Showing posts with label Estrogen. Show all posts
Showing posts with label Estrogen. Show all posts

Thursday, 23 July 2020

How to increase Oxytocin (OT) effects in the autistic brain? OT nasal spray, L. reuteri DSM 17938, Magnesium, Estradiol, Nicotinamide riboside …

 Struggle to make friends? Consider Oxytocin

Today’s post was going to be about FMT super-donors, but instead we have a post about new insights into using oxytocin to treat autism.  From personal experience I can say that you really can target oxytocin receptors to affect mood/behavior; I have no personal experience of FMT (fecal microbiota transplants), but thousands of people use it for many conditions.  The FMT post will be next.

Oxytocin and vasopressin are two hormones, made in the hypothalamus, that are established targets for autism treatment. They are released into the bloodstream where they carry out their best-known functions, but they are also released from the hypothalamus directly into the brain where these hormones have entirely different functions.

Both oxytocin and vasopressin can be given as nasal sprays to enter the central nervous system (CNS) rather than just the blood stream.  This means you get the brain effects of the hormone, also known as the “central effects”.

As was discussed previously in this blog and is highlighted more recently in the article below, you can use certain bacteria in the gut to signal to the hypothalamus to produce more oxytocin.  This is really clever and it works in humans, not just research animals.  It also has the advantage of producing a more continuous effect than is found using the intranasal method to deliver oxytocin. 

When you sever the vagus nerve, the bacteria in the gut continues to produce the required chemicals, but the signal to the brain has been lost. The hypothalamus no longer produces increased oxytocin and so the behavioral/mood effect is lost. This has been proven in the research.

Gut microbes may treat social difficulties in autism mice

In science speak, “the results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals”.  It also appears that oxytocin improves wound healing. So perhaps old people with leg ulcers, which never seem to get better, might benefit from a daily dose of L. reuteri DSM 17938, it also might make them feel better due to those central effects.

Oxytocin in the brain acts via oxytocin receptors

As we learned years ago in this blog, you can increase the effect (turn up the volume) of receptors using a PAM (positive allosteric modulator).  Interestingly, magnesium is a PAM of the oxytocin receptor (OTR).  Many people with autism are supplementing magnesium, perhaps those using intranasal oxytocin should join them. 

A very recent paper has investigated in detail how oxytocin receptors function.

The peptide hormone oxytocin modulates socioemotional behavior and sexual reproduction via the centrally expressed oxytocin receptor (OTR) across several species. Here, we report the crystal structure of human OTR in complex with retosiban, a nonpeptidic antagonist developed as an oral drug for the prevention of preterm labor. Our structure reveals insights into the detailed interactions between the G protein–coupled receptor (GPCR) and an OTR-selective antagonist. The observation of an extrahelical cholesterol molecule, binding in an unexpected location between helices IV and V, provides a structural rationale for its allosteric effect and critical influence on OTR function. Furthermore, our structure in combination with experimental data allows the identification of a conserved neurohypophyseal receptor-specific coordination site for Mg2+ that acts as potent, positive allosteric modulator for agonist binding. Together, these results further our molecular understanding of the oxytocin/vasopressin receptor family and will facilitate structure-guided development of new therapeutics. 

Magnesium and mood disorders: systematic review and meta-analysis

Another consequence of ERβ under-expression in autism

Also interesting to those following autism research, is the role of ERβ (estrogen receptor beta).  It is well known that in the brains of those with autism, there is a lack of ERβ.  A lack of ERβ is likely to lead to lower oxytocin in the brain and CSF (spinal fluid).  In many types of autism, we know that the level of oxytocin in CSF is reduced.

If you activate ERβ you both increase expression of oxytocin receptor (OTR) and also increase the level of oxytocin measured in the CSF.  You can activate ERβ with estrogens, like estradiol or even phytoestrogens like soy.  The ideal therapy to use would be DHED.

The cheap diuretic spironolactone may very well indirectly increase the level of oxytocin in CSF.

Oxytocin and Estrogen Receptor β in the Brain: An Overview

Oxytocin (OT) is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release OT into the bloodstream to promote labor and lactation; however, OT neurons also project to other brain areas where it plays a role in numerous brain functions. OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor β-mediated anxiolytic effect. Further research is needed to identify modulators of OT signaling and the pathways utilized and to elucidate molecular mechanisms controlling OT expression to allow better therapeutic manipulations of this system in patient populations.

