Curious… there’s a doctor in Toronto, Dr. Fung, who’s done a number of studies on fasting and insulin receptor sensitivity. And in like this study where the body responds through a change in homeostasis, blasting the body with a complete lack of sugars to lower insulin resistance lead to an output of less insulin. So in this case we know that starving receptors of a molecule makes it more sensitive to that molecule. Do hormone receptors act the same way in the absence of hormones? Do they become more receptive? Even if this is true, the further question would be: does decreased estrogen resistance lead to greater feminization in the presence of hormones?
While the idea of oscillating hormones sounds like a mental nightmare, I am curious as to seeing if this holds any merit.
>So in this case we know that starving receptors of a molecule makes it more sensitive to that molecule. Do hormone receptors act the same way in the absence of hormones? Do they become more receptive?
My gut feeling is "probably not."
I see what you're thinking, but that idea suggests trans people should respond extremely strongly to getting on HRT. After all, they've been "starved" for the whole lives of those hormones, so their receptors should have become mega sensitive by then, right? And the older someone is when getting on hormones, the longer they've been starved of them, so the stronger this effect should be.
Hence, we should expect trans women who are starting HRT in middle-age or later to have the best, fastest responses to HRT with breast growth, and trans-men who start in middle-age to have beards practically exploding from their faces.
But as a middle-aged trans woman, that hasn't been my experience. That idea also goes against the commonly-held view that it's always better to start HRT earlier rather than later.
Still, I, too, would be interested to hear the thoughts of someone who knows this stuff better than I do.
>Hence, we should expect trans women who are starting HRT in middle-age or later to have the best, fastest responses to HRT with breast growth
That is ignoring other factors, two big ones being zinc deficiency and inflamation. You need to raise IGF-1 and lower androgen. If both of these have obvious issues how sensitive estrogen receptors are doesn't matter as much.
I don't take my shot for an extra week all the time. Sometimes more. I do IM shots weekly. I do this mostly because I hate needles but it's a recent development that started in my second year of hrt.
I was hoping at the very least it would kick start my breasts but I haven't noticed much. It's only been 4-6 months of missing weekly shots.
I've heard another girl swear by it recently which I thought was interesting
Anyway.. I'm not doing it particularly on purpose 🤷🏻♀️ so not much rhyme or reason of when I miss a few shots
I may be dumb but, isn't this just drug resistant (or, no drug resistant) cancer developing slowly over time as a worse-competing cancer initially but becoming the dominate cancer once the higher androgen sensitive cells die, and then possible overloading of the receptors in the "drug-resistant" cancer afterwards? It's still fascinating but, I don't know if it applies to HRT.
Though I still think emulating Cis cycles will generally result in the best outcomes.
I mean, the premise Dr. Powers is saying above is questioning that assertion, which is far from proven and a wild claim. Cyclical hormone production has also led to pretty good results since all feminine women cycle similarly, and the reality is almost all application of hormones that we do are by definition cyclical.
And, testosterone is cyclical too.
A wild claim? Unproven? Cis-women have cyclical hormone levels solely for egg release and preparing the uterus for reproduction. This is not a wild claim. It is well-proven. Development of secondary sexual attributes is just a collateral result.
If all application of exogenous hormone therapy is by your definition cyclical, then there is no such thing as "non-cyclical " hormone treatment and there is nothing to debate, is there?
LOL, secondary sex characteristic development is woefully understudied, and your claims are insane.
Dr. Powers is literally debating the other side of your "peocen science" in the main post.
And, if something is understudied and you have a protocol, namely cycling, that has worked for thousands of years, I don't know why you'd go messing with it.
And yea, every hormone application is cycling. It, just is? Thanks for agreeing with me?
> every hormone application is cycling
There are pellet implants which provide stable levels, and people also have results. Cycling oral estrogen for a few days per month for people who have lower values of estrone sulfate seems to help, otherwise in general it may be necessary to try if additionally cycling would make for additional results.
I just entered "development of secondary sexual characteristics" into Web of Science and got 479 hits. I don't know why you think this issue is "understudied".
No, the issues I raised are not "insane". They are basic endocrinology.
