| Summary:
The Endometriosis Research Center has issued a formal
position paper on the use of GnRH agonists in a pre-diagnostic
setting, due in part to a recent article in Fertility
& Sterility advocating such manner of usage. It
is becoming an increasingly popular trend among certain
physicians to push for pre-diagnostic GnRH usage; that
is, administering Lupron®, Zoladex® or Synarel®
to their patients in whom surgical confirmation of the
disease has not been obtained. The ERC does
not advocate the use of GnRH agonists in this manner
and strongly opposes such practice.
USE OF GnRH AGONISTS PRIOR TO AN ENDOMETRIOSIS
DIAGNOSIS
In today's age of rapid-paced medicine, the premise
of "faster, better, more" pervades the healthcare
industry. To be certain, a multitude of positive developments
has been made in the realms of disease research and
treatment. For every ailment, there is a readily available
solution in our doctors' offices. In the interest of
"faster, better, more," however, is the single
most important piece of the healthcare puzzle - the
patient - being trodden on? Have some industry players
begun overstepping their bounds?
An example of such conduct is the ideology of a number
of practitioners and pharmaceutical corporations that
GnRH agonists can - and should - be used to diagnose
Endometriosis. This practice is inherently flawed at
best; of questionable ethics at worst.
A case in point is the recent "Consensus
Statement Regarding the Management of Chronic Pelvic
Pain and Endometriosis[1]." The statement,
issued on behalf of a self-appointed "expert panel"
comprised of 52 gynecologists and experts in consensus
guideline development, concluded that "for women
in whom Endometriosis is the suspected cause of pain,
laparoscopic confirmation of the diagnosis is unnecessary."
The authors instead recommend a course of medical therapy,
including Danazol, GnRH agonists and progestins to potentially
diagnose and treat the symptoms. For the purposes of
this document, we will be limiting our statements to
the use of GnRH agonists in such a manner; specifically,
the most commonly prescribed agonist in the United States,
Leuprolide acetate (Lupron®).
Presumably, an "expert" is one who has dedicated
the majority of his or her practice to the study, care
and treatment of Endometriosis. Said expert would most
undoubtedly be well researched on Endometriosis and
highly trained in thorough surgical eradication of the
disease, utilizing medical therapy only when specifically
relevant to the patient's unique situation. Unfortunately,
such Endometriosis experts are in the minority; there
are but a few of these true authorities practicing within
the United States. Interestingly enough, the
participation of such experts was conspicuously absent
from this consensus panel. David
Redwine, MD, of the St. Charles Endometriosis Treatment
Center in Bend, OR is one such pioneer.
Dr. Redwine has advanced not only the understanding
of the disease, but has pioneered the most effective
treatment approaches as well.
Unfortunately, Dr. Redwine's successes were minimized
in the consensus paper, his studies called "inconsistent[2]."
Other highly regarded experts in Endometriosis
are markedly missing from the Panel as well, including
those from The Center for Endometriosis
Care in GA; The Center for Advanced Laparoscopic Surgery
in NY; The Athena Institute of Health in CA; The C.
Paul Perry Chronic Pelvic Pain Clinic in AL; Georgia
Reproductive Associates in GA; and Helena Women's Health
in CA, just to name a few.
There are, however, several "Advisors" to
Takeda Abbott Pharmaceuticals, the manufacturers of
Lupron®, present on the panel[3]. Inevitably, their
presence naturally leads to speculation as to the validity
of their conclusions and raises the question of bias.
Having noted the lack of many recognized experts from
the panel, we believe it is unjust to arrive at a conclusion
advocating the use of pre-surgical GnRH therapy (i.e.,
Lupron®) in Endometriosis patients, without considering
the contributions of those experts who effectively treat
the disease without GnRH intervention everyday. We further
recommend that far more research be performed on the
long-term effects of GnRH therapies such as Lupron®
before advocating their usage in a manner which may
ultimately prove more harmful than helpful.
Research data is replete with confirmation of the fact
that Endometriosis, while suspected, cannot be firmly
diagnosed without biopsy. GnRH therapy has a place in
Endometriosis treatment; however, it lacks good judgment
on the part of the physician to put his or her undiagnosed
patient on such a powerful medication without a confirmed
diagnosis via laparoscopy or where appropriate, laparotomy.
To do so thereby causes further delay in offering a
true diagnosis; delays surgical removal of the Endometriotic
implants; exposes her to potentially negative and lasting
side effects as a result of GnRH usage; and in many
cases, fails to resolve her pain, thereby extending
the length of time she continues to suffer. Lupron®,
for example, is known far and wide throughout the Endometriosis
patient community for significantly negative and long-lasting
side effects, yet the many complaints of those patients
suffering from such effects are largely ignored and
invalidated by the medical community. This situation
is difficult enough for those who know the cause of
their pain; are we to now expect undiagnosed patients
to undergo the same maltreatment?
