Why did three journals reject my puberty-blocker study? (By Sally Baxendale)
Trans children deserve to know the facts
What happens during puberty? And what happens if we try to stop it? It’s one of the most fraught questions of our time. Given its significance and the vulnerability of the people it involves, you might be surprised to learn that there have been more studies assessing the impact of puberty blockers on cognitive function in animals than humans. Of the 16 studies that have specifically examined the impact of puberty blockers on cognitive function, 11 have been conducted in animals. And most found some detrimental impact on cognitive function when the researchers gave these drugs to mice, sheep or monkeys.
The sheep studies were particularly interesting as they used twin lambs,
administering the puberty blockers to only one in the pair. More than one year
after stopping the medication, the sheep who had taken the puberty blockers had
still not “caught up” with their untreated siblings in their ability to
complete a test of spatial memory. It can, however, be fairly argued
that we can only extrapolate so much from the abilities of sheep to remember
the way through a maze of hay bales. It is really the studies in humans that
are of most interest to those considering prescribing or taking these drugs.
Yet such studies are hard to come by. There are only five that have
looked at the impact of puberty blockers on cognitive function in children, and
only three of these have looked at these effects in adolescents given the
medication for gender dysphoria. In one of these
studies, the researchers didn’t measure how well the children were
doing before they administered the drugs, so it is difficult to know whether
the subsequent difficulties they had on a strategy task could be attributed to
the medication. A second study established an excellent baseline, and the
researchers employed a gold-standard measure to test the cognitive abilities of
the children in the programme before they started the puberty blockers.
Unfortunately, they didn’t re-administer these tests to assess the
impact of the medication, but chose instead to report how many of a subset of
these children completed a vocational education and how many completed a higher
vocational education years later. No outcomes at
all were reported on 40% of the children who started out in the study.
The final study, however, was beautifully designed: the researchers assessed IQ
prior to the administration of puberty blockers and regularly monitored the
impact of the treatment over 28 months on a comprehensive battery of cognitive
tasks. The results were concerning and suggested an overall drop in IQ of
10 points which extended to 15 points in verbal comprehension. But regrettably,
this was a single case study, and while alarming, the conclusions we can draw
from one person’s experience are limited.
Last year, I wrote a paper to summarise the results of these studies. The paper explained in relatively simple terms why
we might think that blocking puberty in young people could impact their
cognitive development. In a nutshell: puberty doesn’t just trigger the
development of secondary sex characteristics; it is a really important time in
the development of brain function and structure. My review of the medical
literature highlighted that while there is a fairly solid scientific basis to
suspect that any process that interrupts puberty will have an impact on brain
development, nobody has really bothered to look at this properly in children
with gender dysphoria.
I didn’t call for puberty blockers to be banned. Most medical treatments
have some side effects and the choice of whether to take them depends on a
careful analysis of the risk/benefit ratio for each patient. My paper didn’t
conduct this kind of analysis, although others have and have judged the
evidence to be so weak that these treatments can only be viewed as experimental. My summary merely provided one
piece of the jigsaw. I concluded my manuscript with a list of outstanding
questions and called for further research to answer these questions, as every
review of the medical literature in any field always does.
As a scientific paper, it was not ground-breaking — reviews rarely are.
But by summarising the research so far, I thought it would serve as a
convenient resource for the numerous authorities currently examining the efficacy
of these treatments. It also provided key information for parents and children
currently considering medical options. Every patient needs to be aware of what
doctors do and do not know about any elective treatment if they are going to
make an informed decision about going ahead. Doctors have a duty of candour to
provide this.
I was surprised at just how little, and how low quality, the evidence
was in this field. I was also concerned that clinicians working in gender
medicine continue to describe the impacts of puberty blockers as “completely
physically reversible”, when it is clear that we just don’t know whether this
is the case, at least with respect to the cognitive impact. But these were not
the only troubling aspects of this project. The progress of this paper towards
publication has been extraordinary, and unique in my three-decades-long
experience of academic publishing.
The paper has now been accepted for publication in a well-respected,
peer-reviewed journal. However, prior to this, the manuscript was submitted to
three academic journals, all of whom rejected it. “Academic has paper rejected
from journal” is not headline news. I have published many academic papers and
have also served on the editorial boards of a number of high impact scientific
journals. I have both delivered and received rejections. In high-quality
journals, many more papers are rejected than accepted. The reasons for
rejection are usually a variation on the themes that the paper isn’t telling us
anything new or that the data is weak and doesn’t support the conclusions that
the authors are trying to draw. In a paper that is reviewing other studies,
reasons for rejection typically include criticisms of the ways the authors have
looked for or selected the studies they have included in their review, with the
implication that they may have missed a big chunk of evidence. Sometimes the
subject of the review is too wide, too narrow or too niche to be of value to
the wider readership.
