Breast growth with bicalutamide and tamoxifen

Chris

I've been looking at tamoxifen dosing, and how it works.

When I started developing tenderness and breast buds, I asked for it, and got a prescription from oncology for 20mg daily, but with the suggestion to try 20mg twice a week to start with. I didn't ever speak with whoever prescribed it, so was somewhat short on any more detailed instructions.

The 20mg twice a week only relieved the tenderness (which I didn't much care about anyway) for that day, and the breast buds continued to grow. I adjusted the dose up in steps to 20mg/day, and that did work, but by that time the breast buds had grown, and it took time for them to shrink.

I subsequently tried modifying the dose according to symptoms, but the results didn't match what I expected.

This caused me to go off and do some research on tamoxifen dosing, and it's much more complicated than I had imagined, but I'll go through it, because it might be useful to understand this for some people.

The active ingredient is tamoxifen citrate, 3/4 of each tablet (the rest being inactive things to make it into a tablet). When you take a tablet, it takes 5-7 days for your liver to breakdown half of the tamoxifen citrate (this is known as the chemical's half life), according to manufacturer data. They also give some other figures of blood concentrations after many months, from which I could work backwards to 5.4 days half life. This means if you take one tablet, 5.4 days later, half of it is still in your system, and after another 5.4 days, 1/4 of it is left in your system, and after another 5.4 days, 1/8th of it is left in your system, etc. This type of logarithmic decay is typical of the way most drugs are removed from the body (alcohol being a notable exception), although all drugs have different half lives.

Since the half life is quite a bit more than the dosing frequency (certainly for daily doses), this means the quantity of tamoxifen citrate in your blood once you've been on it a while will actually correspond to several day's dosage, because several days worth add together before they get removed by the liver. The dose is calculated to take this into account.

However, tamoxifen dosing is more complicated than this simple model. Tamoxifen citrate is metabolised (broken down) by the liver mainly into N-desmethyl tamoxifen. This works just as well as tamoxifen citrate to block estrogen, so although the liver has broken down half the tamoxifen citrate in 5 days, the breakdown product continues working as an estrogen blocker.

It gets even better... The N-desmethyl tamoxifen has an additional half life of about 14 days meaning almost 3 times as much builds up in the body as the original tamoxifen citrate, so it is actually the N-desmethyl tamoxifen which is the main estrogen blocker, rather than the tamoxifen citrate.

This combination is known as a biphase decay, because it relies on the half life decay of a second follow-on decay product.

However, because of this biphase decay, and in particular because it's the metabolite which produces most of the estrogen blocking effect, it takes a long time for the active concentration level to build up in the blood. I modeled this in an Excel spreadsheet, and it takes 3 months to build up to the final stable blood concentration level, and probably at least 2 months to get near enough to be working well.

Now, this probably works fine if you start taking it when you start on HT as you won't need it to be effective for a few months, but if you start taking it in response to breast pain and growth as I did, this allows quite some considerable time before it builds up a strong enough concentration in the blood to stop growth, and start reduction.

Using my Excel spreadsheet model, I can play around with dosing and see the impact it has on blood concentrations. For a target concentration level corresponding to 2 x 20mg/week, you can get there in 8 days by starting off with 20mg/day for the first 8 days, and then dropping back to 2 x 20mg/week, and this is probably what I would have done if I'd known this at the outset. (I did end up doing something not very dissimilar to get the effect I wanted, but I didn't realise I could have pulled the dose back down so quickly after 8 days, not knowing the mathematical model behind the dosing at the time.)

Now, this is totally non peer reviewed private research, so I'm certainly not suggesting anyone else should try this, particularly if your oncologist has prescribed a specific dose (mine didn't). But you might talk with your oncologist if you are starting out on tamoxifen due to breast pain/growth having started. I couldn't find any such research on dosing, probably because use in men for gynaecomastia is not covered anywhere near as well as use for breast cancer treatment.

I have another interest in making my dose as small as I can get away with. My liver is not overly happy with tamoxifen, which has raised my alanine aminotransferase levels. This means tamoxifen could give me non alcoholic fatty liver disease (NAFLD) with long term use. There are other potential side effects from it too, such as blood clots. I don't want to have to come off it, so I'm hoping minimising my dose will keep me safe on it, and the mathematical modeling may help me do this.

50% of women taking tamoxifen after breast cancer treatment for 5 years to reduce chance of recurrence do end up with fatty liver disease. There is also an interesting correlation in that those women who do get NAFLD are also only half as likely to get a breast cancer recurrence as those on tamoxifen who don't get NAFLD, although the mechanism behind this correlation are not known.

[EDIT 18/4/2019: Correct description of N-desmethyl tamoxifen blood concentration.]

Edited by member 18 Apr 2019 at 15:31  | Reason: Not specified

I read lots of research papers on it when I was diagnosed and started on HT, so I was well prepared with the questions and requests. Body image and not growing boobs was one the few concerns I identified on my Macmillian holistic needs assessment. My mother has large breasts, so I suspect there's a reasonable chance mine would be too if allowed to grow.

I initially asked for the one-shot RT blast, as mentioned in the HT handbook they gave me, but my CCG doesn't do it, and Mount Vernon don't even do it privately. The research papers I read said that had to be done within a month of starting HT and before growth started. I made inquires about doing it privately elsewhere, and they would only do it after growth started, so that was inconsistent. It only has about a 50% success rate, and it causes heart muscle damage in 1-2% of cases (although this hasn't been known to cause any issues and only comes to light up if the heart is being checked for some other reason afterwards). In retrospect, I think I'm glad I didn't go this route. It might still be open to me if I had to stop the tamoxifen for any reason, but would have to be done privately.