In their Newsletter, Endometriosis experts at the Center
for Endometriosis Care wrote, "Lupron doesn't
get rid of Endometriosis. It is expensive and has significant
and sometimes permanent side-effects. That's a lot of
items in the "no" column[4]." This is
not an appropriate or acceptable standard of care for
Endometriosis patients.
Rather than promoting "quick fix" injections
which enable practitioners to spend less time studying
expert surgical techniques and thereby reducing their
hours in the operating room, but allows them to spend
many billable hours in the office setting, we should
instead be focusing on the best way to serve Endometriosis
patients: rapid diagnosis and thorough disease removal
- both of which can be accomplished via the laparoscopic
excision procedure pioneered by Redwine et. al.
To be certain, a decrease of pain during Lupron®
therapy does not prove that the patient has Endometriosis[5],
and proven Endometriosis experts have shown time and
again that medications are only short term relievers
for Endometriosis in many cases. Timely and efficient
diagnosis accompanied by careful and thorough removal
of the disease offers far better results - without exposing
the patient to harmful and potentially long-term side
effects.
There are a number of discussions attempting to rationalize
the use of pre-diagnostic GnRH therapy as a cost-effective
treatment approach. What about the cost to the patient's
well being? Again, the significantly negative effects
of GnRH therapies like Lupron® are not adequately
addressed; rather, the side effects are referred to
repeatedly in the literature as "temporary and
related to hypoestrogenism, including vasomotor flushes,
headache, and vaginal dryness." Also of note is
the "reversible" vertebral bone density loss.
There are hundreds, if not thousands, of women in the
Endometriosis community who suffer far worse effects,
and have been for upwards of 5 years since their last
injection. The ERC hears from many such women, who convey
to us that the effects they suffer from GnRH therapy
"are worse than their Endometriosis pain ever was."
One must ask, why are the concerns of these women not
being addressed?
In two data collection studies performed by the Endometriosis
Research Center, women were asked to share feedback
about their experience with Lupron®. The results
(both data collections were limited to Lupron® users
only):
- 27.71% found Lupron® to be tolerable and
helpful at symptom relief;
- 7.23% found Lupron® to be tolerable, but
not helpful at symptom relief;
- 16.87% found Lupron® to be intolerable,
but nonetheless helpful at symptom relief;
- 48.19%, almost half of the participants,
indicated that Lupron® WAS INTOLERABLE AND NOT
HELPFUL AT SYMPTOM RELIEF.
These impartial and unbiased results are strikingly
different from the experiences propagated throughout
the medical community and TAP's various websites.
For example, one woman, "Lisa," tells her
positive Lupron® experience on TAP's corporate site
at http://www.tap.com/patients/endometriosis:
"I felt awesome after I started the treatment,"
Lisa said. "I know that endometriosis is not a
'curable' condition. But I'm glad I took this treatment
[sic]." "Lisa's" story becomes questionable
when we read further down the page, where it is revealed
that she is an "employee of TAP."
In a second study, patients were asked for feedback
regarding their POST-Lupron® experience. The results
were even more startling:
- 21.67% did not suffer any lasting effects from
Lupron®;
- 26.67% suffered lasting effects for up to 6
mos. after Lupron®;
- 10.00% suffered lasting effects for up to 1
year after Lupron®;
- 5.00% I suffered lasting effects for up to
2 years after Lupron therapy®;
- 6.67% suffered lasting effects for up to 3
years after Lupron therapy®;
- 6.67% suffered lasting effects for up to 4
years after Lupron therapy®;
- 23.33%, a staggering amount of participants,
suffered lasting effects for UP TO 5 OR MORE YEARS
after Lupron®.
"Effects" included but were not limited to
seizures, cardiac problems, and fibromyalgia. Yet, these
effects are largely unrecognized in the medical literature.
Again, such effects continue to be ignored and invalidated
by healthcare providers at large.
Our results strongly contradict Takeda Abbott's own
statements, which claim that Lupron® is "well
tolerated." TAP's literature also acknowledges
only those side effects "related to hypoestrogenism,
including vasomotor flushes, headaches, vaginal dryness
and an average of 3.2% reversible bone loss;" and
states that "side effects will also disappear as
your estrogen levels gradually return to normal once
you have finished your course of treatment with Lupron
Depot®" [see www.endofacts.com/expect/after.htm].
According to TAP, no patient should suffer any effects
beyond approximately 3-6 months after terminating Lupron®
therapy. On the contrary, as reflected in the ERC's
second data collection study, this is simply not the
case for many who have undergone treatment with Lupron®.
We also know that young women treated with GnRH agonists
for Endometriosis may never achieve peak bone mass density,
increasing their risk for osteoporosis later in life[6].
