Immunology & Infertility2022-12-08T17:00:01+00:00

Reproductive Immunology

Autoimmunity * NK Activated Cells * Infertility

Reproductive Immunology

Autoimmunity * NK Activated Cells * Infertility

More on Reproductive Immunology

Reproductive immunology is concerned with the way a woman’s immune system reacts if she becomes pregnant. Usually, your immune system works by fighting off any invading cells that it doesn’t recognize because they don’t share your genetic code. Some scientists have suggested that the same thing may happen to a fetus because it has a different genetic code from its mother’s. A woman’s body may ‘reject’ the fetus because her immune response is not being properly suppressed.

This theory has been widely discredited and there is no convincing evidence that immune rejection of the fetus ever happens in women with fertility problems. Instead, scientists now know that during pregnancy, the mother’s immune system works with the immune system of the fetus to help the placenta develop.

The information below is based on the latest research and expert views about reproductive immunology (to February 2015).

The term autoimmune disease refers to a varied group of more than 80 serious, chronic illnesses that involve almost every human organ system. In all of these diseases, the body’s immune system becomes misdirected, and attacks the very organs it was designed to protect. About 75% of autoimmune diseases occur in women, most frequently during the childbearing years.

“Affected women need two layers of treatment: a first layer to conceive, and a second to prevent pregnancy loss after conception.”

Autoimmune diseases can affect connective tissue, the tissue that binds together various tissues and organs. It can also affect the nerves, muscles, endocrine system, and gastrointestinal system. There are a large number of autoimmune diseases, with multiple sclerosis, Hashimoto’s thyroiditis, rheumatoid arthritis being some of the most common.

Because an abnormal immune function can affect fertility as well as miscarriage risk, affected women need two layers of treatment: a first layer to conceive, and a second to prevent pregnancy loss after conception. This is a very important point: it would not make sense to receive fertility treatment to get pregnant, only to experience an emotionally painful and potentially preventable pregnancy loss.

Hashimoto’s & Infertility

What do women with Hashimoto’s disease have in common?

They are often struggling with infertility and miscarriage. By addressing the potential immune dysfunction upon the T-cells, we aim to rebuild new uninfected T-cells with our Immune Balancing Protocol that have improved fertility outcomes from 42% to 65% without moving to IVF and getting 96% of recurrent miscarrying patients to carry to term. As a sideline, patients have related improvement in their Inflammatory Bowel Disease, Primary Biliary Cirrhosis, Chronic Urticaria, Migraines, and FMS. Hashimoto’s thyroiditis or chronic lymphocytic thyroiditis is thought to be an autoimmune disease in which the thyroid gland is attacked by a variety of cell- and antibody-mediated immune processes. It was the first disease to be recognized as an autoimmune disease but this presumes the immune system is the primary inciting event. It was first described by the Japanese specialist Hakaru Hashimoto in Germany in 1912.

This disorder affects women, 7x more than men and in women who develop hypothyroidism in pregnancy, 20% of these women will manifest Hashimoto’s disease years later. The hallmark of Hashimoto’s is lymphocytic infiltration and injury to cells with replacement by fibrosis. Although thyroid antibodies with elevated TSH are the most commonly used criteria these days, thyroid ultrasound is useful for the enlargement and fibrosis that comes on slowly. In the early days, thyroid biopsy was needed to confirm the high lymphocytic infiltration. For most patients, normal thyroid levels and size will persist for many years, and yet they consider this to be “hypothyroidism”. In essence, elevated TSH with normal free T3 and T4 is called subclinical hypothyroidism, but whatever doctors wish to call it, they still treat the TSH with thyroid replacement to normalize this number. Many people with Hashimoto’s disease develop an underactive thyroid. They may have mild or no symptoms at first. But symptoms tend to worsen over time. There may be no symptoms to symptoms of low thyroid levels such as Fatigue; Weight gain; Pale, puffy face; Feeling cold; Joint and muscle pain; Constipation; Dry, thinning hair; Heavy menstrual flow or irregular periods; Depression; A slowed heart rate; Problems getting pregnant or adverse pregnancy outcomes.

