|Year : 2019 | Volume
| Issue : 2 | Page : 57-61
Oocyte embryo and ovarian tissue freezing in endometriosis: Food for thought
Umesh Jindal, Swati Verma
Jindal IVF and Sant Memorial Nursing Home, Chandigarh, India
|Date of Submission||20-Nov-2019|
|Date of Acceptance||26-Nov-2019|
|Date of Web Publication||31-Jan-2020|
Dr. Umesh Jindal
Jindal IVF and Sant Memorial Nursing Home, Chandigarh
Source of Support: None, Conflict of Interest: None
Fertility preservation by oocyte, embryo, or ovarian tissue in females is an established technique now. In addition to oncology patients, the indications have been extended to other benign diseases such as endometriosis which carry a significant risk of decrease in ovarian reserve due to disease or therapy instituted. Fertility preservation is not without its pros and cons. All young women need to be counseled regarding the decrease in ovarian reserve with endometriosis, age and/or surgery. Fertility preservation options need to be discussed whenever immediate childbearing is not possible or desired.
Keywords: Endometriosis, fertility preservation, in vitro fertilization, oocyte freezing
|How to cite this article:|
Jindal U, Verma S. Oocyte embryo and ovarian tissue freezing in endometriosis: Food for thought. Onco Fertil J 2019;2:57-61
| Introduction|| |
With the advancements in cryobiology, freezing oocytes and embryos is a routine in assisted reproduction technique (ART) units. Ovarian tissue freezing is also becoming an accepted method of preserving fertility for long periods although still categorized as experimental. Fertility preservation techniques have now been well accepted and practiced in young women affected with cancer who face the loss of ovarian function due to cancer or chemotherapy. Fertility preservation is also being increasingly opted by women who wish to delay childbearing to a later date for various personal and social reasons. Although endometriosis is a benign disease, it behaves in a similar fashion to malignancy. Endometriosis spreads, invades, and recurs as a cancer, leading to repeated surgeries, which is associated with increased risk of decreased ovarian reserve, poor response to stimulation, and premature ovarian failure (POF). The disease affects young women during the reproductive years and associated with serious risk of decrease in ovarian reserve and fertility due to disease per se or the treatment modalities employed. Endometriosis should be considered a valid and logical indication for fertility preservation.
| Endometriosis and Ovarian Reserve|| |
Endometriosis is an enigmatic disease involving the presence and growth of endometrial tissue outside the uterus. The etiology of endometriosis is ill understood. It is said to be a “heritable and hormone-dependent gynecological disorder.” Various inflammatory and immunological mechanisms are involved in the pathogenesis. The presentation varies from minimal and mild disease in the form of subclinical diffuse peritoneal implants to extensive spread in the abdomen. Ovaries are the most common organs involved. There could be diffuse involvement of ovaries or varying sizes of localized cysts and the endometrioma may be present. These could be single, multiple, and/or bilateral. Ultrasound (USG) has a good sensitivity and specificity for the diagnosis of ovarian endometriomas (83% and 89%, respectively). It is difficult to diagnose the disease in the absence of endometriomas, i. e., in case of early endometriosis. There are no reliable serum markers for the diagnosis or to estimate prognosis of endometriosis. Laparoscopy is the “gold standard” for the diagnosis of endometriosis.
Most women with advanced endometriosis present with pelvic pain, dysmenorrhea, dyspareunia, pelvic masses, and infertility. Unfortunately, in the cases of deep infiltrating endometriosis, the involvement of the uterosacral ligaments, rectovaginal septum, vagina, and bladder, diagnosis is often delayed. In these cases, surgery becomes imperative but not without collateral damage to the ovaries. The best marker for ovarian reserve still remains anti-Müllerian hormone (AMH) and gives a fair estimate. Antral follicle count is not very reliable in these cases as the presence of endometrioma or diffuse endometriosis may alter the ovarian architecture and misinterpretation of ovarian reserve.
