The published research in the past few years on the clinical effects of estrogen in males shows that there is no upside at all. And surgeries make things even worse.
Thank you. My son is a conscientious and kind doctor in the UK, and it frightens me that he still believes that puberty blockers and hormones are acceptable treatments for young people.
My words are falling on deaf ears even though I study gender issues, having worked in NHS mental health.
He doesn't work in this field luckily. But people like him need to read this...and listen to the detransitioners who are dealing with the personal fallout.
Thank you for this amazing research. I just sat through a lecture at my medical school by a woman with a PhD from OHSU gender clinic. She presented claims that gender affirming care for minors is "curative and preventive." Her presentation had ZERO references to back up her claims. She also contradicted herself multiple times. One such contradiction was in her attempt to debunk what she called a myth, that adolescents could outgrow gender dysphoria. Her debunk went like this: “If an adolescent is in puberty, it is unlikely a phase. However, adolescence is a time of identity exploration and experimenting with expression. By supporting them in their gender identity, we can help facilitate healthy exploration of all the aspects of their identity.” Exact quote. This woman claims to be a professional in the medical field and yet she presents this topic without references, contradictions, and outrageous claims. Unbelievable hubris. What is sounds like from her presentation is she is knowingly and willingly sterilizing young people from poor families, POC and homosexuals.
The Economist, seldom a magazine that minces its words, recently wrote an article titled "Trans ideology is distorting the training of America’s doctors" (https://www.economist.com/united-states/2022/01/08/trans-ideology-is-distorting-the-training-of-americas-doctors). The sub-heading reads "Fear and ignorance are infecting medical education." I don't think it could have been stated any more clearly. I don't for a second think that these young men aren't suffering. And I also do not think that the medical professionals, like the woman from the OHSU gender clinic, are inherently evil. It's just that they are not very bright, are they? They went into medical school and got a degree - heck, a PhD - because PhDs are nowadays handed out like candies on Halloween. And they have been told that what gets published in a journal is to be regarded as sacrosanct. At the same time, they lack the intellectual firepower to actually understand the shoddy experiment design, the questionable statistics, etc. And then, to top it all, we have got some not-very-academically-brilliant-but-clever-enough-to-game-the-system researchers who have caught on to the topic du jour and keep publishing awful research. To be clear, this happens within every discipline in academia: knowledge creation is measured in terms of NIH grant dollar amounts, the number of papers published, the number of PhDs produced. None of these measures have to do with creating knowledge per se. However, in those other disciplines, it is just wasting public finances. In gender research, it is not only wasting public finances but also wasting lives of young people. So, when these people produce abstracts which even their shoddy data doesn't support, they end up creating foot soldiers like this OSU woman who then end up killing people. Especially young men.
I talked to a research-active endocrinologist and told her some snippets of what I had found. She encouraged me to send her whatever I had found, fully expecting a crank sending out those weird emails that sometimes the spam filters fail to catch. Instead, I quoted published research - a fraction of what I wrote here. She sent an email saying that she will get back to me in a few days. It has been three weeks since! I genuinely wanted her to come back to me and say, nah, you see, you did quote this research, but this is why it is not applicable in these cases. I WANTED to be wrong. Because it does not feel good to know that our medical profession, the one that we rely on, day in and day out, has no clue as to what it is doing. Even worse, it doesn't care about the casualties it creates.
And I genuinely believe that she is a conscientious researcher. However, which researcher will want to crane her neck out and go against the wind, only to lose her job? So, I can't blame her. Especially when the Endocrine Society, the AMA, the APA, and others are captured by ideologues and/or pragmatists who know that the only way they can keep their jobs and produce the "research" using public money is to tow the ideology line? If science is politicized and weaponized, whether by the left or the right, no wonder what gets produced is ideological drivel, be it economics or medicine.
By handing out PhDs willy-nilly, we have created a class of "researchers" for whom research - true RESEARCH - does not ring a bell. They wouldn't know what true research is if it were handed to them on a plate. They lack intellectual curiosity, they lack the intellectual firepower. To them, research is NIH grants, and publications, and conferences, and invited talks. And Twitter self-promotion. No wonder we are where we are.
And they live in such ideological bubbles that they do not even know what their peers are producing! I (and several others) did not have to go "deep state" to find out these publications. You just need the intellectual curiosity (which they lack). It is as if their research "feed" has been decided by Facebook and Twitter algorithms where only their own worldviews are amplified.
And one more thing before I stop my rant, which is something I mentioned in the post. The "research" that these researchers produce: they are primarily concerned about how the patients "feel" after the administration of hormones or surgery. They are not concerned about the body’s physiological response to these medical interventions. If, instead of estrogen, the drug was cocaine, and the patients reported feelings of euphoria, these researchers would report this euphoria but not consider the other long-term effects of cocaine on the body and the brain. How brain-addled is that? 🤦♂️🤦♀️
I agree, the emphasis on how patients feel doesn’t give us many objective measures to rely on. It also makes space for patients to fall into mental trap where in they made this huge medical leap into irreversible hormonal or surgical interventions based on how they were “feeling.” They were affirmed, never challenged and should they come to actually regret that decision to transition, they may have a very difficult time coming to grips with the regret and the irreversible damage done to their once healthy body. This could create a painful conflictual reality especially in someone who was already mentally vulnerable. Admitting to their regret and bad choices along with coming to grips with the gaslighting from their “loving and supportive” trans community might be too much to bear.
