In this article we are covering the topic (AMH) which is an extremely very important for the students pursuing Fellowship in Reproductive Medicine in India. AMH as we all know is one of the ovarian reserve tests. There is an innovative terminology called preventive infertility management wherein if there is one test which can predict or forecast the reproductive life of a woman. And if it gives us a hint that the woman is not going to conceive naturally or her fertility window is quite small. So, is there any way that we can apply the fertility preserving techniques that we have now either like oocyte freezing or embryo freezing and make it better for her to have her own biological child. Is AMH one of those ORTs.
And it is important that whenever we are trying to talk about AMH, we should understand how this entire thing of AMH works. Being a pivotal topic for reproductive medicine, the Fellowship in Infertility in India covers a great extent of this topic in depth in their curriculum.
Inside the ovary there are millions of such small follicles. These are called as primary follicles.
- From primary follicles, there is one stage above where they form some number of granulosa cells besides them, very small quantity granulosa cells.
- This stage where very small prime is formed is called as primordial.
- Following this, there is one more stage above this. This is called as pre-antral follicle. Now this pre-antral follicle has some granulosa cells around it.
All this pre-antral follicle, these are the people who are going to get recruited. Above this, you have small antral follicles, which we normally see. And above this, you have the large antral follicles. So now the anti-Mullerian hormone is going to be predominantly secreted by this category, small antral follicles and pre-antral follicles. These secrete the anti-Mullerian hormone. The most important function of anti-Mullerian hormone is to inhibit further growth of primordial functions.
This is inhibitive. Why? It's very simple. It doesn't want your ovarian reserve to deplete. As a result of which, when your AMH value is high, that means the number of pre-antral follicles you have in the system is high. Which means it is trying to protect your reserve for primordial follicles and primary follicles.
When you have a normal AMH, which is between 2 to 8.5, this is considered to be our normal AMH values based on age dependent parameters.
What typically happens is commonly when the AMH value is down?
When the AMH value is less than 1 it means the total number of pre-antral follicles are very, very less due to which the AMH value is low. This low value is causing less inhibition on the primordial follicles. And it is stimulating more of them to grow up. That's why these come inside the system and we need more for reproduction. Simultaneously, this low value of AMH also allows FSH values to go up so that these small follicles, just in case one of these missed out this high natural induced FSH value. Can inhibit the threshold of recruitment and can recruit as many follicles as we can. As a result of which in patients with low AMH, you have an increased FSH value as well.
Predominantly the AMH is going to get secreted from this granulosa cells. These granulosa cells know it is this who are going to secrete all the AMH inside the blood circulation. As the follicle grows larger in size, E2 values of the follicles keeps on growing up because the E2 value in the follicle grows up, E2 directly inhibits the AMH inside that follicle.
And it ensures that there is no further expression of AMH from the large enteral follicle onwards, because E2 is inhibitory over the AMH values. We have one condition, which is polycystic ovarian syndrome. And in polycystic ovarian syndrome, when AMH values are more than 10, we feel that, okay, if the AMH is more than 10, that means there are a greater number of follicles which are recruited, but it can also mean that there are a greater number of apoptotic follicles. The predominant reason why in PCOS the AMH value rises is because there is an abnormal granulosa cell response.
It is believed that this abnormal granulosa cell response occurs due to increased values of LH, which is common in PCOS patients. And because there is increased value of LH, granulosa cell response is very, very poor. And it causes E2 to stay low because it causes androgen values to go high. And because the androgen value goes high in PCOS, there is reduced E2, because there is reduced E2, there is reduced negative feedback onto AMH due to which in PCOS patients, AMH value is normally very high.
