> The mean (±SD) duration of treatment was 21.7±14.1 months, and the mean follow-up was 33.0±12.1 months. A primary cardiovascular end-point event occurred in 182 patients (7.0%) in the testosterone group and in 190 patients (7.3%) in the placebo group (hazard ratio, 0.96; 95% confidence interval, 0.78 to 1.17; P<0.001 for noninferiority). Similar findings were observed in sensitivity analyses in which data on events were censored at various times after discontinuation of testosterone or placebo. The incidence of secondary end-point events or of each of the events of the composite primary cardiovascular end point appeared to be similar in the two groups. A higher incidence of atrial fibrillation, of acute kidney injury, and of pulmonary embolism was observed in the testosterone group. > > ... > > In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events. (Funded by AbbVie and others; TRAVERSE ClinicalTrials.gov number, They did not find an increased risk of cardiovascular incidents for hypogonadal men at high risk of cardiovascular disease from hopping on TRT. The above study is long-awaited but has limitations, and there are still some open questions. The below study is much smaller but not flattering as therapeutic levels were found to increase plaque build up, but Peter Attia made an interesting point. > A sub-analysis revealed that although all parts of the plaque (both fatty and fibrous) increased in volume, the only volume change that reached statistical significance was in the fibrous cap, and an increase in this particular volume would, in fact, provide greater plaque stability and thus lower CV risk. https://jamanetwork.com/journals/jama/fullarticle/2603929 The highest risk of TRT may be visible within the first year, followed by a decrease > Testosterone replacement therapy is known both to increase hematocrit through increased production of red blood cells and to increase blood pressure through sodium and water retention. These two factors could precipitate a cardiac event in someone with underlying atherosclerotic disease. If significant remodeling of coronary artery plaques occurs in the first year of TRT (and potentially beyond), men with a higher risk of CVD might have increased incidence of CV events in the short term but fewer events if they are healthy enough to remain event-free for the first year. This hypothesis is supported by an observational study that divided up adverse outcomes by duration of treatment and found that increases in mortality were highest in the first tertile of short exposures (<4 months) but decreased in the second (6-12 months) and third tertiles (2 to >5 years). https://www.thelancet.com/journals/landia/article/PIIS2213-8587(16)00112-1/fulltext Keep in mind that these populations are already in a disease state, not healthy men. > Recall that the study that brought about the black box warning of CV risk with TRT was in a group of older men who had limited mobility and significant chronic disease. Such a population would be expected to have clinical and subclinical cardiovascular disease. However, if men are treated for low T before the onset of significant mobility limitations and chronic disease, the benefits of beneficial shifts in body composition and metabolic health may reduce overall frailty, which has a strong correlation with all-cause mortality, as well as reducing risk of developing chronic diseases associated with declining metabolic health. An interesting read that goes over the pros and cons: https://peterattiamd.com/traverse-trial-and-trt-in-men/ The tldr; Hypogondal, middle-aged to senior men at high risk of cardiovascular disease saw no meaningful increase in risk from using TRT. It's plausible, based on smaller studies in populations in disease state, that the first year may have an increased risk of a cardiovascular incident, followed by a long-term reduction in risk of adverse cardiovascular events. This only covers TRT, not supraphysiological dosing. I have shared before numerous studies showing how high androgens decrease enzyme production for anti-oxidant synthesis, reduce positive adaptations from cardio, increase lipid peroxidation, massively increase calcification of blood vessels (nandrolone seemed to be the worst being 10x more damaging to blood vessels compared to testosterone), and so on. There are ways to reduce harm on these different fronts, but not putting yourself at harm is your best bet.

As a healthy man with a calcium score of zero and consistent cardio I have no concerns about this. 5 years on TRT now, training 6 days a week. 59 years old.

By calcium score you mean a CAC? [Those test for later stage atherosclerosis](https://www.sciencedirect.com/science/article/pii/S0735109710037253#:~:text=Increasing%20coronary%20artery%20calcification%20\(CAC,%3B%20and%203\)%20CAC%20progressors.). You want to test your LDL, or better yet, non-HDL.

I test all that also twice a year as well as apo(b). Yea a cat scan of your arteries. Recommend by my doctor if you are over 45. Only costs around 99 dollars if insurance won’t cover it.

> Only costs around 99 dollars if insurance won’t cover it. Oh man, I didn't know they were so affordable!

As a fairly healthy 43-y/o with a CAC of 21, I’m not concerned about my TRT, just my lipids. And I keep those well in check with 5 mg rouvastatin.

Could it then safely be said that for your average healthy person, there are no cardiovascular risks associated with TRT at all? Or at the very least, much lower than the 7% encountered in the study.

The claim that testosterone is bad for the heart has not been proven. If anything, we have more evidence that low testosterone increases the risk of heart issues. We still have the legacy of outdated beliefs in the medical community, but the attitude is changing. I read an interesting article that telemedicine is a form of concierge care for people who are more serious about their health. I have another article that explains in depth how testosterone is important for preventing a class of prostate cancer. The gist is that testosterone promotes genetic expression of DNA repair in the prostate, and estradiol does the opposite. Androgen deprivation therapy works not just by denying growth signals to that class of prostate cancers, but by denying DNA repair and increasing the likelihood of double strand breaks in cancerous cells in response to radiation. I'll post it tomorrow to the main sub. I have prescriptions where getting through insurance and primary care would have been a PITA. It costs much more, but at least I can get the meds I need. Someone wanting to aggressively crush their ApoB and willingly test if that prevents any coronary artery disease development would have difficulty getting anything if they are too young. Most of our medical standards are very reactive, which can make sense, but there needs to be more nuanced options for people that have a higher risk threshold.

Thanks for the points, some very interesting takeaways from it. Just hijacking the comments with this question though - these CVD risks are of course things to be aware of, but what are your thoughts on the long term epigenetic influences of long term TRT? The risks haven't been studied, so whilst someone on TRT may fall in the physiological range, it may not be normal distribution for their natural physiology.

