A new leuprorelin study has published.
Here is the abstract and reference.
REF: Kang MG, et al. Effect of leuprorelin in bulbar function of spinal and bulbar muscular atrophy patients: observational study for 1 year. J Neurol. 2021 Mar 6. doi: 10.1007/s00415-021-10503-y. Online ahead of print.
Background: This study aimed to investigate the effect of androgen suppression therapy using leuprorelin focused on the bulbar function of patients with spinal and bulbar muscular atrophy (SBMA).
Methods: Genetically confirmed SBMA patients who consented to participate in this observational study were enrolled. Leuprorelin was subcutaneously injected every 12 weeks. Videofluoroscopic swallowing study was performed at baseline and after androgen suppression therapy for 1 year. The primary outcome measures were the changes in the vallecular residue and pyriform sinus residue. The videofluoroscopic swallowing study data were analyzed and interpreted by two experienced physiatrists.
Results: A total of 40 patients with SBMA were analyzed in this study. The inter-rater reliability testing showed good agreement for the pharyngeal residue (ICC = 0.84) and videofluoroscopic dysphagia scale (ICC = 0.75). The vallecular residue and pyriform sinus residue after swallowing 9 mL yogurt were significantly reduced (26.8 ± 22.6 to 14.6 ± 14.5, p < 0.001, 14.9 ± 16.9 to 7.6 ± 9.9, p < 0.001, respectively). The swallowing subscore of amyotrophic lateral sclerosis functional rating scale-revised improved after androgen suppression therapy (3.3 ± 0.5 to 3.5 ± 0.6, p = 0.041).
Conclusions: Leuprorelin significantly reduced the pharyngeal residue in patients with SBMA after 1 year of treatment without any serious adverse events and longitudinal studies are needed to confirm these results.
Unfortunately, the full text is behind a paywall.
My opinion based on the abstract:
It is a promising result. Both pharyngeal residue and dysphagia strongly relates to aspiration and pneumonia.
However, the study has some limitations. It is not a prospective, randomized, blind trial, therefore you cannot exclude some sort of bias. The number of patients is quite low.
It has some strengths. It has published in a peer-reviewed neurological journal. The endpoints are clinically relevant, measurable parameters. It is in line with some other studies. Leuprorelin is the only drug registered in SBMA, but in Japan only.
If I manage to read the full text, I will update. If somebody has a full copy, I kindly appreciate to send it to me.
Warning: It is not a medical advice. Please consult your physician before any decision.
Location: Chicago, IL
Istvan, thanks for posting this study. I checked on sci-hub for the full article but it isn’t available there yet.
I agree with all your points pro & con but have additional thoughts. The abstract only discusses positive findings but previous studies of leuprorelin have had mixed results. Established side effects of the drug include things such as fatigue, weakness, muscle atrophy, increased body fat especially gynecomastia, lethargy, loss of libido, constipation and depression. Considering many of us struggle with one or more of these there could be heavy prices to pay especially over a long time frame for a possible reduction in neuropathy and swallowing issues.
I’m also concerned they used the ALSFRS scale as a measure of evaluation. It is a coarse, sloppy and subjective measure. It is a set of questions regarding aspects of physical function scored from 0 for complete disability to 4 for no loss of function. For example a question on swallowing:
Early eating problems; occasional choking = 3
Dietary consistency changes = 2
Needs supplemental tube feedings = 1
The distinction between 3 and 2 is modest and muddy. The distance between 2 and 1 is vast. For most if not all of the questions my answers would be the same now as it would have been 20 years ago. Their choosing to use this scale makes me doubt their competence and reporting a significant finding with this scale on a time frame of 1 year makes me doubt their integrity. I don't know much about their other measures but I think it is a bad idea to take measures infrequently such as at the start and end of the study. Doing so means you fail to see if there is noise in the measurement or if there are other significant influences on the measure such as seasonal allergies, colds or people's day to day fluctuations in energy/fatigue. Thus it is very hard to know to what degree the results are due to meaningful change.
For the past 5 years I’ve been focused on improving my health and fitness with emphasis on things believed to raise GH/IGF-1 which is easy to track and for which I have gone from below the reference range to above the reference range, ie from being in the bottom 2.5% of men my age to the top 2.5%. And at the same time my testosterone both total and free have more than doubled despite having been above normal at the start. And during this period of time all of the symptoms I attribute to KD including swallowing and choking have gotten dramatically better. Perhaps this biases me to a critical view of the approach in this study although I truly hope those who try this drug find it helpful. I strongly encourage everyone with KD to do their best to get in tune with their bodies and work on the skill of evaluating their condition through things such as photos, journaling and tracking physical performance to better judge this drug or any other interventions they try.This message has been edited. Last edited by: ToddAllen,
Istvan, it is extremely difficult to do a blinded trial for a drug such as leuprorelin. The effects of the drug are immediately obvious to both patients and the investigating physician, so everyone will know who is taking the drug vs. the placebo.
