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How safe is safe?
My apologies for dropping this post in the forum at holiday time – but perhaps it will give something to read and think about when the crackers are all pulled and the puddings eaten.
Summary
This post explores what is known about the safety of HRT for transgender patients.
It finds that there is very little published data, and much of what is recorded only applies to transsexuals seeking sex reassignment. The hormone doses currently prescribed are not underpinned by research determining the most effective hormone regime for patients. However, despite this lack of knowledge about efficacy there is no indication that the use of HRT is unsafe even at relatively high levels.I would welcome responses to this post that identify any clinical data that escaped my search. And of course, I look forward to feedback on the conclusions I drew from my research.
How safe is safer?
“Why”,”if”, and “how” to take hormones – these are questions that many of us will find ourselves seeking an answer at some time.
Some elect to experiment themselves, some seek medical advice, and others follow medical advice.When the subject of hormone therapy appears in these forums it generally attracts the advice that the safer thing is to do it under the guidance of an endocrinologist.
Safer it may be, but I started to ask myself “safer than what?” and “how safe is safe?”.
What evidence does this advice rest on?
Join me on my quest for the holy grail of transgender HRT.
Who has scientifically tested hormones on transgender patients?
The hormones that are used to help reconcile our gender identity are being used off-label. So that eliminates one source of evidence – the pharmaceutical company and regulatory bodies.
Off-label means that the drug manufacturer has not performed any testing to determine if they can be safely used in this way. Neither has the manufacturer performed any studies to see if there are long term side effects, or to determine what the optimal dose might be.
So, if the manufacturer and the TGA haven’t assessed the safety, who has?
I turned to Google to find follow-up studies done on a large, statistically significant, cohort of transgender patients. And found there are very few. Most of the studies that have been published only address a small part of the transgender spectrum, transsexual patients undergoing sex reassignment. I found nothing that was applicable to the vast majority of gender diverse – those who feel some degree of gender dysphoria (or mismatch) but who do not need to, wish to, or are not able to, pursue surgical options.
But as it is all there appears to be available, let’s look at what is known about transsexual health outcomes on HRT.
A study into the long term health outcomes of transsexuals
In 2011 the European Journal of Endocrinology published the results of study into the adverse long-term effects of cross-sex hormone administration.
http://www.ncbi.nlm.nih.gov/pubmed/21266549They looked at 966 (MtF) and 265 (FtM) transsexuals who started HRT before July 1997 and compared outcomes with the general population.
In the MtF group they found mortality was 51% higher than the general population with a higher incidence of suicide, AIDS and cardiovascular disease. The propensity for cardiovascular disease was attributable to the use of oral ethinyl estradiol – trending similar results with post-menopausal natal women. Oral estrogen is no longer a recommended treatment. HRT was found to have no effect on cancer mortality rates.
The study concluded that
Quote:the higher mortality rate in MtF transexuals was mainly due to non-hormone related causes.Which of course makes the hormones totally safe…or does it?
A study into the long term health outcomes of transsexuals undergoing sex reassignment
It was a surprise to find that suicide was the most significant adverse outcome – not liver failure or cancer. So I looked for data that would explain why endocrinologists assert that the hormones have nothing to do with this outcome.My search brought me to “Long-Term Follow-Up of Transsexual Persons Undergoing Sex Reassignment Surgery: Cohort Study in Sweden”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3043071/?tool=pubmedThis study looked at 324 sex-reassigned persons in Sweden, 1973–2003. They found that the sex reassigned cohort were 20 times more likely to die from suicide.
Their conclusion was that
Quote:“Our findings suggest that sex reassignment, although alleviating gender dysphoria, may not suffice as treatment for transsexualism, and should inspire improved psychiatric and somatic care after sex reassignment for this patient group.”(underline is my emphasis)
Perhaps the real risk is mental health?
Perhaps electing to pursue sex reassignment is actually the main risk, and not specifically the high-dose estrogen regimens associated with that pathway.The subsequent disapproval and confusion of friends and family creates a burden of stress that apparently continues past physical sex reassignment. Add to that more stress caused by it finding difficult to obtain and keep jobs. Then the cocktail of hormones kicks in with heightened emotional sensitivity and often irrational behaviour.
But even if HRT is just one factor that leads to heightened psychological stress, it does seem to be stretching things a bit to say it has no bearing on the adverse outcomes.
