Exercise and Epigenetic Regulation

I would like to dedicate this thread to discussing the effects of exercise on gene expression. Is it possible to recover from PFS or at least improve using exercise?

There is at least a theoretical plausibility about this as apparently exercise changes gene expression in a great number of genes.

There has also been many patients on PH throughout the years who have claimed exercise had a long-term beneficial effect.

It would be good to gather in this thread as much evidence about this as possible (both for and against) and have it discussed by people who understand biology but also based on personal experience.

I will be posting more papers soon but here is the first paper:


Exercise Training and Epigenetic Regulation: Multilevel Modification and Regulation of Gene Expression.

Abstract

Exercise training elicits acute and adaptive long term changes in human physiology that mediate the improvement of performance and health state. The responses are integrative and orchestrated by several mechanisms, as gene expression. Gene expression is essential to construct the adaptation of the biological system to exercise training, since there are molecular processes mediating oxidative and non-oxidative metabolism, angiogenesis, cardiac and skeletal myofiber hypertrophy, and other processes that leads to a greater physiological status. Epigenetic is the field that studies about gene expression changes heritable by meiosis and mitosis, by changes in chromatin and DNA conformation, but not in DNA sequence, that studies the regulation on gene expression that is independent of genotype. The field approaches mechanisms of DNA and chromatin conformational changes that inhibit or increase gene expression and determine tissue specific pattern. The three major studied epigenetic mechanisms are DNA methylation, Histone modification, and regulation of noncoding RNA-associated genes. This review elucidates these mechanisms, focusing on the relationship between them and their relationship with exercise training, physical performance and the enhancement of health status. On this chapter, we clarified the relationship of epigenetic modulations and their intimal relationship with acute and chronic effect of exercise training, concentrating our effort on skeletal muscle, heart and vascular responses, that are the most responsive systems against to exercise training and play crucial role on physical performance and improvement of health state.

Full Text:

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It is known that exercise increases DHT and 5a-reductase expression in skeletal muscles (I will post papers about this later), but it is important to know that it has similar effects in other parts of the body - most notably in the brain.


Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

Abstract

Mild exercise activates hippocampal neurons through the glutamatergic pathway and also promotes adult hippocampal neurogenesis (AHN). We hypothesized that such exercise could enhance local androgen synthesis and cause AHN because hippocampal steroid synthesis is facilitated by activated neurons via N -methyl- D -aspartate receptors. Here we addressed this question using a mild-intense treadmill running model that has been shown to be a potent AHN stimulator. A mass-spectrometric analysis demonstrated that hippocampal dihydrotestosterone increased significantly, whereas testosterone levels did not increase significantly after 2 wk of treadmill running in both orchidectomized (ORX) and sham castrated (Sham) male rats. Furthermore, analysis of mRNA expression for the two isoforms of 5α-reductases ( srd5a1 , srd5a2 ) and for androgen receptor (AR) revealed that both increased in the hippocampus after exercise, even in ORX rats. All rats were injected twice with 5′-bromo-2′deoxyuridine (50 mg/kg body weight, i.p.) on the day before training. Mild exercise significantly increased AHN in both ORX and Sham rats. Moreover, the increase of doublecortin or 5′-bromo-2′deoxyuridine/NeuN-positive cells in ORX rats was blocked by s.c. flutamide, an AR antagonist. It was also found that application of an estrogen receptor antagonist, tamoxifen, did not suppress exercise-induced AHN. These results support the hypothesis that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases AHN via androgenenic mediation.

Full Text:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3420174/

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Exercise and sex steroid hormones in skeletal muscle.