The literature has suggested causes of Hashimoto’s to be related to genes, gender, pregnancy, exposure to iodine or some drugs, radiation exposure and viruses such as HHV6. At IVF Phoenix™, I have been associating herpes viruses with adverse pregnancy outcomes since 2002. There are 9 viruses in the human family. HSV1 and 2 are well known to the public, but the most common herpes virus is varicella or chickenpox. (99.9%). The fourth virus is Epstein-Barr (EBV) or Mono and 95% of patients over 30 will have been exposed.

The fifth virus is Cytomegalovirus, (CMV) and 80% of the population will be exposed. I find it no fluke that we tend to see clusters of infertile and miscarrying patients to be in healthcare and teaching and airlines and feel strongly that this is associated with viral exposure earlier than most. The sixth virus is called Human herpes virus-6, (HHV6) and there are two variants. Type B is associated with high fever in childhood, roseola exanthem and Type A is considered adult associated and may be a chimera. While HHV-6 was strictly latent in positive samples from controls, a low-grade acute infection was detected in Hashimoto’s thyroiditis samples. HHV-6 variant characterization was carried out in 10 HT fine needle aspirate samples, determining that all specimens harbored HHV-6 Variant A. CMV and HHV6 are associated with vascular inflammation independently and synergize when active together.

I have been measuring antibodies to these viruses in my patients since 2002, over 2000 patients, and have never seen a patient have positive anti-thyroid antibodies without having positive HHV6 Abs. I suspected that HHV6 has a predilection for the thyroid tissues and injures the tissues and this has been confirmed in the literature. This creates damage, as well as tissue ischemia due to associated vasculitis.

This thyroid tissue damage initiates an immune response to scavenge the good parts of the damaged cells to be used in making new cells. These thyroid antibodies have been interpreted to be an initial inciting event, but I disagree. Components of several viruses such as hepatitis C virus, human parvovirus B19, coxsackievirus and herpes virus are detected in the thyroid of Hashimoto’s thyroiditis patients. Bystander activation of autoreactive T cells may be involved in triggering intrathyroidal inflammation. Signaling molecules associated with antiviral responses including Toll-like receptors may participate in Hashimoto’s thyroiditis induction. However, studies have provided insufficient direct evidence for the viral hypothesis in Hashimoto’s thyroiditis until a recent article, Caselli et al. (Oct 2012).* Preliminary studies have suggested a correlation between Hashimoto’s Thyroiditis and Celiac sprue. [14]

While it has not been rigorously explored, there is anecdotal evidence that a gluten-free diet may reduce the autoimmune response responsible for thyroid degeneration.[15] A study published in January 2012 compared a group of confirmed celiac patients to a control group of healthy individuals, starting a gluten-free diet and continuing for one year. [16] While there was a higher occurrence of thyroiditis found amongst the Celiac group, there was no reduction in their level of anti-TPO antibody, improvement in thyroid function, or change in thyroid volume reduction after one year without gluten. The study mentions that its results disagree with other studies, such as a prospective study published in August 2000 with 90 celiac patients, which found that thyroid-related serum antibodies tended to reduce during a gluten-free diet. [17]

The paradigm that we at IVF Phoenix™ have been working under, considers a virally induced, T-cell

mediated dysfunction. One good article that I have come across touches on many of the connections

that I have been suggesting, and provides a coherent scientific background of support.** The viruses are cousins of the human herpes virus family, specifically VZX, EBV,CMV and HHV6. As a later part of the dysfunction, women can manifest thyroid antibodies, and progression into Hashimoto’s thyroiditis. It is understandable that pregnancy is highly related with future HT, given the immunosuppressed nature of pregnancy and likelihood of herpes virus accumulation and progression during this susceptible time. At this stage, simple exposure to antivirals is not fully optimal given that these viruses have been shown to create chronic mild immunosuppression.

Physician Bio: Dr. John Couvaras is double Board Certified in OBGYN & in Reproductive Endocrinology &

Infertility. He founded IVF PHOENIX™ and has served as its Medical Director for more than 20 years. In 2012, he was recognized as being in the Top 10% for Reproductive Endocrinology by US NEWS. He was awarded & recognized by his peers as a TOP Doctor (Phoenix Magazine) multiple times. He is an active member of the American Society of Reproductive Medicine. He is past director of Reproductive Endocrinology and Assisted Reproductive Medicine and past chairman of the Department of Obstetrics and Gynecology at Paradise Valley Hospital. He is certified in CO2 and YAG laser surgery, operative laparoscopy and hysteroscopy, and microsurgical tubal and pelvic surgery. His expertise includes all aspects of female reproductive medicine and surgery.

