“Has anyone been prescribed Zoladex/Prostap?” “How did people get on with Zoladex/prostap?” “Im experiencing terrible side effects with Zoladex/prostap, has anyone else suffered these too?” These are just a few of the many questions we see asked regarding zoladex and Prostap on this support group as well as across multiple support groups on a whole host of different social media platforms and they are entirely valid. Recent surges in people asking for advice about the long term effects of these drugs prompted this weeks Fact Friday piece so.. here we go. Zoladex is the Brand name for a drug called Goserelin. This is a gonadotrophin releasing hormone (GnRH) agonist medication that when first administered produces an initial phase of stimulation in the glands responsible for releasing hormones (which is why in the first few months, our symptoms appear to spike or get worse) followed by a down regulation of these hormone receptors over time. This down regulation leads to the production of oestrogen (which is what is believed to feed our Endometriosis) stopping entirely. Now, oestrogen plays an enormous role within our bodies and not just in response to our menstrual cycles. Oestrogen is also responsible for maintaining our cholesterol at adequate levels (high cholesterol is a major contributor in cardiac issues such as funny rhythms and heart attacks) but also helps to protect our bone health. This makes it all the more evident why our consultants are often concerned with long term usage of Zoladex and its impact on our bodies. Currently, Zoladex is licensed for use in patients with Endometriosis for 6 months. Licensing aims to ensure that harmful medication is not sold to the public and that products are used appropriately and for the conditions indicated. Prolonged treatment with GnRH is associated with an acceleration in loss of bone density - this is what a lot of zoladex research is focused on studying. Ive tried over the last few weeks to access research on the drug and its longer term impacts but have struggled to find more up to date research - so much of what I found and read was published in the early 1990’s when Zoladex was considered a magic, first line treatment for endometriosis. Over the last 20 years, it has become more apparent that whilst it treats our symptoms short term, longer term Zoladex may not be as safe and effective as we first thought. This report on Zoladex will look at the benefits of the drug as well as what we can expect going forward and identify possible areas for further research. I hope you find it helpful. According to Olive (2008) in their research piece “Gonadotropin - Releasing Hormone Agents for Endometriosis” back in the 1980’s, a variety of small pilot studies (studies carried out to determine the need for much bigger research proposals) showed that GnRH was very effective in suppressing ovarian hormone secretion causing endometrial deposits in the body to shrink and relieve people of their pain. Frequency of Dysmenorrhea (pain with periods) decreased from 97% to just 7% and Dyspareunia (pain during sexual intercourse) was also significantly reduced. Whilst this is positive, doctors concerns have predominantly been focused around bone health during and after administration of Zoladex. A study by Zupi et al (2004) and Al - Azemi et al (2009) both report the need for Add Back hormonal therapy such as HRT. Zupi (2004) compared patients receiving GnRH alone with those having GnRH AND HRT. In their study, the treatment duration was 12 month and follow up was 6 months. Both groups had significant bone mass density (BMD) loss which was more pronounced in those who hadn’t received HRT. These changes to BMD were still evident 6 months after treatment had ended. Similar findings were also found by other investigators - Franke et al (2000), Moghissi et al (1998), Prentisse et al (2000) and Lindsay et al (1996). It seems likely that the low oestrogen induced by long term use of GnRH is only partially helped by the use of HRT but the impact of this treatment is so small, it renders it largely insignificant. Al - Azemi (2009) did identify sustained bone mass density loss in the lumbar region of the spine at 12 months post treatment but that this is equivalent to the effect of moderate cigarette smoking on BMD. Pierce et al (2000) also looked at BMD in a trial with a 6 year follow up. Their findings found that BMD is reduced during longer term usage of GnRH and had not fully recovered 6 years after treatment had ended. The use of HRT alongside the GnRH medication does not seem to have a significant impact on BMD either. They found that to have clinically significant effects on endometriosis, prolonged GnRH treatment is often required however they also highlighted that usage over 6 months greatly increases our risk of osteoporosis. This is where research into BMD and GnRH gets confusing. Some studies suggest that BMD is recovered when treatment is discontinued - Dawood et al (1989) Cann et al (1987) and Matta et al (1988) - whilst other, more up to date research suggests a sustained decrease without recovery - Orwoll et al (1994), Taga et al (1996) and Caird et al (1997). A lot of these studies use very small sample sizes which in turn, makes it difficult to generalise to the whole population. The most up to date research I found on this was Olive (2008) who claimed that the loss of BMD is approximately 6% annually and the reason why the treatment limit is 6 months. Whilst a lot of the studies I have mentioned state that ‘add back’ therapy such as HRT helps reduce this effect, it brings about a whole host of its own adverse side effects - mood swings, bloating, depression, headaches and irregular uterine bleeding are just some of those documented. I mentioned earlier about the need for oestrogen in our cholesterol health and so will now look at some of the evidence regarding GnRH medication and its impact on our cardiac function. Some of you may or may not know that Zoladex/Prostap is often used in the treatment of Prostate cancer. Prostate cancer, as with Endometriosis, is fed by oestrogen therefore prostate cancer treatment is often focused around stunting the production of oestrogen hence why Zoladex is used in those instances. A lot of research around cardiovascular risk associated with GnRH usage is focused on prostate cancer patients but I will do my best to decipher how this may impact us Endo sufferers too. So, men with prostate cancer are often treated with something called Androgen Deprivation therapy which includes Goserelin (Zoladex). Perrone et al study from earlier this year (2020) looked at the cardiovascular risk profile for prostate cancer patients being treated with GnRH agonists such as Zoladex. Perrone et al stated that a huge number of patients with prostate cancer are being exposed to medication such as Zoladex and its side effects. These can include hot flushes (due to its impact on our vasomotor centres in the body), loss of libido, sexual dysfunction, fatigue, anaemia, bone loss and metabolic changes that include weight gain, insulin resistance and lipid alteration which can contribute a significant increased risk of diabetes and cardiovascular events. Based on the most up to date research, European guidelines advocated special attention to the risk - to - benefit ratio of such medication in patients with high risks of cardiovascular complications. In America, the Food and Drug administration mandated the inclusion of additional safety information to GnRH drug labels. Perrone et al (2020) found that use of GnRH medication can lead to an increased risk of cardiovascular events, even during the first year of treatment. They did also state that findings are often not conclusive and new evidence is highly required to address the risks. Another side effect identified by Olive (2008) was memory impairment. Newton (1996) stated that 44% of people treated with GnRH such as Zoladex experience issue with memory, specifically verbal memory and new learning. Fortunately, research suggests that this is often resolved and completely reversible once treatment is stopped. Olive (2008) also expressed concern of the use of GnRH for prolonged periods of time and strongly urged this to be adequately investigated. Adding in HRT appears to lessen potential damage but studies up until now have been limited to 1 year. There is also limited information on the safety and efficacy of repeated courses of treatment with or without HRT involvement. Furthermore, the optimal interval between repeated courses has not be identified. Olive (2008) also expressed concern for the use of GnRH medication in adolescents with Endometriosis. There is a distinct lack of information on the use of GnRH during a period of bone growth in young people which makes it use particularly problematic. Olive states that optimal treatment regimens and durations in adolescents with endometriosis must be identified and further researched. Now, that was the medical research side of GnRH medications. The age of social media has meant we all now have far greater access to information and support groups - these include groups of people who have been prescribed medication such as Zoladex/Prostap and are now suffering long term side effects as a result. These are often side effects that have yet to be properly researched and so remain anecdotal. Some people state prior to taking GnRH medication, they were healthy, active, employed and “physically vibrant”. After taking Lupron (similar medication to Zoladex) for 9 months for the treatment of endometriosis and for 3 months prior to beginning IVF, this woman states that the progression of severe osteoporosis, severe scoliosis (sideways curve of the spine) and kyphosis (curvature of the top of the spine, leading to breathing difficulties) has left her incapacitated and in horrendous pain. She also states that these changes were evident in X-rays from the early 1990’s, just a few short years after commencing Lupron. The deterioration has been gradual but has become much, much worse in the last 5 years. Lupron is also believed to have effected receptors in the gut meaning her bowel has become almost stagnant and doesn’t empty properly. She also highlights multiple heart arrhythmia (funny rhythms) in the 5 years post Lupron administration. Like I said, this can all be looked at as circumstantial evidence - without the research to back this up, its hard to put all that this woman suffers with down to Lupron or GnRH drugs entirely. However, there has been a growing number of people coming forward expressing the same concerns and issues as the woman I mentioned above. For more information, there are a couple of groups on Facebook that Jodie very kindly provided. One of them is called “Poisoned by Prostap/Lupron/zoladex”. The other is “Prostap/ zolidex/lupron/Triptorelin/GRHA action/ support group UK”. I would 100% go into these groups with an open mind. Like I said, without clear research to back up peoples claims, its difficult to determine whether there was a definitive cause and effect - so they took Zoladex and, as a direct result, were diagnosed with various medical issues. As I have said throughout this piece, there is SO MUCH MORE research that needs to be done with regards to the impact long term of GnRH medication. From a personal perspective, I was placed on Prostap in January 2016 after many an argument with Mr Guyer about it. I felt like I was giving in to my condition at a time when I had yet to get my head around the disease and the fact that yes, I did indeed have this for life. I eventually agreed and spent a whole year on it with just a few weeks of HRT in the September of 2016. HRT sent me absolutely loopy and so I came off it and then Prostap entirely in the December of 2016. I was given it again for 4 months in the summer of 2018 to combat a prolonged period of bleeding after my second surgery. For me, Prostap worked really well. I had no pain, no bloating, no bleeding. But, I did experience violent mood swings and hot flushes (these were manageable compared to what some experience). Years later, my endometriosis/adeno symptoms are very much a daily thing. I bleed more often than I don’t and Im hyper aware of my left ovary all the time. My joints ache every day and my poor brain can’t cope with much - ask me too many questions and I shut down. So, brain fog is a very real thing in my post Prostap world. Going forward, there is an awful lot of research that needs to be done to identify the long term impact of the these drugs on our bodies and the risk versus benefit aspect needs to be properly addressed. For now, I think its very important that we do our own research and that we speak with people who have had experiences of these drugs too. We all have very different experiences with endometriosis itself anyway and so it isn’t for me or anyone else to say whether it will be a good or bad option for any of us. I hope this has helped you understand what Zoladex/Prostap/Lupron is and how it works whilst also addressing some of the side effects we have come to be aware of over the years.