Before any discussion can be had about what is in the ‘drug cupboard’ for endometriosis, it is imperative that we know what and who we are dealing with.
At the outset, it must be emphasised that the diagnosis of endometriosis must be made surgically. The best tool at our disposal for this purpose is the laparoscope, in the hands of an experienced operator, ideally in a team setting. The pre-operative work up should include a directed history, a vaginal examination and, more importantly, imaging of the pelvis using a trans-vaginal ultrasound or magnetic resonance imaging (MRI). Imaging is especially useful to exclude deep infiltrating endometriosis, recto vaginal septum endometriosis and endometriomas. MRI is becoming increasingly more useful for ruling out adenomyosis. Tumour specific markers add dimension to this plan.
Firstly, let me start by describing why I do not use two specific drugs at all and have not done so for almost 20 years. Depo Provera (a progesterone), approved as a contraceptive, can be, and has been, widely used. However, for significant endometriosis, the frequency of injections is far greater (MIMS Annual) than that used for contraception and the number of side effects, including significant weight gain, fluid retention, mood change and thin, dry vaginal mucosa, puts this drug at the bottom of my list. There is also a long washout period for this drug, which is important if pregnancy is planned.
Similarly, danazol (Danocrine), which is highly efficacious, has unacceptable side effects, including weight gain in the order of 10kg, acne and possible irreversible hair growth. It is imperative to discuss these side effects with young fertile women. Invariably, in my practice, the response from the woman is ‘no thanks’.
Having discarded two previous main contenders, we are left with the pill in various guises: progesterones; the Mirena intrauterine contraceptive device (IUCD); the Nuvaring; the two GnRH analogues (Zoladex and Synarel); and newer drugs that have potential for clinical use in the future. Rather than approach this task by simply describing each drug, I am going to describe the various clinical situations in which each drug might be used, alone or in combination.
The teenager with endometriosis only
Laparoscopic diagnosis and treatment is undertaken with the aim of surgically removing all endometriosis at the first operation. Provided the patient has reached her full height potential, and with parental consent, the combined oral contraceptive pill is used. Ideally, I use Brevinor 1 (Norimin 1) supplemented with a small dose of Primolut N if spot bleeding is a problem. The problems here can be weight gain, depression, fluid retention and acne. I switch to Diane 35 (or similar) if acne becomes a problem. Adequate counselling needs to be given to teenagers and their parents about the need to take this medication on time, to continuously cycle packets (skipping the sugar pills) and to avoid antibiotics where possible.
I try to avoid the use of the Mirena and GnRH analogues in this very young age group with endometriosis. The ‘crampy’ pain in the developing uterus when the Mirena is added to the mix often means that the four months needed for the Mirena to settle in is just not reached.
The older teenager with adenomyosis
This is where a pre-operative workup with an MRI scan is imperative. A good endometriosis unit must be backed up with a radiologist who is aware of the fact that adenomyosis should no longer be a disease where the diagnosis is made at hysterectomy in the 40-year-old woman! I commonly see adenomyosis in teenagers and young women and the patient may or may not have peritoneal endometriosis (personal experience of over 500 unpublished MRI scans over eight years in teenagers).
In my practice, I offer the teenage or young patients a pre-operative MRI with the sole purpose of discussing, before surgery, whether a Mirena should be inserted at the time of the first surgery. If a Mirena is to be inserted, adequate counselling of the patient as well as her parents is mandatory. The likelihood of the patient needing even more pain relief in the first few months needs to be discussed. Of course, the need for safe sex is also an imperative discussion because of the increased risk of chlamydia infection in this age group.
Once over the three-to-four month hump, improvement is more likely than not if adenomyosis has been minimal (infiltration of the junctional zone limited to less than 1.4cm into the myometrium and no adenomyomas).
A Mirena device contains 52mg of levonorgestrel and initially releases 20µgs every 24 hours. Levonorgestrel is a potent progesterone that also has anti-oestrogenic properties resulting from modification of peripheral oestrogenic effects as opposed to binding to oestrogen receptors. Levonorgestrel is also used in combined oral contraceptive pills and progesterone only pills. The advantage of the Mirena IUCD delivery system is that it allows delivery of the drug directly to the target organ, in other words the endometrium. After five years, the daily delivery halves to 10µgs.
Because a Mirena allows high levonorgestrel concentrations in the endometrium, oestrogen receptors are rendered insensitive to oestrogen (MIMS Annual 2013).
Women in their 20s not yet wishing to conceive
Again, pre-operative work up with a vaginal ultrasound scan and MRI will allow planning for adequate surgical excision at the first attempt. For Grade III/IV endometriosis, deep infiltrating endometriosis or endometriosis in association with MRI-proven adenomyosis, I prefer a combination of the Mirena and a high progesterone pill or a Mirena and a GnRH analogue (usually Zoladex) in an attempt to eradicate the maximal amount of disease possible. My reasoning here is that in Australia, the patient gets only one six-month subsidised course of Zoladex paid for in her lifetime. Therefore, it is my belief that we should maximise drug and surgical treatment early on and not wait for disease to progress before bringing in the big guns. Once a course of Zoladex has been completed, I then add in a combined oral contraceptive pill (COCP) with a high dose of progesterone for two reasons. Firstly, there is a reduced risk of the patient bleeding with a higher dose of progesterone and secondly, to avoid the 11 per cent risk of large painful follicular cysts that comes with Mirena use.