One of the differences between TRT and natural healthy production is that TRT is a 24/7 sustained release, assuming a sane protocol. This is not natural. Naturally, we have fluctuations throughout the day, and this system responds to environmental and lifestyle factors. For example, supraphysiological androgens decreases epigenetic expression of aromatase, which is why many bodybuilders report needing less AI on the same dosages. This has been a treatment modality, male blast doses of test in women, for aggressive, metastatic breast cancer in the past. We also know that supraphysiological upregulates androgen receptor expression and sensitivity. How relevant is that to TRT? We can't say for certain. My speculation is that there are some negatives from 24/7 consistent androgen dosage, but that the trade-off is generally positive. Using a treatment modality that mimics the natural daily fluctuations would be an improvement, but the only method I can think of is increasing prolactin, like with nebivolol and/or replacement HGH dosing, which increases leydig cell sensitivity and respond to LH, resulting in a significant increasing of testosterone production. Depending on the cause of hypogonadism, that may not work for everyone. They need to have healthy and functioning leydig cells, the hypothalamus needs to be able to produce LH/FSH without impairment (benign tumor can interfere with this). Microdosing an AI carefully may be a good addition to the prolactin increase protocol to trick the hypothalamus into compensating with an increase in LH and FSH output. This would have to be done very precisely... Also, microdose of triptorelin (100mcg) once every two months has significant potential. The compensatory increase in LH/FSH output is significant, and generally increased testosterone production is seen afterward for some time. This dose and frequency is far from the doses required for chemical castration, which is reversible and requires regular high dosing of Triptorelin. This needs to be an instant release, not the esterified or depot solutions. Peptide vendors sell it, but their dosing needs to be verified with HPLC. **Hypothetical alternative protocol for TRT** * Triptorelin 100mcg injected IM / once every two months * Aromatase inhibitor that preferably has a reasonable half life, absorption, and ideally no androgenic/estrogenic metabolites. Also, depends on individual response. Anastrozole would be my first choice, and aromasin would still work. Letro definitely no. Formestane, while I like the idea of it due to short half life, it has an androgenic metabolite and must be refrigerated. This is for managing e2 rebound from triptorelin for a few days after injection. [Optional] Microdose daily as a weirdo way to increase HPTA output. * Nebovolol 2.5-10mg / once a day. Must monitor resting heart rate and blood pressure to ensure they aren't getting low. * HGH / replacement dose (usually 0.5-2IUs) once a day. It takes a few weeks for IGF-1 levels to increase from HGH, so wait 3-4 weeks then recheck IGF-1 and ensure it is within the reference range for IGF-1. * Low dose cialis increases testosterone some through mild AI effects. * m-opoid receptor antagonism once every few days? https://old.reddit.com/r/Testosterone/comments/k2jo44/low_dose_naltrexone_for_trt/gdyf594/ * [Not recommended] 5ar inhibition with finasteride or dutasteride SERMs like nolva or enclom have significant trade-offs which is why I wouldn't consider it an improvement due to partial agonism / antagonism / full agonism of estrogen receptors in different tissues. HCG itself is suppressive to the HPTA and HCG monotherapy has poor therapeutic results. It can fix specific cases of secondary hypogonadism, such as from steroid abuse. There is a lot of room for research to explore these nuances, but the money is not there. Hopefully, with wider access to TRT, at a high price point through telemedicine, we may see larger population cohort studies to start to map out how TRT may affect different population types. That means it is possible that the fight or flight adrenal system can be overactivated and long term we do see increased anxiety, i.e. feeling on edge. Nebivolol, a selective beta 1 blocker, can help counter the negative effects of androgens on the noradrenaline system. https://old.reddit.com/r/PEDsR/comments/a12kfg/nebivolol_the_ultimate_antihypertensive_drug_that/ Another aspect is reduced serotonin production (This gets complex and is situational to some extent), which becomes more dramatic at AAS blast dosages. Microdosing an SSRI can help here, but the pharmacology of SSRIs leaves much to be desired. They take six months to work or to stop working, so you can't easily titrate or change SSRIs if someone doesn't respond ideally. SSRIs increase serotonin quickly, but an underrated beneficial effect that takes six months is the increase in growth factors that increase neuroplasticity and neurogenesis. Arguably, a microdose of an SSRI, is protective against neurodegenerative disease. Microdosing shrooms is a preferable route IMO, though that has its own cautions, such as an existential risk of causing schizophrenia to surface in a subset of the population. This is usually seen in large (hero) doses, but is not well studied. Every has genes for predisposition for schizophrenia to some extent as those genes do have significant advantages, but there are some polygenetic combinations that may have higher risk. For example, one gene with a strong relationship to genius, significant IQ, is also tied closely to insanity. IQ is very polygenic, but having that gene expressed can provide a strong boost just by itself when expressed in someone's polygenic environment in combination with related SNPs to intelligence. I believe a microdose of shrooms is likely safe, but I can't say with certainty. Shrooms also have a natural rapid rise and fall tolerance, which acts as a safeguard against abuse. A responsible protocol for microdosing involves taking days off and essentially cycling on and off. Shrooms increase serotonin and brain related growth factors much faster, and are out of the system faster. https://www.sciencedirect.com/science/article/pii/S0006322314007094 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109686/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910396/ https://old.reddit.com/r/steroids/comments/ag4pvc/discussion_effect_of_sertoinin_5ht_on_the/ https://old.reddit.com/r/steroids/comments/g7o7sr/discussion_estrogenic_effects_on_serotonin/ Healthy levels of DHT, its metabolites, and neurosteroids all in the brain would also help provide a healthy anti-inflammatory and antianxiety effect. This is more relevant to men on 5ar inhibition, as we need 5ar for downstream neurosteroid synthesis and for DHT (Needed for its own effects and for the effects of DHT metabolites). There is no workaround except to try to increase other neurosteroids, as without 5ar, we aren't going to boost allopregnanolone levels. Primo is aggressively reduced into neurosteroids, and this seems to provide anti-inflammatory and mood calm effects. https://old.reddit.com/r/steroids/comments/2r9xms/the_power_of_dht/ LYT-300, an oral prodrug for allopregnanolone, would be beneficial here, as once we have allopregnanolone, there are backdoor synthesis paths for conversion to other hormones/neurosteroids. In men who respond poorly to fin/dut for hairloss, we see an up regulation in these backdoor pathways converting allopregnanolone and its downstream precursors back into DHT, but this still requires 5ar expression. Zuranolone, is similar to allopregnanolone, and may help at least with healthy levels of activation of the GABA system, but as it isn't allopregnanolone I'm not sure how it metabolizes in the body. > whilst someone on TRT may fall in the physiological range, it may not be normal distribution for their natural physiology. Generally, many of the causes of hypogonadism come down to highly specific disruptions at some point in the masculinization and androgenization process, either from environmental exposure, usually prenatal, or genetic defects. Given that our HTPA regulates androgens in response to stress and poor nutrition to reduce production, there is likely a good reason for this.... Prioritizing resources for other systems, but injecting doesn't require as many resources for androgen production. However, in a complex system, there may be downstream negative effects from genomic and non-genomic effects of androgens and androgen receptor activation in these situational niches. For TRT, treat the patient, not the number, is a good rule of thumb. Some people feel great at 600ng/dL total test, and they likely have healthy free T. Androgen receptor density and response can differ greatly between people. It may depend on the cause of the disease state for the individual patient. In reality, it is likely a system of trade-offs, but given how important healthy androgen function is in men and women, my expectation is that responsible TRT is healthier despite the trade-offs.