Abstract

Sex steroid hormones are secreted mainly by the ovary and testis and regulate diverse physiological processes in target tissues. Recent studies have shown that sex steroidogenesis-related mRNA and protein expressions, such as for 17β-hydroxysteroid dehydrogenase (HSD), 3β-HSD, 5α-reductase and aromatase cytochrome P-450 (P450arom) enzymes, are detected in the skeletal muscle, while testosterone, estradiol, and 5α-dihydrotestosterone (DHT) were locally synthesized in skeletal muscle from dehydroepiandrosterone (DHEA). Moreover, in animal and human studies, the sex steroidogenesis enzymes and sex steroid hormone levels in skeletal muscle are upregulated by acute and chronic exercise stimulation. The enhanced muscle sex steroidgenesis is associated with glycemic control via upregulation of muscle glucose transporter-4 (GLUT-4) signaling in obese and diabetic rats and with muscle mass and strength in older men. Thus, an exercise-induced increase of sex steroid hormone in muscle may positively impact age-related concerns such as life-related diseases and sarcopenia.

https://www.ncbi.nlm.nih.gov/m/pubmed/24704257

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Resistance training restores muscle sex steroid hormone steroidogenesis in older men.

Abstract

Skeletal muscle can synthesize testosterone and 5α-dihydrotestosterone (DHT) from dehydroepiandrosterone (DHEA) via steroidogenic enzymes in vitro, but hormone levels and steroidogenic enzyme expression decline with aging. Resistance exercise has been shown to increase in plasma sex steroid hormone levels. However, it remains unclear whether resistance training can restore impaired steroidogenic enzyme expressions in older individuals. Six young and 13 older men were recruited, and muscle biopsies were taken from the vastus lateralis at basal state. The same group of older subjects underwent resistance training involving knee extension and flexion exercises for 12 wk, and post-training biopsies were performed 4-5 d after the last exercise session. Muscular sex steroid hormone levels and sex steroidgenesis-related enzyme expressions were significantly lower in older subjects than younger ones at baseline, but 12 wk of resistance training significantly restored hormone levels (DHEA: 432±26 at baseline, 682±31 pg/μg protein, DHT: 6.2±0.9 at baseline, 9.8±1.4 pg/μg protein). Furthermore, the steroidogenesis-related enzymes such as 3β-hydroxysteroid dehydrogenase (HSD), 17β-HSD, and 5α-reductase expressions were significantly restored by resistance training. We conclude progressive resistance training restores age-related declines in sex steroidogenic enzyme and muscle sex steroid hormone levels in older men.

Full Text
https://doi.org/10.1096/fj.13-245480

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The following paper has been posted before but I think it belongs to this thread as well.

It shows that lifestyle factors such as obesity but also age are associated with 5ar2 methylation.

There is another paper which shows losing weight, independently of exercise, can decrease genome wide methylation. Will post below.

An important conclusion of this paper is this:

“Taken together, these findings suggest that dynamic changes in methylation status may be associated with lifestyle modifications that lead to BPH regression and improvements in LUTS.”

Importantly, the methylation changes happen not just in skeletal muscles but also in tissues not directly involved in metabolism, such as the prostate.

I think this is good news for us because it suggests methylation and demethylation of 5ar2 (or other genes) are modifiable in principle.


Age and Obesity Promote Methylation and Suppression of 5-Alpha Reductase 2–Implications for Personalized Therapy in Benign Prostatic Hyperplasia

Abstract

Purpose

5α reductase inhibitors (5ARIs) are a main modality of treatment for men suffering from symptomatic benign prostatic hyperplasia (BPH). Over 30% of men do not respond to the therapeutic effects of 5ARIs. We have found that 1/3 of adult prostate samples do not express 5AR2 secondary to epigenetic modifications. We sought to evaluate whether 5AR2 expression in BPH specimens of symptomatic men was linked to methylation of the 5AR2 gene promoter and identify associations with age, obesity, cardiac risk factors, and prostate specific antigen (PSA).

Materials and Methods

Prostate samples from men undergoing transurethral prostate resection were used. 5AR2 protein expression and gene promoter methylation status were determined by common assays. Clinical variables included age, body mass index (BMI), hypertension, hyperlipidemia, diabetes, PSA, and prostate volume. Univariate and multivariate statistical analyses were performed, followed by stepwise logistic regression modeling.