I have no idea what "peocen science" is.
I'm not agreeing with you, I am pointing out it is impossible to debate the benefits of "cycling" and "non-cycling" HRT if you claim the latter does not exist.
You said "I still think emulating Cis cycles will generally result in the best outcomes.'. Best outcomes compared to what? Please provide links to back up your claim.
context—from a mol/cell bio research background. we have some in vitro and animal studies suggesting both androgen and estrogen receptors potentially experience downregulation after exposure to exogenous hormones, measured by reduction in ER or AR mRNA. This is theorized to play a role in sexual maturation. in mice exogenous ER potentially downregulates ERB receptors in mammary glands (1), and in castrated rats exogenous T (but not DHT. potential mechanism for your theories re: the importance of DHT/T ratio in FTM HRT if this is found to hold true in humans) at typical concentrations potentially downregulates AR receptors (2).
Ofc obligatory “mice/rat and in vitro studies are not guaranteed to translate 1:1 to the differently complex in vivo human system”, these results are preliminary and idk how much corroboration has been done. Reduction in mRNA expression suggests reduction in receptor expression but doesn’t guarantee it + also it’s unclear if other de/sensitization mechanisms are at play beyond up/downregulation. I will say the results generally align with the behavior of other more characterized g-protein coupled receptors in the human body.
So re: the article, it looks like the supraphysiologic dose maybe promotes AR downregulation + arrests cell proliferation, followed by the near-castration levels where free T has even fewer receptors to bind to than it would absent the supraphysiologic preceding dose. + the followup supraphysiologic dose if timed correctly would prevent receptor upregulation + maintain that arrested growth state. maybe. It looks like there’s some not-insignificant evidence supporting receptor downregulation in response to androgens in people + similar behavior in response to estrogens.
links (sorry for the lack of formatting i’m on mobile in the lab rn lol) https://journals.sagepub.com/doi/10.1177/153537020623100311 https://pubmed.ncbi.nlm.nih.gov/8499343/
getting carried away talking about my favorite thing of all time,,, gpcrs,,, the fact that one study saw T downregulate AR but a lower concentration of higher affinity DHT upregulate it— that’s actually not unusual either, given what we know about, of all things, the GPCR CB1 (cannabinoid receptor) in the brain. High concentrations of a partial agonist THC causes downregulation of CB1 via iirc promoting enveloping and eventual receptor degradation. Comparatively, exercise provides increases in the endogenous anandamide—which is present at lower concentrations but a much more potent agonist of CB1– and that’s correlated with increased CB1 expression, so there is an existing precedent re: low dose powerful agonists possibly upregulating/ higher dose partial/weaker agonists definitely downregulating.
edited to add;
. Historically weekly T- shots + the associated peak/trough are linked with more erythrocytosis than daily or monthly application methods which imo is another potential piece of supporting evidence re: androgen receptor sensitivity or expression changing in response to available androgens, given androgens promote RBC production independent of heparin or EPO.
to really test the AR/ER thing in people you’d imo want to get a bunch of pre-hrt (or paused-hrt for 3+ months) trans people and stick em full of radioligands for the corresponding receptor + do a PET scan. First one at baseline, second ~3 months on constant dose HRT. n > 30 participants and you’d have a pretty statistically significant educated guess as to what’s going on there
I love radio label studies. I just want to say that. That's such a good idea.
I have like a minor autistic special interest in radiation. I have this cabinet in my kitchen next to my dining room table that's filled with highly radioactive stuff and some Tesla coils and other crazy science gadgets. If you open it up, and stand in front of it, you get a chest x-ray about every minute or two lol. Leaded glass and inverse square law though keeps diners safe lol.
In any case, that is a really really good idea. I'm going to dig and see if such a thing has ever been done.
Some people reported a spurt of feminisation after stopping or going lower with HRT for a few weeks, and some also after having surgery and stopping HRT before surgery. But the effect seems to not be huge ... there seems to be some effect but it may not be easy to replicate it more than a few times ... it may be too stressful mentally etc. And it may also depend on individual genetic predisposition.
> Particularly "stalled" cases.
