autoimmune Archives - Fertility Fact Checker

5 easily overlooked things to check before your IVF cycle

Your anti-müllerian hormone (AMH) is checked, you can tell to the hour when you are ovulating and you are pretty sure you’re the only one of your friends who uses acronyms such BFP, DPO and CD* in their every day life. You are just about ready to go for your next IVF cycle.

But here are 5 tests that may significantly impact on your fertility and IVF success.

As always though, don’t just start supplementing and self treating these things without medical advice as if your levels are already spot and you start self-prescribing, supplementation could do more harm than good. But they are definitely worth chatting to your fertility specialist about if you are concerned or have had recurrent failures.

Vitamin D

Like everything in fertility the research is mixed, but low levels of Vitamin D has been associated with endometriosis, the development of insulin resistance in women with PCOS and uterine fibroids¹. When the vitamin D in follicular fluid (the fluid surrounding each of your eggs) was measured in a group of women doing IVF, it was found that when women were deficient in vitamin D, for every one unit increase in vitamin D there was a 6% increase in the chances of an ongoing pregnancy rate². I’d take that.

Speak to your fertility specialist to see what your levels are (when you are pregnant they will test you for it anyway) and in the meantime focus on absorbing vitamin D from the sun – in a completely sunsmart way of course.

Thyroid function

That pesky thyroid has a big role to play and if it isn’t working properly can impact pretty much everything you can think of to do with reproducing life. This includes impaired ovulation, fertilization, implantation, miscarriage, and late pregnancy complications³. The acceptable levels of thyroid hormones can vary and there is some debate whether or not things like thyroid autoimmunity even matters enough to need to be tested³; though a recent meta-analysis suggests that although it does not impact number of eggs retrieved, fertilisation, implantation or clinical pregnancy rate thyroid autoimmunity may be implicated in miscarriage rates (this is still overwhelmingly unlikely to happen though and certainly not something to add to your worries – I have high thyroid antibodies and still got a take home baby. Two, infact.)⁴. What it does highlight though is that completing thyroid testing is a worthwhile activity, especially because depending on your medical history thyroid problems can often be treated.

Immunology issues

The role of autoimmunity in fertility is becoming more accepted and many doctors may test for immunology issues as standard when you start treatment. Some autoimmune tests include anti-nuclear antibodies, anti-DNA/ histone antibodies, antiphospholipid antibodies, antisperm antibodies, natural killer assay and cardiolipin antibodies. That is a lot of antibodies and only the tip of the iceberg.

Not all these markers are always a direct reason for infertility and some women can have them and oops! just happen to fall pregnant accidentally. They all are implicated in infertility though and it is certainly worth another blood test or two to ensure that they aren’t a hiding passenger on your fertility journey. Again, if something is found, depending on your circumstances, your fertility specialist may have a suitable treatment.

Melatonin

Melatonin is a powerful antioxidant and may benefit fertility by helping to keep oxidative stress in ovaries and eggs to a minimum which in turn improves egg quality. Several studies have been conducted investigating melatonin as a supplement for women undergoing IVF and found that when the optimal level of melatonin was reached that it was associated with a higher number and quality of mature eggs at harvest⁵. It has also been found to support the production of progesterone in women with luteal phase defect (though don’t even think about stopping those progesterone suppositories if you doctor has prescribed them; although a significant difference was found the impact on actual progesterone levels was still relatively small)⁵.

As always, do not go self-medicating, as although melatonin has not been found to be poisonous, supplementation is not always recommended in women undergoing IVF for a number of reasons. Supplements can sometimes interact with the prescribed medications taken and in women with autoimmune conditions melatonin supplements can have immune-stimulatory capabilities. Speak to your doctor before starting any supplements and in the meantime try to balance your melatonin levels by ensuring you get adequate sleep and natural daylight.

Sperm fragmentation

This isn’t a blood test but rather a sperm test for the men. Ideally it should be done as part of your initial work up at your clinic but it can easily get overlooked – particularly if you and your partner already have an obvious reason for your difficulty with fertility. In fact one study suggests that for couples with unexplained infertility, 80% of these couples later had their reason ‘explained’ as being due to sperm defragmentation when the appropriate tests were done⁶. That does seem a little amazing…

After a sperm sample is provided, in a sperm fragmentation test, the sperm is looked at to see if the DNA is healthy and intact. If DNA fragmentation is high this means that a high percentage of sperm is damaged. The treatment options are limited, though Menevit supplements may be of assistance (your doctor may have recommended this anyway), and it may mean that ICSI will have a greater chance of success for you than standard IVF.

Please note that this list is not exhaustive. They are just a few points designed to open up the conversation with your fertility specialist. Iron, zinc and magnesium levels are just a few others you might want to discuss.

*If you’re not quite there with the acronym thing BFP means big fat positive, DPO is days post ovulation and CD is cycle day.

