Hypoandrogenism in Association with Diminished Functional Ovarian Reserve
CHR research has found a relationship between low testosterone levels and diminished ovarian reserve, and is developing individualized infertility treatments, explains Dr. Norbert Gleicher.
Title: Low Testosterone Associated with Diminished Ovarian Reserve
Speaker: Dr. Norbert Gleicher
Research publication discussion: Hypoandrogenism in association with diminished functional ovarian reserve
What are the main findings of the study?
As we have been investigating DHEA effects, and as we recognized that the DHEA effects are exerted through the conversion of DHEA to testosterone, and as we recognized that the lower the testosterone level of a patient was when she came to us, and the higher we got it with DHEA supplementation the better her pregnancy chances subsequently in IVF were, that suddenly raised for us the question whether the diminished ovarian reserve in itself may not represent simply a low androgen situation — hypo-androgenism as we call it medically. And so the paper that we just recently published in human reproduction investigated that question.
What we basically did here is we took two distinct patient groups with diminished ovarian reserve. We took the typical older woman, who develops diminished ovarian reserve because she is getting older, meaning above age 40. And secondly, we took younger women, with what we call premature ovarian aging, who at very young ages already show significantly diminished ovarian reserve by FSH and/or lower MH levels. And we looked at their androgen levels, and we compared those androgen levels to young women with normal ovarian reserve, egg donors.
Not surprisingly — based on what we had recognized previously in our analysis of our patients undergoing DHEA treatment — we found that really both premature ovarian aging and ovarian aging due to advanced age are characterized by unusually low androgen levels. And this is actually quite interesting because it is expected that androgen levels decline as we get older, so finding low androgen levels in women above age 40 was not a surprise, even though 40 is not a real old age, and, you know, the degree of low androgens even at that point could be seen as somewhat surprising. But what really surprised us is that women with premature ovarian aging even showed lower androgen levels than women at older ages with diminished ovarian reserve, and this is a very important finding potentially, because, like frequently in medicine, the question is: what’s first, the chicken or the egg? Is the low androgen the initial defect leading to diminished ovarian reserve or is diminished ovarian reserve the initial defect leading lower androgen? And the fact that you find low androgens also in young women with premature ovarian aging, and even to a more extreme degree, strongly suggests that the androgen defect may come first, and that in turn is very interesting because a large portion of androgens in women is produced by the adrenals; the other portion is produced by the ovaries, particularly DHEA is exclusively produced by the adrenals.
And so that may suggest that POA, premature ovarian aging, is maybe not, at least exclusively, only an ovarian disease or an ovarian condition, but may actually represent an adrenal insufficiency. And this is very, very interesting because it is the mirror image of what we now know already for a number of decades about PCOS, Polycystic Ovarian Syndrome, where the high androgen levels are coming both from adrenal and ovary. And so a concept is evolving here — and that was really the main, or one of the main messages of our paper in human reproduction — that diminished ovarian reserve, at least in its POA form, in its premature ovarian aging form, may be the functional counterpart to PCOS.
In PCOS, you have high androgen, lots of follicles, very high functional ovarian reserve. In POA, you have exactly the opposite, you have diminished functional ovarian reserve, very low androgen levels, and very few follicles, and both of those appear to have adrenal as well as ovarian components. And so they may represent opposite extremes of the same physiological process, not dissimilar to hypo- or hyper-thyroidism, for example for the thyroid, or other endocrine organ conditions where you can have over- or under-functioning. And so in that sense this is a very important paper that may shed new light on the path of physiology of the process.
Low testosterone is detrimental to fertility, but high testosterone, as in PCOS patients, is also detrimental to fertility. How could this be explained?
Now, the question of why testosterone, or higher testosterone levels, are good for fertility when very high testosterone levels such as in PCOS, Polycystic Ovarian Syndrome, are bad, is a very good question. And it is indeed not only a question that has been puzzling us in this field for a very long time, but it was actually the fact that very high androgen levels in PCOS are perceived as being bad, which is a big reason why high testosterone levels for decades have been considered a bad thing in infertility.
What we are now understanding is that, probably like almost anywhere in medicine, what is important is a range: if you fall below the range, it is bad, but if you exceed the range and go into toxic levels, it is also bad. And that very likely applies to androgen levels as well. Too low levels will stop the growth of early small growing follicles. On the other hand, if you get too-high androgen levels, then you may get into toxic range, and you may also get adverse effects. That is one issue. So the concept of range is a very important concept to consider.
The second very important issue here is — not reported in our paper, but another topic that we are currently very actively pursuing is — that once again, from animal models, we know that in these early stages of follicle maturation, there is a synergistic, meaning a “cooperative effect”, between androgens, between testosterone, and FSH, follicle stimulating hormone. And that is also a somewhat surprising finding because these early stages of follicle maturation have been in general considered not to be FSH dependent. In other words, FSH sensitivity was believed to kick in only at much later stages of follicle maturation. Animal work now very strongly suggests that even at those early follicle stages what androgens do is they sensitize to FSH effects. And so androgens and FSH kind of work together, making 2+2 appear to be 5 or 6 rather than just 4, and that is a very important potential concept, clinically as well, because it allows us to manipulate our treatments of patients.
But more importantly, what it demonstrates is something that we here at CHR have been developing for quite a while (and I actually, with Dr. Vacopher, who is a visiting scientist from Vienna University in Austria, a few years back wrote a paper in human reproduction on this subject), we believe that increasingly, as we are trying to develop individualized treatments, we will go away from working towards certain specific hormone levels, lets say wanting to get a certain androgen level, or a certain testosterone, or a certain FSH level, or want to stay below a certain level, and instead we’ll start looking at how different hormones interact with each other. In other words, in this example, where we know that testosterone or that FSH work together, the important thing may not be what’s the absolute level of FSH and what’s the absolute level of androgen, but what is the ratio between the two. If one goes up, the other one needs to go up, too, and if they are not in sync, then even though you may have good levels in one you may still not have an ideal environment where you want to be. So this is a very quickly evolving concept here at CHR, and we are doing a lot of research on this, and again I think the androgens are leading here and, once again, the idea came from what some of our colleagues recognized happening in most models.
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