The Unexpected Connection Between Estrogen and Autism

Science has been studying autism spectrum disorder for better part of a century, and yet there’s one thing they can’t seem to figure out: why the brain of people with autism develop differently. But because it’s more common in boys, some researchers have long suspected that testosterone levels in the womb are the key.

The only problem is, their evidence has become up short. Turns out they might have been looking at the wrong hormones. Just this week, a team of scientist at the University of Cambridge and the State Serum Institute in Denmark announced that they’ve identified a link between autism and a different sex hormone: estrogen.

While it might sound like the complete opposite of what you’d expect for something more prevalent in boys, it actually lines up with our understanding of autism better than you’d think.

Autism spectrum disorder affects about every on of 59 children, but even after correcting for underdiagnosis and misdiagnosis, it’s roughly three times more likely in boys than in girls. Girls with autism also generally have fewer autism traits than boys. And all that may imply that there’s some kind of connection between autism and the physiological difference that generally come with Y chromosome.

Some even suggested that autism is basically what happens when you take typically male neurological traits and dial them up to 11. This is what’s known as the “extreme male brain theory” of autism. Now, it’s important to note that this doesn’t mean that the autistic people are super masculine overall–it just mean that they have more of the traits that you see more frequently on average, in the brains of men. And the difference is very small.

Studies consistently show that men and women are more psychologically similar that they are different. But there are some traits that, again, on average more common or more pronounced in the brains of people with Y chromosome or who identify as me. And it does seem like the traits are amplified in people with autism. To give one example, the brains of men tend to have weaker connectivity in the brains default mode network.

There’s a group of brain region that’s most active when you’re not focused on the outside world. And it turns out that both men and women with autism have even lower connectivity on this region than the average neurotypical man. Because there does seem to be some merit to this extreme male brain idea, researchers have suggested that the biological pathways involved in the development of typically masculine traits might be at the root of autism. And all traces back to fetal sex differentation:

The biological cues that lead to the development of typically masculine or feminine traits So in recent years, researchers begin to look for clues to autism in fetal development and conditions fetuses experience in-utero. And at first, many thought androgens- the hormones involved in typically male traits- might be to blaim, which makes intuitive sense.

The thing is, studies on prenatal testosterone levels alone- which is arguably the most important androgen–have found no relationship between it and autistic features. Then in the study published in 2015, Cambridge and Danish researchers found elevated levels of several sex hormones in the amniotic fluid of male fetuses that went on to develop autism. And while that did include testosterone and another androgen, it also included progesterone: which got the researchers thinking maybe they needed to widen their scope. Which brings us to estrogen.

Estrogen actually refers to the group of hormones which includes estriol, estradiol, estrone, and estetrol–none of which tested in the 2015 study. And these so called “female” hormones are very important for fetal development regardless of sex. Estradiol, in particular, contributes a lot development. It helps to form and prune neurons and synapses, and it regulates the activity of neurotransmitter GABA. In the brains of people with autism, synapses and neuron formation and GABA regulation are all typical.

So it might make sense that estrogen levels in the womb could play a role in the development of autism, too. To find out, those same researchers returned to the amiotic fluid samples they used in their 2015 study. These initially came from the Danish Historic Birth Cohort: a set of biological samples are more than a hundred thousand pregnant people collected between 1980 and 2004 who were followed up with the monitor the children’s health overtime, including whether they were diagnosed with autism. The researchers ended up with amniotic fluid samples from 98 males with autism and 177 neurotypical males. They then analyzed the samples for various forms of estrogen.

They found that elevated levels of estradiol and estriol, and estrone were all associated with an autism diagnosis. Estradiol has the biggest effect: a rise in this hormone from the 25th to the 75th percentile came with an almost 50% increase in the likelihood of autism. What this study suggests is that high level of estrogen, at least at about 15 weeks gestation, it might lead to differences in the brain development. As for why estrogen levels are higher at that time, the researchers suggested the placenta may have something to do with it. It acts as a hormone regulator between mom and fetus, and it’s fetus’ main source of estrogen.

And all that said, the researchers didn’t find that amniotic fluid hormones perfectly predict autism.

Alcohol Dependent People May Lack Important Enzyme

Alcohol Dependent People May Lack Important Enzyme

Summary: Researchers identify a role for the enzyme PRDM2 in alcoholism.