There are some issues with your main point. You are comparing people with dysphoria (an often crippling mental condition) to non-dysphoric control groups. I highly doubt that a dysphoric individual not undergoing medical transition would emulate the physical and mental health of non-dysphorics, especially considering the social withdrawal, depression, and self-hatred that goes hand-in-hand. Brain shrinkage from external estrogens seems to line up, and has been verified by many researchers. Other studies you link to sometimes do not suggest estrogen as being the main cause of health issues, but rather lifestyle choices from transness that may be more attributable to depression, isolation, and inaction, which could partially be attributed to hormonal changes, but not entirely. These symptoms of depression are partially caused by societal hostility to transness, something you do not seem inclined in weakening. Some studies show feminizing HRT brings people to health risks on par with natal women, which, while not great, isn’t usually cause for huge alarm either.
You make a very valid point about the *suffering* of someone who is gender-dysphoric, which can be triggered by - among other things - social withdrawal, depression, and self-hatred (to quote you). As it is stated somewhere in the article, "[o]ne does not decide to start with off-label and clinically untested medication for the rest of their life unless they are suffering immensely." The question is whether these off-label and clinically untested medications actually help or not. I have also heard that there are reliable studies that show that feminizing HRT brings risks on par with natal women, but I could not find that literature. All I could find in the literature are the extremely elevated levels of risk when it comes to acute cardiovascular events, as well as evidence of cognitive impairment, autoimmune diseases, diabetes, pancreatitis, thyroid cancer, and harm to fertility and genital physiology. (After speaking with several transgender women, there seems to be anecdotal evidence - the medical literature equivalent of case studies - about the risks of these diseases.) Finally, we have quite a bit of solid evidence over several decades (within the US and the Netherlands) about elevated risks of early mortality, which deviates significantly not only from that of cisgender females but also from cisgender males (who tend to die earlier than females), which seems to contradict the idea that the health risks are on par with natal women (however, as you point out, not all of that can be attributed to estrogen alone; but then again, we have to operate with the evidence that we have).
There is no doubt that the overall state of evidence in this area of medicine is not very encouraging (as is probably true with quite a bit of the evidence in healthcare in general - the book "Unhealthy Politics" by Eric M. Patashnik, Alan S. Gerber, and Conor M. Dowling, Princeton University Press, https://press.princeton.edu/books/hardcover/9780691158815/unhealthy-politics, is a very sobering read in this regard; one might also follow the Sensible Medicine substack - https://www.sensible-med.com/ - in this regard). All of this behooves the medical establishment to tread carefully when it comes to "helping" people with off-label and clinically untested medication. All we can say that we know - with some degree of confidence - is that HRT does not help with the psychosocial outlook of those AMAB (the HRT, in this case, being estrogen with or without antiandrogens) and that whatever evidence we *have* got about estrogen from clinical studies should set the alarm bells ringing. At the risk of repeating myself, there is no doubt that transgender women are suffering - possibly immensely. However, to quote from the article, "It is as if the medical community is saying that since cancer patients are suffering, we should administer cyanide capsules because some “experts” within the community have suddenly decided, without evidence, that cyanide will help these patients. The patients desperately need help, but cyanide is not the answer." In a similar vein, given all that we know, no medical professional can reasonably claim that estrogen therapy is the right answer for transgender women.
There is so much to read that I feel that I am always catching up. I would always be happy to read more if you sent me links to some of the literature. The mortality results from the Netherlands (Lancet, 2021) that I mention in my post do indicate that cancer is one of the leading causes of death.
Thank you. This is just a preliminary search, but I did find references in the literature to prostate and breast cancer (other than the possibility of liver cancer that has been noted among women). I added a section on that https://mungeribabu.substack.com/i/108593522/estrogen-and-cancer-among-men. Thank you so much 🙏
This is from a very quick perusal –merely a google-search! But it appears there may be some studies linking exogenous feminizing hormones to cancers. I can’t access some without needing to feed a paywall, (and others that are accessible, are beyond my capacity to fully understand, as I’m not a scientist!) I think you will see links between estrogens and progestins with cancers below.
I admit I'm particularly anxious as my son is likely to have inherited BRCA-genes, which are known factors to increase risks for breast and prostate cancers, (and potentially, pancreatic cancer, too.) It would appear that exogenous hormone use would increase such risks further:
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2021. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2020.
Thank you for the comment. The research that you mention is by more or less the same set of researchers, all of them from Amsterdam UMC (with one difference: there is one additional researcher in the newer study - 9 - who is also from Amsterdam UMC), who conducted the later study, with the same lead author, Jason O. van Heesewijk. Their more recent research in 2023 had a larger sample who were on GAH therapy for a longer period of time than the study they published in 2021. If I remember right, the researchers, in fact, mention that their newer study with a larger sample and longer follow-up negates their earlier findings.
In their most recent study in 2023, https://www.scopus.com/record/display.uri?eid=2-s2.0-85179973149&origin=inward&txGid=c26df70f323525e27fcca09df8a9f60a they credit the declines of cognitive function due to mental/social health and say the research is basically inconclusive and needs further research. The difference of the 21/23 study they point to is the massive increase of distal stress, violence many face, and disapproval by people in society like you spreading biased information to stoke the fire of fear and hatred.
