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Infertility


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Infertility


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Infertility: “a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse.”-International Committee for Monitoring Assisted Reproductive Technology & the World Health Organization

NEW: Be sure to check out these educational links for more information on Low AMH and "Silent Endometriosis" by Dr. Jeffrey Braverman, renowned Infertility expert & Medical Director of Braverman IVF & Reproductive Immunology:

LOW AMH (ANTI-MULLERIAN HORMONE) & ENDOMETRIOSIS

SILENT ENDOMETRIOSIS: DIAGNOSIS BASED ON IMMUNE FINDINGS WITHOUT TYPICAL SYMPTOMS - HIGH INCIDENCE IN PATIENTS WITH REPETITIVE IVF FAILURES AND MISCARRIAGE

Special thanks to cec former fellow & mayo scholar, Dr. zaraq khan for his contributions to this article.

Without question, endometriosis remains a top cause of infertility, gynecologic hospitalization and hysterectomy.1,2,3 In fact, although recent data [Missmer et al.] indicates the risk may be less than originally suspected, it remains a top cause of female primary and secondary infertility, prevalent in 0.5%-5.0% of fertile patients and 25%-40% of infertile patients.1   Studies indicate that infertile women are 6-8 times more likely to have endometriosis than fertile women.3 However, early intervention can reduce morbidity, infertility and progressive symptomatology, even in the most advanced disease stages.4

When we talk about statistics in terms of fertility in the presence of endometriosis, most data indicates that the higher the stage, the less of a chance of conceiving naturally exists, especially compared to disease free women without infertility. However, there is only one study that looked specifically at the chances of conceiving in women with different stages of disease: those with stage I and II had a 60% chance of conceiving without surgical treatment; those with stage III had a 15-20% chance of conceiving without surgical treatment and those with stage IV did not conceive in that study (but we realize that even with stage IV, a small percentage will conceive, likely less than 5%). Other studies have also found that conception rates increase following surgical treatment of endometriosis. For those with stage I-II, the chances of conceiving after excision is between 80-85%, almost the same rate as if you did not have endometriosis. Those with stage III will have a 70-75% chance of conceiving and those with stage IV is between 50-60%. If In Vitro Fertilization (IVF) is needed, the rates would usually be higher.

It is also important to rule out – or diagnose and treat – any comorbid concerns that may impair fertility (PCOS, ovulation disorders, uterine or cervical factors, etc.) and adhere to the principles of best practice.

At a glance, there are many ways in which endometriosis may interfere with fertility, including but certainly not limited to:

  • Mechanical interference, such as adhesions which can prevent egg transport or endometriomas that may prevent ovulation, as well as outright anatomical impairment/adhesions which make natural conception impossible;

  • Painful sex, which, for obvious reasons, is not conducive to conceiving;

  • Cellular changes induced by the disease; increased oxidative stress levels which may lead to epigenetic changes;

  • Inducement of a hostile and inflammatory intraperitoneal environment which may impair ovulation, egg capture and quality, tubal function, or further cause damage in tissues;

  • Women with endometriosis may have coexisting endocrine and/or ovulatory disorders, including luteinized unruptured follicle syndrome, impaired folliculogenesis, luteal phase defect, and premature or multiple luteinizing hormone (LH) surge7.

One of the concerns about treating patients with ovarian endometriosis/endometriomas (endometriosis or 'chocolate' cysts on the ovaries) is that ovarian reserve - the amount of healthy eggs you have - may be affected by excising the endometriomas. This is a controversial and constantly evolving issue in endometriosis research and infertility. First, women with other types of cysts have better ovarian reserve before and after surgery compared to women with endometriomas. This suggests that endometriomas may affect ovarian reserve just by their presence. However, if an endometrioma is not removed, the endometrioma may grow in an unpredictable fashion, resulting in a potentially larger loss of ovarian reserve. For these reasons, several professional organizations such as the European Society for Human Reproduction and Endocrinology and the Society of Gynecologists of Canada recommend removal of endometriomas when they are larger than 3 or 4 cm. The eggs next to the endometrioma are of poorer quality, and will allow for better quality eggs to remain and if IVF is needed, there will not be contamination of the eggs that are retrieved which can happen when the fertility specialists removes the eggs for fertilization.

Most studies do find there is a reduction in ovarian reserve as measured by AMH (Anti-Mullerian Hormone) or pre-antral follicle count (number of early eggs that are present in the early part of the menstrual cycle) following excision of endometriomas -- however, if other forms of treatment are used such as drainage or cautery of the cyst wall, there is much higher recurrence of the endometrioma (as much as 100% following drainage and 30-60% following ablation of the cyst wall compared to less than 5-10% with excision). Some specialists recommend remaining on birth control following treatment of endometriomas; this is controversial as some of those studies had much higher rates of recurrence in the 'no birth control' group than we would normally see in our practice in those who do not go on birth control - suggesting that the excision of the endometriomas was not as thoroughly done (as is the case in our practice). We do recommend being on birth control for 3 months after surgery for pelvic rest, not treatment - that is to say, to prevent ovulation in the healing ovary, which can result in more pain and slower healing. After that, discuss with your surgeon to determine if there is continued benefit.

