Getting Attached - Embryo Implantation

By Anja Stojsin Carter, PhD.

 

For a pregnancy to occur, an embryo travels to the uterus via the fallopian tubes and arrives around Day 5 or 6 post-fertilization. At this stage, the embryo is a blastocyst and is made of two layers; the inner layer (Inner Cell Mass) forms the fetus/baby and the outer layer (trophectoderm) forms the placenta. The embryo then hatches through the glycoprotein shell known as Zona Pellucida (ZP) and is ready to make a contact with endometrium (the first layer of the uterine lining).

In an IVF cycle, the embryo is placed into the uterus directly by the fertility physician using a specialized catheter. Once in the uterus, the embryo must still hatch from the ZP shell and begin implantation.

The stages of implantation are attachment, when proteins on the surface of the embryo and the endometrium link and anchor the embryo; invasion, where the embryo starts to “dig” into the lining; and decidualization, where blood flow and immune changes occur in the endometrium, ultimately assuring that the embryo does not get rejected as a foreign body (since it is genetically unique from the uterine cells).

By 10 to 12 days of development, the embryo is completely embedded into the endometrium and ready to start developing into the fetus and placenta.

The presence of the embryo in the endometrium induces production of the human chorionic gonadotropin (hCG) hormone. hCG gets released into the blood and urine and therefore can be detected by the pregnancy tests.  Growth of the embryo and secretion of hCG further signals the ovarian follicle that released the oocyte to begin the production of progesterone, a hormone crucial for further thickening of the endometrium and proper progression of the pregnancy.  

 

There are some things that we can do to help determine if an IVF embryo and the uterine lining are suitable and increase the chance of a successful implantation! With the current scientific knowledge, it is highly recommended that both embryo health and endometrial receptivity is checked in every patient going through the IVF.

The embryo needs to be a euploid, meaning that it has the proper genetic compliment (46 chromosomes). In a spontaneous pregnancy this cannot be tested, but in IVF, the embryo trophectoderm can be biopsied and the cells tested to make sure it is euploid (Pre-Implantation Genetic Testing; PGT). If an embryo is aneuploid, meaning it doesn’t have the proper number of chromosomes, then it is very unlikely to result in a pregnancy or could produce a miscarriage.

The endometrial receptivity assay (ERA) tests the endometrial lining in order to determine the moment when the embryo is most likely to implant. In most people, this is Day 5 of embryo development (5 days post-ovulation) but in approx. 30% of people, this window is shifted earlier or later. If this is known, the day of embryo transfer can be adjusted so it happens during the optimal time.

Last but not least, immunological status of the endometrium can be assessed. More specifically, the increased presence of the Natural Killer (NK) cells could be increasing the risk of the implantation failure. These cells are naturally present at the site of implantation, however, if in high numbers can lead to pregnancy rejection. It has been showed that something as simple as intravenous intralipid injections can be used to decrease the potency of these cells and increase implantation success.

 

In summary, PGT and ERA are becoming the standard of care prior to an embryo transfer. These tests give us information to select the best embryo and transfer it on the optimal day, providing a patient the best chance of becoming pregnant and minimizing risk of implantation failure.

Loud and Proud!

By Sonja Swanson

 

June is Pride Month! During Pride season, we celebrate 2SLGBTQI+ peoples and their history. Pride is a time of joy and celebration of who you are and who you love, but also a time of reflection for those to have been lost too early to violence and the continuing fight again prejudice and ignorance in our society. The rights and freedoms for 2SLGBTQI+ people have been fought fiercely for and rightly won; but there is still a long way to go before everyone is free and equal under the law.

 

Local Pride

KARMA will be attending Pride festivities in the region! We will be at Guelph Pride Family Picnic on June 2nd and also Oxford Country Pride on June 15th! Come stop by our booth, get some KARMA merch, and say hi! These are family-friendly events so we hope to see lots of KARMA babies there too!

For those seeking to build or expand their family, there are many options for 2SLGBTQI+ patients of all ages, genders, sexual orientations, family structure, marital status, socioeconomic background, religion, cultural origin, and physical ability are welcome to pursue their family building journey with us.

