I have low AMH. Will DHEA work to help my IVF outcome?
Ever since I graduated with my Masters I’ve had to use other sources for scientific research, other than our online library. This is mainly Google Scholar. If you are a scientist then you already know the power of studies, which puts the meta-analysis as the top-tiered of all research, and this should include clinical studies, and not just studies in a lab.
I talked about taking control over your fertility a few weeks ago. So, what else do I do on a rainy holiday Monday? Writing, or blogging, reduces my stress. These pages are just where I put my thoughts.
Today’s research topic is DHEA. How did I come across this? First, I am a member of several TTC groups online. Some women have suggested DHEA to improve their fertility. I am also listening to the As a Woman podcast, and Dr. Crawford has mentioned it. It’s fairly new to me, so I thought I would talk about it here as I am doing my own personal research.
What is DHEA?
DHEA is dehydroepiandrosterone. If you are in chemistry, you will recognize the –sterone ending of the word. For the layperson, if you can think of this hormone as a precursor to testosterone it may make it easier to follow. DHEA, like testosterone, is a steroid based hormone that is made in our bodies. DHEA is produced in the adrenal gland in the zone that produces sex hormones. Since DHEA is related to testosterone, and increases testosterone in the body it is considered a banned substance for use in sports and fitness related competitions.
Testosterone? Isn’t that the man’s hormone??? Why would I, the female, want more testosterone in my body? This is precisely why you need to know more about this hormone prior to ingesting it as a supplement when you are TTC.
Is DHEA supplementation right for me?
After you have been assessed by a reproductive specialist and you have found out that you have normal male factor (the semen analysis was normal) and normal tubal factor (your fallopian tubes on both sides were open, and have no endometriosis), and you have been diagnosed with unexplained infertility – but also have low AMH and low AFC, then perhaps you are on to IVF. Have a listen to Dr. Crawford’s podcast episode on unexplained infertility. I already talked about using Ubiquinol to increase your oocyte (egg) quality. But we want to have a baby born with the fewest number of IVF cycles possible, right? Remember, time and money are two of your resources, and multiple IVF cycles uses up both of these.
Before I go into the research using DHEA to improve IVF success, we need to know all the background information.
Do you have diminished ovarian reserve?
Ok, how many times have I mentioned advanced maternal age in this blog?? Basically, if you are 35 and older, you’re considered an older mother. Women who are 35 and older are more likely to have low AMH and low AFC. Wait? What’s AFC? Ok, I put a list of the acronyms below to make it easier for me to just type the acronyms in my blog posts. So try to follow along!
If you have a low AMH and low AFC it is going to be harder for you to have a successful IVF in the first cycle. AMH (Anti-Müllerian Hormone) can be measured with a blood test, which is fairly easy to acquire, compared with an ultrasound to assess the number of follicles that grow (AFC). In Canada, the units of measurement for AMH are in pmol/L, so if you are comparing your AMH levels to someone in the U.S. you will need to convert it to ng/mL.
Here are the results of my AMH and where I stand on the curve. It’s kind of sad actually, when you see it this way. But more on that at a later date.
Once you have your blood test, if your AMH value is low, then you have a 63% chance of having less than 8 follicles on ultrasound (1). Remember that the egg is housed inside a follicle. There is a group or cohort of follicles that are recruited during the follicular phase of the cycle to grow. FSH is the hormone from the brain telling the follicles to grow, and only those follicles in that cohort can be used in IVF. I think I mentioned previously that egg retrieval rates will depend on the skill of the practitioner. I had about a 50-60% egg retrieval rate in cows (meaning if there were 10 follicles available, I could collect 5-6 eggs). To put this into perspective, the AFC is not the number of eggs that undergo the IVF cycle, the AFC is the number of follicles holding an egg that are potentially available to be collected during an egg retrieval. Some women will be disappointed to know that your IVF cycle could be cancelled if you only have 3 follicles.