I asked my GP for tamoxifen as a prophylactic. He wanted it initially prescribed by a consultant. I asked the Macmillan nurse, and they said they don't normally do it as a prophylactic. I was going to ask at my next consultant meeting, but breast growth beat me to it, and so I had to ask the Macmillan nurse again saying growth started, and they got me the prescription to collect next day (might even have been same day). My GP then immediately added it to my repeat prescriptions. In one of the research papers I read which looked at the cost justification, it was a complete no-brainer, with tamoxifen being very cheap, and a 5 year course worked out at £125 (that's some years ago, probably nearer 2012 than 2019, might be more now). The success rate is claimed as 70% (and I suspect it probably reduces the effect even when not a complete success).

Research papers I read indicated tamoxifen can reverse breast growth up to a year old, but works more effectively the newer the growth is, and certainly it worked on my recent growth surprisingly well (although not immediately as I explained above). I think that if I'd got the initial dose right as shown in my subsequent dose modeling, it would probably have reversed the growth in about the same duration as the growth happened. As breasts get bigger, they also form fibrous tissue to support the glands, and tamoxifen cannot reverse the growth of the fibrous tissue. I never found out if it can reduce growth of breast fat tissue, mine didn't get that far and none of the research papers went into that level of detail.

It's also used to reverse gynecomastia which some teenage boys get when entering puberty due to a hormone imbalance between testosterone and estrogen at that time, usually caused by being overweight.

Hi AndyLoates,

I was on 50mg bicalutamide for 6 months (this didn't reduce PSA much and has now been recognised as having been the wrong dose), and changed to Zoladex 8 weeks ago (which brought PSA down from 47 to 5.29 in the first 6 weeks). Breast buds started growing 11-12 weeks into the bicalutamide (one urologist expressed surprise it was that quick), which is when I started the tamoxifen.

When I got the high alanine aminotransferase (ALT) reading, I had just had a full body MRI scan to look for any mets which included a detailed examination of the liver (which was OK apart from 2 cysts, which is apparently very common), so they're not going to do a liver ultrasound to check for NAFLD at the moment (which would be the normal followup to a high ALT reading). My GP is happy for me to manage my tamoxifen dosing, and when I think I've got it stable in a month or two, he's given me a form to get another liver function test done. He included GGT on that form which I haven't had done before (apparently, GGT is not normally included in standard liver function tests if you are a non-drinker like me).

Raised ALT is an alarm bell for fatty liver disease (typically an issue for drinkers). Tamoxifen causes non-alcoholic fatty liver disease (NAFLD) in about 50% of women who take it long term (those doses would be 20mg/day or more), but tamoxifen also causes raised ALT without NAFLD, so ALT cannot be used to check for NAFLD when you're on tamoxifen, and other methods such as ultrasound and platelet count need to be checked too.

You made me go and reread the side effects of Zoladex, and it lists liver problems, and googling suggests raised ALT is a possibility, so I might look in to this some more, thanks.

Hi Chris,
Your timeline from starting taking it to observing effects is a really good match to my theory about the long length of time (2-3 months) it takes to build up to the stable working level in your blood.

I wonder why they don't suggest an initial boosted dose to get to the working level much faster if you are starting it with gynaecomastia symptoms already? I suspect the long lag isn't well known.

In my experimenting with tamoxifen dosing, I haven't taken any for 4 weeks now. Based on my dosing before that period and my calculation of the half-life of the drug, my body should be down to the level representing a continuous daily dose of 3.2mg, which is just slightly more than 20mg weekly, but of course it's still reducing. (A shame I can't post the graph here.)

I've been ready to go straight back on it the moment I get any breast pain or can feel growth, but that hasn't happened as yet. I'm quite pleased it looks like I might not need it continuously for it to be effective, but I haven't yet found out how often I will need it, and at what minimum dose to be effective.

Still lots of unknowns, such as...

It took 11 weeks for pain/growth to start after starting on HT (bicalutamide). When the concentration of tamoxifen in my blood gets low enough (because I'm not taking it at the moment) to allow gynecomastia to start again, does it start another 11 week delay before the gynecomastia, or start immediately?

I did see one reference to breast growth coming in spurts and not being continuous. Maybe the 11 weeks was just the length of time to the first growth spurt, and it could be something completely different next time?

I've since switched from bicalutamide to Zoladex. Will that be better or worse for causing gynecomastia?

Eventually, I might be able to answer some of these, at least for me, providing my onco is as happy as my GP is for me to carry on experimenting on me.

Edited by member 08 May 2019 at 21:35  | Reason: Not specified

Andy

i am very interested in your modelling of Tamoxifen, as I am due to art on it soon - recently diagnosed Gleason 3+4, but ADT intended temporarily solely due to delay because of Covid19.

I am researching side effect therapy, including PDE5 and Tamoxifen.

Please could I ask for a copy of your spreadsheet ? I would like to explore the preloading strategy, and try to get additional 20mg per day for the ?8day startup (currently they are talking 20mg x2 pw).

I would be really grateful if you could pm me, I can’t contact you by pm as I have only recently started responding to posts here.

many thanks

Strad

Best wishes,

Chris

Tamoxifen is around 70% effective at preventing breast growth/pain, so doesn't work for everyone.

There's a wide range of doses too. I seem to recall NICE recommends 1 x 20mg/week, but there seems to be fairly universal acceptance that mostly doesn't work. Most people are given something between 2 x 20mg/week and 20mg daily.

The radiotherapy blast is even less successful at around 50%, but excellent if it worked for you.

I don't believe cost of Tamoxifen is of any consequence in deciding on its use - it's one of the cheapest drugs available (providing you have the 20mg tablets - the other tablet sizes are way more expensive). Total cost for 3 years would be about £45. It's more likely any refusal would be because the onco didn't know, although that's much less of an issue now than it was 2 years ago.