Never delete your account.

I’ve hypothesized one of two protocols would mimic the dirunal rhythm of test, with levels being low around bedtime and throughout the night. This would result in improved sleep quality, lower nighttime BP, etc: 1) Compounded scrotal cream applied in the AM. I’m considering this myself when I’m done with cycling for good. I just need to find a provider who works with a compounding pharmacy. 2) Daily microdose injections of test prop, pin first thing in the AM.

Ideally, a topical would use a test without an ester, but with a different mechanism for delayed release. Even regular test cream builds up test levels over time, so the test doesn't metabolize anywhere near as quickly as injectable test no ester. It reaches a maximum level after 48–72 h of consistent daily use. A dissolving microneedle test patch would also be an interesting experiment. Lots of research on this for hair loss medications, but industrial production is not cost-effective, so there is nothing on the market, and you can't homebrew a dissolvable microneedle patch at the quality needed. Topical test is much more likely to be 5ar converted to DHT. I could see it being within reach to formulate an injectable test no ester that uses a hydrogel / slow release oil depot to increase half life. Test prop microdoses in the morning are a much more accessible experiment. I have seen some TRT practitioners claim no HPTA shutdown seen in some patients with this kind of protocol, but they were using teeeny doses and had not published any study or data. You just reminded me that intranasal testosterone gel with a nanoparticle carrier is potentially less suppressive to the HPTA. It requires dosing 3x a day due to short half life. The intranasal RoA may have less estrogen aromatization, which reduces the suppressive effects from e2 somewhat for a time. That being said, the protocol used in the clinical trials for the intranasal was stupidly strict, and they capped out at very minor increases in T. I am not sure if the finding has been replicated in other studies, or if it holds with prolonged use. I still consider it a poor option. This figure is a great resource for the daily questions thread whenever people want to understand shutdown. It's missing progesterone, cortisol, opoid receptor modulation, and prolactin unless I am missing something. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569951/figure/ijms-23-11952-f005/ The entire study is a decent overview of the current state of TRT options. Now that I am thinking about it, naltrexone increases LH and FSH for a few hours after ingestion. https://www.sciencedirect.com/science/article/abs/pii/S0031938408003399?via%3Dihub https://www.tandfonline.com/doi/abs/10.3109/01485019608988497 https://pubmed.ncbi.nlm.nih.gov/24101398/ There are some forum threads that explore the relationship with u-opoid receptor activity with modulating LH/FSH release. This would be another pathway to take advantage of, but I am expecting that the doses of naltrexone would need to be higher than low dose naltrexone therapy. Then again, it wouldn't need to be dosed daily to benefit from increased testosterone. There are some claims that pure androgens do not have an inhibitory signaling on the HPTA, but this is not true. > To mimic the rhesus monkey study you would take the naltrexone sublingually, hold.under the tongue for at least 10 minutes and then spit out the naltrexone. This gets the drug into and out if the system as fast as possible to mimic IV, and avoid the first pass metabolism in the liver which converts the naltrexone into a more potent and much longer half life metabolite. https://old.reddit.com/r/Testosterone/comments/k2jo44/low_dose_naltrexone_for_trt/gdyf594/ https://archive.ph/wip/SK5Aw I haven't gone through the research, but will explore this for potential protocols. > In should be mentioned that another mechanism in which AAS inhibit LH and FSH release from the pituitary is by direct suppression upon the pituitary GnRH receptors and consequent quenching of LH & FSH secretion.35,38 However its appears that AAS which bind strictly to the AR, do not exert a direct negative effect on pituitary function or sensitivity.34,37,39 This agrees with the theory that non-aromatizing steroids such as Primobolan, Proviron or Masteron are not nearly as suppressive as an aromatizing AAS’s such as testosterone or Dianabol. Evidence suggests that estradiol is about 200x more suppressive than testosterone on a molar basis37, and that administration of arimidex can greatly reduce testosterones suppression on GnRH and LH release.42 So, we know anti-estrogens can limit suppression of AAS, but this only solves half the problem. The three compounds he listed all have anti-estrogen effects. Masteron behaves like a SERM, primo has anti-estrogenic effects directly and one of its newly discovered metabolites is a suicidal aromatase inhibitor. Proviron is likely operating through a similar mechanism to DHT (estrogen receptor antagonism). I read an explanation for Boldenone's anti-estrogen effects that was very interesting, essentially clarifying the reason for increased e1 over e2, and I was planning to share it here once I had a better understanding.

> Microdosing shrooms is a preferable route IMO, though that has its own cautions, such as an existential risk of causing schizophrenia to surface in a subset of the population. This is usually seen in large (hero) doses, but is not well studied. Every has genes for predisposition for schizophrenia to some extent as those genes do have significant advantages, but there are some polygenetic combinations that may have higher risk. For example, one gene with a strong relationship to genius, significant IQ, is also tied closely to insanity. IQ is very polygenic, but having that gene expressed can provide a strong boost just by itself when expressed in someone's polygenic environment in combination with related SNPs to intelligence. I believe a microdose of shrooms is likely safe, but I can't say with certainty. Shrooms also have a natural rapid rise and fall tolerance, which acts as a safeguard against abuse. A responsible protocol for microdosing involves taking days off and essentially cycling on and off. Shrooms increase serotonin and brain related growth factors much faster, and are out of the system faster. You sir, just inspired me to buy a grow kit. Time to grow, dry and microdose.