*”Virologic and immunologic evidence supporting an association between HHV-6 and Hashimoto’s thyroiditis”. In Moore, Patrick S.

PLoS Pathogens 8 (10): e1002951. doi:10.1371/journal.ppat.1002951. PMC 3464215. PMID 23055929


Inflammation & Infertility

It’s well known that inflammation is at the root of so many common health problems – heart disease, arthritis, irritable bowel syndrome (IBS), migraines and diabetes – but infertility? Chronic inflammation can most certainly be the phantom cause behind previously unexplained infertility, says Dr. John Couvaras. “On their own, none of these conditions – migraines or IBS for example – are big enough to take notice,” says Dr. Couvaras. “It’s important to realize that the vast majority of infertility cases are not due to mechanical damage or poor sperm, but something underlying – we have to look at the bigger picture and make the connection.”

This broader view often requires a simple strategy. Dr. Couvaras systematically sets out to reduce sources of inflammation through his Immune Balancing Protocol. It’s important to investigate an immunity imbalance in so-called unexplained infertility cases before skipping straight to in-vitro fertilization, as is the typical strategy of most other reproductive endocrinologists. “The ovary looks dead, but it may only be deaf. The trick is learning to talk differently to it – it doesn’t always necessitate a high-tech solution.”

One of Dr. Couvaras’ patients endured a five-year cycle of unsuccessful IVF treatments quite young at 25 before landing in his office frustrated and no further along. “I had been trying to conceive for years, and had been told I was polycystic ovary syndrome. After trying many rounds of medications to stimulate my ovaries, I attempted IVF at age 25. I did not get pregnant. After five years of trying at 30 years old, I met Dr. Couvaras and did his Immune Balancing Protocol. He discovered some sources of chronic inflammation that he explained may have been restricting the transmission of hormones to my ovaries, which also prevented eggs from growing. We corrected all these things, and with his magic, we delivered our gorgeous daughter. Without Dr. Couvaras’ unique perspective and approach, we would not be parents today. “

Dr. Couvaras is also frequently speaks specifically about unexplained infertility and the treatments he recommends precede IVF, including:

  • the damage chronic inflammation can do to fertility
  • the immune-balancing approach
  • the success rates associated with his holistic, big-picture approach

Dr. Couvaras is board certified in reproductive endocrinology, obstetrics and gynecology and an active member of the American Society of Reproductive Medicine. He is the director of Reproductive Endocrinology and Assisted Reproductive Medicine and past chairman of the Department of Obstetrics and Gynecology at Paradise Valley Hospital. Dr. Couvaras offers a full-service infertility practice, from basics to IVF, embryo biopsy, and cryopreservation. He also provides consultations on non-infertility related concerns, such as recurrent miscarriage, poly-cystic ovary syndrome, ovarian decline and abnormal reserve, hormonal imbalance-related mood dysfunction, weight gain and sleep disturbances, and post-partum depression.

More on NK Activated Cells

Suffering a miscarriage can be a very distressing experience but for many women, their next pregnancy is a normal one. For women, however, who suffer a recurrent miscarriage, where they have three or more in a row, it can be utterly devastating.

More frustrating still is that in many cases – more than half – doctors are unable to find an underlying cause or offer more than just a handful of options for treatment.

Now researchers from Warwick University claim to have made a breakthrough. Not only by making a firmer case for the role of natural killer (NK) immune cells in some cases of recurrent miscarriage, but also in bridging the gap between scientists and the medical profession in what has become a controversial area of research.

Despite their name, NK cells actually play a beneficial role in the development of an embryo. But abnormally high levels of NK cells are found in the uterus of some women (around a sixth) who recurrently miscarry. NK cells are a key player in the innate immune system, which can be triggered to defend the body from infection. One theory is that in some cases they may stop an embryo implanting in the womb.