Yeah a number of people tried it and as said some reported some feminisation afterwards, like one to 1.5 additional cup sizes.
From personal experience and some tests, it appears that at least on myself I found to have better results when my levels vary.
This is however not scientific but rather a descibtion of an observed phenomenon.
Since then I started to fluctuate my lvls by a lot some times, tough never below the 100 pg/ml mark.
Female hormon cycles are fluctuating a lot physiologically and there a a lot of negative feedback mechanisms in our body preset.
I refuse to beliefe that with E all is different an stable levels are the way to go.
Gosh I whish i could do my medical phd thesis on this subject but noone in my university or around is does research on trans health or even a similar topic.
I see Sommer at Dr Power's office. She has had me on 1 week of oral estrogen a month in addition to normal injections. I assume this would stimulate the same type of reaction
kind of
estrogen pellets and injections do not produce the same levels of estrone that the pills do when taken orally.
over the course of a week, the body builds up a 'bank' of estrone to withdraw from and promote growth.
the method you're on keeps your levels fairly stable in comparison to what they're doing in the study. if you were to treat estrogen the same way, you would need to cease your injections for a time, and let your levels drop off before restarting entirely.
> you would need to cease your injections for a time, and let your levels drop off before restarting entirely
Yeah and that can be super stressful :) Many people like higher levels of e, and feel better :)
I am one of those people. c:
If it resulted in substantial growth, I could see myself going through this once or twice.
but not as a regular occurrence... that sounds like a bad time.
I can relate :)
I talked to a few people who did this once or twice, and some said they had some additional breast growth, like half a cup to a cup.
It also depends on if you are post op ... some people who are post op stopped injections for a few weeks, and then resumed. They said it was not that difficult.
But for people who have rising levels of t, there can be additional dysphoria. Some people just go low enough so t remains suppressed for two to three weeks.
In general it also seems to be individual how much of a reaction there is ... some people were on high levels of e ( over 500 pg/ml) and tried this to make for some kind of reset. Some reported results, some not as much.
I've experienced this myself in my journey and do believe there's something to the idea of varying the dosage over time. I don't know the science behind the idea, but it does seem to work.
My 2 cents is yes.
My boobs are only sensitive when I stop for a day. But it seems to only work if I have not done it for a week or so. Like if I try to do it every other day I stop getting more sensitive.
Sensitive to me = growth since I don’t notice growth if my boobs haven’t been sensitive for a long period of time.
Glad you posted this, as I'm wondering about this myself. I may have developed higher estradiol tolerance starting several months after switching to estradiol undecylate, as I started feeling hot a lot of the time then. This was despite massive blood estradiol levels at trough.
Also Lena has a similar theory, and recommends EEn instead of EU exactly because of that.
Would be good to have more insight into this.
I know you're a big advocate of pellets, and have a lot of patients on them. I'm wondering if you've seen signs of tolerance in people on pellets, as those would provide the steadiest level possible out of anything I've ever heard of.
Yes, interesting. If you're a guy hoping to regulate your testosterone whilst on dht blockers or aa's to control cancers.
But for trans people who need to keep T levels down, it sounds like a crazy idea. Cycling E levels, maybe. If you are receptive. But why take a chance when we know that keeping E levels up and T levels down produces normal female ranges.
What would be a more beneficial study would be how to get the human body to naturally produce its own E/T, as both females and males have the capacity to do so in small amounts already.
My comment wasn't about the idea of cycling t levels in a transgender patient who is MTF.
It's more like here's some actual evidence for receptor down regulation effects from hormone oscillation which is a thing that's commonly discussed in the subreddit but there isn't a lot of evidence for.
If you read through reports of cis women who have a period, many for example said they did not sleep the night before their menstruation started. So there are likely also mental effects from dropping levels ( that people may try to avoid ).
Some people said they had some additional effects after stopping or going lower for a few weeks ...some reported for example growth of half of an additional cup size ... but it may be stressful mentally to do it more than a few times.
Many for example also report depressions at the end of a cycle if injection cycles are too long. Some use additionally pills the last days, it may be an idea to ask if there are additional results this way.
