Hormone Treatment During Pregnancy and Gender Variance in Later Life

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Transgender brain
For as long as I can remember, I’ve always had an unusual partially feminine gender identity, but until recently I never consciously acknowledged it. Then, a couple of years ago I realised that, although at a conscious level I identify as male, my body language, my pattern of arousal and orgasm, and my instinctive social behaviour are all very much more like what you’d typically see in a woman rather than a man. In addition, I appear to be suffering from secondary hypogonadism (i.e. my brain regions that control hormones aren’t working correctly), and I have a “eunuchoid” body structure, which indicates that my testosterone production has been below normal all my life.

Is Being Transgendered Just One of Those Things?

Although it never became my career, as a student I excelled at both chemistry and biology, and I’ve retained an amateur interest in the sciences ever since. Most people seem to assume that being transgendered is “just one of those things”, but I resolved to use that background in science to try and figure out whether there was an actual physical explanation for it. Accordingly, I tried to discover as much as I could about sexual development in the unborn child, and the kinds of things that can go wrong with that process.

Sexual Blueprints

Our sex-determining chromosome, the Y chromosome, is far smaller than any of our other chromosome and only has a few dozen functional genes on it. Basically all the Y chromosome does is to tell your undifferentiated gonads to turn into testicles (without it they’ll turn into ovaries instead). All of the genetic blueprints for actually building a male or female body are located elsewhere in your genome, so everyone has the full set of instructions for both sexes.

By default the “female” instructions are what get followed during fetal development, but if there’s testosterone present, the “male” instructions will be followed instead. Ordinarily this system works quite well, and you’ll develop as one sex throughout the pregnancy (which one depending on whether you have testicles churning out testosterone or not).

An Endocrine Disruptor

What appears to have happened in my case is that the pregnancy was no different from that of any other male baby, except that partway through the second trimester, something catastrophic happened that severely disrupted my endocrine system, so that for a few weeks I wasn’t producing any testosterone. Following that, my endocrine system recovered and everything went back to normal for the remainder of the pregnancy. The result is that I was built using the instructions for male development for most of the pregnancy, but during the time I wasn’t producing any testosterone, the instructions for female development were followed instead. That seems to have happened after all my physical development had completed, but very early in the process of wiring up my brain’s permanent structure (all the things that are affected seem to be associated with evolutionarily ancient parts of the brain, which points to the period of female development having happened early on in the process of wiring up my brain).

Based on when genital development takes place and when the process of building the permanent structure of the brain begins, I was able to work out that whatever it was must have happened somewhere around 16 or 17 weeks after conception, at or very soon after the time my mother would have first felt me moving inside her. Knowing what she was like when I was younger, my immediate thought was that she must have had a depressive episode, decided that she couldn’t cope with another child so soon after the first, and taken an overdose of something in an attempt to bring on a miscarriage.

A DIY Abortion that Didn’t Take

A bit of snooping on maternity forums soon revealed that the first thing most unhappily pregnant women contemplating a DIY abortion seem to think of is an overdose of contraceptive pills. I was able to subsequently confirm that my parents were using birth control pills for contraception at the time – the high dosage first generation ones. There was also something otherwise completely inexplicable that happened later in my childhood, which makes me think she must have been hiding a guilty secret along those lines.

My mother passed away in 2010, and in a way I’m glad that happened before I discovered any of this, because I would have been angry with her and she didn’t deserve that. She did her best to be a good mother to me and to all her other children, and I don’t hold her responsible in any way for what happened. I can’t blame my father either. He lost 3 brothers during his childhood and then his first wife died on their honeymoon, so I can understand why he became so obsessed with the idea of having a large family.

Brain Sexual Identity and DES

One further thing that made me think an exposure to artificial female hormones is the cause of my conditions was reading in the book “Brain Sex” about a pattern of behaviour commonly shown by teenage boys whose mothers were given treatment with a drug called diethylstilbestrol or DES in an attempt to prevent miscarriage . The boys in the study were typically very shy, socially withdrawn, had low self esteem, were regarded as sissies, bullied, ostracised by their peers, with no ability to fight back when attacked and no interest in sport. The authors of the book described it as “feminized behaviour”, and my teenage years matched it so closely it could have come straight out of my school report!