The following mechanism may be operating in endometriosis induced compromised ovarian reserve:
Ovarian endometriomas if present adversely affects ovarian reserve. Patients with endometriosis usually present with pelvic pain or the presence of ovarian cysts and the endometriomas. Endometriosis is an inflammatory condition. The tissue surrounding the endometrioma is a pseudocapsule and contains compressed ovarian tissue. This tissue shows a significant loss of ovarian stroma with significantly associated fibrosis which is not seen in other benign diseases. Histological studies done on this tissue show a significantly lower follicular density., The fact that ovarian reserve is adversely affected can be demonstrated by low serum AMH levels in women with endometrioma. The decreased ovarian reserve has been reported not only in patients suffering from ovarian endometriomas but also in patients suffering with minimal to mild endometriosis.
Women affected with big endometriomas frequently require pelvic surgery to remove endometriomas and pelvic adhesions. Severe ovarian damage and extensive follicle loss have been reported after cystectomy for endometriomas. The amount of healthy tissue removed during surgery may be much larger than anticipated or apparent preoperatively. This is greater when there are multiple endometriomas and/or both ovaries are involved and need to be operated upon. Due to the collateral invisible damage, the use of electrosurgical coagulation is associated with a higher chance of tissue loss. There is some amount of inflammation which is associated with any surgery and this may also contribute to the damage. Endometrioma cyst wall contains different amounts of follicles, which are lost during the surgery. In a younger patient, more number of follicular cohort is present in the endometrioma wall which is likely to be lost. Young women also have a more severe type of disease and high rate of recurrence (30%–50%).
Endometriosis is a hormone-dependent disease. Conservative surgery does not eliminate the risk of recurrence in menstruating women. Recurrence is the rule rather than the exception. Young women commonly face multiple surgeries to alleviate their symptoms. Repeated ovarian surgery done even with the utmost care even by experts still leaves a significant impairment of ovarian reserve.
Endometriosis surgery often requires separating stuck together pelvic organs to restore pelvic anatomy and physiology. Ovaries are frequently stuck in the ovarian fossa. Extensive adhesiolysis even without direct insult to the ovaries has been associated with a significant decline in ovarian reserve. This may derive from injury to ovarian vascular bed resulting in reduced ovarian vascularity.
Very big-sized endometrioma
Endometriomas are known to grow to gigantic size. The ovarian tissue may be so compressed and thinned out with very large masses that it may not possible to save functional ovarian tissue during the surgery. Thus, large cysts constitute a risk factor for loss of ovarian function.
Risk of malignancy
Increased risk for malignancy has been reported in patients suffering from endometriosis when large or rapidly growing endometriomas are detected or when suspicious changes appear at sonography. In case of large endometrioma, surgery to establish a histological diagnosis is justified. Such cases of extirpative surgery may have to be done to eradicate or cure the disease. Before contemplating such radical surgery, a complete assessment and discussion with the patient regarding the decrease in ovarian reserve and fertility is required.
Women with endometriosis also are a part of the changing social scenario of delayed marriage and childbearing. The women with endometriosis may not know the full implications of the disease and also age-related fertility decline unless told clearly. The age-related decline may be aggravated or accelerated in these women because of disease or repeated surgeries.
| Endometriosis and Associated Infertility|| |
Endometriosis is frequently associated with infertility. Although the possible mechanisms involved in endometriosis-associated infertility have not been completely elucidated, various biological mechanisms have been suggested. These include progressive loss of follicle reservoir, surgical loss of follicles, recurrence, and pelvic adhesions. There may be altered the tuboperitoneal anatomy and/or mechanical block in Fallopian tube More Detailss. Compromised oocyte quality seemed to play an important role. Inflammatory peritoneal state, oxidative stress-related alterations in the peritoneal, serum, or follicular microenvironments, and increased cytokines may result in poor oocyte quality. A recent study indicates that oocyte quality is decreased in women with even minimal or mild endometriosis. However, there are other studies which do not substantiate these claims.
There is some evidence that women with endometriosis are at increased risk of POF. It has been observed that AMH levels decreased at a faster rate even in the absence of surgery.
