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Showing posts with label Spironolactone. Show all posts
Showing posts with label Spironolactone. Show all posts

Thursday, 24 May 2018

An Autism Case History - EpiphanyASD in a Pill





It is not quite that easy!


Initials:                        LT
Age:                           14 years old

Year
of Birth:              2003

Sex:                            Male

Date:                           24 May 2018

Diagnosis      
LT was diagnosed with autism in January 2007, at a multi-disciplinary assessment in London, at the age of 3 years 6 months.  At that time, LT was non-verbal but had some emerging vocalization. No tics, no seizures, no unusual physical features, no self-injury, no sleep disorder, no feeding disorder. Toilet trained. Very limited attention span. No imaginative play. Liked to jump.

IQ not tested.
No CARS (Childhood Autism Rating Scale) assessment.
TEACCH and PECS were recommended as therapy.
Further medical testing or referrals – none recommended (standard practice in the UK) 

LT has an older brother who is intelligent, multilingual and highly social.
Comorbidities
GI disease:                   None
Epilepsy:                       None
Asthma:                        Yes, mild asthma from early childhood
Allergy:                         Pollen
Sleep disorder:             None 

General Health          
Very healthy and almost never ill. When visiting his GP at the age of 14 the doctor commented how she had not seen him for three years, whereas she has seen his older brother twice a year.

Born via a planned caesarean section, without complications, APGAR score was 10.


Growth                      
Body is well proportioned, no obvious macro/microcephaly. No physical features of any syndromes/metabolic anomalies.

However, LT was initially on the 90th percentile for height and dropped to the 20th by the time he was 5 years old. He was a very muscular baby.  At the age of 10 his bone age (X ray of left hand) was estimated to be two years delayed.  IGF-I was normal, FT3 was slightly above the reference range.

At birth he fitted the research description of hyperactive pro-growth signaling pathways, even though there was no macrocephaly.

Regression at age 8              
Aged 8, a big regression took place with self-injurious behavior (SIB) and aggression to others. He would slam his head into walls, other people, car windows, punch himself etc, but he was still small enough to be physically controlled/restrained by larger adults. He could not be controlled by smaller/older adult family members.

This aggression could occur immediately on waking until finally falling asleep at night, it was not predictable.  At that time in the afternoons, LT had a male 1:1 assistant with experience from a school for severe autism and in the mornings a very firm-minded tall female 1:1 assistant. LT’s father imposed a policy of zero acceptance of any SIB, to avoid it becoming a permanent acquired behavior. SIB was physically blocked.
The regression was triggered by the departure of his long time full-time 1:1 female assistant. It was an emotional trauma.  Occasional visits from her just made the situation worse.  In response no drugs were used, just a consistent firm behavioral approach. Over a ten month period the situation slowly stabilized, but skills were lost and bad habits (SIB) were acquired.  LT subsequently did see his assistant again and sees her regularly to this day.
Throughout this time his classmates and teacher at school were remarkably understanding. He was never excluded from school. His assistant ensured nobody at school got hurt.
Since assistants will inevitably come and go, from the age of 8 LT has had two part-time assistants rather than one full time.  As and when subsequent assistants have left, he has not had any troubling emotional reaction. 

Summer-time raging and loss of cognitive function
Summertime raging with self injurious behavior and aggression to others developed from the age of 9.

Later it became clear that in addition there was a loss of cognitive function during the summer months. This became evident once it was possible to teach mental math, from aged 9 onwards.  For example, at the age of 11, simple verbal tasks like 7 x 8 = ?, that had previously been mastered, could not be answered in the summer months.

The raging and cognitive loss were ultimately treatable.

Winter-time raging

Summertime raging was resolved and then winter-time raging developed. This was traced back to the cytokines released to signal reabsorption of milk teeth roots (a proves that takes months) and the eruption of permanent teeth. It was not tooth ache, i.e. pain. LT has retarded bone age and apparently this applied to his teeth development as well.

He lost his later milk teeth always in the winter.

The winter time raging did not respond to his summertime therapy, but responded very well to a low dose of ibuprofen. Summertime raging does not respond to Ibuprofen 

PANS-like episode aged 13
At Christmas time, following a minor viral infection, LT developed acute onset profound verbal tics. LT does not have Tourette’s type autism and had never exhibited such behavior previously. The tics were treated as a PANS/PANDAS flare-up with 5 days of prednisone. Over a two week period the tics faded away and have never returned.

Intellectual disability 
IQ was never measured, LT’s ABA consultant said there was no point, but the very much more rigorous ABBLS was completed, see below. Evidently, prior to pharmacological treatment at the age on 9, there was a 5 year developmental delay.
With hindsight, IQ pre-treatment was probably in a similar range to Down Syndrome (DS) meaning less than 70.

At the age of 14, LT’s academic performance now puts him in the top half of his class of 12 year old neurotypical peers. His grades are mainly As, with maths and computing being particular strengths. 

Other testing:    No genetic testing, MRI or EEG.

Family History:          

LT has a 7 years younger, very distant cousin who is non-verbal with autistic disorder. They have shared great great great maternal grandparents. The cousin has parents who are both doctors and were high academic achievers as medical students.

The father’s family has a large number of Cambridge-educated doctors on both the grandmother's and grandfather's side; one gave his name to the scale still used to assess severity of Ulcerative Colitis and helped develop the first H2 anti-histamine drug. The father and uncle are engineering graduates from top universities. One distant cousin was a math’s protégé at Oxford University.  One distant cousin has bipolar. One uncle has type-1 diabetes.

The mother is an academic alpha female in a stressful creative profession. The maternal grandmother was a teacher and grandfather was an army Colonel.
The maternal grandmother and her children all had premature hair greying, which may be linked to Bcl-2 expression and Wnt signaling, both implicated in autism. Thickness and greying of hair share biological mechanisms, which overlap with those controlling development of dendritic spines. LT and his father have very dense hair, mother has thin hair.
Maternal grandparents both smoked and the grandfather has COPD (Chronic Obstructive Pulmonary Disease). Oxidative stress is a core feature of COPD, because anti-oxidant genes are silenced; these effects are known to be heritable via epigenetic tags. 
The family fits the high IQ  type of autism (some autism genes are linked to intelligence and some bipolar genes are linked to creativity, which helps explain why some actors/artists are bipolar) with oxidative stress raised during pregnancy, anti-oxidant response possibly weakened, no oxytocin surge during delivery and no microbiota transfer at birth (C-section delivery).  No pets at home during pregnancy (a good source immuno-stabilizing bacteria).  No obesity in the family.