The main hormonal component of the contraceptive pills my parents were using is norethisterone acetate, a progestin, whereas DES is an estrogen. What estrogens and progestins both have in common is that they are female hormone derivatives, and are basically completely incompatible with masculinity. Both types of hormone have the ability to disrupt testicular hormone production at quite modest doses, well below those commonly used for medical treatment for women.

DES was for many years used to chemically castrate men suffering from hormone-sensitive prostate cancer, while progestins are commonly used for chemical castration of sex offenders and transsexuals. If they also suppress testosterone in a male fetus, then any use of them during a pregnancy of a male child carries a risk of creating a baby who developed as the wrong sex for part of the pregnancy. This is what I think happened to me, and to the DES sons.

For nearly two years I’ve been trying to find out as much as I can about DES sons, reading their personal accounts of how they’ve been affected and chatting with them online. Among the ones I’ve had contact with or whose life stories I’ve read, there seems to be a very high incidence of both intersex-related genital abnormalities and gender dysphoria. As a group they seem to commonly experience many of the same problems I have (a genital abnormality, feminized behaviour as a teenager, low testosterone and problems with hormones, gender variance). The key difference is that on the whole they seem to be far more psychologically female than I am (which is exactly what you’d expect, considering that their exposure was for a much larger part of the pregnancy than mine). I think it’s quite likely that for most of them, their testosterone production was completely suppressed and they were developing as female throughout the time their mothers were on the drug!

DES and all other estrogens were withdrawn from use in pregnancy 30 years ago, however, treatments for prevention of miscarriage, based on progestins rather than estrogens, continue to be used to the present day. One of these involves a progestin called hydroxyprogesterone caproate, given as a weekly intramuscular injection of either 250mg or 500mg, starting 16 weeks into the pregnancy – just around the time I think my hormone exposure occurred. The difference is that this treatment continues to be administered for the remainder of the pregnancy. If this drug does suppress testosterone production in a male fetus, then it’s hard to imagine a treatment better suited to creating as baby with a male body but a female brain! I’m fairly sure that if you gave an adult man 250mg per week of this drug, his testosterone production would be seriously impaired. Why wouldn’t the same happen to a male fetus?

Females Affected Too

In this article, I’ve only been looking at the effects of artificial sex hormones on a male fetus, however it’s likely that, under the right circumstances, a female fetus could be affected too. This could happen if the external hormone mimics the action of testosterone (e.g.progestin induced virilization), or if it disrupts endogenous hormone production in a way that causes excessive androgens to be produced (hyperandrogenism).

Postscript: This article was published previously September 2013. 

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21 Comments

  1. Hi Hugh,

    Does this theory relate to synthetic progesterone only? I am in my 12th week of pregnancy and was prescribed Cyclogest (natural progesterone suppositories) as my doctor was concerned about my ability to maintain the pregnancy due to a short lutesl phase. I am going to discontinue these now regardless but I am now concerned about the effects Cyclogest may have already had on the fetus.

    Many thanks,
    Catherine

    1. Catherine, please understand the information provided on this website cannot be construed as medical advice for or against a specific treatment. We present research and personal accounts. Before making changes, please learn as much as you can about the topic and consult your physicians, perhaps other physicians, other researchers.

      1. Thank you. I just wanted to clarify whether High was referring to all progesterone treatment, including natural, or just synthetic progesterone. I understand that this is a theory and cannot be misconstrued as medical advice.

        Best wishes,
        Catherine

    2. Yes, I think it’s the synthetics that are the problem. When synthetics were first developed, doctors, scientists and everyone else seems to have assumed that, because they bind to and activate hormone receptors similarly to the natural hormones, their biological effects would be more or less the same. However, there are two important differences that I know of.

      Firstly, in addition to stimulating hormone receptors, the natural (or bioidentical) hormones all act as raw materials from which other hormones are made. This is particularly important for progesterone, which occupies a key spot in the hormone biosynthesis pathway. The synthetics don’t act as raw materials for anything, instead thy either get excreted unchanged, or broken down by generic toxin-destroying enzymes in the liver. It’s a lot like the difference between saccharin and sugar, both of them activate sweetness receptors, but only one can perform the biological functions of a carbohydrate.

