparoscopy.

Several studies have concluded that laparoscopic removal of  endometriomas before IVF does not improve fertility outcomes

. For example, a study by Garcia-Velasco et al.

  was recently published on this issue. However, the design of this study  may confound interpretation of its results. For example, diagnosis of  endometriomas in the control group was solely based on ultrasound  observation, which has only an 85% positive predictive value. It is  difficult to distinguish by ultrasound the presence of a hemorrhagic  corpus luteum vs. endometrioma. Studies addressing the impact of  endometriosis on IVF outcome often fail to take into account the  intrinsic diagnostic limitations of ultrasound

  reviewed 38 articles related to diagnosis of endometriosis by  ultrasound scan. Although transvaginal ultrasonography was found to be a  useful test to detect or exclude the presence of an ovarian  endometrioma, the mean size of the endometriomas
   included in these studies was 40 mm. This suggest that the resolution  obtained with current ultrasound techniques is inadequate to detect  smaller endometriomas, and most smaller endometriomas are “true”  endometriomas and require complete excision

,  if we are expecting the best results. Ultrasound can be used by the  clinician to help establish a presumptive diagnosis of ovarian  involvement with endometriosis, but laparoscopy is necessary to confirm  the diagnosis

  stated that they were unable to surgically remove the entire  endometrioma cyst wall in some cases. This inability to thoroughly treat  the endometriosis might have also been a contributing factor to the  results of that study. As previously reported we classify endometriomas  into two types

. Type I  endometriomas are smaller and 100% consist of endometrial glands and  stroma. These endometriomas usually result from invagination of  endometriotic plaques into the stroma. They are usually smaller than 5  cm and are more difficult to remove. One often has to piecemeal these  cyst walls carefully. Most often surgeons end up coagulating these  endometriomas, which leads to inadequate treatment

. Type II endometriomas are invasion of functional cysts like corpus luteum in varying degrees by endometriosis plaques

.  Furthermore, in our experience, almost all of the patients with  endometriomas have peritoneal endometriosis, and this should be  thoroughly treated in patients who desire pregnancy

. In the article by Garcia-Velasco et al.

  no mention was made in that regard, except for treating the  endometriomas. The contrast in findings may also be explained by the  presence of varying etiologies or types of endometriosis and  endometriomas, as well as differing approaches and philosophies of  treating endometrial lesions, adhesions, and endometriosis. It has been  proposed that peritoneal endometriosis, ovarian endometriosis, and  adenomyotic nodules of the rectovaginal septum are three different  entities

. It has also been  suggested that if indeed this is the case, then different treatment  modalities may be applicable to certain types of endometriosis

.  It is our belief that the subset of patients with failed multiple  cycles of IVF may harbor a certain type of endometriosis that allows  them to benefit from thorough surgical therapy. Further studies  examining these issues are needed to provide additional clarification.

It is not unusual for patients and healthcare providers to  perceive IVF as the final treatment for infertility. When this  definitive therapy fails repeatedly, clinicians and patients may be  inclined to pursue oocyte donation or elect to forego further treatment  altogether. This is especially true in women of advanced age and in  patients with borderline embryo quality. Presently, as a result of our  clinical observation in patients with failed IVF, before egg donation or  adoption, we offer the option to have meticulous laparoscopic  evaluation
   and treatment by a skilled surgeon. Furthermore, we would not classify  an infertility condition as unexplained without confirming the absence  of endometriosis by a thorough laparoscopy. In our experience, patients  under 35 years old with unexplained infertility who are found to have  endometriosis
   at the time of laparoscopy have an excellent chance of pregnancy  following surgical treatment without ART. However, we acknowledge the  best way to evaluate this issue would be to conduct a multicenter  randomized clinical trial.

NOTE: FET = frozen embryo transfer, N/A = data not available
                 Littman Laparoscopy after failed IVF, Fertil Steril 2005

1. Olive DL, Haney AF. Endometriosis-associated infertility: a critical    review of therapeutic approaches. Obstet Gynecol Surv 1986;41:    538 â55.    

2. Strathy JH, Molgaard CA, Coulam CB, Melton LJ. Endometriosis and    infertility: a laparoscopic study of endometriosis among fertile and    infertile women. Fertil Steril 1982;38:667â72.    

3. Verkauf BS. The incidence, symptoms, and signs of endometriosis in    fertile and infertile women. J Fla Med Assoc 1987;74:671â5.    

4. Nezhat C, Crowgey SR, Garrison CP. Surgical treatment of endometriosis    via laser laparoscopy. Fertil Steril 1986;45:778â83.    

5. Donnez J, Smets M, Jadoul P, Pirard C, Squifflet J. Laparoscopic    management of peritoneal endometriosis, endometriotic cysts, and rectovaginal    adenomyosis. Ann NY Acad Sci 2003;997:274â81.   

 6. Adamson GD. Treatment of endometriosis-associated infertility. Semin    Reprod Endocrinol 1997;15:263â71.    

7. Tanahatoe SJ, Hompes PG, Lambalk CB. Investigation of the infertile    couple: should diagnostic laparoscopy be performed in the infertility    work up program in patients undergoing intrauterine insemination?    Hum Reprod 2003;18:8 â11.   

 8. Nezhat C, Siegler A, Nezhat F, Nezhat C, Seidman D, Luciano A.    Laparoscopic treatment of endometriosis. In: Nezhat C, ed. Operative    gynecologic laparoscopy: principles and techniques, 2nd ed. New York:    McGraw-Hill, 2000:169 â209.    

