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Thursday, 17 May 2018

Statins, SLOS and Hypocholesteraemia – Going Nowhere Fast


Today’s post is about cholesterol, statins and autism. There is a well-documented condition associated with autism called SLOS (Smith-Lemli-Opitz Syndrome). It is caused by mutations in the DHCR7 gene encoding the enzyme that catalyzes the final step in cholesterol biosynthesis.

Toe syndactyly (webbed toes), one symptom of SLOS



Reduced activity of the enzyme 7DHCR typically leads to low levels of cholesterol, but markedly increased levels of precursor 7DHC (and its isomer, 8DHC) in blood and tissues. Typical SLOS manifestations include intellectual disability, growth retardation, minor craniofacial anomalies, microcephaly and 2-3 toe syndactyly (webbed toes).
SLOS is rare, but some cases do get missed because you can have a DHCR7 mutation and have normal levels of cholesterol and have normal cognitive function.

Cholesterol and the blood brain barrier (BBB)
You do have a lot of cholesterol in your brain, but it does not cross the blood brain barrier (BBB), it was made in the brain.  Eating more cholesterol can have no direct effect on cholesterol levels in the brain.
The standard treatment for SLOS has long been oral cholesterol supplementation, but there is no conclusive research to show it helps. There is plenty of anecdotal evidence.

Simvastatin and SLOS
Simvastatin is a drug widely used drug to treat people with elevated cholesterol.
There has been anecdotal evidence that Simvastatin improves SLOS and recently a very thorough study was carried out to establish whether or not it really has a benefit.
In reality the study was comparing:

Simvastatin + cholesterol supplement  vs  cholesterol supplement

The study was carried out by researchers including Dr Richard Kelley (“Dr Mitochondria”) and Dr Elaine Tierney (“Dr Cholesterol”)


Currently, most SLOS patients are treated with dietary cholesterol supplementation. Although cholesterol therapy reduces serum 7-DHC concentrations to a degree, significant amounts of 7-DHC persist even after years of therapy.  Anecdotal case studies and case series support the idea that cholesterol supplementation benefits the overall well-being of SLOS patients; however, the effects of dietary cholesterol supplementation on cognitive or behavioral aspects of this disorder have not been reported by others or substantiated in a limited controlled trial. The efficacy of dietary cholesterol supplementation is probably limited by the inability of dietary cholesterol to cross the blood–brain barrier. Moreover, increased concentrations of 7-DHC or 7-DHC-derived oxysterol could have toxic effects. Specialists have hypothesized that, in patients with mild to classic SLOS, many aspects of the abnormal behavioral and cognitive phenotype could be the result of altered sterol composition in the central nervous system. Thus, interventions that ameliorate the central nervous system biochemical disturbances in SLOS are critical to understanding the pathological processes that underlie this inborn error of cholesterol synthesis and to developing effective therapies to treat the neurological deficits.

Expression of DHCR7 is regulated by SREBP2, which, when activated by low levels of cholesterol in the endoplasmic reticulum, increases the transcription of most genes of the cholesterol synthetic pathway. Having shown that DHCR7 expression is increased in SLOS fibroblasts treated with simvastatin,31 we hypothesized that the paradoxical increase in serum cholesterol could be the result of increased expression of a DHCR7 allele with residual enzymatic function, and we demonstrated that many DHCR7 alleles encode an enzyme with residual activity. Furthermore, both in vitro experiments with human  fibroblasts and in vivo experiments using hypomorphic Dhcr7T93M/delta mice support the hypothesis that increased expression of DHCR7 alleles with residual enzymatic activity can significantly improve plasma and tissue sterol concentrations. Because residual DHCR7 activity varies among patients with SLOS, this hypothesis could explain the paradoxical increase in cholesterol in some patients and the adverse reactions observed in others.

In this study we also evaluated the potential of simvastatin to alter specific aspects of the SLOS behavioral phenotype. Our secondary outcome measures were the CGI-I and ABC-C irritability scores. Although we observed no significant effect on the CGI-I, we did observe significant improvement in the ABC-C irritability score (Figure 4). This article therefore represents the first controlled study to demonstrate improved behavior in subjects with SLOS in response to a therapeutic intervention.




