Spironolactone is a 17B estradiol inhibitor?

[Harley Quinn]

In my seemingly never-ending quest to convince my Endocrinologist that something is off, I ran across this article.  I was hoping that one of the medical lingo gurus could confirm I'm reading this correctly.

Spironolactone binds to estrogen receptors with a mild inherent estrogenic effect.  However, will block 17B-Estradiol access to the mammary receptor by 2x10(-5) mol/l (i'm uncertain how to quantify that number in real-world transition). Am I missing something?

https://www.ncbi.nlm.nih.gov/pubmed/7391714

[Allison S]

I don't know anything medical but does that mean spiro doesn't help with mtf transitioning? What's the alternative?

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[Harley Quinn]

I am unsure. I have been investigating my own hormone therapy, trying to understand what they're giving me. I am unsure, and waiting to hear some clarification on the doctor double speak. We have some super smart people here that I hope will jump in to clarify.

I have a fear of taking too many medications, so I always look to simplify.... Spiro, Finasteride, Prometrium, and estradiol valerate seems like too much to me. 🙄  I opened Pandoras box reading how Spiro may cause pre-mature breast bud fusion do to being too much of an estrogen agonist. Then they say it's an estrogen antagonist. And then you read studies about getting breast growth post SRS even after the 2 year maximal development, which is a shorter development span than natal females. After that you read studies about breast growth in natal females from Spiro, then massive fat accumulation in the stomach area with no breast growth in the next sentence.. and if women experience breast growth after being fully developed, then why would genetically identical breasts in trans women be different... It seems as though they don't really know how people will react. Which leads me to believe that mine could be more effective than what it is. Etc... it's a vicious cycle.

[Colleen_definitely]

It's not quite as simple as the abstract makes it seem.  Is it a competitive inhibition, non-competitive inhibition, or uncompetitive inhibition?  They all behave a bit different.  I could probably make a lot more sense of this thing if I had access to the entire article.

Also keep in mind that mouse studies aren't always 100% directly translatable to human effects.  Mice do things differently in many cases.  Not to say that humans don't react this way but the effect is certainly to a different degree.  We're also missing a lot of data.  How high were their levels?  How much faster do mice metabolize estradiol?  Were these studies done on female mice generating their own estradiol? (likely yes)

As far as the value goes, 2 x 10(-5) mol/l sounds all whiz bang neato, but if your e2 level is say 150pg/ml then you have concentrations of about 5.5 x 10 (-13) mol/l unless I totally bungled my quick and dirty napkin mathematics.

So long rambling story shorter: there's more to the story and we know that people do transition well when taking spiro.  I'm still going to get off of it ASAP and compensate with estradiol but that's so I don't have to pee every 15 minutes and to avoid long term effects.  That's an option you might explore with your doctor.

[LexiDreamer]

I'm sure KayXO will come along and offer some feedback on it as she's done a lot of research.
But, I know that Spironolactone does have side effects that are not necessarily conducive to M2F transitioning.
That's why it should only be used to lower T initially and then tritrated down once E2 takes over as the dominant sex hormone. 
There are some on here that have had good results with lowering their T with Estradiol alone, without the help of anti-androgens.

*** Any suggestions I make should never be used as a substitute for licensed medical advice ***
*** All of my personal pharmaceutical experiences I share, have been explicitly supervised by a licensed medical professional ***
   

[josie76]

Spiro has two positive effects.
1: it interferes with testosterone and DHT's ability to latch to the androgen receptors. In truth spiro actually has a mild activation of androgen receptors. It is so much milder that it appears like a blocker simply by preventing actual androgens from getting to them. Breast tissue development is prevented by androgen receptor activation, so it is possible that spiro could slow breast growth.
2: by and indirect pathway, spiro does decease the output of GNRH and decreases testicular production of testosterone.

Spiro has a number of negative effects. I don't have my spreadsheet on my iPad so I am only working from memory.
It has a very mild affinity for estrogen receptors making it possibly partially block them.
It acts as an inhibitor of a large number of enzyme activity meaning it interferes with a number of neuro-regulating hormone production and others.
It activates mineralocorticoid and glucocorticoid receptors. By doing this it blocks the bodies feedback loop system. Despite its enzyme interruption, by blocking the feedback system it has the net effect of driving stress hormone production extremely high. Specifically cortisol.

One androgen blocker used for prostate cancer which has been used in trans women is Bicalutamide. This blocks androgen receptors but with no other endocrinological activity. It is processed in the liver as are many medications. It has a 3% occurence of elevated liver enzymes and a 0.3% need to stop usage. I have read of only two reported deaths unsung this medication over its decade or more use as a cancer drug in mostly men of advanced age. It has been seen to remain effective in prostate cancer patients for greater than 4 years without other complications in studies for its effectiveness.