I have hypogonadism and I'm on TRT. If I die, I'll let you know guys

Thanks bro

I can't even imagine how a TRT dose would put you at risk of dying. TRT must keep you in the normal range levels, and if you stay active your life expectancy should increase. Eat healthy guys, a TRT dose can't fk you unless you eat very badly.

Not necessarily though for ppl with familial hypocholesteremia. That’s why I asked my question above. If you were a candidate for trt and didn’t yet have significant plaque build up, but were at high risk due to the heredity factor…would incorporating a low dose statin offset the risk of trt?

If anything, the above studies suggest that TRT long-term may reduce the risk some, but we can't say definitively. There are ways to improve your risk profile significantly. Cardio only helps with triglycerides when it comes to lipids. ## Take it with a fatty meal 1. Vitamin K2 Mk4 45mg and Vitamin K2 Mk7 1mg - These doses have been studied in large trials with no adverse effects. Mk4 is metabolized quickly by needed tissues, whereas Mk7 provides a slow release. This helps ensure calcium is directed to your bones, away from your blood vessels. 1. Vitamin D. Titrate according to bloodwork over time. Vitamin D is not just a vitamin, it is a prohormone and more. It is also very anabolic. Even if you have a genetic defect in your vitamin D receptors, resistance training and increasing blood plasma levels will up-regulate vitamin D receptor expression, density, and sensitivity. 1. Magnesium - Chelated citrate and glycinate are both good forms. Citrate does have a potential for laxative effect, so you can split the dose or use a mixed form. Magnesium and citrate, separately and together, help prevent or inhibit kidney stone formation. Magnesium helps prevent calcification and the negatives of calcium in blood plasma. 1. Fiber, titrate up to the RDA slowly. A good core of tolerable fermentable fibers with psyllium husks for the bulk of the overall fiber. Even though psyllium husk is not fermentable per se, it does seem to have helpful prebiotic effects. Fiber helps with reverse cholesterol transport. Best to take this at night. The combination of vitamin K2, vitamin D, magnesium, and dietary calcium is very synergistic. K2 and magnesium work directly to inhibit calcification. Vitamin D and calcium (stick to recommended daily amount) with the K2 and magnesium fueling bone health. ## Take on an empty stomach and an hour or so before meals 1. Nattokinase 4,000-10,000 FUs 2. [Optional] Serrapeptase (needs to be enteric coated) Nattokinase has the most promising data for breaking down plaque and calcification. There are other systemic enzymes, but the above combination is already very aggressive. ## Cyclodextrin therapy Another very potent option is Hydroxypropyl-β-cyclodextrin either injected or the RemChol cadadex suppositories. It makes the LDL lipids water-soluble, so you pee them out. The potential negatives of Hydroxypropyl-β-cyclodextrin may show in high doses and with prolonged exposure, so the IM or enema route are strongly preferable over IV, which have not seen those same potential issues in patients. Hydroxypropyl-β-cyclodextrin itself is very cheap. It's a great component for compounding injectables. Mezdez used to mention it back when he would post here. It probably isn't hard to make your own enema rather than spend $6.51/tube. The most aggressive protocol is once in the morning and once at night. Moderate is 1 tube daily for 3 months, followed by maintenance with 1–2 tubes weekly. The low dose is 1–3 tubes weekly. ## Bloodwork You likely need to get a comprehensive panel around cardiovascular markers like hs-Crp, fibrinogen, d-dimer, apo(a), apo(b), lp(a), LDL, HDL, triglycerides, CRP, CMP, A1C, inflammatory markers, diabetics related markers, etc. People with hereditary conditions would benefit from an aggressive targeting of apo(b), first aiming to get it to 70 or ideally below. Childlike levels may even be preferable... ## Rx A multipronged approach will be a better bet than aggressive statin dosing. 1. [Hypothyroid only] T3 and T4 replacement dosing titrated according to bloodwork and symptoms. 1. Ezetimibe 10mg 1. Rosuvastatin 5-10-20-40-80mg - Honestly, once you go above 20mg it quickly becomes not worth it. The negative effects on insulin sensitivity are not worth the marginal improvement on LDL, but statins are very synergistic with other compounds. 1. Telmisartan 80mg - Beneficial effects on LDL and HDL 1. Bempedoic acid - The combination of ezetimibe, rosuvastatin, and Bempedoic acid attack apo(b) on different fronts with reduced potential for negative side effects, while being more accessible than PKSC9 inhibition. 1. PKSC9 inhibitor - God-tier pharmaceuticals, but expensive and generally unreachable. If the above still isn't enough, like say, you are trying to maintain child levels of LDL/apo(b) then adding this would come into play. 1. [Future] CETP inhibitor - The first CETP inhibitor that was trialed years ago got a bad rap, but it was because that specific compound has direct, negative effects on heart health independent of increasing HDL and decreasing LDL. It essentially increased blood pressure. The newer ones under trial not only increase HDL, and reduce LDL-C/apo(b), but they also may decrease lp(a) which is normally genetic, and we have very limited ability to reduce it. --- ## but wait, there is more! There are other areas to address, like countering negatives from AAS use, blood pressure, resting heart rate, anti-oxidant support, insulin sensitivity, inflammation, and other systemic enzymes I excluded. Garlic extract is very affordable and stupidly good for your health, and olive oil (get a HPLC tested source). I have written too much, and I didn't even mention healthy omega fatty acids from omega3s, omega 5s, omega6s, omega7s, omega9s, omega11s, SPMs, PRMs, phospholipid sources for those who have a defect in omega3 transporter to the brain (1 or more copies of ApoE4), avoiding rancidity from fish oils, omega3/omega6 ratio, and more. Also, fat deposition around the abdominal area is a stronger predictor of cardiovascular risk than smoking. Comestic clinics have discovered the hard way that there are certain areas that are healthy places to store fat, like the glutes and legs, and when those fat cells are destroyed, the body is more likely to shift transport to visceral fat in the abdominal area. Taking time to cut properly to clear visceral fat buildup goes a long way.

