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How successful is egg donation in women with endometriosis?

By I.Soussis MD

Egg donation is a fantastic tool in our hands, that allows us to explore how endometriosis affects the results of IVF.

Its action is through the endometrium or through the quality of the oocytes and subsequently through the quality of the produced embryos?

In trying to answer the question two different approaches have been taken:

1. The eggs of the same donor were shared by two recipients. One recipient is healthy and the other suffers from endometriosis. Data was prospectively collected and the pregnancy rates between the two groups compared.

2. Retrospective studies with oocyte donation cycles, in which a recipient became pregnant and the other not. The data was analyzed according  to the cause of infertility. We also examined the origin of the eggs and compared the pregnancy rates between recipients, receiving ova from donors with endometriosis or without endometriosis.

Diaz et al 2000, from the Valencia Infertility Institute IVI IVF studied 58 recipients. Of these 25 were suffering from severe endometriosis stage III and IV. The remaining 33 recipient did not suffer from endometriosis. Both groups of women followed the same preparation of the endometrium, prior to embryo transfer. The number of fertilized eggs, of transferred embryos, the pregnancy rates and abortion rates were similar in both groups. So severe endometriosis does not affect pregnancy rates when the eggs come from healthy donors.

Similar results were reported from 444 egg donation cycles in 222 recipients from Bodri et al 2007.

Simon et al. 1994 again from I.V.I IVF retrospectively examined 178 embryo transfers into 141 recipients. Significantly lower pregnancy rates were found in women who received oocytes from donors with endometriosis.

To further investigate the influence of endometriosis on the endometrium or the egg, the same group of scientists in Spain, organized a prospective study Pelicer et al 1994.

Patients were divided into three groups. A: 44 donors without endometriosis who gave eggs to healthy recipients, B: 14 donors with endometriosis who gave eggs to healthy recipients, and C: 16 donors without endometriosis donated to recipients with endometriosis.

Significantly lower embryo implantation rates were observed in group B 6.8% versus 20.1% A and 20.8% C.

Significantly lower rates of pregnancy were observed in group B 28.6% vs. 61.4% A and 60% C.

Budak et al 2007 studied retrospectively> 10,000 oocyte donation cycles over a period of 10 years. They confirmed that pregnancy rates in recipients with endometriosis were identical to those women without endometriosis.

In agreement with the mentioned studies, analysis of the results of egg donation  in our IVF Unit in Athens, IVF & Genetics, showed that the recipients with endometriosis have excellent pregnancy rates of 60%.

Conclusions:

1. Pregnancy rates after oocyte donation in recipients with endometriosis are excellent, when the eggs originate from donor without endometriosis and they can reach 61.4%.

2. Pregnancy rates after oocyte donation are lower than expected, even in healthy recipients, when the eggs originate from donors with endometriosis.

3. Endometriosis affects the quality of the eggs.

 

 

 

How successful is intrauterine insemination in women with endometriosis?

By I. Soussis MD

How successful is intrauterine insemination in infertile women with endometriosis?

Tummon et al. 1997 enrolled 103 infertile couples with endometriosis stage I and II in a prospective randomized  study. Of those patients 53 underwent superovulation treatment with gonadotrophins and intrauterine insemination (127 cycles) and  the remaining 50 were the control group and were just observed for 184 cycles. The birth rate in the treatment group were 5-6 higher than the controls.

Cumulative pregnancy rate. Women with IUI and superovulation versus no treatment

Cumulative pregnancy rate.
Women with IUI and superovulation versus no treatment

In another study, initially randomized, Nulsen et al. 1993, compared superovulation with gonadotrophins and intrauterine insemination with insemination without superovulation.

The success rate was 5.7 times higher in the superovulation group.

Werbrouck et al. 2006, studied infertile women with endometriosis, who were treated with gonadotrophins and intrauterine insemination within six months from their laparoscopy. They reported pregnancy rates similar to those with unexplained infertility (20% vs 20,5%).

ESHRE Guidelines 2015:

1. Superovulation with gonadotrophins and intrauterine insemination in infertile women with endometriosis stage I and II increases the birth rate compared with conservative management (observation).

