There has never been a
biopsy-controlled study showing that menopause eradicates, destroys
or cures endometriosis. Nor has there has ever been a
biopsy-controlled study showing that removal of the ovaries
eradicates, destroys or cures endometriosis. One of the oldest
patients with endometriosis, age 78, was reported by Haydon.
The
oldest patient with biopsy-proven endometriosis treated at the St.
Charles Endometriosis Treatment Program was 74. So strong is the
notion that removal of the ovaries will destroy endometriosis, that
this elderly patient had her uterus, tubes and ovaries removed at
the age of 73 in order to "cure" her endometriosis, even
though she was not on estrogen and had received radiation therapy in
the 1940s to destroy her ovaries.
Where did the notion arise
that menopause (and, by inference, removal of the ovaries) could
destroy endometriosis? Since he had not seen endometriosis after the
menopause, Sampson had "hope" that cessation of ovarian
function would "usually, possibly always" "probably"
cause atrophy of endometriosis.
Endometriosis requires more
than verbs and adverbs for its treatment. Meigs aggravated this,
ignoring among his 16 menopausal endometriosis patients the fact
that two still had ovarian endometriomas. He proposed removal of the
ovaries as a method of stopping ovarian function which would make
the cysts within the ovaries stop growing and slowly atrophy. As an
example of the "success" of this therapy, he reported the
case of a patient whose pelvic mass (which was presumed to be
ovarian endometriosis) persisted for 25 months after removal of her
ovaries. (sic)
Proponents of the menopausal eradication
theory seemed to have a knack for offering unsupported opinions or
misinterpreting data. Cattell and Swinton stated that "castration
will cause the lesion to recede and usually relieve symptoms,"
although no data or references were offered in support. Cattell
later noting that 54% of patients with significant bowel disease
continued to be symptomatic or have abnormal GI x-rays after
castration and retention of disease favored removal of the ovaries,
although he did not discuss the rationale of a therapy which left
most patients with abnormalities.
Fallon, writing without
supporting references, stated that "... all endometriosis
regresses after removal of the ovaries..." Counsellor and
Crenshaw stated (without references) that "Obviously, the
quickest and most certain way for the relief of pain is the
destruction of the ovarian function."
Of course, it is
now realized that these early studies on menopause and endometriosis
based their conclusions on observations of symptoms or apparent
rates of diagnosis of endometriosis among menopausal patients:
patients seemed to hurt less or not at all after the menopause, and
since gynecologists rarely saw endometriosis after the menopause, it
was concluded that menopause physically destroyed the disease. They
did not use biopsy-controlled studies to prove these opinions, and
there remains to this day no proof that menopause destroys
endometriosis.
Kempers reported 138 endometriosis patients
who were 2 or more years post-menopausal. Only two had been on
estrogen. Sixty-one percent had been pregnant and 41 had clinically
significant intestinal disease. At St. Charles' Endometriosis
Treatment Program, we have seen 65 patients with biopsy-proven
endometriosis after hysterectomy and oophorectomy. Some of these
patients were in their 20's and had not had children. They were told
that hysterectomy and castration with retention of their disease
would cure their endometriosis.
For a doctor to believe that
menopause is a good treatment for endometriosis, he must believe
that women do not need estrogen. Additionally, for natural or
surgical menopause to work, some as-yet-undescribed, miraculous
cytocidal histo-hormonal effect must occur. So far, the only support
for this mysterious effect is the shrill chorus of those without
historical or scientific perspective who still believe that it
occurs.
Danazol
was the first drug approved in America for treatment of
endometriosis by pseudomenopause, and it came as no surprise to find
out that it does not eradicate endometriosis since it was never
scientifically proved that the menopause eradicates
endometriosis.
It is now realized that danazol does not
eradicate endometriosis of any stage or location, and the hopes
dashed by danazol seem to be a combined result of historically
misplaced expectations, errors of visual identification, and failure
to confirm clinical observations by biopsy. Reports on the use of
danazol for endometriosis have shown an actual decrease in fertility
in treated women with minimal or mild disease compared to operative
laparoscopy or observation only while the improved pregnancy rate
following surgical therapy for disease associated with pelvic
adhesions has long been recognized.
Since there is a
surprisingly high background pregnancy rate of up to 57% in
untreated disease in infertile patients, the true effect of
allopathic medical or surgical therapy on fertility is difficult to
determine, since it may be small. It seems most likely that much of
the "improved" fertility after treatment is due to the
natural history of endometriosis, not to the treatment
itself.
Urologists have questioned the use of danazol for
endometriosis involving the urinary tract, noting it to be
ineffective for relief of obstructive ureteral endometriosis. Since
danazol does not eradicate endometriosis, it is also not surprising
that it is ineffective in long term relief of pain. Just another
money, rather than research based marketing scam.
GnRH agonists such as Synarel,
Lupron and Zoladex are the heirs to danazol. They seek to mimic the
hypoestrogenic menopausal state by inducing a profound suppression
of pituitary gonadotropins. However, since this approach shares
danazol's historical basis of origin, one would naturally predict
that GnRH agonists would replicate danazol's shortcomings, although
with different side-effects.