The number of patients is low due to the small number of people who both have KD, and are willing to try leuprorelin, particularly if the study is limited to one nation.
Although it does say in the study report with reference to blinding:
This message has been edited. Last edited by: Dan B,
The complete text of the article is available at this link.
Location: Chicago, IL
Dan, I was going to thank you for posting the full text link but it no longer works and just gives the abstract with an offer to purchase the full .pdf. Last night when you posted the link, it did go to the full text. It was late and I gave the article a quick scan expecting to give it a slow thoughtful reading today but unfortunately I can not.
My quick scan left me with the impression that they collected data for numerous metrics and just as in previous studies of leuprorelin the results were mixed. The abstract implies the treatment is beneficial as it only mentions the most positive findings and doesn't bother to mention most of the findings were bad or neutral. Of particular concern to me was the results of the 6 minute walk tests buried late in the discussion for which they reported a large drop in performance. Since there was no placebo control group for comparison we have little basis to make conclusions regarding whether the drug treatment made things worse or better than they otherwise would have been for the 6MWT or any of the other measures.
Istvan raised concerns about the small trial size and the risk of bias when studies don't have controls with blinding. You correctly pointed out the challenges to do better larger studies. But the concern of bias still remains and I expect a thoughtful review of the data collected and how it was presented will suggest the researchers are emphasizing potential benefits and deemphasizing potential harms of leuprorelin. They collected before and after data on a large number of metrics without intermediate results, increasing the odds of random noise producing a metric showing a highly favorable result. And there is a widely recognized publication bias making it advantageous to report positive findings. While I share the common desire for good news, I'm aware of my inherent bias and when I see a silver lining I make an effort to pay attention to the dark cloud.
Thank you, Dan and Todd, for your important and valuable comments.
I didn’t notice the publication bias (unfortunately I couldn’t read the full text) and I totally agree with Todd’s warnings. The mentioned methodological problems are concerning. And if they experienced a significant drop in the 6-minute walk distance, it is really bad news. It makes the benefits really questionable.
I really appreciate any personal experience and found yours thought-provoking. Have you any kind of published clinical data (even a case study) about GH/IGF-1? I have heard about the relationship with KD, and GH/IGF-1 as a potential target, but found nothing about its practical use. It would be nice if you could share some more details about your therapy.
Location: Chicago, IL
Istvan, there are numerous papers on the therapeutic effects of IGF-1 in KD mouse models and tissue cultures which lead to a human trial of the drug BVS857 which is IGF-1 slightly modified to reduce clearance by the liver as endogenous IGF-1 has a short half life and like most proteins it is digested when taken orally so must be injected.
A randomized, placebo-controlled study to evaluate the safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy
Previous controlled clinical trials evaluating the effectiveness of dutasteride and leuprorelin have had mixed results.5–8 Cell and mouse studies have shown that insulin-like growth factor 1 (IGF-1) stimulates Akt mediated phosphorylation of the AR which enhances its clearance and ameliorates the disease phenotype.9,10 Overexpression and administration of IGF-1 rescue histopathological and behavioral defects in transgenic mice expressing mutant AR.10,11 Exercise has been shown to increase IGF-1 synthesis and its anabolic effects on muscle, which were potential targets in clinical trials evaluating exercise in SBMA.12–14 Although exercise was not found to have an effect on IGF-1 levels in SBMA, directly targeting the IGF-1 pathway may be a beneficial therapeutic strategy.14
In targeting the IGF-1 pathway in SBMA we aimed to replenish the reduced IGF-1 levels found in the disease, to stimulate downstream Akt activity to reduce the toxicity of the mutant AR,9 and to increase anabolic activity to prevent muscle loss.11,18 This study investigated the safety, tolerability, and preliminary efficacy of BVS857 in patients with SBMA.
The trial was for 12 weeks and DXA scans showed roughly a loss of 0.6 kg of lean mass in the controls and a gain of 0.6 kg of lean mass in those receiving the drug. MRI of their thighs showed a loss of thigh muscle volume in the controls and a slight gain in the treatment group. But the drug was a failure and apparently has been abandoned by the developer Novartis because it was beginning to produce an immune response that not only targeted the drug but also neutralized the endogenous IGF-1 of some participants.