Vanni, V., Vigano, P., Somigliana, E. , Papaleo, E., Paffoni, A., Pagliardini, L. & Candiani, M. 2014 Vitamin D and assisted reproduction technologies: current concepts. Reproductive Biological Endocrinology. 2014; 12: 47. Published online 2014 May 31. doi: 1186/1477-7827-12-47
Ozkan, S., Jindal, S., Greenseid, K., Shu, J., Zeitlian, G., Hickmon, C. & Pal, L. (2010) Replete vitamin D stores predict reproductive success following in vitro fertilization. Fertility and Sterility. Vol 94 (4) 1314–1319.
Unuane, D., Velkeniers, B., Deridder, S., Branvenboer, B., Tournaye, H. and De Brucker, M. (2016) Impact of thyroid autoimmunity on cumulative delivery rates in in vitro fertilization/intracytoplasmic sperm injection patients. Fertility and Sterility. 106 (1) 144 – 150.
Busnelli, A., Paffoni, A., Fedele, L. &, Somigliana, E.(2016). The impact of thyroid autoimmunity on IVF/ICSI outcome: a systematic review and meta-analysis. Human Reproduction Update. 22(6) 775-790.
Fernando, S. & Rombauts, L. (2014) Melatonin: shedding light on infertility? – a review of the recent literature. Journal of Ovarian Research 7 98
Lewis, S. (2013) The place of sperm DNA fragmentation testing in current day fertility management. Middle East Fertility Society Journal. 18 (2) 78 -82

Is a Gluten Free Diet for Fertility Tin Hat Thinking?

Tin hat thinking is when you do something which you can see might be worth a try even though the hard scientific backing isn’t necessarily there. Things that can’t hurt to try and there seems to be loads of qualitative evidence on the internet though the quantitative evidence seems a bit lacking. You know the general sort of things – eating organic, not wearing perfume or cosmetics and perhaps eliminating dairy. They might be things that your naturopath prescribes, but what your fertility specialist doctor might say makes no difference. I realize this sounds quite dismissive to naturopaths and it is really not meant to. The more and more I research into fertility treatments the more and more I can see that sometimes some of the answers are in the way we live our lives rather than being solely dependent on how many units of Gonal F we are injecting into our stomach.

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For me, eating a gluten free diet was one of those tin hat thinking moments. After several failed cycles I felt the need to attempt to take some control back and try something different. So amongst a couple of other things I tried eating gluten free diet starting from cycle day one. I did happen to get a BFP on the cycle I went gluten free, though I was also on some additional medication which also would have made an impact. Saying that though, I also know of others who have also experienced a BFP when eating gluten free (and there is that qualitative evidence again). But was it just coincidence and would it have been ‘our time’ regardless? Who knows. For a significant number of people though, particularly those with unexplained infertility, eating a gluten free diet may be much more than tin hat thinking and might just well be the real underlying cause of their infertility.

Celiac Disease

Celiac disease occurs in up to 1% of the population, but only 20- 50% of those may experience symptoms. As you are probably aware, traditionally people who have celiac disease are required to eat a gluten free diet. This is because celiac disease is an autoimmune condition which is triggered by gluten which is the protein fraction of wheat, barley and rye. There is a bit of a complex biochemistry reaction but essentially the gluten causes a number of chain reactions which results in an inflammatory response in the body and the production of some specific antibodies. It is perhaps the presence of these antibodies that may contribute to difficulty conceiving, recurrent miscarriages and once you are finally pregnant with one that sticks, intrauterine growth restriction, which can result in your baby being born with a significantly lower birth weight and other difficulties.

The evidence for associating gluten with infertility

There has been a bit of research around celiac disease and just last year a meta-analyisis was completed investigating the association between celiac disease and issues of the reproductive system in women (Tersigni, 2014). The meta-analysis included 24 studies that had been completed on this area and here are what I consider the five essential things to know:

1. Women with unexplained infertility or recurrent miscarriage have a 5 or 6 fold, respectively, increased risk of being affected from celiac disease compared with the general population.

2. Classic celiac symptoms are often absent, or at most the symptom may be the very general fatigue associated with iron deficiency anaemia. This means that it can be a significant length of time before diagnosis, and hence treatment is initiated.

3. Before and after studies have been done on women with celiac disease and the number of children they were able to have before and after diagnosis. Before diagnosis women with celiac disease were found to have less numbers of children than women without celiac disease. After diagnosis and treatment this number returned to similar numbers. This indicates that treatment of celiac disease and eating a gluten free diet is beneficial to aiding fertility in women with celiac disease and seemingly reverses the destructive mechanisms.

4. There are two suggested mechanisms by which celiac disease limits fertility: firstly causing malabsorption and nutrient deficiency and secondly, the accompanying automimmune reactions.

It is believed by preventing the absorption of nutrients an imbalance in the reproductive hormones such as luteinising hormone and follicle stimulating hormone is experienced. This in turn prevents normal ovarian functioning and hence causes infertility. Deficiency of nutrients such as folic acid also ultimately leads destruction of the rapidly growing embryo as it needs this acid to develop neurons and develop normally.

The second mechanism being autoimmune factors effects fertility in two ways. One possible way is that the antibodies produced by women with celiac disease destroy the outer layer of the blastocyst. This prevents the embryo from implantation and forming the placenta as it is this outer layer of the blastocyst that gives rise to the developing placenta. Another possible way is that the antibodies prevent the endometrium from growing new blood vessels, again preventing implantation resulting in a BFN once again.

