REVERSAL OF HYPOGONADISM & GLUCOSE METABOLISM DISTURBANCES IN B THAL MAJOR

I think the first question I ever asked of a doctor at a conference was about reversal of the damage that iron causes in the glands. In January, 2006 that answer was no, it can't be reversed. This was something of a disappointment to hear and actually conflicted with what I believed were the body's abilities to regenerate tissue, but I had to believe the well known expert. In February, 2009 I attended a symposium on gene therapy in NYC and one of the speakers addressed this topic in terms of glucose tolerance. I was quite pleased to hear that the ability of the body to tolerate and process glucose was indeed something that could be improved by iron chelation. At the conference in NYC in October, 2009, this topic was expanded on and we learned that hypogonadism, which leads to incomplete sexual maturity in many thal patients, is also reversible with chelation of the iron from the organs and glands. These are very important findings that have brought new hope to many thals around the world who have dealt with these problems and given even more incentive to getting the iron out. Again, combination chelation has been shown to be the most effective method for removing iron from organs, glands and tissue.

This is the summary of the report presented at the NYC conference.

13. REVERSAL OF HYPOGONADISM AND GLUCOSE METABOLISM DISTURBANCES IN β-
THALASSEMIA MAJOR PATIENTS AFTER COMBINED CHELATION AND DECREASE OF IRON
LOAD TO NORMAL LEVELS
Kallistheni Farmaki MD, PhD, Ioanna Tzoumari M.D, Christina Pappa MD, Thalassemia Unit, General Hospital of Corinth,
Greece
The frequency of endocrinopathies in β-thalassemia major patients (TMps) increased as survival improved.
Hypogonadism is the most common (40-91%) and dramatically affects patient quality of life because of fertility problems
and the impact on their psychological outcome. On the other hand, diabetes has a frequency of 6-28% and an established
effect on cardiovascular disease. Data regarding the relationship of endocrine dysfunction and chelation therapy are
conflicting. The primary endpoint of the present study was to place all TMps in a negative iron balance while observing the
evolution of endocrine complications secondary to iron overload.
50TMp, mean age 30.8±2.03, were previously maintained on subcutaneous desferrioxamine (DFO) monotherapy and
switched to an intensive combined chelation with DFO: 40-60mg/kg/d and Deferiprone (DFP: 75-100mg/kg/d), on an
individually tailored regimen. They were investigated initially and annually thereafter. The current analysis reports the
evaluation after 5-8 years. Iron overload was estimated by mean ferritin and hepatic iron quantification by MRI T2
*L and
Liver Iron Concentration (LIC) calculated by Ferriscan. Endocrine function was assessed by dynamic tests (GnRH, OGTT)
and hormonal screening. Statistical analyses were performed using SPSS (p<0.05 was considered significant).
1. Hypogonadism: Initially, 14/24 males (58%) were hypogonadic on testosterone therapy. After intensive combined
chelation, hypogonadic TMps had normal mean testosterone (4.6±0.7 vs. initial 1.5±0.5ng/ml, p<0.0001); this was
correlated with normalization of mean ferritin levels (3,349±882 vs. 108±32g/L, p=0.004), mean MRI T2
*L (32±2 vs. initial
6.5±2msec p<0.0001) & LIC (0,9±0.05 vs. initial 19.5±7mg/g dry weight, p=0.003) (r= -0.634 p<0.04, r=0.668 p<0.03, r= -
0.679 p<0.03 respectively). 7 of these 14 (50%), also normalized their LH-FSH response during GnRH test and
discontinued testosterone injections. One became the father of twins. In the eugonadal group, no new cases of
hypogonadism were observed and similar correlations were observed with the increase in mean testosterone levels
(6.8±0.6 vs. initial 3.6±0.5ng/ml, p<0.0001). With DFO monotherapy 19/26 females TMps (73%) were hypogonadic on
hormone replacement therapy. After combined chelation, a significant increase of FSH excretion (AUC FSH 373±37 vs.
733±58, p<0.0001) was observed; this was strongly correlated with normalization of MRI T2
*L (35±1 vs. 10±4msec,
p<0.0001) and mean Ferritin (114±12 vs. 2,696±587g/L, p<0.0001) (r=0.723 p<0.04, r= -0.936 p<0.01 respectively). A
correlation was also observed between the increase in LH (1.9±0.3 to 3.8±0.5mIU/mL p<0.000) and decrease of LIC
(11±4 to 0.9±0.05mg/g dry weight, p=0.002) (r=0.885 p<0.04). 6 females (32%) became pregnant, 2 spontaneously and 4
by IVF.
2. Glucose metabolism disturbances and Diabetes: Among the 50 TMps in DFO monotherapy 6 had Insulin-dependent
Diabetes, 14 had Diabetes-type 2 (Glucose 0΄>126mg/dl, 2h>200mg/dl), 19 had Impaired Glucose Tolerance (IGT:
Glucose 2h>140<200mg/dl). Following combined chelation 9/14 Diabetic-2 (64%) and 17/19 IGT (90%) normalized their
glucose metabolism. In IGT TMps there was a significant decrease in Glucose secretion (AUC Glucose 13,399±481 vs.
18,101±777, p<0.0001) and an increase in Insulin secretion (AUC Insulin 6,320±665 vs. 4,478±453, p<0.05) which
correlated strongly with the decrease in ferritin [2,690±393 to 113±19g/L, p<0.0001 (r= -0.592 p<0.02, r=0.568 p<0.02
respectively)]. There was also a strong correlation between the decrease in glucose 2h from 152±7 to 105±6mg/dl
p<0.0001 and the normalization of MRI T2
*L (35±2 vs. 8±2 msec, p<0.0001) and LIC (0.9±0.05 vs. 13±4mg/g dry weight,
p<0.008) (r=0.629, p<0.01 & r= -0.619, p<0.01 respectively). Conclusion: Long-term intensive combined chelation with
DFO & DFP cleared iron overload. This study provides insight in the relationship between iron load and the reversal of
Hypogonadism and Glucose metabolism abnormalities. This analysis highlights the possible role of Deferiprone which
was added to DFO monotherapy and reversed the course of these endocrinopathies. Further studies are needed.