 

IUI vs IVF Basics

Intra-uterine insemination (IUI) is when processed sperm is inserted into the uterus and fertilization occurs in the body. This can be done with partner sperm or donor sperm.

IVF is when eggs (oocytes) are removed from the body, they may be own or donor eggs, and inseminated in the lab with partner or donor sperm sample. Embryos are grown and any good-quality embryo(s) are either transferred to the patient or a surrogate in hopes of achieving a pregnancy; or are cryopreserved (frozen) for future use.

If using third party reproduction, the patient(s) who will be parents to any child born are called the Intended Parent(s; or IPs).

 

The Ontario Fertility Program

In December 2015, the province started the Ontario Fertility Program (OFP) to partially cover the cost of IUI and IVF for patients in Ontario.

The services listed below that serve the 2SLGBTQI+ community will be included in the funding and cycles will be partially covered! The OFP made a specific mission to be inclusive and coverage applies regardless of sex, gender, sexual orientation, or family status, and not restricted to those with a specifically medical diagnosis of infertility.

The OFP doesn’t cover all services so some fees will apply depending on the type of cycle. Please inquire for specific pricing of services.

 

Sperm Donation

Donor sperm is a widely used option for patients who do not produce sperm or if there is an issue with the quality/quantity of sperm (e.g. azoospermia).

There are three Canadian distributors that donor sperm can be purchased from. Browse profiles that match your criteria (ethnicity, eye colour, height, etc.) and once you select your donor, the frozen vials will be sent to the clinic for use. Between all the distributors, there are thousands of options to select a sperm donor!

A known donor, friend or family member, can also be the sperm provider. Canadian regulation of donor sperm is one of the strictest in the world! A known donor will be processed at a lab in Toronto then frozen vials are sent to the clinic for use.

The cost of donor sperm (or known donor sperm processing) is not covered under the OFP.

 

Egg Donation

Egg donation is one of the fastest growing areas of in reproductive medicine! There are many options for patients who do not produce eggs or there if there is an issue with egg quality (e.g. premature ovarian failure). Egg donation cycles generally have a very high success rate but it does depend on many other factors.

Egg donor banks will cryopreserve (freeze) the oocytes. You can browse profiles of donors who have their eggs currently stored at the bank and select one that matches your desired criteria (e.g. ethnicity, eye colour, height, etc.), there are hundreds of donors to choose from! Then the bank will send the eggs to the clinic for use.

You can also work with an agency who will help match you with a donor and then coordinate a fresh IVF cycle. Depending on the agency, the donor may come to KARMA for the procedure or the patient will send a frozen sperm sample to the lab where the IVF is done then send back frozen embryos.

A friend or family member can also be an egg donor! They will undergo the cycle and then any eggs will be used for the Intended Parents. There are less restrictions on egg donation in Canada as compare to sperm donation but the physician will help determine if your known donor is a suitable candidate.

The cost of purchasing donor eggs or any costs incurred by the egg donor to be paid by the IPs is not covered by the OFP.

 

Surrogacy

A surrogate (or the more formal term: Gestational Carrier, GC) will carry the pregnancy for a patient who is unable to do so. This may be applicable for patients who do not have a uterus or if a patient has a uterine anomaly (e.g. post-chemotherapy). There is a high demand for surrogates, especially in Ontario!

The IVF cycle can proceed with a patient’s own eggs or using donor gametes and any embryos created would be transferred to the surrogate in the hopes of a achieving a pregnancy. Any children born would then be legally declared the child of the IPs

Surrogacy agencies can help match you with a surrogate and they would assist in coordinating the journey so both you and the surrogate have the best experience possible.  A lot of the management of the surrogate’s process is done through the agency and the clinic.

A friend or family member can also be a surrogate! There have been many news stories like a grandparent carrying their own grandchild! After meeting with the physician, the surrogate can be evaluated to determine if they are eligible to participate in the IVF process.

The expenses incurred by the surrogate during the cycle which is to be paid by the IPs is not covered in by OFP.