AMH and Antral Follicle Count
There are going to be certain instances, especially in cases of low AMH, where there is going to be no correlation of antral follicle count with the value of AMH which is concerned. In that type of situation, should you consider AMH or should you consider antral follicle count? Please remember for that cycle, it is important that you look at antral follicle count as far as stimulation is concerned. The same theory of androgen, which I explained in my previous slide is also going to help you understand what is the role of using testosterone gel in patients with low AMH, especially when you want to use it for 21 days. It has been proven 21 days in the previous cycle. What it does in these 21 days causes oestrogen values and those follicles to go down, which allows for a good amount of reverse negative feedback onto AMH and thereby it increases the FSH in that cycle and it allows more follicles to be recruited. That is the reason why after testosterone gel, one may find a slightly increased antral follicle count in your next cycle.
One more clinical point because AMH is predominantly secreted by the small antral follicles. These small antral follicles are not dependent on exogenous FSH, LH at all. They do not have that dependency because of which AMH can be tested on any day of the cycle and at any time of the day. It usually has got no correlation to all these things. Simultaneously, you do not even need the patient to be fasting. AMH is commonly available in India as a standard ELISA kit. This is a standard kit, which is going to be available in almost all the machines which you are using. Whichever machine you are using, it is going to be the same. Everybody is the same and it uses the same kit. There are just two kits which are predominantly available in India based on which your AMH values are going to be reported. It is a wonderful standardised test. We do it in-house.
What is this Alexis machine? Do you know about it? Is it just a form of another ELISA?
It's a point of care machine. It gives you spot values on the basis of a card. What is your running time for this test in your machines? 1 hour 15 minutes maximum. I think it ranges the cost anywhere between 2000 to 2500. The cost of the kit is 800 rupees. The running cost with this Roche Alexis machine, the Koba is 8000. It is about 500 rupees and they charge around 2200 in Bangalore.
What is about the variations that we get with AMH? Is it like you do a lot of QCs? With every kit, there is a QC code which is available.
You need to configure that QC code. One kit has approximately enough to run around 60 samples. If your volume is good, then you will end up finishing doing 60 samples in let's say 5 days or a week or so. Then you don't have to run repeated QA QCs.
What about external quality assurance? Do you do that like you compare with the other labs?
Honestly, we just do it once in a month with any of the other labs, but not very routinely, not beyond once in a month. Coming to clinical application of this AMH, I think AMH, we all do it to know whether they are hypo-responders or hyper-responders.
Is it for more of hypo-responders or hypo-responders or it is like hyper-responders?
Every value of any hormone is good only when it is in the lower side. So even AMH is the same thing. It is very much more sensitive for lower responders. For higher responders, value more than 9. Your kit will process it that way. Value more than 9. When you dilute this, then you get further values. Let's say 16, 22.3, 28.5. All these values more than a particular threshold is going to indicate that the value is beyond the normal mean deviation. In that situation, no matter how high the value is, it is a poor response only because it is predominantly going to indicate polycystic ovarian syndrome. There is one set of population like PCOS in adolescence where AMH doesn't really correlate well with PCOD. What do you have to say on that? It's a fact. The reason why PCOS in adolescence, AMH alone, I would not say AMH doesn't correlate. I would say AMH alone doesn't correlate because the hypothalamus pituitary ovarian and the hypothalamus adrenal axis is not so well developed in these girls. It takes approximately age of 18 for the axis to be completely mature.
And beyond age 18, you can use AMH as a marker. You told that the AMH will be low, but the AFC may be good in that cycle so that you take the relevance of that AFC to that particular value.
But what is the role of AMH for that patient and how do you counsel them? What do you do in such cases?
The lower the AMH, no matter what you do, it is going to fall by approximately one logarithmic value. So around 8 to 10% every year, no matter what you do. No matter what drugs you give, it will not even increase beyond the logarithmic value. It is not going to happen that AMH from 1.5 has become 5.5. That can never happen. The most important counselling which we must do to people, especially in today's modern fertility practise, especially with this huge amount of fertility clinics which are available, is to ensure the patient that they don't waste time just thinking when they have low AMH. AMH is to be mandatorily done before any oncofertility programme. Mandatory, mandatory. There is no question in that.
