Unexplained infertility and IVF options. Diagnostics and treatment process

Nadia Caroppo, MD
Gynaecologist & Head of the International Medical Team

Failed IVF Cycles, IVF Abroad

Treatment options for unexplained infertility
From this video you will find out:
  • What are the different types of IVF failures?
  • What are the results of natural reproduction vs. egg donation?
  • What can be improved in the next treatment?
  • What are the main causes of IVF failure?
  • What is adenomyosis and how it affects IVF?

Is unexplained infertility really unexplained?

Have you been diagnosed with unexplained infertility? Watch this webinar where Dr Nadia Caroppo, from Equipo Juana Crespo, discusses your IVF options.

Dr Nadia Caroppo started by saying that chance explains 2 out of 3 cases of implantation failure. However, the 3rd case remains unexplained.
If there are repetitive IVF failures, there could be a random failure, but the ones that have a cause may be based on embryonic problems. It is one of the most important parts of IVF failure. Others can be due to bad simulations or bad uterine preparations, while other causes are due to causes such as thrombophilia, etc.

Two graphs show the conception period for natural pregnancies to occur, which showed that 65% of fertile women got pregnant within the first 3 to 6 months of searching for a baby. The same thing happens with oocyte donation, after 5 embryos were transferred, 65% of the couples got pregnant, but after more embryos were transferred, the curve flattens, which shows there is nothing like natural conception. It means, that the more embryos we transfer, the fewer success rates are not going to increase compared to a natural cycle.

There are different ways to work on, such as improving oocyte quality and semen quality using, for example, Fertile Chip or oocyte quality with CoQ10, DHEA, which is an androgen for low responders. It is also possible to improve environmental factors, such as lowering the doses of gluten or lactose, which may give you a pro-inflammatory environment. It is also possible to select embryos by PGT, but it’s also very important to have a very good embryo transfer which will not cause pain or bleeding. It’s also important to check the uterus and the fallopian tubes. There are a lot of things that sometimes are forgotten and may cause failure.

Endometriosis & adenomyosis

Endometriosis occurs when the endometrial tissue is outside the uterus, for example, in the ovaries, fallopian tubes, intestine, peritoneum, bladder, etc. A lot of women suffer from it and are diagnosed because they have a cyst, for example, that’s the most common diagnosis. However, some of them, do not have that clear factor like a cyst, but the endometriosis is there. Adenomyosis is the presence of heterotopic endometrial glands and stroma in the myometrium with smooth muscle, which causes hyperplasia (a growing tissue that does not have to be there). Both of these conditions need to be considered when there is a failed IVF cycle, and there is no known cause.

There are a lot of theories about the origins of endometriosis, it can occur due to genetic and epigenetic reasons, and it can run through the family even though there is no gene that is correctly identified for this. It can undermine the function of every organ in the reproductive tract. There are biochemical alterations, lesions as well as environmental factors that can change the expression of those genes, and make your physiology change and cause endometriosis.

There’s another theory that retrograde menstruation which is coming through the vagina, and some droplets of blood that travel through the fallopian tubes can invade other organs. Another thing is uterine biomechanics when there is a disruption of the sub-endometrial membrane (it separates the endometrial lining from the muscle). When you have very painful periods, your uterus tends to contract and then again some droplets of blood just get through that barrier invade the muscle and can travel through the blood or the lymphatic system to other organs and create endometriosis.

Endometriosis has an inflammatory basis, and when there is inflammation, there is a pattern to repair that inflammation, repair the tissue, and when it’s repaired, scars occur, and in the long run, that can cause superficial endometriosis, cystic or deep endometriosis. Deep endometriosis means that the anatomy has completely changed, and organs can be stuck together, which can disrupt your fertility. Cystic endometriosis is the most common one, superficial endometriosis is an early stage of endometriosis, and it can not be seen easily, but when laparoscopy is performed, there are visible small cystic lumps on the surface of the uterus and the fallopian tubes. It is also known that when there is endometriosis, there can also be adenomyosis.