While imperfect, anonymous peer review remains the foundation of
scientific publishing. Theoretically, the anonymity releases reviewers from any
inhibitions they may have in telling their esteemed colleagues that, on this
occasion, they appear to have produced a pile of pants. When it works well,
authors and editors receive a coherent critique of the submitted manuscript,
with reviewers independently highlighting — and ideally converging — on the
strengths and weaknesses of the paper. If done sloppily, or if the reviewers
have been poorly selected, the author may be presented with a commentary on
their work that is riddled with misunderstandings and inaccuracies. Requests
for information already provided are common, as are suggestions that the author
include reference to the anonymous reviewer’s own body of work, however
tangential to the matter in hand. I have been on the receiving end of both the
best and worst of these practices over the course of my career. However, I have
never encountered the kinds of concerns that some of the reviewers expressed in
response to my review of puberty blockers. In this case, it wasn’t the methods
they objected to, it was the actual findings.
None of the reviewers identified any studies that I had missed that
demonstrated safe and reversible impacts of puberty blockers on cognitive
development, or presented any evidence contrary to my conclusions that the work
just hasn’t been done. However, one suggested the evidence may be out there, it
just hadn’t been published. They suggested that I trawl through non-peer
reviewed conference presentations to look for unpublished studies that might
tell a more positive story. The reviewer appeared to be under the naïve
apprehension that studies proving that puberty blockers were safe and effective
would have difficulty being published. The very low
quality of studies in this field, and the positive spin on any results
reported by gender clinicians suggest that this is unlikely to be the case.
Another reviewer expressed concerns that publishing the conclusions from
these studies risked stigmatising an already stigmatised group. A third suggested
that I should focus on the positive things that puberty blockers could do,
while a fourth suggested there was no point in publishing a review when there
wasn’t enough literature to review. Another sought to diminish an entire field
of neuroscience that has established puberty as a critical period of brain
development as “my view”.
In a rather telling response, one of the reviewers used religious
language to criticise the paper. They argued that the sex-based terms I had
employed to describe the children in the studies — natal sex, male-to-female,
female-to-male — indicated a pre-existing scepticism about the use of blockers.
They suggested that the very presence of these terms would cause people who
prescribe these medications to “outright dismiss the article”, and went on to
say that by using these terms the paper was “preaching to the choir” and would
do a “poor job of attracting new members to the fold”. However, the most
astonishing response I received was from a reviewer who was concerned that I appeared
to be approaching the topic from a “bias” of heavy caution. This reviewer
argued that lots of things needed to be sorted out before a clear case for the
“riskiness” of puberty blockers could be made, even circumstantially. Indeed,
they appeared to be advocating for a default position of assuming medical
treatments are safe, until proven otherwise.
Yet “safe and fully reversible” can never be the default position for
any medical intervention, never mind a treatment that is now deemed
experimental by authorities in Europe and the UK. Extraordinary claims
demand extraordinary evidence, and the only extraordinary evidence here is
the gaping chasm of knowledge, or even apparent curiosity, of the clinicians
who continue to chant “safe and completely reversible” as they prescribe these
medications to the children in their care. It is not the job of a scientific
paper to “bring people into the fold”; it is the job of clinicians to understand
the evidence base of the treatments they offer and communicate this to the
patients they are treating.
I sincerely hope that any arrest in brain development associated with
puberty blockers is recoverable for young trans and gender diverse people, who
are already facing significant challenges in their lives. I would welcome any
research that indicates that this is the case, not least for the significant
insights that would present to our current understanding of puberty as a
critical window of neurodevelopment in adolescence. Puberty blockers almost
invariably set young people on a course of lifetime
medicalisation with high personal, physical and social costs. At
present we cannot guarantee that cognitive costs are not added to this burden.
Any clinician claiming their treatments are “safe and reversible” without
evidence to back it up is failing in their fundamental duty of candour to their
patients. Such an approach is unacceptable in any branch of medicine, not least
that dealing with highly complex and vulnerable young people.
Sallie Baxendale is
a consultant clinical neuropsychologist and a professor of clinical
neuropsychology at University College London.
Why
did three journals reject my puberty-blocker study? - UnHerd