Is there any added benefit of using FSH by AMH ratio?
And what is the peak level of AMH, the highest value? Highest value - It's 31.
So what happened in that case? Very poor response to stimulation. If they mostly, any value more than 20, you know, they will end up with empty follicle syndrome. You know, it is better that when the value is so high up, you know, madam, to do PCOS drilling in these patients, wait for one to two months and then take them up for stimulation.
How accurately can you predict menopause with this AMH values?
FSH must be more than 20 for more than two occasions, two to three months apart. For egg freezing, what is the AMH that you look at and suggest egg freezing? Forget about social egg freezing where they are not sure, but when is it that, at what AMH value that you suggest egg freezing? AMH less than one, AFC less than five. That is our standard counselling. And in that, how many oocytes would you expect to increase? Three, three metaphase two oocytes. So between FSH plus inhibitor plus E2 versus AMH. And post-GNRH administration when FSH and LH increase.
Age is the most important factor. Whether we can really intervene and improve the quality or say like increase the dosage of your gonadotropins or probably like how you said stem cells and all those things. The reason is see whenever the AMH value is low, it also indicates that the oocyte which is harbouring, see it is the oocyte which is going to allow formation of granulosa cells. Then the granulosa cells will secrete AMH. When the AMH value is low, it indicates in itself a slightly inherent problem in the oocyte. The oocyte itself is not very strong enough. AMH is more for poor response.
So at what AMH do you discourage any form of cell cycle?
If AMH is less than 0.1, antral follicle count is 1 and FSH is more than 16. In these type of situations, your response to stimulation will be very poor. Simultaneously, also do one thing. On day two, you should do estradiol. Estradiol on day two is less than 10. It itself indicates that there is no inherent oestrogen, which is being secreted by the follicle.
If there is no inherent oestrogen by the follicle, even if you see the follicle on your antral follicle count, it will most probably come out to be an atretic or an empty follicle. So maybe you can counsel the patient accordingly.
But it is not going to be that value of AMH 8 is going to become 1. It is that that value of 8 AMH might become 6.5, something like that. So these ORTs, whatever we have, it is mainly to counsel the patient about the response or what she can expect as the labour threat for her thing. So whether you can really predict the response just based on these ORTs, that is AMH and AFC, or is it like something where you can still just go ahead and do the first cycle of IVF, keep it as an index cycle and improvise it in successive cycles? I mean, what is the scenario? Because in Western where there are three IVFs, three of course to the patients, so they just go ahead and do one cycle of IVF and then they keep it as their index and they go on changing or manipulating depending on the patient's profile.
It depends on which country you are practising in. For example, if you are practising in China, it has three IVF cycles complementary to every Chinese citizen. If they have two children and they want to have the third one, they can do three IVF cycles, right? But it does not allow you to do the donor programme. But simultaneously, they have a huge AI data of how to stimulate a particular lady at a particular age at a particular AFC. So, they can probably modulate in their country according to that without using index cycles. Countries which do not have that, especially like let us say Belgium, Spain, in all these places, Germany, you can do two IVF cycles which are sponsored by the state following which your rest of the IVF cycles, you must do it on your own cost.
Here in India, as far as IVF is concerned, everybody is doing free IVF OPD. Everybody wants to do IVF cycles in 10,000 rupees, you know, with an asterisk. So, what normally happens is in a country like India, this type of scenario cannot be
AMH test pre- and post-surgery for endometriosis, when to do?
Pre-surgery and post-surgery. Pre-surgery means two days before the surgery and post-surgery, if you do for the first six weeks, your value will crash down. But after three to four months, if your surgery is good, then the values would normally stabilise, but they will go down by, let us say, 10 to 15%.
Does it reduce high AMH like it reduces LH?
Difficult to predict. It may not reduce high AMH, but it will increase the response to stimulation.
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