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naraburns  nihil supernum  1yr ago (text post)   35347 thread views

Culture War Roundup for the week of April 3, 2023

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Okay, that's fair! So, to be clear, this is a question of fact, and if the best estimate we currently have says that puberty blockers are, in particular circumstances, linked to a lower risk of suicide, then you wouldn't have an objection?

they have no evidence that it reduces the risk

I'm aware of Turban et al. (2020) and Tordoff et al. (2022). Note that as of 2018, a literature review concluded that "the psychosocial effects of gender-affirming hormones in transgender youth have not yet been adequately assessed". So at that point, the right thing to tell patients and parents would be different. But it looks like you can reasonably say that puberty blockers are indicated in certain circumstances, and not using them carries an increased risk.

So as promised here's my links.

  • In 2019 the Swedish Agency for Health Technology Assessment and Assessment of Social Services published it's review of the literature on gender dysphoria in children and adolescents concluding there's little evidence (and no randomized controlled trials of children and adolescents). The review resulted in a change in policy on how blockers are administered, first at the Karolinska Hospital, and later nationally. The National Board of Health and Welfare concluded that the risks of puberty blockers currently outweigh the benefits, and they should only be administered under a research framework and in exceptional cases.

  • In 2020 UK's National Institute for Health and Care Excellence published a review of the literature on puberty blockers. The report concludes that to the extent there's evidence for good or bad impacts of blockers, the quality of the evidence is rated at "very low certainty". The review was used in the Cass Report resulting in the shutdown of Tavistock's gender dysphoria clinic.

  • In 2023 the Norwegian Healthcare Investigation Board published their report on Patient safety for children and young people with gender incongruence. They similarly conclude there's not enough evidence to routinely prescribe blockers to children with gender dysphoria, declared blockers experimental, and recommended that the Ministry of Health revise their national guidelines to restrict the administration of blockers.

There's been similar noises out of France and Belgium, but I've only heard about scientists raising an alarm, rather than an official report being published.

Thanks! I'd previously seen the difference between the Swedish model and WPATH recommendations, and kinda dead-ended there, because I'm not a researcher, just a layman trying to do my homework. (For example, I don't know how you could ethically do an RCT on puberty blockers in children and adolescents.)

I do notice that the NICE report excludes Turban et al. (the strongest evidence I'm aware of that puberty blockers reduce the risk of suicide) with the explanation "Intervention – data for GnRH analogues not reported separately from other interventions". (I don't understand why the criteria were set to exclude nearly every study.) On page 19 and following, it relies entirely on de Vries et al. (2011), which is a prospective study of seventy people, to conclude that "This study provides very low certainty evidence that treatment with GnRH analogues, before starting gender-affirming hormones, may reduce depression." So, in plain terms, it looks promising, but we don't have enough information to have a strong opinion.

It looks like the state of evidence is different now than it was in 2018. These questions are, generally speaking, answerable, and it looks like the best information we have indicates that puberty blockers reduce the risk of suicide in adolescents with gender dysphoria. Perhaps a good use of time would be to develop better diagnostic tools so that dysphoric adolescents who will likely not pursue transition aren't offered puberty blockers, and those who likely will, are.

(For example, I don't know how you could ethically do an RCT on puberty blockers in children and adolescents.)

Why is it ethical to RCT every other medication before it gets approval?

I do notice that the NICE report excludes Turban et al. (the strongest evidence I'm aware of that puberty blockers reduce the risk of suicide)

On that one in particular, I'd read some of the comments at the bottom of your link:

Given the controversy surrounding the practice of puberty suppression for gender dysphoric adolescents, the article by Turban et al.1 creates more confusion than clarity. The authors imply causal evidence for a reduction in suicidal ideation with transgender adolescents who received puberty suppression (PS), yet they fail to acknowledge the exceedingly high rates in both groups of suicide ideation (75% and 90%) and suicide attempts (42% and 51%). The cross-sectional design using online survey data is insufficient to validate the efficacy of such a life-altering therapy.

...

What is more disturbing is that the PS treated group actually had double (45.5% versus 22.8%) the rates of the control group for serious (resulting in inpatient care) suicide attempts in the year preceding the data collection (Table 3)

 

Because adolescents with greater suicidal ideation were less eligible for puberty blockers, this automatically created an initial negative association between the two—before the treatment took effect. Therefore authors’ finding, from adults surveyed many years after treatment, is compatible with three scenarios: puberty blockers reduced suicidal ideation; puberty blockers had no effect on suicidal ideation; puberty blockers increased suicidal ideation, albeit not enough to counteract the initial association between suicidal ideation and eligibility.

The authors acknowledge that “the study’s cross-sectional design… does not allow for determination of causation.” (...)

Aside from the spurious leap from association to causation, the analysis is inevitably limited by the poor quality of the data.

Firstly, the survey’s respondents are not sampled from any defined population. The convenience sample excludes those who underwent medical intervention but subsequently stopped identifying as transgender. It also excludes those who did commit suicide.