Poorer in vitro fertilization (IVF) outcome has also been documented in the literature which may be related to poor oocyte quality or impaired endometrial receptivity. The number of collected oocytes, transfer rate, and the rate of cycles with a frozen embryo remains lower in cases of endometriosis. Furthermore, there is a lower response to ovarian stimulation and availability of good-quality embryo cohort. However, some studies documented similar implantation, delivery rates, and cumulative live birth rates per attempt like those of controls.
| The Need for Fertility Preservation in Endometriosis|| |
Thus, low ovarian reserve, higher incidence of infertility, and poorer outcomes of ART procedures have a major impact on future fertility. Therefore, women of young reproductive age with endometriosis who have not yet completed family are at potential risk for future infertility and POF. These women must be counseled for future fertility and should be sensitized regarding the need for fertility preservation options at the time of surgery or ART.
The world consensus for the current management of endometriosis gives simple directions on how to manage infertile patients with endometriosis. Besides describing the principles and requirements of laparoscopic surgery for infertility, it also points out that young patients should be counseled about oocyte cryopreservation before ovarian surgeries.
| Counseling Patients With Endometriosis|| |
Profertility counseling in young women with endometriosis should be done to explain the advantages of early conception which may avoid the need for ART in future for them and attenuate disease progression also. However, advice on early conception may not be practical for many women. In such cases, women should be given the option of ovarian-sparing surgery along with highly successful techniques of cryopreservation of oocytes, embryos, or ovarian tissue cryopreservation.
Fertility preservation techniques (FTP) for patients with endometriosis:
Minimal and mild disease frequently does not benefit from the surgery. Surgery should be avoided in these cases for diagnostic purposes only. Moderate and severe cases often require surgery for various reasons, for example, infertility, pain, menorrhagia, or pelvic masses. Resection and/or ablation of the cyst are preferable over cyst drainage and coagulation, which is associated with a higher recurrence risk. Deep coagulation in the ovaries while achieving hemostasis should be avoided. The blood supply of ovarian stroma which arises from the hilum can get impaired. Due to the significant risk of ovarian reserve loss, surgery is recommended to be performed by an expert and experienced surgeon. Opinion from fertility expert is also recommended before surgery to assess the need for FPT. Advanced moderate and severe stages usually require IVF to achieve a pregnancy before or after surgery. If they do go through the IVF procedure, embryos should be preserved as far as possible to achieve a second pregnancy if the couple desires at a later date when ovarian reserve may be compromised.
It is a good choice and viable option in patients affected by endometriosis as it has no effect on future ovarian reserve and is less invasive than other FPT. Women should be counseled regarding the requirement of several cycles, especially in cases of low ovarian reserve, to aspirate an adequate numbers of oocytes (around 12–20) that may provide a realistic chance for future fertility. The number of ovarian stimulation and IVF cycles has not been associated with an increased risk of disease recurrence., Women should also be counseled regarding the IVF performance which may be impaired (oocytes quality, fertilization rates, embryo quality, and live birth rates) in the presence of endometriosis., In women in whom good-quality oocytes are fertilized, or when a large number of embryos are available, implantation rates seem to be similar to other counterparts.
One needs to weigh carefully the need to do surgery before oocyte retrieval. In some cases, however, surgical removal of the endometrioma before ovarian stimulation should be considered to get access to follicles. It should also be highlighted that in the presence of ovarian endometrioma, oocyte retrieval is associated with an increased risk of pelvic infection or ovarian abscess formation., Studies suggest that surgical removal of endometrioma may increase the response to ovarian stimulation in women with advanced endometriosis. After surgery, early IVF cycles in the immediate postoperative period are recommended when the ovaries are disease-free.,
It is a well-established fact that the oocyte freezing success rate is age related and significantly declines after the age of 36 years. Hence, patients with endometriosis are encouraged to freeze oocytes at a younger age if possible, and consultation should address the yield of age-related gamete freezing.