Education
LT has attended the same mainstream international school, following the English curriculum, since the age of 3. Class sizes are very small, about 12 pupils. From the age of 4 he has had a 1:1 assistant eight hours a day, throughout the year.
LT commenced a parent-managed ABA (Applied Behavioral Analysis) inspired home program shortly after diagnosis.  Both parents attended a 2 day training program to learn the use of PECS (Picture Exchange Communication System).  PECS was applied and shortly thereafter LT became partly verbal at the age of 4, speaking single words.
1:1 assistants were recruited mainly from the local University and trained to apply ABA, with elements from Floortime and the Canadian Hanen Program. There was some supervision from US-trained Behavioral Consultants that would fly in for training. A large collection of specialist training material was acquired from the US. 
Extensive use was made of professional (i.e. expensive) special needs language teaching software (Laureate Learning) from the age of 4 until 8 years old.
Later, web-based reading software (Headsprout) was used and years later special maths teaching software (Math Wizz). Neither are made for special needs, but both are very compatible with an ABA approach.
LT spent an extra year in kindergarten and in primary/junior school was held back 2 years at the age of 9, following a request from the parents.
In primary school (English system) he went Year 1, Year 2, Year 3 (started bumetanide) then back to Year 2, then Year 3, Year 4, Year 5, Year 6 and currently attends Year 7 in secondary/high school
The equivalent in the US system would have been, he went K, 1st, 2nd, then 1st, 2nd 3rd, 4th etc.
From the age of 13, LT attended school full time, prior to that he attended only the morning and then went home after lunch to work 1:1 with his assistant for three hours.
During school holidays LT has a 1:1 home learning program.
LT learnt to read and write at home as result of the unrelenting efforts of his assistant. He started to learn maths from the age of 8, prior to that he could not master the basic concepts, or understand the relevant vocabulary.
From the age of 9, LT has been able to keep up with his new peer group at school, two years his junior.
At the age of 14, in a class with 12 year old neurotypical children, LT takes the same assessments as the rest of the class and his grades currently place him in the top half of the class. He is now particularly good at things like arithmetic, algebra, coordinates, spelling and has neat handwriting (very unusual in autism). He is still clearly autistic and his speech is limited to what he wants to say; there is no small talk.
LT started to learn the piano aged 8. He progressed from an extremely basic level and a desire to hit his teacher to his current level 4 of the popular Faber Music piano course (there are just 5 levels). When he plays in public people are very surprised, he does not play like someone with any cognitive impairment. His peers as school have asked “how can he play like that?” 

Motor Skills
Like many people with classic autism LT had problems with both fine and gross motor skills as an infant. After a great deal of 1:1 therapy, motor skills are now normal.
LT started to learn to ski at the age of 5 with a special needs instructor. Progress was initially slow, but 9 years and one broken collar bone later, LT can confidently ski on red slopes and deal with all the various types of lifts you encounter in the Alps.
Stamina improved considerably after starting to take Agmatine, which is evident at school where they are timed to run 2.5 km (1.5 miles) and when swimming.

Behavioral Treatment (age 3- 8)
From diagnosis aged three, until nine years old, therapy was exclusively based on behavioral interventions. Extensive use of ABA (Applied Behavioral Analysis) and VB (Verbal Behavior) with 40 hours a week with a 1:1 Assistant.
At the aged of 9, LT had mastered almost all the skills in the very extensive ABBLS (Assessment of Basic Language and Learning Skills) assessment. The language skills and other basic learner skills that are tracked by this tool are those that are acquired by most typically developing children by the time they reach four to five years of age. LT’s elder brother had acquired these while he was three years old.
LT’s skill acquisition to the age of eight was seen by the ABA consultants as nothing unusual in someone with classic autism. There was slow but continuous progress. 
All learning was taking place at home with school attended mainly for socialization.

Pharmacological Treatment (age 9 onwards)
In late 2012 a small clinical trial was published by Ben Ari and his clinical associate Lemmonier; it showed the benefit of the NKCC1/2 blocker bumetanide in autism. This paper was studied by LT’s father and contact has been maintained for several years with Dr Ben Ari, who originated and patented this therapy.
Bumetanide (1mg per day) was commenced just before Christmas December 2012, unknown to the school, or LT’s assistants.
On returning to school in January 2013 the Head Teacher summoned LT’s father and asked what had happened to LT. He was “so joyous” and “like a different child”.
At the suggestion of his original ABA consultant, LT’s father had been asking LT every school day for 5 years “what did you have for lunch at school today?”. The usual answer would be no answer, the wrong answer, but sometimes a brief correct answer. From now on LT would say precisely what he had eaten “peas, potatoes and chicken – cake for dessert”. The assistant was there to confirm what had really been eaten for lunch. 
LT’s 1:1 assistant at that time described the effect of bumetanide as making him “more present”. Since his assessment at the age of 3, it was always noted that LT had a very short attention span and would not be able to focus on the class teacher for more than a couple of minutes. LT was never hyperactive, quite the opposite. He was physically present but not mentally.
Later on it would be realized that the most potent effect of long term bumetanide use in strictly defined autism (SDA) is enhanced cognition, which leads to accelerated acquisition of new skills.  IQ has long been seen as the best predictor of more favorable outcomes in autism.  
Bumetanide use has continued for five years, with occasional pauses to confirm it still works.  Different doses were tested and currently the dose is 2mg once a day.
When stopping bumetanide for a week and returning to his web-based maths learning program, LT was unable to complete previously mastered tasks, no matter how many times he tried. Having recommenced bumetanide, the same maths problems were attempted a week later and could be solved. 
Blood potassium levels were checked regularly at the beginning, but were always high normal (5.0 mmol/L).  Bumetanide is taken with 250mg of K+ per 1mg of bumetanide. Diet is rich in potassium, with bananas and other fruit.
Dehydration, another potential problem, is entirely self-regulated with LT drinking more water. Total consumption is 2.5 to 3 liters per day.
Diuresis occurs mainly within one hour of taking bumetanide and has never caused a problem at home or school. LT takes his bumetanide at least an hour before leaving home for school.
Bumetanide’s suggested mode of action is lowering intracellular chloride via blocking NKCC1 cotransporters in the brain.  Bumetanide crosses the blood brain barrier very poorly and many researchers are dubious it can have any effect. Bumetanide is a partial solution.
A new drug is being developed by Dr Ben Ari that will cross the blood brain barrier more effectively than bumetanide and have less effect on NKCC2, so producing less diuresis.
An alternative strategy discussed in the literature is to improve the pharmacokinetics of bumetanide, by slowing its excretion via OAT3 (organic anion transporter 3) and thus increasing plasma concentration. There are many OAT3 inhibitors, the best known and most potent is probenecid, used to treat gout by increasing the excretion of uric acid. Some foods are OAT3 inhibitors. One readily available substance is chlorogenic acid (more precisely 1,3- and 1,5-dicaffeoylquinic acid) which is sold as a coffee-based weight loss supplement. Interestingly, coffee, but not caffeine, has been shown to reduce the risk of gout.
Little is known about exactly how bumetanide is transported/excreted across the blood brain barrier.
Bumetanide’s autism benefit appears to be from lowering intracellular chloride and hence making GABAA become more inhibitory. Excitatory-Inhibitory (E/I) imbalances are widely believed to be at the core of autism.  An E/I imbalance during so-called Critical Periods, will result in permanent changes to the developing brain, nonetheless it appears that correcting an E/I imbalance in later years can still be highly beneficial, though not curative. 
Another experimental therapy also makes GABAA become more inhibitory. This uses very low doses of clonazepam to modify the behavior of GABAA receptors that contain the α3 sub unit.  In LT the effective dose of clonazepam is just 0.03mg, which might be considered sub-clinical, but as predicted by Professor Catterall, it does have a beneficial effect (a bumetanide-like effect). It has no side effects and there is no tolerance develops at this tiny dose, after four years of use.
At the time low dose clonazepam was introduced, LT would go swimming at 5pm most days. He was not really interested to do much independently in the water, he was very passive. This passive behavior was notably changed once the effective clonazepam dose had been found. He became more like a typical child playing in a swimming pool. Instead of sitting on the steps he wanted/demanded interaction/play with the attending adult.  The effect was not as profound as that seen in the first months of bumetanide, but noticeable nonetheless.
After 4 years of bumetanide the effect was still there, but there was a desire to accelerate skill acquisition to keep up with neurotypical school peers.
A new strategy was adopted to further reduce intracellular chloride, this time using a method first documented in the 1850s, when potassium bromide (KBr) was used to treat epilepsy. Reading old case studies from Great Ormond Street Hospital in London it appeared to LT's father that some children with epilepsy, MR/ID and undiagnosed autism improved behaviorally and developed age-appropriate play when treated with KBr. Lack of age-appropriate play is a hallmark of autism.  Modern research shows that bromide ions compete with chloride ions to enter cells and the result is a lower intracellular concentration of Cl-. The limiting factor in the use of KBr is that it increases mucous secretions and so causes acne (and can make asthma worse), in a dose dependent fashion. At a low dose of 400mg per day there is a cognitive gain without significant spots. KBr is still used at high doses to treat pediatric epilepsy in Germany and Austria. Some leading US neurologists regret they cannot prescribe it; technically they could ask the FDA for permission on a patient by patient basis.