However, little is known about this mechanism. And the potential role that NK cells might play in recurrent miscarriage has caused significant controversy.

The authors of the new study, published in The Journal of Clinical Endocrinology & Metabolism, make a link between more NK cells in the lining of the womb and a deficient production of natural steroids. Having this deficiency, in turn, leads to a reduction in the formation of fats and vitamins that provide essential nutrition during pregnancy. They suggest that NK cells can be used as an indicator of steroid deficiency.

Steroids, which are thought to work by reducing the percentage of NK cells in the womb, are commonly used as a treatment for recurrent miscarriage and do appear to help some women to go on to have a normal pregnancy. But many experts agree this is based more on empirical evidence that a firm scientific understanding.

Siobhan Quenby, Professor of Obstetrics at Warwick Medical School and one of the authors of the study, said treatments for recurrent miscarriage often came “out of guesswork, not science” and said the research provided an “excellent scientific justification for steroid-based treatment to prevent miscarriage.”

“If you have NK cells in the blood they do things like fight infection. In the uterus they also have a good function – for example, they help in the development of the blood supply to the fetus.

“But we now have some light at the end of the tunnel; in some ways everyone is right. NK cells are good but high-end NK cells are also associated with local steroid deficiency.” Quenby said that the research suggests the deficiency causes an increase in the higher percentage of NK cells, rather than the other way round.

Nick Macklon, Professor of Obstetrics and Gynaecology at Southampton University and an expert in IVF, said: “The problem is that we haven’t really understood the mechanisms behind recurrent miscarriage. We now know that an important determinant is the lining of the womb and how it helps embryos to implant. A lot of treatment has been empirical, adopting theoretical treatments, not on the science.

“Quenby has done a lot of work to try and understand the role of NK cells, which hasn’t been very clear. The key thing is that the researchers aren’t saying they are bad but when there’s an increase it might be a useful marker. It could allow for treatment to be rationalized. Steroids have side effects and have been used very blindly. But they do seem to make a difference and also to the needs of doctors and patients looking for help.”

Macklon said recurrent miscarriage was probably caused by a number of different factors across different cases. “One possible cause is the ability of the lining of the womb to recognize and select good embryos and in some women, it isn’t able to do this early enough.”

A previous small randomized trial carried out by Quenby showed a marked difference in the chances of going on to have a baby in a group of 20 women treated with steroids versus an identically sized group given placebos. But she admits that to draw solid conclusions, a trial size of around 700 women is needed.

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Hysteroscopy for Fertility and Reproductive problems2022-11-30T19:13:24+00:00

Hysteroscopy is the inspection of the uterine cavity that allows for the diagnosis and treatment of various uterine conditions. Some of which, could lead to fertility problems.

Uterine Septum (Septate uterus)

This is the most common uterine malformation and a common cause of miscarriage. It is unclear whether a uterine septum increases the chances for infertility or not. A wedge of tissue is present inside the uterine cavity, which divides it into two halves (also called uterine horns).

When seen through a hysteroscope, the uterine horns are seen as two dark openings separated by a wedge of tissue. By introducing an electrode through the hysteroscope, the septum can be shaved or vaporized all the way to the top of the cavity. The finished product is a uterine cavity that is unified into one large space instead of divided in two.


These are uterine growths a few millimeters to centimeters in size. Polyps arise from the uterine lining (endometrium). A polyp may be attached to the uterine wall directly or by a thin “stalk”.

Patients often have no symptoms from polyps but will occasionally notice irregular vaginal bleeding. This bleeding may occur in between periods or cause the period to be longer in duration or heavier than normal.

Polyps are also associated with an increased risk for miscarriage. Large polyps, which occupy the majority of the uterine cavity, are also probably responsible for infertility. Small polyps can be most easily vaporized in place. Polyps which are attached by a stalk can sometimes be removed by cutting through the stalk and removing the entire polyp through the cervix. Larger polyps may have to be removed by shaving small strips one at a time until the polyp is completely gone, or slightly deeper, taking a margin of the myometrium.  This tissue is sent out for pathology.