I asked my endo about it. His office called back and just said he has never used it and that he wasn't going to prescribe it. In my first appointment with him, he said estrogen alone would shut down testosterone to female levels in enough time. Spiro just really cuts the time and releases the symptoms to T in the body. My issue is he is very conservative with E dosages based on the patients age. He also only prescribes oral Estrace form not injectable E.

It takes longer on oral to reach body tissue saturation levels and free blood levels drop quickly. In enough time, estrogen levels can build as the body will tend to store extra free estradiol in estrone form which can be stored in fatty and andipose tissues, then be converted back to estradiol in a controlled manner. I know a couple of trans girls who have monthly period like symptoms. Appearently the body can saturate its tissues and begins regulating free blood levels in a cycle. IDK but at least one or two of the HRT doctors offices nearby have said its normal.

[Harley Quinn]

For me, I don't believe that Spironolactone is the best medication.  My potassium levels worry me.  I have been on a strict low potassium diet since starting Spiro, and still maintain a 5.0 to 5.3 mEq/L level.  Which spurs me to look for a better way.  The 15 minute urination cycle 24/7 with my split doses of Spironolactone is annoying as well.  I run into the same issue with my physician who tells me that the methodology is sound.  However, their rush to put me on anti-depressants and attempt to blame my vitamin D levels for a bad reaction to Medroxyprogesterone got me wondering.  I suggested my EV IM injections may be enough to suppress my testosterone levels and it was immediately dismissed.  Although they have never checked my T levels pre-hrt and they were already floored 10 months into transition with a high dose of spiro from my first doctor that didn't believe in blood tests... So doctor #2 doesn't have any information from pre-hrt or the first 10 months of transition.  I have issue connecting the dots and therefore question a lot of what I'm told without supporting evidence.

[Colleen_definitely]

Is there any way for you to see a different doctor?  I'm currently running away from a doc that loved to make assumptions, didn't believe in gathering data points through blood work, and loves a one size fits all approach. 

[Harley Quinn]

Is there any way for you to see a different doctor?  I'm currently running away from a doc that loved to make assumptions, didn't believe in gathering data points through blood work, and loves a one size fits all approach.

There is a way, but I still have hopes that I can work "with" my current endocrinologist.  She is, in fact, the Attending for all the other Endocrinoligists... so I don't know exactly how far I can get away from that oversight.  I kind of liked having interns for my transition care... a decision I didn't like was only a fraction of a year away from a new doctor and a new diagnosis.

[Allison S]

I've considered going to another doctor. I have my 4 months follow up coming up (she said every 3 months after the first time). I want my bloodwork done with the results before I make any rash decision. I've been scared of blood clots so that's my main priority to make sure I don't get any.

Maintaing a healthy diet has been hard and at work I try to get up and move but it's not nearly enough exercise..

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[KayXo]

Spiro (...) interferes with testosterone and DHT's ability to latch to the androgen receptors. In truth spiro actually has a mild activation of androgen receptors. It is so much milder that it appears like a blocker simply by preventing actual androgens from getting to them. Breast tissue development is prevented by androgen receptor activation, so it is possible that spiro could slow breast growth.

I believe that its significantly weaker activation of androgen receptors in breast tissue and all over the body is a POSITIVE. However, its activation of estrogen receptors could *potentially* prevent some of the estradiol reaching receptors and hence, behave as an estrogen antagonist. A NEGATIVE. The end result: who knows? It would depend on a host of factors.

by and indirect pathway, spiro does decease the output of GNRH and decreases testicular production of testosterone.

Incorrect. Spiro inhibits 17-hydroxylase and by doing so, prevents endogenous production of testosterone. The output of GnRHs, LH and FSH can actually go up as Spiro blocks androgen receptors and reduces T output.

It acts as an inhibitor of a large number of enzyme activity meaning it interferes with a number of neuro-regulating hormone production and others.
It activates mineralocorticoid and glucocorticoid receptors. By doing this it blocks the bodies feedback loop system. Despite its enzyme interruption, by blocking the feedback system it has the net effect of driving stress hormone production extremely high. Specifically cortisol.

I have yet to come across a study where the use of spiro results in extremely high levels of cortisol. If cortisol does increase, does this actually translate into actual psychological and physical problems such as what is seen in people with Cushing's syndrome? This needs to be demonstrated.

One androgen blocker used for prostate cancer which has been used in trans women is Bicalutamide. This blocks androgen receptors but with no other endocrinological activity. It is processed in the liver as are many medications. It has a 3% occurence of elevated liver enzymes and a 0.3% need to stop usage. I have read of only two reported deaths unsung this medication over its decade or more use as a cancer drug in mostly men of advanced age. It has been seen to remain effective in prostate cancer patients for greater than 4 years without other complications in studies for its effectiveness.