Maternal age is related to oocyte quality. Listen to Dr. Crawford again, because she can explain it much better than I can. In case you have forgotten. You are born with all your eggs as a female. Each month a cohort grows, one follicle is selected to be the dominant follicle, and this becomes the ovulatory follicle – releasing an egg in response to LH. If you grow 10 follicles, and one ovulates, the other 9 undergo regression and essentially die through apoptosis. As time progresses, you have a smaller cohort of follicles that grow each month, just based on age-related ovarian decline.
What is Diminished Ovarian Reserve?
DOR or diminished ovarian reserve is a term that women are given when they have a low number of oocytes left, or are getting close to menopause. It’s mainly related to age, but younger women can have DOR too.
Diminished ovarian reserve (as per 3):
1) AFC < 4 follicles
2) FSH > 10 IU/mL
3) AMH < 1 ng/mL
So for me:
1) I haven’t gone for my AFC yet because of COVID-19 restrictions, the fertility clinics were closed
2) FSH = 12.7 IU/L – well, we can do math right?
3) AMH = 2.3 pmol/L – remember that I said you have to convert this into ng/mL to be in the units that the U.S. uses just so you can compare your values. So mine is 0.32 ng/mL
I wouldn’t be writing this blog post if I didn’t fall into these categories. So, like I said above, I have been listening to the As a Woman podcast. First, you need to set a goal. Our goal is to create a family. If we could have everything we wanted in the world it would be two children. I think there is some power in speaking these things into existence. So, that means if we successfully got pregnant this year, I’m 40 years old having my first baby. And maybe, just maybe we are successful and I can have a second child at the age of 42. We already know that I have DOR based on my blood work. So now is the time to invest in our second baby. Why second when I haven’t had one?? Because time is my most valuable commodity and we are running out of it. Dr. Crawford says you have four resources: money, time, physical health and mental well-being. I believe that I will run out of time first, before I wane on the other three - though my husband may question the fourth at times. ;)
So what will improve my success for IVF?
I just picked up the book “It Starts with the Egg” and I just started it. I think I already talked about nutrition, diet and maintaining a healthy BMI. I haven’t really gotten into toxins, that is decreasing your use of plastics that could be leaching BPA into your water or food, pollution, smoke, etc. I wrote about supplements and vitamins, but now I need to add to that with DHEA.
DHEA when given 2 to 3 months prior to IVF:
1) Improved spontaneous pregnancy rate during the waiting period prior to IVF (3)
3) Improved oocyte quality (2)
4) Increased MII oocytes (3)
5) Improved embryo quality (2)
9) Reduced miscarriage (6)
11) Decreased day 3 FSH (5)
That all sounds darn promising!
Here’s the information from the studies on the dosing.
Dose = 25 mg micronized DHEA administered for 12 weeks prior to IVF (3)
“Our results show that DHEA supplementation improves the ovarian function in poor responders and in women over 40 years, suggesting that this molecule alone can raise fecundity and fertility treatment success in women with poor prognosis for pregnancy.”
Dose = 30 mg TID for 12 weeks (5)
So why wouldn’t you try it?
First, you need to know that you fall into the category above. If you haven’t already been to see a reproductive specialist, you don’t want to start taking an androgen without your doctor’s guidance. If you have normal hormones, taking an androgen could mess with your normal hormones. It can be harmful in some cases - so please, please consult your doctor.
Since I think knowledge gives you power, let's dig in further.
How does DHEA work in my body?
Let’s take a look at how it might be working in your body. The below image is just one of many flow charts online that show how steroids are produced in our bodies. The arrows indicate an enzyme - the protein molecule that makes the steroid hormone. The names of the enzymes are written beside the arrows. DHEA is converted to androstenedione which is then converted to estrogens (estrone and estradial) and testosterone.
