LDN's Impact on Infertility, AutoImmune Disease and Epigenetics

Dr. Phil Boyle, MB BCh NUI, MICGP, MRCGP, CFCP is the Director of the NaPro Fertility Care Clinic in Dublin, Ireland, and President of the International Institute for Restorative Reproductive Medicine. He is an active member of the American Academy Fertility Care Professionals (AAFCP), a certified Fertility Care Physician (CFCP), and an active member of the Irish Fertility Society. He possesses 17 years of clinical experience - nearly 3,000 successful pregnancies, many after years of infertility, previous failed IVF and repeated miscarriage. Dr. Boyle has published: "NaProTechnology - A multifactorial approach to the chronic problem of infertility" in June 2011, "Outcomes from Treatment of Infertility with Natural Procreative Technology in an Irish General Practice" in September 2008, and 2 chapters of the textbook "The Medical and Surgical Practice of NaProTechnology" published in July 2004. He is married, has 4 children, and lives in Dublin, Ireland. Dr. Boyle kindly agreed to be interviewed by LDNscience.org.

I'm a family physician by training. While I was going through my training, I discovered the NaProTechnology approach to evaluation and treatment of infertility (developed by Dr. Thomas Hilgers), and it really appealed to me. I figured there are many factors related to infertility that we can treat with medical intervention without needing to be an obstetrician. So I started out doing so in 1997 and I've been busy with it ever since.

I was familiar with Naltrexone as a treatment option for patients with fertility issues from Dr. Hilgers' approach, but he was using the "normal" dose of Naltrexone to fully block the opioid receptors in order to improve fertility for patients. Later, through my sister Mary Boyle Bradley, I came across a different type of approach: boosting endorphins through a low dose of Naltrexone. In this strategy, you aim for endorphin stimulation rather than blocking. So that was a completely new concept, and it didn't occur to me at first that this would have a role for fertility. But then I attended a presentation by a patient who had rheumatoid arthritis and had a dramatic improvement on LDN. I thought, "The next time I see somebody with an autoimmune condition, I'm going to try them on this."

After attending that presentation, one of my fertility patients who had an autoimmune condition came into the office. I put her on Low Dose Naltrexone, because unlike many disease modifying drugs you can conceive while taking it. Her symptoms improved dramatically and then her fertility responded really nicely as well.

I then started by prescribing LDN to the very obvious autoimmune patients, such as patients with active rheumatoid arthritis. In addition to improvements in their autoimmune condition, often patients would also report back to me, 'You know what? I used to have horrible premenstrual syndrome and now that's gone too.' Or 'I used to have low mood, fatigue and anxiety, and that's no longer an issue.' Or they had brown bleeding that has now stopped. Gradually I began to realise that these symptoms (PMS, polycystic ovaries, endometriosis, persistent fatigue, low mood, anxiety, sleep disturbance, brown menstrual bleeding, family history of autoimmune disorder) can be associated with clinical endorphin deficiency.

I was able to see over the course of about a year of prescribing LDN to the occasional autoimmune patient that not only did the endorphin deficiency symptoms improve with LDN, but it actually helped with fertility as well.

It was deductive reasoning through clinical observation that led me to this conclusion.

I then decided that if we have patients who don't have an obvious autoimmune diagnosis but have symptoms of possible clinical endorphin deficiency, we could try them on the LDN to see if the symptoms improve. Eight times out of ten symptoms like PMS and fatigue would improve. So now I use the presence of such symptoms as a guide for determining probable clinical endorphin deficiency. While other conditions can potentially cause these same symptoms, having low endorphins is a very common root cause, and therefore it's worth a trial of LDN to see if the symptoms respond.

Interestingly, I have also seen patients with autoimmune conditions that have none of the obvious symptoms of clinical endorphin deficiency. Because we use those symptoms to infer about the level of endorphins present (and therefore the relevance of trying LDN), patients who don't present with those symptoms may be missing out on a trial of LDN.

It depends on whether they need it in the first place. I try and make a clinical judgment about a patient's probable endorphin levels. I think, 'Does this person need LDN?' If it looks like they probably do, we'll try it and then we'll listen to what their body tells us.