And again we see at the end of the report, further studies are needed. And of course, the funding is always lacking. And I'm going to ask everyone point blank, why are we allowing politicians to keep us frightened into spending trillions of dollars foolishly to prepare for war and to wage wars? Not a single war that the US has been involved in since World War II has been justified and the money wasted in the past 60 years could finance every single piece of research needed to find treatments and cures for a host of diseases and disorders. And it is not just the US. How many nations have joined with the US in waging these wars of aggression? Why are we allowing these people to ruin the world, while we pay for it?

Umair,

Please pay special attention to this one line.

Long-term intensive combined chelation with DFO & DFP cleared iron overload.

You have made great progress but to continue to restore your body you need to continue your combination chelation. I recently read that it takes 17 months to remove half the iron from an overloaded heart. It takes patience and perseverance, but it can be done and although you have made such good progress, there is still work to be done. As I mentioned to you on MSN, continuing desferal a couple days a week, along with daily Ferriprox, can help you achieve your goals.

Andy,
Thanx alot for  searching and sharing this useful information which is covering my concerns .... ofcourse, m not gonna quit chelation at this poiint of treatment , i will keep 2 days desferal after Tx plan On for coming couple of months, to wipe out iron completely from organs ... hoping to get more better results in future , the only thing that is out of control and pinching me  is Diabetese .... i myself mentioned this in my threads :
something about Liver, iron overload, chelation, diabetes and hepatitis
http://www.thalassemiapatientsandfriends.com/index.php?topic=1870.0
good news or bad i didn't judge ..!
http://www.thalassemiapatientsandfriends.com/index.php?topic=1825.0 ,
that  when iron come's  towards normal ranges it decreas's the need of insulin too ... but i dont know why my insulin need increased once again after decreasing significantly .....  but ,  hopefuly i will get ride over it  again ....  thanx again , Andy !! for all this info that has alot of hope for me in it   ...

Umair

Umair,

Things won't change so quickly and this is why I highlighted "long-term". Both the iron removal and the regeneration of tissue take time, and with the pancreas, no one will say that full function can be recovered, but glucose tolerance can be improved, making it easier to regulate diabetes. I do believe that regenerative herbs like nigella and milk thistle can also play a positive role in improving liver and pancreatic function.

You progress is astounding and worthy of commendation. I would really recommend the approach to diabetes where you take 5 small meals daily. This makes it much easier to control the highs and lows when you are taking insulin. Often with diabetes, it has much more to do with the properties of insulin than it does with diabetes. Taking insulin creates requirements that have to be met, and frequent meals can provide for these requirements.

Hey Umair,

I agree with Andy, for you the best is yet to come.  Although your ferritin levels have decreased, your tissue and organ overload are continuing to improve everyday - only then will the tissue have a chance to repair itself.  This is when you will feel the true benefits.