Results

BMI and age were significantly correlated with methylation of the 5AR2 gene promoter (p<0.05), whereas prostate volume, PSA, or use of BPH medication were not. Methylation was highly correlated with 5AR protein expression (p<0.0001). In a predictive model, both increasing age and BMI significantly predicted methylation status and protein expression (p<0.01).

Conclusions

Increasing age and BMI correlate with increased 5AR2 gene promoter methylation and decreased protein expression in men with symptomatic BPH. These results highlight the interplay between age, obesity and gene regulation. Our findings suggest the presence of an individualized epigenetic signature for symptomatic BPH, which may be important for choosing appropriate personalized treatment options.

Full Text:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761873/

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This is another important paper. Beyond the main message that expression of SRD5A2 is not static, there is another notable finding: “inhibition with tumor necrosis factor α inhibitor reactivates SRD5A2 expression.”

Many people with PFS report reduced symptoms when ill, when supposedly tumor necrosis factor α is increased. This would suggest, contrary to what I expect, that decreasing expression of SRD5A2 improves symptoms.

To the extent that I am interpreting this correctly, this phenomenon is puzzling to me and is not consistent with my theory of the etiology of PFS. It may be consistent with the dominant theory.

There may be an alternative explanation however as tnf-a increases stimulation of the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH), which stimulates the production of DHEA and may increase the substrate for 5a-reduction.


DNA Methyl Transferase 1 Reduces Expression of SRD5A2 in the Aging Adult Prostate

Abstract

5-α Reductase type 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Inhibition of SRD5A2 by finasteride is used commonly for the management of urinary obstruction caused by benign prostatic hyperplasia. Contrary to common belief, we have found that expression of SRD5A2 is variable and absent in one third of benign adult prostates. In human samples, absent SRD5A2 expression is associated with hypermethylation of the SRD5A2 promoter, and in vitro SRD5A2 promoter activity is suppressed by methylation. We show that methylation of SRD5A2 is regulated by DNA methyltransferase 1, and inflammatory mediators such as tumor necrosis factor α, NF-κB, and IL-6 regulate DNA methyltransferase 1 expression and thereby affect SRD5A2 promoter methylation and gene expression. Furthermore, we show that increasing age in mice and humans is associated with increased methylation of the SRD5A2 promoter and concomitantly decreased protein expression. Artificial induction of inflammation in prostate primary epithelial cells leads to hypermethylation of the SRD5A2 promoter and silencing of SRD5A2 , whereas inhibition with tumor necrosis factor α inhibitor reactivates SRD5A2 expression. Therefore, expression of SRD5A2 is not static and ubiquitous in benign adult prostate tissues. Methylation and expression of SRD5A2 may be used as a gene signature to tailor therapies for more effective treatment of prostatic diseases.

Full Text
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348471/

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Weight loss after gastric bypass surgery in human obesity remodels promoter methylation.

Abstract

DNA methylation provides a mechanism by which environmental factors can control insulin sensitivity in obesity. Here, we assessed DNA methylation in skeletal muscle from obese people before and after Roux-en-Y gastric bypass (RYGB). Obesity was associated with altered expression of a subset of genes enriched in metabolic process and mitochondrial function. After weight loss, the expression of the majority of the identified genes was normalized to levels observed in normal-weight, healthy controls. Among the 14 metabolic genes analyzed, promoter methylation of 11 genes was normalized to levels observed in the normal-weight, healthy subjects. Using bisulfite sequencing, we show that promoter methylation of PGC-1α and PDK4 is altered with obesity and restored to nonobese levels after RYGB-induced weight loss. A genome-wide DNA methylation analysis of skeletal muscle revealed that obesity is associated with hypermethylation at CpG shores and exonic regions close to transcription start sites. Our results provide evidence that obesity and RYGB-induced weight loss have a dynamic effect on the epigenome.

https://www.ncbi.nlm.nih.gov/pubmed/23583180

This paper has also been posted before but is relevant to this thread as well.


Endurance exercise training enhances local sex steroidogenesis in skeletal muscle.