2. Superovulation with gonadotrophins and intrauterine insemination in infertile women with endometriosis stage I and II increases the birth rate compared with intrauterine insemination alone.

3. Superovulation with gonadotrophins and intrauterine insemination in infertile women with endometriosis, within six months of laparoscopy, is equally effective as in those with unexplained infertility.

Good Practice Point (opinion of the ESHRE specialists). IVF treatment is advised if there is tubal factor, sperm problems or other treatment have failed.

How endometriosis is poisoning the ovary?

By I.Soussis MD

The reputable journal Human Reproduction Update in  2014 published an excellent study by ΑΜ Sanchez et al., on how an endometrioma ( a chocolate cyst) affects the surrounding healthy ovarian tissue. They reviewed the scientific literature of the last 25 years on the subject. They excluded all the clinical articles and they focused on what is known on basic science.

The endometrioma contains toxic substances such as free iron, free oxygen radicals, proteolytic enzymes and chemicals of inflammation in a concentration of tens and even hundreds of times higher, than those in blood or in non endometriotic benign cysts.

The concentration of CA-125 in the endometriotic cyst is 100 times higher than in the blood. The reason why this happens is unknown. It is however known that the CA-125 is a strong indicator of inflammation.

Toxic factors affect the endometriotic cells with which they come into contact. They may alter their gene expression or they can even cause genetic mutations.

The wall of the chocolate cyst is thin and consists of connective tissue and the cortex of the ovary.

Oxygen free radicals (which are powerful cellular stress factors), proteolytic enzymes and other toxic substances diffuse through the cyst wall to the adjacent healthy ovarian tissue. The healthy ovary is reacting with the creation of scar tissue, in an attempt to limit the damage.

The smooth muscle fibers in the region undergo metaplasia and the small vessels of the ovary also sustain damages . As a consequence of the vascular lesions, the follicles are not fed properly, they do not mature and finally they regress. Their numbers decrease.

Indeed many histological studies have shown reduced follicular density  in the ovary, in areas neighboring with ovarian endometriomas.

Now we believe that the damage of the ovary is more due to the action of these toxic agents, rather than the stretching of the tissues, caused by the cyst.

Knowledge of the pathophysiology can lead to the introduction of new drug therapies, that neutralize the action of these toxic agents. We could thus protect the ovary from damages caused by endometriosis.

The distinguishing cellular and molecular features of the endometriotic ovarian cyst: from pathophysiology to the potential endometrioma-mediated damage to the ovary A.M. Sanchez1, P. Viganò2,*, E. Somigliana3, P. Panina-Bordignon1, P. Vercellini3,4,5 and M. Candiani2 http://humupd.oxfordjournals.org/content/20/2/217.long

Drawing showing the ovarian damage caused by toxic factors in the endometriotic cyst AM Sanchez et al. Human Reproduction Update 2014

Drawing showing the ovarian damage caused by toxic factors in the endometriotic cyst
AM Sanchez et al.
Human Reproduction Update 2014

Antral follical count as a predictor of ovarian responsiveness in women with endometriosis or with a history of surgery for endometriosis

A vaginal ultrasound scan showing an ovary with an endometrioma. no other small follicles can be seen

A vaginal ultrasound scan showing an ovary with an endometrioma. no other small follicles can be seen

By I.Soussis MD

Antral follicle count AFC, has proven to be one of the most reliable predictors of ovarian response to the drug stimulation during IVF treatment. It refers to the number of small follicles counted at the ovary prior to starting the stimulation.

In 2015 Benaglia et al. researched AFC as a predictor in 83 women undergoing IVF due to endometriosis. These women had undergone surgery in the past for the removal of endometriosis(chocolate cyst) or had a cyst during their IVF attempt.

The ovaries were divided into four groups:

1-Ovaries without previous surgery and without endometriomas(42)

2-Ovaries without previous surgery, with endometriomas(46)

3-Ovaries with previous surgery without endometriomas(55)

4-Ovaries with previous surgery, with endometriomas(23)

The ovaries with surgery(78) and those with endometriomas(69) were analyzed statistically. The AFC was also investigated to see if it could predict poor ovarian stimulation (2 or less oocytes per stimulation) as well as hyperstimulation(7 or more oocytes per stimulation).

