Estrogen resistance

[Lucie]

I was wondering whether estrogen resistance/insensitivity might be induced by continuous high estrogen level in blood (in the same way as high blood insulin levels produce insulin resistance).
I have found only reports about very rare cases of estrogen insensitivity caused by a gene mutation, nothing about non genetic estrogen insentivity.
If some of you have an opinion on this subject I'd appreciate your comments.

[Randi]

Look into SHBG.  Sex Hormone Binding Globulin.

High estrogen levels can raise SHGB, which makes much of your estrogen ineffective.

[Lucie]

Look into SHBG.  Sex Hormone Binding Globulin.

High estrogen levels can raise SHGB, which makes much of your estrogen ineffective.

Ok, I see: more SHBG implies less free estrogens. But this should be true only if total estrogen level remains unchanged. Is there a reason that high total estrogen level might decrease the ratio free estrogen / total estrogen ?

[Randi]

Certainly.  When estrogen levels increase, the liver produces more SHBG.  This binds more of the free estradiol, and the ratio of free/total estrogen decreases.  Excess estrogen can also be converted to estrone sulfate, which can be stored in fat cells for a long time.  Conversion between estradiol and estrone sulfate works both ways, so eventually you can get the estradiol back.
 

Is there a reason that high total estrogen level might decrease the ratio free estrogen / total estrogen ?

[Lucie]

Certainly.  When estrogen levels increase, the liver produces more SHBG.  This binds more of the free estradiol, and the ratio of free/total estrogen decreases.  Excess estrogen can also be converted to estrone sulfate, which can be stored in fat cells for a long time.  Conversion between estradiol and estrone sulfate works both ways, so eventually you can get the estradiol back.

Thanks Randi for that very clear explanation.
Thus I understand that in case of suspicion of estrogen insensitivity one should ask first for testing SHBG.

However my initial concern was about insentivity at estrogen receptor level. I observe that pre-menauposal cis women are not at risk of permanent estrogen insensitivity (except in rare cases of gene deficiency). I was wondering whether this might be related to the fact that their blood estrogen level fluctuates a lot all along the monthly cycle. If so, perhaps trans women should have a cycled varying intake of estrogens in order to avoid any kind of estrogen resistance ?

[Randi]

This goes beyond my level of expertise.  My personal belief, and it's no more that, is that is cycling hormones to mimic a cis-woman's cycle is counter productive.  The only likely effect would be gaining solidarity with cis-Women by sharing PMS, bloat and other feminine travails.

At any given time there are only a certain number of estrogen receptors.  Once the receptor accepts a molecule of estradiol, it's locked in and can't use any more.

Here's where it gets a bit murky.  There are several different types of estrogen receptors and the number and type of receptors vary from time to time.

[Dena]

In the good old day, we didn't cycle before surgery but we did after. The reason was to reduce the risk of cancer. Premarin was a witches brew of estrogens and may have had a higher cancer risk than estradiol because of the non estradiol estrogens in the mix. From what I have seen on the site, a continuous dosage is effective and hasn't been proven harmful so I am not worried about it in my own treatment.

[Lucie]

In the good old day, we didn't cycle before surgery but we did after. The reason was to reduce the risk of cancer. Premarin was a witches brew of estrogens and may have had a higher cancer risk than estradiol because of the non estradiol estrogens in the mix. From what I have seen on the site, a continuous dosage is effective and hasn't been proven harmful so I am not worried about it in my own treatment.

I have no fear of bio-identical estradiol having adverse effects (when taken by non oral route). However, what I note is that I need growing dosages for feeling good, psychically and physically as well.
Also, several trans women posters at Susan's Place have reported that after some time they were feeling that HRT had less positive effects and even in some cases that their feminization was regressing (breast size, skin, male sex drive, etc).
This is the reason why I was wondering whether continuous estradiol intake at same dosage could lead to some kind of insensitivity or resistance to that hormone.