Zoladex is a 3.6mg implant of goserelin acetate. It is injected subcutaneously, biodegrades over at least 28 days and is used for endometriosis and adenomyosis as well as breast and prostate cancers. Goserelin acetate is a decapeptide analogue of LHRH/GnRH. There are two phases to its action. Initially, within the first week, there is a flare reaction leading to a transient rise in serum LH and FSH concentrations. This is followed by the chronic phase in which potent inhibition of gonadotropin production occurs, leading to dramatically reduced levels of oestradiol and thus regression of endometriosis and adenomyosis.
Gonadal (and therefore oestrogen) suppression is sustained for as long as administration continues. Oestrogen levels diminish within 21 days and are comparable with postmenopausal levels, hence patients must be warned that they will suffer temporary, iatrogenic, menopausal symptoms. Similarly, bone mineral density should be measured in at-risk patients before therapy. Most patients tolerate the hot flushes, headaches and/or vaginal dryness well and only seldom is add-back HRT required. The company’s product leaflet warns that bioavailability may be variable, which may explain why some women continue to bleed while on the treatment.
Pre-treatment of endometriosis for fertility
In 2011, a paper in ANZJOG discussed the effect adenomyosis can have on pregnancy rates with IVF.1 I have adopted a policy of pre-treating all my MRI-proven adenomyosis patients with a minimum of three months of Synarel nasal spray before commencing FSH injections for IVF cycles. I also start prednisolone 15mg on day seven of the FSH injections as recommended by this same article.
Treatment of patients undergoing a hysterectomy
Either Zoladex or Synarel (nafarelin, another GnRH analogue) can be used on patients who elect to have a hysterectomy for their endometriosis. Often, adenomyosis co-exists with the endometriosis, but this, of course, is treated surgically by the hysterectomy itself. I adopt a surgical approach in removing any visible peritoneal disease at the time of the laparoscopic hysterectomy. Even if an abdominal hysterectomy is performed, I remove any additional peritoneal disease laparoscopically. I then post-treat the woman with three months of either Synarel or Zoladex, followed by the option of a COCP in those patients wishing to retain their ovaries.
Lipiodol ultra fluid
Delivered as a sterile ethyl ester of poppy seed oil (with an iodine content of 480mg/ml), Lipidol was originally used as a radio-opaque fluid for diagnostic hysterosalpingography. With the development of ultrasound-visible agents, Lipiodol has recently rarely been used in gynaecology. However, evidence indicates that flushing the uterine cavity with Lipiodol significantly increases fertility for a period of up to six months, but only in endometriosis patients. In Australia, Lipidol must be applied for on a case-by-case basis.2
The problem with drugs
Just as surgical procedures have known risks and limitations, so do drugs. I often say to my patients ‘endometriosis is a bit like rheumatoid arthritis. If there was one drug that worked 100 per cent of the time, we would use it!’ The use of medical treatments for endometriosis is restricted by limited efficacy of the drugs, side effects, patient compliance and recurrence of the disease after a course has come to its end.
The problem of side effects is perhaps made worse by the internet and ‘Dr Google’ who so many patients will consult prior to starting medical therapy. In my opinion, patients sometimes have a biased opinion towards their treatment after consultation with their cyber physician, which possibly makes compliance worse and may exaggerate their experience of side effects. Danazol suffered such a plight. I have virtually stopped prescribing Danazol because of the perceived risk of severe side effects in the community, which is not completely unfounded of course. The GnRH analogues suffered a similar plight because patients hear they cause menopause. Their perception is that menopause symptoms will be life-long and make them old.
Careful patient counselling is of paramount importance if we are to have any hope of good compliance. Patients need to be educated about the need for drug treatment after surgery to decrease recurrence rates and avoid, where possible, too many surgeries.
Given females represent only 50 per cent of the population, only five-to-ten per cent of women suffer from endometriosis, those women are affected for perhaps three decades only and only a proportion of affected women will respond to any particular drug, any pharmaceutical company that wishes to ‘invest’ in a new drug for this disease will do so at a huge expense for a rather limited reward. Any new drug development programs must also bear in mind possible teratogenic risks. Potential treatments for the future include anti TNF alpha, a monoclonal antibody, which may offer hope for women suffering from painful deep deposits of endometriosis, where surgery has failed. Other possibilities include aromatase inhibitors, selective progesterone receptive modulators and new oral GnRH antagonists.
Certainly, of all the treatments we have, the progesterones are cheap, effective and relatively well tolerated. Perhaps any new treatments should be compared to them. For the foreseeable future, a surgical diagnosis, followed by excisional surgery, histological confirmation and, where possible, immediate follow-up drug therapy aimed at ceasing menstruation and limiting recurrent disease, forms the backbone of treatment for endometriosis.
- Tremellen, K. and Russell, P. Adenomyosis is a potential cause of recurrent implantation failure during IVF treatment. ANZJOG. 2011; 51: 280-283.
- Johnson NP. Treat Endocrinol. 2005; 4(4) 233-243.