NAD and Nicotinamide Riboside to boost Oxytocin

Today we see that recent research from Japan shows that in those people with autism who have reduced NAD, they may well be able to improve behavior/mood by increasing the level of their oxytocin using Nicotinamide Riboside (NR).

Nicotinamide riboside (NR) is a special form of vitamin B3, sold as an expensive supplement.  The FDA say it is safe for use in humans.

Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder

Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

NR elevates brain NAD+ and cerebrospinal OT

Social preference deficit and anxiety of CD157KO males are best corrected at a relatively low dose of NR

The results demonstrated that the daily oral administration of NR rescued the social behavioural impairments observed in male CD157KO mice. NR had essentially no effects on social behaviour in wild-type male mice. The beneficial effects of NR appear to depend on restoration of CSF OT levels because the NR-induced OT elevation was only detected in CD157KO mice, which have a CSF OT deficit.

In the course of identifying a nutritional intervention for CD157KO mice, we reproduced the anxiety-like and social-avoidance-like deficits reported previously. Reproducibly lower levels of CSF OT in male CD157KO mice make these mice an attractive model of autism, anxiety disorder, or social avoidance in neurodegenerative diseases. Significantly, this model responds to both OT and NR as a treatment.
The challenge of polygenic diseases of incomplete penetrance is that they are difficult to understand mechanistically. Multiple genetic and environmental (biochemical) factors may converge to dysregulate pathways that are altered in common conditions such as ASD. We note that one potentially hopeful point when studying polygenetic diseases is that brain systems are redundant, and thus, it may be possible to increase normal functions that are only partially encoded by genetically damaged circuitry.
NAD+ is consumed by CD38 in formation of cyclic ADP-ribose. It then participates in OT release in the hypothalamus. In our study, ADP-ribosyl cyclase activity was maintained at a similar range as that in wild-type animals (data not shown). A recent study suggested that NR supplementation did not change CD38 expression. However, in vitro studies have shown that NAD+ applied to the mouse hypothalamus leads to OT release. It is reasonable to assume that an elevation in NAD+ levels by NR in the hypothalamus is responsible for repair of the OT release.

Future work will probe CD38 dependence and the cell-type dependence of the beneficial effects of NR on CD157KO behaviour, the potential benefits of NR in other ASD models, and the potential of NR to become a safe nutritional intervention, in addition to OT, for at least some types of ASD in human populations.

NAD+ is reduced in older people

There is a lot of research into combating the effects of aging.  It is agreed that the older you get, the less NAD+ you have and so research has looked at numerous ways to raise it.

The CD157KO mice model of autism does feature reduced NAD+, but nobody knows how common reduced NAD+ is in autism.

If you have low levels of NAD+ there will be negative consequences.

I think you can consider NAD+ depletion in a similar way to oxidative stress, both are inevitable and damaging features of aging.

Most healthy younger people are likely wasting their time and money worrying about oxidative stress and NAD+.  These are the people with “detox” diets and juices.

However, most old people and some young people with autism really stand to benefit from correcting oxidative stress and any reduced NAD+.

Therapeutic potential of NAD-boosting molecules: the in vivo evidence

Hallmarks of NAD homeostasis
NAD+ is not merely a redox co-factor, it is also a key signaling molecule that controls cell function and survival in response to environmental changes such as nutrient intake and cellular damage. Fluctuations in NAD impact mitochondrial function and metabolism, redox reactions, circadian rhythm, immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin and epigenetics.
There are many ways to boost NAD+.

NAD+ Precursors              
Niacin/ nicotinic acid (NA), Nicotinamide riboside (NR) Nicotinamide (NAM) etc.

CD38 Inhibitors                 
Flavonoids (Quercetin, Luteolin, Apigenin, fisetin, rutin and naringin)             
Luteolinidin.  Kuromanin/ Chrysanthemin, an anthocyanin (food pigment)    

PARP Inhibitors    
BGB-290, Olaparib, Rucaparib, Veliparib, CEP-9722, E7016, Talazoparib, Iniparib, Niraparib, PJ34, DPQ, 3-aminobenzamide
SARM Inhibitors

NAMPT Activators


Some readers of this blog do give intranasal oxytocin as a therapy.  There have been numerous studies on children with autism, some discussed in earlier posts.  Oxytocin needs to be kept chilled, not to lose its potency.