In summary, this study represents the first controlled trial of simvastatin therapy in SLOS and the first controlled trial demonstrating the potential of drug therapy to modulate sterol composition and to improve behavior in SLOS. We have established that treatment with simvastatin is relatively safe, can decrease DHC levels, and can improve at least one aspect of the behavioral phenotype. These data support continued efforts to identify and rigorously evaluate potential therapies that may have clinically meaningful benefits for patients with SLOS.










Plasma sterol levels

Cholesterol and dehydrocholesterol (7DHC + 8DHC) levels were measured at baseline (B), washout (W, 14 mo) as well as at 1, 3, 6, 9 and 12 months in both the placebo and simvastatin treatment phase. Plasma cholesterol levels (A, B) and DHC (C, D) decreased significantly during the simvastatin phase compared to the placebo phase. The plasma DHC/Total Sterol ratio (E, F), which was the primary outcome measure of this study, also decreased significantly. Data expressed as mean ± SEM.


Hypocholesterolemia (low cholesterol) and some Autism
Ten years ago, Tierney and Kelley published research showing that about 20% of autism is associated with very low cholesterol levels (less than the 5th centile for typical young people) but in their sample of 100, none had an abnormally increased level of 7DHC consistent with the diagnosis of SLOS or abnormal level of any other sterol precursor of cholesterol.


Tierney went on to patent cholesterol as a therapy for autism.


The present invention relates to the field of autism. More specifically, the present invention provides methods for treating individuals with autism spectrum disorder. Accordingly, in one aspect, the present invention provides methods for treating patients with autism spectrum disorder. In one embodiment, a method for treating an autism spectrum disorder (ASD) in a patient comprises the step of administering a therapeutically effective amount of cholesterol to the patient. In more specific embodiments, the ASD is autism, Asperger's disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS), Rett's syndrome and childhood disintegrative disorder. In one embodiment, the patient has autism. 


Tierney has a clinical trial registered that was to start in 2009.


Three sites (Kennedy Krieger Institute [KKI], Ohio State University [OSU], and the National Institutes of Health [NIH]) will collaborate to accomplish the objectives of this study. In addition to defining the frequency of altered cholesterol homeostasis in ASD, 60 youths (20 at each site) with ASD plus hypocholesterolemia will enter a 12-week, double-blind, placebo-controlled trial immediately followed by a 12-week open-label cholesterol trial to test the efficacy of dietary cholesterol supplementation. Outcome measures will include standard tests of behavior, communication, and other autism features.


It appears that the study has not been completed.


Dr. Elaine Tierney and her colleagues are studying different metabolic disorders that can present with autism spectrum disorder through the Autism Metabolic Research Program at Kennedy Krieger. In 2000 and 2001, this group of researchers identified that Smith-Lemli-Opitz-Syndrome (SLOS) is associated with autism spectrum disorder. Since SLOS is known to be caused by a defect in the body's biosynthesis of cholesterol, SLOS may provide clues to the biochemistry of other autism spectrum disorders (ASD).

Dr. Tierney and colleagues published a paper in 2006, in the American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), in which they describe finding that a subgroup of children with ASD have abnormally low cholesterol levels. The children's low cholesterol levels were apparently due to a limited ability to make cholesterol. This finding, in concert with their work with SLOS, has led them to believe that cholesterol may play a role in the cause of some cases of autism spectrum disorder. Dr. Tierney and colleagues at Kennedy Krieger, the National Institutes of Health and Ohio State University are performing a double-blind placebo-controlled study of cholesterol in individuals with ASD.

Cholesterol as a marker of inflammation
Nowadays, hypercholesterolemia and inflammation are considered as “partners in crime”.  Statins do lower bad cholesterol, but they also have broad anti-inflammatory effects.