But they never ask the question why men with SBMA have low IGF-1? I think the reason is hyperinsulinemia. Insulin is our nutrient uptake and storage hormone and is our main hormone to lower elevated blood glucose. The primary insulin sensitive glucose absorbing tissues are muscle and adipose. In KD as our muscles degrade they become less responsive to insulin. Our insulin rises higher and stays higher longer as it takes more and more time for our blood sugar to normalize after each meal. IGF-1 (insulin like growth factor 1) has similarities to insulin and even activates insulin receptors so it also promotes nutrient uptake and IGF-1 production like insulin is stimulated by high nutrient levels such as glucose but especially amino acids. But IGF-1 production is also dependent on growth hormone. GH is a counter regulatory hormone to insulin. It promotes the release of fats and sugar into the blood stream while inhibiting the break down of muscle protein. GH is suppressed when insulin is high and GH is elevated most when we are fasted and insulin is lowest. When we break a fast the surge in blood nutrients in the context of still high GH promotes IGF-1 and the repair and growth of muscle and other nutrient demanding tissues. When insulin stays high we get less GH and we miss out on the rebound surge of IGF-1.
The fix for me has been to eliminate most carbohydrates from my diet, especially refined sugars and starches. Carbohydrates raise insulin very strongly. Protein does so modestly and fat hardly raises insulin at all. At first my protein tolerance was poor and I needed to get most of my calories from fat which stabilized my blood sugar and allowed my insulin to drop low. Lately I’ve been eating a higher protein diet with good results, mostly red meat, eggs, fish and some dairy. I eat a big breakfast typically about 10 AM and a large dinner at 3 PM without lunch or snacks to maximize my swings between fasted and fed states and the resultant surges in GH and IGF-1.
In addition to my dietary changes I incorporated frequent brief sessions of maximal effort strength training as additional stimulus to raise GH/IGF-1. A bit over a year ago when I learned I had severe lead poisoning I converted our bathroom into an infra-red sauna to speed my detox by sweating out some lead. But on our existing electrical circuits I could only install a couple thousand watts of infra-red bulbs which does not get hot enough to sweat profusely. Until I started doing strength training in the sauna. That has been the game changer for me, now every night before bed I do a brutally intense strength training session which in the heat maximizes my heart rate and blood flow increasing strength and reducing muscle and joint pain enabling better workouts. The resulting heat exhaustion promotes amazing sleep and excellent recovery such that most mornings I feel very refreshed and energetic with minimal muscle soreness. As I’ve regained fitness I’ve increased the amount of exercise and lately most days I do 3 to 5 strength training sessions throughout the day of between 5 and 15 minutes each plus the sauna training session before bed which is lately between 20 and 60 minutes long depending on how I am feeling and my selected exercises for the day. Sauna is also a strong stimulator of GH/IGF-1 which likely is helping too.This message has been edited. Last edited by: ToddAllen,
Todd, thank you for the details -- I really appreciate your effort. Since there is a scarce of studies - especially human - studies of KD, we have to use and share our personal experiences.
Your concept seems worth considering. Let me add some thought - however, you may know some of them.
I totally agree. BVS857 study was a failure, but not the concept behind it. I think KD and diabetes have some common points and pathways, related to each other, however, these are two different diseases. Elevated insulin level and/or decreased insulin sensitivity may play an important role in both of them, and it is a potential target in KD. You can improve your insulin sensitivity with diet, lifestyle and physical activity - exactly as you described. It is a good thing to do, even it wouldn't beneficial specifically in KD, but I guess it is.
There are some completed and ongoing clinical studies with bimoclomol and arimoclomol, two similar developmental drugs, in diabetes and - what a surprise - ALS, Niemann-Pick disease C, Gaucher disease and inclusion body myositis. There are promising animal experiments. Some of the human trials failed, but they continue other studies. Arimoclomol is believed to function by stimulating a normal cellular protein repair pathway through the activation of molecular chaperones (which are another potential target in KD), and activates the heat shock proteins. There are animal studies in KD models with arimoclomol, and they showed good results.
Heat shock proteins are a part of the cellular response to stress. Many pathological states such as diabetes, dyslipidemia, cardiovascular disease, neurodegenerative diseases, cancer and the ageing process are characterized by a deficiency or dysregulation of the heat shock response. You may know that activation of heat shock proteins is another potential therapeutic target in polyglutamine diseases, such as KD. Your positive experiences with sauna may support this concept? I speculate that sauna may provoke the production of heat shock proteins, and that may benefit in KD.
Another point is metformin. Metformin is a well-known antidiabetic. It improves insulin sensitivity, has a documented anti-androgen effect(!) and has widely studied indication of PCOS (polycystic ovarium syndrome) in women. Pretty weird, that it is not an approved indication despite of evidences and even though it is recommended by NICE in UK as off-label therapy in PCOS. Women with PCOS have high androgen levels and metformin helps to lower it. Another off-label use of metformin is prostate cancer. It downregulates androgen receptors.
