Image by Sarah Pflug
Polycystic Ovarian Syndrome affects 1/10 women. PCOS is a widely known and extensively studied medical diagnosis, closely associated with female infertility but also later in life with the so-called metabolic syndrome, characterized by significantly increased risks for type II diabetes mellitus, hypertension, and atherosclerotic heart disease.
Are your periods irregular? Do you have acne on your chin or neckline? Do you have extra long dark hairs growing? If you answered yes to these, you may need to be screened for Polycystic ovary syndrome (PCOS). Classic PCOS is characterized by overweight, excess hair, acne, brown spotting on the skin or the back of the neck BUT there is a “lean” phenotype as well.
A good differential diagnosis looks at FSH, androgens, insulin sensitivity and follicle ultrasound to see if the classic “pearl” appearance is present.
PCOS is partially genetic: 24% of women with polycystic ovary syndrome had a mother with PCOS and 32% of the women had a sister with the condition.
Researchers have shown that women with PCOS regardless of their weight (overweight and lean) will experience insulin resistance as compared to women of the same age and weight who do not have PCOS.
If you have PCOS, multiple bubble-like cysts may form on the surface of one or both of your ovaries as eggs partially mature but are not released. These eggs remain in their follicles, which swell but don’t open. A woman with PCOS may have 25 or more cysts on a single ovary.
Lean PCOS patients, however, have normal and, often, even low weight may be hyperandrogenic but usually do not demonstrate signs of hirsutism and do not demonstrate an increased risk for metabolic syndrome. They also often present with regular menses and are, therefore, not anovulatory; yet often, still, do not conceive. Though they represent approximately equal numbers to classical phenotypes, the perception of PCOS as an anovulatory condition, nevertheless, persists not only among the lay public but also within the medical community.
Some women have no symptoms of endometriosis!!
NO symptoms of endometriosis?? How?
Endometriosis is a debilitating disease for some (ie. painful periods, bleeding and pain during ovulation, uncomfortable intercourse, heavy bleeding and chronic pelvic pain). However, many women don’t know they have it, they just can’t fall pregnant.
When uterine endometrium is located in places other than the uterus, thats endometriosis. Want to know all science? Then technically speaking, endometriosis is a pelvic inflammatory process with altered function of immune-related cells and increased number of activated macrophages in the peritoneal environment that secrete various local products, such as growth factors and cytokines. What does all that mean? The endometriosis cells implant and respond to the body’s hormone before becoming endometriotic lesions and then scars.
As horrific as all that sounds, there is “sub clinical” endo.
“Sub Clinical” means a disease is not severe enough to present definite or readily observable symptoms. The incidence of “subclinical” endometriosis is thought to be around 42%. It doesn’t seem to matter how healthy you are or what your BMI is.
What we call Endometriosis is probably several different diseases lumped together, not just “one” thing. We suspect it is caused by multiple factors. Unfortunately, much more research is needed!! There are several theories as to why endometriosis occurs. We have not yet found a definitive answer.
Want to know something truly alarming??? There is an average delay of four to 11 years from the onset of symptoms to diagnosis.
Women who are unaware of their diagnosis (obvi) can’t get it treated!!
Untreated Endometriosis and Infertility
Fertility is impacted by endometriosis in many different ways. Scar tissue and adhesions can block the fallopian tubes and uterus. Therefore, the uterus is inhospitable for embryo growth and egg quality is damaged.
During the time you go untreated, the symptoms can get worse and multiply. Pain increases, further negatively impacting fertility.
One reason for this delay, is that endometriosis (many times) needs to be diagnosed through an invasive surgical procedure. Additionally, you may have to CONVINCE your doctor that the pain is not just “normal” period cramps.
Women report that when their OBGYN, or fertility doctor is not the same gender, race, or sexual orientation as as them, they are belied less, and have a hard time convincing. In psychology, this is called “affinity bias” but there are other reasons of historical racial prejudice too.
Women are believed less about their pain, and some minority women have reported being endlessly questioned for “drug seeking” behavior, or essentially accused of having an STI (STD) i.e. pelvic inflammatory disease (PID).
How is Sub Clinical Endometriosis Diagnosed?
How is sub-clinical endometriosis diagnose? There is one test, called ReceptivaDX.
ReceptivaDx is a first of its kind test for the detection of inflammation of the uterine lining. Women who test positive for ReceptivaDx are 5 times less likely to succeed in IVF.
Do you know how to broken by infertility and TTC?
It’s NOT funny how cruel we can sometimes be to ourselves.