Thank you again for the comment. As I stated, these young people are suffering. They absolutely are. One does not decide to start with off-label and clinically untested medication for the rest of their life unless they are suffering immensely. I don't ever doubt the immense problems that these young people face. The only question is, are cross-sex hormones the answer? Especially when there is no good *clinical* evidence that they work, and quite a lot of signals to indicate that they might be immensely harmful.
The large majority of trans youth who do anything for affirming care get put on hormone blockers until they are old enough to decide for cross sex hormones which is different depending on where they are located. The other option aside from doing nothing, is ‘conversion’ therapy which doesn’t work, is very damaging, and kids who are trans who go down similar routes learn to hate themselves from suppressing and denying who they are causing extreme difficulties that generally onset mid/late 20’s when they have no identity or clue to who they are or how to live life because they’ve been playing a role society has told them to do. Sure some kids get confused and are not trans, just like some kids get confused about their sexuality, and there are also plenty of kids that gender affirming care vastly improves quality of life but you choose to ignore that side of things because you’re clearly biased. The problems with youth aren’t limited to trans though. It’s easy to point the finger at something you clearly hate but it’s not what you are making it out to be. Mental health issues in our youth are at an all time high across the board and highest in cis gender females.
I think you are conflating the issue to something that this Substack post does not mention anything about. This post is not about puberty blockers or the effects of testosterone. It is about the many documented safety signals of estrogen when it is given to a section of trans-identified youth, specifically those AMAB. As a recent paper said, "Patients deserve comprehensive information when deciding and selecting a therapeutic pathway for sex reassignment" (https://journals.sagepub.com/doi/full/10.1177/10600280241231612). To quote a bit more from that paper, "There is a pressing need for clinicians to receive more comprehensive training in the area of gender dysphoria. Historically, this topic has not been adequately represented in medical school curricula, resulting in a knowledge gap. It is imperative that physicians gain a more in-depth understanding of gender reassignment treatments and their potential adverse effects. Such knowledge would empower clinicians to engage in informed discussions with their transgender patients, facilitating a balanced consideration of the benefits and risks associated with gender reassignment treatments." As I mentioned at the beginning of the post, advocacy for care and standards of care are two very different things. Trans-identified youth who wish to get proper medical care deserve proper care and should expect such care. Most fundamentally though, they deserve *evidence-based* care: they are not guinea pigs that the medical establishment can try unproven stuff on them just to see what sticks. The fullness of their lives and their sufferings are not the playgrounds of either the medical establishment or anyone else. Medical care, especially in the US, is rife with examples of "care" that is not evidence-based. In this context, you might be aware of the book "Unhealthy Politics: The Battle over Evidence-Based Medicine" published a few years back by Princeton University Press (https://press.princeton.edu/books/hardcover/9780691158815/unhealthy-politics), which goes over several such examples: "Treatments can go into widespread use before they are rigorously evaluated, and every year patients are harmed because they receive too many procedures—and too few treatments that really work." The patients and those who pay for such unfounded "care" deserve better.
good thing no ones giving estrogen to men then. (trans women are women)(stop being bigots)(let trans people live their lives)(trans people existing doesnt affect you in any way)
Please can you comment on Doye et al 2023. Nature Human Behaviour. "A systematic review of psychosocial changes after gender-affirming hormone therapy among transgender people".
Thank you for your comment. This is a very recent paper and I was not aware of it. I went through it today. First of all, let me clarify that my comments would be somewhat beyond the area of research that I have read the most, which is the effect of estrogen on the male body. And in that respect, the Doyle et al 2023 paper seems to be quite behind the times. The paper mentions: "A growing body of research, principally from the field of social neuroendocrinology, has suggested that both endogenous and exogenous hormones influence psychosocial functioning via biological pathways," but then its references are quite a few years old, and does not mention the recent research, including those that appear in journals like Psychoneuroendocrinology that the authors mention (e.g., a 2018 paper that appears in Psychoneuroendocrinology finds that high levels of estrogen are associated with depression in males, but this finds no mention in this review). As a result, the authors then blithely go on to state that "Comparatively less research has been devoted to studying the psychosocial effects of exogenous administration of [o]estrogens in humans, but some work suggests that they may improve mood in *cisgender women*, particularly for those diagnosed with depressive disorders." Note the words - cisgender women. The next statement is on the effect of progesterone, again on *cisgender women*. Thus, it appears that Doyle et al. are *completely* unaware of the research that has appeared in the last five years that demonstrates the depressive effects of excess estrogen on natal males (which I mention in my review). (Even though they mention that the research included in their review include "all empirical research published or in press by May 2022.")
And it is not only depression. There's the heightened risk of cognitive decline that leads to a much higher incidence of neurological diseases like Alzheimer's and schizophrenia. There's associations with cognitive impairment that has been noted in research by Jason van Heesewijk, who is from the Amsterdam University Medical Center, that was presented at the EPATH 2023 conference in April (it is ironic that Doyle himself is from the Amsterdam University Medical Center, so this seems truly a case where one hand does not know what the other hand is doing!). There's an increased risk of MDD (major depressive disorder) that has been noted after 12 months of estrogen treatment among trans women, as a result of reduced serum BDNF levels. None of this research seems to have made it to the desk of Doyle et al. More importantly, there's empirical evidence that has been published in the last three to four years of the much higher incidence of psychiatric disorders in the US transgender population (e.g., https://doi.org/10.1016/j.annepidem.2019.09.009 in Annals of Epidemiology - I mention this and two other papers that estimate the significantly higher incidence of psychiatric and somatic disorders in the transgender population than their cisgender counterparts). So, when it comes to the effect of estrogen in the natal male body, Doyle et. al have completely missed their mark. So, when they say "Gender-affirming hormone therapy was consistently found to reduce depressive symptoms and psychological distress," you really have to take that conclusion with bushels of salt.