We can shunt the direction of hormone production by changing the activity or genetic expression of the enzymes to produce the hormone that we want. We can do this through lifestyle changes (reducing stress) and through diet or we can use medications to inhibit certain enzymes. Another alternative is giving one of the steroid hormones as a medication - via injection, suppository/topical or oral. But our focus for this one is on DHEA.
As mentioned, DHEA in the female is produced only in the adrenal gland (85% DHEAS) and a smaller amount from the ovary (15% DHEA)(7). There are three zones in the adrenal gland cortex (the outer part). As veterinarians we learn them as Salt, Sugar, Sex to distinguish the three adrenal cortical zones - from outside to inside. The outer most zone is responsible for Salt (NaCl) regulation in the body with mineralocorticoids (aldosterone), the middle being responsible for Sugar (glucose) regulation in the liver with corticosteroids (cortisol - one of the stress hormones), and Sex hormones in the third zone (zona reticularis below). DHEA is one of these sex hormones.
As a side note for my veterinary student readers: Cushing's disease and Atypical Hyperadrenocortism in Ferrets causes disregulation of the Sex hormones.
Now we know where the DHEA is produced in our bodies and which hormones it can be metabolized into. How would it work to increase your chances of developing a healthy embryo?
We know that it takes a few months of priming with DHEA to see a significant effect. That means it's working earlier in the growth of follicles. Let's zoom into the ovary for a minute.
The Ovarian Cortex
Did you know that my Master's supervisor teaches the veterinary students histology? First year vet students might cringe, but here we go!!!!
In the cortex of the ovary (cortex = outside part - similar to the cortex of the adrenal gland) there are follicles. Follicles contain oocytes (eggs). BUT not all follicles are large enough to see with the naked eye. There are antral follicles - the follicles with a fluid filled cavity - the fluid you can see on ultrasound - and there are follicles that do not have an antrum - no fluid filled cavity. The tiniest of which are called Primordial Follicles. These are oocytes (eggs) surrounded by a single layer of squamous epithelial cells (see thin layer of cells versus thicker cells). As time progresses through the egg's life to ovulation, the cells surrounding the oocyte start to divide, they become cuboidal (cube-shaped - single layer of cells = primary follicle), then there are two layers of cells surrounding the egg, then three and so on (secondary follicles). In the simplest of terms, the cells release fluid towards the oocyte in the middle to nurture it - creating the antrum (tertiary or antral or Graffian follicles).
Below is a cross-sectional view of a tiny slice, of a tiny part of the ovary, stained with special stains and viewed under a microscope. Who knew that my first year histology notes would come in handy when I went to create this blog!! Exciting!
The oocyte in the primordial follicles is tiny, and it grows as well through time towards ovulation. This "life cycle" of a dormant primordial follicle to an antral follicle releasing an egg takes a long time. The term is folliculogenesis - just in case you wanted to know.
AMH Tells Follicles to Start Growing
As you can see in the diagram above, AMH is one of the cell signals that tells the follicle to start growing during the early stages of folliculogenesis. That means, if you have a low signal of AMH, only a few cells are able to get the message. A higher signal of AMH will allow more follicles to get this message. AMH in the ovary is produced by the granulosa cells - yet another cell type that you didn't want to learn about - but for veterinarians - you have to - sorry!
Now, let's talk about IVF. You want to have a good selection of larger follicles (antral follicle) with a mature egg inside that can be retrieved to be fertilized. You don't want to retrieve immature eggs in the individual woman - you want them already mature and ready to be fertilized, and essentially have all the embryos grow together. For those of you trying to conceive, you may have heard of the Trigger shot - this is to mature your follicles and eggs.
Ok, so how to we get more follicles to grow and mature when we know our AMH is low? The exact mechanisms of how DHEA increases the intrafollicular androgens which then contributes to an increase in AMH is uncertain (7, 8).