1 in 8 couples (or 12% of married women) have trouble getting pregnant or sustaining a pregnancy. (2006-2010 National Survey of Family Growth, CDC)
7.4 million women, or 11.9% of women, have ever received any infertility and TTC services in their lifetime. (2006-2010 National Survey of Family Growth, CDC)
Approximately one-third of infertility is attributed to the female partner, one-third attributed to the male partner and one-third is caused by a combination of problems in both partners or, is unexplained. (American Society For Reproductive Medicine)
A couple of ages 29-33 with a normal functioning reproductive system has only a 20-25% chance of conceiving in any given month (National Women’s Health Resource Center). After six months of trying, 60% of couples will conceive without medical assistance. (Infertility and TTC As A Covered Benefit, William M. Mercer, 1997)
That makes you pretty “normal” actually. you are in plenty of good company- we can’t all be broken, can we? It almost seems like infertility is a common and normal part of the human condition, Infertility and TTC doesn’t it?
Stop blaming yourself.
Stop feeling hopeless.
Stop basing your self-worth on your fertility.
Stop suffering silently.
Get solutions from here, broken by infertility and TTC
I’m afraid to ask… what are the worst things you have said to yourself in your darkest moments?
Infertility research priorities have been proposed for 2021. Healthcare professionals, people with fertility problems and infertility researchers (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process resulting in an article that was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions.
The top 10 infertility research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. These top ten research priorities in each topic area outline the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, to assist research funding organizations and researchers to develop their future research agenda.
Blog Series: Top Ten IVF Research Priorities
- An article was published in Human Reproduction in November 2020 outlining the top future infertility-related research priorities. The top ten ART research priorities are;
- What are the causes of implantation failure?
- What is the optimal treatment for women undergoing IVF who are poor responders to increase live birth rates?
- What is the optimal method of sperm selection in IVF cycles?
- In couples with unexplained infertility, does IUI increase live birth rates when compared with other ARTs, including IVF?
- In couples with unexplained infertility, what is the optimal number of IUI cycles before moving to IVF?
- What is the optimal method of embryo selection in IVF cycles?
- What are the factors that affect cycle to cycle variability in the number and quality of oocytes produced in an IVF cycle?
- What is the optimal time interval between ovulation and IUI?
- What is the emotional and psychological impact on children born using donor gametes?
- What is the emotional and psychological impact of repeated fertility treatment failure?
The first of the top ten infertility research priorities for medically assisted reproduction is “What are the causes of implantation failure?” In this post we will dissect the various hypotheses, tests, treatments and potential avenues of research.
The placental paradox
The riskiest moment in any human pregnancy is when the fertilized egg attaches to the uterine wall and tries to establish a link between embryo and mother. About half of IVF pregnancies fail during this implantation stage, and we all know how many natural pregnancies end at that time as well.
At some stage in the evolution of animals, we went from mammals that lay eggs, like the monotreme family (the platypus and echidna are the living members of), to marsupials or pouch gestating mammals like kangaroos, koalas and possums, to placental mammals like us. But even among placental mammals NOT all placentas are the same.
For example, in cows there are specific spots of attachment between the fetus and the mother called cotyledons, and this is so different than in humans where we have a total attachment between the placenta and the uterus. That is why you do NOT see cows bleeding out form a uterine rupture or suffering from, for example gestational diabetes or high blood pressure. Their blood supply is just not that connected to the developing fetus. We really see that our complex placenta developed evolutionarily to protect the embryo from our own immune system.
There is a kind of paradox that perplexes researchers of infertility, a mother’s inflammatory reaction to the embryo is the biggest threat to pregnancy, it also seems necessary for the pregnancy to be successful.
Implantation Failure
Implantation failure or RIF is an imprecisely defined clinical disorder characterized by failure to achieve pregnancy after repeated embryo transfers with genetically normal embryos. multicomponent, bidirectional signaling between the embryo and endometrium. A healthy uterus, free from endometriosis, polyps, fibroids, and with a thick lining is one piece of the puzzle, a euploid, or chromosomally normal embryo is another piece, less than 60% of euploid embryos result in pregnancy.
There are 4 main culprits or areas of active infertility research investigations. The 4 are; progesterone resistance, shifted window of receptivity, decreased integrin expression, and immune system disturbances.
Infertility researchers are identifying all of the biological components involved, developing tests to definitively say if that process is in a disease or abnormal state, and then drug treatments that work!
Progesterone resistance and infertility research
Estrogen stimulates endometrial proliferation, estrogen also causes an increase in progesterone receptor expression, enabling the establishment of the “window of receptivity”. Progestogen is directly responsible for the timing – the opening and closing of the window of receptivity. Endometriosis can actually cause progesterone resistance, disrupting the establishment, and opening or closing of the window.