Source: Linköping University

A research group under the leadership of Linköping University Professor Markus Heilig has identified an enzyme whose production is turned off in nerve cells of the frontal lobe when alcohol dependence develops. The deficiency in this enzyme leads to continued use of alcohol despite adverse consequences.

The discovery is now published in the number-one ranked psychiatric journal from the Nature Publishing Group, and could mean completely new possibilities for treating alcoholism.

“We’ve worked hard for this. The enzyme, PRDM2, has previously been studied in cancer research, but we didn’t know that it has a function in the brain,” says Markus Heilig, professor of psychiatry and head of the Center for Social and Affective Neuroscience (CSAN) at Linköping University.

He and his research group are linking together research into alcoholism and other addictive illnesses with advanced brain research. It has long been suspected that people with alcohol dependence have impaired function in the frontal lobes of the brain, but the underlying biological mechanisms have not been known. The research team behind the paper, which includes researchers from both Linköping University and University of Miami, is the first to identify this molecular mechanism.

If frontal function is impaired, it is difficult for us to control our impulses. A person with intact impulse control can walk past a bar on a warm day and think ‘A beer would be nice, but I can’t have one now because I have to get back to work’. An alcoholic does not have sufficient impulse control to refrain, thinking: ‘It’s hot and I’m thirsty’.

“PRDM2 controls the expression of several genes that are necessary for effective signalling between nerve cells. When too little enzyme is produced, no effective signals are sent from the cells that are supposed to stop the impulse,” Professor Heilig tells us.

Several years of dedicated research lie behind this breakthrough. The research, in which Dr Estelle Barbier – post-doctoral fellow at CSAN – had a central role, has shown that alcohol dependence in rats leads to a down-regulation of PRDM2 production, which in turn leads to disruption of impulse control. This is why the laboratory animals continue to consume alcohol, even when it is unpleasant. If they are subjected to stress, they also quickly relapse into drinking alcohol.

Image shows a man drinking beer.

In the next step, the researchers knocked out the production of PRDM2 in the frontal lobes of rats that were not dependent, and they observed the same behaviour – impulse control was disrupted.

“We see how a single molecular manipulation gives rise to important characteristics of an addictive illness. Now that we’re beginning to understand what’s happening, we hope we’ll also be able to intervene. Over the long term, we want to contribute to developing effective medicines, but over the short term the important thing, perhaps, is to do away with the stigmatisation of alcoholism,” Professor Heilig says.

ABOUT THIS GENETICS AND ADDICTION RESEARCH ARTICLE

LiU researchers have worked together with colleagues including Professor Claes Wahlestedt and his co-workers at Miami University.

Source: Monica Westman Svenselius – Linköping University 
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2” by Barbier E, Johnstone AL, Khomtchouk BB, Tapocik JD, Pitcairn C, Rehman F, Augier E, Borich A, Schank JR, Rienas CA, Van Booven DJ, Sun H, Nätt D, Wahlestedt C, and Heilig M in Molecular Psychiatry. Published online August 30 2016 doi:10.1038/MP.2016.131

CITE THIS NEUROSCIENCENEWS.COM ARTICLE
Linköping University “Alcohol Dependent People May Lack Important Enzyme.” NeuroscienceNews. NeuroscienceNews, 4 September 2016.
<http://neurosciencenews.com/alcoholism-enzyme-prdm2-4960/&gt;.

Abstract

Dependence-induced increase of alcohol self-administration and compulsive drinking mediated by the histone methyltransferase PRDM2

Epigenetic processes have been implicated in the pathophysiology of alcohol dependence, but the specific molecular mechanisms mediating dependence-induced neuroadaptations remain largely unknown. Here, we found that a history of alcohol dependence persistently decreased the expression of Prdm2, a histone methyltransferase that monomethylates histone 3 at the lysine 9 residue (H3K9me1), in the rat dorsomedial prefrontal cortex (dmPFC). Downregulation of Prdm2 was associated with decreased H3K9me1, supporting that changes in Prdm2 mRNA levels affected its activity. Chromatin immunoprecipitation followed by massively parallel DNA sequencing showed that genes involved in synaptic communication are epigenetically regulated by H3K9me1 in dependent rats. In non-dependent rats, viral-vector-mediated knockdown of Prdm2 in the dmPFC resulted in expression changes similar to those observed following a history of alcohol dependence. Prdm2 knockdown resulted in increased alcohol self-administration, increased aversion-resistant alcohol intake and enhanced stress-induced relapse to alcohol seeking, a phenocopy of postdependent rats. Collectively, these results identify a novel epigenetic mechanism that contributes to the development of alcohol-seeking behavior following a history of dependence.