5. Women with celiac disease also show an increased risk of miscarriage, intra-uterine growth restriction, low birth weight and preterm delivery. This indicates that the implications for having celiac disease go far beyond difficulties at conception and that a long term gluten free is essential in women with celiac disease who achieve preganancy.

Take action!

Especially if you have ‘unexplained’ infertility or recurrent miscarriage, at your next appointment ask your doctor if you have been screened for a sensitivity to gluten. The symptoms are not always the typical responses and can easily be missed. One of the first screens to do is to test for endomysial and anti-TG antibodies (Tersigni, 2014)

Check out the possibility of eating a gluten free diet. Although on the one hand it has never been easier to knowingly eat gluten free – there is pretty much a gluten free substitute for EVERYTHING these days, on the other hand it is nearly impossible to cut out all the hidden gluten – it sometimes seems gluten is everywhere… there is wheat syrup and hence gluten in that Cadbury’s chocolate bar you have just eaten!

If you are just starting out to eat gluten free the big things to avoid are foods containing wheat. That includes pretty much all cereals, baked goods, bread, cakes, pastry, noodles and pasta. Vegetables, fruit and meat are fine as is rice and some other non-wheat grains. Like I said though, the ‘hidden’ gluten is in a lot of things including salad dressings, soups and beer. If you are serious about going gluten free it is therefore essential to check the back of the pack before eating.

As for me, although I did decide to stop eating gluten I have not yet been tested for the specific antibodies that often present with a gluten sensitivity. I will request these at my next appointment but in the mean time I found it ‘worthwhile’ eating gluten free if for no other reason than knowing that I had given things my ‘best shot’. Anyway, as previously discussed, for a significant number of women with infertility the idea of eating a gluten free diet is perhaps based in science and not so ‘tin hat’ as what I first thought.

Reference

Tersigni, C., Castellani, R., deWaure, C., Fattorossi, A., De Spirito, M., Gasbarrini, A., Scambia, G. & Di Simone, N. (2014) Celiac disease and reproductive disorders: meta-analysis of epidemiologic associations and potential pathogenic mechanisms. Human Reproduction Update. 20 (4) 582–593

Antinuclear Antibodies and Infertility

Antinuclear antibodies (ANA’s) is a grey area in infertility. Some doctors will tell you testing positive for ANA’s it doesn’t make any difference to your fertility, some believe it may be the reason why you still don’t have that take home baby and others may try you on some medication, just…because.

Testing for ANA’s comes under the umbrella of testing for ‘immune problems’ and seems to be a growing area of interest. And whilst for some a diagnosis of ‘unexplained’ is exactly that, for others ‘unexplained’ may sometimes become explained when immunological issues are investigated.

Without sounding too hippie, there seems to be many more allergy suffers today then there was of days gone by. An allergy is ‘a damaging immune response by the body to a substance, especially a particular food, pollen, fur, or dust, to which it has become hypersensitive.’ Especially with today’s chemicals, sprays, laundry detergents! and extreme levels of cleanliness in general it is difficult to know exactly what allergens people may be allergic to and what impact it is having on the body. Having these allergies can trigger immune responses in the body which can also be associated with infertility.

The doctors willing to consider immune issues in infertility seems to be growing. There is also a growing amount of research and literature further investigating immunology problems and its negative impact on fertility. Regardless of this though, it still seems as if it is not necessarily routine to have all your immunology tests completed at the outset. If you take nothing else out of this blog post, take away this:

make sure you discuss immunology problems as a possible source of infertility with your doctor and that they have requested the relevant blood tests.

Sometimes in fertility, the problem you initially thought that was the cause of your infertility spirals and spirals until you don’t know what is going on. For the sake of a blood test, it is well worth ruling this one out.

There are lots of different markers and factors to consider in immunology. There are antisperm antibodies, antiphospholipid antibodies, natural killer cells and leukocyte antibodies and a whole heap more that I haven’t even heard of. Each of these should be tested and evaluated by your doctor. Then there is my favourite: antinuclear antibodies.

A…N… what??

For some women, including myself, having high levels of antinuclear antibodies (ANA’s) can be the, or one of the, reasons behind difficulty conceiving. Although many people can have higher ANA’s then normal and be completely healthy it can also be an indicator of an autoimmune response where your body is producing a type of antibody that starts attacking the nuclei in the cells of your normal tissue. As my specialist described it, its like your immune system is constantly switched on and is possibly considering an embryo as a foreign body that needs to be eliminated. But there are different levels of ‘high’ ANA’s, or ANA positives.

