Infertility

Supplements-are you taking the good ones?

We know we are born with our ovarian reserve, and the number of our “eggs” can only decrease, from the moment we are born until we completely run out of them, by the time we get to menopause. We also know the quality of our oocytes starts to decrease by the time we reach our thirties, and the chances of ovulating abnormal eggs unable to create normal embryos are higher the older we get. But is there really nothing we can do to improve this egg quality?

The truth is, this a very controversial subject. The efficiency of a treatment, be it a subscription med or a dietary supplement, can only be proven by studies. While medicines benefit from multiple studies, dietary supplements receive far less attention from the part of the medical community. Therefore less studies are performed and easier to say “we don’t know if this supplement really improves oocyte quality, because there are not enough studies out there to confirm it”. Lots of REs though, consider that even if there is not enough proof some supplements help to improve your fertility, they don’t hurt either, so you might as well take them, if only for your peace of mind. And that’s already a great starting point, in my opinion, for having the impression of doing something, instead of just playing the wait and see game, means a lot for an infertility patient. There are some supplements out there who are more spoken about, and who also benefit from some studying. Those are the ones we will discuss today.

COENZYME Q10 – is one of the most important coenzymes. It is a substance made naturally in the body and it plays a critical role in the creation of cellular energy. CoQ10 is found inside the tissue of  organs such as the brain, heart, liver and kidneys (which demand more energy) but  it exists in virtually all our cells and tissues. There are two main forms of this coenzyme, and this creates confusion.

Ubiquinone is the conventional form of CoQ 10. That is what we used to take before 2007, when a better form of CoQ10 was discovered, the Ubiquinol. The problem with Ubiquinone (the basic form of CoQ10) is that your body needs to convert it into Ubiquinol before it can improve the cellular energy your organs need to function at best levels. As we age, the body struggles harder to convert the Ubiquinone in Ubiquinol, hence the recommendation to use directly the Ubiquinol form, for better results.

Ubiquinol is known to be a very strong antioxidant and its main role is to neutralise the free radicals that can harm your cells.

MYO INOSITOL- initially used in PCOS patients and for fighting insulin resistance, this nutrient has become the golden weapon in the infertility battle. It has been proven that, at a dosage of 4 g daily (most studies use this amount as reference) it has improved the ovarian function and number of oocytes retrieved in patients undergoing IVF cycles, and who have previously been considered poor responders.

The following is a link to a 2011 study aiming to evaluate the pregnancy outcome after the administration of myo-inositol combined with melatonin (will talk about it later in this article) in women who failed to conceive in previous IVF cycles, because of low egg quality. The results were crystal clear, everything was better post treatment : number of mature oocytes retrieved, fertilization rate, number of total embryos and number of top quality embryos.

https://www.ncbi.nlm.nih.gov/pubmed/21463230

Here is a more recent study (2015) showing Myo-Inositol supplementation might be beneficial for previous poor responders during IVF cycles.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464995/

MELATONIN is a hormone produced by the pineal gland, and it regulates sleep and wakefulness. Many of its biological effects in humans and animals are produced through activation of melatonin receptors, while others are due to its role as an antioxidant. As a medicine it is used to treat insomnia, and is usually sold over the counter in many countries. The negative effect of the oxidative stress on fertility is no longer a secret. Clinical studies have tried to prove the effect of melatonin as an antioxidant on egg quality. The results of those studies suggest that melatonin supplementation (in conjunction with Myo-Inositol or not) may lead to better pregnancy rates in IVF cycles. Amazingly, not only egg quality was improved in  patients who were administered melatonin during the follicular period, but progesterone levels were also significantly higher in patients who received melatonin during the luteal phase.

Here is a review of several studies with very interesting findings https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209073

The majority of the studies have used 3mg of Melatonin every evening as standard dosage. You will also want to be very careful when taking melatonin during a natural cycle, not to go over the standard dose. It has been proven that taken at high doses (6mg and more) melatonin actually prevents ovulation.

DHEA– naturally existing hormone, the most abundant circulating steroids in humans, that the female body converts into androgens, mainly testosterone. That means DHEA already exists in our bodies, we are producing it, but its levels decrease with age. It is sometimes used as an androgen in hormone replacement therapy for menopause. Lately it has been more and more used particularly during IVF cycles to treat women with DOR (diminished ovarian reserve).