If somebody's endorphin levels are already pretty good and you over-boost their endorphins with LDN when they don't need it, they actually feel unwell and their fertility will be impaired. There's also a really interesting scenario where, for a small number of people, we do the complete opposite of LDN: people whose endorphin levels are far too high and we need to block their endorphins with "high-dose" Naltrexone (which in fact is the normal dose of Naltrexone - 25 milligrams twice daily.) When we block the endorphins, they ovulate better. So the assessment involves a clinical judgment.

Dr. Hilgers was able to measure serum endorphin levels using a blood test. However, the company that was making the endorphin level blood test kit discontinued making it because it wasn't profitable enough, so for the last 7 years or so he has not been able to do the blood test either. We've never been able to test these levels in my practice because there isn't any Irish lab or any lab in the United Kingdom that can do an endorphin level blood test. Instead, we look at a variety of factors that can be indicators of an underlying endorphin deficiency such as the presence of PMS, polycystic ovaries, endometriosis, persistent fatigue, low mood, anxiety, sleep disturbance, brown menstrual bleeding, and family history of autoimmune disorder.

I would say I've put about 2500 people on Naltrexone. At this point, I find it's clinically appropriate to try LDN in up to 50% of my subfertile patients. Of those, about 80% experience a positive response to the LDN.

Initially I did not continue LDN during pregnancy as I was unsure of its safety. When I stopped LDN for women who really needed it, we had more miscarriages and less healthy pregnancies - lower birth weight and premature delivery. In an attempt to improve pregnancy outcomes, I continued LDN initially until 16 weeks; in my current practice, I recommend LDN until 37 weeks. A recent survey of patient experience using LDN in pregnancy shows better outcomes for those who continue it throughout pregnancy.

I'm mostly known for fertility treatment but yes, I see a small handful of people with only autoimmune conditions, MS, or fibromyalgia; these can respond really well to treatment with LDN. I'm very quick to tell people I'm no expert in any of these kinds of conditions, but I've got a lot of good clinical experience with Naltrexone. I'm happy to give it a try for these patients because it's safe. The worst case scenario is that it doesn't work. It won't do you any harm at least, apart from short-term transient side effects for a week or two while you get used to it.

If somebody has an autoimmune condition and they go on these super expensive, very strong immunosuppressive drugs to get relief of their symptoms but they've taken out their immune system by using them, while you may not see any immediate problems, you're potentially putting yourself in harm's way. You're at risk of developing new additional autoimmune conditions, and you may potentially increase your risk of tuberculosis and different cancers because of the profound immune-suppression that you go through. So it's not a great solution even if you can observe great clinical relief. LDN is so much more attractive. It's inexpensive, has few side effects, has no special training is required to use it, and it's safe and easy to use compared to the alternatives out there.

When I first found how well the Low Dose Naltrexone was working for autoimmune conditions, I thought everybody would latch onto this. You just find out what it is, you prescribe it, and you see your patients getting better up to 8 times out of 10. It works really well for a lot of people. And the drug interactions are quite minimal as well.

I think one of the reasons for the reluctance to prescribe it is because it's licensed (approved) for alcohol and heroin addiction. I think that's probably the biggest thing that scares physicians off, to be honest, because they've no clinical experience of using it at all. In Ireland there's about a hundred licensed medications like Naltrexone that have off-label uses (uses other than the condition for which they were licensed/ approved). A very common example of that is hormonal contraception: it isn't licensed as a treatment for period pain or endometriosis but nearly every doctor prescribes it for that. So they're very quick to prescribe an unlicensed treatment in that type of scenario. Similarly, for primary progressive MS. Interferons aren't licensed for that. But there's clinical experience using it for relapsing remitting MS, as studies indicate that it seems to offer some benefit. So we physicians say, 'We know this. We've used it before. Sure, we'll try it in this other condition.' And they use it in an unlicensed way. But Naltrexone comes from a big unknown because most physicians generally have no clinical experience of using it.

Another factor may be the side effects of the 50 milligram dose can be most unpleasant; you really just don't see those at the real low doses that we're using, but that may also contribute to a physician being hesitant to use it. There may be a sense of, 'If I've got no experience of doing this, I'm going out on a limb- will I be covered by my medical malpractice insurance?' It's a very real fear. Lots of doctors have been sued for less, and they're just scared. They may turn to ask a specialist or a colleague if they use it, and if those people haven't, it makes it more challenging to overcome their reluctance. It's called the Bolam Principle: if everybody else is doing it then it's easier for you to justify doing it. So we need a sizeable number of physicians who have clinical experience of using it and a sizeable number of patients in order for it to gain the necessary momentum.