You may get a ANA positive result of 1:160 and because ANA results are reported in titres, what this means is that when 1 part of your blood was mixed with 160 parts of a diluting substance laboratory staff are still able to detect the ANA’s. Different labs have different ways of reporting when is considered ‘positive’ and when they stop diluting. For me, I had ANA of 1:2560 which means that when 1 part of my blood is mixed with 2560 parts of another substance they can still detect the antinuclear antibody, which as far as I am aware is as high as the scale goes. Mixing your blood with so much of the other substance you would expect to not see any of the ANA’s at this point. This is going to sound contradictory to what I have said, but being ANA positive in itself is not a diagnosis or an indicator that anything is necessarily wrong. In a review done in 2009 (1) it was found that having low titre antibodies (for example around 1:160) does not impact IVF success rates. Depending on your clinical symptoms, what being ANA positive can be though is an indicator to do further immunological testing for things such as lupus or connective tissue conditions, like rheumatoid arthritis. Positive ANA’s can also be present in a healthy population as well so just because you receive a positive result does not necessarily mean anything is wrong per se.

When getting your results back regarding ANA’s there may also be information on what pattern is present, such as homogenous or speckled. Different patterns can be associated with different autoimmune conditions and your own situation needs further discussion with your specialist or GP.

ANA +ve + TTC = ?

Despite it seemingly being a bit of a ‘Wild West’ topic to some fertility specialists and the fact that it does not necessarily always mean something is wrong, there does seem to be a link between being ANA positive and experiencing infertility issues.

One study investigating the presence of immunological markers in IVF patients noted that in the general population 5% of people have elevated ANA’s where as in their infertile cohort, 30% of patients undergoing IVF were ANA positive (2).

That is there are a lot more ANA positive people in those that are known to be reproductively challenged then those in the general population. Another study looked at 560 Iranian women who had experienced 3 or more miscarriages. They found that 13% of women who had experienced recurrent miscarriage were ANA positive and only .9% of their control group, that is the healthy population who did not experience recurrent miscarriage, were ANA positive (3). It should be noted that about half of these ANA positive women also had antibodies associated with Lupus – so when you get your test results back, make sure you aren’t jumping to conclusions or worrying without getting more of the picture.

From the above studies it appears that there does seem to be some association with being ANA positive and having difficulty either conceiving or continuing a pregnancy (at least in the early stages of pregnancy).

The different areas of fertility ANA’s can impact

Premature Ovarian Failure

ANA’s can possibly have an impact fertility at various stages – whether that be by affecting implantation rates to having an impact on oocyte, or egg, quality. Carp and colleagues (4) speculate that autoimmune conditions can be responsible for premature ovarian failure to implantation failure and pregnancy loss. And the boys aren’t ‘immune’ either by the way, with Carp also mentioning that autoimmune conditions could be responsible for testicular failure as well. Carp mentions that 10 – 30% of women with premature ovarian failure (when the ovaries fail before the age of 40) have some type of concurrent autoimmune condition. There are many other reasons for premature ovarian failure and often a reason is not found. When it is associated with an autoimmune condition however, it is usually associated with high levels of follicle stimulating hormone, anti-muellerian hormone and inhibin – measurements that many women with infertility will be familiar with (4). The good news here is that if you do experience premature ovarian failure due to autoimmune conditions then with addressing the autoimmune conditions at play, along with any subsequent hormonal conditions such as diabetes, then recovery of ovarian function may occur (4). Unfortunately though it is not the magical answer and even if your autoimmune complications are resolved, if the damage has already occurred and there are no eggs remaining then it is suggested, in this study at least, that donation is the only option in the cases of severe premature ovarian failure (4), but like always discuss your options with your doctor.

Follicular Fluid and oocyte (egg) quality

Just as ANA’s can show up in your blood, they can also show up in follicular fluid. Follicular fluid is the fluid that surrounds the oocyte, or the egg, in its follicle. You will recall that when you have an egg collection, follicles are extracted from your ovaries and from the follicles eggs are extracted. Recently follicular fluid has been recognised as being a key indicator of the environment that eggs are housed in and the substances that are in the fluid can impact egg quality and hence subsequent fertilisation and pregnancy rates (5). For women where ANA’s have been detected in follicular fluid, this has been associated with typically producing smaller amount of embryos. Not only is there less quantity produced but it seems that those that are produced are generally also of lower quality than ladies who are ANA negative (ie have normal levels of antinuclear antibodies.

Implantation and pregnancy rates

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Assuming that by running the gauntlet so far you have kick started your ovaries into action as well as produced some fantastic quality embryo’s. So far so good. Before we get too ahead of ourselves unfortunately elevated ANA’s can also influence implantation and overall success rates even where good quality embryo’s are produced. One study done in 2012 (2) compared the overall implantation and success rates of women experiencing infertility who were ANA positive (ie had more antinuclear antibodies then normal) to those that were ANA negative. Although there sample size was quite small only comparing 96 cycles for the ANA positive women to 285 cycles of ANA negative women it was enough to significantly indicate that women who were ANA positive had lower numbers of embryo’s and a lower proportion of good quality embryos. Additionally in this group the pregnancy rate for ANA positive group was 28% compared to 46% in the ANA negative group. This understandably lead the authors to conclude that the

‘presence of ANAs significantly interfere with the oocyte and embryo development, as well as reduce implantation and pregnancy rate in patients undergoing IVF treatment’ (2).