Endometriosis is found during laparoscopy in 35%-70%
of adolescents (including ages 12-17) presenting with
chronic pelvic pain[7]. Lupron® has only been approved
for treatment in those women ages 18 and above. How
then does the consensus panel address the patients'
age as well as the bone mass density concern? Should
these young patients presenting with possible Endometriosis
be forced to wait until their late teens or early twenties
- or even beyond - to have their pain adequately diagnosed
and treated?
One need only open a newspaper to note that Takeda
Abbott Pharmaceuticals has been the subject of ongoing
investigations and was in fact fined $875 million for
illegal promotion of their drug, Lupron®. Yet, they
continue to spend thousands of dollars marketing the
drug direct to patients via no less than four patient
oriented websites[8] and through the financial support
of various physicians and organizations within the Endometriosis
community. Again, the question of bias comes to the
forefront of the issue. Are their efforts paying off?
Drug company ties sometimes "influence and/or distort
study results," according to Yale University researchers,
who noted "strong and consistent evidence [exists]
that industry-sponsored research tends to draw pro-industry
conclusions[9]."
Beginning in 1938, DES (Diethylstilbestrol) was prescribed
to an estimated 4.8 million pregnant women in the U.S[10],
touted as the recommended prophylaxis "in ALL pregnancies."
Advertisements for the drug at the time boasted "96%
live delivery with desPLEX in one series of 1200 patients
- bigger and stronger babies, too. No gastric or other
side effects with desPLEX - in either high or low dosage[11]."
It was not until over 30 years later in 1971 that researchers
began realizing the extremely dangerous effects DES
held for the woman, her children and possibly her grandchildren.
We are still researching the extensive and injurious
effects of DES today. Lupron has only been used in Endometriosis
treatment since the early 1990s. Must we wait 20 more
years to discover that Lupron®, like DES, has far-reaching
consequences? Are we creating another generation of
women who have been harmed by overzealous utilization
of a so-called "miracle drug?"
The Endometriosis Research Center strongly
maintains: the long-term effects of Lupron® (and
GnRH medications in general) is not known. The application
of GnRH therapy to those women who have not been surgically
diagnosed must stop. More research must be
given to the long-term effects of GnRH therapy on a
woman - and possibly her offspring. Indeed, GnRH medications
have a place in Endometriosis treatment; however, caution
must be exercised to avoid the cookie-cutter approach
to therapy. What works for one patient will not work
for another. Subjecting patients to potential negative
effects that outweigh the benefits of treatment is unethical.
Patient needs and the uniqueness of each case must be
thoroughly considered before any therapies are offered.
References:
1, 2: Gambone, Joseph C.; Mittman, Brian S.; Munro,
Malcolm G., Scialli, Anthony R.; Winkel, Craig A.; &
the Chronic Pelvic Pain/Endometriosis Working Group.
Concensus Statement for the Management of Chronic Pelvic
Pain & Endometriosis: Proceedings of an Expert Panel
Concensus Process. Fertil Steril 2002; 78: 961-72
3: Takeda Abbott Pharmaceuticals website, "Advisors"
page: www.endofacts.com/support/advisors.htm
4: "Drug Therapy for Endo Answers." Center
for Endometriosis Care website, www.centerforendo.com/learn_more/center_questions/drug_therapy.htm.
5: David Redwine, MD; St. Charles Medical Center Endometriosis
Newsletter, Summer 2000; "Treatment before Diagnosis?
Website www.endometriosistreatment.org/html/endoteen.html
6: Agarwal, Sanjay K. GnRH Agonist May Prevent Young
Women From Reaching Peak BMD. J Reprod Med 2002;47:530-534.
7: Jancin, Bruce, OB/GYN Update/Geisinger Health System.
"Typically early-stage disease Endometriosis Is
Easily Missed in Adolescents;" October 15, 2002.
8: websites: Lupron.com; Endometriosis1.com; Endofacts.com;
EndoFactsProfiler.com.
9: Tanner, Lindsey, Associated Press. Pervasive Medical
Research Conflicts Found. January 23, 2003.
10: DES Action Organization. Website: www.desaction.org
11: "DES Basics," Division of Cancer Control
& Population Sciences, NIH, website www.dccps.nci.nih.gov/ACSRB/pubs/DES_Pubs/The_Basics/desbasics.html
All material © 2003 by the Endometriosis
Research Center except where otherwise explicitly noted.
All rights reserved. No part of this presentation may
be reproduced or utilized in any form, electronic or
mechanical, including photocopying, recording, or by
any information storage and retrieval system, without
written permission from the ERC.
Date of Publication: January 2003. Revised:
February 2003.
Disclosure: The ERC has no financial affiliation
with any sources named herein.
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