PRDM2

This tumor suppressor gene is a member of a nuclear histone/protein methyltransferase superfamily. It encodes a zinc finger protein that can bind to retinoblastoma protein, estrogen receptor, and the TPA-responsive element (MTE) of the heme-oxygenase-1 gene. Although the functions of this protein have not been fully characterized, it may (1) play a role in transcriptional regulation during neuronal differentiation and pathogenesis of retinoblastoma, (2) act as a transcriptional activator of the heme-oxygenase-1 gene, and (3) be a specific effector of estrogen action. Three transcript variants encoding different isoforms have been found for this gene.[4]

Interactions

PRDM2 has been shown to interact with Estrogen receptor alpha[5] and Retinoblastoma protein.

Melatonin counteract estrogen’s tendency to stimulate cell growth

Oct 10, 2013  Melatonin is a powerful antioxidant that helps protect you against heart disease, diabetes, migraine headaches, Alzheimer’s disease, and cancer. … When this hormone latches onto a breast cancer cell, it has been found to counteract estrogen’s tendency to stimulate cell growth. In fact, melatonin has a …
https://articles.mercola.com/…/alzheimers-dementia-treatment.aspx
Jun 13, 2013  A study reveals that vitamins B6, B12, and folic acid, as well as cinnamon, may help slow the progression of Alzheimer’s disease.
Sep 12, 2013  When used at extreme levels, copper can be very toxic and can increase your risk of Alzheimer’s disease.
Nov 8, 2008  Eating the wrong diet could increase your risk of developing Alzheimer’s disease. Scientists have found a link between the degenerative brain disease and raised levels of an omega-6 fatty acid. Researchers compared the brains of mice bred with a condition that mimics Alzheimer’s to those of normal mice.
https://articles.mercola.com/…/estrogen-levels-and-cognitive-decline.aspx
Jan 2, 2008  Another nail in the coffin for postmenopausal estrogen therapy. Last year, NEJM published a study that suggested that estrogen helps prevent Alzheimers disease in women. This information provided another false justification for traditional medicine to prescribe it. If you have not purchased Dr. Lee’s book, …
Apr 27, 2017  Mounting research also suggests Alzheimer’s disease is intricately connected to insulin resistance; even mild elevation of blood sugar is associated with an elevated risk for dementia. Diabetes and heart disease are also known to elevate your risk, and both are rooted in insulin resistance.
Feb 11, 2010  Copper pipes have no place in your home. Learn why installing special filters can help you avoid heart disease, Alzheimer’s disease and diabetes.
Aug 4, 2013  Not only heart disease and stroke, but I’m thinking cancer, Alzheimer’s, multiple sclerosis, or any illness that requires good oxygenation to the tissues. … One of the mechanisms that causes this increased risk is that synthetic estrogens and progesterones increase blood viscosity, i.e., they decrease the zeta …
Feb 16, 2010  Alzheimer’s disease is not the only reason to ditch your aluminum-containing antiperspirant and deodorant, as this metal has also been linked to cancer. A 2006 study found that aluminum salts can mimic the hormone estrogen, and chemicals that imitate that hormone are known to increase breast cancer …
Nov 6, 2014  A six-year study reveals that those with vitamin D deficiency are more than twice as likely to develop dementia and Alzheimer’s disease.

Estrogen and Alzheimer

Estrogen and Alzheimer’s. Hormone replacement therapy does not appear to reduceAlzheimer’s symptoms, but it may help to prevent the disease in healthy women.. At menopause, the level of the hormone estrogen in women’s bodies begins to decline, marking the end of their childbearing years.

Estrogen Therapy Could Hold Back Alzheimer’s, Shrink the Brain …

Sep 3, 2015 – On a positive note, a large epidemiological study found that estrogen given early in menopause reduced Alzheimer’s risk, and results from a small cohort indicated that early treatment with the hormone may have slowed amyloid accumulation.