Clinical studies have proven that at a dosage of 75 mg daily for a period of at least 3 months, DHEA increased IVF pregnancy rates, increased antral follicle counts, increased quality and quantity of eggs and embryos, decreased risk of miscarriage and chromosomal abnormalities. DHEA supplementation works by restoring the abnormally low androgen levels in patients with DOR due to advanced maternal age or premature ovarian failure.

Here is one link to two of these studies

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3112409/

https://academic.oup.com/humrep/article/25/10/2496/2385689/Addition-of-dehydroepiandrosterone-DHEA-for-poor

ARGININE- is an amino acid that plays an important role in cell division, the healing of wounds, removing ammonia from the body, immune function, and the release of hormones. It can be found in almost all dietary protein : eggs, meat, fish, nuts and supplementation has been proven efficient in improving fertility in both women and men. How does it work ? Arginine is believed to improve blood circulation to the uterus, promote healthy sperm production, improve the production of cervical mucus and increase the libido. There are not many studies focusing on arginine, more research needs to be done, but many fertility specialist recommend this « miracle mollecule » which is already included in most prenatal vitamins anyway.

ROYAL JELLY-Royal Jelly is a strong nutrient produced by young worker bees in the hive. For 2-3 days, these bees are fed only on royal Jelly until they reach maturation and produce enough Royal Jelly to feed the female larva, which develops into Queen Bee. Queen bees are fed their entire life only Royal Jelly while worker bees are feed Royal Jelly for only the first three days of their life. This diet is responsible for making the queen bee 40 to 60 percent larger than a worker bee. There are not many studies on humans, but there some on animals amnd their conclusions suggest Royal jelly might improve fertility. Beware of adverse reactions thouugh : those with allergies to bee products are to avoid this supplement.

FOLIC ACID (Folate, Vitamin B9) is a form of Vitamin B. It is no longer a secret for anyone trying to conceive, that the first supplement you will be recommended by your doctor is going to be the Folic acid. It has been proven for years and years to prevent neural tubes defects and congenital heart defects in newborns, and actually low levels in early pregnancy are believed to be the cause for more than half of babies born with neural tube defects. There are no common side effects, even if taken for long periods of time. Humans can not produce it so it is important to get it from diet (and supplements). Food supplement manufacturers often use the term folate for something different from “pure” folic acid: in chemistry, folate refers to the deprotonated ion, and folic acid to the neutral molecule—which both coexist in water.

There have been lots of studies proving the importance of Folic Acid intake before and during early pregnancy.

Here is one you might want ot read

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218540/

and also the reccommendation of the World Health Organization on this subject

http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/neural_tube_defects.pdf

There are of course, other supplements more or less proven to increase fertility: Vitamin D (previously discussed in the article about the AMH), Vitamin E (used usually during the follicular phase in order to thicken the lining), DHA (not to be confounded with DHEA), Maca, Vitex…and many more.

I tried to focus on the ones who have been more or less medically proven to actually help on improving pregnancy outcomes after administration, during natural or medicated cycles.

Obviously,   not everything is for everyone, and in order to avoid doing more harm it is best to discuss supplements intake with your doctor. In case your doctor is not very pro-supplements, you can always pull out “the study” and show him you did your research. That is what I did, and frankly…it worked 🙂

Sources: NCBI, WHO, OXFORD ACADEMIC

 

Advertisements
Ivf

Priming protocols-what with and who for?

I am going to address a very debated topic and one of huge interest for those who carry the tags DOR or POF and need ovarian stimulation for assisted reproduction.

The way IVF works, we all know the more eggs we make, the better it is. And this because in vitro fertilisation is all about narrowing down the chances to finding the best egg(s). It is a matter of logic because more eggs retrieved will give us more fertilised eggs, hence higher chances of pregnancy. Also, women who respond better to stimulation protocols usually have a better egg quality (PCOS do not enter in this category of better egg quality, we will discuss this later on). Last but not least, “the more eggs the merrier” principle has also financial connotations. With prices so high for stimulation meds, monitoring, retrieval and laboratory, you’re far better off paying thousands and thousands for ten eggs than for one.