Of course, you also get the detractors who view the often profound and immediate clinical response of many patients and are very quick to say, 'Oh, that's just placebo effect. It's because they believed it.' Well, that'll only account for a 30% response rate. We're seeing at least double that... more like 80%. So our percentages are too high to say that it's explainable by placebo effect.

There is this condition in medicine where we have a resistance to new ideas. We're stuck in our current way of thinking, and as a profession we've always been very slow to embrace new ideas.

Recently we saw this with Helicobacter Pylori. The idea that stomach ulcers could be caused by a chronic low-grade bacterial infection in your stomach was just seen as ridiculous, and was rejected out of hand for years until finally the guy who was convinced of it consumed the bacteria, developed some nice stomach ulcers, and then healed them by taking the antibiotics. He did it on himself personally. And it caught so much interest and attention that they said, 'He really believes that stuff.' Eventually - with better properly designed studies- it became recognized as fact. So it's just part of the nature of medicine.

Dr. Burt Berkson (who was a biologist before he became a physician) made an interesting point about this in Julia Schopick's book "Honest Medicine". He said he was educated as a biologist but trained as a physician. He said there's a big difference between education and training. With education, he was taught to think and to ask questions. With training he was taught just do it this way. He says doctors are trained, not really educated. That is his attempt to explain why as a profession we can be so slow to consider and embrace new ideas, because most of the time questioning within medicine isn't welcomed. You just do what the expert tells you. You just do it and that's it. You don't ask questions. I think Dr. Berkson articulates it very well.

Try to work in conjunction with your specialist or family physician point out a few things. In addition to it being well-documented, LDN's attractiveness comes from the fact that it actually strengthens the immune system, reduces the risk of autoimmune conditions in the future, and is potentially protective against cancers. That is massively more attractive as a treatment compared to putting yourself at more risk through long-term immunosuppressant use. If your physician is still resistant, introduce the physician to an N-of-1 trial. Say, 'Let me be an N of 1. Let me take it for two months on and a month off and then two months on again and let's compare symptoms and see what it's doing for me. I'll sign any disclaimer about side effects.' Work with your physicians or specialists, and be active advocates for your own care.

One issue is that it needs to be published in high impact journals, whether case reports or randomized controlled trials. While there have been randomized placebo-controlled clinical trials published, including one by Dr. Jill Smith about LDN for Crohn's disease which it was shown to be effective, we still don't have widespread use of it. Why is that?

One possible reason the major academic journals may have a publication bias about off-label treatments like LDN is that they stand to lose advertising revenue from the companies of the big expensive on-patent drugs. Because of this, you have to try to get a little journal to publish it, and then the findings don't get the exposure or the acknowledgement they deserve.

With LDN, these obstacles are so frustrating because the clinical impact of it is so profound and so strongly beneficial for many people. When people are saying, "I've got my life back. I'm me again. I can't believe how well I am doing on this," it's disturbing that it is taking so long for something that can be that good to actually catch on. But the positive impact of it in many ways is so strong that I think in time it's just going to have to get more and more acceptance.

One way to know that LDN is not working well for a patient is through observing side effects. It's very common to get vivid dreams, sleep disturbance, nausea, headache and dry mouth (probably the top 5 symptoms people report) for a week or even two weeks. But if those negative symptoms persist into weeks 3 and 4 then I would clinically judge that as an excess of endorphins and either we'd drop the dose of the Naltrexone or reconsider if they should be on it at all.

I typically start everybody at 3 milligrams, and if those transient symptoms that I mentioned disappear then I would often try and push the dose up to 4.5mg, which is probably the best dose for most people. But if the negative symptoms don't disappear then I'm quick to drop it down to the 3 milligrams again. So I adjust the doses. But I'd say somewhere on average between 2 to 4.5 milligrams are the doses used for most people. We commonly use liquid Naltrexone, 1 milligram per ml, and the beauty of that is that it allows us to adjust the doses very easily- much more than you would be able to with capsules.