There is a gene called BCL6 and its expression in the endometrium has been correlated in patients with unexplained or endometriosis-associated infertility. There is a test to see what the activity of this gene is called the Receptiva DX test.
Shifted window of receptivity
The window of receptivity itself has a molecular signature – meaning certain genes are expressing certain proteins- and this can be determined with a test called the ERA test. Implantation itself is actually a tightly controlled inflammatory response that coordinates the embryo “invasion”.
The embryo is essentially a foreign invader. It is half NOT your own DNA but the partner or sperm source. So the uterine lining and muscular wall must allow invasion by this foreign entity, without alerting your immune system to attack, and establish a vascular blood supply that can support pregnancy.
Decreased integrin expression and infertility research
Integrins are cell to cell adhesion molecules. They are the principal receptors on animal cells for binding most extracellular matrix proteins. They are basically a little ladder that crosses the membranes of both cells, in this case the embryo’s and the uterine endometrium.
Endometrial integrins are key molecules that promote embryo attachment. Right now, we have one good drug candidate to increase integrin expression, called letrozole. Letrozole is known as an “aromatase” inhibitor there is another very common mild aromatase inhibitor – Aspirin! Aromatase, is also called estrogen synthetase or estrogen synthase, because it is an enzyme responsible for a key step in the biosynthesis of estrogens.
There are so many features of embryo implantation that are consistent with the hallmarks of cancer and tumor invasion. In fact, it is often noted that “all the tricks cancer knows, were learned from the embryo”. The tricks here being invading tissue, establishing a blood supply for uncontrolled cell growth, and evading detection by the immune system. There are dozens of drug molecules from the cancer treatment world that can inhibit aromatase.
The immune system and infertility research
Two immune system components cytokines (which are generally associated with inflammation) and uterine natural killer cells have important roles in successful implantation.
Excessive and altered inflammatory signaling has long been suspected in implantation failure and recurrent pregnancy loss. Natural killer (NK) cells are members of a rapidly expanding family of innate lymphoid cells (ILCs). During pregnancy, NK cells are the most abundant lymphocytes in the uterus at the maternal-fetal interface and are involved in placental vascular remodeling. So discovering the complete set of cells and all their functions is still necessary.
We had one good drug molecule called glucocorticoids to investigate – they are a type of corticosteroid hormone that is very effective at reducing inflammation and suppressing the immune system. Glucocorticoids were selected to study, based on the biologic plausibility of restoring a normal immunologic response in the endometrium to promote healthy embryo implantation- however many gold standard clinical trials and meta-analysis of the data have failed to show improvement. For this reason, ASRM guidelines currently recommend against the routine use of glucocorticoids to improve implantation rates.
But there are dozens of other suspected immune pathways and drug molecules to explore.
It is common to change our minds about things. We might decide we want spaghetti instead of tacos for dinner. We might even decide on spaghetti tacos (that is a thing). However, it becomes a little more complicated when the decision is regarding having children and permanent birth control has already been put in place. A common form of permanent birth is tubal ligation or as most people refer to it “tying your tubes.” In this procedure, the fallopian tubes are cut and tied. By doing so, eggs can no longer travel down the fallopian tubes and no sperm can climb up the fallopian tubes to reach the egg. This will prevent any contact from occurring between the two gametes.
Is it permanent?
You might have noticed we said “permanent.” For the most part that is true. Once a woman undergoes tubal ligation, she does not need to worry about an unwanted pregnancy from that point onwards. Is it possible to reverse this procedure? In fact, it is! This does not necessarily mean that you are guaranteed a pregnancy after reversal. In fact, only approximately 50-80% of women become pregnant after reversing the ligation.
Why might IVF not work after tubal ligation?
There are several reasons for this. One of them is that when trying to undo the procedure, the stumps left after the procedure are beyond repair and scarred. Another reason is the development of another condition such as pelvic inflammatory disease or endometriosis. Lastly, it might not have anything to do with your body. Your partner’s sperm count or motility could be very low. Yes, male factor infertility is a thing. Infertility is not only a woman’s problem.
Ectopic pregnancies might occur after the reversal procedure. This is when the egg implants itself in the fallopian tube rather than the uterus. The chances of this happening post-reversal is 10% and the consequences could be fatal. Age is another factor. Women in their 40s have lower chances of conceiving and IVF is not recommended. Even if there are no complications witht he reversal, low egg reserve may end up preventing a pregnancy. Nevertheless, IVF will increase the chances of a successful pregnancy after tubal ligation rather than trying to conceive naturally.