Another strategy to reduce intracellular chloride is to target chloride ions that enter neurons via the AE3 exchanger, this is possible using Acetazolamide (Diamox). This therapy does seem to work for some people, but was not tolerated by LT, it caused reflux.
KBr has a very long half-life and so it takes 4-5 weeks to reach the maximum effect. 
Bumetanide took about two weeks to lower chloride and show behavioral and cognitive improvements.
Low dose clonazepam takes three days, as was predicted by its half-life.
The cognitive loss in severe autism has parallels with that in Down Syndrome (DS). Bumetanide has been patented as a therapy for DS by Ben Ari, based on the results from mouse studies.
In mouse models of Down Syndrome both a negative allosteric modulator and a selective inverse agonist of α5 sub-unit of the GABAA receptor improve cognition. 
Mouse research has shown that poor learners have greater GABRA5 expression than good learners and that in mice GABRA5 expression can be normalized by eating cinnamon, or its metabolite sodium benzoate (NaB); this makes a poor learner become a good learner, at least in mice.
So it may be that increasing the effect of α3 sub-unit of the GABAA and reducing the effect of the α5 sub-unit of the GABAA can both improve cognition. For the moment the latter remains unproven. NaB is an approved food additive, E211. Ceylon cinnamon, which is safe for long term consumption, is metabolized to NaB. People who are histamine intolerant have to avoid DAO inhibitors such as cinnamon and NaB. 

Summertime raging and loss of cognitive gains
From the aged of 8 it became apparent that summer provoked behavioral deterioration. At this point there was no obvious allergy, but behavior improved when moving to the mountains in summer. At first, OTC mast cell stabilizers were investigated; some common H1 antihistamines are partial mast cell stabilizers. Rupatadine, azelastine, ketotifen, loratadine and cetirizine were all tried, as was the flavonoid quercetin.
Some of the above did indeed help reduce the summertime self injury, but not to a satisfactory level.
A final solution was found in a small dose of the Cav1.2 blocker, verapamil. 
When mast cells degranulate, one step requires activation of an L-type calcium channel. This is why most mast cell stabilizers are actually calcium channel blockers.
It should be noted that mutation in the CACNA1C gene, which encodes the Cav1.2 ion channel, leads to a severe kind of autism called Timothy Syndrome. Because Cav1.2 is widely expressed in the heart those affected have a very poor prognosis.
In addition, verapamil blocks the potassium ion channel Kv1.3.  Potassium channels, Kv1.3 and KCa3.1, have been suggested to control T-cell activation, proliferation, and cytokine production. Kv 1.3 is widely regarded as a therapeutic target for immunomodulation in autoimmune diseases.  Research has shown that peptides from parasitic worms that suppress the body's immune response do so by blocking Kv1.3. A drug therapy based on these peptides is being developed.
Verapamil also upregulates autophagy, which is impaired in many neurological disorders, such as Huntington’s. Lack of autophagy has been linked to the synaptic pruning deficits found in autism.
Verapamil has a short half-life of about 3 hours. Only a small dose is required to prevent the onset of SIB and the preceding agitation (described by LT as “spray the fire in my head”).
From the age of 10, LT’s summertime raging has been treated with 40-80 mg of Verapamil split into 2-3 doses from May until late November.
On the occasions that he has missed his 1pm dose in the peak allergy period, he has repeatedly developed aggression and self-injury by 4 or 5pm.
When he has taken verapamil there has never been any aggression and or self-injury.
Once self-injury was removed as a concern, learning progressed during the long summer school holidays. It became clear that during summer cognition was reduced as if bumetanide was no longer working.
It has been shown that the expression KCC2, the cotransporter that allows Cl- to leave neurons is affected by inflammatory cytokines like IL-6. It therefore appears plausible that the histamine and IL-6 released directly and indirectly by mast cell degranulation was causing an increase in neuronal Cl- and thus undoing the good work being done by bumetanide. Inflammation also increases α5 GABAA receptor activity and can thus reduce cognitive function.
At this point, the bumetanide dose was raised from 1mg once a day to 2mg in the morning and on occasion 1mg in the late afternoon.
The combination of an increased dose of bumetanide and the use of verapamil, cetirizine and azelastine has produced a very favorable result (no SIB and minimal summertime cognitive decline). Perhaps of note is that cetirizine is an eosinophil stabilizer, which may also be helpful and not just for asthma.
OTC therapies that have a helpful effect in summer are L-histidine, curcumin and L. reuteri DSM 17938 (sold as Biogaia Protectis). The amino acid histidine is a precursor to histamine and it seems that the body’s feedback loops can be tricked into not degranulating mast cells by slightly increasing the level of circulating histidine. The immunomodulatory effects of L. reuteri DSM 17938 have been well studied; the effect however does not continue after prolonged use. Curcumin is a very widely studied natural substance that performs much better in vitro than in vivo, due to very poor bioavailability. Modified versions of curcumin have been developed and there is a marginal benefit. Histidine is extremely cheap and easy to administer. Modified curcumin and L. reuteri are quite expensive.
It is reported by others that at a higher dose verapamil is as effective as an H1 antihistamine in treating allergy. 