Secondly, the key questions on puberty blockers confused some of the respondents. The survey report cautions that “a large majority (73%) of respondents who reported having taken puberty blockers [in question 12.9] ... reported doing so after age 18 [in question 12.11] ... This indicates that the question may have been misinterpreted by some respondents who confused puberty blockers with the hormone therapy given to adults and older adolescents” (James et al. 2016: 126). To mitigate this problem, Turban et al. follow the survey report in ignoring those respondents who reported taking puberty blockers after the age of 18. No such adjustment is possible, however, for the question asking whether the respondent had ever wanted puberty blockers, which Turban et al. use to define the subset of respondents in their analysis. Therefore the comparison group will include an unknown number of respondents—possibly the majority—who actually wanted cross-sex hormones rather than puberty blockers.

Thirdly, many questions have a large number of missing values. Of the 89 respondents who took puberty blockers, only 11 answered the question on whether they had been hospitalized as a result of attempting suicide in the last 12 months (question 16.5).

 

to conclude that "This study provides very low certainty evidence that treatment with GnRH analogues, before starting gender-affirming hormones, may reduce depression." So, in plain terms, it looks promising, but we don't have enough information to have a strong opinion.

I don't think studies at "very low certainty" can be considered promising. From what I understand we're still in the midst of a replication crisis, so between that and publication bias, "positive finding at very low confidence" should probably default "it's probably just noise".

It looks like the state of evidence is different now than it was in 2018. These questions are, generally speaking, answerable, and it looks like the best information we have indicates that puberty blockers reduce the risk of suicide in adolescents with gender dysphoria.

It might be answerable eventually, but the question is too complex to settle on the basis of the latest paper. Keep in mind we're not talking about the optimal way of setting a broken bone, or even about the best therapy for cancer, which has a lot more pitfalls. We're talking about psychiatry, a field that spent years prescribing SSRIs for depression only to go "oops, they might actually be no better than a placebo". With things like suicide in particular, we know there's a significant social contagion component, where even a silly Netflix show for teenagers can trigger a wave of suicides. So with ubiquitous messaging about trans healthcare saving lives, "would you rather have a happy daughter or a dead son?" etc, you don't even know if you're measuring the impact of the puberty blockers, or the impact of the messaging.

Finally, there being a positive signal in the literature that blockers may reduce suicide risk does not justify scaring the parents into allowing blockers for their kids. Far more confidence is needed to make such statements ethically.

Why is it ethical to RCT every other medication before it gets approval?

You're right; I'm not sure what I was thinking. I guess you'd enter adolescents with gender dysphoria into a study, and either give them puberty blockers or a placebo, would be hard to keep secret from the patients. But I'm reminded of AIDS patients desperately trying to beat the blinding system in the AZT trials. ("There were also stories of patients from the 12 centers where the study was conducted pooling their pills, to better the chances that they would get at least some of the drug rather than just placebos.") And a story I can't find right now about a teenager who stole HRT from their mother back in the sixties or seventies.

My concern is less that people are ignoring the evidence we have (as you point out, the best we have is an uncontrolled retrospective study), and more that the people fighting the use of puberty blockers in teenagers have no interest in answering these questions. I see this in the pre-emptive excuse-making; if we did do an RCT and puberty blockers saved lives, maybe the whole thing is still social contagion?

Finally, there being a positive signal in the literature that blockers may reduce suicide risk does not justify scaring the parents into allowing blockers for their kids. Far more confidence is needed to make such statements ethically.

And here we're back to the beginning. If you say, "a massive uncontrolled retrospective study found that kids who present with the symptoms your kid is presenting with were less likely to commit suicide when given this treatment", are you "scaring the parents into allowing blockers for their kids"?

But I'm reminded of AIDS patients desperately trying to beat the blinding system in the AZT trials.

Right, and I'm reminded of lobotomies and psychosurgery, where people were told to trust the experts sticking electrodes in their brains supposedly for their own good.

and more that the people fighting the use of puberty blockers in teenagers have no interest in answering these questions. I see this in the pre-emptive excuse-making; if we did do an RCT and puberty blockers saved lives, maybe the whole thing is still social contagion?

It's not that they're not interested in answering the question, it's that they don't think society should bend itself around the latest idea coming out of academia.

Like I said, there's place for experimental medicine, and I'm ok with blockers being used in that context. Once we gather enough data, and it's blindingly obvious blockers do more good then harm we can move towards mainstream usage.

What we shouldn't do is prescribe blockers to every kid with dysphoria, just because the latest hottest RCT came out. What would you think of a doctor that started prescribing Ivermectin for COVID because a positive study just came out (and those were actual RCTs by the way)? Should they be allowed to say "people who don't take it have a much higher chance of dying" as they prescribe it?

If you say, "a massive uncontrolled retrospective study found that kids who present with the symptoms your kid is presenting with were less likely to commit suicide when given this treatment", are you "scaring the parents into allowing blockers for their kids"?

If you're hiding the base rate of risk, and neglecting to inform them the study has no way of determining the direction of the causality, then obviously yes.

I'll gather my links tomorrow, but there are a more recent reviews from several European countries concluding that to the extent there is evidence for puberty blockers, it's quality is poor.

Aside from that, in the case of most other medications, you don't get to make such sweeping claims on the back of a few studies, and you have to go through blinded clinical trials before you can perscribe them for a given condition.

At best blockers could be considered experimental, and anyone trying to scare people into taking them is acting extremely unethically.

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