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Under 38 and Unexplained Infertility Study Enrollment
We have started enrolling patients into our new DHEA study: To qualify, patients have to be under age 38 and have to be diagnosed with so-called “unexplained infertility.” In practical terms this means that they have at least one year of infertility with regular sexual intercourse, have regular periods and were found by hysterosalpingogram (HSG) to have normal tubes. In addition, the male partner has to have had a normal semen analysis.
Women who qualify will receive free care and free medication for the length of the trial. They, however, have to be willing to be randomized to either DHEA or a placebo. With these qualifications, patients are encouraged to contact usand ask for possible enrollment in the DHEA Unexplained Infertility Study.
Does Unexplained Infertility really exist?
Many standard professional textbooks suggest that Unexplained Infertility
(UI) represents the most frequent infertility diagnosis in women, encompassing
up to approximately 30% of all cases. Yet, we here, at CHR, are not
convinced at all that such a diagnosis actually exists and, even
if it were to, we believe that Unexplained infertility would represent
a misnomer that should be changed.
If you wish to determine your options,
currently, we are offering a Free
Unexplained Infertility E-Mail Consultation.
With this free e-mail consultation we will advice you as to the technical
options that exist today for those diagnosed with Unexplained Infertiliity.
Defining
the Unexplained Infertility Diagnosis
A couple that has been assigned the diagnosis Unexplained Infertility,
obviously suffers from infertility and has undergone a diagnostic work
up which failed to reveal a credible underlying cause for their condition.
In other words, the diagnosis of UI is reached by default; it is a
negative diagnosis, suggesting that a clinical problem exists but that
the probable cause for this problem has remained elusive.
The reasons why underlying problems may not be recognized can, of
course, vary. One possibility is that there, indeed, is no one obvious
cause for a couple’s infertility and that their problem may be
the result of multiple minor aberrations in how their respective reproductive
systems cooperate. After all, the successful establishment of pregnancy
is a highly complex process and, at least on a theoretical level, one
can assume circumstances where male and female fertility, each, are
affected only to such a mild degree that standard diagnostic tests
would still be considered within normal parameters. Yet, together,
the reduction in the couple’s combined fertility potential is
large enough to cause infertility.
Whether such a circumstance, indeed, exists is, however, highly questionable.
Moreover, even if it were to exist, it would behoove us to improve
the sensitivity of our diagnostic testing, so that testing procedures
become able to detect even subtle and multifactorial abnormalities
in the reproductive processes which can lead to infertility. Any such
improvement in diagnostic abilities would then, of course, eliminate
the need for a diagnostic entity, called UI, which brings us to the
main rational of our argument against the continuous usage of this
terminology: Since the diagnosis of UI is a diagnosis of exclusion,
it will be only as good (or bad) as the diagnostic work up that has
been performed.
Another way of saying this is, that the more comprehensively and the
more accurately the diagnostic work up is performed, the more likely
will a cause for a couple’s infertility be detected and the less
likely will they end up with a diagnosis of UI. The opposite is, of
course, also true: the shoddier a diagnostic evaluation, the more often
will it end up with a diagnosis of UI.
This, of course, creates a rather peculiar incentive structure: the
poorer the medical care, the more likely a couple will end up with
a diagnosis of UI; - exactly the opposite of what one would like to
see with good medical practice where, of course, good care should be
rewarded by better diagnostic accuracy, and not by less.
Physicians and their professional organizations disagree on what constitutes
a complete infertility evaluation. The hypothetical conclusion that
a couple suffers from UI will, therefore, greatly vary between practitioners,
and what is considered UI in one practice may have a very specific
diagnosis in another. Indeed, at CHR we have become convinced that
four very specific conditions are frequently overlooked and, therefore,
misdiagnosed as UI. We have reached this conclusion not only based
on observations in or own patient population but also from a careful
analysis of the medical literature. And, while the brief summary, presented
here, does not allow us to offer the necessary detail of our medical
literature review (inclusive of references), we encourage our readers,
who are interested in more detail, to contact us and we will gladly
provide you with a more detailed manuscript.