Arteries do clog up with cholesterol, but a big part of why this happens is inflammation. Cholesterol deposits are initially a protective mechanism, like a band-aid. Treat the inflammation and cholesterol will not need to be deposited.
An altered immune response is a feature of many people’s autism, and you can measure it.
As Paul Ashwood’s research has shown, there are different immune sub-groups that people with autism fall into, and so you could treat each cluster with a specific therapy.

Cholesterol and Thyroid Hormones
Your thyroid produces hormones that control your metabolism. Metabolism is the process your body uses to convert food and oxygen into energy.

Your body converts the circulating pro-hormone T4 into the active hormone T3 locally. So, in your brain T4 has to be converted to T3. If you lack enough T4 coming from your thyroid gland or the special enzyme called D2 you are going to feel lethargic.
Your body needs thyroid hormones to make cholesterol and to get rid of the cholesterol it doesn’t need. When thyroid hormone levels are low (hypothyroidism), your body doesn’t break down and remove LDL (“bad”) cholesterol as efficiently as usual. Elevated LDL cholesterol will show up in your blood tests.
Hyperthyroidism has the opposite effect on cholesterol. It causes cholesterol levels to drop to abnormally low levels.
So best to check thyroid function and cholesterol levels.



Conclusion
My main interest is autism with a tendency to big heads (hyperactive growth signalling pathways) and an overactive immune system. This is the opposite of SLOS and hypocholesterolemia (low cholesterol).
For the 20% with low cholesterol, I think this is a very important biomarker.

.Is supplemental cholesterol the answer? I am not so sure it is.
Hopefully one day soon Dr Tierney, at Kennedy Krieger, will publish her results of cholesterol as a therapy for people with autism and low cholesterol.
For me it is good to see that Simvastatin was well tolerated in a 12 month long trial in children from 4 to 18 years of age. I have the very similar drug, Atorvastatin, in my Polypill.
Interestingly, in a paper that I will cover in later post, increasing HDL (good cholesterol), a feature of Atorvastatin and Simvastatin, was one marker of behavioral improvement in the Ketogenic Diet.







22 comments:

  1. Peter, fascinating post in particular since our biomed recently found low cholesterol in my son with ASD and introduced me to this theory (see slides by Dr. William Shaw on youtube - low cholesterol in autism). Two points for you: (1) interesting perhaps that my son definitely tends to the large head (macrocephaly?) yet had below 140 cholesterol readings, no SLOS. We have been on cholesterol supplementation about 6 weeks, biomed doc was unwilling to consider statin with his blood test results. The study you cite will make an interesting counterpoint in the discussion. (2) is it appropriate to ask Dr Tierney if she is planning to release any results?
    Best,
    Mira

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    Replies
    1. Mira, since your son has low cholesterol but no SLOS, why not send Dr Tierney an email and ask her what she has learnt from her research. She probably will tell you.

      Did your doctor check thyroid hormones?

      For most people, statins seem very well tolerated, even those with low cholesterol.

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  2. Though not specific to autism and ID, a new study suggests that intelligence tracks negatively with the number of dendrites per neuron in the brain:

    Press Release:

    https://www.sciencedaily.com/releases/2018/05/180517102236.htm

    Paper:

    https://www.nature.com/articles/s41467-018-04268-8

    Dendritic overgrowth is a hallmark feature in many autism studies and according to this research, the more connections you have in the brain, the lower your intelligence which may be a finding that is counterintuitive to some. Obviously, having too few dendrites will cause problems as well, but this research strongly suggests that people with less dendrites have more efficient networks and therefore need "less" to do "more".

    So with respect to autism and the ID that usually comes with it, the question is whether excessive dendritic overgrowth is the cause of decreased intelligence or the effect in the sense that if there is a deficiency in dendrite functionality, is the overgrowth a compensating factor with the tradeoff of increased noise for boosting the overall communication signal (this is commonly known as "stochastic resonance" where noise is added to a system to boost the detection of an otherwise weak signal to reach a particular threshold).

    If this is the latter case, it might mean that by reducing noise via dampening dendrites might also reduce weak signals from propagating throughout the brain, therefore harming cognition as well. This seems to be the effect of prescription benzodiazepine use which is linked to cognitive decline from long-term use.

