Over the past year, there have been mounting criticisms of a study into the effects of puberty-blocking drugs when used to treat young people with gender dysphoria - including concerns raised by Newsnight.
The study was carried out at the Gender Identity Development Service (Gids) at London's Tavistock Clinic - England's only NHS youth gender clinic - and partly led to the clinic lowering the age at which it offers children puberty blockers. The clinic started recruiting young people to the study in 2011.
Puberty blockers are given to young people who are struggling with their gender identity. They work on the brain to stop the rise in sex hormones - oestrogen and testosterone - that accompanies puberty. These are the hormones that lead to changes in the body, such as periods, breasts or voice-breaking.
In the study, young people with gender dysphoria and their carers were told: "Hormone blockers will make you feel less worried about growing up in the wrong body and will give you more time and space to think about your gender identity."
In July, Newsnight reported on early data from the study, which showed some taking the drugs reported an increase in thoughts of suicide and self-harm. These claims, along with others, were passed on to the NHS's Health Research Authority - which ensures medical studies are ethical and transparent - which prompted the investigation.
An official review by the HRA into the conduct of the study, has cleared the researchers of any wrongdoing.
It found that researchers worked "in accordance with recognised practice for health research" adding that in some areas they were "ahead of normal practice at the time".
The Tavistock and Portman Trust welcomed the findings. A spokesperson said: "The early intervention study was undertaken after nearly a decade of consultation with international experts, was fully approved by a research ethics committee and has followed good research practice."
The BBC has found the scientific debate around blockers increasingly fractious, with experts only prepared to comment off the record for fear of reprisal. However, the HRA - who would not name the authors of the report - praised the researchers for being "open and transparent"
The results of the study are yet to be published, but a number of concerns were raised to BBC Newsnight and the British Medical Journal:
- The process used to get ethical approval was not appropriate
- Early results reported to the Tavistock board by the researchers had suggested a "statistically significant" increase in suicidal thoughts in those taking the blocker for a year
- The researchers failed to comply with HRA requirements to give them annual updates on the study
- Information was missing from consent forms including a 2010 Dutch study which showed "no adolescent withdrew from puberty suppression, and all started cross-sex hormone treatment"
In response to the key allegations, the HRA said:
- Many researchers don't submit updates, despite routine requests
- There were no serious adverse events - such "worsening behavioural and emotional symptoms" would not "be unexpected"
- Ethical processes were followed but the members of the ethics committee that approved the study should have declared any conflicts of interest. There was "no such record in the minutes of this meeting"
- The publication of the Dutch study did not "warrant changes" to study documents
The HRA point out that it is not in its remit to "comment on the interpretation of any of the publications referred to in this study," something over which there has been debate.
It could also not provide comment on the clinical services provided by Gids, or the policy decision approved by NHS England in 2014 to allow children in the early stages of puberty access to hormone blocking drugs.
The question will be whether the publication of the full study results will answer some serious questions at the heart of the debate around the purpose of puberty blockers - and indeed whether you can predict in which young people gender dysphoria is most likely to persist.
The HRA said clinicians and researchers should "avoid referring to puberty suppressing as providing a 'breathing space' to avoid risk of misunderstanding".
Rather, the purpose of the treatment should be described as being offered to children demonstrating strong and persistent gender identity dysphoria "such that the suppression of puberty would allow subsequent cross-sex hormone treatment without the need to surgically reverse or otherwise mask the unwanted physical effects of puberty in the birth gender".
In clinical practice, several former Gids clinicians question whether people can accurately predict this pathway.
"That would mean Gids has accurate procedures that can differentiate between those whose gender dysphoria in childhood will desist and those for whom it will persist," one ex-Gids clinician, who wished to remain anonymous, told Newsnight.
"The service is not able to do this for a number of reasons, including the nature of the assessment process, research in this field is still lacking, and that the patient cohort has changed significantly in the last few years."
Evidence is also emerging that provides insights into whether puberty blockers are a treatment to help alleviate gender dysphoria, or if they're fundamentally part of the pathway to full medical or surgical transitioning.
"We were constantly told, and told to tell patients that the blockers provided a pause. There was no doubt that that is what we were saying," the former Gids clinician said.
Indeed, last year Dr Polly Carmichael's - director of Gids - team wrote in a journal: "Puberty suspension with GnRHa [puberty blockers] constitutes a treatment in its own right, meaning that it is not indicated purely as a preliminary stage before the next stage of treatment towards gender reassignment, namely gender-affirming cross-sex hormones."
Yet another study by the Dutch team this year found that treatment with puberty blockers "is described as an extended diagnostic phase" and that many transgender adolescents seem to experience them as the "first 'necessary' medical step of a seemingly indisputable trajectory with permanent physical changes (through gender affirming hormones and/or surgeries) in the end".
But as Newsnight has reported, there are methodological issues with many of these studies - they lack control groups and are often quite small. This limits what can be inferred from them.
While the evidence continues to emerge, debate will no doubt continue about use of puberty blockers in young people.
If you are affected by any of the issues raised in this article, you can find support and advice via BBC Action Line.