It was found that this predictor was prognostically useful, not only in ovaries with endometriomas but also in those without endometriomas and in those that had undergone surgery for endometriomas.

The most useful predictors of ovarian response and IVF success is the combination of the woman’s age, the antral follicle count and the levels of the hormones FSH and AMH.

Fertil Steril. 2015 Apr 29. pii: S0015-0282(15)00218-6. doi: 10.1016/j.fertnstert.2015.03.013. [Epub ahead of print]

Antral follicle count as a predictor of ovarian responsiveness in women with endometriomas or with a history of surgery for endometriomas.

Benaglia L1, Candotti G2, Busnelli A3, Paffoni A2, Vercellini P3, Somigliana E3.

Men living with endometriosis: insights and experiences of male partners, living with women with endometriosis

Image courtesy of holohololand at FreeDigitalPhotos.net

Image courtesy of holohololand at FreeDigitalPhotos.net

By I.Soussis MD

Hudson et al. from the UK, presented an interesting study at the latest ESHRE conference, held in Lisbon Portugal in June 2015.

The main question was: How do partners of women with endometriosis perceive the disorder and how do they help their wives/partners to deal with their symptoms and to seek medical help?

Endometriosis is a chronic gynaecological condition(disorder), affecting 5-15% of women, during their reproductive age.  The symptoms include painful menstruation, painful intercourse, tiredness, chronic pelvic pain and heavy periods.  Furthermore, 40% of visits to  fertility clinics are due to endometriosis.

Many studies show the negative effect endometriosis has on social and marital relations, as well as the help that the male partner provides.  However, most of these studies focus on the women’s experiences.

In this study “Endopart UK”, 22 heterosexual couples were interviewed.  The inclusion criteria were, a laparoscopic diagnosis of endometriosis and the cohabitation of the couple.  Both men and women were interviewed separately.

It was found that the impact endometriosis had on the daily lives of the men and on their feelings was impressive.

Every long term disorder affects the healthy partner, but endometriosis more than any other, because it affects the reproduction and sex life of the couple.

The partners took an active role during doctor’s appointments and helped their female partners to choose the right treatment. Their support during the implementation of the treatment was significant.

In the future, the treatment should not just focus on the woman, but should take into account the effect that endometriosis and its treatment have on the quality of the couple’s life and also that of the male partner.

ESHRE 2015, O-080: Men living with endometriosis:perceptions and experiences of male partners of women with the condition. N. Hudson, L.Culley, H. Mitchell, C.Law, E. Denny, N. Raine-Fenning

Natural conception in women with deep infiltrating endometriosis

By I.Soussis MD

How high is the percentage of natural conception and pregnancy in women with untreated colorectal endometriosis?

Erasmo et al. from Genova, Italy attempted to answer this question. Their study was presented at the ESHRE annual conference in Lisbon in 2015.

The study involved 55 patients with colorectal endometriosis, attempting to get pregnant, between 2009 and 2014.  Their partners all had normal sperm count.  All patients with a bowel stenosis (narrowing) greater than 60% and those who had undergone surgery for endometriosis, were excluded from the study.

 

Results:

The average age of patients was 33 years.  Natural conception happened in 17 patients(30.9%).  The average time to conception was nine months(2-32).

Twelve patients conceived with IUI or IVF(21.8%) over an average of 21 months (2-54).  After the first pregnancy, 3 out of 7 patients conceived naturally the second time.

The total percentage of pregnancies was 52.7% (29/55 women) with an average follow up of 21.5 months (2-54).

 

Conclusion:

At least half of women (50%) with deep infiltrating endometriosis can spontaneously conceive following IUI or IVF without having to undergo surgery for the removal of endometriosis.

P-324,ESHRE 2015. Fertility in patients with untreated colorectal endometriosis.