Abstract

PURPOSE:

Endurance training improves skeletal muscular function including energy metabolism and structure. Sex steroid hormones partly contribute to the exercise-induced muscular adaptations. Recently, we demonstrated that skeletal muscle contains steroidogenic converting enzymes to synthesize sex steroid hormones and an acute endurance exercise activates local steroidogenesis in skeletal muscle. However, whether chronic endurance training leads to enhanced steroidogenesis in skeletal muscle is unknown. Here, we examined changes in steroidogenic enzymes and sex steroid hormones in the skeletal muscle after chronic endurance exercise training.

METHODS:

Eleven male rats were divided into two groups: sedentary (n = 6) and trained (n = 5). Endurance training was performed on a treadmill (30 m·min(-1), 30 min) for 5 d·wk(-1) for 12 wk. The posttraining harvesting was performed 48 h after the last exercise training.

RESULTS:

The mRNA expressions of 3β-HSD, aromatase cytochrome P450, and 5α-reductase in the skeletal muscle of trained rats were significantly higher than those of sedentary rats (P < 0.05). The protein expressions of aromatase cytochrome P450 and 5α-reductase in the skeletal muscle of trained rats were also significantly higher than those of sedentary rats (P < 0.05). The muscular dihydrotestosterone (DHT) concentrations in the skeletal muscle of trained rats were significantly higher than those of sedentary rats (P < 0.01), but there was no change in dehydroepiandrosterone, total testosterone, free testosterone, and estradiol. Furthermore, muscle weight corrected for body weight of trained rats was moderately correlated with the level of muscular DHT concentration in trained rats (r = 0.41, P < 0.05).

CONCLUSIONS:

Endurance exercise training enhances the muscular DHT concentration through 5α-reductase in the skeletal muscle of rats, suggesting that local bioactive androgen metabolism may participate in exercise training-induced skeletal muscular adaptation.

https://www.ncbi.nlm.nih.gov/pubmed/21502890

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Another paper showing exercise changes gene methylation patterns not only in skeletal muscles but also in sperm.


Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans.

Abstract

AIM:

DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation.

MATERIALS & METHODS:

Twenty-four men were recruited and assigned to an exercise intervention or control group. Clinical parameters were measured and sperm samples were donated by subjects before and after the 3-month time-period. Mature sperm global and genome-wide DNA methylation was assessed using an ELISA assay and the 450K BeadChip (Illumina).

RESULTS:

Global and genome-wide sperm DNA methylation was altered after 3 months of exercise training. DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson’s disease.

CONCLUSIONS:

Our study provides the first evidence showing exercise training reprograms the sperm methylome. Whether these DNA methylation changes are inherited to future generations warrants attention.

https://www.ncbi.nlm.nih.gov/pubmed/25864559

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I can keep adding papers to this thread, and no doubt more specific papers can be found that are even more informative for our purposes, but I would like to hear people’s opinion on this - both based on the science but also based on personal experience.

I know there have been many threads about the potential benefits of exercise for us, including recovery stories. It would be good to hear both from (or about) people who have improved and also who have not improved with exercise.

Presumably there are many long-term sufferers who have not improved even with a lot of exercise. It would be good to hear from those - how much exercise they have done, what type, how often, what intensity, etc.

Basically I would like to have a realistic expectation about the possible benefits from embarking on a regular and strenuous exercise regimen. I hope I will be able to do that soon, joint pain permitting.

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The impact of sensory and motor enrichment on the epigenetic control of steroidogenic-related genes in rat hippocampus.

Abstract

In the present study, we analyzed the effects of a short-term environmental enrichment on the mRNA expression and DNA methylation of steroidogenic enzymes in the hippocampus. Thus, young adult (80-day-old) and middle-aged (350-day-old) Wistar female rats were exposed to sensory (SE) or motor (ME) enrichment during 10 days and compared to animals housed under standard conditions. SE was provided by an assortment of objects that included plastic tubes and toys; for ME, rodent wheels were provided. In young adult animals, SE and ME increased the mRNA expression of cytochrome P450 17α-hydroxylase/c17,20-lyase, steroid 5α-reductase type 1 (5αR-1) and 3α-hydroxysteroid dehydrogenase and decreased the methylation levels of 5αR-1 gene. In middle-aged rats, ME and SE upregulated the gene expression of aldosterone synthase and decreased the methylation state of its promoter. These results propose that SE and ME differentially regulate the transcription of neurosteroidogenic enzymes through epigenetic mechanisms in young and aged rats.