Without more data it would be prudent to acknowledge the potential mental health risk of HRT.
How little we know
These two studies served to illustrate to me how little is known about HRT.Sex reassignment has been practised for more than half a century and is the internationally recognized approach to ease gender dysphoria. But I found no data to show if it yields better long-term outcomes for all patients than non-surgical treatments.
Also I found no data showing how the outcomes of HRT are affected by the choice (or lack of) medical professionals involved. There is no data comparing adverse outcomes from self-prescription, monitoring by a GP, or prescription through an endocrinologist. It is tempting to assume that there may not be a significant difference, particularly between the last two.
Finally I found no evidence to determine the optimal hormone dose to achieve the desired outcomes whilst minimising adverse long-term effects.
I find the last unknown particularly troubling.
Determining the correct treatment regime
I’ve worked for much of my life in the medical industry, and I know the painstaking process that has to be followed to establish the safest and most effective treatment. If there are no published studies, then how is the best hormone dose determined?The Wold Professional Association for Transgender health (WPATH) publishes regular guidelines in the “Standards of Care”. HRT is a criteria for sex reassignment surgery and so the standards of care address the use of HRT in this context, and also for hormonal minimization of existing secondary sex characteristics. WPATH notes the lack of medical data saying:
Quote:To date, no controlled clinical trials of any feminizing/masculinizing hormone regimen have been conducted to evaluate safety or efficacy in producing physical transition.WPATH does not advocate any specific hormone doses but does refer to The Endocrine Society Guidelines (2009) which
Quote:provide specific guidance regarding the types of hormones and suggested dosing to maintain levels within physiologic ranges for a patient’s desired gender expression (based on goals of full feminization/masculinization).The Endocrine Society in the USA guidance on the Endocrine Treatment of Transsexual persons is available on-line. http://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Practice%20Guidelines/Endocrine-Treatment-of-Transsexual-Persons.pdf
The guidelines describe the two major goals of HRT in the context of treating transsexuals as:
Quote:“1) to reduce endogenous hormone levels and, thereby, the secondary sex characteristics of the individual’s biological (genetic) sex and assigned gender and
2) to replace endogenous sex hormone levels with those of the reassigned sex..”More specifically for natal males, the endochrinologist sets a target of achieving the serum estradiol and testosterone levels of pre-menoplausal women. The guidelines assert that this hormonal regime results “in physical changes and, usually, an improvement in mental well-being”.
It isn’t clear where the propensity for suicide fits into those preferred outcomes. But perhaps this reflects a general attitude that mental health issues resulting from the journey to sex reassignment are not related to the HRT regime. A cross-disciplinary approach might call this assumption into question.The possibility of adverse outcomes is considered in Section 4 where it is stated that
Quote:“The risk of cross-sex hormone therapy arises from and is worsened by inadvertent or intentional use of supraphysiologic doses of sex hormones or inadequate doses of sex hormones to maintain normal physiology (81, 89).”So the risks associated with having too many or too few hormones appears to be the reason for recommending what are in practice high cross-sex pharmacologic doses.
The evidence for using female-equivalent target hormone levels
So I looked at the two references (81 & 89) for the medical research on which this apparently higher-risk strategy rests.
Reference 81 only addresses the risks of HRT in F2M patients.
So I was left with reference 89 “Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience. 2008”.
http://www.ncbi.nlm.nih.gov/pubmed/17986639This study considers 2236 male-to-female transsexuals treated at a gender clinic in the Netherlands. The cohort for this study once again only included transsexuals who proceeded with reassignment surgery.
The conclusion of the referenced study wasQuote:“Cross-sex hormone treatment of transsexuals seems acceptably safe over the short and medium term, but solid clinical data are lacking.”I looked into the report for the detail as to why too few or too many hormones are considered to have higher risk. But it turns out the study didn’t investigate the effect of varying dose on outcomes. It only concerned itself with the implications of a post-operative transsexual ceasing HRT later in life.
The study considered osteoporosis, cardiovascular disease and cancer as possible risk factors – but identified no significant concerns.
I can’t see any reason why this study was quoted in the context of setting a HRT regime. Except perhaps to appear to add scientific weight to what appears to be an arbitrary guideline.The search for the holy grail of HRT safety abandoned
At this point I stopped my search for the elusive truth about HRT safety.