    Ideally, as an intervention under the assumptions of this research, the goal is to randomly dampen dendritic activity, thereby reducing noise, while selectively boosting the proper signalling at synapses (of which much autism research centers around these days). This would mean a multidrug approach where you are trying to put the gas on presynaptic activity, while putting the brakes on postsynaptic activity. Unfortunately, I don't know of any good options, but perhaps this is where a particular neuromodulator like serotonin, oxytocin, or vasopressin may not be doing its job properly in some autisms.

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    Replies
    1. Tyler,Metabotropic glutamate activation, MGLUR inhibits postsynaptic dopamine neurons.Do you know of any MGLUR agonist that we can use?
      Valentina

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    2. I will write to Dr Tierney and let you know what I find out. Our doc did check thyroid (TSH, thyroxine and triiodothyronine) all normal, though homocysteine low as is typical in a subclass of autism.

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    3. Peter, Dr. Tierney replied that they unfortunately did not complete the cholesterol trial and she is unable to state that cholesterol supplementation helps any individuals with ASD. I have asked now whether others are pursuing similar trials and if the trial could resume with funding or whether it is deemed not a good avenue for further exploration. It could be, could it not, that low cholesterol is a serious issue but that it cannot be raised in the manner hypothesized. As to whether statins could have good effect in ASD kids with already low cholesterol - I will continue discussing with our DAN doctor. But fundamentally, does it not seem that the benefit would have to be very significant to overcome the disadvantage of abnormally low cholesterol? - e.g. (1) Fleck CJ et al. Pediatr Res. 1994 May;35(5):602-10. Hypocholesterolemia (low cholesterol), hypertriglyceridemia, suicide, and suicide ideation in children hospitalized for psychiatric diseases; and (2) Jian Zhang et al. Association of Serum
      Cholesterol and History of School
      Suspension among School-age Children
      and Adolescents in the United States.
      Am J Epidemiol 2005;161:691–699 "Non-African-American children with a serum total cholesterol concentration below the 25th percentile (<145 mg/dl) were almost threefold more likely to have been suspended or
      expelled from schools than controls with higher cholesterol" (Dr William Shaw slide presentation 2010/2015)

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  3. A friend of mine forwarded this link to me discussing a new autism drug that I was unaware of that has been fast-tracked through the FDA:

    http://www.empr.com/drugs-in-the-pipeline/autism-spectrum-disorder-socialization-communication-symptoms-treatment-yamo-fast-track/article/deeplink/765593/

    The drug is a tyrosine hydroxylase inhibitor which is likely much preferable to the use of dopamine receptor blockers like risperidone and other related antipsychotics.

    I have no other information at this time other than what is in the press release. I doubt the drug will be useful on all autism cases, or even a majority, but for those people with autism who have excessive catecholamines in the brain, this drug could potentially help a lot if it ends up working as advertised.

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  4. Tyler, Peter,
    I also saw this announcement. The question is how does one know if a child has excessive catecholamines in the brain, i.e., fits into that subclass. Related to this, it seems of interest to understand the relationship between tyrosine hydroxylase deficiency (which can lead to Parkinsons) and tyrosine hydroxylase inhibition - would that mean direct inhibition or rather inhibition in its reuptake, or some other mechanism. In either case, it would seem that targeting tyrosine hydroxylase would apply in cases where the autism is strongly a neurotransmitter disorder?
    Thanks,
    Mira

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    Replies
    1. Mira, my son fits in that category,:neuronal hyperexitability,OCD,hypomanic,automatisms,tardive dyskinesia.Now he is much better.
      Valentina

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    2. Well the easy solution to a tyrosine hydroxylase deficiency is to take L-DOPA. One way to get a hint if there is a problem with excess dopamine in someone with autism, besides of course getting indirect tests for homovanillic acid (a dopamine metabolite), is to give someone a non-trivial dose of L-DOPA and see if autism symptoms get worse. This is similar to seeing what happens via the use of 5-HTP (precursor to serotonin) to see if it makes symptoms worse.