In terms of 'complications' related to endometriosis, as far as actual pregnancy is concerned, the good news is, by and large, most individuals will not have significant issues. Indeed, studies indicate there is a very high overall rate of live birth children - 95.8% - in women with the disease, and there is no correlation between endometriosis and c-section or AFS-R stage/adverse pregnancy outcomes.8 There is also a decrease in gestational diabetes.9 However, there does exist a small risk in some individuals of complications such as spontaneous hemoperitoneum in pregnancy [SHiP], antenatal bleeding, pregnancy-induced hypertension, preeclampsia or preterm birth.10

Adenomyosis is another condition which may also affect women with endometriosis. The actual incidence is not known, but Dr. Sinervo feels that as many as 20-30% of endometriosis patients may have adenomyosis. Evidence shows a link between adenomyosis and infertilit however, there is no direct link. There is currently no consensus regarding the impact if adenomyosis on embryo implantation potential. While some studies have identified alterations in the endometrial milieu in adenomyosis patients that may impact implantation, others have shown no such impairment.  Increased risk of preterm birth and preterm premature rupture of membranes in women with adenomyosis is noted incertain reports. If you are suspected of having adenomyosis, we would probably consider your pregnancy higher risk. As well, you may be offered a presacral neurectomy, which may result in you not being able to feel contractions; this would be an issue if you were in pre-term labor, so we recommend having the length of the cervix measured every 2 weeks beginning from 24 weeks through 36 weeks to make sure that you are not having pre-term contractions that could result in early delivery.

In addition to excising endometriosis, we will also often assess the conditions of the fallopian tubes during surgery as well to ensure that there is not a tubal factor of infertility, which may be able to be overcome with a cannulation of the tube if there is not a hydrosalpinx (a fluid-filled tube). A chromotubation (instilling dye into the uterus to see if it comes out the fallopian tubes) is done during the surgery. If a hydrosalpinx is present, it is often recommended that the fallopian tube is removed if significant since the fluid within the tube is embryo-toxic - likely to kill the embryo if it were to reach the uterus from the other healthy tube if present or with IVF if necessary. This can also be discussed based on the individual findings present in your specific case.

Uterine Fibroids is another condition we sometimes address within the uterus during surgery. Uterine fibroids, though one of the most common benign gynecologic conditions, impacts fertility in ways undescribed. Currently the recommendations are to excise fibroids when they are immediately below the endometrium (the inner lining of the uterus into which the embryo implants) or in a location where they are pushing on the uterine cavity and distorting it. If you were to have a fibroid in those location,we would usually recommend removing it. We may also recommend removing them if they are larger, as this may affect fertility and bleeding as well. However, they may increase the rate of adhesions, so the decision is always made based on size, symptoms and concerns about adhesions after surgery.

Role of Medical Therapy:

Frequently offered as a mainstay of endometriosis treatment despite its lack of efficacy, drug suppression therapy (agonists, antagonists, Aromatase inhibitors, etc.) may also be suggested in some settings as a primary option. Medical therapy does not eradicate endometriosis, however, and the disease does not simply ‘go away’ as a result of drug suppression. At best, such a course of therapy provides only a temporary means of symptom improvement, not definitive treatment. Fertility is also eliminated during suppressive treatments, importantly, and hormonal suppression has ‘no effect on endometriosis and cannot improve fertility’ [Aznaurova et al.]. In our practice, a significantly higher percentage will conceive following LAPEX.

Moreover, drug therapies are often limited in usefulness by the length of time they can be safely taken (usually six-twelve months) and commonly incapacitating side effects. Likewise, when used either or both as part of a fertility workup and/or symptomatic intervention, such medications contribute to increased total costs of treating the disease. Still; given the number of barriers to adequate care faced by so many, it is not unusual for hormonal agents to be used before, after or both before and after either conservative or radical surgery.  Of course, for some patients, this may be the right answer. Nevertheless, we must be cautious in our use of medical manipulation as a “treatment” for the disease or infertility, and be careful to not over-prescribe or inappropriately use it.

Importance of Surgical Excision:

Many who specialize in endometriosis agree that complete surgical excision of all disease is the cornerstone to obtaining maximal pain relief and return to fertility. Surgery should be judicious and based on not latest technology, but on evidence, and always with the goal to preserve vs. remove tissue and healthy organs. In experienced hands, Laparoscopic excision can result in long-term symptomatic relief, improvement of pregnancy rates and reduction of recurrence of disease, while largely avoiding complications.11 For example, in our own Center, we have tracked post-operative spontaneous pregnancies among those trying to conceive in nearly half of our advanced stage 3/4 cases, and in almost 70% of our lower stage patients.