While women over 35 and those under 35 but dealing with POF and DOR might be worse responders than the fertile population generally is, lots of protocols have been invented and experienced over the years, some of them with great results and quite encouraging pregnancy rates. One of the approaches is that of using luteal phase adjuvants, hoping to create a better environment for the follicles and preparing the ovaries for the following stimulation cycle.

BIRTH CONTROL – By far the most used approach before a medicated cycle. Its main purpose is to give your ovaries a rest, and give them the chance to start the next cycle with a clean slate. Useful for reducing cysts, it also comes, unfortunately, with a bad side effect: the dreaded suppression. BC pretreatment in IVF protocols establishes an estrogenic environment and increases sex hormone-binding globulin levels while decreasing follicular androgen levels. But by putting the ovaries to sleep the risk is they might not wake up well enough… Sometimes, we end up with a lower antral follicle number, and we are facing the need of stimulating for a longer period of time, and with higher doses of stims, which might in turn, affect egg quality for older patients.

Here is a very interesting study, where  even young egg donors have experienced lower AMH levels and lower numbers of oocytes after being put on birth control.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637242/

If in the case of a young donor, having  5 eggs retrieved  instead of 10 might not make much of a difference, because donors are chosen to be young and healthy, therefore having a great egg quality, things are quite different with us, older women, where quality as well as quantity might be a problem.

TESTOSTERONE PRIMING- Relatively new,  and controversial. If you listen to Dr Sher, a very famous and respected Reproduction Endocrinologist, you should run away from testosterone exposure, especially if you are not very young anymore. If you listen to me, LOL, my biggest failure of a cycle was the one I primed with testosterone gel. While I usually would have an antral follicle count of 9-10, one week of testosterone gel reduced my AFC to a whopping 2 (two), and thats what I got until the end of stims, when I told my RE there is no way I am going to waste an IVF cycle on two eggs, and converted to IUI. Even he himself later admitted that testosterone priming was a mistake in my case (I was 41 at the time, this might have been a reason) and he is known to be a very stubborn and proud one…And it was no coincidence: all the other cycles I ever did (and we are talking 12 with full protocol, my afc was never under 8)

This being said, there are many studies out there who scientifically prove testosterone priming works for many low responders. If you read this analysis of several studies (https://http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061182/) you will see the mean age of the patients was 36-37, so there….probably that’s the key, being younger is better for testosterone priming. I personally guess there is no way of knowing until you try.

Oh, and most important: I grew no beard during the treatment, neither did I engage in violent exchanges with people in pubs 😛

ESTROGEN PRIMING– It avoids the suppressive effect of BCP on the ovaries. In addition, the use of estrogen during the pretreatment cycle prevents premature recruitment of follicles that can reduce the number of follicles available for stimulation. Studies have shown that this protocol allows more gradual and coordinated growth of follicles resulting in improvement of embryo quality and quantity. For me this has been the only way I could avoid the growth of the horrible LEAD follicle, the scarecrow of IVF…I personally took estrace pills, but patches are used with the same success.

You might want to read this study https://www.ncbi.nlm.nih.gov/m/pubmed/22160464/ and also this analysis of several studies https://www.ncbi.nlm.nih.gov/pubmed/23887073

I believe it is essential to have a doctor you really trust. I, for one, could not trust any doctor who insults my intelligence by imagining that in this age and time I have no ways of gathering enough information as to educate myself on matters concerning my health and my life. Would this auto-education give me a medical degree? Obviously not! And I do not pretend it does. What it does give me, is at least basic knowledge, so useful in understanding where I stand, and if the direction I am heading to is the good one. It gave me the power of standing up and saying NO, when I knew for a fact that the approach I was suggested would be wrong for me (I wish I knew what I know now, when I was suggested the testosterone priming…) It gave me the power to fight me RE for the estrogen priming protocol, that as an anecdote he himself invented, but not so much used afterwards, for fear of oversupression. I fought him and he gave in, and later admitted I was right. It also gave me the power to say NO to him for yet another high dose stimulation protocol, and when he wouldn’t give in and would insist low dose is “counterproductive” for low responders (sic!) I would say bye to him, and find another RE who was willing to try on me my estrogen priming low dose protocol. And we got 8 eggs, instead of my usual 2-3.

I don’t know if it is my journalistic background, or maybe just me being a stubborn Aries, but I am a strong believer in the “Knowledge is power” part, as much as it might sound  like a cliche.