[Lucie]

This goes beyond my level of expertise.  My personal belief, and it's no more that, is that is cycling hormones to mimic a cis-woman's cycle is counter productive.  The only likely effect would be gaining solidarity with cis-Women by sharing PMS, bloat and other feminine travails.

At any given time there are only a certain number of estrogen receptors.  Once the receptor accepts a molecule of estradiol, it's locked in and can't use any more.

Here's where it gets a bit murky.  There are several different types of estrogen receptors and the number and type of receptors vary from time to time.

I agree with you that mimicking cis woman's cycle has basically poor rationale for trans women since they can't procreate. But one can't ignore that woman procreation cycle has as a side effect wide fluctuations of estrogen and progesterone blood levels. These fluctuations are physiological and might contribute by themselves to the well being of pre-menopausal cis women. The question is: Could such fluctuations, of estrogen blood level especially, be beneficial to trans women ?
Unfortunately my knowledge of physiology and biochemistry is far from being sufficient for finding and understanding by myself argued answers to such questions. The only thing I can do is to experiment varying dosages and see what are the effects in short and medium term (e.g. a three week cycle with half dose during first week, plain dose during second week and one and a half dose during third week).

[KayXo]

I don't really buy into the SHBG hypothesis for three reasons:

1) pregnant women have very high levels of estrogen that gradually increase over the course of 9-10 months. Their breast growth is significant.
2) I had better breast growth on a higher dose of oral estradiol when SHBG was higher than on a lower dose
3) If I take some oral E in addition to my injectable E, which further increases SHBG, breast growth is restarted.

Premarin has been associated with a reduced incidence in breast cancer, when taken alone, in post-menopausal women. Same thing for bio-identical E. Breast cancer is very rare in transwomen who, for decades, took high doses of non bio-identical estrogen.

There are two estrogen receptors found, thus far. ER-alpha and ER-beta. The latter trigger proliferation, the former inhibits it, apparently. Number of receptors varies in time.

Could well be that estrogen delivered in a non-pulsatile manner, akin to LHRH agonists, induces desensitization.

[RobynD]

I'v often wondered about Estrogen tolerance or whatever you call it. I've also wondered if taking your doses at different times helps keep your system guessing as it were, and increases effectiveness. For various reasons i sometimes dose first thing in the morning or wait until as late as noon.

[Lucie]

Could well be that estrogen delivered in a non-pulsatile manner, akin to LHRH agonists, induces desensitization.

I understand that endogenous LH and FSH also are secreted in a pulsatile manner in response to GnRH pulses. But what about E ? Do the ovaries produce it in a lissed way or in a pulsatile way ? I could not find anything on that point.

[Mohini]

Hello everyone.  I'm new HERE, but I've been living full-time as a woman for 17 years.  I had the orchie (all I can afford) about 10 years ago.  I'm a writer in a very male-dominated area, and I've known about hormone cycling, but never put much thought about it until I realized that a reason that drug addicts go for higher dosages is because of insensitivity to the drugs if taken continuously over a period of time, and noticing that if I was on a steady diet of alcohol (2-3 beers per week) and stopping, then noticing sensitivity after picking up again a few months later, and then noticing the effect dropping after a month (I don't drink anymore because I don't want health issues with it).

I've thought about the cycling of estrogen...  In recent weeks, I've begun to understand what could be happening as one goes through the menstrual cycle.  It seems to be that the effect of such a cycle intended for the "cycling" of the uterus lining and the ovulation is that when estrogen levels are low, the body maintains its shape or female fat levels in the body; when it ramps up for a few days towards the peak, the feminization effect steps up and is reached for that cycle; and then it drops back down fairly hard before gradually increasing up to less than half the peak level for a few days before returning towards the "base line" level near the end of the cycle.  That hard drop down seems to give the estrogen receptors a quick break before the level goes back up partially for a second time.  I would think that because the receptors are "freshly exposed" from the high peak of a few days before, they are able to respond "anaphylactically" to that second smaller peak before leveling down to the base level for the next 7-10 days for the next cycle, meaning a higher response to a smaller level of estrogen than the peak level.  I assume that in a woman's body, the amount of feminization "lost" during the "base line" period would be less than what was gained in the previous cycle, assuming no pregnancy happens.  So the amount of feminization increases to its maximum potential for the body through periodic resting and restoration of maximum response to estrogen and layering the results one on top of the other.  Your body this cycle is slightly more feminized than it was last cycle (though it takes several cycles for something to become noticeable).