When you are diagnosed with endometriosis, you will need to start by trying to improve your egg quality with CoQ10, inositol or a diet with low gluten and lactose, sometimes it is necessary to undergo a surgical treatment to treat endometriosis. The doctors need to clearly understand how to restore the morphology and the functionality of an affected ovary, personalized protocols are needed, this disease is estrogen-dependent, so if estrogen levels are increased, endometriosis will be much worse. Plus, the embryology lab has to be prepared to work with possible bad-quality embryos.

The contraction of the uterus is called peristalsis, a woman has peristaltic contractions during the whole menstrual cycle, 1.5 per peristaltic contractions during a menstrual cycle, she has 10 million contractions during the first 10 years after the first menstrual period, and there are 30 million of peristaltic contractions during her whole reproductive life. This can be the origin of that unexplained infertility. You always need to remember that periods should never be painful.

How can you know that you have adenomyosis or endometriosis? It’s important to remember that 30% of people are asymptomatic. Adenomyosis can also cause abnormal uterine bleeding, it’s when you bleed in between periods, and you can have spotting before your period or after your period. Most women have chronic pelvic pain, they can experience pain during intercourse or they may have dysmenorrhea and lots of them have reproductive failures.

Adenomyosis affects a woman’s reproductive tract because there is a disruption and dysregulation in the architecture of the uterus. The walls become a little bit harder. There can also be an altered endometrial function because, as it is a pro-inflammatory disease, sometimes the endometrium does not work as it should. Adenomyosis and endometriosis are progressive benign diseases that can change their appearance, and morphology over time. There are 2 subtypes of adenomyosis, the first one is caused by mechanical stress or trauma involved in fibrosis, and subtype 2, its pelvic endometriosis which is more linked to deep endometriosis. The prevalence of endometriosis in adenomyosis is 80.6%, and the prevalence of adenomyosis in endometriosis is 91%. Therefore, usually, a patient will suffer from both diseases, this is very common.

Adenomyosis increases the risk of miscarriages, preeclampsia, placenta malposition, preterm birth, cervical incompetence, uterine infection and alteration of the endometrial microbiome

Uterine functionality

There are 2 types of uterine uteruses, the hyper-fertile uterus will get you pregnant, which means it’s a very receptive uterus, and that uterus may cause lots of miscarriages because any embryo bad or good quality embryo passes by may cause a miscarriage. There is also a hostile uterus, which is more affected by these 2 diseases, and a good selection of embryos and treatment has to be made to make the implantation possible. The implantation itself is not a passive process, there’s a crosstalk between the embryos and the uterus, and we know that very good embryos have a higher chance to implant. w

How can we evaluate the uterus if it suffers from endometriosis and adenomyosis? There are 2 types of assessment, morphological assessment and functional assessment. Morphology is usually assessed by ultrasound and pelvic MRI and the functionality can be checked with hysteroscopy or video MRI. Video MRI assesses the contractions, it’s very difficult to diagnose correctly with the video MRI because it’s very difficult to understand if it is a contraction or if the membrane that separates the endometrial lining is thick because of the adenomyosis itself, so the doctors also use pelvic MRI and the 3d ultrasound. During hysteroscopy, the doctors can assess lots of things, such as endometritis, fibroids, synechia, adenomyosis, caverns, istomocele, etc.

Apart from hysteroscopy, it is possible to restore uterine functionality with medical treatments. Surgical treatment is not the only treatment, sometimes surgical treatment needs to be combined with medical treatment depending on each case. You may need to use GnRH analogues that are anti-estrogens that are also used for stimulation processes. You can also use IUD that liberates progesterone, such as Mirena or contraceptive pills or only progesterone pills, there are lots of things that can be used, but each case needs to be evaluated depending on each case. Depending on the case, laparoscopy might be necessary to remove masses of adenomyosis, but it’s important to remember that surgical treatment is a very radical treatment and is offered in particular cases because it’s very difficult to operate on such uteruses.

It’s very difficult to rule endometriosis and adenomyosis out if you don’t have proper training, the most difficult part of all this is just knowing how to treat it from the reproductive point of view.

- Questions and Answers

How often is adenomyosis or endometriosis the cause of infertility?