Apparently you believe so too, or else you wouldn’t be here, trying to find out more ❤

Sources: NCBI

 

Infertility

The CD 3 tests-how important and what do they predict?

If you are familiar with fertility treatments or  if you just had an assessment of your ovarian reserve because you are trying to conceive, the term “3 day tests” rings a bell to you.

Day 3 testing (can also be done and day 2 or 4) consists of bloodwork used to measure hormone levels (FSH, Estrogen, Progesterone, LH) and a scan, meant to measure the number and size of your Antral Follicles. Your AMH level can be measured anytime and if you need to have it measured more than once, it is preferred to do so using the same laboratory, because measurement scales vary for every lab.

E2 (Estrogen) is the main female reproductive hormone, it is being secreted by the ovary and helps to stimulate follicle growth and prepare the lining for implantation, in case conception occurs. The majority of the fertility clinics would want you to have an E2 level under 50 (some under 80) on your day 3. Too high an estrogen level on this day might suggest you have a cyst producing estrogen, in which case stimulation might not be advised. Feeding it stimulation meds, the cyst might not only “eat up” the meds destined for your other normal sized antrals, but also grow and grow until it bursts. A too low estrogen level is not ideal either, suggesting diminished ovarian reserve and possibly  peri/premenopause. Also, very important, when your Estrogen levels are high, the value of the FSH is artificially lowered.

FSH (Follicle-stimulating hormone) as the name tells us, is the hormone that stimulates the ovary to make the eggs grow. Released by the brain, the FSH tends to get higher and higher as we age, and our ovaries struggle more and more to produce an egg. The ideal FSH level is under 10, the lower the better. Some clinics would accept you for fertility treatments with an FSH under 15, but there are tons of studies out there showing success rates diminish seriously as 3 day FSH levels increase. That might explain why older women with high FSH have better chances getting pregnant naturally than with IVF treatments. This being said, if you need help to procreate, there are lots of clinics who offer natural IVF for women with high FSH-meaning no meds, egg retrieval for possibly just one egg, and fertilisation as needed (normal or ICSI, IMSI etc)

LH (Luteinising hormone) helps mature the follicle and eventually, when an LH surge occurs in the end of the follicular phase, helps the release of the mature follicle. The ideal level is under 7 mIU/ml with a ratio LH:FSH of 1:1. An LH much higher than the FSH might be an indication of PCOS (Polycystic Ovary Syndrome).

P4 (Progesterone) should remain low during the follicular phase (under 1ng/ml) and rise after ovulation, as proof the ovary released the egg. The low limit used as indicator for ovulation at 7dpo is 5, but the higher the better. Some women with low progesterone might need progesterone supplementation in order to maintain pregnancy.

AMH (Anti Mullerian Hormone) is a free circulating hormone released by the small antral follicles present in your ovaries, and it is used to assess your ovarian reserve, as in “how many eggs do you still have”. Taken alone, it doesn’t amount for much, and it is far more reliable when discussed in conjunction with the other day 3 levels, and most important, with the day 3 scan. Also, it is important to know that the AMH level has been proven to be artificially lowered by low Vitamin D levels.

Ovarian ultrasound/scan: it is meant to count and measure the antral follicles. The antral follicles are small follicles (between 2-10 mm) found in your ovaries at the beginning of the follicular phase. They are an extremely important and very useful assessment of the way your body might respond to fertility treatments. Each antral contains an immature egg that might develop and ovulate. During natural cycles, the body recruits what is thought to be the best follicle, and makes it grow and eventually ovulate once the Estrogen level is high enough (200-600 E2 level/mature follicle) and the LH surge occurs. In stimulated cycles, all antrals have potential to grow, and even sometimes, some more follicles pop up during stims.

Those are the main tests performed during the day 3 assessment. The list is not exhaustive, though. Depending on your clinic and your health issues, you might have your prolactin and thyroid levels checked, or any other test your doctor might consider appropriate.

Unfortunately, there are some clinics who perform this testing once a year, and consider it available in subsequent cycles. Whether for logistic or financial reasons, this is bad. Hormones fluctuate every God given month, and once you have your period, they are reset and you start the new month with a clean slate. It is possible to have an FSH of 6 in January, and an FSH of 14 the next month, and you surely won’t have the same response to meds during those two months if you are to cycle. Hence the importance of demanding those 3 day tests at the beginning of each and every cycle using stimulation meds, to spare you the heartbreak, the false expectations and yes, the waste of money.