Sharmin

Umair,

Good luck my friend, we are all backing you 

Andy

Speaking of combined chelators in NYC conference, does this show that doctors are starting to agree on using two chelators at the same time. Has this been agreed by doctors or not yet??

Manal

Manal,

The desferal/deferiprone (Ferriprox, Kelfer) combination is the only one with much of a track record, so it's the one that is always talked about at every conference. At this conference, the frustration over the lack of approval by the FDA of Ferriprox, was quite evident. After over 20 years of use, most doctors just do not understand why the drug is not readily available to patients in the US. There was also some talk about using desferal and Exjade together, but there is a scarcity of data at this point. My opinion is that for iron overload, there is currently no better possible combination than desferal and deferiprone, because deferiprone is a smaller molecule that can penetrate where the other two chelators cannot. For those who have never had a serious iron overloading condition, this may not be so important, but for those cleaning out a significant iron load, deferiprone is recommended in combination with desferal. Almost all doctors agree on this combination. The one very well known doctor who has opposed the approval of deferiprone in North America for many years, was scheduled to speak but never showed up at the conference (which was predicted by those in the know at the conference). Aside from that no-show doctor, I know of no other doctor who does not accept the vast evidence about the efficacy of the desferal/deferiprone combination.

Andy,

Unfortunatly i know many doctors here who don't agree of combination therapy because they didn't see any records of using any of the chelators togather.

Are there any online studies on combined chelators??

manal

Manal,

There have been studies done all over the world on this. You can see links to some of these below. Dr Antonio Piga, who we met at the Singapore conference, would be an excellent guest to consider inviting to the conference in Egypt. His work has pioneered this combination use of desferal and Ferriprox, and he also really enjoys the interaction with patients and parents at conferences.

http://jcmr-online.com/content/10/1/12

Greece  http://informahealthcare.com/doi/abs/10.1080/03630260701680474?journalCode=hem

Oman   http://www.springerlink.com/content/0620u72v2pk10788/

Iran  http://www.ams.ac.ir/aim/09125/0011.pdf

Turkey  http://www.haematologica.org/cgi/content/full/92/12/1599

Taiwan  http://www.springerlink.com/content/wcn5q238ggwge86n/


Summaries of the topics at the NYC 2009 conference concerning current thinking in iron chelation can be seen below. Please note the line in bold at the end of these summaries. I have mentioned this before and parents and patients should be advised that if you have access to an expert center, you may get the opportunity to try new techniques, like combination chelation, before they are subject of trials. Almost from the point it was released, Exjade has been used in combination with desferal in patients when warranted. I have heard several success stories with this combination. One point I often see about combination therapy, is that in the long run, the patients will be exposed to lower doses of each specific chelator, which does reduce the side effects associated with that chelator.

SESSION III: IRON OVERLOAD AND CHELATION THERAPY

Deferiprone
Antonio Piga, MD, Simona Roggero, MD, Ilaria Salussolia, MD, Valeria Orecchia, MS, Filomena Longo, MD Thalassemia Center, University of Turin, Orbassano, Italy
Deferiprone (1,2-dimethyl-3-hydroxypyridin-4-one, or L1, DMHP, Ferriprox®), was synthesized in 1984 and then extensively evaluated in a wide range of disorders; most of the available data have been obtained in transfusion-dependent thalassemia.
The safety and tolerability profile, as for the other two chelators deferoxamine and deferasirox, is peculiar. Side effects include gastrointestinal problems, raised liver enzymes, weight gain, arthropathy, neutropenia and agranulocytosis. This precludes the use of deferiprone in conditions with bone marrow activity abnormalities and requires close monitoring of blood count.
The efficacy profile is more similar among the three chelators. For deferiprone the choice of dosage is crucial to optimize the effect on liver iron concentration, according to the iron load degree, the transfusional iron input. Differences in hepatic glucuronidation
efficiency may account for individual variability. Growing evidence, also from controlled studies, indicates that deferiprone is cardio-protective and effective in removing cardiac iron, alone or in combination with deferoxamine. In some studies, the effect on cardiac function is even more pronounced. These advantages may be explained by its physical characteristics
and kinetics.
These data as a whole create a non marginal role for deferiprone in the management of iron overload. There is a need to weight by randomized controlled trials the relative value of deferiprone, deferasirox and deferoxamine in the long-term prevention
of iron toxicity.