Eleven previous posts in this blog refer to Oxytocin.

As to whether stimulating oxytocin receptors is going to be worthwhile in your case of autism, you will just have to try it and see.
I found that the Biogaia Protectis probiotic (L. reuteri DSM 17938) had very clear effects, which were very much hallmark effects of oxytocin.  This is easy and inexpensive to try.
Some readers of this blog do use Nicotinamide Riboside (NR), which we saw today can increase oxytocin by increasing NAD+.
There are very many reasons why you do not want to be lacking in NAD+, other than oxytocin, but if you already have plenty NAD+ you will unlikely see a benefit from yet more.
Magnesium is a very common autism supplement; it is often given with vitamin B6; both can be used to treat stress.

Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial

Thursday, 3 October 2019

Elevated Prenatal Estradiol in Mothers/Babies – a protective reaction to stress that also predicts who will develop Autism? Time for Fetal Medicine?

There has been little mention in this blog about fetal medicine, but it is an area that does hold great promise.  At the Children’s Hospital of Philadelphia, they have been surgically treating babies with spina bifida prior to their birth for nearly twenty years. Early surgical intervention to the spine even allows for malformation of the brain to be self-repaired and this is visible on MRI scans. Such prenatal treatment can be 100% successful, resulting in there being no physical disability in adulthood. 

The more you read about neuroscience the more you realize how little we really know and so encouraging the brain to self-repair may indeed be the best strategy.  This is an avenue of research and not just with stem cells.  A similar approach is proving successful in treating skin cancer, you do not attack the cancer with drugs, you modify the immune system with a drug so it "wakes up" and does its job and kills the cancer cells.

        Skin cancer: Half of people surviving advanced melanoma

Hormones are an often-ignored area of autism research, but they are they on my Venn diagram simplification of autism.

We have seen how female hormones can be highly neuroprotective and that the estradiol/testosterone balance affects a key “switch” that controls gene expression RORalpha.

Today we see that researchers in Utah suggest that stress in the developing fetus with autism causes an increase in estradiol, as a protective mechanism, and this increase in estradiol can then be measured in the mother’s blood. They propose that this elevated estradiol is an advance warning of a baby with autism.

University of Utah researchers have discovered a link between increased levels of a type of estrogen in babies in their second trimester and risk for autism, according to a new study.

The findings could eventually help doctors identify babies at risk of autism early in their mothers’ pregnancies and monitor them more closely, as well as provide early interventions to ensure the children’s well-being, said Dr. Deborah A. Bilder, the study’s first author.

Both the control group and the group of mothers whose children had autism were selected so that 50% of each group had an exposure to a condition such as gestational diabetes, hypertension and preeclampsia. Previous studies have shown links between those conditions and autism risk.

The researchers looked at several different steroids in the blood samples. Bilder said she expected to find increased levels of steroids that were known to be associated with the conditions, like testosterone. She found those steroids, but they did not reach a statistical significance, according to Bilder.

Bilder also expected progesterone and testosterone in the kids who developed autism to be elevated.

“But that’s not what I found. Instead, what I found, is estradiol being elevated in the children who developed autism,” she said.

Estradiol is a type of estrogen. Lower levels of estradiol in a baby usually indicate a concern with the baby, and high estrogen levels are not currently associated with abnormal conditions.

But as the researchers looked at the steroid hormones that were measured, “what we realized is that the higher estrogen levels being produced by the placenta actually may be stimulating the baby’s development of his or her stress response.”
Usually, a baby’s stress response takes time so that when the pregnancy reaches full term, the baby has developed its own stress response. But elevated levels of estrogen cause the baby’s stress response to develop early, Bilder said.
That prepares babies, when there is an issue, to survive outside the mom. It causes early growth of the lungs, gut and skin so that if the baby doesn’t make it all the way through pregnancy, it’s more likely to survive, she said.

The findings indicated that in the babies with autism, something set off their stress response early.

Studies have shown that children with autism have an abnormal stress response, according to Bilder. She believes the mechanism that triggers the early stress response during pregnancy may still be affecting children with autism past delivery.

Bilder doesn’t think doctors should target the higher estradiol levels or try to lower them. Instead, because it signals a “protective mechanism, that baby is surviving,” doctors should target something that doesn’t jeopardize the baby’s survival.