Moreover, in animal model, they showed that metformin combined with aspirin can synergistically reduce the number of aggregates produced after polyglutamine expression. There are no human studies, however, all these proteins are well conserved (similar to human) and they used the drugs in low doses. I feel met+asp has some therapeutic potential in KD, and really supports your "antidiabetic" experiences. (Unfortunately, when I asked the experts at 2020 KD Conference about met+asp, they didn't seem to be familiar with the idea...)
In summary, my opinion is that your report is really in accordance with my thoughts. I have considered for a while to start a low dose met+asp, and you added to it some valuable experiences. Lifestyle, diet, physical training, sauna are all beneficial even without KD. A lot of us with KD are either diabetic or near to it, and both metformin and aspirin are quite safe and well-known for decades.
Disclaimer: this is not medical advice, and you have to consult your physician.
Some references: met+asp in polyQ,
met in PCOS and anti-androgen effect, met in prostate cancer, [URL=https://www.discoverymedicine.com/Indira-Padmalayam/2014/07/the-heat-shock-response-its-role-in-pathogenesis-of-type-2-diabetes-and-its-complications-and-implications-for-therapeutic-intervention/ ]HSP in diabetes[/URL], HSP in polyQ and KD, arimoclomol in KD
Location: Chicago, IL
Istvan, yes metformin is definitely interesting. Mouse studies showing improved lifespan on metformin suggest it may have anti-aging benefits. A few people are taking low dose metformin for that purpose and I considered it but there is some data suggesting metformin might reduce the muscle growth response to strength training:
Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial
Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults
If I wasn't able to fix my poor blood sugar through diet then I'd be inclined to give metformin a try despite the possible impact on muscle growth as it would be fairly easy to get a prescription for that purpose and I expect poor blood sugar is a bigger problem.
Sauna enhancing heat shock proteins may also be helping me. It may also be boosting BDNF and sirtuins both of which have shown benefit in mouse models of KD and tissue cultures. But I don't know how to measure them. Similarly my dietary practices may be helping through enhancing autophagy, sirtuins, PACAP, HDAC inhibition and a few other things found beneficial for KD but again these are things I can't measure.
Location: Chicago, IL
I got blood work done last week. I was roughly 16 hours fasted at an 8 AM blood draw so it is a good estimate of the lowest my IGF-1 now drops and that is too high to qualify for the BVS-857 trial. I'm doubtful blocking testosterone/DHT is needed or even a good approach to managing KD as you can see mine are high and have been rising for the past 5 years as I have been focusing on improving my health and fitness. Instead of killing me I feel young again and am regularly setting new personal records for strength and walking speed. All of my KD symptoms such as abrupt weakness, post exertion fatigue, tremors, cramps and choking are fading and harldly bother me at all any more.
TESTOSTERONE >1500 ng/dL 264 - 916 ng/dL
FREE TESTOSTERONE 31.6 pg/mL 7.2 - 24.0 pg/mL
DIHYDROTESTOSTERONE 142 ng/dL 30 - 85 ng/dL
ESTROGEN 263 pg/mL 40 - 115 pg/mL
IGF-I 179 ng/mL 68 - 247 ng/mL
INSULIN GH BP-3 4,366 ug/L 2,133 - 5,711 ug/L
CHOLESTEROL 395 mg/dL 100 - 199 mg/dL
TRIGLYCERIDE 67 mg/dL 0 - 149 mg/dL
HDL CHOLESTEROL 100 mg/dL >39 mg/dL
VLDL CHOLESTEROL CALC 8 mg/dL 5 - 40 mg/dL
LDL CHOL CALC 287 mg/dL 0 - 99 mg/dL
Cholesterol is the precursor for sex hormones and mine have been rising together. Some believe a low ratio of triglycerides/HDL indicates minimal heart disease risk making LDL irrelevant. A significant percentage of people who adopt a ketogenic diet have a lipid response similar to mine. In general the more muscular and the lower the body fat the higher their cholesterol earning the nickname "Lean Mass Hyper Responders". There is a facebook LMHR group and it isn't just my numbers but increasingly my appearance fits in with those in the cover photo:
https://www.facebook.com/group...nMassHyperResponder/This message has been edited. Last edited by: ToddAllen,
Location: Chicago, IL
I found this article which may explain my elevated sex hormones.
Increased Estrogen Rather Than Decreased Androgen Action Is Associated with Longer Androgen Receptor CAG Repeats
"Taken together, men with longer AR CAG repeats had higher T levels, which could compensate partly or totally for the weaker activity of their AR. This is a highly plausible explanation for the lack of any clear signs of androgen deficiency in the EMAS men with longer CAG repeats. A potentially more important finding was the higher E2 levels in men with longer repeats, which paralleled with phenotypic effects indicative of elevated estrogen action. Hence, our current findings suggest that the increased estrogen action and increased estrogen/androgen ratio in association with longer AR CAG repeats is paradoxically the main determinant of phenotypic effects of this polymorphism, rather than an androgen-AR effect."
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