https://www.ncbi.nlm.nih.gov/pubmed/30721712

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“We have shown that SRD5A2 is absent in 30% of adult human prostatic tissues, owing to methylation of the SRD5A2 promoter, regulated by the DNMT1 family of genes (a process that is enhanced by conditions associated with increased inflammatory mediators), ageing, and obesity.”


Androgenic to oestrogenic switch in the human adult prostate gland is regulated by epigenetic silencing of steroid 5α-reductase 2

Abstract

Benign prostatic hyperplasia is the most common proliferative abnormality of the prostate. All men experience some prostatic growth as they age, but the rate of growth varies among individuals. Steroid 5α-reductase 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Previous work indicates that one-third of adult prostatic samples do not express SRD5A2, secondary to epigenetic modifications. Here we show that the level of oestradiol is dramatically elevated, concomitant with significant upregulation of oestrogen response genes, in prostatic samples with methylation at the SRD5A2 promoter. The phosphorylation of oestrogen receptor-α in prostatic stroma is upregulated when SRD5A2 expression is absent. We show that tumour necrosis factor (TNF)-α suppresses SRD5A2 mRNA and protein expression, and simultaneously promotes expression of aromatase, the enzyme responsible for conversion of testosterone to oestradiol. Concomitant suppression of SRD5A2 and treatment with TNF-α synergistically upregulate the aromatase levels. The data suggest that, in the absence of prostatic SRD5A2, there is an androgenic to oestrogenic switch. These findings have broad implications for choosing appropriate classes of medications for the management of benign and malignant prostatic diseases.

Keywords: androgenic to oestrogenic switch, prostate, epigenetic silencing, methylation, steroid 5α-reductase 2

Full Text:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212292/

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While this paper is not related to exercise, I believe it is a very significant paper.

It shows that NF-kB increases expression of all three SRD5A2s. Nf-kB is stimulated by viral and bacterial infections.

This can potentially explain the reduction of PFS symptoms during episodes of cold/flu that is consistently reported by PFS patients.

This mechanism may also potentially explain the reported positive effects of certain probiotics, although this is widely speculative.

@awor @axolotl @orthogs @Dubya_B @Frustrated @Famajor


NF-κB and androgen receptor variant 7 induce expression of SRD5A isoforms and confer 5ARI resistance.

Abstract

BACKGROUND:

Benign prostatic hyperplasia (BPH) is treated with 5α-reductase inhibitors (5ARI). These drugs inhibit the conversion of testosterone to dihydrotestosterone resulting in apoptosis and prostate shrinkage. Most patients initially respond to 5ARIs; however, failure is common especially in inflamed prostates, and often results in surgery. This communication examines a link between activation of NF-κB and increased expression of SRD5A2 as a potential mechanism by which patients fail 5ARI therapy.

METHODS:

Tissue was collected from “Surgical” patients, treated specifically for lower urinary tract symptoms secondary to advanced BPH; and, cancer free transition zone from “Incidental” patients treated for low grade, localized peripheral zone prostate cancer. Clinical, molecular and histopathological profiles were analyzed. Human prostatic stromal and epithelial cell lines were genetically modified to regulate NF-κB activity, androgen receptor (AR) full length (AR-FL), and AR variant 7 (AR-V7) expression.

RESULTS:

SRD5A2 is upregulated in advanced BPH. SRD5A2 was significantly associated with prostate volume determined by Transrectal Ultrasound (TRUS), and with more severe lower urinary tract symptoms (LUTS) determined by American Urological Association Symptom Score (AUASS). Synthesis of androgens was seen in cells in which NF-κB was activated. AR-FL and AR-V7 expression increased SRD5A2 expression while forced activation of NF-κB increased all three SRD5A isoforms. Knockdown of SRD5A2 in the epithelial cells resulted in significant reduction in proliferation, AR target gene expression, and response to testosterone (T). In tissue recombinants, canonical NF-κB activation in prostatic epithelium elevated all three SRD5A isoforms and resulted in in vivo growth under castrated conditions.