Ovarian tissue cryopreservation
In cases of ovaries with endometrioma, the ovarian cortical tissue can be harvested and stored, thereby sparing the follicles from a potential future disease progression that could occur in the ovary if left in situ. However, this approach is not practical and not recommended. Moreover in the modern era, most of the surgeries being done laparoscopically, it becomes technically more difficult to harvest ovarian tissue and carries significant additional operative risks in cases of pelvic adhesions. In an attempt to cryopreservation of ovarian tissue, there could be the possibility of removing healthy cortical tissue away from endometriomas which can further deteriorate ovarian reserve. However, during surgical removal of endometrioma, if healthy fragments of ovarian cortex can be isolated properly, cryopreservation of ovarian tissue can be done. For patients with endometriosis undergoing surgery, decision on ovarian tissue storing should be individualized according to the patients' age, ovarian reserve status, presence of bilateral ovarian lesions, and repeated surgery. Further, storing the ovarian tissue surrounding the cyst or pseudocapsule of endometrioma is questionable due to lesser number and poor quality of follicles. Ovarian tissue cryopreservation is still categorized as experimental. In endometriosis, very few data exist in literature, and currently, the possibility remains more theoretical.
| Conclusion|| |
Counseling for all cases of endometriosis in young women should include a long-term prognostic plan and a fertility plan. The disease extent, risk of recurrence, association with current or future fertility, and need for repeated surgeries, ART and FPT should be discussed. Young women suffering from endometriosis need to be apprised of all the options for fertility preservation. Deciding definitive guidelines for FPT in endometriosis at the current stage is not possible because of the lack of sufficient evidence-based data. However, few general comments can be made. First, surgery should be done only if it has some therapeutic benefits and not diagnostic unless malignancy is suspected. Second, surgery should be done by an experienced surgeon conversant with the pathophysiology of endometriosis. Third, all precautions have to be taken to prevent damage to the ovary. Fourth, all women who wish to delay childbearing for any reason, fertility preservation option should be given.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bedoschi G, Oktay K. Current approach to fertility preservation by embryo cryopreservation. Fertil Steril 2013;99:1496-502.
Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N, De Vivo I, et al
. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun 2017;8:15539.
Guerriero S, Mais V, Ajossa S, Paoletti AM, Angiolucci M, Labate F, et al
. The role of endovaginal ultrasound in differentiating endometriomas from other ovarian cysts. Clin Exp Obstet Gynecol 1995;22:20-2.
Lemos NA, Arbo E, Scalco R, Weiler E, Rosa V, Cunha-Filho JS. Decreased anti-Müllerian hormone and altered ovarian follicular cohort in infertile patients with mild/minimal endometriosis. Fertil Steril 2008;89:1064-8.
Kitajima M, Defrère S, Dolmans MM, Colette S, Squifflet J, Van Langendonckt A, et al
. Endometriomas as a possible cause of reduced ovarian reserve in women with endometriosis. Fertil Steril 2011;96:685-91.
Maneschi F, Marasá L, Incandela S, Mazzarese M, Zupi E. Ovarian cortex surrounding benign neoplasms: a histologic study. Am J Obstet Gynecol 1993;169:388-93.
Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, Webb PM, et al
. Association between endometriosis and risk of histological subtypes of ovarian cancer: A pooled analysis of case-control studies. Lancet Oncol 2012;13:385-94.
Hwu YM, Wu FS, Li SH, Sun FJ, Lin MH, Lee RK. The impact of endometrioma and laparoscopic cystectomy on serum anti-Müllerian hormone levels. Reprod Biol Endocrinol 2011;9:80.
Li CZ, Liu B, Wen ZQ, Sun Q. The impact of electrocoagulation on ovarian reserve after laparoscopic excision of ovarian cysts: A prospective clinical study of 191 patients. Fertil Steril 2009;92:1428-35.
Romualdi D, Franco Zannoni G, Lanzone A, Selvaggi L, Tagliaferri V, Gaetano Vellone V, et al
. Follicular loss in endoscopic surgery for ovarian endometriosis: Quantitative and qualitative observations. Fertil Steril 2011;96:374-8.
Tandoi I, Somigliana E, Riparini J, Ronzoni S, Vigano' P, Candiani M. High rate of endometriosis recurrence in young women. J Pediatr Adolesc Gynecol 2011;24:376-9.