Hormonal Influences on Cognition and Risk for Alzheimer Disease

by SC Janicki – ‎2010 – ‎Cited by 79 – ‎Related articles

Jump to Estrogen in Men – Support for the role of estrogen in neuroprotection has come from epidemiologic studies of gender differences in risk for cognitive decline and dementia; from observational studies; from clinical trials of the effects of hormone replacement therapy; from studies of risk for cognitive decline and dementia associated …

Estrogen and Alzheimer’s – Memory Loss & the Brain

Estrogen and Alzheimer’s. Hormone replacement therapy does not appear to reduce Alzheimer’ssymptoms, but it may help to prevent the disease in healthy women.. At menopause, the level of the hormone estrogen in women’s bodies begins to decline, marking the end of their childbearing years.

New Debate on Hormone Replacement Therapy and Dementia Risk …

Mar 22, 2017 – It included over 4,500 postmenopausal women and examined the effects of estrogenplus progestin HRT on the incidence of dementia and mild cognitive … period after menopause did not have a lower risk of Alzheimer’s disease, while treatment lasting over 10 years was associated with decreased risk [9].

Estrogen & Your Brain | Cognitive Vitality | Alzheimer’s Drug Discovery …

Jul 1, 2016 – The term “estrogen” refers to a broad range of natural and synthetic molecules that affectestrogen receptors. Estrogen hormone therapy usually consists of estrogens alone or combined with a progestogen and can be used to treat symptoms of menopause. While estrogens do have some potentially …

Estrogen and Alzheimer’s Disease: What Is the Connection? – Medscape

Estrogen use was identified based on the women’s questionnaire responses at the time of entry into the retirement community. The women without AD were more likely to have taken estrogen (odds ratio 0.69; 95% CI=0.46-1.03), with the risk of Alzheimer’s decreasing as dose and duration of estrogen use increased.

Estrogen Patch in Newly Postmenopausal Women May Reduce …

Jul 12, 2016 – ROCHESTER, Minn. — Can estrogen preserve brain function and decrease the risk ofAlzheimer’s disease when given early in menopause? Newly postmenopausal women who receivedestrogen via a skin patch had reduced beta-amyloid deposits, the sticky plaques found in the brains of people with …

Menopause, Female Hormones, and Alzheimer’s Risk – Awakening …

Feb 23, 2017 – Estrogen and Alzheimer’s Disease. Estrogen and progesterone are steroid sex hormones that not only contribute to female fertility but also play an important role in brain functioning for both men and women. Estrogen is part of the brain’s signaling system, and it helps direct blood to parts of the brain that …

[PDF]Anti-Amyloid Therapies – Alzheimer’s Association

Hormone replacement therapy and Alzheimer’s disease. What is hormone replacement therapy? Hormone replacement therapy substitutes estrogen from a pharmaceutical source for a woman’s natural supply. Production of estrogen by the ovaries declines as women age and then virtually stops around menopause.

Estrogen supplements may protect against dementia — ScienceDaily

Jan 22, 2016 – Must start estrogen from the late 40s. Pintzka’s findings show that boosting estrogenlevels increases the volume of the hippocampus. As of yet there are no drugs that stop or prevent the course of Alzheimer’s disease, and the focus has shifted towards strategies to prevent or delay the onset of dementia.

Spearmint herbal tea has significant anti-androgen effects in polycystic ovarian syndrome

Spearmint herbal tea has significant anti-androgen effects in polycystic ovarian syndrome (PCOS). A randomized controlled trial

Abstract

Hirsutism in polycystic ovarian syndrome (PCOS), consequent to elevated androgen levels leads to significant cosmetic and psychological problems. Recent research in Turkey has shown that spearmint tea has antiandrogenic properties in females with hirsutism. No research has yet been undertaken to assess whether a reduction in androgen levels brought about by spearmint tea, translates to a clinical improvement in the degree of hirsutism.

This study was a two centre, 30 day randomized controlled trial. Forty two volunteers were randomized to take spearmint tea twice a day for a 1 month period and compared with a placebo herbal tea.

At 0, 15 and 30 days of the study serum androgen hormone levels and gonadotrophins were checked, the degree of hirsutism was clinically rated using the Ferriman-Galwey score and a questionnaire (the modified DQLI = Dermatology Quality of Life Index) was used to assess improvements in the level of self-reported hirsutism. Forty one of 42 patients completed the study.

Free and total testosterone levels were significantly reduced over the 30 day period in the spearmint tea group (p < 0.05). LH and FSH also increased (p < 0.05). Patient’s subjective assessments of their degree of hirsutism scored by the modified DQLI were significantly reduced in the spearmint tea group (p < 0.05). There was, however, no significant reduction in the objective Ferriman-Galwey ratings of hirsutism between the two trial groups over the trial duration (p = 0.12). There was a clear and significant alteration in the relevant hormone levels.