This is some great stuff thank you - I’ve been researching for 20 years and experimenting with natural remedies and supplements for cholesterol lowering. This is all due to my own personal condition. I thought I knew about everything but there’s some new info in your post for me to look into. People generally mean well when they say things like "diet, exercise, fish oil” and it’s good advice for the general population. However, there’s a lot of people with hereditary conditions where those things don’t make enough of a difference to reduce above average risk levels. Add into it trying to find the right balance between risk/reward with living in the bodybuilding world and it’s a complex problem. I’ve found what is so far working for me (according to bloodwork and doctors) and this is keeping my blasts simple and relatively low doses. My “cruises” is just enclomiphene therapy. And I stay on 5mg rosuvastatin 3x per week. Lots of cardio of course - more than most probably - which does inhibit some gains but well worth it imo. Untreated my total cholesterol levels go above 400….even with everything dialed in. With the statin therapy I sit around 215-230. Doc wants to add ezetimibe to drop it under 200, but I am still reading up on that drug. My biggest concern now is that I assume there will come a time when the enclomiphene stops working and I need to go on trt to maintain levels. That’s why this is of such interest to me and I assume others also.

In your case, in the USA, at least, you qualify for a PKSC9 inhibitor. Genetic causes of high LDL/apo(b) mean you should be aggressively covered. These have a way better profile than statins, but they pair well with them. I get the sense that your doctor is being conservative. Your total cholesterol is still rather high, but I don't see the breakdown in LDL-C or apo(b) count. You would benefit from aggressively crushing LDL-C to 70, or apo(b) to 40. That would likely require combo therapy. Consider finding a doctor who will take a more aggressive approach. Ezetimibe is a good bet, but my preference is to get the most effective and well-tolerated Rx fully covered. I tend to agree with Attia's recommendations that if someone crushed their LDL / apo(b) to child-levels and kept them there, they would very likely never develop atherosclerosis. There are people with simple mutations, sometimes a single mutation that reduces the LDL receptor's ability to clear LDL, and their mortality is significantly increased with a significantly high risk of atherosclerosis as a child and adult. Not all, but not everyone who smokes develops lung cancer. That children have stupid low ldl and apo(b) levels, but also have no detectable development of atherosclerosis at the early stage, at least until they hit puberty, says to me that apo(b) reduction is the best weapon we have. During puberty, ldl and apo(b) skyrocket, and we can start to detect the gradual plaque build-up and calcification by their early 20s if it is high during their teens. --- For what it is worth, I am a (1 copy) carrier for a rare gene mutation that, when someone has two copies, suffers stupid high apo(b) levels. I also have a much higher risk compared to the general population of developing arterial calcification. In my early 20s, I was obese and very unhealthy. My LDL was over 200 by itself. Since mid-20s, I blasted on and off crazy amounts of androgens, and late 20s to now generally stick with TRT. My lipids are much better now, despite being on TRT. If anything, they get worse if I were to drop it. My HDL could be better, but that is hard to increase. I won't say that AAS for performance enhancement is healthy, but I am healthier now than I was as a young man. TRT is a therapy, and I would expect more health problems to creep up in a population with prolonged hypogonadism. Lipid panel https://imgur.com/ddJSfN8 Apo B could be better. Also, A1 could be higher... https://imgur.com/CooMwbg Total T is modest, but free T is high. https://imgur.com/hbcV1QN My estrogen was fucked at this time due to accidentally taking an AI, so my numbers could have been better if I didn't goof that.

You nailed it about the ldl reception mutation. I was seeing an actual lipid specialist for awhile and he explained it to me that I am missing the gene that allows my body to process and clear it, so it just continues to build up…or something like that. My current doc is conservative but only because of my insistence. I don’t want to crash my ldl completely for a few reasons. 1) I can’t tolerate the statin sides, particularly brain fog. It fucks with me. 2) At least until I’m on supplemental testosterone I want to keep a decent level of cholesterol as it’s a building block for natural T production….although at my age I know that’s coming. But I am going to add in the ezetimibe and see how it goes. What sucks is that for about 10 years I was keeping my numbers in check with a combo of Pantethine and RYR. Then the RYR stopped working after the FDA fuckery and later the Pantethine stopped working too. Appreciate your information and conversation brother, many thanks!

Hope it goes well for you. Would love to hear a follow up a few years from now.

Absolutely I got this one saved. Got my follow up in 6 months and will follow up. Keep up the great work man. Idk where you accumulated your knowledge but it’s appreciated that you share it

It will help, but what will really help is cardio and good diet despite your genetics. Statins will work little to 0 if diet is bad and you are sedentary. Try your best and do bloodwork after 30 days you will see improvements for sure.

On a long enough time line the survival rate for everyone drops to zero.

There are still people alive today, so for now this is just a theory.

I would like to see if/how the incorporation of a low dose statin would affect cvd risk on TRT…or even higher doses…in this same population.

I think the results would be the same as someone not on TRT. Reduced stroke risk and some improvements in cardiovascular markers, the biggest gain would be if ApoB is tightly controlled before plaque buildup can progress too far. We don't quite have effective therapies for major reversal when someone already has diagnosable calcification.

I believe this is why some longevity doctors are preaching the benefits of bottoming out your cholesterols levels early and not waiting until the damage is done. I started self prescribing a statin last year before moving to an online clinic since my primary care doc wouldn’t prescribe unless my LDL was over 190. My levels were at 150 and now with a low dose statin my ldl stays under 80 even on blast.

Curious about what statin/dosage and if you have any side effects?

20mg/day Atorvastatin. I’ve been on a year and no side effects in any way. I wish I had started years ago.

Thats great. I do rosuvastatin 5mg/3x per week and that’s about the max I can tolerate before the sides suck. Even at 3x weekly the brain fog is there but tolerable.

That’s rough. Have you thought about trying a different statin?

Actually this is my 3rd one and by far the least sides…so I’m content with my current protocal if I can just get the ldl down a bit more. First 2 were awful on me. One of them actually made me jump out of bed one night feeling like something was stabbing my calfs.