How often? That’s a tough question because, in our clinic, 95% of our patients have endometriosis/adenomyosis. The fact is that the younger you are, the less it will affect you if you have endometriosis. If you get pregnant in your mid-20s or early 30s, you may get pregnant by yourself. Maybe the difference between us, our generation is that even if we have endometriosis or adenomyosis, and our mothers or grandmothers got pregnant being very young, and maybe they had endometriosis or adenomyosis. The younger you are when you get pregnant, the better the prognosis. In our clinic, we have a 90-95% incidence of endometriosis and adenomyosis, which’s a cause. When you don’t have any cause, that accounts for 30% of all patients with unexplained sterility, in general.

To which degree do adenomyosis or endometriosis lower my chances of a successful IVF?

As I told you before, it depends on a bunch of things. It depends on how that endometriosis has affected your ovaries. If we see that the ovaries do not have a good follicle count or that the follicles do not have a good regular shape, if we see that the ovaries are very fibrotic – that may account for lower quality eggs and embryos and lower quantity of eggs, too. So that can account for a lower percentage in IVF success. As I told you before, it’s not only the problem of an embryo. It’s a whole problem that has to be evaluated, so if you’re not correctly treated, the chances will get lower and lower. It also depends on age. So there’s not a perfect percentage just to tell you. It depends on a lot of factors, but, yes, it can um diminish your chances to get pregnant.

What vitamins should I take to reduce endometriosis, and for how long should I take them before my round of IVF?

This is a good question. We usually give Coenzyme Q10 600 milligrams per day, Myo-inositol – 4 milligrams per day. We also gave some preparations accounting for multi-vitamin preparations, Omega-3, DHEA. Furthermore, we advise lowering the intake of gluten and lactose for at least four to six weeks before you undergo an IVF. It’s not to reduce endometriosis. It’s to reduce inflammation. Usually, we also give probiotics, and we are finding out that curcumin is also a good anti-inflammatory compound that can increase the quality if I have endometriosis.

What are the main reasons for a missed heartbeat with successful implantation? I recently lost a pregnancy at eight weeks. There was no cardiac activity. I had Asherman’s syndrome and was successfully treated for it in 2019.

First, if you have Asherman’s syndrome, we have to understand that Asherman’s syndrome was provoked because of other miscarriages, D&C, other surgical procedures. If that Asherman’s syndrome is provoked because of adenomyosis, that’s very difficult for us to treat. When embryos implant, there are two waves of implantation. The first wave of implantation is when the embryo attaches to the endometrial lining and starts scratching in. That’s around four to five weeks, and the second wave of implantation is around the sixth to seventh week of pregnancy, and that accounts for the scratching into the uterine muscle. If you have the heartbeat of an embryo stops beating around those weeks, we have to know, first, if it is a normal or an abnormal embryo. Because if you’re miscarrying a normal embryo, probably the reason is because of bad uterine functionality. Maybe the treatment that you received in the past is not sufficient just to have a successful pregnancy. A hard wall. You have to understand that if an embryo finds itself with a concrete wall beneath it, the scratching process can be altered, and the heartbeat can stop. It may also account for other factors, not only adenomyosis. Sometimes thrombophilia has to be ruled out when that happens several times. But you have Asherman’s syndrome – maybe the uterine functionality is not the best one. 

What can I take before my next transfer to promote optimal uterine lining?

We usually prepare the endometrial lining in natural cycles or substitute cycles, and we usually give oral probiotics just to make sure that the normal microbiome, the normal flora of the uterus, is obtained. We give oral probiotics generally, and you can also have vaginal probiotics. Regarding vitamins, we sometimes use vitamins A and E, but we stop them once we have a positive pregnancy test. It depends on whether the endometrium lining is correctly growing, the thickness – it depends on a lot of things. There’s not one thing we do usually give. We always give probiotics to our patients and vitamins, too. 

Have you heard of Coenzyme Q100 or CoQ30 supplements to improve egg quality?