An early report on the efficacy
of one GnRH agonist, buserelin, assessed response of the endometrium
rather than endometriosis, assessed the visual appearance of
endometriosis at the conclusion of therapy when errors of visual
identification are common, and spoke of disappearance and resorption
of lesions without biopsy proof. The definite impression was left
that GnRH agonist therapy resulted in physical eradication of
disease.
The large multicenter randomized,
danazol-controlled, study of nafarelin-treated patients which helped
gain its FDA approval, although impressive on the surface, repeats
some of the errors found in earlier studies of medical therapy. The
study was based on the undefined and unreferenced statement that
"endometriosis resolves after ovariectomy and menopause."
(emphasis added) Of 236 patients begun on therapy with either of two
doses of nafarelin or one dose of danazol, almost 10% were
immediately censored from the study for various reasons.
Visualization at laparoscopy before and at the end (when ovarian
suppression can give the false impression that disease has been
eradicated) of Synarel therapy was used to assess response of the
disease.
The undefined concept of "resolution" was
the endpoint of therapy. "Resolution" may mean many things
to many people, including such disparate results as physical
destruction or eradication ("cure"), partial eradication,
visual improvement which indicates physical eradication, or visual
improvement alone with no implication as to the physical eradication
of disease. Biopsy control was not used to ensure that all patients
had endometriosis or that all lesions visualized were indeed
endometriosis.
It is not known whether all of the eighteen
investigators in the study had the same degree of expertise in
diagnosing endometriosis in all of its subtle manifestations. Other
peritoneal changes such as chronic inflammation or
microcalcification can sometimes mimic endometriosis, and without
biopsy, there is no way to be certain what is or is not
endometriosis. Patients treated with Synarel were compared to
danazol, but not to placebo. The decision not to compare Synarel to
placebo was made on ethical grounds. Although the ethical concerns
were not detailed, presumably it was because an earlier study had
shown pain relief during therapy.
Concern has been voiced
that medical (or surgical) studies of infertility which do not
include a placebo group may over-represent the fertility results,
since the background pregnancy rate with untreated endometriosis is
up to 57%. Detailed analysis of this study indicates it is actually
not a study of infertility patients, however. Nonetheless, the crude
pregnancy rate among the unstated number of patients treated with
Synarel who later attempted pregnancy was between 30-52% by 12
months after treatment ended. Since the group attempting pregnancy
presumably included patients with normal but untested fertility,
this is not an impressive pregnancy rate following
therapy.
Long-term follow-up was not done; patients were
followed only until they became pregnant, or until 12 months after
treatment ended. Follow-up was apparently done primarily for
patients attempting pregnancy. By 6 months after the end of
treatment, 15% of the original 236 patients entered in the study had
been censored or apparently lost to follow-up.
The choice of
symptoms and methodology of study of symptom response during
treatment was somewhat illogical. Ironically, dysmenorrhoea (painful
menstruation) was clustered with dyspareunia (painful intercourse)
and pelvic pain not related to menstruation, and a total symptom
score was developed to assess symptom response during treatment.
Since nafarelin in high dose is a potent inhibitor of ovarian
function, most women can be expected to become amenorrheic while on
therapy. Since dysmenorrhoea is usually thought of as pain or cramps
due to the menstrual flow, cessation of menses for any reason will
obviously result in improvement of dysmenorrhoea.
Since this
improvement is assured by amenorrhoea (absence of menstruation),
this may skew the results of symptom response in an artificially
favorable direction by lumping a symptom which will always respond
to amenorrhoea (dysmenorrhoea) with symptoms which may not respond
to amenorrhoea (dyspareunia, pain not associated with the menstrual
flow). It would have been more helpful to assess the individual
response of each symptom. Since it is known that other causes of
pelvic pain are also estrogen-responsive (such as fibroids or
adenomyosis), improvement of symptoms during therapy cannot be
ascribed with absolute certainty to improvement of symptoms caused
by endometriosis. Improvement of symptoms is therefore based on the
assumption that symptoms were all due to endometriosis.
While
endometriosis is a potent cause of pain, and while it may be true
that much of the pain relief experienced during treatment may truly
have been caused by endometriosis, we simply do not know for certain
that the observed improvement represented a favorable response of
symptoms due to endometriosis. This is a reprise of Kistner's
postulate of an "assumed fact." This is why it is much
safer to study biopsy-proven evidence of persistence or recurrence
of endometriosis after medical or surgical treatment, since this is
the only measurement which is absolutely indicative of the true
response of the disease to treatment. Anything else is just a matter
of opinion, not fact. This study was recently sent to all
gynecologists by Syntex after FDA approval of Synarel as a promotion
of the drug.