Having said all that, what about the review of the literature that Doyle et al. conduct? As has been said many, many times, there's no dearth of "research" on the psychosocial effects of hormone therapy among the transgender population. And it has also been pointed out repeatedly that the quality of the evidence is hopelessly poor. Overwhelmingly, some of the oft-repeated evidence in the media talk about research that often (a) relies on non-probability samples from anonymous online surveys; (b) distorts their findings; or (c) creatively interprets them in a more favorable light. For more on this, see, for example, Abbruzzese, et al. (2023), https://doi.org/10.1080/0092623X.2022.2150346.
So, what we need is not just a review of the literature that goes through the laundry list of papers in the area and does a perfunctory evaluation of what they state but a review that objectively evaluates the quality of the evidence based on well-defined criteria like GRADE (https://training.cochrane.org/grade-approach). And whenever that kind of review has been conducted, the quality of evidence was deemed to be very poor. This was true with the NICE evidence reviews conducted by the NHS in 2020 (https://cass.independent-review.uk/nice-evidence-reviews/), which evaluated the studies using GRADE criteria. And this is true with the systematic review of hormone treatment for children with gender dysphoria (https://doi.org/10.1111/apa.16791) that appeared a couple of months earlier in 2023.
If we take the review of Doyle et. al at face value (regardless of their omission of the effects of estrogen, about which they seem to be blissfully unaware), the conclusion that they arrive at seems to be the same as these other studies - the overall evidence is very poor. Look at what they say themselves: while some studies show improvements, others do not. And each have varying levels of bias. Small sample sizes, Lack of RCT. And on, and on, and on. And this is a consistent theme across all psychosocial variables that are measured, whether it is well-being, interpersonal functioning, or anything else. (BTW, there seem to be at least some references that are not correct. E.g., Ref. 51 ("Effects of testosterone treatment and chest reconstruction surgery on mental health and sexuality in female-to-male transgender people"), which gets referred to under several headings, appears under "Feminizing hormone therapy." A bit better copy-editing, perhaps?). The authors mention many possible risks of contamination in the evidence. And in the end, in spite of all the sources of potential problems, the authors conclude that there is some evidence of benefit.
I will go back to the area of focus of my review: the physical effect of excess estrogen on the natal male body. And in that area, Doyle et. al are completely silent. As I stated in my review: "Before we dive into the effects of estrogen on the male body, we should clarify something about the affirming stream of literature...They are primarily concerned about how the patients *feel* after the administration of hormones or surgery. They are not concerned about how the body responds physiologically to these medical interventions. To take an extreme example, if a drug like cocaine was administered to these patients who then reported feelings of euphoria, this stream of literature would report this euphoria but not consider the other long-term effects of cocaine on the body and the brain (ironically, estrogen fails even to give that “high” that cocaine does – instead, it causes depression)."
My review is about the long-term effects of estrogen on the body and the brain. Even if estrogen *did* give a high (which, once again, it does not - excess amounts of it are associated with depressive disorders), its deleterious effect on the body and the brain is enough to state categorically that it should *not* be given to any gender-dysphoric made. To quote from my review again: "An analogy might help here to understand the absurdity of the situation here. It is as if the medical community is saying that since cancer patients are suffering, we should administer cyanide capsules because some “experts” within the community have suddenly decided, without evidence, that cyanide will help these patients. The patients desperately need help, but cyanide is not the answer."
Thank you so much for looking at this so quickly. I will go through your reply carefully so I can understand all the points you are making better. I certainly agree that a literature review is unhelpful if the quality of the papers reviewed is poor….and I think Doye et al do finally arrive at the idea that more research is needed and their conclusions seem dependant on a handful of studies in most cases…. Interesting too that you feel they have managed to exclude relevant studies and have not portrayed the state of the current field accurately. Perhaps whether a matter is “known” or not, is more subjective that we like to imagine. I fully understand your article is not primarily about the topic Doye et al are addressing either, but you do say that there is little evidence to suggest any upside to estrogen therapy in MTF so I wanted to bring this very recent review to your notice, especially as I know many tend to trust publications in the Nature family of journals. I will be reading your rebuttal carefully with interest and might come back with further questions. Thank you again.
Thank you. My son is a conscientious and kind doctor in the UK, and it frightens me that he still believes that puberty blockers and hormones are acceptable treatments for young people.
My words are falling on deaf ears even though I study gender issues, having worked in NHS mental health.
He doesn't work in this field luckily. But people like him need to read this...and listen to the detransitioners who are dealing with the personal fallout.