Role of Assisted Reproductive Techniques (ART):

Fertility Preservation, IVF and Assisted Reproduction Techniques are efforts to help patients retain their fertility options and/or achieve pregnancy. The overarching sentiment is that infertility related to endometriosis does indeed play a role in how we approach each individual case, and options must tailored to her circumstances and integrated with the overall treatment regimen. Certain preservation options and ART protocols often associated specifically with endometriosis may be worthy discussions with those individuals for whom infertility persists despite medical or surgical treatment, including:

  • Embryo freezing (most common and successful)

  • Oocyte freezing (costs around $10,000+/- per freeze,  plus storage fees (+/- $500 annually) and thaw, fertilization and transfer (around $5,000) – similar to an IVF cycle)

  • Intrauterine Insemination/Artificial Insemination (most effective in cases of cervical defects or scarring)

  • In Vitro Fertilization/IVF (a 4 step process including stimulation, egg maturation/retrieval, fertilization and embryo transfer); specific medications often used to stimulate the ovaries include Clomid®, Femara®, Gonal-F®, Cetrotide®, Menopur® and others, as well as certain GnRH drugs (specific use for ovarian stimulation is different than protocol prescribed for treatment of endometriosis symptoms)

  • Third Party Assist (sperm donation, egg donation, surrogates/gestational carrier)

Final Thoughts:  

As with all aspects of the disease, multidisciplinary and collaborative approaches to endometriosis-related infertility are key towards achieving best outcomes. The fertility team, which usually consists of reproductive endocrinologists, embryologists, clinical nurses, technicians and lab staff, represents a vital part of that collaborative, especially for those patients in whom infertility persists despite gold-standard surgical intervention. Despite the many options that exist, there is no facile answer or ‘one size fits all’ approach; each case must be individualized. For some, simply flushing the tubes during Laparoscopy might restore fertility. For others, Fertiliscopy or MiniLap might offer better outcomes than traditional Laparoscopy. For still others, adenomyosis or other pathology may be a complicating factor requiring additional care. All approaches, and perhaps a combination thereof, can be helpful, but depends on the individual’s circumstances.

Many patients ask us how soon after surgery they can start trying to conceive. We always recommend waiting at least 2 weeks before intercourse to prevent infection within the uterus as the cervix closes. However, if there was no work done on the ovaries or the removal of fibroids from the uterine wall, you can try conceiving the next cycle. However, if you have had endometriomas removed or fibroids removed, we would usually recommend waiting 3 months to allow the ovaries to heal and the uterus to heal before conception is attempted.

Ultimately, the sooner in an individual’s life endometriosis can be correctly diagnosed and truly eradicated, the better their long-term outlook becomes, from quality of to life to physical symptoms to improvement and/or preservation of fertility. Ultimately, each situation will be approached on its own merits, but what matters most is the skill of the provider, their understanding of the disease and fertility-sparing principles, and of course - the patient’s needs above all else.

FOR MORE INFORMATION AND RESOURCES:

http://www.sart.org

http://www.ivf.com

http://www.resolve.org

http://www.asrm.org

http://www.reproductivefacts.org

http://www.preventmiscarriage.com

Sinervo, Guidone, Khan. Updated October 2016. Special thanks to Dr. Braverman.

1. Ozkan, Murk, Arici. Endometriosis & Infertility: Epidemiology and Evidence-based Treatments. Annals of the New York Academy of Sciences Vol 1127, Assessment of Human Reproductive Function pages 92–100, April 2008

2.  Murphy. Clinical aspects of endometriosis. Ann N Y Acad Sci. 2002 Mar;955:1-10; discussion 34-6, 396-406

3. Verkauf. The incidence, symptoms, and signs of endometriosis in fertile and infertile women. J Fla Med Assoc. 1987;74(9):671–675

4. Yeung Jr, Sinervo, Winer, Albee Jr. Complete laparoscopic excision of endometriosis in teenagers: is postoperative hormonal suppression necessary? Fertil Steril. 2011 May;95(6):1909-12, 1912.e1. Epub 2011 Mar 21

5. Bulletti, Coccia, Battistoni, Borini. Endometriosis and infertility. Journal of Assisted Reproduction & Genetics. 2010;27(8):441-447

6. Gupta, Ghulmiyyah, Sharma, Halabi, Agarwal. Power of Proteomics in Linking Oxidative Stress and Female Infertility. Biomed Res Int. 2014; 2014: 916212

7. Practice Committee of the American Society for Reproductive Medicine (ASRM) Endometriosis and Infertility. Fertil Steril. 2006;14:S156–S160

8. Carassou-Maillan A, Pouly JL, Mulliez A, Dejou-Bouillet L, Gremeau AS, Brugnon F et al. Adverse pregnancy outcomes after Assisted Reproduction Technology in women with endometriosis. Gynecol Obstet Fertil. 2014 Apr;42(4):210-5

9. Giudice L, Evers JLH, Healy DL. Endometriosis: Science and Practice. Chichester, West Sussex: Wiley-Blackwell; 2012.

10. Brosens IA, Fusi L, Brosens JJ.  Endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. Fertil Steril. 2009 Oct;92(4):1243-5

11. Shah PR, Adlakha A.Laparoscopic management of moderate: Severe endometriosis.J Minim Access Surg. 2014 Jan;10(1):27-3b