Combined Therapy
Renzo Galanello, MD1, Annalisa Agus MD1, Simona Campus MD1, Fabrice Danjou MD1, Robert Grady PhD2. 1Pediatric Clinic 2 and Thalassemia Unit Asl8 - University of Cagliari Italy, 2 Weill Cornell Medical Center, New York, NY
Combined therapy consists in the administration of two iron chelators in the same day simultaneously or sequentially. Combined chelation offers several potential advantages, including the concurrent access to multiple iron pools by different
chelators, the achievement of iron excretion levels higher than those obtained by either drug alone, the possibility of decreasing the chelator dose while maintaining high iron excretion levels, better tolerability and greater compliance. Several retrospective and some prospective studies have shown that combined therapy with deferiprone and desferrioxamine is effective in reducing cardiac and hepatic iron overload, in improving cardiac function, in the management of iron-induced heart failure and in the reversal of some iron-induced endocrine complications. To date, combined therapy has shown no unanticipated side effects. No studies on other types of combined therapy (i.e. desferrioxamine and deferasirox, deferiprone and deferasirox) have been reported to date.

Deferasirox: An Update
John Porter, MD, University College London, London, UK
Over 3000 transfusionally iron overloaded patients have been studied in prospective trials, allowing for evidence-based conclusions
about the safety and efficacy of deferasirox across a range of underlying anaemias. Initial pharmacokinetics and metabolic balance studies demonstrated a long plasma half-life, suitable for once daily oral dosing, and a fecal route for iron excretion. Pivotal pre-registration studies established the relationship between dose, iron excretion and tolerability using changes in liver iron concentration (LIC) to measure changes in body iron. The dose allowing the rate of transfusional iron loading to be balanced by iron excretion can now be predicted across a range of underlying diagnoses. Unwanted effects included skin rash, and gastrointestinal disturbances. Serum creatinine increments ≥ 30% were seen in about one third of patients but this was not progressive, rarely exceeding the upper limit of normal. Study extensions of these patients at 4.5 years, including over 160 pediatric patients, show no progression of renal effects and a decrease in the frequency of skin, gastrointestinal and other unwanted effects. The proportion of patients with serum ferritin <1000μg/L has risen from 14% at y1 to 37% at 4.5y without an increase in adverse events. Doses >30mg/kg/day has been given in > 200 patients in trial settings without an increase in adverse events. The large-scale EPIC trial involving > 1600 patients has revealed further insights about the interaction of dose with ferritin trends and safety markers. Cardiac sub-studies of this trial, in >100 patients with established mild to moderate myocardial iron loading by T2*, show a significant reduction in cardiac iron.

Monitoring the Efficiency of Iron Chelation Therapy
Robert C. Hider, PhD, Andre Silva, BSc, Yongmin Ma, PhD, Pharmaceutical Science Division, King’s College London, Franklin-Wilkins Building, 150 Stamford St. London, UK
With the introduction of orally active iron chelators a wider range of patients are now being treated for iron overload. Consequently there is an increased requirement for efficacy monitoring of these therapeutics. The application of MRI to
estimate liver and heart iron content and the measurement of serum ferritin levels, transferrin saturation, and hepcidin levels, now offers an effective means of monitoring many of the effects of iron chelation. One parameter which is still not reliable and sufficiently reproducible to be used as a clinical test is the measurement of nontransferrin-bound iron (NTBI). There are a variety of measurements available, some claiming to measure the entire NTBI pool, others the redox active component of the pool. However to date none of these methods has attained general approval at the international level. In this presentation
an update will be made on the chemical nature of NTBI and a novel fluorescence-based method for its measurement will be described.

Survival Trends Using Combination Chelation Therapy (CCT)
Paul Telfer, DM, FRCP, Barts and the London School of Medicine and Dentistry, UK
Iron chelation with a combination of deferoxamine (DFO) and deferiprone (DFP) has been used in Europe and the Middle East over the past 10 years for intensification of therapy in patients with thalassemia major who have moderate/heavy total iron load, have significant myocardial iron load, or are unable to adhere to sub cutaneous desferrioxamine at the recommended
frequency. Various regimens have been described and most published reports show a more rapid reduction of iron loading compared with monotherapy. Adverse effects are frequent and intensive monitoring is required. Most of these are short term trials, and mortality rates while on CCT have been very low. The chelation protocol adopted in Cyprus provides useful quantitative data on the long-term effects of CCT on survival. A large cohort has been treated with a relatively uniform
protocol and analysis has included all eligible patients in the south part of the Island, thereby reducing bias inherent in long-term follow-up of a non-randomised groups. Independent predictors of improved survival were female sex (Hazard Ratio (HR) 0.43, 95% CI 0.25-0.73); Birth >1973 (HR 0.3, 95% CI 0.17-0.51) and CCT (HR 0.14, 95% CI 0.04-0.41 for each year after switching therapy. Patients switched from DFO were 7 times more likely to survive per year of CCT, the majority of the survival benefit was due to reduction in cardiac deaths. This study provides further evidence for the cardioprotective effect of DFP. CCT given as a sequential regime is effective in controlling iron loading and preventing iron-related deaths in patients with iron accumulation after many years of DFO monotherapy, but should be supervised and monitored in a specialised centre.

