Question about Animal Research

[FWRLurker]

I'm wondering whether anyone knows if there is peer reviewed research on animals studying the effects of using hormone blockers to prevent natural puberty followed by cross-sex hormones at the age of puberty on laboratory mammals, such as chimpanzees, or even mice or rabbits. Then presumably following on with long-term assessment of physical and behavioral health in the animals...?

Because if there is not any animal research then it is pretty nuts we are doing this type of experiment on adolescent humans without at least first seeing if it is safe to do in non-human mammals. If you want any new drug regimen approved you would usually need to do an animal study first, then followed by a "safety only" study including appropriate and if possible double blind controls... Can anyone clarify? If there is animal research I'd appreciate any links to the studies. If not... then... huh?

Hormone blockers will absolutely have been tested for safety on mammals before progressing to human trials, before they were originally approved for use (e.g. for preventing precocious puberty etc). For many drugs this data is not in the public domain, but is submitted directly to the FDA/EMEA/NICE etc for approval.

I think you may be overestimating the extent to which animal testing is done for other drugs. New drugs are tested for safety in animals before being tested in humans. But once safety/tolerability of the drug is fairly established, they don't do animal trials for every possible new combination of drugs, every different dosing regimen, etc. They definitely don't do long-term assessments of physical and behavioural health in animals, at least not for the majority of drugs. Especially behavioural studies.. animal testing has limited utility for assessing safety and dosing, because of physiological differences, I can't imagine it is anywhere near justifiable for assessing behaviour - especially for something related to gender dysphoria which is presumably not a condition that one can find or induce in lab animals

Please don’t ever go to Cambridge and shout that animals should be tortured.

"Please don’t ever go to Cambridge and shout that animals should be tortured."

Surely it's at least slightly morally preferable to torturing children

ExplodedPeach Thanks for the information on animal testing. So you're basically saying that no drug needs to be tested for long-term effects on nonhuman animals prior to approval of human trials?

I would think that it is reasonable to test long term health effects of something as drastic as attempting to "reverse puberty" in animals prior to testing on humans. Surprised this isn't the case.

Puberty blockers are being used ''off label'' for children. That means they have not been tested or approved for this purpose.

I think the idea is that in the past animals were indeed tortured for pointless experiments that did nothing to help humans so the idea is to minimise their suffering by not doing pointless work.

If I understand it rightly, exploded peach is saying that animal bodies are so different to ours (as are their lifespans) that using puberty blockers on them wouldn't be useful. And obviously disphoria is not a condition animals can have.

I see the OP's point though, that if there is a fear that puberty blockers have long term detrimental physical effects then there would be an argument for trying them in rats.

Yes and no. To pass the clinical trial process the blockers will have undergone animal testing before being allowed to phase 1 of trial. However, that is basically to look at specific safety/pharmakokinetics. It wouldn’t have been looking at ‘what happens long term to mouse puberty.’ It would look at things like lifespan, tumours, reproductive toxicity etc. The experiments should be available somewhere

Remember that a lot of the effects in humans wouldn’t be visible in mouse - human cognition isn’t modelled there, bone density over many years isn’t either.

So they will have passed specific tests in animals but those tests won’t be too informative on what happens when you delay puberty in humans.

I guess my overall thought is basically this. There is a specific theory being put forth by those using the drugs that whats being done is artificially inducing a puberty normally experienced by the opposite sex. If this is really the case it should be testable in primates which indeed go through a puberty involving basically the same hormones. Instead were experimenting in human children...

The posts above show why the 'specific theory' has to be in terms of animal testing is used. I recommend you quote from them, if someone drags you into a misguided conversation about this. Recommending Bad Science, by Ben Goldacre is often a good step, bu it doesn't cover this directly.

But probably better to leave well alone, in the hope it'll die out. Though I suppose the right thing to do would be to explain, before those espousing this become discredited or even complete laughing stocks.

Primate research is (rightly, imo ) very difficult to do and subject to extremely strict rules. You need to pass very high hurdles and it’s very expensive and not many places do it. The chances of doing more retrospective work on an already approved drug is slim to none.

So it’ll be post marketing safety that picks this up. All drugs and devices are subject to this, even after they’ve been approved by the FDA or relevant national body (MHRA in Uk.) safety reporting continues because as you get more people taking a drug you see more of the rarer side effects simply because of population size, and you see long term effects.

So alas, it is and it will continue to be humans that these drugs are tested in. I think the FDA is investigating the class of drugs blockers belong to due the negative effects reported? They can and do pull drugs (vioxx for example) from market. However I doubt these will be pulled simply because they aren’t livenced for treating gender questioning in the first place. They do have a role in treating prostate cancer for example. What’s needed is very clear guidelines for prescription, and possibly a black box warning for anything to do with gender - that would maybe change the liability balance for those prescribing?

Long ramble post sorry:

The clinical trial number for the paediatric trial of Lupron (triptorelin is used in the Uk, but it’s a very similar drug that can be expected to have a similar side effect profile) is : NCT00660010

There should, in an ideal world, be more data online and filed publically. The investigators brochure would be very useful (that’s the document that they give to doctors who help to run the trial to inform them of all the animal work and preclinical work done, along with the design of the trial) however I can’t see it online. I’ve only had a quick look so it may be worth a poke around.