      To test for a possible deficiency in dopamine or serotonin, you would employ the ATD (Acute Tryptophan Depletion) protocol to reduce the levels of aromatic amino acids in the blood stream (tryptophan, tyrosine, phenylalanine) and see what happens in terms of autism symptoms.

      That being said, I don't think autism is a neurotransmitter disorder, rather I think dopamine seems to add fuel to the fire in some parts of the brain (striatum especially) and why dopamine is dysregulated could be many different reasons, perhaps all at the same time. I just know that in my son keeping dopamine levels manageable helps a lot, while letting him spike his insulin with too much sugar (which dumps BCAA's into muscle causing a surge of aromatic amino acids into the brain) causes him big mood problems.

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    3. Mira, here is an old post that may be of interest:-

      Secondary Monoamine Neurotransmitter Disorders in Autism – Treatment with 5-HTP and levodopa/carbidopa?

      https://epiphanyasd.blogspot.com/2017/02/secondary-monoamine-neurotransmitter.html

      Delete
    4. While you're at the subject of neurotransmittors, I have a question.

      In the long list of gene dysregulation I am working through I've found a downregulated DRD1 gene coding for the dopamine D1A receptor.
      I've also found a growth factor gene (GDF5) that enhances survival of dopamine neurons which also is downregulated.
      Lastly, there is a gene that reduces MAO-A expression (NHLH2) and it is also downregulated a lot.

      So, this could possibly mean that we have a situation with very little dopamine, few dopaminergic neurons and few D1 receptors. Unfortunately I don't know yet if these genes have a common source, or if one of them is regulating the others.

      My simple and awfully hard to answer question is: Is there anything I can do about this? It could definitely explain the "slowness" in my daughter.
      My knowledge on neurotransmittors is still very limited, all I remeber is Tyler telling us to focus on receptors or something similar.

      /Ling

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  5. Tyler, Corydalis,a tyrosine hydroxylase blocker, chineese herb,should work.
    Valentina

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  6. HI Peter,
    Our doctor recently suggested we trial 900-1000 mg of ibuprofin with my 24 yr old son as a possible indicator of PANDAS/PANS.
    I also started Alka Seltzer Gold recently.
    My son's renewed frequent rages immediately stopped.
    He has been taking the ibuprofin for over a week.
    I am very fearful to stop as I suspect the rages will return.
    Thoughts around this?
    Thanks
    Nancy

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    Replies
    1. Hi Nancy, I am sorry your son's rages have returned.

      I would first check obvious things like tooth decay or anything else that may be causing pain.

      PANDAS/PANS has the very obvious symptom of acute-onset (i.e. overnight) OCD/tics. If there is no OCD/tics PANDAS/PANS is unlikely.

      If ibuprofen resolves the problem, and there is no underlying pain evident, then something in your son has changed and resulted in an increase in pro-inflammatory cytokines. These cytokines (e.g. IL-6) are likely what causes the raging.

      Many different things cause increases in cytokines like IL-6.

      GI problems ranging from esophagitis/gastritis to ulcerative colitis are common in autism. It could be that.

      Some rare conditions are much more common in autism, juvenile arthritis is one example. This would increase Il-6.

      I think you and your doctor need to do some detective work to see what has changed and caused the behavioural change.

      Some people with autism use an NSAID like Ibuprofen long term. They can cause GI side effects and some may be better tolerated than others. Some you need take once a day.

      Alka Seltzer Gold is good to try, the bicarbonate should tamp down the immune system, but perhaps not enough if there is an acute underlying issue.


      Are you sure it is the Ibuprofen and not the bicarbonate that is helping (maybe it is both).

      Delete
  7. I just came across another couple of provocative studies for a drug called PLX5622 which I posted about not long ago here:

    https://epiphanyasd.blogspot.com/2017/06/modulating-wnt-signaling-in-autism-and.html?showComment=1499299094124#c1084736538888593119

    Here are the two press releases:

    https://www.sciencedaily.com/releases/2018/05/180521143909.htm

    https://www.sciencedaily.com/releases/2018/05/180517113755.htm

    The first study concerned addressing a problem with neuroinflammation in human beings while in deep space. What they found was that microglia seemed to be the main culprit and that inhibiting them with PLX5622 improved symptoms a lot (cosmic radiation is still very damaging to DNA, but the hyperactive response from brain microglia seems to cause the most harm).