I started to suspect it does not exist, or perhaps it is written in language I don’t understand.
And I am left to draw my own conclusions:
[ul]A) The current practice of endocrinologists is based on untested assumptions which have subsequently been validated empirically.
It appears that only two acceptable hormonal states are considered – male and female . However the extreme male to female cross-sex treatment regime adopted has been shown to have no adverse outcomes directly attributable to HRT. It may not however be safe.
[/ul][ul]
Subject to appropriate monitoring, HRT does not elevate mortality through osteoporosis, cardiovascular disease or cancer.
[/ul][ul]C) It is possible that less extreme HRT doses could produce equally good outcomes, particularly in transgender males not seeking sex reassignment. But there is no data because no one is reporting and analysing adverse effects outside gender clinics.[/ul][ul]D) Finally, there is compelling data to indicate that the transsexual journey through sex reassignment is high risk. This is not a physical risk attributable directly to HRT, but rather a mental health risk following from heightened psychological stress.
[/ul]
What is safe?
Without the benefit of controlled clinical trials working out what is safe is going to involve some uncertainty. But from my research I think I can point to what is likely to lower risk.If you are diagnosed as transsexual and this leads you to seek sex reassignment then:
[ul]- HRT is relatively safe (provided you have regular blood tests). The testing for blood hormone levels may be justified to avoid any risks associated with excessive doses of sex hormones but there is no clinical evidence to determine if measured hormone levels are, or are not, desirable.[/ul][ul]- Your main risk in the long term is probably not HRT but the effects of psychological stress. So ensure you establish a relationship with a psychiatrist – and not just to get some paperwork to allow sex reassignment surgery but for the rest of your life.[/ul]If you do not immediately seek sex reassignment, but wish to take hormones to reconcile your physical gender then
[ul]- You have more treatment options to consider – but you will have to make your choice without the benefit of any medical data. If anyone tells you one option is safer than another then they are probably expressing an opinion and not a fact.[/ul][ul]- The treatment options offered by endocrinologists may actually be less appropriate for you if they are based on the experience of preparing transexuals for surgery. [/ul][ul]- Avoiding, if possible, the treatment pathway established for transexuals will probably be safer, as there are data pointing to adverse long term mental health outcomes of sex reasignment.[/ul]Moderator
Quote:WARNING
TgR is not a medical forum and any comments you may read in TgR forums are only the opinions of the member posting. You should not assume that a posting on TgR implies any verification or independent review and whilst the advice is honestly offered it is made without knowledge of your particular medical conditions. You should always seek professional medical advice before taking any action that might affect your health. -
7 Replies
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Thank you A/A for addressing such a daunting topic. I have been researching this topic for many years. Both for my own information & to garner the world’s best practice so that I can apply that to my patients . So a number of the references that you quoted are already familiar to me.
My conclusion is similar to yours & that is; evidenced based medicine as regards HRT for transsexuals does not exist. The Royal College of Psychiatrists in their 2013 “Good practice guidelines for the assessment & treatment of adults with gender dysphoria” state under the heading Guidelines for hormonal interventions “accepting the desire for the guidelines to be evidence based, there is a great paucity of such evidence.”The most accurate estimation of the rate of gender dysphoria in the UK population is 1%. Given the fact that multinational drug companies do most of the world’s research, they are not going to invest many millions of dollars into the best treatment options for us because they are not going to get a return on investment. Therefore what research is done, is done by gender clinics & universities. The most identifiable transgender group are those wanting SRS & therefore they are the ones that are studied. Other gender diverse groups are too hard to identify or do not attend gender clinics.
There are a number of statements in your excellent post that I would like to comment on.
There was a significant “typo” in your critique of the Asscheman et al paper. The number of FTM transsexuals was 365 not 265.
You have also left off two other causes of increased mortality in the MTF group – drug abuse (which was significant) & “unknown”. You have inferred that the authors state that oral oestrogen is no longer recommended. That is NOT true. They recommend that ethinyl oestradiol should not be used but low dose oral oestrogen is acceptable.In the section on SRS you implied that suicide was the major adverse outcome. Yet the above paper states “Psychological evaluation has shown that sex reassignment increases the well-being of transsexuals, but it should not be considered as a cure-all; it is rehabilitative relieving gender dysphoria, but some transsexual subjects may still experience other problems (e.g. comorbid psychiatric problems, social isolation, troubled relationships, prejudice, and discrimination). “
Therefore assessment of other psychological factors is very import & I agree with your conclusion that the “real risk is mental health” & the conclusions of the second paper that you quote.
