Diagnosis and long-term management of endometriosis

Professor Anthony Luciano and Professor Thomas D'Hooghe
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Prof Thomas D’Hooghe:  I am Thomas D’Hooghe from Leuven University Fertility Centre in Belgium and I have the honour of interviewing Professor Luciano from Connecticut University Medical School.  Professor Luciano, I very much enjoyed your lecture and I would like to ask you a couple questions.  First of all, I would like you to comment on the diagnosis of endometriosis and to which extent laparoscopy should be done in every woman with a combination of endometriosis and pain. 

Prof Anthony Luciano:  For several years, we have thought of diagnostic laparoscopy as the gold standard for the diagnosis of endometriosis and, indeed, it may still be in some centres;  however, there is new data suggesting that perhaps a less invasive approach may be equally good, perhaps even better, in selected patients with chronic pelvic pain.  A wonderful study was published in 2000 in Fertility and Sterility by Ling et al, where 100 women with chronic pelvic pain suspected to have but not surgically documented to have endometriosis were prospectively randomised to either GnRH-analogue therapy (they used Lupron in this case, 3.75mg every 28 days for three months) or to placebo, and they were followed (blindly) to see whether or not their pelvic pain improved. 

They found that 82% of patients randomised to GnRH-analogues experienced a significant improvement of all aspects of pelvic pain.  It should be said that 100% responded to dysmenorrhoea, as you would expect, as well as dyspareunia and other symptoms of pain. Whereas those women who were randomised to placebo, only 38% to 40% responded with some improvement of their symptoms.  They then proceeded with laparoscopy on all of these patients  and found that,  80% of those patients who were randomised to GnRH-analogues, and a similar percentage, 80% to 83% of them had endometriosis whether they were randomised to placebo or GnRH-a. 

What this study tells us is that if you have excluded all other causes of chronic pelvic pain - gastro-intestinal causes, muscular-skeletal causes, neurological, etc. - you can empirically treat them with GnRH-a and expect a good response since at least 80% will have endometriosis. 

In patients with chronic pelvic pain, the diagnosis of endometriosis by laparoscopy is made in 30% to 80% of cases, depending on the level of experience that the surgeon has in recognising the various appearances of endometriosis by laparoscopy.  In other words, endometriosis may be misdiagnosed by laparoscopy by as much as 50% of cases.  It turns out, according to Dr. Ling’s study, that a 3-month empiric trial with GnRH-a is at least as accurate, and perhaps better than laparoscopy, in correctly diagnosing endometriosis, in properly selected women with chronic pelvic pain. 

Prof Thomas D’Hooghe:  You also briefly mentioned that women, who in the end turn out not to have endometriosis also improved in terms of pain scores during this three-month trial.  Can you comment on the mechanisms and the difference from placebo? 

Prof Anthony Luciano:  Yes, indeed.  Although endometriosis was diagnosed in 78% of the patients randomised to GnRH-analogues, more than 80% responded, which suggests that some of the women who did not have endometriosis at laparoscopy, or were at least not diagnosed with endometriosis after laparoscopy, responded to GnRH-analogues.  Now, who were these women?  Did they not have endometriosis?  Or did they have endometriosis but it was misdiagnosed by laparoscopy?  Or were they women who suffered pain that was not due to endometriosis yet they responded to the GnRH-analogue?  At the end of the day, what is important is not whether they have endometriosis, but whether or not you successfully suppressed thei symptoms.  Did you improve the quality of their lives?  Did you make them better?  If the GnRH-analogue does that, even in those who do not have endometriosis, then it has done its job. 

Prof Thomas D’Hooghe:  Interesting.  Now the agonist treatment combined with add-back has been known for several years.  What do you think is the current indication to give such medication? 

Prof Anthony Luciano:  I think that GnRH-analogues are terrible drugs on their own.  They produce so many side effects that the patients often suffer more from the adverse effects of the agonists than the disease itself.  To the rescue, we have add-back therapy which has made a huge difference in improving the quality of life by eliminating most of the major adverse effects of GnRH-analogues, such as mood swings, hot flashes, night sweats, vaginal dryness, decreased libido, etc..  Add-back therapy has made GnRH-analogue a much more viable therapeutic alternative, because not only are their symptoms suppressed but the side effects are virtually eliminated.  Moreover, the risk of bone mineral loss, which can predispose them to osteoporosis, is also negated by add-back therapy.  Thus not only the quality but also the quantity of their lives will be improved with the combination of GnRH-analogues and add-back therapy.  Add-back therapy also allows us to prolong the therapy beyond the recommended 6-month period in women who may have severe and deep disease that may require longer treatment duration.  I was mentioning earlier about a patient of mine, who has pulmonary endometriosis, and she has had two spontaneous pneumothoraxes from endometriosis.  After the diagnosis of pulmonary endometriosis was made at the second pneumothorax,  she was started on GnRH-analogue with add-back therapy.  She has been on this combination therapy for a year and a half with absolutely no pulmonary or pelvic symptoms with excellent response and no adverse effects. 

Prof Thomas D’Hooghe:  What about these women who take this medication, a combination of analogues and HRT, for years?  Might they have an increased risk of breast cancer? 

Prof Anthony Luciano:  That is a very good question and one that many women are very concerned about.  They have all heard about the Million Women Study, they have heard about the Women’s Health Initiative study and they have heard that hormone replacement therapy significantly increases the risk of stroke, heart events, and breast cancer.   