Conditions Misdiagnosed
We very carefully evaluate patients, who reach us with a presumptive
diagnosis of UI, for the following four conditions: (1) Endometriosis; (2)
Tubal Disease; (3) Prematurely Aging Ovaries; and (4) Immunological Infertility.
In our experience, we will find evidence for one, or more, of these conditions
in an overwhelming majority of cases. technique embryos are produced from eggs
and sperm
Endometriosis
This condition is one of the great mimics in medicine. It may be present
to a very mild degree and cause considerable symptoms, or affect a patient
very severely without her even being aware that she has the condition.
Diagnosis is further hampered by the fact that endometriosis often is only
microscopic in nature, which means that, even during laparoscopy, the by
far most reliable diagnostic technique available, the condition can be
overlooked and/or underestimated in severity.
Whether so-called mild endometriosis affects fertility has remained
under dispute. We very strongly believe that it does and, even more
importantly, that it affects fertility adversely in many different
ways. The strongest support for this position comes from research data
on IVF and GIFT cycles where the consensus now increasingly suggests
that women with endometriosis do poorer than age-matched controls without
the disease.
And they do poorer in practically all the aspects of the process,
from having fewer eggs at time of retrieval, poorer quality eggs, and
having lower implantation- as well as pregnancy rates. Additional investigations,
which have attempted to elucidate why that would be the case, suggest
(as we will discuss below in more detail) that their fallopian tubes
may function abnormally, that ovarian function may be adversely affected
and that endometriosis may release toxic substances which may harm
embryos and/or their implantation capacity.
There are also many studies in the literature which point towards
similar patient profiles between women with endometriosis and UI. Putting
all of this information together, we are, therefore, convinced that
at least some women, erroneously labeled with a diagnosis of UI, in
reality suffer from endometriosis – related
infertility.
Tubal Disease
The high rate of misdiagnosis of tubal disease has been well documented in
the medical literature. Most of this misdiagnosis can be attributed to the
limitations of hysterosalpingography (HSG), the principle diagnostic screening
technique utilized world wide in the diagnosis of tubal disease. Indeed, CHR
has been in the forefront of research on the reliability of HSG and quite convincingly
demonstrated a number of years ago the limitations of the technique, as it
is utilized in most radiology suites (at CHR we perform HSGs in a more sophisticated
and, therefore, more reliable way, called a Gyneco-Radiologic Study, or GRS).
As also reported by others, HSG is particularly poor in diagnosing
correctly distal (i.e. fimbrial) tubal disease and peritubal adhesions.
In addition, the literature suggests that the reliable interpretation
of HSGs suffers from considerable variability of interpretation. This
is also confirmed by a currently ongoing study at CHR in which we review
outside HSG films and compare our, to the original, reading of the
films by the radiologist. So far, we have, in a review of over 100
HSGs, significantly disagreed in over 60% of cases with the diagnostic
reports that accompany the original films.
HSGs have only the ability to investigate the anatomic condition of
the fallopian tubes. While obviously important, at least equally important
is the functionality of the oviducts. This can, as we reported a number
of years ago, and as a number of investigators in Europe have since
confirmed, be assessed by measuring the tubal perfusion pressure (TPP)
of the fallopian tube. When competent HSG is performed in combination
with a TTP evaluation, this modified form of a HSG is called a GRS.
Elevated TPPs are in over 80% of cases associated with the laparoscopically
confirmed presence of endometriosis, once again confirming not only
that tubal disease is greatly under-diagnosed but that endometriosis
is, as well.
Little doubt is, therefore, left that at least some cases of UI represent
the failure of proper diagnosis of tubal disease, especially distal
and functional tubal disease, frequently associated with endometriosis.