I. Erasmo, F. Sozzi, A Racca, U. Leone Roberti Maggiore, P. L. Venturini, V. Remogida, S. Ferrero

University of Genoa

Spontaneous Miscarriage In Women With Endometriosis

Image courtesy of imagerymajestic at FreeDigitalPhotos.net

Image courtesy of imagerymajestic at FreeDigitalPhotos.net

By I.Soussis MD

If women suffering with endometriosis have a higher risk of adverse pregnancy outcome in early pregnancy, such as spontaneous miscarriage or ectopic pregnancy, was not well documented up to now.

A study from Japan compared 49 pregnant women with endometriosis to 59 without the disease. They found that the incidence of spontaneous miscarriage was not  statistically significant different among the two groups. (18,4% in women with and 18,6% in women without endometriosis). Obviously in this study the numbers are small and its statistical power is rather weak.

Aris  studied the impact of endometriosis  on adverse pregnancy outcome in the Eastern Townships of Canada, over a 12 year period. The pregnancies studied were 31068 and of those 784 were in women with endometriosis (2,5%). In 183/784 pregnancies in women with endometriosis, an adverse outcome was recorded (23,3%). The risk of spontaneous miscarriage in women with endometriosis was statistically significant higher than the general population. The risk of miscarriage was almost twice than in women without endometriosis (1,89).

Saraswat et al. presented in Lisbon at the annual meeting of ESHRE 2015, an extremely interesting linkage analysis of the Scottish national registry. They studied 14655 women discharged from all Scottish national hospitals over a period of 30 years (1981-2010). They compared the pregnancy outcome in  5375 women with surgically confirmed endometriosis to 8280 women without endometriosis, who were pregnant at the same period. The chance of adverse pregnancy outcome in the first trimester was significantly higher in women with endometriosis. More specific the risk of spontaneous miscarriage was 1,7  and the risk of ectopic pregnancy was 2,7 times higher, than in women without endometriosis.

The statistical power of the last two studies is extremely strong. Indeed Saraswat et al. studied the whole population of Scotland over a long period of time.

Conclusions: The presence of endometriosis increases the risk of spontaneous miscarriage and ectopic pregnancy. Women with endometriosis should be followed closely in the first trimester of pregnancy. They should also be informed of the increased chances of adverse pregnancy outcome.

Eur J Obstet Gynecol Reprod Biol. 2014 Jan;172:36-9. doi: 10.1016/j.ejogrb.2013.10.024. Epub 2013 Oct 31. Endometriosis and pregnancy outcome: are pregnancies complicated by endometriosis a high-risk group? Mekaru K1, Masamoto H2, Sugiyama H2, Asato K2, Heshiki C2, Kinjyo T2, Aoki Y2.

Gynecol Endocrinol. 2014 Jan;30(1):34-7. Doi:10.3109/09513590.2013.848425. Epub 2013 Oct 17.  A 12 year cohort study of adverse pregnancy outcome in Eastern Townships of Canada: impact of endometriosis. Aris A.

ESHRE 2015, O-122. Reproductive and pregnancy outcomes in women with endometriosis: a Scottish national record linkage study L.Saraswat, D.Ayansina, S.Bhattacharya, D.Miligkos, A.Horne, K. Cooper, S. Bhattacharya.

How successful is IVF treatment in women with endometriosis?

By I.Soussis

During the early days of IVF treatment, patients were placed into two groups; one which dealt with tubal factors and which was considered to have a better outcome and a second one, which encompassed all other causes of infertility.  Patients with endometriosis were placed into this second group, with a less favorable prognosis.

Women with endometriosis do not respond as well to ovarian stimulation, producing less oocytes, less embryos and have a smaller percentage of implantation.  Most doctors report a lower number of pregnancies for them.

This bias regarding the outcome of IVF treatment in women with endometriosis, was reinforced in 2002, by a study carried out by Barnhart et al.

This meta-analysis of 22 published studies showed that those women with slight endometriosis, had a similar percentage of pregnancies to those with tubal problems.  However, those with severe stage 3-4 endometriosis, had a 50% lower pregnancy rate.  The major flaw of  this study though is, that it was based on studies performed from 1980-1999, days in which drug protocols, as well as the procedures used in the laboratory, were very different and much less successful.