IPR3
It appears that aberrant calcium channel signaling is a key feature of much autism. Gargus has suggested that IP3R is a nexus for different dysfunctions that lead to autism. IP3R controls the release of calcium stored within cells (the endoplasmic reticulum).
Excessive calcium within cells is known to be damaging. L-type calcium channels that remain open will raise intracellular calcium and the same is true with IP3R. Caffeine can be used to inhibit calcium release via IP3R.
Gargus has not proposed an IP3R therapy.  


RORα

RORα is another proposed nexus where different dysfunctions  that lead to autism may converge. One potential RORα agonist is estradiol.  We know that in much autism there is elevated testosterone and reduced estradiol; we also know that estrogen receptor beta is under-expressed. Estradiol is known to be highly neuroprotective and may help protect females from developing autism. Females lacking in estradiol, for example in Turner Sydrome, may exhibit features of autism. A logical therapy would be to either use estrogens, or reduce testosterone (effectively the same thing). Ideally you would do this just in the brain; a brain selective pro-drug of estradiol, called DHED, actually exists. Less ideal therapies range from estradiol itself, to phytoestrogens or a high soy diet, to drugs reducing testosterone, like spironolactone; these will have effects beyond the brain.

Wintertime raging
Having solved summertime raging, wintertime raging appeared. As expected, verapamil had no effect.
Ultimately the likely trigger was traced back to the very slow loss of milk teeth and eruption of permanent teeth. Both reabsorption of roots and the eruption new teeth is signaled using pro-inflammatory cytokines.
Moderate use of Ibuprofen, as and when behavior began to deteriorate, resolved the problem. Ibuprofen has no effect on summertime raging.

PANS-like episode aged 13
PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) and PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections) are infection-induced autoimmune conditions that disrupt a patient’s normal neurologic functioning, resulting in a sudden onset of Obsessive Compulsive Disorder (OCD) and/or tics and cognitive loss.
The import part is acute-onset; behavior changes overnight.
LT exhibits the classic traits of autism including stereotypy/stimming but never tics, which are a feature of Tourette’s-type autism.
Just before Christmas LT was recovering well from what presented as mild viral infection that had not warranted any medical intervention. He suddenly developed very loud verbal tics.
It is well known in PANS that delayed treatment severely affects prognosis. The sooner the patient is treated, the more complete recovery will be. Diagnosis is based on a very specific set of laboratory tests, only available in the US.
LT was treated from the third day of the tics as if he had PANS flare-up. He was treated with 40mg of prednisone for 5 days, requiring no taper.
Over a two week period the tics faded away. There have been no more tics.

Use of antioxidants
A recurring feature in autism research is oxidative stress. Two clinical trials have shown the benefit of the antioxidant NAC (N-acetylcysteine) in autism.
In LT the effect of NAC is the immediate disappearance of stereotypy and a type of anxiety. Without NAC, LT always wants to know what is happening next, to the point of obsession.
Oxidative stress has been shown to vary throughout the day and LT’s therapy is tailored to match it. Oxidative stress causes a cascade of further disruptions and causes many of the side effects of type-1 diabetes, for example.
LT takes 2,400 mg of NAC per day (a dose slightly lower than in the clinical trials). He has 600mg immediate release NAC at 7am, 600mg sustained release at 7am and then 600 mg sustained release at 1pm and 5pm. 
There have been no side effects after more than 4 years. 

Anti-inflammatory
Numerous studies (e.g. Ashwood) show elevated pro-inflammatory cytokines and reduced  anti-inflammatory cytokines as a feature of autism; but specific subgroups exist. Activated microglia is another feature of autism, which also suggests chronic inflammation.
Numerous anti-inflammatory strategies have been researched.
Atorvastatin has potent anti-inflammatory effects that are very well studied. It also affects the autism/cancer proteins RAS, PTEN and BCL2.
RASopathies are associated with MR/ID and indeed autism. Mutations in PTEN generally cause loss of function in PTEN and are associated with macrocephaly, enlarged corpus callosum, MR/ID and autism. Loss of function of PTEN is also found in some cancers, for example prostate cancer.
Because autism is polygenic and hundreds of genes are over/under expressed, it is not necessary to have a mutation to have misexpression. The mutation is just the extreme case (be it Cav1.2 or PTEN).
The effect of Atorvastatin is visible from the first dose and fades away the next day if therapy is stopped. The effect is very specific, it releases cognitive inhibition; it is as if the person with autism has the desire and capability to do something, but some barrier prevents him from doing it.
In broader severe autism, this is very important, Why does a child with autism who can verbalize never speak?
At the age of 9, LT was having piano lessons at home twice a week. He would practice the piano only if his assistant or father sat beside him. He never played independently.
After taking 10mg Atorvastatin for the first time, the next day LT went himself to his piano and started playing, without any prompting of any kind. He then began to practice on a daily basis.
As a child aged 3, LT had the habit of coming to the entry of the room with the television and watching from around the corner of the wall. He wanted to watch but could not enter the room. At the time it was thought he somehow just liked the visual sensation of peering around corners.
When he later moved to a multi-level house, LT would not come downstairs by himself; he would wait at the top of the stairs for someone to lead him down, every morning.  With atorvastatin not only did this behavior disappear, but it reappeared the day after Atorvastatin was withdrawn.
During one test withdrawal of the treatment, he got “stuck” in the kitchen and could not leave the room.