Hirokawa W, Iwase A, Goto M, Takikawa S, Nagatomo Y, Nakahara T, et al
. The post-operative decline in serum anti-Mullerian hormone correlates with the bilaterality and severity of endometriosis. Hum Reprod 2011;26:904-10.
Nezhat F, Apostol R, Mahmoud M, el Daouk M. Malignant transformation of endometriosis and its clinical significance. Fertil Steril 2014;102:342-4.
Da Broi MG, Navarro PA. Oxidative stress and oocyte quality: Ethiopathogenic mechanisms of minimal/mild endometriosis-related infertility. Cell Tissue Res 2016;364:1-7.
Lin XN, Wei ML, Tong XM, Xu WH, Zhou F, Huang QX, et al
. Outcome of in vitro
fertilization in endometriosis-associated infertility: A 5-year database cohort study. Chin Med J (Engl) 2012;125:2688-93.
Xu B, Guo N, Zhang XM, Shi W, Tong XH, Iqbal F, et al
. Oocyte quality is decreased in women with minimal or mild endometriosis. Sci Rep 2015;5:10779.
Chauffour C, Pouly JL, Brugnon F, et al
. Effect of endometriosis on IVF outcomes in cases of single embryo transfer for first IVF attempt in patients under 35. J Endometr Pelvic Pain Disord 2016;8:13-8.
Busacca M, Riparini J, Somigliana E, Oggioni G, Izzo S, Vignali M, et al
. Postsurgical ovarian failure after laparoscopic excision of bilateral endometriomas. Am J Obstet Gynecol 2006;195:421-5.
Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility: A committee opinion. Fertil Steril 2012;98:591-8.
Ebner T, Sommergruber M, Moser M, Shebl O, Schreier-Lechner E, Tews G. Basal level of anti-Müllerian hormone is associated with oocyte quality in stimulated cycles. Hum Reprod 2006;21:2022-6.
Johnson NP, Hummelshoj L, World Endometriosis Society Montpellier Consortium. Consensus on current management of endometriosis. Hum Reprod 2013;28:1552-68.
Muzii L, Marana R, Angioli R, Bianchi A, Cucinella G, Vignali M, et al
. Histologic analysis of specimens from laparoscopic endometrioma excision performed by different surgeons: Does the surgeon matter? Fertil Steril 2011;95:2116-9.
D'Hooghe TM, Denys B, Spiessens C, Meuleman C, Debrock S. Is the endometriosis recurrence rate increased after ovarian hyperstimulation? Fertil Steril 2006;86:283-90.
Benaglia L, Somigliana E, Santi G, Scarduelli C, Ragni G, Fedele L. IVF and endometriosis-related symptom progression: Insights from a prospective study. Hum Reprod 2011;26:2368-72.
Suzuki T, Izumi S, Matsubayashi H, Awaji H, Yoshikata K, Makino T. Impact of ovarian endometrioma on oocytes and pregnancy outcome in in vitro
fertilization. Fertil Steril 2005;83:908-13.
Garcia-Velasco JA, Arici A. Is the endometrium or oocyte/embryo affected in endometriosis? Hum Reprod 1999;14 Suppl 2:77-89.
Yaron Y, Peyser MR, Samuel D, Amit A, Lessing JB. Infected endometriotic cysts secondary to oocyte aspiration for in-vitro
fertilization. Hum Reprod 1994;9:1759-60.
Elizur SE, Lebovitz O, Weintraub AY, Eisenberg VH, Seidman DS, Goldenberg M, et al
. Pelvic inflammatory disease in women with endometriosis is more severe than in those without. Aust N
Z J Obstet Gynaecol 2014;54:162-5.
Practice Committee of American Society for Reproductive Medicine. Ovarian tissue cryopreservation: A committee opinion. Fertil Steril 2014;101:1237-43.
Cil AP, Bang H, Oktay K. Age-specific probability of live birth with oocyte cryopreservation: An individual patient data meta-analysis. Fertil Steril 2013;100:492-9.e3.