“By being able to have a way of looking at the baby’s well-being in that regard, I think that opens up the door to considering how can you reduce the stress on that baby?” Bilder explained.
The full paper:-

Early Second Trimester Maternal Serum Steroid-Related Biomarkers Associated with Autism Spectrum Disorder

Epidemiologic studies link increased autism spectrum disorder (ASD) risk to obstetrical conditions associated with inflammation and steroid dysregulation, referred to as prenatal metabolic syndrome (PNMS). This pilot study measured steroid-related biomarkers in early second trimester maternal serum collected during the first and second trimester evaluation of risk study. ASD case and PNMS exposure status of index offspring were determined through linkage with autism registries and birth certificate records. ASD case (N = 53) and control (N = 19) groups were enriched for PNMS exposure. Higher estradiol and lower sex hormone binding globulin (SHBG) were significantly associated with increased ASD risk. Study findings provide preliminary evidence to link greater placental estradiol activity with ASD and support future investigations of the prenatal steroid environment in ASD.

Fig. 1 The placenta produces estradiol from DHEA of both maternal and fetal origin and shunts over 90% of estradiol into the maternal circulation. The volume of DHEA substrate determines placental estradiol production and subsequently maternal serum estradiol levels. DHEA exists primarily in its conjugated form DHEAS

This is interesting as are some other findings linking steroid hormones to future autism. Another paper highlights a mechanism where maternal stress only has damaging effects on the male fetus (Placental adaptation in response to PNMS is sex-dependent, leading to an increased risk of adverse neurodevelopmental effect in male compared to female).

This paper looks at the effect of maternal stress on serotonin and another group of hormones (Glucocorticoids).

Effects of prenatal maternal stress on serotonin and fetal development

Fetuses are exposed to many environmental perturbations that can influence their development. These factors can be easily identifiable such as drugs, chronic diseases or prenatal maternal stress. Recently, it has been demonstrated that the serotonin synthetized by the placenta was crucial for fetal brain development. Moreover, many studies show the involvement of serotonin system alteration in psychiatric disease during childhood and adulthood. This review summarizes existing studies showing that prenatal maternal stress, which induces alteration of serotonin systems (placenta and fetal brain) during a critical window of early development, could lead to alteration of fetal development and increase risks of psychiatric diseases later in life.


         Fig. 1. Proposed mechanism of fetal programming of psychiatric disorders involving placental serotonin system. Cortisol and placental serotonin are essential for fetal brain development. Prenatal maternal stress alters glucocorticoid (11b-HSD2, GR and CRH) and serotonin (SERT, 5-HT1A and 5-HT2A) systems as well as serotonin and glucocorticoid interaction in the placenta. These placental alterations lead to adverse neurodevelopment and programming leading to psychiatric disorders later in life. Placental adaptation in response to PNMS is sex-dependent, leading to an increased risk of adverse neurodevelopmental effect in male compared to female. 11b-HSD2: Type 2 11-beta hydroxysteroid dehydrogenase, GR: Glucocorticoid receptor, CRH: Corticotrophin releasing hormone, SERT: Serotonin transporter, 5-HT1A: Serotonin 1A receptor, 5-HT2A: Serotonin 2A receptor

It should be noted that estradiol is supposed to be elevated during pregnancy. Indeed, this elevation is suggested to explain why females with ADHD have far less symptoms during pregnancy (estradiol is good for ADHD). The study is highlighting a level of estradiol during pregnancy that is even higher than that normally expected.

Spina bifida is normally detected by ultrasound before 18 weeks of pregnancy. This is around the same time that in autism there appears to be elevated estradiol.  Hopefully other biomarkers will also be found.

Given this advance warning, there is potential for fetal medicine.

Only very recently was the first person in the UK treated for spina bifida using fetal surgery, almost two decades after the first operations in the US.

Fetal medicine for autism would not be surgical, rather pharmacological.  In mouse models it has already started.

Estradiol has many effects and I did write about DHED, an orally active, centrally selective estrogen and a biosynthetic prodrug of estradiol. DHED is estradiol just for the brain, without affecting the rest of the body.  I think many people would benefit from DHED, across the range from ADHD to TBI (Traumatic Brain Injury).

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

Estradiol may indeed prove to be a fetal biomarker for autism and DHED might be a useful drug for someone with autism (via ERβ and RORalpha).

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


·         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:-

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.