Thank you for your question. There are a lot of compounds. Studies show that generally, with 600 milligrams, you can improve egg quality. Coenzyme Q10 acts on the mitochondria, which are the engine of the oocyte. You will find preparations in different milligrams, in different dosages. It doesn’t matter if you have six tablets of coenzyme Q100 or Q30, you just need to arrive at 600 milligrams. There are more pure forms of coenzyme Q10. The one that you will get will be the best. The dosage recommended is around 600 milligrams.

What about PCOS and the impact on unexplained infertility?

Good question. PCOS patients tend to have lots of estrogens because they have lots of follicles, and each follicle accounts for an increase in estrogen levels. Sometimes we see lots of patients who have polycystic ovaries, and they have painful periods, and that may account for adenomyosis and bad uterine functionality. But that has to be something that we have to investigate because not all PCOS patients have adenomyosis. We see it a lot in patients who have had surgical procedures before, undergoing IFVs, miscarriages, etc., and also who have painful periods. If you have both, you just remember that adenomyosis and endometriosis are estrogen-dependent diseases. If you have very high levels of estrogens that may, in the long run, undermine uterine functionality. Yes, PCOS may be related to an increased rate of adenomyosis if other things coexist, such as painful periods, etc. 

Is there any benefit of endometrial scratching before IVF?

This is a very controversial topic in assisted reproductive technologies because the results are not conclusive and do not show clear benefits when you perform endometrial scratching. There are a lot of papers that do not show any benefits and other papers that tell that there is a 20% increase in the implantation rate if you do endometrial scratching. Personally, and in the clinic, we do not do endometrial scratching. We do not believe that it improves the implantation rate.

What are your thoughts on endometrial scratching? Some doctors claim that this inflammation helps implantation.

It’s just the question that I’ve already answered. We do believe that inflammation can help implantation, but we do it in another way. We generally do it with hysteroscopy. We work with subendometrium differently. Furthermore, we create inflammation just to make sure that we have new vascularization and new cells arrive at the subendometrium. Superficial endometrial scratching – we have not seen any improvement doing that in the consultation room. We create inflammation when hysteroscopy is needed to restore uterine functionality.

How about EmbryoGlue?

We don’t use it. Some clinics use it. Embryo glue is just a more sticky medium just to make sure that it sticks to the endometrial lining, but that will not account 100% for implantation. There has to be a correct endometrial lining. The embryo has to understand itself within the material lining, and it has to be able to scratch into the subendometrium. So embryo glue may help, yes, but if the crib is not in a super shape, embryo glue will account for nothing.

Can you spell the name of the probiotics you recommend?

In Spain, they are called Dona Plus Flora Intima, and we give that one per day, orally.

I had an ectopic pregnancy 12 months ago with both embryos in the right fallopian tube, and since then, I have experienced right-sided pelvic pain. I don’t seem to have other symptoms, is it likely this could be caused by endometriosis? Would you suggest I explore this, and if yes, in which way?

Ectopic pregnancies and biochemical pregnancies can have the same or two origins. Maybe the embryo just went to the fallopian tube that had more inflammation, maybe because that fallopian tube did not work correctly or was ill from the first time. Or ectopic pregnancies and biochemical pregnancies may account for some embryos who escape from the uterus because the uterus is not correct. The first thing I can recommend you is if you did not have a right salpingectomy is to do a hysterosalpingogram; that it’s a radiograph of the fallopian tubes with injecting a contrast inside just to make sure that the fallopian tube has a normal caliber, it’s permeable and that it’s functioning correctly. If you have had a laparoscopy and your fallopian tube has been removed, probably if endometriosis has been seen, they should have told you something. If not, I would suggest investigating your uterus a little bit more, your uterine functionality. As I told you, the gold standard for endometriosis diagnosis is a laparoscopy; for adenomyosis, you can have a 2D ultrasound, pelvic MRI, and the correct assessment of an expert who can help you with that.

Which vitamins with folate, not folic acid should my surrogate take? Likewise, which probiotics? Vitamin D? Doses of each? What about organic flaxseed oils during pregnancy? Should she stay away from fish oils?