CONCLUSION:

Increased BPH severity in patients correlates with SRD5A2 expression. We demonstrate that NF-κB and AR-V7 upregulate SRD5A expression providing a mechanism to explain failure of 5ARI therapy in BPH patients. Prostate 76:1004-1018, 2016.

Full Text:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912960/

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Effects of swim stress on mRNA and protein levels of steroid 5alpha-reductase isozymes in prefrontal cortex of adult male rats

Abstract

The metabolite of progesterone, allopregnanolone, is among the most potent known ligands of the gamma-aminobutyric acid receptor complex (GABA(A)-R) in the central nervous system. This neuroactive steroid is markedly increased in an animal model of acute stress. Allopregnanolone is synthesized from progesterone by steroidogenic enzymes 5alpha-reductase (5alpha-R) and 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), with the former being the rate-limiting enzyme in this reaction sequence. In this paper, a quantitative RT-PCR method coupled to laser-induced fluorescence capillary electrophoresis (LIF-CE) and Western blot were used to measure both mRNA and protein levels of 5alpha-R type 1 (5alpha-R1) and 5alpha-R type 2 (5alpha-R2) isozymes in prefrontal cortex of male rats after acute swim stress situations. Our results demonstrate that both 5alpha-R isozymes are significantly higher in prefrontal cortex of male rats after acute swim stress in comparison with control rats. These data may open up a new research line that could improve our understanding of the role of 5alpha-R isozymes in processes that accompany stress situations.

https://www.ncbi.nlm.nih.gov/pubmed/17826869

Expression of steroid 5α‐reductase isozymes in prostate of adult rats after environmental stress

Abstract

The elevated incidence of prostate cancer and benign prostatic hypertrophy is a cause of increasing public health concern in the Western world. The normal and pathological growth of the prostate are both dependent on stimulation by dihydrotestosterone, which is synthesized from circulating testosterone by two 5α‐reductase (5α‐R) isozymes, 5α‐reductase type 1 (5α‐R1) and 5α‐reductase type 2 (5α‐R2). Both isozymes have been implicated in prostate disease. We used quantitative RT‐PCR and immunohistochemistry, respectively, to quantify mRNA and protein levels of 5α‐R isozymes in the ventral prostate of adult rats under environmental stress conditions analogous to those found in some common workplace situations, i.e. artificial light, excessive heat, and the sensation of immobility in a small space. Transcription and expression levels of both 5α‐R isozymes were significantly higher in environmentally stressed rats than in unstressed rats. Increased 5α‐R isozyme levels may play a role in the development or maintenance of prostate disease. Further research is warranted to explore these effects of environmental stress on human health and their implications for environmental and occupational health policies.

Full Text
https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.12052

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Effects of environmental stress on mRNA and protein expression levels of steroid 5alpha-Reductase isozymes in adult rat brain.

Abstract

Environmental stress conditions are important factors in human health and should be considered in the development of appropriate health policies, since they have been associated with psychological disorders and even with death. A link between stress and changes in 3alpha,5alpha-reduced neurosteroids has been reported. Steroid 5alpha-Reductase (5alpha-R) is the rate-limiting enzyme in the biosynthesis of 3alpha,5alpha-reduced neurosteroids. Using reverse transcription-polymerase chain reaction and immunohistochemistry, 5alpha-R isozymes (5alpha-R1 and 5alpha-R2) mRNA and protein levels were detected in prefrontal cortex of male and female rats after they underwent environmental stresses, i.e., excessive heat, artificial light, and the sensation of immobility in a small space, similar to those found in common workplace situations. Results showed significantly higher 5alpha-R2 mRNA and protein levels in environmentally-stressed versus control rats. Interestingly, a sexual dimorphism in 5alpha-R1 mRNA and protein levels was observed after environmental stress, with an increase in males and a decrease in females. This fact might explain gender differences in the incidence of some type of minor depression.

https://www.ncbi.nlm.nih.gov/pubmed/19615370

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Great thread, Sibelio. Bookmarked for future reference.