These benign tumors arise from the muscle layers of the uterus. Often they will stay in the muscle layer but on occasion, fibroids can grow into the uterine cavity. Like polyps, fibroids can cause bleeding, infertility, and as well as miscarriage. Removal of fibroids from the uterine cavity is performed using the same methods as for polyps.

Scar tissue

Scar tissue inside the uterine cavity, also called adhesions, can arise from infection or trauma to the uterine lining. Although rare, the most common cause for uterine adhesions to form is from a previous D&C procedure. Scar tissue inside the uterus can be small and isolated to a certain spot. This type of adhesion looks like a band running from one wall of the uterus to another. Sometimes adhesions take the form of two walls that are stuck together causing the cavity at that spot to be completely obliterated. In rare instances, the entire cavity can be obliterated. Uterine adhesions can cause infertility or miscarriage. If the uterine cavity is partially or completely obliterated, a woman may notice that her period are lighter or even stop altogether. Band adhesions can be easily cut restoring the normal anatomy of the uterine cavity. When the walls are stuck together, the surgeon must carefully dissect between them in order to separate the walls. This can be a very difficult process if there is little normal uterine cavity that remains to serve as a guide.

What do you need to do after a sonohysterogram?2022-11-30T19:12:35+00:00

You will be able to watch the sonohysterogram on a monitor while it is being performed. Afterwards, the doctor will review the findings with you and answer any questions about those findings. If there are any abnormalities that are found on the inside of your uterus, don’t worry! Nearly all of these conditions are easily corrected with minimally invasive, outpatient surgery (usually with hysteroscopy).

What do you need to do before a hysterosonogram?2022-11-30T19:11:52+00:00

Occasionally, a woman might experience some cramping during or after a hysterosonogram. If she desires, she may take 1-2 tablets of ibuprofen (Motrin or Advil) 1-2 hours before the procedure to decrease cramping. This may be repeated 3-4 hours later in the unlikely event that cramping persists.

How is a sonohysterogram performed?2022-11-30T19:14:53+00:00

The procedure for performing a sonohysterogram is very simple and usually takes about 5 minutes. In order to schedule a sonohysterogram, you will need to call with the first day of your period. You will be given an appointment for some time point after the bleeding from the period has ended but before it is thought that ovulation might occur. This ensures that the uterine lining is as thin as possible. This is important since it will assist the doctor in the visualization of the cavity. The hysterosonogram is performed in the office. Using a speculum, a very thin, soft, flexible plastic catheter will be inserted through the vagina and cervix into the lower part of the uterine cavity and a balloon is inflated.  The speculum is then carefully removed so as not to disturb the catheter. A vaginal ultrasound probe is then placed into the vagina. Through the catheter, a small amount of saline (sterile salt water) is injected into the uterine cavity to separate the walls.

During a sonohysterogram, the ultrasound probe can be rotated to show the long axis of the uterus or a transverse axis. In the long axis, the uterine cavity appears long and ovoid. Sometimes after the procedure, a small amount of the saline fluid may leak out of the vagina. It is also possible that the patient may experience some bleeding or spotting. It is recommended that the patient wear a light pad or tampon for the rest of the day.

What kind of problem can a hysterosonogram diagnose?2022-11-30T19:16:24+00:00

A hysterosonogram is often recommended for women who are having difficulty conceiving a pregnancy or for women who are having recurrent miscarriages. In some cases, a hysterosonogram may be used for a woman who is having abnormal vaginal bleeding. Since a sonohysterogram gives such a detailed view of the inside walls of the uterus, it can identify many abnormalities that might prevent a normal pregnancy from developing. Studies have shown that it can detect over 90% of abnormalities inside the uterus. Some of these abnormalities include:

  • Polyps
  • Fibroids
  • Scar tissue
  • Uterine septum
  • Bicornuate Uterus
What is a Sonohysterogram?2022-11-30T19:15:21+00:00

sonohysterogram or SHG is a saline ultrasound, saline sonogram, or saline infusion sonogram. A sonohysterogram is a minimally invasive ultrasound procedure that can determine if there are abnormalities inside the uterus that might interfere with pregnancy. It is important to have an evaluation of the uterine cavity with a sonohysterogram or other method before proceeding with an IVF cycle. This test involves no radiation, and there are very few risks from the procedure. Compared to a regular ultrasound, a sonohysterogram is better at detecting abnormalities on the inside walls of the uterus because it involves infusing sterile fluid inside the uterus. This way, the walls of uterus separate from each other and any abnormalities that might have been hiding right along the sides of the walls will be easily identified.