Our final thoughts
IVF is expensive and tubal ligation is essentially a surgery that will also cost money. When making these decisions, make sure you are financially planning ahead of time. Whether you think the risk is worth it is completely up to you. No one is able to gauge the benefit of taking risks regarding your fertility except you. You will know what choice is right and not another individual. IVF after tubal ligation is a complicated topic. Every woman’s body is different and as we have seen even with a successful reversal of the ligation, the development of certain conditions and as a woman ages, the chances of pregnancy may decrease. Make sure you confide in your reproductive endocrinologist to find what is best for you. If you have not had ligation done yet, and are not sure if you want it, also confide in your doctor and they can walk you through the pros and cons of the different options. It’s a tricky road to navigate, but not impossible!
References:
- “IVF After Tubal Ligation: University Reproductive Associates ….” https://www.uranj.com/blog/ivf-after-tubal-ligation. Accessed 18 Sep. 2020.
- “Tubal Reversal vs. IVF? | Shady Grove Fertility Blog.” 4 Feb. 2020, https://www.shadygrovefertility.com/blog/diagnosing-infertility/tubal-reversal-vs-ivf-0/. Accessed 18 Sep. 2020.
“Tubal Ligation | Johns Hopkins Medicine.” https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/tubal-ligation. Accessed 18 Sep. 2020.
Alright, I know what you’re thinking. What in the world is a mosaic embryo?!
The best way to explain it is by picturing a soccer ball. An embryo is also essentially a ball of cells. A soccer ball is mostly made of white pentagons with some black pentagons here and there. Imagine that the white pentagons are the healthy cells and the black pentagons are the unhealthy or abnormal cells. A mosaic embryo is an embryo with some abnormal cells scattered throughout it.
Does this affect a chance at a successful pregnancy?
The answer is very inconclusive. Recently, the American Society for Reproductive Medicine provided guidelines for the clinical management of mosaic embryos. There have been cases observed where mosaic embryos develop into perfectly healthy fetuses and other cases where the chromosomal abnormalities result in conditions such as Down Syndrome. They also have lower implantation and clinical pregnancy rates. Their developmental potential is approximately 40%, and 40% of mosaic embryos result in pregnancy.
Keep in mind, however, that this largely depends on how many abnormal cells are present in the embryo and the percentage of chromosomes affected. If there are normal embryos available (also called euploid embryos) then those should be given first priority and transferred first as they do have the lowest risk of a miscarriage. It may be easy to avoid using a mosaic embryo if there are other embryos that look like they possess much better potential. However, in the cases where there aren’t many embryos left, or the remaining embryos do not look promising, a mosaic embryo might be what an embryologist thinks is the best chance. Then there are “cutoff mosaic embryos.” These are borderline mosaic and shouldn’t have too much of a problem resulting in successful implantation.
It is often suggested to avoid the transfer of mosaic chromosomes X, Y, 13, 18, 21 and uniparental disomy (UPD) of 7, 14 and 15 as well as, IUGR chromosome 16 because these are often viewed to be risky in the “pure aneuploid (abnormal embryo) form.” However, there is currently no published relationship between embryo pre- implantation mosaicism and detection of mosaicism during prenatal diagnosis.
Image by Andrew Apperley
How can a mosaic embryo result in a successful pregnancy?
Good question! An embryo is constantly growing and that means it’s constantly changing! Those abnormal cells might separate themselves to a part of the tissue that doesn’t really affect the chromosomal development of the embryo and hence not cause any health conditions in the fetus.
What causes a mosaic embryo in the first place?
Mosaicism has been linked to culture conditions, technician effect, and company “threshold”. Age surprisingly does not seem to influence mosaicism. Many infertility issues are often linked to age but mosaicism is not one of them. Even egg donors often provide eggs and lead to mosaic embryos up to 30% of the time.
Are the patients notified of a mosaic embryo?
Yes! There is a step in IVF called the embryo biopsy. It’s when a little sample (a clump of cells) is extracted from the embryo and sent for pre-implantation genetic testing (PGT). This test identifies any genetic abnormalities in the cells of the embryo. If there are abnormal cells identified, then the patients are informed. PGT testing can also provide other information about the embryo that might also help the patients and providers come to a decision about which embryo to transfer.
Interestingly, sometimes PGT provides so much information that it makes it a little harder to decide if the embryo should be transferred or not! What I mean by that is sometimes the samples from one embryo might not agree with each other. There is a part of the embryo called the trophectoderm which is the outer layer. There is then the inner cell mass which is quite self-explanatory: the inner part of the embryo.
