Months ago, I set up a Google Scholar alert (it’s easy!) to keep on top of any science mentioning ‘Anti-Mullerian hormone’. This means that I regularly get an email alert of newly published studies/articles. It’s a broad search term, there are dozens of new articles each month, and a lot of them are not relevant/interesting, but I’ll aim to discuss any interesting findings about ovarian failure/insufficiency here.
Here is an article (1) that caught my eye recently. The article raises the problem of defining the term ‘Diminished Ovarian Reserve’ (DOR). I actually found this funny, because I’ve mentioned in earlier posts that whatever is going on with my ovaries, it’s hard to know what to call it. And funny that they chose this term to try and define, because it’s not one that I like to use, for what I think are pretty good reasons. The unfortunate thing is that the authors seem unaware of the term ‘ovarian insufficiency’ (although I haven’t read the full article, just the abstract), because this is my favourite word to describe my ovaries. The terms I could chose from are: primary/premature ovarian failure, ovarian insufficiency, DOR and also LFOR (low functional ovarian reserve). Some articles also discuss ‘poor responders’ for women like me, although I’d prefer to take that term at face value, and use it for women who have had a chance to respond to something! The term is used when women have had a failed response to a stimulated cycle, whereas I’ve never tried assisted reproduction (I’m not a good candidate and I’m not really into gambling, at least not with these odds).
The authors (Cohen et al.) also state that the term POF is clearly defined. This is not the case, as I’ve mentioned above it even stands for two slightly different terms: Primary Ovarian Failure or Premature Ovarian Failure. More importantly though, POF is not a single disease. I’ve cited a great article by Lawrence M. Nelson before, and I’ll do that again here (2), where he states that POF/POI is “a rare disease consisting of multiple ultra-rare diseases”. What that means is that although the outcome is the same in these cases (non-functioning ovaries, in that ovulation is not occurring), the underlying causes are many and varied. As far as I know, it was Dr. Nelson who came up with the newer term of ‘ovarian insufficiency’, prompted by the adverse emotional aspects of patients being told that their ‘ovaries had failed’, especially when total ‘failure’ is not always the outcome.
So I prefer ‘insufficiency’ to ‘failure’ but I also prefer it to any mention of my ovarian reserve. Why is that? Because I have no idea what my reserve is! This is a good explanation of ‘ovarian reserve’:
“When clinicians and zootechnicians talk about ovarian reserve, they usually refer to this dynamic reserve of small antral follicles. However, the wording ‘‘ovarian reserve’’ can be confusing, since the growing follicles themselves develop from a first reserve of primordial follicles, which is constituted early in life”; from here (3). Basically, when some mention ‘ovarian reserve’ they are talking about growing follicles, the ones you can see with a vaginal ultrasound, but these arise from smaller (less than a millimeter) follicles, which are your true ‘reserve’.
The problem is, as stated here “There is a good reason for the paucity of knowledge of human ovarian reserve throughout life: direct longitudinal assessment is currently impossible, and is likely to remain impossible for the foreseeable future. No in vivo technique for counting NGFs [non-growing follicles] exists. All studies involving the estimation of NGF populations for ovaries at various chronological ages have analysed tissue post-mortem or post-oophorectomy” (4). In other words, the only way you can count your actual ovarian reserve is take out an ovary; cut it up; and measure the very very small follicles under a microscope.
The article quoted from above (Kelsey et al. 2012) then goes on to give evidence that measuring the ‘dynamic pool’ is still a good approximation. The authors assert that measuring the follicles that we can see, or anti-mullerian hormone (AMH) in a blood sample, should still tell us what the actual ovarian reserve of a woman might be. Therefore, doctors make these measurements and might talk about ‘ovarian reserve’ and might even make all sort of simplifications such as ‘you don’t have many eggs left’. By the way, there is also the controversial idea of ‘ovarian stem cells’, which might yet overturn the idea of ‘a woman is born with all the eggs she will ever have’, which is worth a passing mention even if it hasn’t been proven in human subjects yet.
When I first started looking into all this, I was surprised by how little was known about how ovaries functioned. I really shouldn’t have been. I’ve worked as a scientist myself, and in all areas of biology the fundamental processes at play are usually only sketched out. We’d like to think that we have a lot of it worked out (whether it is human biology, or agricultural science or anything else we’ve been researching for a while) but the truth is that science is really expensive, and we often don’t have the right equipment/techniques to shine a light.
Essentially, the technology that we have at the moment has shown us that over a population we see lower numbers of growing follicles and smaller amounts of AMH as women age, and that this correlates with their declining numbers of non-growing follicles, their ovarian reserve. And once again, I’m aware of my bias. I am not growing many follicles, I have very very low AMH (and high FSH). So I’d like to think that there is more to it than this correlation.
And maybe there is…
Another article (5) that caught my eye this month looked into follicle dynamics (how many were growing over the course of a month) of two groups of women; women of mid-reproductive age (MRA, 18-35) or advanced reproductive age (ARA, 45-55). None of the women were menopausal (even though the average age of menopause is around 50), they all had fairly regular cycles and were ovulating. The thing that really stood out to me was that all of the older women had low AMH (<1 ug/L) and 50% of this group had undetectable AMH. This is to be expected, in this age range. BUT these women were ovulating and were seen to be growing plenty of small follicles as well (each time you ovulate there is more than one follicle growing).
Maybe it doesn’t mean much, it was only a small study. Also, they only followed women with regular cycles, so women like me are still in the dark as to what our ovary dynamics might look like. Certain women were not included in the study because they ‘developed a lag phase of follicle development’, defined as no follicles larger than 6mm growing 20 days after either menstruation or ovulation*. This to me sounds a lot like intermittent ovulation/recruitment of follicles, which is not supposed to happen! But which could be what is going on in my case? We’ll only ever know with more research, I guess.
So my lack of growing follicles means I’m not likely to fall pregnant, and my low AMH probably does signal that something is not quite as it should be. I’m not convinced that this means that I’ve used up my egg supply early though. For all I know there could be thousands still there yet they are stubbornly refusing to grow. So while ‘insufficient’ might mean ‘insufficient eggs’ to some people, to me it means that the functioning of my ovaries is insufficient, but there are plenty of things that can go wrong to cause that unlucky state.
*we now know that follicles don’t just grow in the ‘follicular’ phase after menstruation. This article in fact was looking at follicles that start growing in the luteal phase.
- Cohen et al. 2015 ‘Diminished ovarian reserve, premature ovarian failure, poor ovarian responder – a plea for universal definitions’. Journal of Assisted Reproduction and Genetics, pg. 1-4; DOI 10.1007/s10815-015-0595-y
- Nelson, L. M., 2011 ‘One world, one woman: a transformational leader’s approach to primary ovarian insufficiency’. Menopause. 18(5): 480-487; DOI 10.1097/GME.0b013e318213f250
- Monniaux, D., et al. 2014 ‘The ovarian reserve of primordial follicles and the dynamic reserve of antral growing follicles: what is the link?’. Biology of Reproduction. 90(4): 1-11; DOI 10.1095/biolreprod.113.117077
- Kelsey, T.W., et al. 2012 ‘Data-driven assessment of the human ovarian reserve’. Molecular Human Reproduction. 18(2): 79-87; DOI 10.1093/molehr/gar059
- Vanden Brink, H., et al. 2015 ‘Associations between antral ovarian follicle dynamics and hormone production throughout the menstrual cycle as women age’ Journal of Clinical Endocrinology and Metabolism. in press; DOI 10.1210/jc.2015-2643