Prematurely Aging ovaries (PAO)
It is now widely believed that ovaries age in a very specific pattern,
along a typical aging curve, which, in turn, is defined by the number
of remaining follicles within the ovaries.
Women are born with approximately 300,000 follicles and that number
declines by approximately one half every 10 years. In parallel to this
modest decline in follicular numbers, female fertility declines only
modestly until approximately age 37.5 years, when roughly 25,000 follicles
are left over. From that point on, the decline in fertility accelerates
in parallel with accelerated follicular loss until menopause sets in
at average age of 51. It is now assumed that the period between acceleration
in fertility decline (age 37.5 and 25,000 follicles) and menopause
(age 51 and 1,000 follicles) is fixed at approximately 13.5 years.
Women with PAO follow a similar curve; however their ovarian aging
curve is, for reasons which are still often unclear, moved to the left
of the chart. In other words, they reach all the key points on the
aging curve, noted above, at much younger age, though at equal time
intervals. This, of course means that these women will not only face
a dramatic decline in their fertility potential prematurely but will
also enter menopause early. Indeed, the literature suggests that approximately
11% of women encounter menopause early. Many from amongst this very
large pool of women can, therefore, also be expected to experience
an accelerated fertility decline much before the usual age of 37.5
years and, since they usually do not exhibit any specific symptoms,
they are frequently mistakenly diagnosed with UI.
We believe that in infertility practices, where women with PAO can
be expected to be concentrated, they will represent a surprisingly
large pool of patients. At CHR, during 2004, we found evidence of PAO
in over 60% of our patients under age 38.
A timely and correct diagnosis in these women is of crucial importance
because, if such women are correctly diagnosed with PAO and if their
medical treatment is then geared towards their ovarian, - rather than
their chronological, age, pregnancy rates with IVF will still be surprisingly
excellent, as we demonstrated in a soon to be published study of over
60 women with PAO under the age of 35.
The literature, therefore, quite convincingly suggests that quite
a considerable number of women with the presumed diagnosis of UI, indeed,
suffer from PAO.
Immunological Infertility
Whether abnormal immune function can affect female fertility has remained
a highly contentious subject. Many much esteemed colleagues vehemently argue
that there is no evidence for such a connection. At CHR we strongly disagree
with them, even though we have to acknowledge that, so far, no treatment for
immunological infertility has proven its value in properly conducted clinical
trials.
The fact that we do not have a good treatment for immunological infertility,
however, does not mean that it does not exist or does not require proper
diagnosis. Indeed, we believe that the auto-immune literature provides
overwhelming evidence in support of the fact that (auto)immune mechanisms
can reduce female fertility potential. The most poignant one lies in
the observation that women with classical auto-immune diseases, such
as rheumatoid arthritis, systemic lupus erythematosus, scleroderma
and otheres, long before they become clinically symptomatic and, therefore,
are diagnosed with their diseases, already demonstrate a significant
decline in fertility. This has, by now, been demonstrated in a large
number of studies all over the world, including a recent study conducted
at CHR.
We, therefore, are convinced that immune abnormalities, especially
auto-immune factors, can adversely affect female fertility and need
to be recognized as such, if for no other reason because the same abnormalities,
once the patient does conceive with treatment, increase the risk of
pregnancy loss, if left untreated. In contrast to immunological infertility,
immunological pregnancy loss can in many cases be successfully treated.
Following this argument, it also appears logical to assume that at
least some cases, wrongly diagnosed as UI, in reality suffer from immunological
infertility.
Unexplained Infertility Next Steps
The first step is easy, simply complete the Unexplained
Infertility
E-Mail Consultation Form. Whenever
patients are referred to us with such a diagnosis, we very
carefully reevaluate their diagnostic work-ups, with special
concentration on the four medical conditions, described
above, which, in our opinion, so often are missed, leading
to the misdiagnosis of UI. Following such a policy, the
prevalence of cases where we can not identify the presumptive
cause of a couple’s infertility has become very small.
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