Thank you for this amazing research. I just sat through a lecture at my medical school by a woman with a PhD from OHSU gender clinic. She presented claims that gender affirming care for minors is "curative and preventive." Her presentation had ZERO references to back up her claims. She also contradicted herself multiple times. One such contradiction was in her attempt to debunk what she called a myth, that adolescents could outgrow gender dysphoria. Her debunk went like this: “If an adolescent is in puberty, it is unlikely a phase. However, adolescence is a time of identity exploration and experimenting with expression. By supporting them in their gender identity, we can help facilitate healthy exploration of all the aspects of their identity.” Exact quote. This woman claims to be a professional in the medical field and yet she presents this topic without references, contradictions, and outrageous claims. Unbelievable hubris. What is sounds like from her presentation is she is knowingly and willingly sterilizing young people from poor families, POC and homosexuals.
The Economist, seldom a magazine that minces its words, recently wrote an article titled "Trans ideology is distorting the training of America’s doctors" (https://www.economist.com/united-states/2022/01/08/trans-ideology-is-distorting-the-training-of-americas-doctors). The sub-heading reads "Fear and ignorance are infecting medical education." I don't think it could have been stated any more clearly. I don't for a second think that these young men aren't suffering. And I also do not think that the medical professionals, like the woman from the OHSU gender clinic, are inherently evil. It's just that they are not very bright, are they? They went into medical school and got a degree - heck, a PhD - because PhDs are nowadays handed out like candies on Halloween. And they have been told that what gets published in a journal is to be regarded as sacrosanct. At the same time, they lack the intellectual firepower to actually understand the shoddy experiment design, the questionable statistics, etc. And then, to top it all, we have got some not-very-academically-brilliant-but-clever-enough-to-game-the-system researchers who have caught on to the topic du jour and keep publishing awful research. To be clear, this happens within every discipline in academia: knowledge creation is measured in terms of NIH grant dollar amounts, the number of papers published, the number of PhDs produced. None of these measures have to do with creating knowledge per se. However, in those other disciplines, it is just wasting public finances. In gender research, it is not only wasting public finances but also wasting lives of young people. So, when these people produce abstracts which even their shoddy data doesn't support, they end up creating foot soldiers like this OSU woman who then end up killing people. Especially young men.
I talked to a research-active endocrinologist and told her some snippets of what I had found. She encouraged me to send her whatever I had found, fully expecting a crank sending out those weird emails that sometimes the spam filters fail to catch. Instead, I quoted published research - a fraction of what I wrote here. She sent an email saying that she will get back to me in a few days. It has been three weeks since! I genuinely wanted her to come back to me and say, nah, you see, you did quote this research, but this is why it is not applicable in these cases. I WANTED to be wrong. Because it does not feel good to know that our medical profession, the one that we rely on, day in and day out, has no clue as to what it is doing. Even worse, it doesn't care about the casualties it creates.
And I genuinely believe that she is a conscientious researcher. However, which researcher will want to crane her neck out and go against the wind, only to lose her job? So, I can't blame her. Especially when the Endocrine Society, the AMA, the APA, and others are captured by ideologues and/or pragmatists who know that the only way they can keep their jobs and produce the "research" using public money is to tow the ideology line? If science is politicized and weaponized, whether by the left or the right, no wonder what gets produced is ideological drivel, be it economics or medicine.
By handing out PhDs willy-nilly, we have created a class of "researchers" for whom research - true RESEARCH - does not ring a bell. They wouldn't know what true research is if it were handed to them on a plate. They lack intellectual curiosity, they lack the intellectual firepower. To them, research is NIH grants, and publications, and conferences, and invited talks. And Twitter self-promotion. No wonder we are where we are.
And they live in such ideological bubbles that they do not even know what their peers are producing! I (and several others) did not have to go "deep state" to find out these publications. You just need the intellectual curiosity (which they lack). It is as if their research "feed" has been decided by Facebook and Twitter algorithms where only their own worldviews are amplified.
And one more thing before I stop my rant, which is something I mentioned in the post. The "research" that these researchers produce: they are primarily concerned about how the patients "feel" after the administration of hormones or surgery. They are not concerned about the body’s physiological response to these medical interventions. If, instead of estrogen, the drug was cocaine, and the patients reported feelings of euphoria, these researchers would report this euphoria but not consider the other long-term effects of cocaine on the body and the brain. How brain-addled is that? 🤦♂️🤦♀️
I agree, the emphasis on how patients feel doesn’t give us many objective measures to rely on. It also makes space for patients to fall into mental trap where in they made this huge medical leap into irreversible hormonal or surgical interventions based on how they were “feeling.” They were affirmed, never challenged and should they come to actually regret that decision to transition, they may have a very difficult time coming to grips with the regret and the irreversible damage done to their once healthy body. This could create a painful conflictual reality especially in someone who was already mentally vulnerable. Admitting to their regret and bad choices along with coming to grips with the gaslighting from their “loving and supportive” trans community might be too much to bear.
There are some issues with your main point. You are comparing people with dysphoria (an often crippling mental condition) to non-dysphoric control groups. I highly doubt that a dysphoric individual not undergoing medical transition would emulate the physical and mental health of non-dysphorics, especially considering the social withdrawal, depression, and self-hatred that goes hand-in-hand. Brain shrinkage from external estrogens seems to line up, and has been verified by many researchers. Other studies you link to sometimes do not suggest estrogen as being the main cause of health issues, but rather lifestyle choices from transness that may be more attributable to depression, isolation, and inaction, which could partially be attributed to hormonal changes, but not entirely. These symptoms of depression are partially caused by societal hostility to transness, something you do not seem inclined in weakening. Some studies show feminizing HRT brings people to health risks on par with natal women, which, while not great, isn’t usually cause for huge alarm either.