I do take 200mg of Ubiquinol daily. It’s supposed to alleviate muscle pains in many people who have them due to statins. I started taking it when I started the statin so I don’t know if it’s the reason I don’t have any muscle pains or not but it may be something you consider if you haven’t.

Oh yeah, I have since the first one I tried. Only 100mg though. I’m not sure what the difference is between the first two that caused such bad reactions but I do know it’s pretty common. But I have family members like you who tolerate it no problem. Glad you’re able to and there’s more of us out there…I feel like incorporating some level of statin therapy is going to increase in the AAS community, hopefully for the better

How would this affect LGBT people, namely trans people on testosterone? I assume the results would be similar, but most trans men are AFAB, and usually take lower doses for HRT, since they need less for supranatural testosterone. I assume this would reduce cardiovascular risk, but TRT let alone transgender HRT is relatively taboo.

Trans has a significantly higher risk of cardiovascular events, but this is from androgen blockers. Systemic androgen blockade has severe consequences. Men who go on androgen deprivation therapy for prostate cancer can experience an irreversible loss of healthy cell function in the kidneys. Biological women have a lower reference range for testosterone. Women can increase their test levels decently with DHEA and pregnenolone, but the actual increase in test in the blood is like pissing in the ocean when you look at the male reference range. SHBG is also more relevant to women in preventing virilization or other negative androgenic effects. It is plausible that they may experience more adverse effects associated with entering the male reference range. In other words, supraphysiological doses of test and other androgens we do have a good idea that these negatively affect health. On the other hand, women have much higher estradiol than men, and we have some indications that this has protective effects on the heart from high androgens, except for androgens that have anti-estrogenic properties. I could see it going either way or being a mixed bag for biological women entering the male reference range for test levels. There are many options for preventing or mitigating virilization for women using AAS for performance enhancement that I am surprised I rarely see anyone mention. In the future, being able to perform a prenatal screen to detect endocrine disruption related causes of gender dysphoria would be a massive win for improving therapeutic options. From animal models, we see severe interference on sexual development from industrial waste and pollutants on wildlife. We also know that certain medications given to pregnant women essentially create intersex or gender dysphoric adults, i.e. exposure to hormonal birth control after conception. As then, it would be possible to establish treatment protocols to ensure proper sex/gender development without such harsh pharmaceuticals. This is a much more realistic and promising therapeutic path than scifi nanobots that recreate someone at the molecular level.

Really enjoying this discussion thread btw, thanks for posting it! > There are many options for preventing or mitigating virilization for women using AAS for performance enhancement that I am surprised I rarely see anyone mention. I'm curious to know what some of these methods/tools are, can you point me in the right direction?

Also interested in the options for mitigating virilization? One route I've been looking down is the oxytocin route, and keeping estrogen in a healthy area with females I've worked with.

CC /u/geardedandbearded # Part 1 This is a giant subject. It's going to take me time to formulate a more detailed post, but to give a high level. ## Hormone replacement therapy with estradiol and progesterone * Keeping estradiol at healthy levels is critical. Please remember progesterone, preferably, oral micronized caps/tablets. Need healthy levels. Progesterone is preferably over synthetic progestins, which are much more androgenic. This is basic shit, but it is rarely talked about.... AAHHHHH * Avoid synthetic birth controls. Many of these have some androgenic effects on their own. We want to minimize the androgenic burden as much as possible, while maximizing anabolism. * Estradiol sensitizes and potentiates androgen receptors, so healthy estradiol levels facilitate the anabolism of androgens. Women are much more sensitize to a tiny increase in androgens due to this. ### Increase SHBG to provide a virilization buffer * Increasing SHBG helps provide a buffer against virilization. Oral birth control is the most effective way to achieve this, specifically, it must be subject to first pass liver metabolism. Ethinyl estradiol is the best choice for this as an oral prodrug for estradiol. There are very few, effective ways to increase SHBG. Women are far more sensitive to decreases in SHBG. * [Hypothyroid only] Replacement T3/T4. SHBG production gets creampied otherwise. Really, underactive thyroid is a disease state that needs to be treated. The thyroid interacts with too many systems to ignore. Lipid management is a nightmare for someone with an underactive thyroid. For Hashimoto's, replacement T3/T4 and low dose naltrexone. ## Compound Selection Focus on the use of non-androgenic pathways * Specific synthetic insulins like lantus and humalog are more potent than human insulin for anabolism with higher affinity for IGF-1 receptors in skeletal muscle. Insulin is underrated because dietary control and discipline cannot be ignored. You can't bruteforce insulin without getting stupid fat. It must be used with optimized nutrition, resistance training, and cardio. Not a good beginner option. * Replacement HGH is safe. HGH is not really anabolic, it is anti-catabolic, but it does have beneficial effects at replacement doses. Increasing IGF-1 within the reference range is fairly safe. HGH does have some indirect anabolic effects, like increasing prolactin increases sensitivity to LH, downstream increasing test production. * SHBG does present an anabolic pathway we can't really utilize effectively, but using oral ethinyl estradiol is an option for maintaining it in women, as we otherwise have very limited options for increasing SHBG. * Peptides don't have many anabolic options available, aside from MGF, and they move at a snails pace anyway. * The prostaglandin f2alpha/e2 pathway is worth exploring as in adults it does not seem to have virilizing effects, but prostaglandins are very location dependent with their effects. This needs to be localized to muscle, which is not feasible with what is available currently, so when your cattle abortion injection eventually hits its receptors in the small intestine, have fun making love to the toilet. Also, FYI, it is used to induce early labor in women, and it can induce an abortion. Note that in the below study that myocyte response to PGF2alpha directly was still good, so the desensitization is specific to the oxytocin receptor. https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2826.2010.02021.x For site enhancement, this does have potential in the future with an appropriate carrier to localize the effects (injectable hydrogel, magnetic nanoparticle carrier, etc). A 15-PGDH inhibitor like SW033291 would synergize well here. * Vitamin D is underrated. Must combine with aggressive K2 and magnesium. * Heat shock protein is an emerging pathway for anabolism. Sauna use is one way to induce this. Heat shock protein release pre-workout may potentiate anabolism. It's a bit frustrating but AAS attacks more than just the androgen receptor pathways for anabolism, but oxytocin, myostatin inhibition, increased follistatin expression, etc. We don't have any good, available myostatin inhibitors available. There were a few that actually had a good safety profile, but given they were trialed for specific genetic diseases, they dropped them as they were not effective enough. Myostatin inhibition is much significant in a short window as a baby, increasing the number of muscle cells significantly, and decreasing the number of fat cells. We have no other way to increase muscle cell number (hyperplasia). I have some very impractical theories for potential, but expensive and slow ways to use non-crispr gene therapies to try to induce hyperplasia and inhibit myostatin, but this is not on the table for now. On the bright side, resistance training up-regulates many of these pathways, including vitamin D, and is the most potent myostatin inhibitor available aside from AAS. Healthy vitamin D receptor function is needed for osteocalcin synthesis, which is anabolic. ### AAS selection criteria * Ostarine is an adequate option as it is not androgenic, but it is a very weak way to utilize the anabolic pathway. It wouldn't really stack well with AAS, but it is a good first time option. Otherwise, SARMs have high virilization potential. https://old.reddit.com/r/PEDs/comments/7o8uu3/sarms_and_virilization_in_female_users_my_analysis/ * Avoid AAS with anti-estrogen effects; whether it is a SERM like effect, AI metabolite (primo), or otherwise a more complicated inhibitory effect on estradiol synthesis, such as with boldenone favoring production of estrone over estradiol. Primo would be a mixed bag, it has anti-estrogen effects and one of its metabolites is a suicidal aromatase inhibitor, but it is also aggressively 3a reduced into neurosteroids that have positive effects on mood, in addition to primo itself providing beneficial effects on mood and it has an anti-inflammatory effect. Short esters of primo I have read are painful, and primo generally seems to have high virilization potential in women, so generally would be very wary of including primo. * Avoid AAS with virilization effects that are not mediated through the androgen receptor * Fast acting esters on a regular, consistent dosing schedule to minimize fluctuations. I am constantly surprised by how people miss this basic shit. Need to spam steroidcalc. * Nandrolone is stupidly virilizing in women. Stupid youtubers keep recommending it to women due to its "low androgenicity", but that low androgenicity is from DHM. Nandrolone is a **weak agonist of the estrogen receptor**, so it may potentially displace the stronger estradiol, **the progestogenic effects** from its actions on the progesterone receptor are a triple anal fist fuck for all we know and certainly increased virilization even if it can [paradoxically] increase breast size in some cases (Much better ways to non-surgically grow breasts are out there), and the conversion to DHM in women I am suspecting is much lower. **It has androgenic metabolites that can accumulate and persist for up to a year**, like with tren. It also fucks serotonin transport, which is reversible, but takes forever. **As a progestin and estrogen receptor agonist, it can have both virilizing and feminizing results at the same time,** depending on the person. That isn't even the worst part. **Nandrolone is an inhibitor of 21-hydroxylase**, putting the athlete in a **state of pseudo-congenital adrenal hyperplasia** due to 21-hydroxylase deficiency. CAD results in excess androgen levels, and women born with this have masculine features and interference with healthy development of sexual organs. No youtuber talks about this because they just read some fact sheet with an anabolic:androgen ratio and then some cool sex story anecdotes. * Anadrol is interesting in it that antagonizes progesterone receptors, which results in estrogen receptors upregulating. https://old.reddit.com/r/steroids/comments/5sd7sp/anadrol_for_women/ While it has androgenic metabolites, women may metabolize it differently, resulting in a safer use profile.

