Gonadotropin Releasing Hormone Side Effects Versus Surgery for the Treatment of Endometriosis

Endometriosis Zone Editorial Board Chairman, Mark Perloe, MD, presents an OP/ED written in response to Newsgroup Messages on use of GnRH-agonists in Endometriosis.

A common consensus in patient circles is that the benefit of GnRH treatment is counter-balanced by side effects.  In this editorial, Dr. Perloe will address some of the issues in this debate.

While Endometriosis does in fact show an increased ability to convert normally circulating male hormones to oestrogen (aromatization), the levels of oestrogen provided is negligible in women who still have ovaries.  Where aromatization comes in to play, is after hysterectomy and removal of the ovaries. One recent patient had vaginal Endometriosis after hysterectomy and removal of ovaries (many physicians fail to excise deep Endometriosis in the space between the vagina and rectum at the time of hysterectomy).  She did not desire additional surgery.  A trial of an aromatase inhibitor has been recently reported to offer benefit to these women.  Unfortunately, when used with women who still have ovaries in place, the result is ovarian cysts, severe hot flashes and all the symptoms associated with leuprorelin.

This brings me to the fact that as far as I am aware, all the symptoms that occur with leuprorelin are due to low oestrogen. They would likely occur with goserelin or even buserelin nasal spray if a high enough dose was used to suppress oestrogen to a similar level.  So, can anything be done?  I can assure you that surgery is not the sole answer.  Many women who have undergone extensive resections still experience recurrence regardless of with whom or where their surgery was performed.

We now understand that there are genetic differences in how the body produces cytokines and various chemofactors that allow the ever-present tubal effluent of endometrial cells to attach, invade and avoid clearance by immune cells. These genetic and immune factors have never been show to undergo modification with surgery.  So while aggressive excisional surgery that does not make excuses for leaving Endometriosis behind is the best approach to immediately address symptoms, the factors that allowed the Endometriosis to grow in the first place are still present. How do we modify these?

Hormonal suppression with a GnRH-agonist seems to improve immune factors that would block clearance as well inhibiting VEGF responsible for blood vessel growth at the site of implantation and MMP's, enzymes that allow the implant to invade deeply.  But - those side effects.  Well, there is an option.  Addback therapy can be started at the same time the GnRH agonist is initiated. However, some MD's have little experience with addback and often those who use it are unaware that it can be effectively used immediately.  For many women, the use of oestrogen AND progesterone (I prefer micronized natural hormones in an oral lozenge) can prevent symptoms and prevent bone loss and cardiac effects while maintaining suppression of those factors that allow Endometriosis to grow unchecked.  While on therapy we can titrate the dose to provide sufficient hormones to maintain pain relief.  Monitoring urine NTx on a regular basis will inform us if the patient is losing bone and is at risk for osteoporosis developing.

One of the drawbacks of starting leuprorelin or a similar GnRH agonist is that there is often a surge of oestrogen that can make pain and symptoms worse. This can be avoided by the addition of higher dose progesterone for a few days, if treatment start does not coincide with a menstrual period.  Alternatively, we may soon have GnRH antagonists which will not exhibit the initial flare effect of current GnRH agonists.  Whether or not these medications will truly offer an advantage is unknown. Overall the long-term effect will be the same-lowering the oestrogen levels. These medications may also be combined with hormone addback therapy to avoid hot flashes.