You make a very valid point about the *suffering* of someone who is gender-dysphoric, which can be triggered by - among other things - social withdrawal, depression, and self-hatred (to quote you). As it is stated somewhere in the article, "[o]ne does not decide to start with off-label and clinically untested medication for the rest of their life unless they are suffering immensely." The question is whether these off-label and clinically untested medications actually help or not. I have also heard that there are reliable studies that show that feminizing HRT brings risks on par with natal women, but I could not find that literature. All I could find in the literature are the extremely elevated levels of risk when it comes to acute cardiovascular events, as well as evidence of cognitive impairment, autoimmune diseases, diabetes, pancreatitis, thyroid cancer, and harm to fertility and genital physiology. (After speaking with several transgender women, there seems to be anecdotal evidence - the medical literature equivalent of case studies - about the risks of these diseases.) Finally, we have quite a bit of solid evidence over several decades (within the US and the Netherlands) about elevated risks of early mortality, which deviates significantly not only from that of cisgender females but also from cisgender males (who tend to die earlier than females), which seems to contradict the idea that the health risks are on par with natal women (however, as you point out, not all of that can be attributed to estrogen alone; but then again, we have to operate with the evidence that we have).
There is no doubt that the overall state of evidence in this area of medicine is not very encouraging (as is probably true with quite a bit of the evidence in healthcare in general - the book "Unhealthy Politics" by Eric M. Patashnik, Alan S. Gerber, and Conor M. Dowling, Princeton University Press, https://press.princeton.edu/books/hardcover/9780691158815/unhealthy-politics, is a very sobering read in this regard; one might also follow the Sensible Medicine substack - https://www.sensible-med.com/ - in this regard). All of this behooves the medical establishment to tread carefully when it comes to "helping" people with off-label and clinically untested medication. All we can say that we know - with some degree of confidence - is that HRT does not help with the psychosocial outlook of those AMAB (the HRT, in this case, being estrogen with or without antiandrogens) and that whatever evidence we *have* got about estrogen from clinical studies should set the alarm bells ringing. At the risk of repeating myself, there is no doubt that transgender women are suffering - possibly immensely. However, to quote from the article, "It is as if the medical community is saying that since cancer patients are suffering, we should administer cyanide capsules because some “experts” within the community have suddenly decided, without evidence, that cyanide will help these patients. The patients desperately need help, but cyanide is not the answer." In a similar vein, given all that we know, no medical professional can reasonably claim that estrogen therapy is the right answer for transgender women.
You've done some amazing research. Thank you! Have you come across data on feminizing hormones and cancer risks?
There is so much to read that I feel that I am always catching up. I would always be happy to read more if you sent me links to some of the literature. The mortality results from the Netherlands (Lancet, 2021) that I mention in my post do indicate that cancer is one of the leading causes of death.
I believe there is a fair amount of literature on estrogen and progesterone-dependent cancers of the breast and prostate....
Thank you. This is just a preliminary search, but I did find references in the literature to prostate and breast cancer (other than the possibility of liver cancer that has been noted among women). I added a section on that https://mungeribabu.substack.com/i/108593522/estrogen-and-cancer-among-men. Thank you so much 🙏
This is from a very quick perusal –merely a google-search! But it appears there may be some studies linking exogenous feminizing hormones to cancers. I can’t access some without needing to feed a paywall, (and others that are accessible, are beyond my capacity to fully understand, as I’m not a scientist!) I think you will see links between estrogens and progestins with cancers below.
https://www.sciencedirect.com/science/article/abs/pii/S0889852919300106?via%3Dihub
https://www.sciencedirect.com/science/article/abs/pii/S0889852911000582?via%3Dihub
https://pubmed.ncbi.nlm.nih.gov/18642351/
https://www.mdpi.com/1422-0067/22/1/173
In the popular press:
https://www.breastcancer.org/research-news/feminizing-hormones-increase-risk-in-trans-women
I admit I'm particularly anxious as my son is likely to have inherited BRCA-genes, which are known factors to increase risks for breast and prostate cancers, (and potentially, pancreatic cancer, too.) It would appear that exogenous hormone use would increase such risks further:
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2021. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2020.
https://www.nejm.org/doi/full/10.1056/NEJMra1707939 seems to indicate elevated levels of estrogen + BRCA = recipe to predispose one to breast cancer in men…
Brilliant article. Thank you. Do you have a similar one about testosteron for girls ? About puberty blockers ?
Perhaps you should add this. It seems you’re clearly biased and probably transphobic. This study found cognitive function to increase in older trans women https://www.sciencedirect.com/science/article/pii/S1743609521005191
Thank you for the comment. The research that you mention is by more or less the same set of researchers, all of them from Amsterdam UMC (with one difference: there is one additional researcher in the newer study - 9 - who is also from Amsterdam UMC), who conducted the later study, with the same lead author, Jason O. van Heesewijk. Their more recent research in 2023 had a larger sample who were on GAH therapy for a longer period of time than the study they published in 2021. If I remember right, the researchers, in fact, mention that their newer study with a larger sample and longer follow-up negates their earlier findings.