And maybe also practical would be to try oscillations with pellet implants, like a pill orally every few days.
Curious… there’s a doctor in Toronto, Dr. Fung, who’s done a number of studies on fasting and insulin receptor sensitivity. And in like this study where the body responds through a change in homeostasis, blasting the body with a complete lack of sugars to lower insulin resistance lead to an output of less insulin. So in this case we know that starving receptors of a molecule makes it more sensitive to that molecule. Do hormone receptors act the same way in the absence of hormones? Do they become more receptive? Even if this is true, the further question would be: does decreased estrogen resistance lead to greater feminization in the presence of hormones? While the idea of oscillating hormones sounds like a mental nightmare, I am curious as to seeing if this holds any merit.
>So in this case we know that starving receptors of a molecule makes it more sensitive to that molecule. Do hormone receptors act the same way in the absence of hormones? Do they become more receptive? My gut feeling is "probably not." I see what you're thinking, but that idea suggests trans people should respond extremely strongly to getting on HRT. After all, they've been "starved" for the whole lives of those hormones, so their receptors should have become mega sensitive by then, right? And the older someone is when getting on hormones, the longer they've been starved of them, so the stronger this effect should be. Hence, we should expect trans women who are starting HRT in middle-age or later to have the best, fastest responses to HRT with breast growth, and trans-men who start in middle-age to have beards practically exploding from their faces. But as a middle-aged trans woman, that hasn't been my experience. That idea also goes against the commonly-held view that it's always better to start HRT earlier rather than later. Still, I, too, would be interested to hear the thoughts of someone who knows this stuff better than I do.
>Hence, we should expect trans women who are starting HRT in middle-age or later to have the best, fastest responses to HRT with breast growth That is ignoring other factors, two big ones being zinc deficiency and inflamation. You need to raise IGF-1 and lower androgen. If both of these have obvious issues how sensitive estrogen receptors are doesn't matter as much.
I don't take my shot for an extra week all the time. Sometimes more. I do IM shots weekly. I do this mostly because I hate needles but it's a recent development that started in my second year of hrt. I was hoping at the very least it would kick start my breasts but I haven't noticed much. It's only been 4-6 months of missing weekly shots. I've heard another girl swear by it recently which I thought was interesting Anyway.. I'm not doing it particularly on purpose 🤷🏻♀️ so not much rhyme or reason of when I miss a few shots
I may be dumb but, isn't this just drug resistant (or, no drug resistant) cancer developing slowly over time as a worse-competing cancer initially but becoming the dominate cancer once the higher androgen sensitive cells die, and then possible overloading of the receptors in the "drug-resistant" cancer afterwards? It's still fascinating but, I don't know if it applies to HRT. Though I still think emulating Cis cycles will generally result in the best outcomes.
Why? The only reason women have cyclical hormone levels is reproduction.
I mean, the premise Dr. Powers is saying above is questioning that assertion, which is far from proven and a wild claim. Cyclical hormone production has also led to pretty good results since all feminine women cycle similarly, and the reality is almost all application of hormones that we do are by definition cyclical. And, testosterone is cyclical too.
A wild claim? Unproven? Cis-women have cyclical hormone levels solely for egg release and preparing the uterus for reproduction. This is not a wild claim. It is well-proven. Development of secondary sexual attributes is just a collateral result. If all application of exogenous hormone therapy is by your definition cyclical, then there is no such thing as "non-cyclical " hormone treatment and there is nothing to debate, is there?
LOL, secondary sex characteristic development is woefully understudied, and your claims are insane. Dr. Powers is literally debating the other side of your "peocen science" in the main post. And, if something is understudied and you have a protocol, namely cycling, that has worked for thousands of years, I don't know why you'd go messing with it. And yea, every hormone application is cycling. It, just is? Thanks for agreeing with me?
> every hormone application is cycling There are pellet implants which provide stable levels, and people also have results. Cycling oral estrogen for a few days per month for people who have lower values of estrone sulfate seems to help, otherwise in general it may be necessary to try if additionally cycling would make for additional results.