 

Fertility Preservation

Fertility Preservation (FP) is a process by which gametes (sperm or oocytes) are cryopreserved (frozen) for future use by the individual. This is an often-neglected area of reproductive medicine; the most common reason this is done is prior to chemotherapy but it can also be done prior to gender confirmation treatment! FP can also be done for social reasons; commonly oocyte or sperm freezing prior to 35 years old to preserve gamete quality if the person isn’t ready to begin a family.

If a patient is undergoing gender confirmation treatment (hormone or surgery), this gamete preservation is covered by the Ontario Fertility Program! Then the person may be able to have genetically related children in the future if that is an important factor for them.

 

Conclusion

The Pride season is to celebrate 2SLGBTQI+ peoples; who they are and who they love! At KARMA, we want to help any 2SLGBTQI+ patients who wish to add more love to their lives by building or expanding their family! Most importantly, Pride doesn’t have to end in June, every month is an opportunity to be more inclusive and increase representation and equality for everyone!

Just Keep Swimming - Understanding Your Semen Analysis Results

By Sonja Swanson

 

Sperm are the often-forgotten component of fertility; there is a focus on oocyte (egg) quality, maternal age, and follicle count, but eggs are only half of the puzzle. It is not only important to have sperm present, but they need to have the correct DNA structure and capacity to successfully transfer the genetic material into the egg. The sperm must also be able to attach and penetrate the outer shell of the egg (zona pelucida). That is a lot to do for such a little cell!

 

Biology of Sperm Production

Sperm production generally happens during the entire lifespan following puberty. Sperm begin as stem cells in the testes then go through many different stages of maturation: spermatogonial stem cell → primary spermatocyte → secondary spermatocyte → spermatid → spermatozoa (fully mature sperm cell). It takes between 75-90 days to go from a stem cell to a mature sperm cell. Once produced, they pass from the testes into the epididymis where they are stored until ejaculation. It is in the epididymis where they gain motility, sperm in the testes are generally immotile. Once ejaculation occurs, muscle contractions push the sperm through the rest of the reproductive tract where secretions from different glands (prostate, seminal vesicles, bulbourethral/Cowper’s gland) come together to form the semen.

Sperm production is regulated in a similar way to the menstrual cycle, using Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). However, the presence of Testosterone is a critical component for sperm maturation and circulates in the blood as well as locally in the testes.

 

Fertility Assessment

How to we assess the sperm and determine a treatment plan for someone seeking fertility care? At KARMA, we use a variety of tests to help us understand the qualities of the sperm; there is the “standard” semen analysis that looks at concentration (count), motility, and morphology (shape) as well as other physical properties of the semen but there are also new advanced tests that can give is even more insight!

All normal values are taken from the World Health Organization Semen Analysis Manual (2010).

 

Standard Semen Analysis

Volume – The expected volume of a semen sample is 1.5 mL or greater. If the sample is less, it may indicate that one of the accessory glands is not functioning properly. If a person is unable to produce any volume of semen, it is called aspermia.

pH – A measure of the acidity-alkalinity of the sample; semen is usually basic as the vaginal environment is more acidic. The expected value is around 8.0 and if it is much higher or lower, it may indicate that one of the accessory glands is not functioning properly.

Viscosity – Immediately after a sample is produced, the proteins in the semen will gel and become slightly solid. Over time (within 1 hour), the sample will liquefy and become more water-like. If the sample does not liquefy properly, the proteins keep it in a gel or viscous (thick) state. If a sample is very viscous, it may be more difficult for sperm to swim out.

Colour – A normal semen sample is white-grey and opaque. It may have a more yellow tint depending on diet or some medications. If a sample is brown, it indicates that there is blood and may indicate infection or damage to the reproductive tract.