Agreement of mosaicism between the two samples is only seen 55% of the time. That means that nearly half of the time, one of those two cell regions demonstrated abnormality while the other doesn’t. Additionally, some PGT labs define mosaicism using a broad range of percentages of cells affected. This range is often 20-80% of cells. If there is ever any noise in the data, this broad range might actually be counterproductive and lead to false-negative and positive results. That simply put-is not good.
Is there a “cut-off” for deeming an embryo a mosaic embryo?
When DNA is sent to a PGT lab, the DNA must be amplified. This means a large number of copies of the sample of DNA are produced. This creates a library of data. When the DNA sequences are being read, there is going to be a minimum placed on reliability of the reading. If the quality of the samples are high, then then the lowest limit of reliability is 20% variance. If the quality of the sample isn’t as high, that limit might go up to 30% variance. With the limit being so low, the process is stricter. For example, if the limit is 20%, and a sample has only 22% variance, it is a mosaic embryo. With lower limits, more embryos are considered mosaic and this process is hence stricter. This limit changes from company to company.
Wrapping it up
To sum it all up, mosaic embryos do tend to have less potential to result in successful pregnancies. Does that mean there is a zero percent chance? No, of course not! We’ve explained earlier how mosaic embryos can result in successful pregnancies. IVF is filled with ups and downs and unexpected surprises! But all in all, if you are told one of your embryos is mosaic, consult with your physician on what you think is the best route to take from there. An IVF cycle requires making many tough decisions, but always remember you are not on your own! Your fertility clinic and physician are rooting for you and will help you make the best decision possible!
Quick Facts:
- A considerable number of embryos are being classified as clinically unusable- i.e. “Abnormal.” And have previously been recommended to be discarded. The thought is shifting in the field, that mosaic embryos should be classified as a third category and deprioritized for transfer after euploid embryos.
- Mosaicism is related to culture conditions, technician effect, and company “threshold” (Ovation reports abnormal above 50%, Igenomix reports Abnormal about 75%)
- PGT provides additional information about each embryo, so that patients and providers can determine the optimal transfer order to maximize the chance of a successful pregnancy and to reduce miscarriage rates.
- Depending on the distribution of cells a biopsy can contain all euploid, all aneuploid or a mixture of cells.
- Concordance between TE and ICM has only been demonstrated 55% of the time (in a small study 232 samples, obtained from 58 embryos). 31.3% of embryos with a mosaic aberration reported in the original TE biopsy revealed a euploid profile in the ICM and all three TE samples.
- Some PGT labs use a broad range (20-80% mosaic). Noise in the data mimics low- level mosaicism, therefore using a broad range results in false negatives and positives.
- Only the highest quality DNA samples are reliable down to 20%. Ovation and Igenomix use 30% as a lower limit.
- Mosaic embryos have a reduced but residual developmental potential- up to 40%
- One study found no difference in implantation rates between trisomic, monosomic, or segmental mosaics. *complex mosaics were found to have very little implantation potential.
- Mosaicism does not appear to be age related (even egg donors display 30% mosaicism).
- A recommendation exists to avoid transfer of mosaic chromosomes X, Y, 13, 18, 21 and UPD of 7, 14 and 15 and IUGR chromosome 16, are based on these being incompatible with life in the “pure aneuploid form.” However, there is currently no published link between embryo preimplantation mosaicism and detection of mosaicism during prenatal diagnosis.
- 40% of mosaic embryos result in pregnancy. 40% of mosaic embryos have euploid ICMs and fully abnormal non-mosaic embryos had no normal ICMs.
Munné S, Blazek J, Large M, Martinez-Ortiz PA, Nisson H, Liu E, Tarozzi N, Borini A, Becker A, Zhang J, Maxwell S, Grifo J, Babariya D, Wells D, Fragouli E.
Fertil Steril. 2017 Jul;108(1):62-71.e8. doi: 10.1016/j.fertnstert.2017.05.002. Epub 2017 Jun 1.
Fragouli E, Alfarawati S, Spath K, Babariya D, Tarozzi N, Borini A, Wells D.
Hum Genet. 2017 Jul;136(7):805-819. doi: 10.1007/s00439-017-1797-4. Epub 2017 Apr 9.
Healthy Babies after Intrauterine Transfer of Mosaic Aneuploid Blastocysts.
Greco E, Minasi MG, Fiorentino F.N Engl J Med. 2015 Nov 19;373(21):2089-90. doi: 10.1056/NEJMc1500421. No abstract available.