In their most recent study in 2023, https://www.scopus.com/record/display.uri?eid=2-s2.0-85179973149&origin=inward&txGid=c26df70f323525e27fcca09df8a9f60a they credit the declines of cognitive function due to mental/social health and say the research is basically inconclusive and needs further research. The difference of the 21/23 study they point to is the massive increase of distal stress, violence many face, and disapproval by people in society like you spreading biased information to stoke the fire of fear and hatred.
Thank you again for the comment. As I stated, these young people are suffering. They absolutely are. One does not decide to start with off-label and clinically untested medication for the rest of their life unless they are suffering immensely. I don't ever doubt the immense problems that these young people face. The only question is, are cross-sex hormones the answer? Especially when there is no good *clinical* evidence that they work, and quite a lot of signals to indicate that they might be immensely harmful.
The large majority of trans youth who do anything for affirming care get put on hormone blockers until they are old enough to decide for cross sex hormones which is different depending on where they are located. The other option aside from doing nothing, is ‘conversion’ therapy which doesn’t work, is very damaging, and kids who are trans who go down similar routes learn to hate themselves from suppressing and denying who they are causing extreme difficulties that generally onset mid/late 20’s when they have no identity or clue to who they are or how to live life because they’ve been playing a role society has told them to do. Sure some kids get confused and are not trans, just like some kids get confused about their sexuality, and there are also plenty of kids that gender affirming care vastly improves quality of life but you choose to ignore that side of things because you’re clearly biased. The problems with youth aren’t limited to trans though. It’s easy to point the finger at something you clearly hate but it’s not what you are making it out to be. Mental health issues in our youth are at an all time high across the board and highest in cis gender females.
I think you are conflating the issue to something that this Substack post does not mention anything about. This post is not about puberty blockers or the effects of testosterone. It is about the many documented safety signals of estrogen when it is given to a section of trans-identified youth, specifically those AMAB. As a recent paper said, "Patients deserve comprehensive information when deciding and selecting a therapeutic pathway for sex reassignment" (https://journals.sagepub.com/doi/full/10.1177/10600280241231612). To quote a bit more from that paper, "There is a pressing need for clinicians to receive more comprehensive training in the area of gender dysphoria. Historically, this topic has not been adequately represented in medical school curricula, resulting in a knowledge gap. It is imperative that physicians gain a more in-depth understanding of gender reassignment treatments and their potential adverse effects. Such knowledge would empower clinicians to engage in informed discussions with their transgender patients, facilitating a balanced consideration of the benefits and risks associated with gender reassignment treatments." As I mentioned at the beginning of the post, advocacy for care and standards of care are two very different things. Trans-identified youth who wish to get proper medical care deserve proper care and should expect such care. Most fundamentally though, they deserve *evidence-based* care: they are not guinea pigs that the medical establishment can try unproven stuff on them just to see what sticks. The fullness of their lives and their sufferings are not the playgrounds of either the medical establishment or anyone else. Medical care, especially in the US, is rife with examples of "care" that is not evidence-based. In this context, you might be aware of the book "Unhealthy Politics: The Battle over Evidence-Based Medicine" published a few years back by Princeton University Press (https://press.princeton.edu/books/hardcover/9780691158815/unhealthy-politics), which goes over several such examples: "Treatments can go into widespread use before they are rigorously evaluated, and every year patients are harmed because they receive too many procedures—and too few treatments that really work." The patients and those who pay for such unfounded "care" deserve better.
good thing no ones giving estrogen to men then. (trans women are women)(stop being bigots)(let trans people live their lives)(trans people existing doesnt affect you in any way)
They are men. Women can't be a "transwomen" (you literally have to be a man to be a "trasnwoman"). You know this.
Please can you comment on Doye et al 2023. Nature Human Behaviour. "A systematic review of psychosocial changes after gender-affirming hormone therapy among transgender people".
Thank you for your comment. This is a very recent paper and I was not aware of it. I went through it today. First of all, let me clarify that my comments would be somewhat beyond the area of research that I have read the most, which is the effect of estrogen on the male body. And in that respect, the Doyle et al 2023 paper seems to be quite behind the times. The paper mentions: "A growing body of research, principally from the field of social neuroendocrinology, has suggested that both endogenous and exogenous hormones influence psychosocial functioning via biological pathways," but then its references are quite a few years old, and does not mention the recent research, including those that appear in journals like Psychoneuroendocrinology that the authors mention (e.g., a 2018 paper that appears in Psychoneuroendocrinology finds that high levels of estrogen are associated with depression in males, but this finds no mention in this review). As a result, the authors then blithely go on to state that "Comparatively less research has been devoted to studying the psychosocial effects of exogenous administration of [o]estrogens in humans, but some work suggests that they may improve mood in *cisgender women*, particularly for those diagnosed with depressive disorders." Note the words - cisgender women. The next statement is on the effect of progesterone, again on *cisgender women*. Thus, it appears that Doyle et al. are *completely* unaware of the research that has appeared in the last five years that demonstrates the depressive effects of excess estrogen on natal males (which I mention in my review). (Even though they mention that the research included in their review include "all empirical research published or in press by May 2022.")