Fish oils are given in pregnancy. Folate – there are a lot of compounds. There’s an active compound of the folic acid or folate called a metaphor that is the already metabolized folic acid that does not saturate the receptors of folate – so that’s an option. Nearly all pregnancy vitamins have folates. The dosage we recommend is 4 milligrams of that. Probiotics – there are a lot of probiotics: Lactobacillus are very important, so you have lots of lactobacilli, osmosis, there are a lot of them. Depending on where you live, sometimes you can find that in one preparation. Vitamin D – if you have correct levels of vitamin D, that being 30 micrograms, above 30 micrograms, you do not have to have another intake. It depends on if you have a very severe deficit or just a medium deficit of vitamin D, we give different dosages of vitamin D. It depends. There are a lot of schemes that your doctors will just manage regularly. Organic flaxseed oils – I don’t know if you have to get them in pregnancies because we don’t use them. We are not keen on using that.

I didn’t have the tubes removed. I had HyCoSy and the die did come out via both tubes but was not visible in the right tube?

First, HyCoSy is just injecting water and seeing with an ultrasound if the water is drained from the tubes. It’s different from a hysterosalpingogram. It’s different. A HyCoSy does not permit you to see whether the tubes are dilated or not. If the liquid was not visible in the right tube, maybe you have a blockage of that right tube, and maybe that right tube is ill. Maybe, it should be removed. My advice is for you to do a hysterosalpingogram even if you did the HyCoSy – one of the things does not account for it. They are not the same type of tests.

I’ve had five donor cycles, one implementation but miscarriage at 6 weeks. I’ve had an ERA map, a period blood test for bacteria, a course of antibiotics, EMMA and ALICE tests test, and an ERA mapping receptivity test. Presumed immune issues. I’ve had two cycles on prednisolone, aspirin, clexane, tacrolimus, granulocyte, intralipids. Do you recommend any other treatment or tests? I also had KIR, and the endometrial thickness is around 8 mm in all transfers.

You have a very strong story on your back. I think if you have failed with five donor cycles, and you had a miscarriage at six weeks, even if you have the ER map all the other things done, there’s something else that is wrong. I believe that you have to search for some help just to study your uterus from another point of view. Because, eventually, your endometrial lining is perfect because of the thickness, your ERA map is receptive, the EMMA and ALICE tests are good. You had immunological issues that were treated regardless of the KIR, the intralipids, you got lots of things. I think that you have to be assessed from another point of view. If you never got hysterosalpingography, just go ahead and do it. If you have the chance to do the pelvic MRI during your post-ovulatory phase, just do it because it’s very important to know if you have something else going on if your uterus is that receptive or not. I think that we are talking about a hard uterus here, we are talking here probably about adenomyosis.


What are the advantages and disadvantages of PRP therapy to improve endometrium lining?

Now there are a lot of studies going on with PRP. There are no conclusive recommendations. What it means is just taking the growth factors that are produced by the plasma rich platelets. There are several ways of using that; just making an infusion inside the uterus or injecting it in the uterus. But we do not know the implications yet. We have done some studies ourselves. We have used it, and in some patients, it has worked, and in some other patients, it has not worked. Furthermore, we don’t know what the indications are to do it or not. There are some studies also going on to try to rejuvenate the ovaries with PRP and make them more functional, but the results are not conclusive. I cannot tell you about the advantages and disadvantages. It’s not a very difficult process to do: it’s just having your blood sample, processed and just infused back at a certain time during your preparation. It may or may not help, so I cannot enlighten you with a correct answer for that because it’s all understudy right now.

How long should one use Prednisolone before and after IVF?

It depends on the timing. We usually, give it if needed during the endometrial preparation, just when we start the endometrial preparation. If we have a positive pregnancy test, we continue it until we see a heartbeat, and then we just start lowering the doses of Prednisone. So if you start taking it just when you are under preparation, it would be OK. We generally use 15 milligrams of Prednisone per day when we start doing the endometrial preparation.

What happens in the uterus if the progesterone does not increase after transfer? What is a good value of progesterone after the embryo transfer?