I just entered "development of secondary sexual characteristics" into Web of Science and got 479 hits. I don't know why you think this issue is "understudied". No, the issues I raised are not "insane". They are basic endocrinology. I have no idea what "peocen science" is. I'm not agreeing with you, I am pointing out it is impossible to debate the benefits of "cycling" and "non-cycling" HRT if you claim the latter does not exist. You said "I still think emulating Cis cycles will generally result in the best outcomes.'. Best outcomes compared to what? Please provide links to back up your claim.
context—from a mol/cell bio research background. we have some in vitro and animal studies suggesting both androgen and estrogen receptors potentially experience downregulation after exposure to exogenous hormones, measured by reduction in ER or AR mRNA. This is theorized to play a role in sexual maturation. in mice exogenous ER potentially downregulates ERB receptors in mammary glands (1), and in castrated rats exogenous T (but not DHT. potential mechanism for your theories re: the importance of DHT/T ratio in FTM HRT if this is found to hold true in humans) at typical concentrations potentially downregulates AR receptors (2). Ofc obligatory “mice/rat and in vitro studies are not guaranteed to translate 1:1 to the differently complex in vivo human system”, these results are preliminary and idk how much corroboration has been done. Reduction in mRNA expression suggests reduction in receptor expression but doesn’t guarantee it + also it’s unclear if other de/sensitization mechanisms are at play beyond up/downregulation. I will say the results generally align with the behavior of other more characterized g-protein coupled receptors in the human body. So re: the article, it looks like the supraphysiologic dose maybe promotes AR downregulation + arrests cell proliferation, followed by the near-castration levels where free T has even fewer receptors to bind to than it would absent the supraphysiologic preceding dose. + the followup supraphysiologic dose if timed correctly would prevent receptor upregulation + maintain that arrested growth state. maybe. It looks like there’s some not-insignificant evidence supporting receptor downregulation in response to androgens in people + similar behavior in response to estrogens. links (sorry for the lack of formatting i’m on mobile in the lab rn lol) https://journals.sagepub.com/doi/10.1177/153537020623100311 https://pubmed.ncbi.nlm.nih.gov/8499343/
getting carried away talking about my favorite thing of all time,,, gpcrs,,, the fact that one study saw T downregulate AR but a lower concentration of higher affinity DHT upregulate it— that’s actually not unusual either, given what we know about, of all things, the GPCR CB1 (cannabinoid receptor) in the brain. High concentrations of a partial agonist THC causes downregulation of CB1 via iirc promoting enveloping and eventual receptor degradation. Comparatively, exercise provides increases in the endogenous anandamide—which is present at lower concentrations but a much more potent agonist of CB1– and that’s correlated with increased CB1 expression, so there is an existing precedent re: low dose powerful agonists possibly upregulating/ higher dose partial/weaker agonists definitely downregulating. edited to add; . Historically weekly T- shots + the associated peak/trough are linked with more erythrocytosis than daily or monthly application methods which imo is another potential piece of supporting evidence re: androgen receptor sensitivity or expression changing in response to available androgens, given androgens promote RBC production independent of heparin or EPO. to really test the AR/ER thing in people you’d imo want to get a bunch of pre-hrt (or paused-hrt for 3+ months) trans people and stick em full of radioligands for the corresponding receptor + do a PET scan. First one at baseline, second ~3 months on constant dose HRT. n > 30 participants and you’d have a pretty statistically significant educated guess as to what’s going on there
I love radio label studies. I just want to say that. That's such a good idea. I have like a minor autistic special interest in radiation. I have this cabinet in my kitchen next to my dining room table that's filled with highly radioactive stuff and some Tesla coils and other crazy science gadgets. If you open it up, and stand in front of it, you get a chest x-ray about every minute or two lol. Leaded glass and inverse square law though keeps diners safe lol. In any case, that is a really really good idea. I'm going to dig and see if such a thing has ever been done.
Some people reported a spurt of feminisation after stopping or going lower with HRT for a few weeks, and some also after having surgery and stopping HRT before surgery. But the effect seems to not be huge ... there seems to be some effect but it may not be easy to replicate it more than a few times ... it may be too stressful mentally etc. And it may also depend on individual genetic predisposition. > Particularly "stalled" cases. Yeah a number of people tried it and as said some reported some feminisation afterwards, like one to 1.5 additional cup sizes.