Sulforaphane Nrf2 and HDAC
In 2014, and again in 2017, Talalay/Zimmerman published research that sulforaphane from broccoli showed a benefit in autism. Sulforaphane is an HDAC inhibitor and thus has potential epigenetic properties, like some cancer drugs. Sulforaphane may also activate the Nrf2 redox “switch” and so be protective in conditions associated with oxidative stress.
LT’s father did contact the researchers and shortly after the first research was published LT started to take a broccoli sprout supplement. It did produce a very obvious effect and within 30 minutes; LT was laughing so much, be went to look at himself in the bathroom mirror. The more general effect was an unmissable increase in speech.
After three years of use the positive effect of sulforaphane/broccoli is no longer visible, even trying alternative brands.
In the 2017 clinical trial the authors found one responder retained the benefit of sulforaphane after the trial ended. They suggest an epigenetic switch may have been activated.  

Mitochondria and Microvasculature
A distinct type of autism has been characterized by Kelley at Johns Hopkins, Autism Secondary to Mitochondrial Disease (AMD). Kelley suggests that almost all regressive autism is caused by mitochondrial dysfunction and usually deficiency of the rate-limiting complex 1.
By stabilizing the mitochondria with antioxidants and then trying to stimulate more complex 1, a gradual improvement can occur.
Mitochondrial disease effectively starves the brain and body of energy (ATP), so lack of exercise endurance is exhibited in people with a genuine mitochondrial dysfunction.
One feature of autism is that growth factors (BNDF, IGF-1, NGF, VEGF etc) are disturbed, but the disturbance varies greatly by the type of autism.  Vascular endothelial growth factor (VEGF) in particular and its receptors are known to be disturbed and this has implications for microvasculature. Studies suggest that unstable, rather than reduced blood flow occurs in autistic brains.
In sports medicine, exercise endurance is a key target and it can be raised by improving the energy production from mitochondria and by improving the circulation of blood throughout the body by targeting eNOS (Endothelial Nitric Oxide Synthase) and NO (Nitric Oxide).
In Mild Cognitive Impairment (MCI) studies have shown the benefit of improved cerebral blood flow using cocoa flavanols to indirectly affect NO and hence improve memory.
Studies show that eNOS and NO can be safely increased by Agmatine and NO can be increased  using L-citrulline, which then produced more L-arginine. These supplements are widely used by sportsmen and women.
A small dose of Agmatine (1 g) has a near immediate substantial effect on LT, making him far more energetic.  It moved him from being rather passive physically, to being active. This has been very evident from his performance at school during physical activities, where it has been widely noted. At home LT started trampolining before breakfast and late in the evening.

Sensory Overload and Sensory Gating
An apparent over-sensitivity to sensory stimuli is a common observation in autism and is often the precursor to behavioral problems. In some younger children these can be trivial, but in more severe autism it can produce profound behavioral problems that never fade away.
Hypokalemic sensory overload and hypokalemic periodic paralysis are described in the literature. LT had sound sensitivity as a young child, in particular an inability to cope with the sound of crying. Tests were carried out to establish whether LT’s tolerance to the sound of crying improved after oral potassium. He consistently tolerated a high volume of a recording of this sound, when played 20 minutes after 250mg of potassium. Following ABA, he was purposefully exposed to this sound and taught to understand why people cry and modify his response, to the extent that his response changed to laughter, which again has to be modified towards empathy. 
Aged 10, LT developed a phobia to traveling in elevators/lifts. This was because the elevator he regularly used to visit his Grandparents was the old-fashioned type, with an internal sliding gate that you close by hand, which is extremely noisy.  He refused to use the elevator from that point on.  People with autism very easily form habits, or are allowed to form them, following the path of least resistance.  Elevators are a part of modern life and hard to avoid.
After a few weeks of this behavior, LT was given 500mg of potassium and half an hour later willingly entered the elevator and coped with the ride. The behavior has never recurred.
Sensory gating is another common issue in autism and schizophrenia, the individual is not able to filter out repetitive background sounds, like a clock ticking or the sound of a noisy eater. Sensory gating can be measured by looking at the P50 response on an EEG. α7 nicotinic acetylcholine receptor (α7 nAChR) agonists, like nicotine, can correct impaired P50 gating. A low dose of a PDE4 inhibitor is another suggested therapy
LT does exhibit was presents as impaired P50 gating. It is really only evident when his pharmacological therapy is halted for a few days. Then he finds all kinds of unavoidable noises very annoying, even the sound of a person sitting next to him eating. 

Typical Psychiatric Drugs
LT has never been treated with any of the usual antipsychotics, stimulants, anti-depressants, or anti-anxiety drugs sometimes prescribed in autism. His use of clonazepam is at a dose far below its standard clinical use.

Current status
In September 2017 LT moved to secondary/high school where some of the teachers recall how he used to be 10 years previously. Initially there was some trepidation and the view by some that a boy with classic autism should not be there. The school does have a boy with Asperger’s. However, LT surprised his new teachers, achieving grades placing him in the top half of his class. He is now extremely attentive in class, no attention deficit anymore, and has clearly not reached his intellectual limit. He has likely already far surpassed his intellectual limit, had he remained untreated.
As the end of the first year of high school approaches, LT continues to keep up academically with his peers. His agmatine-boosted physical performance has been maintained and he competes very well in long distance running and swimming.
LT is still intellectually far away from the trajectory followed by his older brother, but LT is keeping up academically with many of his classmates who are neurotypical, with average IQs.
A significant number of people diagnosed very young with autism do indeed make dramatic progress by the age of 6.  Zappella proposed his Dysmaturational Syndrome that he says applies to about 6% of early childhood autism, but they all have Tourette’s type autism (with tics).   There is an additional group without tics that also achieve what Fein calls Optimal Outcome, essentially they lose their autism diagnosis. In total it is 10-15% of cases that seem to “get better” all by themselves, regardless of intervention. As more diagnosis takes place even before 2 years of age and autism threshold grows ever wider, Optimal Outcome may become even more common.  
The definition of autism has been greatly watered down in recent years (DSM3 to DSM5). LT started with DSM3-type autism and by the age of 8 he still had it. DSM5 autism includes very much milder variants, some of which are trivial.
Each therapy used by LT has been found to be reversible based on careful withdrawal trials.



People with strictly defined autism (SDA) start to acquire skills with a delay compared to NT peers and thereafter acquire skills at a slower rate and hence fall ever further behind, making inclusion at school a delusion. The aim is to have similar skills to NT peers to make inclusion effective.
People with SDA often leave high school with an educational level of a 7 to 10 year old.

From the age of 12, LT ceased having any autism-specific learning curriculum; he just follows the curriculum of his mainstream school.  