I bring this up now because I'm not happy with the long-term dosage  (I weigh 122 lbs).

Mod Edit:Dosage

[Dena]

Welcome to Susan's Place. I am a long term lab experiment on HRT theory and practice so I have a little feel for this. My first round of HRT involved Premarin and cycling. The net result was I had very little development. I believe the reason was because some of the estrogens contained in Premarin didn't cleave into a form that my body was able to use. My current dosage is estradiol at less than what you are using and at just over the 6 month mark, I have sore, itchy and growing breast that hadn't responded with years of past exposure, I am on a constant dosage and it feels like the estradiol may be 5 times as effective as my past treatment. Breast growth takes time and a genetic woman can take between 5 and 10 years to reach full development and not everybody ends up with large breasts. For a woman at a reasonable weight, an A or B cup is normal and it's only the trend toward overweight that's resulting in larger breast sizes.

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[Lucie]

Thanks Mohini for these thoughts which echo what I feel myself with estrogen therapy administered at steady dosage.
Unfortunately endocrinologists seem not to be aware of this aspect, or at any rate they do not address it.

[Lucie]

Dena, in my experience the problem is not specifically about breast growth or other body changes. It's more related with overall well being. I note that I need higher and higher dosages for feeling fine in my head (mood, self estim as a woman) and in my body (especially maleish sex drive which comes back). One endo tells me that it suffices to increase the dosage, an other one tells me that estrogens are dangerous (which is false as concerns bio-identical and non oral forms) and that she can't increase the dosage even if I need it. Perhaps some of us are more prone to estrogen resistance.

[Dena]

I had to go back in the posting history to figure this one out. You are not on a blocker and are only using estrogen and progesterone. I didn't see T or E levels so I can only assume that you estrogen levels may not be high enough to block the T resulting in the uncomfortable feeling you are having. I am post surgical and lost the discomfort after surgery. My estradiol dosage is about half the normal transition dosage but emotionally I feel little difference between when I was off HRT and returning to it. I don't know if you can do it but you either need an estrogen delivery method that will block the T or use a T blocker followed by blood test measuring your T, total estrogen and estradiol. When these levels are correct, you will feel like a woman which could be described as emotionally boring.

[Lucie]

I had to go back in the posting history to figure this one out. You are not on a blocker and are only using estrogen and progesterone. I didn't see T or E levels so I can only assume that you estrogen levels may not be high enough to block the T resulting in the uncomfortable feeling you are having. I am post surgical and lost the discomfort after surgery. My estradiol dosage is about half the normal transition dosage but emotionally I feel little difference between when I was off HRT and returning to it. I don't know if you can do it but you either need an estrogen delivery method that will block the T or use a T blocker followed by blood test measuring your T, total estrogen and estradiol. When these levels are correct, you will feel like a woman which could be described as emotionally boring.

My last E level was 125 pg/ml (not so low) and T level was 0.28 ng/ml (not so high). As you noted this was without any anti-androgen, at least until two days ago.
Anyway, from what I know there are several other factors than blood level which impact the real action of a given hormone: number of relevant receptors, their localization in different parts of the body, their sensitivity, etc. On some people a low blood level will have a strong impact. On some other ones a high blood level will have a weak impact only.
As regards A-A I started taking bicalutamide (low dose) yesterday. I have some hope that it will help estradiol action.

[Dena]

If the 125 pg/ml is estradiol, your levels look good. If that's total estrogen, you may be on the low side depending on your estradiol levels.

[Lucie]

Yes, it is estradiol level.