Here is an example to help understand why we do a sonohysterogram. Think of your uterus like a collapsed balloon. If there was a small growth or bump on the inside wall of the collapsed balloon, it might be hard to see since the top and bottom walls are touching each other. However, if we inflated the balloon, the small growth will be easier to see since it will likely be able to hang away from the wall.

Traditionally, the “best” way to look for abnormalities inside the uterus was a test called a hysteroscopy, which involves an out-patient surgery using a type of endoscope to look inside the uterus. However, in recent years, the techniques for a sonohysterogram have become so advanced that it has usually replaced hysteroscopy as the first procedure to look for abnormalities in the uterus. Compared to a hysteroscopy, a sonohysterogram is less invasive, less expensive and nearly as effective at detecting abnormalities.

What is an AMH test and what does it mean?2022-11-30T19:07:32+00:00

AMH or anti-mullerian hormone is a hormone produced by the viable follicles (which contain eggs) that remain in the ovary. It is an excellent indicator of ovarian reserve. Young women with large numbers of healthy eggs tend to have high AMH levels whereas older women or women with a low number of healthy eggs will have lower levels of AMH.  New information is suggesting that very high levels of AMH may not simply indicate a plethora of antral follicles, but may indicate a follicular dysfunction.

AMH levels do not fluctuate very much throughout the cycle and are not impacted by the levels of other hormones such as estrogen or progesterone.

Abnormal AMH levels are usually determined by comparing a woman’s own AMH level with that of a large group of women her own age who do not have infertility. For example, an AMH of 1.4 would be considered very low for a fertile 18-year-old but would be considered average for a 36-year-old.

Fertility decreases with age. This decrease is most likely due to aging of the eggs and the chromosomes inside them. The risk of miscarriage and chromosomal abnormalities in babies also increase with age. The most successful method for achieving a pregnancy and taking home a baby at advanced female age is with the use of egg donation.


From the moment we met Dr. Couvaras, My husband and I felt totally comfortable, secure, and well informed. Additionally, the nurses and staff at IVF Phoenix provided prompt, efficient care with both expertise and patience. Whether ordering prescriptions, educating me on how to properly administer medications or explaining options and probable outcomes of specific treatment protocols, Dr. Couvaras, and his team were simply remarkable. I never felt alone, and appreciated the close guidance they provided throughout our entire treatment. I couldn’t be happier with the results! My husband and I are now 12 weeks pregnant, and are absolutely thrilled! I would recommend Ivf Phoenix to anyone who is interested in finding the cause of their infertility. We love and appreciate everyone at Ivf Phoenix, they are a 2nd family to us. We still can’t thank them enough for making our dreams come true!

Jaden, From Facebook Page

Dr. Courvaras is the best there is in the infertility world!! Our first baby is here because of him and his team. Our baby is 17 and will be graduating from high school in less than a month!! We have never forgotten him and the gift he helped us have!!

Zena, From Facebook

This is hands down the BEST fertility clinic in all of Az. Dr. Couvaras and Rhoda are amazing!! Not only are they compassionate and helpful beyond expectations they really look at the whole body and systems and get to the root of the problem. If you are even thinking about fertility go see this place first!

Hope L. , From Yelp

The staff and Dr. Couvaras were so kind and understanding. They called me by name as soon as I walked in. Dr. Couvaras was incredibly knowledgeable and knew from the first visit what was going on and after tests came back he was 100% right. He was informative, personable and took care of my health needs as a priority. I never felt left on the back burner. Innovative for sure because now I have 3 amazing children!

Source Fertility IQ

My husband and I are so thankful for Dr. Couvaras and staff. We were struggling to have a family and stumbled across the IVF Phoenix website. We are from Canada and the staff was fantastic to deal with and very accommodating to work with. We always had support no matter what time of the day. We now have the most perfect beautiful little boy to complete our family!!! So grateful and blessed!!!

Jolene, From Facebook Page

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