Anecdotal Evidence
LT’s piano teacher exclusively teaches people with disabilities (mainly severe autism and a few with Asperger’s) and so has great experience of the disorder. She says while she has taught people who learnt to play as well as LT does today, this has never happened before with a child who started in his kind of condition at 8/9 years old.
The American ABA consultant (with Ph.D. and 20 years of experience) knowing LT from the age of 8, before he started bumetanide, told the family that of all her clients, LT is the one she sees the least but has improved the most and how strange that is. 


Current Therapy

The current therapy, called the Autism PolyPill, may be found in the link below.  

https://epiphanyasd.blogspot.com/p/polypill-for-autism.html

Autism is a highly heterogeneous condition, but there appear to be broad sub-types. At least some people with an autism diagnosis respond to each individual therapy in the PolyPill. Some people respond to almost the entire combination of therapies; other people respond to none.


Future Therapy

Some other interesting therapies remain to be investigated and it is clear that more improvement is possible because short term therapy with the flavones nobiletin and tangeretin produces a marked change in cognition and behaviour. The effect only lasts two or three days.  Tangeretin is a PPAR gamma agonist, among other properties. It reduces cholesterol when used long term, but its autism benefit is transient.  

The ketone Beta-Hydroxy Butyrate (BHB) also looks interesting; it has epigenetic properties amongst its other effects. 






Thursday, 8 February 2018

DHED, delivering Estradiol only to the Brain, also Lupron and Spironolactone










The Hungarian flag, for clever Laszlo Prokai

  

Lupron – partially right, but for the wrong reason? 

In the US there undoubtedly are some quack therapies for autism, however on occasion we have seen that you can stumble upon an effective therapy for entirely the wrong reason. In the history of medicine there are drugs that were stumbled upon, or created by accident.
In the case of the “Lupron protocol” which was promoted by a father and son (Geier and Geier), an extremely expensive therapy was apparently applied to hundreds of children, before being shut down by the medical regulators.
Without going into all the details, Geier’s therapy combined chelation (antioxidants) and a drug called Lupron that causes a dramatic reduction in testosterone levels.  In the jargon, it causes hypogonadism - diminished functional activity of the gonads (the testes in males or the ovaries in females). Lupron is another of those drugs that costs ten times more in the US than in the normal world. So a single injection of Lupron, depending on the dose,  costs up to $1000 in the US. Lupron is approved for use in children, male and female, with early onset puberty.
The case attracted media attention because Geier was also heavily involved in the idea that vaccines could cause autism and because patients were reportedly paying up to $50,000 for the complete therapy.
Geier was naturally a target for the anti-quack movement and why treat autism at all movements. He features in their books and blogs. 

Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure  (no link provided on purpose)

Still making the news in 2018.

Regulators who targeted controversial autism doctor may pay millions for humiliating him 

In this case I think Geier stumbled upon a rather extreme, partially effective therapy but for the wrong reason. I doubt such an expensive  potent drug is needed to produce the same beneficial effect, in that sub-group that appear to respond.

The fact that Lupron is so expensive in the US, may indeed contribute to the desire parents had for it.  There is a term in economics called a “Giffen good”; it is for the type of good that the more it costs the more you want it, like those very expensive hand bags people buy.

Personally I like inexpensive autism therapies, available to all.

Having read so much about autism, I am much less critical of those putting forward alternative ideas and therapies. It is very easy to get something right for entirely the wrong reason in medicine, which is something that is highly unlikely in many areas of science.

What I do not like is the predatory nature of some people with unusual ideas and therapies who treat autism. This is almost exclusively a North American phenomenon. Some parents will pay nothing to treat autism, for example some in countries with socialized medicine, while others would sell their house for a hope of an improvement.

The name Geier comes from the German word for vulture, maybe not the ideal surname for a healthcare worker.

If you read the following article from the Baltimore Sun you will see that there likely were some responders to this therapy:-

Lupron therapy for autism at center of embattled doctor's case 

"Wessels, who lives in Rock Rapids, Iowa, took Sam to see Geier in his Indianapolis office two years ago. She said there were months of genetic and hormone tests, and then the diagnosis. She began injecting Sam with Lupron daily.
She said the diagnosis made sense to her. Sam was not only having trouble communicating and difficulty learning, but he was tall for his age, had hair on his legs and began constantly masturbating by the time he was 5.
She said there was no "wow" moment where Sam snapped out of his autism, a spectrum of disorders where sufferers lack an ability to communicate and interact properly. But in the course of the next year, Sam's reading improved from 35 words a minute to 85 and he focused in class. He stopped masturbating as much.
Wessels thought Sam was naturally advancing and planned to taper the Lupron at some point — at 9, he had reached the generally accepted age limit for a precocious puberty label.
The day came abruptly four months ago when a nationwide shortage cut off Sam's supply. Wessels said she saw Sam return to his old habits, from flapping his hands, to pacing, to forgetting how to get to his classes.
"I felt like I got a glimpse of the child my son was meant to be, not the one autism gave me," said Wessels, fighting back tears. "It's so sad to watch your child fade away again."


Lupron and RORalpha

Regular readers of this blog may have noticed an entirely different reason Lupron might be beneficial in a sub-group of people with autism. It has nothing to do with vaccines and mercury-containing thimerosal preservative.

Reducing testosterone in boys is going to have effects like increasing estradiol.
















The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER. 

androgen receptor = AR 
estrogen receptor = ER 

We have seen that RORA is suggested to act like a central point/nexus that affects dozens of biological processes disturbed in autism, making it a key target for therapy.



Other drugs that affect androgen receptors and are suggested in some autism?

Are there any other alternative autism therapies that affect testosterone and so androgen receptors? The answer is yes; this time a very cheap one called Spironolactone, that has been mentioned earlier in this blog.
The MAPS doctor known to some readers of this blog, Dr Rossignol, was one of the coauthors with the late Dr Bradstreet, in a hypothesis regarding Spironolactone.


Spironolactone is a potassium sparing diuretic, but also has the effect of shifting the balance between testosterone/estradiol towards estradiol, this makes it a useful therapy to treat acne for which it is sometimes prescribed. It seems to help some with autism.

I think any drug/supplement suggested to affect RORA in the right direction, will likely be reported to also improve acne, even if that sounds rather odd. If it does not improve acne, it lacks potency. Not all acne remedies will affect RORA.
In fact there are numerous ways to affect testosterone and estradiol and they are well documented on the internet because of all the males who are trying to become females (the transgender community).
Donald Trump and his personal physician declared they take a small daily dose of the drug finasteride, which is why both of them have such a full head of hair, and why Trump can brag about his low PSA result. This drug is used to treat an enlarged prostate and at a lower dosage, hair loss.  It works by decreasing the production of dihydrotestosterone (DHT), an androgen sex hormone, in certain parts of the body like the prostate gland and the scalp. 
Lupron might be too expensive in the US for males becoming females, but the other testosterone/estradiol modifying drugs seem to be very widely used/abused, depending on your views.