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S…should I travel to Wuhan?

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@Sibelio I really thank you for all of your findings I’m to much of a dumb ass these days to even comprehend this stuff but thanks for doing research

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Thanks for the papers.

I´ve not really been exercising for the last 2 months actually, just some pushups here and there. After a lifetime of chronic exercising. Been really sedentary, and even though I have been improving my condition, I feel like no exercise hasn’t really been serving me well. I’m thinking about starting up again, but not like I was doing in the past. I used to do a 2-split, 6 days a week, high reps; 20-30 reps, 3 sets, and 3 exercises each time. It always left me feeling exhausted, irritable and with worse brain fog/head pressure. Seemed like it increased a stress/estrogenic response, and I tried “forcing” it through hoping it would get better, but it never did and I just decided I’m not going lift more weights for a while.

But yeah, I think movement is crucial, and I think I will try doing less but heavier, accompanied by more walking outside to get sun/daylight. Maybe just 1 exercise pr day, 3 sets of 10.
For example:
Day 1: Dips 3x10. Walking.
Day 2: Barbell rows 3x10. Walking.
Day 3: Sumodeadlift 3x5-8. Walking.
Repeat.

I think for me at this point, a stronger “androgenic stimulus” is needed to really activate more androgen receptors or increase their expression… this is what my intuition tells me, and a sedentary/mostly housebound lifestyle is not cutting it. Exercise clearly increases 5-ar levels and DHT, but does this equal increased AR expression? I would guess it does… My current theory is that retinoic acid is somehow attached to the AR, or a retinoic acid receptor nearby, effectively antagonizing/inhibiting DHT from attaching to the AR and expressing it. So it wouldn’t matter if I just increased DHT through whatever means, if it doesn’t actually bind to the AR… but if RA and DHT competes for the same receptors, then increased DHT would perhaps increase the “pressure” on RA at the AR, and eventually if the “androgenic stimulus” is strong enough, force RA off of the receptors and remove it from the body.

Well, I might be wrong on this lol, but this what I’m thinking now anyway.

https://www.ncbi.nlm.nih.gov/pubmed/12457868
Down-regulation of androgen receptor expression and inhibition of lacrimal gland cell proliferation by retinoic acid.

"Androgens and retinoids are known to be involved in control of lacrimal gland function. Because retinoids generally antagonize androgen function it was the purpose of this study to investigate interactions of retinoic acid and androgens in rabbit lacrimal acinar cells in culture by determining effects of retinoic acid on androgen receptor (AR) mRNA expression, AR protein levels and androgen-stimulated cell proliferation. Experiments were conducted using primary rabbit lacrimal acinar cells and a transformed rabbit lacrimal acinar cell line. Exposure of primary lacrimal acinar cells in culture to 10(-10)-10(-6)M all-trans retinoic acid for 4-24hr causes an approximately 50% decrease in AR mRNA expression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367184/
“RA and androgen responsive elements (RARE and ARE) were mapped to the hTGP promoter by chromatin immunoprecipitation (ChIP), which also indicated that the active ARE and RARE sites were adjacent, suggesting that the antagonistic effect of androgen and RA is related to the relative position of binding sites.”

https://iovs.arvojournals.org/article.aspx?articleid=2412497
Retinoic Acid Inhibits Androgen-Stimulated Up-Regulation of Androgen Receptor Expression in Lacrimal Glands of Orchiectomized Rats

For me, the things I clearly feel the most dopaminergic/androgenic from doing is: approaching girls, and camping in nature (but I also feel worse and crash from them). Lifting weights doesn’t come close to those, but there is probably a cumulative positive effect in the long-term from doing the right type of training. I´ll ponder this a little more, but the high rep, high lactic acid/time under tension training definitely makes me worse.

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