As
noted above, lack of biopsy-controlled studies has led to ambiguous
results which are made all the more so by the now well-known concern
over accurate identification of endometriosis. Have all clinicians
participating in medical studies had the same expertise in the
diagnosis of disease? Why Choose Homeopathic Infertility Treatment? - Read here Understanding Infertility Terminology - Read here
Lack of long-term follow-up makes it
difficult to know where to put medical therapy in the context of
treating endometriosis. What happens to these patients later? How
many require surgery later? How many have persistent endometriosis?
These are important common-sense questions that patients and
practicing gynecologists need to have answered.
The
assumption has been made in medical therapy studies that the
symptoms of pain and infertility are caused by endometriosis, and
that resolution of either symptom meant that the disease was
responding to treatment, perhaps even being physically destroyed by
that treatment. In fact, many pain symptoms may not be due to
endometriosis, yet may respond during cessation of ovarian function
by medical therapy, dysmenorrhoea will always improve with cessation
of menses, and inclusion of this symptom in a global score for pain
is misleading. Medical therapy for endometriosis is non-specific and
will always seem or pretend to be better than it really is.
The
lack of untreated control groups in studies of infertility patients
is disturbing in light of recent concern that patients with Stages I
and II endometriosis (most patients who have endometriosis are in
these two stages) conceive without treatment at rates equal to or
better than the rates of patients undergoing medical therapy. There
is increasing recognition that this means endometriosis may not be
the potent cause of infertility it was once thought to be. Actually,
many studies have found that fertile women predominate in
populations of patients with endometriosis.
One of the most
important, fundamental errors of the past is the notion that
infertility is the most common symptom of the disease. As a result,
success in treatment of the disease is still measured primarily in
terms of pregnancy rates. Even though pain seems to be a more common
symptom of endometriosis than is infertility, the patient with pain
has been largely ignored, both by gynecologists in search of
patients for study and by the current measure of successful
treatment, i.e. pregnancy. These patients have also been slighted by
the AFS Classification System of Endometriosis, which exists
primarily for comparing infertility patients.
These problems
continue to be magnified today. Thus, many endometriosis patients
targeted for study are recruited from the ranks of the infertile
rather than the ranks of pain sufferers. Many papers on
endometriosis are produced from departments of
infertility/reproductive endocrinology at metropolitan medical
schools rather than from clinicians in general practice. Once this
infertile minority is selected out, they are subjected to medical
treatments based on scientifically unproven clinical impressions
(that menopause or pregnancy makes endometriosis go away or get
better). Many modern studies have shown these medical therapies to
be ineffective in eradicating endometriosis and to have no apparent
beneficial effect on pregnancy rates. Therapy based on these errant
findings is then offered to the majority of patients with pain as a
primary symptom.
A final difficulty facing medical treatment
is the finding that many recent studies have shown that individual
endometriosis lesions have widely varying concentrations of estrogen
and progesterone receptors, and that these hormones are usually
present in amounts lower than the native endometrium. For this
reason, endometriosis does not bleed predictably or reliably with
the menstrual cycle as generations of gynecologists have been
taught. (This is one of the explanations for atypical, subtle or
non-hemorrhagic forms of the disease.)
For pregnancy, birth
control pills, danazol, GnRH , or menopause to have a beneficial
hormonal effect on endometriosis, the lesions would have to respond
to the presence of estrogen and progesterone (birth control pills or
pregnancy), or lack of estrogen and progesterone, (danazol, GnRH,
menopause.) The first problem is that these therapeutic endpoints
are diametrically opposed and irreconcilable. You can't have it both
ways. Progesterone and estrogen cannot have both a positive and a
negative impact on the disease (many would argue that they have no
impact at all). In addition, for any of these hormonal states to
have a therapeutic effect, the estrogen and/or progesterone would
have to have a fairly uniform effect on all populations of
endometriosis cells.
The low and varying population of
estrogen and progesterone receptors in endometriosis cells in the
same patient predicts that any hormonal effect based on our current
knowledge would be erratic, inconstant, ineffective and therefore
irrational. If we have been putting most of our eggs in the
infertility basket, and we now realize the basket has holes and the
eggs have cracks, why do we persist in using obsolete thought
processes which run down our legs like yolk? Why do we still try to
cram the square peg of endometriosis into the round hole of
infertility? Why is this happening? Who is in control?
One
argument is often offered in support of medical therapy. One
traditional theory of origin proposes that endometriosis is caused
by monthly regurgitation of viable endometrial cells in a reverse
flow through the fallopian tubes. These cells are thought to fall
like seeds on fertile soil, implant and grow. Following this theory,
if the monthly regurgitation could be stopped or reduced, it might
reduce the likelihood of future implants and perhaps allow
resorption of implants already there.
For starters, this
theory of reflux menstruation and implantation is just one of at
least 10 theories of origin and it has not been proven. The real
problem, however, is that physicians continue to prescribe
ineffective and experimental medicines in a relative vacuum
populated only by words such as "perhaps," "might,"
and " is thought to." Greater insight is needed into the
basics of this disease before rational medical treatment can be
offered. Actually, it will be impossible ever to study the effect of
medical therapy on endometriosis for a simple reason: you can't
biopsy the same cell twice to study it.