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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 at 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. And so the
paper that we just recently published in human reproduction investigated that question and
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;
and 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 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.
Now the question 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 giving,
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.