And it is not only depression. There's the heightened risk of cognitive decline that leads to a much higher incidence of neurological diseases like Alzheimer's and schizophrenia. There's associations with cognitive impairment that has been noted in research by Jason van Heesewijk, who is from the Amsterdam University Medical Center, that was presented at the EPATH 2023 conference in April (it is ironic that Doyle himself is from the Amsterdam University Medical Center, so this seems truly a case where one hand does not know what the other hand is doing!). There's an increased risk of MDD (major depressive disorder) that has been noted after 12 months of estrogen treatment among trans women, as a result of reduced serum BDNF levels. None of this research seems to have made it to the desk of Doyle et al. More importantly, there's empirical evidence that has been published in the last three to four years of the much higher incidence of psychiatric disorders in the US transgender population (e.g., https://doi.org/10.1016/j.annepidem.2019.09.009 in Annals of Epidemiology - I mention this and two other papers that estimate the significantly higher incidence of psychiatric and somatic disorders in the transgender population than their cisgender counterparts). So, when it comes to the effect of estrogen in the natal male body, Doyle et. al have completely missed their mark. So, when they say "Gender-affirming hormone therapy was consistently found to reduce depressive symptoms and psychological distress," you really have to take that conclusion with bushels of salt.
Having said all that, what about the review of the literature that Doyle et al. conduct? As has been said many, many times, there's no dearth of "research" on the psychosocial effects of hormone therapy among the transgender population. And it has also been pointed out repeatedly that the quality of the evidence is hopelessly poor. Overwhelmingly, some of the oft-repeated evidence in the media talk about research that often (a) relies on non-probability samples from anonymous online surveys; (b) distorts their findings; or (c) creatively interprets them in a more favorable light. For more on this, see, for example, Abbruzzese, et al. (2023), https://doi.org/10.1080/0092623X.2022.2150346.
So, what we need is not just a review of the literature that goes through the laundry list of papers in the area and does a perfunctory evaluation of what they state but a review that objectively evaluates the quality of the evidence based on well-defined criteria like GRADE (https://training.cochrane.org/grade-approach). And whenever that kind of review has been conducted, the quality of evidence was deemed to be very poor. This was true with the NICE evidence reviews conducted by the NHS in 2020 (https://cass.independent-review.uk/nice-evidence-reviews/), which evaluated the studies using GRADE criteria. And this is true with the systematic review of hormone treatment for children with gender dysphoria (https://doi.org/10.1111/apa.16791) that appeared a couple of months earlier in 2023.
If we take the review of Doyle et. al at face value (regardless of their omission of the effects of estrogen, about which they seem to be blissfully unaware), the conclusion that they arrive at seems to be the same as these other studies - the overall evidence is very poor. Look at what they say themselves: while some studies show improvements, others do not. And each have varying levels of bias. Small sample sizes, Lack of RCT. And on, and on, and on. And this is a consistent theme across all psychosocial variables that are measured, whether it is well-being, interpersonal functioning, or anything else. (BTW, there seem to be at least some references that are not correct. E.g., Ref. 51 ("Effects of testosterone treatment and chest reconstruction surgery on mental health and sexuality in female-to-male transgender people"), which gets referred to under several headings, appears under "Feminizing hormone therapy." A bit better copy-editing, perhaps?). The authors mention many possible risks of contamination in the evidence. And in the end, in spite of all the sources of potential problems, the authors conclude that there is some evidence of benefit.
I will go back to the area of focus of my review: the physical effect of excess estrogen on the natal male body. And in that area, Doyle et. al are completely silent. As I stated in my review: "Before we dive into the effects of estrogen on the male body, we should clarify something about the affirming stream of literature...They are primarily concerned about how the patients *feel* after the administration of hormones or surgery. They are not concerned about how the body responds physiologically to these medical interventions. To take an extreme example, if a drug like cocaine was administered to these patients who then reported feelings of euphoria, this stream of literature would report this euphoria but not consider the other long-term effects of cocaine on the body and the brain (ironically, estrogen fails even to give that “high” that cocaine does – instead, it causes depression)."
My review is about the long-term effects of estrogen on the body and the brain. Even if estrogen *did* give a high (which, once again, it does not - excess amounts of it are associated with depressive disorders), its deleterious effect on the body and the brain is enough to state categorically that it should *not* be given to any gender-dysphoric made. To quote from my review again: "An analogy might help here to understand the absurdity of the situation here. It is as if the medical community is saying that since cancer patients are suffering, we should administer cyanide capsules because some “experts” within the community have suddenly decided, without evidence, that cyanide will help these patients. The patients desperately need help, but cyanide is not the answer."
Thank you so much for looking at this so quickly. I will go through your reply carefully so I can understand all the points you are making better. I certainly agree that a literature review is unhelpful if the quality of the papers reviewed is poor….and I think Doye et al do finally arrive at the idea that more research is needed and their conclusions seem dependant on a handful of studies in most cases…. Interesting too that you feel they have managed to exclude relevant studies and have not portrayed the state of the current field accurately. Perhaps whether a matter is “known” or not, is more subjective that we like to imagine. I fully understand your article is not primarily about the topic Doye et al are addressing either, but you do say that there is little evidence to suggest any upside to estrogen therapy in MTF so I wanted to bring this very recent review to your notice, especially as I know many tend to trust publications in the Nature family of journals. I will be reading your rebuttal carefully with interest and might come back with further questions. Thank you again.