    The second study is notable because it shows how strong PLX5622 is reducing microglia numbers in the brain, as a large dose of the drug made the animals more susceptible to prion diseases. Obviously, microglia are essential to living but having too many of them or else too many "activated" microglia seems to cause a set of symptoms common to many brain disorders including autism itself.

    ReplyDelete
  8. I just came across a new study which I hypothesize might explain the lack of gut diversity in many with autism:

    Press Release:

    https://www.sciencedaily.com/releases/2018/05/180515092931.htm

    Paper:

    http://msystems.asm.org/content/3/3/e00031-18

    The most interesting takeaway from this study that is relevant to autism is that it was found that the diversity of plants eaten, rather than the total amount, correlated strongly with increased gut diversity and a lack of antibiotic resistant flora as well.

    So it would be reasonable to conclude that many people with autism who are put on restricted diets and who also happen to have a limited range of palatable foods are not going to be eating a wide diversity of plants, which could lead to a reduction of gut biodiversity relative to control subjects in studies covering the matter.

    Now of course getting kids to eat vegetables is hard enough as it is, but getting autistic kids to eat a salad comprising many different plant ingredients is both really hard to enforce and really expensive (ironically fresh plants are only economical to upper middle class people in the USA). So this makes me wonder if some sort of nutraceutical product that simply mixes a bunch of plants together and somehow miraculously preserves the freshness of the plants and makes the product not taste absolutely terrible might be a good autism intervention. I know there are companies that sell veggie powders and stuff like that, but I am thinking of a product that literally might have 100 different plants in it, but that does not also cost an arm and a leg. If anyone has any good suggestions if they exist, I would be interested in knowing what those products are.

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    Replies
    1. A very simple but likely hypothesis, Tyler.

      I think we would have known about such plant products if they existed. And even if there was products like that, you would not get any beneficial bacterias from the dirt on the veggies if you ate them as some sterilized powder...
      /Ling

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  9. Tyler, do you have any suggestions about tyrosine hydroxylase blockers?What do you think about Corydalis?
    Valentina

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    Replies
    1. Other than the drug I cited above, I know very little about other drugs that inhibit tyrosine hydroxylase or Corydalis for that matter. I know a lot more about AADC which is the last rate limiting step in the production of serotonin as well as dopamine.

      Delete
    2. Thanks Valentina Tyler and Peter for comments on the tyrosine hydroxylase deficiency discussion. In fact my son does respond well to 200 mg 5HTP. Its not miraculous but the mood lifts. Increasing dosage of NAC to a better level (3 of 600 mg in morning and 2 of 600 mg in evening) has also had a really good effect. I would not have been able to do that without studying dosage information here.
      Valentina, I have not tried Corydalis but will investigate that. Not sure I could access a non-trivial dose of L Dopa for trial purposes.

      Tyler - many 'green powder' products aim to do what you are describing in terms of extracting nutrients from many fruits and vegetables. Take a look at ORAC Green. For my kids, drinking a green glass of water is not going to fly but with behavioral incentives they do eat vegetables. - Mira

      Delete
  10. Fascinating and I appreciate you reviewing this. We have an appt. with Children's genetics this week to have my daughter tested for SLOS. When they ran a routine cholesterol panel, it came back at 90 with only 32 LDL, but normal TG and HDL. Our family genetically is predisposed to really low cholesterol, but nothing below 120. We started her on cholesterol pills, but no changes have been observed yet. The only thing to date that's helped irritability is NAC and that wiped her aggression away nearly overnight. It was prescribed by a psychiatrist.

    Another fact is that sex hormones are also made from cholesterol. Hypocholestremia can seriously mess up the body.

    ReplyDelete

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