This is associated clinically with a reduction in the self-reported degree of hirsutism but unfortunately not with the objectively rated score. It was demonstrated and confirmed that spearmint has antiandrogen properties, the simple fact that this does not clearly translate into clinical practice is due to the relationship between androgen hormones and follicular hair growth and cell turnover time.

Simply put, the study duration was not long enough. The original studies from Turkey were in fact only 5 days long. The time taken for hirsutism to resolve is significant and a much longer future study is proposed as the preliminary findings are encouraging that spearmint has the potential for use as a helpful and natural treatment for hirsutism in PCOS.

Benign prostatic hyperplasia (BPH), estrogen and phytoestrogens

Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate.Estrogens in men

Estradiol-17β (E2) is considered the most potent estrogen in men and is important for a variety of physiologic processes including bone maturation and mineralization, peak bone mass, and skin and lipid metabolism [114]. In men, the majority of circulating E2 is formed from aromatization of T, mainly in fat and muscle, while up to 20% is secreted by Leydig cells of the testes [114]. However, serum levels of E2do not necessarily reflect tissue levels of E2 [114]. In this regard, prostate in situ E2 production may influence local estrogen regulated processes. Such local production of E2 has been implicated in prostatic hyperplasia and loss of aromatase expression causes decreased estrogen-induced prostate proliferation [62, 115]. However, an important question remains: which estrogens or estrogen interactions affect prostate pathologies?

The prostate is commonly thought of as an androgen target tissue, but it is also an important target of estrogens. Although E2 is the primary estrogen evaluated in prostate research, a number of other potential estrogenic sources may play significant positive or negative roles in the prostate, as outlined in Figure 2. These estrogens can be divided into multiple categories including those that are found systemically (in serum) or those produced in situ in the prostate. Local steroids with estrogen receptor agonist activity include E2, 5α-androstane-3β, 17β-diol (3βAdiol), and 7α-hydroxy-DHEA (7HD). The effects of these sex steroids are not fully appreciated but are likely to influence prostate hyperplasia. Their mechanism of action, including promotion or suppression of proliferation and differentiation is dependent upon their specificity and activation of estrogen receptors (ERs).

Figure 2

Estrogenic sources

Estrogens within the circulation can be endogenous or exogenous (Figure 2). Commonly found endogenously derived estrogens include estrone (E1), E2 and estriol (E3). E1 is a weak estrogen formed mainly from peripheral aromatization of adrenal androstenedione, and as such is considered to have minimal influence on estrogenic pathways within the prostate. However, E2 (as discussed above) has been shown to be a potent estrogen and a powerful inducer of prostatic proliferation. In men, serum concentrations of E3, the predominant estrogen of pregnancy, are minimal, and the potential role of E3 in male physiology and in the prostate is not well understood. Recently another endogenous estrogen, 27-hydroxy-cholesterol (27HC), an oxysterol, was found to bind ERs and regulate ER mediated transcription [116]. Although the affinity of 27HC for estrogen receptors is lower compared to E2, the concentrations of 27HC in serum and tissues are significantly higher [116120]. This suggests that 27HC may be an important regulator of ER activity in estrogen target organs such as the prostate. Circulating exogenous estrogens may also affect estrogen action in men. Serum levels of xenoestrogens are dependent upon dietary and other environmental exposures and as such, levels may vary among different populations. Such estrogens include phytoestrogens, therapeutic selective estrogen receptor modulators (SERMs), and endocrine disruptors (e.g. BPA, insecticides, etc.) (Figure 2).

Phytoestrogens are commonly associated with various diets (e.g. Western vs. Eastern diets) and are generally assumed to have a positive effect on the prostate. Phytoestrogens include polyphenols, flavonoids, and isoflavanoids, reviewed by [121]. An example of a polyphenol is resveratrol, which is commonly found in grape skins and red wine. Flavonoids are subgrouped into flavanones, flavones, flavonols, and catechins and are found in many foods including fruits, parsley, celery, kale, broccoli, chocolate, and green tea. Isoflavanoids are categorized into isoflavones, isoflavans, and coumestans and are found in foods like legumes, clover, and spinach.

Phytoestrogens have been suggested have a role in the prevention of estrogen associated diseases such as prostate cancer [122]. The role of phytoestrogens in BPH remains unclear, but they may act as inhibitors of proliferation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179830/