Other important issues are unemployment & harassment.I agree with your conclusion that there may not be any difference in seeing an endocrinologist & an experienced GP who is familiar with managing TG issues. In fact I would argue that the GP is better because, the Endo is seen once or twice a year. Yet the GP may be seen very often & thus he/she would be more in touch with social or mental issues.
The optimum hormonal dose! What a thorny issue. Assuming that treatment should produce oestrogen levels similar to that of a cis woman. The problem is that during her monthly cycle there are 4 different hormonal phases. Which one do you pick? There is no EBM for guidelines here. The easy answer is the one that gives the desired results with the lowest oestrogen dose & that it is in the most appropriate delivery form. I aim for 2/3 of the cis woman’s oestrogen level in the follicular phase. But my opinion is not EBM.
One of the major problems I have found is that MTF’s want to develop breasts overnight.A/A I fully endorse your conclusion that the major problem is not HRT but the psychological stresses of being transgendered.
I think that we would both agree with the 10th recommendation of the RCPsych Guidelines;
“There remains a paucity of research in the field. Research should be
encouraged and funding set aside to offer specific grants looking at
outcome and satisfaction with interventions and transition.”Thank you once again A/A on a thoughtful post.
On re-reading my post, I think that I could be considered going off topic. I will leave that to your discretion.
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Ok im going to jump in here a little hesitant as I do not possess the medical background and expertise you do. But I do have my own life experience to offer . Firstly you are right in my view there has been very little research done on this and i am certain anybody with the slightest regard for their own well being has indeed searched for this holy grail as you put it, and the limited studies conducted thus far ,vary greatly as to recomended dosages and possible risks for M2F embarking on hrt and most that I have found, focus on a fast maximum change in the shortest time frame approach, obviously aimed at those wishing for srs and full transition again as you stated this approach may not be the appropriate route for all as we vary greatly in our need and desires ie a minimal dose or possibly just AA alone may be sufficient for those who do not wish to transition but need to reduce/ease GID we can however take sollise in the fact we do have as to known risks like dvt osteoporosis ect as well as accepting risks that affect genetic woman such as breast cancer and other possible complications that go with elevated e levels. Here is another one progesterone ,in my research I cannot find any evidence it has any positive effect for m2f it MAY assist in breast nipple development really ? prove it, also MAY cause depression ,ok so why am I taking progesterone ? I think in our quest to be female we get tunnel vision and and are willing to do almost anything to achieve this post haste, including taking risks that logically when you look at it would seem unacceptable. Now the suicide issue, it doesn’t take a Harvard degree to establish an answer to this one ,the simple fact its not just a case of start hrt then srs ffs ect ect the end, all better ,start your life as your desired gender live happily ever after, the stress and pressures and isolation can be truly mind boggling . Whilst I never assumed it would be easy and I’ve planned this for a very long time issues are popping up left right and center ,ones I did not factor in not simple issues life changing ones that affect you to your very core both mentally and phisically and I’m only at the start ,I am still yet to face some of my biggest hurdles ,now you add estrogen and progesterone to the mix and you have the potential for disaster I fact I’m surprised the suicide rate isn’t higher .Another factor misdiagnosis by oneself or by medical professionals and I’m not blaming Dr’s here they are only human lets face it we are all well crafted in the art of deception through necessity ,therefore possible to slip through the crack of the medical professionals possibly harbouring an underlying issue that could have been treated differently .But due to the lack of evidence and research we are left to come to our own conclusions sometimes for the better sometimes not .we need so much more research in all these areas not just focusing on one specific area of our very diverse group. Also agreed that continued counselling support and monitoring after SRS is a wise move.
Scylla -
The journey we travel as gender diverse persons will at some time lead us to the HRT quandary. I have observed it in many of my friends and of course in myself.
I am not medically trained or in any way connected to the medical profession but in my research I wondered just how endocrinologists arrived at their prescribed dosages for TG individuals and in fact how they decided on what should be administered and how.
In my layperson’s research I have read of problems related to progesterone, taking oestrogen orally, and of course the osteo, dvt, migraine and increased cancer risk. I wondered of the sample size, the control element of the research and of the accuracy of these findings due to the secrecy and reluctance to speak up often associated with people undertaking this kind of medical treatment.