      The second difference is that synthetics can be quite strong inhibitors of important hormone enzymes such as 5-alpha reductase and 3-betahydroxysteroid dehydrogenase. Again, this appears to particularly be a problem with the progestin class of hormones (although it’s not a well documented property of synthetics, so it may just be that more research has been done into enzyme inhibition by progestins than with other classes of synthetics). In our trans HRT group on facebook, we’re speculating that this causes depletion of neurosteroids, and could explain why trans women placed on progestins often become severely depressed and suicidal. In an unborn baby, some of the same enzymes inhibited by progestins also cause congenital adrenal hyperplasia (CAH) when they’re deficient. CAH is well known as being a cause of intersex in female babies, and what I’m thinking is that fetal exposure to progestins (and maybe other synthetics) may give rise to a kind of chemically induced CAH, which would lead to masculinization of female babies (even though the progestins used in pregnancy today don’t have any direct androgenic effects).

      Some forms of CAH (in particular the 3-BHSD type) can also be a cause of intersex in male babies, and of course progestins in general are good inhibitors of testicular hormone production (the archetypal progestin, medroxyrogesterone acetate, is one of the most popular drugs for chemically castrating sex offenders), which is an obvious route for them interfering with normal male development.

      Bioidentical hormones are chemically identical to the hormones that occur naturally in your body, so are processed and metabolised in exactly the same way as your own hormones. As long as their level is kept within the range that would normally occur at that stage of your pregnancy, I don’t see why they would cause a problem. So I wouldn’t be too concerned about taking bioidentical progesterone. That’s only my opinion of course; as Chandler says, we’re not medical professionals, so can’t offer medical advice.

  2. My mother-in-law took DES when she was pregnant with two out of three of her kids, my husband being the exception. My sister-in-law had issues with her uterus and wasn’t expected to be able to have kids. Thankfully, she had one girl. My brother-in-law had four kids. The weird thing is, two of the grandchildren are transgendered, one we suspect is gay, one is a bi and one is CIS, straight. Are there any studies on how the drug can affect the third generation, or if there is any link at all?

    1. There’s a known link to hypospadias in the sons of DES daughters. In this study:

      https://www.ncbi.nlm.nih.gov/pubmed/11943257

      of DES grandsons in the Netherlands, the incidence was found to be more than 20x higher. This study:

      https://academic.oup.com/humrep/article/21/3/666/770378/Hypospadias-a-transgenerational-effect-of

      found an increased risk too, albeit quite a bit smaller (around 2.5 x), A big problem with studies of this nature is that hormones are so widely used in women’s medicine, that by now it must be difficult to put together a truly unexposed control group. That probably at least partly accounts for why some studies are finding a greatly increased risk of hypospadias, and others not so much. In any case, there does appear to be a definite increased risk for hypospadias in DES grandsons, which is important as far as your question is concerned, because hypospadias is a marker for abnormally low prenatal androgen levels.

      If DES grandsons have an increased incidence of hypospadias, then it seems reasonable that they should also have an increased incidence of other things that are thought to result from low prenatal androgens, two of which include: developing a female gender identity, and developing same-sex attraction. I don’t know of any actual studies proving a connection to those things in the grandsons, but that may just be because they’re a lot more difficult to measure than something like hypospadias, which usually becomes apparent at or soon after birth.

  3. After my mothers first miscarriage when she was pregnant with me they gave her DES to prevent another one. It resulted in my having PAIS Partial Androgen Insensitivety Syndrome. Oii-usa.org How do you get doctors to stop doing unneeded unwanted Plastic surgery on babies like me?

    1. You might not actually have PAIS at all, it may instead be that your mother was commenced on DES very early in the pregnancy, resulting in your testosterone production already being heavily suppressed during the critical period for genital development (weeks 7 to 12 after conception). If this happens, it’s likely to result in highly anomalous genital development, which could look very similar to what happens with PAIS. Later in life, many of us (even where exposure commenced too late for it to affect our genital development) suffer from hypogonadism, or chronic below normal male testosterone production. This can result in you developing a “eunuchoid” body structure (where your bone structure and physical proportions end up more like a woman’s than a man’s), which, once again, could look a lot like androgen insensitivity.

      I think doctors often hand out PAIS as a convenient diagnosis when a patient with intersex-related anomalies shows up and they can’t identify the cause. It’s a rare condition, rarer than CAIS, which itself is only around 1 in 10,000 births. I found a paper in which the researchers gene tested people who’d been given a diagnosis of PAIS, and only around a quarter of them had any identifiable fault with their androgen receptor gene. That suggests it’s being way overdiagnosed, and the majority of people with a PAIS diagnosis actually have some other form of intersex. In your case, since your mother was given DES, I’d say the chances are you’re completely genetically normal, and it’s entirely because of the DES that you have an intersex condition.