Our overall concept is that in order for somebody to achieve a successful pregnancy we want them healthy, happy, have a balanced cycle and good hormones.

If somebody has an autoimmune condition, I would use a combined approach: Low Dose Naltrexone, a dietary strategy (preferably doing a blood test to look for IgG food antibodies and change the diet accordingly) and I'd recommend a few supplements including high levels of vitamin D3 with omega-3. That would be my overall immune-modifying strategy. I would do that for anybody with an autoimmune complaint, but also if I'm dealing with fertility and want to get the immune-modifying benefits.

There are a sizeable number of patients who would fit the category of unexplained infertility. When we're trying to understand the root reason why some couples can't get pregnant, a good number of those with unexplained infertility would have what I would consider clinical endorphin deficiency and respond favorably to Naltrexone. But the cause is rarely a single factor... that might be just one contributing component. Fertility is really quite interesting. In our practice the cause of subfertility is usually multifactorial. We look at about 14 different factors we're aware of that can contribute to fertility issues. LDN would be part of the equation for I'd say nearly 50% of people we see.

I think that people must be careful not to over-rely on LDN. There are times when different or additional therapies are appropriate. When somebody's in an acute phase or at a point of extreme stress or distress, LDN doesn't seem to work. That's when you use immunosuppressive treatment as a short-term strategy. You're not exposing someone to the long-term potential risks, but you're preventing the immediate damage that a flare-up can cause (e.g. joint preservation for rheumatoid arthritis or maybe preventing progression of MS, etc.). Then we try to balance it with LDN to prevent recurrence. In this way, you may have the best of both worlds.

For example, I have a patient with rheumatoid arthritis, whose condition was beautifully controlled on LDN for 5-6 years. Then her house flooded and she was hugely stressed/distressed over the situation. She didn't come to see me during that time, but 3 months later when she came in, her joints were badly damaged in her hands. I thought, "Oh my! What happened to you?!" She told me what happened, and I explained to her that she needed an immunosuppressive treatment when she has a flare-up. When people hit a period of stress or distress I consider steroids to try to temporarily keep them stable. If we can prevent too big of a flare-up, then hopefully we won't get any further progression of their condition. So one message to patients is about over-reliance on LDN: don't just assume that if you're taking LDN that everything will always be fine. If you hit a time of stress and your autoimmune condition gets worse, immunosuppressive treatment may be needed during that time.

Yes, we are very interested in how LDN may impact epigenetics (chemical tags that influence gene expression) of endometriosis in particular, and autoimmune factors associated with the development of autism spectrum disorders.

Epigenetic issues may develop in utero and I think epigenetics has a significant part to play with endometriosis. We suspect endometriosis develops in females in utero. A growing number of women are presenting with endometriosis in their early teens and we think it's of developmental origin: the endometrial tissue sometimes develops outside of the fetus' uterus and it presents with the onset of puberty and menses in their teens. Because there's a strong autoimmune association with endometriosis, if you're clinically endorphin-deficient and your physiology isn't working like it should, and you can normalize that with the Low Dose Naltrexone, then it may positively influence the genetics of the next generation. I'm hoping that by giving LDN to women who have endometriosis, we may also have a positive impact on the epigenetics of females born to them - reducing their likelihood of developing endometriosis. By using LDN in women who have endometriosis, we've observed a lower incidence of miscarriage and better, healthier pregnancies for women who continue using it during pregnancy. So that's the immediate reason for using LDN. But there may be an even greater impact in the form of positively affecting the health of future generations of women as well.

Furthermore, there is evidence that autism has an autoimmune component. A large 2013 study provided strong evidence that a certain antibody called "brain-reactive" antibodies are increased in mothers of at least one child who has an autism spectrum disorder (ASD). These antibodies penetrate brain tissue early in development, can cause brain damage and contribute to autoimmune disease. Because of the potential harm these antibodies present to the developing brain of a fetus during pregnancy, I believe we can reduce the incidence of autism by giving "at risk" women LDN during the entire pregnancy. This is what we now do in my current practice, and we hope to contribute future research to this area.

So that's me taking a walk on the wild side and '..... if I dare to dream' , but these are topics I'm curiously looking at and considering. We clearly need much more research to look more closely at these issues - but the potential exists that LDN may prove beneficial in these cases.