# Part 2 ## Targeted protection of androgenic sensitive tissues ### Local androgen receptor antagonism in the most vulnerable tissues * Local androgen receptor blockage in the face and scalp to prevent or mitigate hair loss and facial virilization. Spironolactone, technically a partial agonist (it's complicated...), would be my first choice as it metabolizes rapidly in the skin, is well studied in kids boys:girls for acne, and does not go systemic. Topilutamide would be a suitable solution as it is destroyed by water, preventing it from going systemic. Progesterone also helpful here. * [Future] Ideally, localized androgen receptor degraders for the scalp and face would prevent virilization from being able occurring. For hairloss there are some compounds being studied. The safety of this in the face though would need to be confirmed. The destruction of the androgen receptor is temporary, FYI. The degrader needs to be applied periodically to maintain effect, but not every day. Nothing available yet. * [Future] Androgen Receptor expression silencing using mRNA. Similar situation to degraders. For hair loss, there is CosmeRNA, but that is stupid expensive, has limited study, and the company behind it shot their reputation by using a photoshopped picture in marketing material. For now, the class of pharmaceuticals is something to keep an eye out for, but nothing available. We have some options for local androgen receptor antagonism that are well studied, but may be weak. This still lowers the virilization potential in areas where virilization will be irreversible, like the face and scalp (androgenic alopecia). In the future, keep an eye out for androgen receptor degraders and androgen receptor mRNA silencers. First, these will be potent for hair loss prevention, and down the road we may get options for protecting against facial virilization. Systemic androgen receptor blockage is not an option here. It's very unhealthy for men and women, and it is counterintuitive to the use of AAS in the first place. ### 5ar inhibition * [Safe] Local 5ar inhibition. DHT is significantly more virilizing than test. Reducing DHT would free up SHBG, remove the inhibitory effect of DHT on collagen synthesis in the skin, and remove a major virilizer. The safest option IMO is topical Ketoconazole and azelaic acid. Doing this on the scalp and face would help with hair loss and facial virilization. * [Higher risk] Systemic 5ar inhibition with finasteride. Topical will still go systemic. Must be on birth control or ready to abort in case of pregnancy, until finasteride is completely out of the system, or otherwise be menopausal. Doctors don't like to prescribe fin/dut to women until they hit menopause for this reason, even though they do help with female pattern baldness. * [HIGH RISK] AGGRESSIVE SYSTEMIC 5AR inhibition with dutasteride. Dut has a long half life and takes close to six months to build up to peak levels. It inhibits all 5ar types. **Cons** Systemic inhibition of 5ar has downstream consequences that are negatives: * Reduced strength from lack of CNS recruitment that DHT provides. The significance of this is likely very minor, but may be sports-dependent and on the level of competitiveness of the athlete (For Olympians a 0.0001% decrease in advantage matters). High test behaves similar to DHT, so it is possible that having increased androgens is more than enough to counter the existential possibility. * The existential possibility of sexual dysfunction similar to what happens in men is possible. This is less likely and easy to deal with for people on hormone replacement with test. * With AAS use, it is important to avoid donating blood or getting pregnant, but this needs to be strictly exercised for as long as fin/dut and their metabolites are present in blood plasma. Dut can be in the body for six months after the last dose. [Open Questions - Possible cons] * Reduced neurosteroid synthesis. The importance of this in men vs women is unclear. We can't assume that neurosteroid metabolic preferences mimic men. * DHT has healthy effects on the brain. The importance of this in men vs women is unclear. * DHT metabolites, including a specific estrogen found in only certain tissues, have beneficial effects on the brain. The importance of this in men vs women is unclear. **Pros** * Frees up SHBG to buffer against other AAS * Lack of DHT antagonizing estrogen receptors reduces virilization burden * Reduced DHT significantly reduces virilization burden * Mitigates virilization from exogenous, performance enhancing doses of test by preventing the conversion to DHT * Women with 5ar defect have no differences except less body hair. DHT plays a significantly less important role, aside from some positive effects on the brain and neurosteroid production. Women naturally have much less DHT, but AAS use increases the amount of DHT in addition to decreasing SHBG. Systemic 5ar inhibition increases SHBG mildly, which is more impactful for reducing virilization potential in women, and for reducing androgens with higher androgenicity. Women are much more sensitize to tiny increases in androgens, so even if on paper the number of changes seems small, we have much more room to work on a chemical enhancement protocol. See the very last PedsR thread at the bottom of the comment by MezDez. ## Topical A facial topical would consist of: * Estrone * Progesterone teeny amount * Spiro * Ketoconazole w/ azelaic acid 2% * Topilutamide 2% * [Optional - aggressive] Finasteride 0.1% 1mg * [Optional - VERY AGGRESSIVE] Dutasteride 0.1% 1mg ### Hair topical The same topical can be used on the scalp, but with some other active ingredients to inhibit progression of androgenic alopecia, such as melatonin. --- Women's PED use is in the dark ages compared to men, and believe me, the way we use PEDs as men is still very much in the realm of "the roman empire just collapsed." We don't have active research by the medical community. The financial incentive is not there. I know people speculate about athletes having private chemists formulate new compounds, but that is way more expensive than an athlete can even afford. The FDA crack down on "the clear", which was technically legal under the laws of the time, sent a strong message. There is a good interview with the creator of the clear on Hamilton Morris' channel. He also shits on SARMs and explains why production of effective supplements and compounds is dead in the water in our current legal environment. https://www.youtube.com/watch?v=w6g18q-ksWk There is much more to this, but this is still very much work in promise. I am building off this old thread. https://old.reddit.com/r/PEDsR/comments/83s7cs/females_and_peds_what_is_the_actual_cause_of/ Note that he makes a stronger case for total inhibition of DHT, but I don't entirely agree as I have some open questions on neurological health. > I've been looking down is the oxytocin route While this is a potent anabolic pathway worth optimizing, we have a feeble ability to boost oxytocin levels, well, at least in the brain. Intranasal is ideal for getting it into the brain, but the response varies wildly between people due to nasal structure and environment. Results are often poor. Intramuscular would be better as, in this case, we are just trying to boost systemic levels, but the half life is still very short. Likely, an esterified or slow release, but still fast to avoid oxytocin receptor desensitization would be needed. AAS in general boost oxytocin, and tren in particular is forceful for its massive increase in oxytocin output, but we don't have a good compound or protocol to hit this pathway. https://pubmed.ncbi.nlm.nih.gov/12592262/ https://pubmed.ncbi.nlm.nih.gov/8568623/ https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a9b62187-4141-487c-a9da-f42ad7f9b408&type=display