Some good news

Although this study was done back in 2003 and was only a small sample size it had some interesting findings (6). Essentially what the researchers did was assess the IVF success rates of women testing positive for ANA’s and for those testing negative. In the first cycle women testing positive achieved lower pregnancy rates then those that were ANA negative. This is what we would expect given all of the above. The cumulative pregnancy rates though were not significantly different. AND that’s without the ANA positive women even taking specific medications to address their ANA. As the authors note

This indicates that the mechanisms of implantation failure by ANA could be solved, and effective and safe medication should be developed for better implantation rates

The treatment for ANA’s seems to vary and if you look at the notice boards you will find women taking different medications. Treatment will depend on your lab results and the type of patterning found. Prednisolone together with aspirin before conception and into pregnancy seems to be common treatment; however, again, discuss what will be best for you with your doctor.
INTERPRET IN CONTEXT OF OTHER TESTS

It is important to be mindful that when interpreting your ANA results that is only in the context of a ‘bigger picture’ taking into account other symptoms you may or may not be having and other blood tests that your practitioner completes. For example, in my case the fact that the ENA Panel (extractable nuclear antigen test) was negative, and the anti-DNA was also negative was an indicator that there were not necessarily any other autoimmune conditions under the surface and that by treating the impact of the ANA’s themselves that success may be just around the corner. And it was.

Being ANA positive is only one of many other antibody tests out there that may or may not impact on fertility. These can include antiphospholipids and immunoglobulins (IgA, IgG and IgM) and are also worth discussing with your specialist.

It is also important to remember that as previously highlighted being ANA positive can come in varying degrees. For example 1:80 indicates that there are far few antibodies in the blood then a result of 1:640. Having only ‘mildly’ positive ANA result may be less of an issue then a very high result and may influence you and your specialists decision as to whether or not the side effects of any treatment is more detrimental then not treating at all.

THE TAKE HOME ANA MESSAGES

Being ANA positive does NOT necessarily indicate that you have an underlying autoimmune condition or that anything is wrong, perfectly healthy, fertile people can be ANA positive
There is some research though that indicates being ANA positive is more common in women that need to receive fertility treatments
The presence of excessive ANA’s may be implicated in premature ovarian failure, embryo quality, implantation and recurrent miscarriage.
More research in this area is required and many fertility specialists do not believe that the presence of ANA’s on their own are worth treating

I am always worried about ‘scare mongering’ when I mention to my friends who are having fertility treatments to get their ANA’s (and other autoimmune markers) checked. There are so many things to worry about in the fertility world and just because this was one of my problems, it may not be yours. But given that the presence of excessive ANA’s does appear in a significant proportion of women yet to conceive, for the inconvenience of a blood test and a chat with your doctor its certainly something worth considering.

Finally, for those women who are interested in exploring ANA’s and other immunology issues there is a book by Dr Alan Beer entitled ‘Is Your Body Baby Friendly’. Dr Beer was an incredibly respected fertility specialist in California and assisted many women who had given up their fertility dreams to go on and get that take home baby. In his book it states that there is no such thing as ‘unexplained’ infertility and for everyone there is a reason. The book goes into some details about the different immunological problems that exist and also have some very inspiring case studies. A word of caution though the book is not necessarily for the faint hearted and may get you self diagnosing all sorts of issues! If you have run out of conversation or options with your fertility specialist though it may just very well give you a few things to discuss with them and for that reason is very well worth a look.

If you are doing or are thinking about doing IVF, don’t forget to get your free IVF guide with 19 evidence based ways that are designed to increase egg quality, implantation rates and hopefully IVF success!

References

1. Cline, A. & Kutteh, W. 2009. Is there a role of autoimmunity in implantation failure after in-vitro fertilization? Current Opinion Obstetrics and Gynecology. 21(3):291-5

2. Ying Ying, Yi-ping Zhong, Can-quan Zhou, Yan-wen Xu, Qiong Wang, Jie Li, Xiao-ting Shen, and Hai-tao Wu 2012. Antinuclear Antibodies Predicts a Poor IVF-ET Outcome: Impaired Egg and Embryo Development and Reduced Pregnancy Rate. 41 (5): 458-468 (doi:10.3109/08820139.2012.660266)

3. Molazadeh M., Karimzadeh, H. & Azizi M. 2014. Prevalence and clinical significance of antinuclear antibodies in Iranian women with unexplained recurrent miscarriage. Iranian Journal of Reproductive Medicine 12(3): 221 – 226.

4. Carp, H. Selmi, C. & Shoenfeld, Y. 2012. The autoimmune bases of infertility and pregnancy loss. Journal of Autoimmunity (38)J266 – J274

5. Revelli, A., Delle Piane, L., Casano, S., Molinari, E., Massobrio, M. & Rinaudo, P. 2009. Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics. Reproductive Biology and Endocrinology 7:40

6. Kikuchi, K., Shibahara, H., Hirano, Y., Kohno, T., Hirashima, C., Suzuki, T., Takamizawa, S. & Suzuki, M. 2003. Antinuclear antibody reduces the pregnancy rate in the first IVF-ET treatment cycle but not the cumulative pregnancy rate without specific medication. American Journal of Reproductive Immunology. 50 (4):363 – 7

What to expect when not expecting – the initial appointment

With approximately 15% of all couples now reportedly experiencing difficulty getting pregnant (1) its no surprise that there is generally a bit of a wait to see a fertility specialist. You may want answers straight away but if a fertility specialist can fit you in tomorrow I’d be wondering why. Before you see a fertility specialist you will need a referral from your GP. GP’s will generally advise you to be trying for 12 months if you are under 35 and have no obvious reason why you are having difficulty conceiving or six months if aged over 35.