  4. Im not a DES son… I think, but i know my mom did take some medicine while she was pregnant of me. She had renal colic and high blood tension. I am transgender and I think this have something to do with my identity. Tell me your thought about it plz, thanks.

    1. It’s highly likely that members of the progestin class of hormones can do the same thing, since they are also female hormone mimics, and also act as chemical castration agents in adult men. Unlike DES, progestins were never withdrawn from use, and some are used during pregnancy even now. Other drugs I know of that have testosterone suppressive effects in adult men and are used during pregnancy include corticosteroids, opioid analgesics, and the two epilepsy drugs phenobarbital and phenytoin. There’s certainly a possibility that any of these drugs could interfere with testosterone production in a male fetus, and thereby interfere with that person’s brain masculinization.

  5. Hi Just wanted to say that you are spot on the money. From my own research what I think needs to be done is more research on the dose of EDCs or estrogens/progesterone that will terminate a newly conceived fetus. The abortion pill or the morning after pill that a lot of females take is set to terminate a female fetus. To terminate a male fetus I suspect that a does many hundreds of times lower is required.
    Male births world wide are slowly decreasing. If a female that has just conceived comes into contact with environmental estrogens I believe that a single small dose is enough to terminate any male fetus. The closer to conception the smaller the dose required. The younger the fetus is the weaker it is. As it has no defences of its own yet. It completely relies on it’s mothers defences. Of course mother has no defences against EDC’s as the body considers them hormones. So why would it fight it. It wont. Other than try to regulate amounts to maintain homeostasis.

  6. I have a young son with gender identity issues and my doctor prescribed progesterone during my first trimester for repeat miscarriage. My first thought in analyzing his situation was the progesterone was the cause. I wouldn’t have not taken it since I ended up with a wonderful son who is dearly-loved. But there should be a discussion by the docs to the Mom about the timing of using progesterone. In my case I’m wondering if I may have continued its use past what my doc recommended just to be sure. I can’t remember for sure. But it would have been nice for the doc to let me know the importance of using it only as directed. And the possible consequences of doing otherwise. I researched it thoroughly at the time and saw nothing problematic. I have been researching the possible link between gender and progesterone use for 6 years and yours is the first writing I’ve found. I would like to suggest you add a survey for moms in my situation so guage the numbers out there. Thanks for your efforts on this.

    1. hi I am transgendered woman and I think my mother took the DES but after researching the topic I can see no positive connection. maybe we, transgender , are just a naturally occurring phenomena? i just saw on Nova in a tribe where 1/90 men are born without penises but at the age of 12 y o due to the second wave of testosterone the penis develops. it is so common that at first they are raised as girl then one day they come to school as boys with no problems with other children. this says so much about their culture. take care RAchel

    2. Juanita, Did you ever hear from or find anyone else? I have four sons. Only one of them has gender identity issues and he is the only one for whom my doc at the time put me on large amounts of intramuscular progesterone injections. I am convinced that this is not a coincidence.

      1. Carmen & Juanita,
        I am additionally interested in the progesterone/gender identity connection. I had intramuscular progesterone injections through both of my two successful pregnancies (following 3 miscarriages without the injections). My first child, born male, is transitioning MtF after years of gender dysphoria. My second child, born female, is also now “gender nonconforming”. I have suspected that the hormone treatments I received during both pregnancies played a part in the gender dysphoria of both children, but can find little data to support this theory.

    3. Hi. May I ask your sons age now? I had progesterone injections for the majority of my pregnancy over 30 years ago. My son is very intelligent, lacks motivation, suffers depression but more importantantly can’t seem to feel emotion…..almost asexual. Wish I could find some studies on this.

  7. Thank you for writing this. I’m a DES son and post-op transwoman, and will check out your links as I have time.

    Best,
    Kate

  8. “Phearless Phemme”, yes, it’s highly counterintuitive, but whether you develop as male or female is entirely determined by hormones, not by whether you have a Y chromosome or not. Given that fact, whenever a pregnant woman is given external hormones, there’s an obvious risk of causing abnormalities of sexual development in her unborn baby. DES has been shown to cause female development in biological males in a wide range of bird and mammal species, so it should come as no surprise that it does the same in human beings too!