Therefore, will it do the same to them?  They must realise that they are very different from the post-menopausal women in whom hormone replacement therapy is administered because their ovaries are no longer functional.  Endometriosis patients on the other hand are young women who have normal ovaries, which make lots of oestrogen, significantly more oestrogen than what they receive from add-back therapy.  Consequently, the amount of oestrogen that their breasts are exposed to with add-back therapy is significantly less than what they are exposed to by their own ovarian function if the ovaries were allowed to function without GnRH-analogues.    In conclusion, the combination of GnRH-a and add-back therapy exposes women to much less estrogen than no therapy at all. Such combination therapy will not increase their risk of breast cancer, stroke, or heart events. In fact, if anything, they will be protected. 

Prof Thomas D’Hooghe:  Most of the issues look all right.  Lone, do you want to add something to this discussion? 

Lone Hummelshoj:   No, I think this has been very interesting, indeed.  One thing I would like to ask Professor Luciano, is what next?  I mean, right now we are talking about GnRH-analogues and add-back because . . . 

Prof Anthony Luciano:  I think it is important to realise that GnRH-analogues and add-back therapy is a temporary therapy.  It is very useful for a year at most, maybe even a year and a half, to suppress the symptoms and to provide the patient with the add-back therapy to remove the adverse effects of GnRH-analogues, but once that has been accomplished, then you have to put her on some sort of maintenance dose or some sort of therapy that would minimise the risk of recurrence.   

Just start with surgery.  Once you remove the endometriosis, if you are not aggressive and diligent in decreasing the risk of recurrence, these women will have a recurrence of disease.  Why?  Because they still have ovarian function, they still menstruate, they still have the genetic predisposition to develop the disease.  So you can remove every little cell of endometriosis, which we never do, no matter how good a surgeon you are, you still have the patient with ovaries and a uterus and a predisposition to the disease and she will have a recurrence.  So what do we have to do?  We have to put these women on some sort of therapy that will minimise menstruation, the menstrual flow, the number of days they menstruate, the amount of menstrual flow they have.  That will suppress the oestrogenic milieu to some extent, and so retard or hopefully prevent recurrence of symptoms and recurrence of disease. 

So after they have been on GnRH-analogues and add-back therapy for six months or a year or so, then most of my patients, unless they want to become pregnant, they will go on some sort of hormonal suppressive therapy.  By now you have decreased the bulk of the disease, you have decreased the activity of disease, now you have a fairly good chance of slowing down the recurrence if you put her on low-dose birth control pills continuously so that you minimise menstruation in these women.  I think they do very well, most of them do.  Or you can put them on progesterone-only therapy, low-dose progesterone-only therapy, which will suppress whatever endogenous progesterone they make and suppress endometrial proliferation and ultimately suppress menstruation.  It is not going to be successful in all of the patients, but if you are successful in 70% of them, you will have done them a great service. 

Lone Hummelshoj:  Any comments to that, Dr D’Hooghe? 

Prof Thomas D’Hooghe:  No, not really.  There is a still a question I would like to ask:  if you stop with the agonists and add-back, you show some data that for dyspareunia, for chronic pain, the pain-suppressing effect lasts for six months to one year even after stopping the dysmenorrhoea; and if it comes back, then dysmenorrhea comes back, is that correct?

What time period would you say one would expect the beneficial effect of this agonist effect? 

Prof Anthony Luciano:  It varies from woman to woman.  In some women, the dysmenorrhoea will probably come back right away.  For some, it would take a year or two or three.  That is why I emphasised the importance of keeping them suppressed with progestins or low-dose hormonal contraceptives which are usually well tolerated and not very expensive.  I think that low-dose birth control pills, low-dose patch, birth controls like the ring, the Nuvo Ring, is wonderful - it has the least amount of oestrogen and progestin for contraception, works locally extremely well, and it does cause hypomenorrhoea anyway.  It may not cause amenorrhea but hypomenorrhoea, and if you keep the ring in all the time, you just change it every three weeks without a week off of intervals, you may have amenorrhea with very low doses of oestrogen and progestin, so you may have your cake and eat it, too.  The goal is really to develop a hypo-oestrogenic milieu or a progestational milieu to reduce menstrual flow in both duration and quantity.  If you can do this, you will probably minimise the recurrence of endometriosis.  Would you agree? 

Prof Thomas D’Hooghe:  I totally agree.  Our approach is, after surgery it it has been a second or third surgery, to then put a woman on a combination of either progestin only, sometimes with Mirena, the IUD, which has the same effect, and leave that for a couple years and then you see very few recurrences.  But it is needed.  I totally agree with you.  We did the study looking at women starting IUI or IVF having been operated on in the past for severe endometriosis and we found out in the group, before doing IVF, the cumulative recurrence range was 50% over two years. That was operations in a centre, which is known for endometriosis surgery.  I think that is important; gynaecologists do not tend to like to hear that, but recurrences are a part of the practice, even in very skilled hands with a lot of experience. 

Prof Anthony Luciano:  Absolutely. 

Prof Thomas D’Hooghe:  So you need to have something additional after surgery. 

Lone Hummelshoj:  Thank you, Professor D’Hooghe and Professor Luciano, for participating in this discussion which has highlighted the issue of recurrence when it comes to endometriosis and, indeed, the need for individual long-term treatments and, not least, the continued challenge to address both.  Thank you for your time.