So, you’ve got your referral, googled the success rates of different clinics in your area and waited out the couple of months before your first appointment. Although each clinic will vary, here is what to expect:

Questionnaire

You will most likely be sent out a questionnaire to complete prior to your first appointment. This will ask you all sorts of details and will be reviewed by your specialist with you and your partner as part of your initial appointment. It will include queries regarding:

past medical history (bring any blood tests or other pertinent information you have had collected in the past year)
your cycles (length of cycle and length and heaviness of bleed – it may be useful to write down the dates of your last six months of periods)
how long you have been trying to conceive including how many times a week you have sex and if you experience any pain or discomfort (no such thing as privacy from here on in!)
any past investigations
any past pregnancies, miscarriages and terminations
Your partners past medical history and any previous children
Any past sexually transmitted diseases. Everything you answer matters, for example, although it may have been treated long ago, chlamydia can cause pelvic inflammatory disease which is infection in your cervix, uterus and fallopian tubes. This can potentially block your fallopian tubes meaning that the eggs will not be fertilised by the sperm and can also cause difficulty with implantation. It is also associated with ectopic pregnancy, so obviously you want to make sure that the fertility specialist has all the information straight up.

It may seem a little invasive, and yes, it is!, but it is your first step forward to getting ‘things’ sorted.

Internal Exam

The internal exam will be done by the doctor and will generally have a nurse in the room. You will need to completely undress from the waist down and is a quick and generally painless digital examination looking for signs of any structural abnormalities or endometriosis (for example, pain when pressing in a particular spot).

If the men are even suspected of having any difficulties they will also be assessed, but again it is quick and painless and nothing to worry about.

Blood Tests

Although these probably wont be done in the actual appointment, they will most likely form part of your initial work up. They include, but definitely aren’t limited to the following:

AMH – antemullarian hormone. At its most simplest, AMH is the hormone that dictates your ovarian reserve and measures how loudly the ‘biological clock is ticking’. AMH is a hormone that is excreted by the immature, or antral and preantral, follicles that are in your ovaries waiting to become ‘lead’ follicles. The result of this test can be useful to determine the amount of eggs, or ovarian reserve, that you have left with generally a higher number indicating a higher amount of eggs that can be retrieved. It is also useful in helping to diagnose polycystic ovaries as ladies with PCOS will generally have more antral follicles and hence higher levels of AMH.

Interpretation (women under age 35)	AMH Blood Level
High (often PCOS)	Over 4.0 ng/ml
Normal	1.5 – 4.0 ng/ml
Low Normal Range	1.0 – 1.5 ng/ml
Low	0.5 – 1.0 ng/ml
Very Low	Less than 0.5 ng/ml

Source: advancedfertility.com (2)

I have included the levels above just because some of the more obsessive of us like to know our results and compare against the ‘normal’. Be very careful though, as advancedfertility.com highlights all these figures are on a sliding scale and you should NOT be disappointed if you happen to be categorised as ‘low’ as opposed to ‘low normal’. The clinical difference is very small, though has been categorised for the purposes of putting it in a nice chart. Also, normal or expected AMH levels are highly dependent on your age, so it is best to speak to your specialist about your particular levels.

2. Prolactin – for this test you will be required to sit for around 20 minutes before the blood being taken and because prolactin levels can vary throughout the day it is usually preferred to take it within a couple of hours of waking and in a fasting state (3). Prolactin is important to measure as if your prolactin level is high it can inhibit the action of the follicle stimulating hormone (FSH) and gonadotropin releasing hormone (GnRH) which are needed for a lead follicle to mature and hence ovulate. If these levels are low then ovulation may not occur or may cause a shortened luteal phase (7). The normal range for women is 85 – 500 mIU/L (7) Women who are breastfeeding tend to have higher levels of prolactin which is why some people consider breastfeeding as a form of contraception (its not!). If your levels are high (and significantly high, not just marginally high) these get be treated with medications such as bromocriptine and cabergoline (4,6), but there can be other reasons for high prolactin such as any other medications, stress or if you have PCOS (5). If your male partner has low sperm count it may also be worth checking his prolactin levels as it can be associated with low sperm count, low testosterone and erectile dysfunction (3). The normal range for men is 150 – 500 mIU/L (7)

3. Leutinizing Hormone (LH). LH is the hormone that in your regular cycle will experience a sharp rise just prior to ovulation, roughly 24- 48hours. It is this ‘surge’ of LH that ovulation predictor kits often rely on to predict ovulation and hence indicate to you to have sex. LH also helps develop the corpus leuteum which is important in manufacturing progesterone after ovulation to support a pregnancy and also to limit the follicle stimulating hormone.