Hypotheses come from curiosity. So we can hypothesize that it could be binding in the ovary itself, or perhaps shifting the metabolism within the adrenal gland. Does it have something to do with the cortisol shunting of progesterone in the adrenal gland? Within the ovary, it may increase the androgens in the theca cells and with this cross talk between the theca cells and granulosa cells, then produce more AMH, rescuing more primordial follicles from atresia or death. Chances are that it does not just have one mode of action. However it happens, make sure your doctor is monitoring your endogenous levels so that you don't over-supplement!
For more on my fertility journey, click here.
Acronyms Used
AFC – antral follicular count – the number of follicles that seen by ultrasound per menstrual cycle – also the number of follicles that can be recruited for IVF
AMH – Anti-Müllerian Hormone – AMH is used as a marker in the blood stream to let us know how close we are to menopause – low AMH closer to menopause, higher or normal AMH not as close to menopause
DHEA – dehydroepiandrosterone – the topic of this blog post! So see what is DHEA? above
DOR - diminished ovarian reserve
ET – embryo transfer
FSH – follicle stimulating hormone – the hormone that is released from the brain to tell the follicles to grow – wen measured on day 3 of the menstrual cycle, higher FSH is a marker in older women of how hard the brain is trying to signal to the ovary to grow follicles for ovulation
IVF – in vitro fertilization – where egg and sperm are combined in a petri dish
MII – metaphase II – it’s a phase in meiosis during the development of the oocyte (egg) after ovulation. You need the egg to develop to MII phase in order for fertilization to occur
TID – three times a day
TTC – trying to conceive
References
1) Anderson, R. A., Anckaert, E., Bosch, E., Dewailly, D., Dunlop, C. E., Fehr, D., ... & Geistanger, A. (2015). Prospective study into the value of the automated Elecsys antimüllerian hormone assay for the assessment of the ovarian growing follicle pool. Fertility and sterility, 103(4), 1074-1080.
2) Al-Aabdeen, M. Z., Taha, S. A., Ahmed, H. H., & Khodry, M. M. (2019). The effect of dehydroepiandrosterone on anticipated normal ovarian responders among infertile patients undergoing intracytoplasmic sperm injection. SVU-International Journal of Medical Sciences, 3(1).
3) Fusi, F. M., Ferrario, M., Bosisio, C., Arnoldi, M., & Zanga, L. (2013). DHEA supplementation positively affects spontaneous pregnancies in women with diminished ovarian function. Gynecological Endocrinology, 29(10), 940-943.
4) Li, J., Yuan, H., Chen, Y., Wu, H., Wu, H., & Li, L. (2015). A meta-analysis of dehydroepiandrosterone supplementation among women with diminished ovarian reserve undergoing in vitro fertilization or intracytoplasmic sperm injection. International Journal of Gynecology & Obstetrics, 131(3), 240-245.
5) Tsui, K. H., Lin, L. T., Chang, R., Huang, B. S., Cheng, J. T., & Wang, P. H. (2015). Effects of dehydroepiandrosterone supplementation on women with poor ovarian response: A preliminary report and review. Taiwanese Journal of Obstetrics and Gynecology, 54(2), 131-136.
6) Zhang, M., Niu, W., Wang, Y., Xu, J., Bao, X., Wang, L., ... & Sun, Y. (2016). Dehydroepiandrosterone treatment in women with poor ovarian response undergoing IVF or ICSI: a systematic review and meta-analysis. Journal of assisted reproduction and genetics, 33(8), 981-991.
7) Fouany, M. R., & Sharara, F. I. (2013). Is there a role for DHEA supplementation in women with diminished ovarian reserve? Journal of assisted reproduction and genetics,30(9), 1239-1244.
8) Narkwichean, A., Maalouf, W., Campbell, B. K., & Jayaprakasan, K. (2013). Efficacy of dehydroepiandrosterone to improve ovarian response in women with diminished ovarian reserve: a meta-analysis. Reproductive Biology and Endocrinology,11(1), 44.