I asked my endo about it. His office called back and just said he has never used it and that he wasn't going to prescribe it. In my first appointment with him, he said estrogen alone would shut down testosterone to female levels in enough time. Spiro just really cuts the time and releases the symptoms to T in the body. My issue is he is very conservative with E dosages based on the patients age. He also only prescribes oral Estrace form not injectable E.

It takes longer on oral to reach body tissue saturation levels and free blood levels drop quickly. In enough time, estrogen levels can build as the body will tend to store extra free estradiol in estrone form which can be stored in fatty and andipose tissues, then be converted back to estradiol in a controlled manner. I know a couple of trans girls who have monthly period like symptoms. Appearently the body can saturate its tissues and begins regulating free blood levels in a cycle. IDK but at least one or two of the HRT doctors offices nearby have said its normal.

I personally (I am not a doctor and I am not condoning anything) prefer the anti-androgens bicalutamide and LhRh agonists such as Lupron. Or just taking estrogen and this alone bringing T levels down, over time.

[Harley Quinn]

"I believe that its significantly weaker activation of androgen receptors in breast tissue and all over the body is a POSITIVE. However, its activation of estrogen receptors could *potentially* prevent some of the estradiol reaching receptors and hence, behave as an estrogen antagonist. A NEGATIVE. The end result: who knows? It would depend on a host of factors."

So, thinking out loud... if IM injections break down into roughly 66% E2 and 33% E1 (which is a less effective oestrogen), and Spiro will further block E2 action on the estrogen receptor, then it may be reasonable to deduce that the estrogen receptor may in-fact be binding to E1 nearly exclusively due to the E2 antagonist activity and E1 agonist properties of the Spiro/E1's natural affinity to estrogen receptor binding when the ratio of E1 and E2 is factored into the saturation point of the body's Estrogen Receptors?

[KayXo]

No. Spironolactone binds to estrogen receptors and by doing so, may *potentially* prevent all estrogens, be it Estrone, Estradiol or even Estriol from binding to receptors, to a certain degree. The ratio shouldn't be affected.

[Harley Quinn]

Thanks.  KayXo, your explanations are way better than what I get at the doctor's office. 

[SadieBlake]

Harley, this is why I've been so glad to have been prescribed intramuscular estradiol valerate, for me that alone blocked testosterone. At least anecdotally, others have had the same finding. I agree simpler is always my first choice.

[Harley Quinn]

Harley, this is why I've been so glad to have been prescribed intramuscular estradiol valerate, for me that alone blocked testosterone. At least anecdotally, others have had the same finding. I agree simpler is always my first choice.

Out of curiosity, at what level do they keep your Estradiol levels to keep your testosterone levels in check?  My IM injections keep me at a low of 190 pg/ml on a 7 day cycle.

[KayXo]

Harley, this is why I've been so glad to have been prescribed intramuscular estradiol valerate, for me that alone blocked testosterone.

Estradiol doesn't BLOCK testosterone, it REDUCES testosterone production. Bicalutamide and to a lesser degree, cyproterone acetate, spironolactone BLOCK androgens (androstenedione, testosterone, dihydrotestosterone) at receptors. Lupron and all LhRH agonists don't block androgens but reduce androgen output. It's important, in my opinion, to clearly differentiate between the two.

[SadieBlake]

Sure Kay, whatever. Since the normal terminology for this revolves around T blockers, that's the language I used and I don't think it's inaccurate to say that it's blocking the production of testosterone. Agreed, it's not binding to receptors / blocking the endpoint effectiveness.

HQ:
Over the course of a year as we titrated dosage my E/T levels ran as follows, pg/ng per ml respectively:

702/12
353/12
225/17
210/20

And then post op

263/13

All those measurements were made at 3.5-4 days into a 7 day schedule. My most recent test was on day 6 and my numbers were 180/<8.

I should note that my only measurement of T prior to HRT had been done 17 years ago and came out at 350 which is quite low for a natal male, 5th percentile, so blocking my T may be inherently easier in my body than in most people's.

[Deborah]

I need a clarification.   If you say that spiro blocks T at the receptors rather than inhibits T production then if T has been reduced to minimum levels in the bloodstream it follows that it is independent of spiro.  So, at that point one could discontinue spiro entirely with no rise in T levels. 

Is that correct?  If so, my Dr. doesn't know that.


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[KayXo]

I need a clarification.   If you say that spiro blocks T at the receptors rather than inhibits T production then if T has been reduced to minimum levels in the bloodstream it follows that it is independent of spiro.  So, at that point one could discontinue spiro entirely with no rise in T levels. 

Is that correct?

No. Spiro both BLOCKS and REDUCES T. In some, even at high doses, it may not reduce T at all but will usually block androgens to a certain degree from binding to receptors.