Current Strategies for Chelation Therapy – How will we Choose the Best Approaches in Thalassemia?
Ellis J. Neufeld MD, PhD, Division of Hematology/Oncology, Children’s Hospital Boston, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA
The 9th Cooley’s Anemia symposium is a timely occasion to reflect not only progress over the last few years in monitoring and treatment for transfusional iron overload, but also to consider where we are heading. Two key improvements even since the 8th symposium are wide use of non-invasive MRI assessments for iron overload, and regulatory approval and launch of deferasirox as an oral chelator. These advances are presented in many other talks at this symposium. This talk will consider how we can integrate these factors for optimum modern chelation practice. Underlying principles for this discussion include (i) the fact that many patients have suboptimal iron status in 2009; (ii) a consensus that wherever possible, prevention of iron overload and iron-related end-organ toxicity is preferable to “rescue therapy,” and (iii) monotherapy with deferasirox will not be a solution for all patients. The latter principle is based not only upon the evolving post-marketing data from the manufacturer,
but also from investigator-initiated trials of deferasirox poor responders (Chirnomas et al, Blood, 2009, in press), and of combination therapy strategies, including deferoxamine with deferiprone for patients with or without heart disease, and deferasirox with deferoxamine. The two oral chelators have not been combined in any active trials to date. Current clinical practice at expert centers is substantially ahead of published clinical trials, in terms of dosing and combinations. Longitudinal observational studies of broader populations, including the NIH-sponsored Thalassemia Longitudinal Cohort study of the Thalassemia Clinical Research Network, may by the fastest and most reliable way to gain knowledge in the field.

There is no doubt of combination therapy being the best ever therapy for iron overload-- and iron load.
The desferal-ferriprox combination therapy has saved thal lives-- at least I saw it happen in Greece. I myself have experience a rapid drop from 1500 to 45 within the first 5 months I applied this therapy to myself. Do not doubt the use of it. Monotherapy is long overpassed. Whichever monotherapy - desferal only or exjade only -- but not ferriprox only if you are on a low ferritin level. This is my opinion, of course, based on my experience - of course.
We may say the same about ferriprox-exjade combination therapy in a few years but now we are very doubtful about it- and that's logical. The unknown is always scary. It just takes a little bravery to proceed with it- on the doctor's part and on the patient's part, too. We'll see what years will bring.

The only thing I would like to underline to all thals and I take the chance to do it after something I saw written about Umair:
 DO NOT RELAX WITH YOUR CHELATION -- KEEP CHELATING EVEN IF YOU REACH LOW FERRITIN LEVELS -- IT IS EASY TO DROP THE CASE BELIEVING YOU ARE ON THE SAFE SIDE --  NOTHING COULD BE MORE WRONG THAN THAT.

Lena.

Thank you so much Andy and Lena for your great input

Manal

Thank  You  All  for your valuable input ..  i  m working hard to control my diabetes ... m still using desferal  and of course  Ferriprox too .. hopefully , soon i will b ale to get it under-control ...  .. once agian a big Thanx to you all ... hope you all r doing well , and enjoying ur life at its best. ...

Umair

I have hypogonadism as a thal minor.  Is this due to thal minor or just coincidence? 
TH

Hi TDHen and welcome to the site. 

Actually this could be a coincidence. There is no study that relates hypogonadism with thal minor

It will be great if you have time reading in the section of thal minor and the section of nutrition and supplements, you will find many good information that help.

Also feel free to ask whatever you want

manal

Hypogonadism is found in thal majors but it has never been associated with thal minor. I don't want to dismiss the possibility though, because it might be a contributing factor under certain circumstances, such as a chronically low hemoglobin level and a high rate of blood turnover (hemolysis). If iron absorption from the diet is also high, this could also be a factor. So, if you have a long term low Hb or have been diagnosed with high bilirubin levels, which would indicate a high rate of red cell turnover, or a higher than normal iron load, thal minor could be a contributor to hypogonadism. If your Hb level is not significantly lower than normal and bilirubin and iron tests are normal, it would be unlikely that there is any connection. A diet high in antioxidants would be recommended regardless of the cause.