Concentration – This measure is how many sperm are present in the sample (in millions per mL). The normal value is 15 million/mL or greater (normozoospermia). If a patient has less that that, it is called oligozoospermia. If it is very low (< 1M/mL) it is called cryptozoospermia. If there are no detectable sperm in the sample, it is called azoospermia. The concentration of sperm is a significant factor in determining a treatment plan. Patients with normozoospermia or mild oligospermia may try timed intercourse (TIC) or intrauterine insemination (IUI), patients with lower concentrations will be recommended to do IVF with intra-ctyoplasmic sperm injection (ICSI). A patient with no sperm may be referred to a urologist for further investigation and possible surgical sperm retrieval or advised to use donor sperm.

Motility – The number and type of motion of the sperm is very important. If the number of moving sperm is > 40%, this is considered normal. Sperm should also be progressive, meaning they swim quickly in approximately a straight line. Sperm that are sluggish or swimming in circles are not considered to be normal. Motility is also a significant factor for treatment as successful TIC or IUI requires a good overall motility and progression. Patients with samples below normal parameters may be referred to IVF with ICSI.

Viability – This test is performed when motility is very low (<15%). The sperm is mixed with a dye to determine if sperm are viable (alive). Sperm that does not allow the dye to penetrate are alive, sperm that are dead will have a leaky outer membrane and the dye will get in and they change colour.

Morphology – The shape of the sperm can help indicate the quality of the DNA and proteins inside. Sperm cells are judged using a “Strict” criterion and the normal value is >4% normal shaped cells. Defects in the cells are most commonly found in the head (e.g. large or small, misshapen) but abnormalities are also present in the midpiece/neck (e.g. bent, thin, thick) and the tail (e.g. short, coiled, multiple tails). Poor morphology has a decreased association with TIC and IUI, a patient may be referred directly to IVF with ICSI.

Culture & Sensitivity – If a sample has more than 1 million/mL of “round cells,” which usually consist of white blood cells from the immune system, then we send a portion to an external lab for bacterial culture. A sample may come back positive for a specific bacterial strain; these infections are quite common and are not considered sexually transmitted. A patient with a positive culture will be put on antibiotics then repeat the analysis to make sure the infection has cleared prior to beginning treatment.

Anti-Sperm Antibody Assay – Antibodies are produced by the immune system to help identify foreign objects, if there is injury or an error making sperm, they may be seen as foreign and are targeted for destruction. This would inhibit the cells from being able to move freely or can damage the proteins or DNA inside. A normal result is < 50% antibody attachment. A patient with a high result may be referred for IUI as the processing will help eliminate the antibodies or possibly IVF with ICSI depending on other sperm parameters.

 

Advanced Sperm Diagnostics

Survival Assay – This test selects the best sperm from a semen sample (the ones that would be used for IUI or IVF) and incubates them for 24h. This will show if the sperm are capable of surviving long enough to reach the egg if swimming in the fallopian tubes or if they will live long enough to fertilize an egg in culture.

DNA Fragmentation (SCSA) – The integrity of the DNA inside the sperm head is incredibly important, this is the genetic material that will combine with the egg DNA to create the embryo. The Sperm Chromatin Structure Assay (SCSA) is the gold standard for testing for breaks in the DNA chain. High DNA Fragmentation (>30%) is correlated with longer time to pregnancy and miscarriage rate in people doing Timed Intercourse or IUI and fertilization failure in IVF. A high DNA Frag can potentially do IUI or IVF, but a very high result (>50%) would likely be referred for IVF with ICSI.

 

Conclusion

One of the most common questions we receive is “what can I do to improve my sperm?” Sperm health is linked to overall health: eating well, moderate exercise, getting enough sleep, reducing or eliminating alcohol, cigarettes, and marijuana; avoiding injury to the testes (incl too much heat or pressure), and not using voluntary medications (like Testosterone for working out) that have a known impact on sperm are all ways to help make your little swimmers the best they can be. There are causes of sperm-factor infertility that cannot be helped with lifestyle changes like non-obstructive azoospermia, genetic conditions like Y-microdeletions, necessary medical treatments like chemotherapy, and many more.

Sperm quality is a critical component of fertility and a thorough assessment is needed to develop an effective treatment plan. If you have any concerns about your sperm quality, contact us to schedule a standard semen analysis or advanced semen diagnostics today!