Therefore the question remains. Is it true that women with endometriosis have a lower pregnancy rate during IVF treatment?

The answer is definitely NO.

By studying National IVF registries that follow all IVF cycles on a yearly basis, the results clearly show that patients with endometriosis have an exceptional number of births, even higher than those with tubal factors.

Τhe CDC in the USA, the FIVNAT in France and the HFEA in the UK are responsible for the collection of IVF cycles in their jurisdiction and the maintenance of these huge databases.

Births according to the cause of infertility  CDC 2012

Births according to the cause of infertility
CDC 2012

 

The first graph from the CDC, represents the outcome of 400.000 IVF cycles in the USA in 2012.  The number of births from women with endometriosis is 31.1%, which is much higher than those with tubal factors of 28.5 %.

 

Birth rates according to the cause of infertility FInvat France

Birth rates according to the cause of infertility
FIvnat France

The second graph from France (FIVNAT) shows the results of about 250.000 IVF cycles from 1998-2002.  The births by women with endometriosis is 24% compared to 21% from women with tubal factors.

The statistical power of these huge numbers can not be matched by any study.

Therefore, in reality, women with endometriosis have exceptional results with IVF treatment.  They may have less oocytes or embryos, but the percentage of births is outstanding.  It is a quantitative matter and not a qualitative one.

http://www.cdc.gov/art/pdf/2012-report/slides/art-2012-graphs-charts-figure-19.pdf

Fertil Steril. 2002 Jun;77(6):1148-55. Effect of endometriosis on in vitro fertilization. Barnhart K1Dunsmoor-Su RCoutifaris C.

Smoking and endometriosis

Image courtesy of pat138241 at FreeDigitalPhotos.net

Image courtesy of pat138241 at FreeDigitalPhotos.net

By I.Soussis

The relationship between smoking and endometriosis is not very clear.  The conclusions of many studies are rather conflicting and opposing.

In a study from Portugal, women who smoked or had stopped smoking, had a smaller chance of getting endometriosis, than non smokers.

A Turkish study found just the opposite from the Portuguese one.

In the USA infertile women with endometriosis were compared to fertile women.  With regards to smoking, there was a slightly reduced chance of endometriosis in heavy smokers, who also had started smoking at a young age.

Francesca Bravi, together with collegues from different Italian universities, carried out a meta-analysis of published studies, to clarify the danger of endometriosis in smokers.  The study was published in the prestigious British Medical Journal(BMJ) in 2014.  A total of 1758 articles were reviewed, of which 38 met the inclusion criteria for this new analysis.  The new study included  13.129 women with endometriosis.  For study purposes,  the women were separated into groups of never smokers, smokers and those who had stopped smoking, as well as classifying them as light or heavy smokers.

It is well known that endometriosis is dependent on oestrogen, which is the female sexual hormone, regulating the menstrual cycle.

How can smoking affect the development of endometriosis?

The answer lies in the effect smoking has on the production of oestrogen as well as on inflammatory compounds.  Smoking reduces the production of oestrogen and progesterone and increases the secretion of inflammatory substances, not only in the lungs, but in all body tissues.  Both of which are mechanisms that influence the development and expansion of endometriosis.

 The present study did not prove any relationship between smoking and endometriosis.

 Conclusion: Smoking does neither stop nor cause the appearance of endometriosis.

F. Bravi et al.,BMJ Open 2014:4(12) e006325

Calhaz-Jorge C, Mol BW, Nunes J et al. Clinical predictive factors for endometriosis in a Portuguese infertile populationHum Reprod 2004;19:2126–31 doi:10.1093/humrep/deh374 [PubMed]

Aban M, Ertunc D, Tok EC et al. Modulating interaction of glutathione-S-transferase polymorphisms with smoking in endometriosisJ Reprod Med 2007;52:715–21. [PubMed]

Cramer DW, Wilson E, Stillman RJ et al. The relation of endometriosis to menstrual characteristics, smoking, and exerciseJAMA 1986;255:1904–8 doi:10.1001/jama.1986.03370140102032 [PubMed]
 
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