From the pediatric package insert:

Discontinuation of LUPRON DEPOT-PED should be considered before age 11 for females and age 12 for males. so these drugs are supposed to be taken for a short period of time only. Then you’re supposed to discontinue them and allow natural puberty to kick in. (A reminder for those reading that opposite sex hormones do not induce a correct opposite sex puberty in a child.)

And animal work .. in rats, a dose-related increase of benign pituitary hyperplasia and benign pituitary adenomas was noted at 24 months when the drug was administered subcutaneously at high daily doses (0.6 to 4 mg/kg). There was a significant but not dose-related increase of pancreatic islet-cell adenomas in females and of testicular interstitial cell adenomas in males (highest incidence in the low dose group

This bit is worth highlighting in flashing red capitals: no clinical studies have been completed in children to assess the full reversibility of fertility suppression.

www.accessdata.fda.gov/drugsatfda_docs/label/2005/020263s026lbl.pdf

So they do not know if the effects of the drug are fully reversible

The insert goes on to state that: immature male rats demonstrated tubular degeneration in the testes even after a recovery period. In spite of the failure to recover histologically, the treated males proved to be as fertile as the controls. Also, no histologic changes were observed in the female rats following the same protocol. In both sexes, the offspring of the treated animals appeared normal. The effect of the treatment of the parents on the reproductive performance of the F1 generation was not tested. The clinical significance of these findings is unknown.

What does that mean in layman’s terms? Basically that at a cellular level, the testes of the rats didn’t recover - permanent changes were seen. The rats remained fertile (remember that rats breed like, well... rats ) and the effects of the fertility of their offspring were not investigated at all.

I would be very interested to see the full data package that was submitted to the FDA. I don’t know if under whatever they have in the USA as freedom of information legislation would allow you to ask for the minutes of the pane that approved it. The actual data is confidential (and in a raw form wouldn’t be useful to you anyway)even though good practice is to be as open as possible and file redacted and processed data.

If anyone does have time to poke, the approval data for trelstar (triptorelin) would be v useful.

Thanks bowl very interesting.

So they gave it to juvenile male rats for a short time and saw some effects on testes growth. I assume any sensible scientist / endocrinologist would realize that it would if not discontinued, sterilize the rats, so perhaps they don’t feel the need to go further.

I still think long term exposure to the cross sex hormones should be done on animals. Docs and activists are literally telling people they are safe and induce a natural puberty of the opposite sex without any evidence of this...

So you're basically saying that no drug needs to be tested for long-term effects on nonhuman animals prior to approval of human trials?
As I understand it, that's right - early phase/animal trials aren't my area of expertise (I work in a different area of health/drug research) but I've never heard of it happening.

I still think long term exposure to the cross sex hormones should be done on animals. Docs and activists are literally telling people they are safe and induce a natural puberty of the opposite sex without any evidence of this... I think it is very obvious that they do not induce a natural puberty of the opposite sex (although I'm not denying people may be being told/believing this to be true).

But animal trials assessing whether they are 'safe' long-term, and whether they have long-term effects, are not realistic for a number of reasons (beyond the obvious cost, time, and ethics of them). But these are very complex questions...

From a scientific perspective, it is very obvious that cross-sex hormones suppress some sexual characteristics, and promote others. Normal puberty is the process of the body developing so that it is ready for sexual reproduction. So a "normal" puberty of the opposite sex is impossible as you lack the primary sex organs (ovaries/testes, etc). You cannot produce sperm without a Y chromosome, you cannot produce and release eggs without ovaries, and you cannot grow a foetus without a uterus.

Ok, but we can do research on other long-term effects, sure. Bone density, fertility, cancer risk, the list goes on. But for many of these things, we don't have a really good grasp on what is "normal" for humans, because we vary in weird and wonderful ways which are sometimes linked to health issues and often not. There are lots of things we have observed to be true, but do not come anywhere near understanding the causes of. Our multidimensional understanding of biology and medicine is even worse.

To do long-term cross-sex hormone trials (or indeed, any other really long-term drug trials) in animals we would first need a really incredibly detailed understanding of long-term human risks, then the same for what is "normal" for animals, and then the long-term studies of the changes in animals, which then may or may not be able to be extrapolated to humans.
The amount of time and money that would cost, not to mention the ethics of doing that much animal testing, for knowledge that is ultimately of limited use because animal results are always limited in how well they apply to humans.. means it is totally unrealistic.

So you're basically saying that no drug needs to be tested for long-term effects on nonhuman animals prior to approval of human trials?

Correct. An investigational product (or ‘IP’, basically a new drug /vaccine/device etc) only has a limited patent life. To make a profit you need to test and get it to market with a few years left on that life while you have patent rights. No long (decades) studies are done. Couple of years absolute max.

Long term tests on animals would be unlikely to produce very meaningful results in this specific case.

Also, the very idea or stopping the natural puberty of a healthy child would have been considered beyond the pale ethically until very recently. It would have been seen as completely unacceptable ethically. It was a Dutch group in the 90s who first did this stuff. Before that, if you’d said ‘I’m going to use these drugs to stop puberty permanently in healthy life and then give them cross sex hormones and see what happens’ you’d have been met with ‘Mengele.’ And I don’t say that lightly.

These are experiments on children. Physically healthy children. It is obscene.