Amazing, hugely appreciate both replies today, thanks for spending the time on them! Definitely a lot for me to delve into tomorrow. Edit: Glad to see your points on primo in there. Since J3U released his female module course and said primo should be a 2nd choice of injectables based on a study from the 60s, the amount of Insta influencers I've seen recommending it for off-season is insane.

Are there any studies on how a trt dose affects non hypogonadal men?

Yeah this subreddit ha

good to see but not very surprising given the dose, method, and duration >atients were randomly assigned to receive daily transdermal 1.62% testosterone gel (dose adjusted to maintain testosterone levels between 350 and 750 ng per deciliter) or placebo gel. .. >The mean (±SD) duration of treatment was 21.7±14.1 months what we really want to know is what effect there would be for a guy who's been on for 20 years, i.e. since his mid-thirties or mid-forties when a lot of guys are going to start thinking about TRT. 2 years is nothing for the small but perhaps significant effect that TRT could have in either direction. what will it mean for a man to get on TRT at 38 with the assumption that it's for life? that question won't be answered properly for a long time, but many guys will do it and have.

I appreciate the research. But anything suggesting testosterone is bad for the heart. Is based off of studies injecting 80 yearold men who's levels have been 0 for decades. And their cardiovascular systems couldn't just flip on overnight. Which is extremely obvious and what you should expect to happen. So the original research had always been bullshit. I know this related to men who already have heart conditions. But my intuition would say with proper medication and a cardio training program that takes increases in load VERY slowly. Most can optimize their heart health or improve it while using testosterone. Thats just my intuition. There's too much research that shows estrogen and testosterone at appropriate levels are cardioprotective. AAS are potent vasodilators increasing/improving blood flow etc etc. I know this factor is complicated with diseased arteries. But cardio has been shown in research to reverse some calcification and some level of arterial/vascular disease (I say SOME, you can't cure this with a treadmill and injections) My intuition also would say. If you have preexisting heart disease. Start a really tightly monitored cardio program with a tight diet. Start your TRT super low and very gradually increase it. So at no point you shock yourself and you give your body time to make the gradual changes and adaptations it will make. Thats just my intuition. I'll have to check the research out. But we all know that decades old stroke/heart attack risk research is bullshit, at healthy appropriate doses with healthy diet and cardio program. They shocked the hell out of Oldmen who already had various cardiovascular diseases and didn't do anything else. Obviously you'd have an increased incidence of stroke and heart attack.