In a future article I will bring to your attention a list of supplements with great effects on your fertility, and the links to the medical studies that attest it.

 

 

Infertility

Low AMH- the villain, but how bad indeed?

A rather recent discovery (1990’s) the Anti-Mullerian hormone has become the bad guy of fertility assessments. Lots of medical articles about it on the web, but in normal non medical language, what is the AMH, where does it come from, why is it low (if it is low), can we make it grow, and most importantly: how big a role does it play in our fertility?

We, females, are born with a certain ovarian reserve, i.e a certain number of eggs. We are born with them and we grow old with them, ovulating more ore less one egg every month, ever since we start having our period and until we get menopaused, unless we are pregnant, on birth control or having anovulatory cycles.

This means our eggs age as we age, which is not fair, but hey…what is fair when it comes to women and their womanhood, compared to men? (don’t get me started…)

It has been discovered that the shell of our eggs produce this hormone, the AMH, and it circulates in the blood, where it can be tested any day of the month, unlike the other fertility assessment tests known as Day 3 tests, that we will talk about later. We know AMH can fluctuate, but not by much, and that different labs can produce very different results, which is why it is essential to have this test done in the same lab, if you need to have it tested several times.

AMH being the reflection of our ovarian reserve, it is natural it decreases with age, as our ovarian reserve is depleted. Therefore, women over 40 are expected to have lower AMH levels. Fertility wise, a low AMH is considered to be under 1 ng/ml. This being said, pregnancies are known to occur even when AMH is undetectable. We all know someone who knows someone who, in their early or mid-forties thought to have reached menopause, only to discover the menopause was in fact a baby 🙂 So basically, every woman in her late 30’s and early to mid 40′ who getting pregnant, gets pregnant despite low AMH levels (we might safely assume that practically every woman of this age has low (er) AMH levels, cause that is the way things are)

And we get to the burning question: is low amh REALLY linked to infertility? Does having low AMH mean we cannot get pregnant? The answer is NO.

More and more reputable reproductive endocrinologists worldwide admit lately that AMH is actually too new to be able to give an accurate image all by itself. That while it can give us an idea of how a woman might respond to fertility treatments (in case she ends up needing them, that is) AMH doesn’t mean much when taken separately. Instead, a better view on the female fertility is given by the AMH level corroborated with the Day 3 Tests and the Antral Follicle Count.

One thing is clear and most experts agree on it: AMH has to do with egg quantity, not quality. Therefore, while you may produce less eggs for IVF in case IVF is what you need to get pregnant, they can still be of decent quality, depending on your age. Or, better yet, if you do not have any reason to do IVF, and so you are not interested in the number of eggs, you can relax, low AMH doesn’t mean your eggs are not good anymore. Again, depending on your age.

When we find out our AMH is on the low end, the first question that comes to mind is “can I make it grow”? Well, no you can’t, not really. Since AMH is a reflection of the quantity of eggs we have left, it is just logical that not being able to increase the egg reserve, it is impossible to “grow” the reflection of it in your blood stream.

But there might be a catch here. It has been discovered that Vitamin D, one of the vitamins with crucial role in conception (and not only) might influence our AMH levels. If your Vitamin D level is low, this may artificially lower your AMH levels. Once you get proper supplementation of Vitamin D and your vitamin D levels get back into the normal range, you may have the surprise to discover your AMH level is higher. Which again, doesn’t actually mean your AMH has “grown” but just that it has been brought back to its place.

Studies show that humans do lack Vitamin D as a general rule, and more than that, there is also a matter of proper absorption when it comes to vitamin D. Here is a good read that might bring a scientific view on the matter

https://www.ncbi.nlm.nih.gov/pubmed/22508713

How much Vitamin D is needed? Read here to find out:

http://www.health.harvard.edu/blog/vitamin-d-whats-right-level-2016121910893

And last but not least: when you are told your AMH is “low”, what exactly does “low” mean? We shan’t forget that AMH has different values for different ages, and what is low for a 25 year old, might be perfect for a 38 year old. Here is a chart explaining it clearly

amh-levels-and-age

Sources: Harvard Health Publications/The National Center for Biotechnology Information