9. Nezhat F, Nezhat C, Allan CJ, Metzger DA, Sears DL. A clinical and    histologic classification of endometriomas: implications for a mechanism    of pathogenesis. J Reprod Med 1992;37:771â 6.    

10. Nezhat C, Nezhat F, Nezhat C, Seidman DS. Classification of endometriosis.    Improving the classification of endometriotic ovarian cysts.    Hum Reprod 1994;9:2212â3.    

11. Mahutte NG, Arici A. Endometriosis and assisted reproductive technologies:    are outcomes affected? Curr Opin Obstet Gynecol 2001;13:    275â9.    

12. Giudice LC, Telles TL, Lobo S, Kao L. The molecular basis for    implantation failure in endometriosis: on the road to discovery. Ann N    Y Acad Sci 2002;955:252â 64.    

13. Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, et al.    Expression profiling of endometrium from women with endometriosis    reveals candidate genes for disease-based implantation failure and    infertility. Endocrinology 2003;144:2870â81.    

14. Surrey ES, Schoolcraft WB. Does surgical management of endometriosis    within 6 months of an in vitro fertilizationâembryo transfer cycle    improve outcome? J Assist Reprod Genet 2003;20:365â70.    

15. Alborzi S, Momtahan M, Parsanezhad ME, Dehbashi S, Zolshadri J,    Alborzi S. A prospective, randomized study comparing laparoscopic    ovarian cystectomy versus fenestration and coagulation in patients with    endometriomas. Fertil Steril 2004;82:1633â7.    

16. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on    in vitro fertilization. Fertil Steril 2002;77:1148 â55.    

17. Jacobson T, Barlow D, Koninckx P, Olive D, Farquhar C. Laparoscopic    surgery for subfertility associated with endometriosis. Cochrane Database    Syst Rev 2001;4:CD001300.    

18. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile    women with minimal or mild endometriosis. Canadian Collaborative    Group on Endometriosis. N Engl J Med 1997;337:217â22.    

19. Garcia-Velaso JA, Majutte NG, Corona J, Zuniga V, Giles J, Arici A,    et al. Removal of endometriomas before in vitro fertilization does not    improve fertility outcomes: a matched, case-control study. Fertil Steril    2004;81:1194 â7.    

20. Parazzini F. Ablation of lesions or no treatment in minimalâmild    endometriosis in infertile women: a randomized trial. Gruppo Italiano    per lo Studio dell’Endometriosi. Hum Reprod 1999;14:1332â 4.    

21. Pal L, Shifren JL, Isaacson KB, Chang Y, Leykin L, Toth TL. Impact    of varying stages of endometriosis on the outcome of in vitro fertilization    âembryo transfer. J Assist Reprod Genet 1998;15:27â31.    

22. Azem F, Lessing JB, Geva E, Shahar A, Lerner-Geva L, Yovel I, et al.    Patients with stages III and IV endometriosis have a poorer outcome of    in vitro fertilizationâembryo transfer than patients with tubal infertility.    Fertil Steril 1999;72:1107â9.    

23. The Practice Committee of the American Society for Reproductive    Medicine. Endometriosis and infertility. Fertil Steril 2004;81:1441â 6.    

24. Schenken RS. Modern concepts of endometriosis. Classification and its    consequences for therapy J Reprod Med 1998;43(3 Suppl):269 â75.    

25. Somigliana E, Ragni G, Benedetti F, Borroni R, Vegetti W, Crosignani    PG. Does laparoscopic excision of endometriotic ovarian cysts significantly    affect ovarian reserve? Insights from IVF cycles. Hum Reprod    2003;18:2450 â3.    

26. Strandell A. Surgery in contemporary infertility. Curr Womens Health    Rep 2003;3:367â74.    

27. Brosens I. Endometriosis and the outcome of in vitro fertilization. Fertil    Steril 2004;81:1198 â200.    

28. Moore J, Copley S, Morris J, Lindsell D, Golding S, Kennedy S. A    systematic review of the accuracy of ultrasound in the diagnosis of    endometriosis. Ultrasound Obstet Gynecol 2002;20:630â4.    

29. Nisolle M. Ovarian endometriosis and peritoneal endometriosis: are    they different entities from a fertility perspective? Curr Opin Obstet    Gynecol 2002;14:283â 8.    

Endometriosis is one of the most common gynecologic disorders and is significantly more prevalent in the setting of infertility. The prevalence of endometriosis in infertile women ranges from 25% to 50% compared to 5% in fertile women. Successful laparoscopic management of all stages of endometriosis was reported as early as 1986. This has revolutionized the management of endometriosis. The benefits of surgical therapy for infertility associated with endometriosis have been well documented.

Laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles

Dr. Nezhat is the current president of The Society of Laparoendoscopic  		Surgeons as well as Clinical Professor of Ob/Gyn and Clinical Professor  		of Surgery at the Stanford School of Medicine, Stanford University  		Medical Center, Palo Alto, California.
  		
 		Dr. LaShay is participating in a Fellowship Research under Dr. Nezhat  		where she is analyzing surgical techniques that effectively treat  		infertility and severe chronic pelvic pain from endometriosis.

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OBGYN.net Conference CoverageSLS, Society of Laparoendoscopic Surgeons Annual Meeting 13th International Congress and Endo ExpoSeptember 29-October 2, 2004 - New York, New York