Prednisone levels should be above 10 picograms – that’s the rule. Under that value, we see difficulties in getting pregnant. Some women get pregnant .with lower levels, but that’s not the rule. If you do not get a good impregnation with progesterone, you are not collaborating with the changes that the endometrial lining has to have to help the embryos attach and eventually implant. It’s good if you have to test for progesterone, just test it 1-2 days before the embryo transfer just to make sure that the levels are above 10. 

In what way can we improve the endometrium lining when it is too thin?

It’s difficult. We call it a refractory uterus – they are difficult to treat. Sometimes we give vitamin E, 400 units per day. We can give Viagra, also just to make sure that you have correct blood reception in the sub endometrium. We use pentoxifylline 600 milligrams every 12 hours. Not only that, but we also look inside the cavity to rule out that there is no Asherman syndrome and see even if you have a very thin endometrial lining. If the quality of that endometrial lining is good. Some women get pregnant even with five millimeters of endometrial lining if the endometrial lining is good. It’s very difficult. Sometimes we have to also do a hysteroscopy, not only to see the endometrial lining but to work on the subendometrium just to create inflammation, new vascularization and make sure that the endometrium starts working again. It’s very. It depends on what you have done before just to know where we have to go afterwards.

How long should one take Prednisone after the transfer, and is there better progesterone?

After transfer, if we have a positive pregnancy test, we continue with the prednisone until week six or seven. After that, we diminish doses weekly. Progesterone – we tend to use vaginal pessaries of micronized progesterone, the natural progesterone, and we use intramuscular progesterone or subcutaneous progesterone to associate it with vaginal pessaries whether you are on a natural cycle, we use 400 milligrams per day pessaries, if you are in a substitute cycle with estrogen, we use 800 milligrams pessaries per day plus injected progesterone that being daily subcutaneous injections or intramuscular injections on alternate days.

I have read a study that PQQ (pyrroloquinoline quinone) supplement works similarly to Coenzyme Q10. I’m interested to know if you recommend it.

If it’s similar, I didn’t know about that because we managed very well with Coenzyme Q10. If the results are the same, yes, go on to take it. There’s no point in not taking it. You can use it, but studies are recommending Coenzyme Q10, 600 milligrams dosage up to now.

Coenzyme Q10 is 600 before retrieval or transfer?

Before retrieval.

I have unexplained infertility. We’ve had one failed IVF attempt transferring, two grade 5AA embryos. We have some frozen embryos. Our clinic is recommending a frozen transfer, but they won’t do any additional testing or suggest a different process. What do you think we should try?

I would study you a little more. Usually, what we do is we see patients prepared for the failure, for example, if they prepared you in a substitute cycle which is preparing you the same way as you were transferred, just to understand how the uterus was working on that day and understanding if we have to do anything else. I would recommend studying your uterus and tubes a little better and see if there are other causes, maybe endometritis or some other factors that are altering those results and giving you a negative result with very good embryos. If you get together in the biology lab and nothing is happening in your uterus, I have to think that something is happening in your in vivo lab, that it’s your uterus and your fallopian tubes. Uterus meaning endometrial lining and uterus itself and the fallopian tubes, so I suggest investigating a little more. 

Can we get a personal online consultation?

Yes, of course. You can contact us here. We can give you all the information you need. We do online Skype consultations, we can give you some feedback on your case. You can contact us, and we will give you everything you need and offer an appointment. 

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Nadia Caroppo, MD

Nadia Caroppo, MD

Dr Nadia Caroppo is a gynaecologist and the Head of the International Medical Team at Equipo Juana Crespo, an IVF clinic from Valencia, Spain. Dr Caroppo has 8 years of experience and speaks Spanish, English, Italian, and French. She has obtained her Bachelor of Medicine (Hons) from the University of Buenos Aires and an expert in Gynaecology and Obstetrics. Her residence was at the Italian Hospital in Buenos Aires, Argentina. Her qualifications have been recognized in Spain and Italy. An expert in reproductive medicine both for patients and egg donors. Co-author of numerous scientific publications and an international conference speaker, a specialist in lower genital tract and colposcopy.
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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