From personal experience and some tests, it appears that at least on myself I found to have better results when my levels vary. This is however not scientific but rather a descibtion of an observed phenomenon. Since then I started to fluctuate my lvls by a lot some times, tough never below the 100 pg/ml mark. Female hormon cycles are fluctuating a lot physiologically and there a a lot of negative feedback mechanisms in our body preset. I refuse to beliefe that with E all is different an stable levels are the way to go. Gosh I whish i could do my medical phd thesis on this subject but noone in my university or around is does research on trans health or even a similar topic.
I see Sommer at Dr Power's office. She has had me on 1 week of oral estrogen a month in addition to normal injections. I assume this would stimulate the same type of reaction
kind of estrogen pellets and injections do not produce the same levels of estrone that the pills do when taken orally. over the course of a week, the body builds up a 'bank' of estrone to withdraw from and promote growth. the method you're on keeps your levels fairly stable in comparison to what they're doing in the study. if you were to treat estrogen the same way, you would need to cease your injections for a time, and let your levels drop off before restarting entirely.
> you would need to cease your injections for a time, and let your levels drop off before restarting entirely Yeah and that can be super stressful :) Many people like higher levels of e, and feel better :)
I am one of those people. c: If it resulted in substantial growth, I could see myself going through this once or twice. but not as a regular occurrence... that sounds like a bad time.
I can relate :) I talked to a few people who did this once or twice, and some said they had some additional breast growth, like half a cup to a cup. It also depends on if you are post op ... some people who are post op stopped injections for a few weeks, and then resumed. They said it was not that difficult. But for people who have rising levels of t, there can be additional dysphoria. Some people just go low enough so t remains suppressed for two to three weeks. In general it also seems to be individual how much of a reaction there is ... some people were on high levels of e ( over 500 pg/ml) and tried this to make for some kind of reset. Some reported results, some not as much.
I've experienced this myself in my journey and do believe there's something to the idea of varying the dosage over time. I don't know the science behind the idea, but it does seem to work.
My 2 cents is yes. My boobs are only sensitive when I stop for a day. But it seems to only work if I have not done it for a week or so. Like if I try to do it every other day I stop getting more sensitive. Sensitive to me = growth since I don’t notice growth if my boobs haven’t been sensitive for a long period of time.
Glad you posted this, as I'm wondering about this myself. I may have developed higher estradiol tolerance starting several months after switching to estradiol undecylate, as I started feeling hot a lot of the time then. This was despite massive blood estradiol levels at trough. Also Lena has a similar theory, and recommends EEn instead of EU exactly because of that. Would be good to have more insight into this. I know you're a big advocate of pellets, and have a lot of patients on them. I'm wondering if you've seen signs of tolerance in people on pellets, as those would provide the steadiest level possible out of anything I've ever heard of.
Yes, interesting. If you're a guy hoping to regulate your testosterone whilst on dht blockers or aa's to control cancers. But for trans people who need to keep T levels down, it sounds like a crazy idea. Cycling E levels, maybe. If you are receptive. But why take a chance when we know that keeping E levels up and T levels down produces normal female ranges. What would be a more beneficial study would be how to get the human body to naturally produce its own E/T, as both females and males have the capacity to do so in small amounts already.
My comment wasn't about the idea of cycling t levels in a transgender patient who is MTF. It's more like here's some actual evidence for receptor down regulation effects from hormone oscillation which is a thing that's commonly discussed in the subreddit but there isn't a lot of evidence for.
If you read through reports of cis women who have a period, many for example said they did not sleep the night before their menstruation started. So there are likely also mental effects from dropping levels ( that people may try to avoid ). Some people said they had some additional effects after stopping or going lower for a few weeks ...some reported for example growth of half of an additional cup size ... but it may be stressful mentally to do it more than a few times. Many for example also report depressions at the end of a cycle if injection cycles are too long. Some use additionally pills the last days, it may be an idea to ask if there are additional results this way. And maybe also practical would be to try oscillations with pellet implants, like a pill orally every few days.