“Normal” levels of male/female hormones  
One criticism of Geier was that while he did many different tests to measure testosterone in his patients, he seemed over willing to prescribe his highly potent testosterone reducing drug. It was reportedly not the case that he only used Lupron on patients with extremely elevated levels of testosterone.
In fact what are normal levels of male/female hormones?
There does not seem to be a normal level, rather a very wide range. the charts below are in adults.


Serum total T (A) and bioavailable T (B) levels as a function of age among an age-stratified sample of Rochester men (solid lines, squares) and women (dashed lines, circles).



Serum total estrogen (A) and bioavailable estrogen (B) levels as a function of age among an age-stratified sample of Rochester men (solid lines, squares) and women (dashed lines, circles).



Affecting Testosterone/Estradiol Just in the Brain
I do sometimes receive comments asking about possible future autism drugs in the pipeline, I even once had a section called “Future Drugs”. Things move so slowly I now really only focus on repurposing what is already available.
However, a really interesting new drug, DHED, is being developed to increase the level of the hormone estradiol just in the brain. Now as regular readers will know, in autism there is a lack of estradiol and a reduction in the expression of estrogen receptor beta. We know that estradiol is highly neuroprotective and that estrogen receptors in the brain modulate RORa, which is one of those switches that control a large group of genes often disturbed in autism. So a new drug developed to help post-menopausal women has potential to be repurposed to treat neurological disorders like autism and indeed Alzheimer’s. 
Interestingly for me is that the lead researcher, a Hungarian called Laszlo Prokai, also researches another hormone, TRH, that I wrote about extensively a long ago in this blog. TRH is potentially another very useful therapy inside the brain.  
Thyrotropin-releasing hormone (TRH), is a releasing hormone, produced by the hypothalamus, that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary.  Thyroid-stimulating hormone (TSH) then goes on to stimulate the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body.
As I discovered a few years ago, TRH does much more within the brain, as a result it has antiepileptic properties and mood enhancing properties. The US Army is funding the development of a TRH nasal spray for ex-combatants with mood disorders and a risk of suicide. Antidepressants like Prozac have the odd side effect of increasing suicidal tendencies.
A TRH super-agonist (Ceredist) already exists in Japan, so I could never really understand why the US Army did not just get that drug approved by the FDA.  

More Laszlos please
The big gap in all neurological disorders is translational research, which means actually converting all the existing knowledge into usable therapies for humans.
So it looks like we need more people like Laszlo; in fact there is another - Katalin Prokai-Tatrai, I assume it is his wife.
So like we already have the very talented duo Chauhan & Chauhan, we have Prokai & Prokai. What we would ideally want is Prokai & Prokai to translate the knowledge of Chauhan & Chauhan into human therapies.
As described in one of their papers:
Our laboratory has been involved in medicinal chemistry-driven research with attention to facilitating drug delivery of central nervous system (CNS) agents via prodrug approaches.

This is important because there are clever drugs that would be useful to treat brain disorders but you cannot get them through the blood brain barrier (BBB). So making a new compound that can cross the BBB and then converts back to the original drug is a neat solution. 

Dr. Prokai's current research focuses on
(1) Novel therapies against neurodegenerative and ophthalmic diseases using site-selective prodrugs
(2) Development and use of proteomics in aging research, studying neurodegenerative diseases and cancer, with especial attention to quantitative expression profiling and oxidative stress-associated posttranslational modifications
(3) Discovering new therapeutic agents based on neuropeptides and peptidomimetics as lead molecules.

In particular:
·         Molecular mechanisms of estrogen neuroprotection

·         Molecular pharmacology of thyrotropin-releasing hormone




“10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) is an orally active, centrally selective estrogen and a biosynthetic prodrug of estradiol which was discovered by Laszlo Prokai and colleagues. Upon systemic administration, regardless of route of administration, DHED has been found to selectively and rapidly convert into estradiol in the brain, whereas no such conversion occurs in the rest of the body. Moreover, DHED itself possesses no estrogenic activity, requiring transformation into estradiol for its estrogenicity. As such, the drug shows selective estrogenic effects in the brain (e.g., alleviation of hot flashes, neuroprotection) that are said to be identical to those of estradiol, whereas it does not produce estrogenic effects elsewhere in the body.  DHED has been proposed as a possible novel estrogenic treatment for neurological and psychiatric conditions associated with hypoestrogenism (e.g., menopausal hot flashes, depression, cognitive decline, Alzheimer's disease, and stroke) which uniquely lacks potentially detrimental estrogenic side effects in the periphery


Highlights


·         Treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, for 8 weeks decreased amyloid precursor protein in APPswe/PS1dE9 double-transgenic mice
·         DHED treatment reduced brain amyloid-β peptide levels
·         DHED-treated APPswe/PS1dE9 double-transgenic mice had higher cognitive performance compared to untreated control animals
·         DHED treatment faithfully replicated positive neurobiochemical effects and consequent behavioral improvement observed for 17β-estradiol
·         DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment did.  

By the same author Laszlo Prokai: 

Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs

Medicinal Chemistry: Compound could lead to estrogen therapies with fewer side effects

Estrogen levels drop in the brains of women who have gone through menopause or had surgeries to remove their ovaries. This hormone deficiency can lead to hot flashes, depression, trouble sleeping, and memory deficits. Hormone replacement therapies can improve women’s quality of life, but taking estrogen has its own problems, such as increased risk of breast and uterine cancer.

A new compound could avoid the source of these side effects—the action of estrogen on cells outside the.

Laszlo Prokai of the University of North Texas Health Science Center and coworkers identified 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), which is converted to the main human estrogen, 17β-estradiol, in the brain and not elsewhere in the body. An enzyme expressed only in the brain reduces DHED to estradiol.

The researchers injected DHED into female rodents without ovaries and showed that estrogen levels jumped in the brain but not in other tissues. Then, through a series of experiments, they demonstrated that the compound had only neurological effects.

“It’s exactly the right strategy for avoiding the cancer risks and gaining the benefits in the brain,” says Bruce S. McEwen, a neuroendocrinologist at Rockefeller University. He thinks the next step is to show that the compound doesn’t have toxicity problems so that clinical trials in people can start.  The researchers are planning such studies in hopes of moving the compound “from the bench to the bedside,” Prokai says.



Why is Estradiol good for your brain?
You may be wondering why I give so much time on this blog to female hormones. There is a lot of evidence beyond RORa, that estrogen/estradiol and its receptors are very important to healthy brain function. 
The paper below is very interesting and worth a read. 

Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer’s disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain. 
However, estrogen actions on mitochondria are not exclusively related to such mechanism. Estrogen also regulates mitochondrial functions through their classical nuclear mechanism, i.e., transcriptional regulation of nuclear-encoded mitochondrial proteins. It is known that estrogen regulates the nuclear transcription of different proteins affecting mitochondrial function such as nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-gamma coactivator 1 (PCG-1). Hence, this regulation is critical for the activation of nuclear genes encoding proteins involved in mitochondrial biogenesis as well as in the mitochondrial electron transport chain complexes. It also regulates the transcription of mitochondrial transcription factor A (TFAM), which translocates into mitochondria and initiates transcription and replication of mtDNA

Note PCG-1 above, (a typo for PGC-1, I believe) for all those interested in treating mitochondrial dysfunction.  We saw previously that PGC-1α is a master regulator of mitochondrial biogenesis.
It turns out that Estrogen is key to many aspects of Mitochondria, and the paper  below from 2017 probably deserves its own post. Lack of estrogen or miss-expression of estrogen receptors in the brain is inevitably going to disrupt mitochondrial function.

Estrogens coordinate and integrate cellular metabolism and mitochondrial activities by direct and indirect mechanisms mediated by differential expression and localization of estrogen receptors (ER) in a cell-specific manner. Estrogens regulate transcription and cell signaling pathways that converge to stimulate mitochondrial function- including mitochondrial bioenergetics, mitochondrial fusion and fission, calcium homeostasis, and antioxidant defense against free radicals. Estrogens regulate nuclear gene transcription by binding and activating the classical genomic estrogen receptors α and β (ERα and ERβ) and by activating plasma membrane-associated mERα, mERβ, and G-protein coupled ER (GPER, GPER1). Localization of ERα and ERβ within mitochondria and in the mitochondrial membrane provides additional mechanisms of regulation. Here we review the mechanisms of rapid and longer-term effects of estrogens and selective ER modulators (SERMs, e.g., tamoxifen (TAM)) on mitochondrial biogenesis, morphology, and function including regulation of Nuclear Respiratory Factor-1 (NRF-1, NRF1) transcription. NRF-1 is a nuclear transcription factor that promotes transcription of mitochondrial transcription factor TFAM (mtDNA maintenance factorFA) which then regulates mtDNA-encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed. 
Estrogens exert direct and indirect effects on mitochondrial function in a cell-specific manner through activation of membrane-initiated ERα, ER β, and GPER activity and by direct genomic binding of ERα and ERβ to regulate nuclear gene transcription. While still controversial, estrogens also activate mitochondrial localized ERα and ERβ in a celltype-dependent manner. One key nuclear gene increased by E2 is NRF-1 that regulates the transcription of nuclearencoded mitochondrial genes, including TFAM which increases transcription of mtDNA-encoded genes. Thus, E2 coordinates nuclear and mitochondrial gene transcription via NRF-1. Activation of UPRmt also activates ERα and increases NRF-1. E2 also regulates the transcription of genes regulating mitochondrial morphology, enzymes in the TCA cycle and OXPHOS pathways, and mitochondrial protein Snitrosylation. Depending on the cell type, E2 regulates mitochondrial biogenesis and bioenergetic function.   

17β-estradiol is not only a reproductive hormone that is important only in women but it is also of immense importance for development and health in men. Although there is strong evidence from both human and animal studies that estrogen is protective in various brain diseases however, its adverse effect in classic target tissues such as uterus (17β-estradiol behaves as a full agonist on both estrogen receptor (ER) isoforms) is a matter of debate. ER subtype selective ligands are valuable tools for deciphering the specific roles of ER (α and β) in physiology and diseases. These compounds have a strong potential for development as therapeutics as these initiate estrogen signaling in brain but lack the mitogenic effects in other tissues such as ovaries and breast. Moreover, the existing and newer ERsubtype selective agonists will continue to be very valuable tool for deciphering the specific roles of ERα and ERβ 

Severity of symptoms of schizophrenia is greater in males as compared to premenopausal females. Women have been shown to differ in symptom severity depending on the phase of the menstrual cycle. Higher rates of relapse in women with schizophrenia are also observed during the postpartum period (low estrogens), whereas relapse is low during pregnancy (high estrogens). During menopause, women are at risk of developing a new schizophrenic illness. Additionally, premenopausal women appear to have a superior response to typical antipsychotics compared to men and postmenopausal women. Estrogen plays a protective role in women with schizophrenia. Estrogen treatment may reduce negative symptoms in schizophrenic women. Estradiol may exert neuroprotection by several mechanism that may even vary among different brain regions.


Non drug therapies:-
Overeating and smoking will increase your level of estrogen. We saw earlier that in males testosterone is converted to estradiol in fat tissue. 

Not to forget the other part of the Mediterranean Diet:-



Conclusion
Just as we saw that using high doses of antioxidants is beneficial in numerous medical conditions, where nobody calls it chelation, drugs that reduce testosterone or increase estradiol in the brain are not quack therapies, even when proposed by apparent vultures. It pays to keep an open mind.
Hormone replacement therapy (HRT) is a big business and if you can introduce a drug with less side effects, it should sell at a premium price, meaning DHED really should get commercialized.
DHED should be more effective than estradiol for treating neurological disorders because it can be given at a higher dose. In males there is no risk of feminization.
Contrary to what is sometimes quoted, estradiol lowers the risk of prostate cancer and is used to treat aggressive forms of it. High levels of testosterone are linked to prostate cancer and that is why Lupron is sometimes used.
Circulating levels of estradiol vary dramatically. People with a low level of estradiol might well be able to safely increase body-wide 17β-estradiol, rather than waiting a decade for DHED.
High levels of estrogen/estradiol in males may contribute to the extended healthy life expectancy in those with a soy-rich diet, as we will see in the forthcoming post on the Okinawan Diet and aging.



Spironolactone does have the advantage of increasing potassium levels, so someone with autism who responds to bumetanide and has high testosterone/ low estradiol and/or reduced expression of ERβ might see a benefit; I think it might require a high dose.
DHED looks interesting particularly for those with higher plasma estradiol but reduced ERβ in the brain.
I think the lady from Rock Rapids, Iowa in the earlier press report on Lupron, whose son had very hairy legs and responded to Lupron, should try some estradiol, or just get him to drink a great deal of soy milk.  This really should have a similar kind of effect.
It appears that some mitochondrial disease is linked to estradiol and estrogen receptors ERα and ERβ. DHED might be a very clever treatment to what is otherwise pretty much un-curable. So there will be a post on estrogens regulating life and death in mitochondria.
The implication is pretty simple – more estrogen/estradiol please, if you want to live a bit longer, or if your brain does not work so well.