Luteinizing hormone in blood
Menstruating women
Follicular phase:	1.68–15 international units per liter (IU/L)
Midcycle peak:	21.9–56.6 IU/L
Luteal phase:	0.61–16.3 IU/L

Source: http://www.webmd.com/women/luteinizing-hormone?page=3 (6)

Again, I have included the above chart, but remember to take all measurements with a pinch of salt and units can alter depending on what country you are in. Some consider a normal range to be below 7 when taken on day 2 to 3 of the menstrual cycle (7)

4. FSH. In the normal cycle FSH is responsible for recruiting and growing to maturity follicles which hopefully contain healthy, viable eggs. Many ladies who have undergone IUI’s or IVF’s will be familiar with FSH in its pharmaceutical form of Gonal-F or Purgeon, to name two, and it is what is injected on a pretty much daily basis until ‘trigger’ and ovulation. FSH should be tested on day 2- 3 of your menstrual cycle and a normal range is typically between 2 – 20 U/L with a level under 6 being excellent and the ratio with LH should be as close as possible to 1:1 (7)

5. Thyroid tests. The thyroid produces T3 and T4 which controls growth, metabolism and energy level. The thyroid itself is influenced by thyroid stimulating hormone or TSH. Thyroid problems are common in women and can be a cause of infertility and having either an over or an under active thyroid can result in infertility though the risk is greater for those with an underactive thyroid (7) The accepted levels of TSH varies but for women wishing to conceive it is optimal for levels to be between .3 and 2mIU/L, though ‘normal’ levels has been altered from 5mIU/L to 2.5mIU/L. It would also be beneficial to test for thyroid antibodies as the presence of these may indicate that your antibodies are attacking your thyroid gland and hence impacting its normal functioning (7). Women with thyroid antibodies may also have elevated levels of NK cells which are associated with infertility and recurrent miscarriage as well as other autoimmune conditions (8)

6. Oestradiol (E2) is the main oestrogen in your body and FSH stimulates the ovaries to make oestradiol. The normal range at day 2 or 3 is 100 -200 pmol/L (7).

7. Progesterone is measured after ovulation has occurred and a reading of progesterone greater then 25nmol/L often confirms ovulation (7). Progesterone is important for preparing your lining to accept an embryo for implantation and also to lower the immune system to accept and support a pregnancy.

8. Free testosterone and androgen. This is useful in assisting in the diagnosis of polycystic ovarian syndrome (PCOS) and women with PCOS typically have higher levels. Free testosterone should typically be below 4pmol/L and free androgen index between 1 and 8 percent (7).

9. Autoimmune tests. The impact of the immune system infertility is not always appreciated by all fertility specialists at the beginning of your ‘journey’. Some specialists may not even test for these before three miscarriages or failed cycles. If your doctor does not test for these and especially if autoimmune conditions such as rheumatoid arthritis or type 1 diabetes is present in your family it may be worth discussing this.

Tests within this group include anti-nuclear antibodies, anti-DNA/ histone antibodies, antiphospholipid antipodies, antisperm antibodies, natural killer assay, cardiolipin antibodies. As I said, some believe that the presence of these markers are not directly relevant to fertility. There are many women on various forums and boards however who have had success only after the investigation and treatment of various autoimmune conditions.

If you have ‘unexplained’ infertility or feel immunology might be playing a part in your medical history you may want to look at Dr Alan Beer’s book, Is Your Body Baby-Friendly, which discusses immune issues in detail. Beware though! If you are just starting your fertility journey this book can be quite detailed and may be a little overwhelming. That is why if you are concerned about your autoimmune response, as a first line of investigation discuss it with your doctor and see how it relates to your specific clinical presentation.

10. Sexually Transmitted Diseases and Infection. These tests are usually done by either blood or urine test and include:

chlamydia
gonorrhoea
syphilis
rubella

Please note that while comprehensive, it is not an exhaustive list of blood tests and your clinic or treating doctor may have other tests they wish to complete depending on your clinical presentation. Conversely, and again depending on your clinical presentation and past medical history, you doctor may not feel all of the above tests are necessary.

Tracking Cycle

The tracking cycle takes place after your initial appointment but is part of the initial work up when starting fertility treatments. A tracking cycle involves you attending your clinic throughout your cycle, starting on Day 2 or 3, Day 1 being the first day of your proper bleed. You usually need to attend the clinic early in the morning when nurses and phlebotomists take the blood. There are often many women attending at the same time as you so sometimes it may take up to an hour depending on the efficiency of your clinic and how many women are waiting. Once the blood is taken the clinics laboratory will measure your blood for hormones such as oestrodial, progesterone and luteinising hormone. This will enable your doctor to compare your cycle with a ‘typical’ cycle and aid in the diagnostic process. You will need to visit the clinic several times throughout the cycle, however, the nurses will tell you when you need to attend depending on your previous blood result.

During the tracking cycle you will also need to have an ultrasound completed to see how many follicles you are producing, the size of these follicles as well as the thickness and quality of the lining in your uterus. This is a transvaginal ultrasound where, as the name suggests, the probe is placed inside of you.