To learn that most of the findings are attributable to the companies manufacturing the HRT drugs has not comforted me a great deal.
It is enlightening to read the posts that are delivered by people who are of the medical profession, are part of the community and perhaps are considering or have embarked on a HRT regime.
I am more likely to value their experiences and their advice.
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Pre established the psychological profile of a person undergoing hrt is always going to play a huge part in the relative outcome . A life influenced by one hormones and the associated effects of flipping to the influence of another is always going to have risks that can’t be clearly defined. The display of disinterest show by the manufacturers and TGA provide an insight into the the value of of being visible. The biggest problem is that being an all but invisible minority we fail to attract the required attention to our needs.
That we maybe a minority of approximately 1% , a figure I have heard on more than one occasion from more than one country and that actually makes us significant. We are though an extremely varied group with no real community front . We are insignificant because of diversity and the disunity that ensues not because of our numbers . For research to be valid it requires numbers and it is critical to find those numbers when research is under way.
I know that I speak not directly to the hrt issues but that’s clearly going to be an opinion based on opinion and nominal amounts of research .The issue that never goes away is the lack of unity costs our community. I hope people realize how much that effects the attention we get on the critical matters of research required for the transgender community to be properly treated.
I am hoping I have added to the conversation here rather than diverge. I feel that Amanda and Lisa covered the hrt matter very clearly.
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https://www.thedailybeast.com/this-top-doctor-says-transgender-hormone-therapy-is-safe
I came across this article outlining the work of Dr Joshua Safer Mt Sinai Hospital New York and it appears that Hormone Administration regimens for Transgender people is receiving increased focus The JCEM has updated its 2009 guidelines in a 2017 document refer to link within above article
Its about time isnt it ? but number of patients needed for proper clinical studies always seem to be the challenge.
At least there is some good news in this article . if you are a smoker deciding to go on HRT you are very likely to quit smoking.!!As always recommended in TGR Forums , it is important to seek professional medical opinion before commencing any form of medication in relation to treatment for Gender Dysphoria.
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Caroline wrote:The actual scientific paper is titled:
Hormone therapy in transgender adults is safe with provider supervision; A review of hormone therapy sequelae for transgender individuals
And can be found hereThe paper’s abstract states:
Quote:Current literature suggests HT is safe when followed carefully for certain risks. The greatest health concern for HT in transgender women is venous thromboembolism. HT among transgender men appears to cause polycythemia. Both groups experienced elevated fasting glucose. There is no increase in cancer prevalence or mortality due to transgender HT.Although current data support the safety of transgender HT with physician supervision, larger, long-term studies are needed in transgender medicine.
The paper is only a summary of other papers and does not reflect any new research. The papers referenced range from 1968 to 2014. So not all of the current literature is particularly current!!
However it is encouraging to see people moving away from the past mantra that HRT is “dangerous”.
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AA and all subsequent contributors to this challenging topic have done us all a great service, appreciated by al who have read the string I’m sure.
I too recently came across the Safer article – with a wry smile at the author’s paradoxical name lol.
The only comment I’d add to AA’s research conclusions is to her advocacy of continued psychiatric support – not just for srs but for life. I have just recently completed a quite helpful psychiatric assessment process, an important contribution to my own understanding of the conscious emergence and rapid progression of gender dysphoria – at least as a clinical formulation. But I know no one here needs any reminder that our gender progression is much more a whole of life experience than it is a simple psychiatric category, classification or disgnosis.
So, while the psychiatric paradigm is probably important as one contribution, we do need to appreciate that its practitioners do start out from a ‘disorder’ paradigm rather than a ‘life & living’ paradigm with all of its emotional, psychological, social, sexual, political and material challenges.
I am a psychotherapist myself, who started out from clinical social work and critical sociology paradigms, progressing through several contributive disciplines and personal and professional experience. So you wont be surprised if I recommend trans gender people look much wider afield for their counselling and therapeutic support for the challenges they face in dealing with the myriad of personal, inter-personal, family and social issues to be confronted throughout life, or for as long as needed.
As most of the above contributors have already commented, it is our mental and emotional health in which lie the most critical risk factors. And to safeguard that we do need look beyond the psychiatric paradigm and the medical model in which it originates.