Hysterosalpingogram … or HSG for short

This will likely to be done at a radiography clinic. It involves injection of a dye into your vagina and cervix which fills up the uterine cavity and fallopian tubes. Several xrays are taken and the dye allows for any blockages, fibroids or structural abnormalities can be seen. There are certainly more pleasant experiences to be had then a HSG so some women may be advised to take pain relief prior to attending. Additionally, there may also be the risk of infection so an antibiotic may also be provided for you to use as a preventative measure. HSG’s should be done in the follicular phase of the cycle (before ovulation) and are definitely NOT indicated for women who might be pregnant (as if!). On a positive note, there is some suggestion that women are able to successfully get pregnant in the cycles immediately after a HSG, the exact cause and success rates for this is unknown, it may just be injecting the dye into your reproductive system ‘cleans it out’ so to speak allowing for the released (and hopefully fertilised egg) to make its journey into the uterus easier.

Laparoscopy

This one will involve you being admitted for day surgery at your local hospital. Depending on the doctor, approximately three small incisions are made in your abdomen area – one in your belly button which you wont see, one under your pubic line and one to the side of your abdomen. These incisions enable the doctor to insert a camera to investigate from the inside, and most frequently, to see endometriosis. If endometriosis is seen, depending on the severity of the endomentriosis your doctor may remove it then and there or otherwise, make a time for you to come back.

Below are two photos from an laparoscopy (apologies, they are a little graphic…). The one on the left, shows severe endometriosis which is the black areas you can see. You can see the ovary to the right of the picture. The one on the right is the same person six years before with only mild endometriosis as indicated by the small black dots. The ovary is seen in the bottom right segment.

MALE TESTS

Sperm Analysis Test

This information is pretty easy to find else where by asking Dr Google so I’ll keep it brief. It is the one where it involves the man producing a ‘sample’. Depending on how far you live from your local clinic though he may be able to produce this at home and drive it in to the clinic, which is obviously a bit more stress free. Also, these are best completed by laboratory technicians specialising in reproductive medicine, such as the lab attached to your fertility clinic. If your GP asks for a sample before making the referral and you are required to take it to a regular pathology laboratory they often lack the expertise to accurately complete a proper count, so therefore take any results with a pinch of salt.

When getting results from a sperm analysis test results will include numbers on

count – overall number
morphology – the shape of the sperm, for example, checking they don’t have two tails etc
motility – how they are moving? are they moving in a straight line? speed, for example
‘marine sperm’ – this might only be how my Dr described it but my clinic does really report on the above as all that all really matters is how many of the best of the best are there?

DNA Fragmentation Test

At its very most basic level this test is evaluating whether or not the DNA contained in sperm is healthy or intact. Even men with seemingly healthy sperm in the sperm analysis test may have DNA fragmentation and one study suggests in 80% of couples with ‘unexplained’ infertility with further investigation, the reason for the infertility was high amounts of DNA fragmentation (10) The clinical threshold for DNA fragmentation is 30%, that is if 30% or greater of sperm is damaged this is associated with lower fertilisation, implantation and pregnancy rates. Although high amounts of DNA fragmentation is associated with poor outcomes, if using ICSI then this may not necessarily be the case due to the ability to ‘pick out’ sperm with DNA strands intact using particular tests and techniques. Additionally, depending on the quality of the oocycte, damaged DNA may also be able to be repaired resulting in a positive result (9)

Blood Tests

1. Testosterone levels in men are generally within normal ranges even if there are significant sperm production difficulties (7). The normal range of total testosterone is 8 – 27 nmol/L with free testosterone being 170 -510.

2. Luteinising hormone stimulates testosterone production and the normal range is 2 – 10U/L.

3. Follicle Stimulating Hormone. Similar to FSH stimulating maturation of ooyctes in women, in men FSH stimulates sperm production. THe normal range in men is 1 – 5 U/L.

Ultrasound

Men may also be required to have a testicular ultrasound done to investigate structural abnormalities in the testes and scrotum.

Done!

Phew! That was a lot, but hopefully it gives you a better idea as to what kind of tests you may expect when visiting a fertility specialist for the first time. As I mentioned the above is not exhaustive and conversely your doctor may not think it necessary to complete all of the above investigations. If you have any questions or disagree with any of the above, please let me know.

References

1. https://www.nichd.nih.gov/health/topics/infertility/conditioninfo/Pages/common.aspx

2. http://www.advancedfertility.com/amh-fertility-test.htm

3. http://www.drmalpani.com/knowledge-center/articles/prolactin

4. http://www.labtestsonline.org.au/learning/test-index/prolactin#tab-index=2

5. http://www.advancedfertility.com/bromocriptine-prolactin-ovulation.ht

6.http://www.webmd.com/women/luteinizing-hormone?page=3

7. Cabot, S. & Jasinska, M. (2011) Infertility: The Hidden Causes. WHAS Pty Ltd

8. Beer, A., Kantecki, J & Reed, J. (2006) Is your body baby-friendly? Ajr Publishing.

9. Sakkas, D. & Alvarez, J. (2010) Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. Fertility & Sterility, 93 (4) 1027 – 1036.

10. Lewis, S. (2013) The place of sperm DNA fragmentation testing in current day fertility management. Middle East Fertility Society Journal. 18 (2) 78 -82