    It’s not just DES either. There’s a condition called progestin-induced virilization, in which the medical use of artificial sex hormones in pregnancy is known to have resulted in babies being born intersexed. DES is an estrogen, and considering that estrogens and progestins are used for contraception and to treat all manner of medical problems in women of childbearing age, I think it’s important that the public knows about the history of abnormalities associated with these substances.

    Since writing the above article for Hormones Matter, I’ve started a petition asking the FDA to own up to what synthetic hormones can do to an unborn baby:

    http://www.change.org/en-GB/petitions/the-us-food-and-drug-administration-fda-acknowledge-that-hormone-treatment-during-pregnancy-can-cause-intersex-and-transgender

    I’d ask anyone reading this to read it, and if you agree, sign. If it gets up to 100 signatures, I’ll try to find a way of delivering it to the head honcho of the FDA!

    P.S. I’ve seen the trailer for “The Disappearing Male”, and heard all about endocrine disruption caused by BPA, pthalates etc. I’m not buying it. If there were a genuine problem with these substances, we wouldn’t be hearing about it (or at the very least, there’s be a concerted media campaign from industry groups to downplay the problems).

    On my facebook page is a note about Michigan’s Firemaster disaster, in which a mixup at a chemical factory led to a truckload of Firemaster, a highly toxic flame retardent, being delivered in place of a feed additive called Nutrimaster, to Michigan’s largest manufacturer of cattle and poultry feed. Rather than own up to what had happened, the state authorities initially attempted a coverup, and more than a year passed before the truth came out. By that time, most of the poisoned poultry, meat and dairy products had already entered the human food chain. Millions of people were needlessly exposed to a highly toxic chemical as a result of their government’s attempt to protect the company responsible.

    The mixup happened in 1973, right around the time the problems with DES came to light, and the number of people affected (around 10 million) was about the same number as were exposed to DES too.

    https://www.facebook.com/notes/hugh-easton/michigans-firemaster-disaster-an-example-of-governmental-cover-up-from-the-des-e/442976639138843

    I find it quite an inspiring story, because the state authorities were ultimately caught out when a farmer took some of the contaminated feed to a laboratory outside the state to be analysed. Although the expose came too late to protect the people of Michigan, the fallout from the incident meant that the chemical involved (PBB) was banned shortly afterwards, along with a whole slew of other toxic chemicals. Today the world is a much safer place, all because of what that one farmer did!

  9. Very interesting!

    Sex hormones in the womb seem like the most logical explanation for all sex-related variances, such as homosexuality, intersex conditions and transgender identity. Indeed, if this were the case, the “born this way” theory would be definitively proven true for gay and trans people who are often accused of choosing their orientation.

    Another thing to consider: synthetic estrogens like dioxins, PCB’s and BPA are now permeating the environment, exposing all fetuses to some level of estrogen. (BPA was first developed in the 1930s as a synthetic estrogen before being used as a hardener in plastics. It was tested by the same man who developed DES).

    These endocrine disruptors can have disastrous effects on both males and females by lowering the male birth rate and promoting reproductive cancers. If you haven’t already, check out “The Disappearing Male” documentary. Scary stuff.

  10. The facebook page DES (diethylstilbestrol) Info has a fair bit of information about DES sons, and here’s some links from it:

    Personal stories:
    https://www.facebook.com/notes/des-diethylstilbestrol-info/dess-other-daughters-neglected-evidence-of-prenatal-gender-development/701785596514129
    https://www.facebook.com/notes/des-diethylstilbestrol-info/a-des-sons-speaks/668300649862624
    https://www.facebook.com/notes/sarah-roberta-wilson/des-and-the-other-half-of-it/317596581602462

    There’s a couple more DES son’s stories in the “Recent posts by others”, and several more that appeared on the timeline in the first half of June (which should still be there if you page back far enough through it). When you start looking at the life stories of a significant number of DES sons, a pattern quickly starts to emerge, of genital abnormalities (particularly cryptorchidism and micropenis), problems with fertility, low testosterone and endocrine problems, and gender variance, often to the point of full transsexuality. There are lots more similar stories in the DES sons yahoo group (which unfortunately appears to be out of action at the moment), and I think it’s highly likely that the entire population of between 2 and 3 million DES sons worldwide have been similarly affected. After all, it’s pretty much what you’d expect to happen if you expose a developing male fetus to the equivalent estrogen content of half a million birth control pills (which is what happened when mothers were given the standard “Smith and Smith” treatment for prevention of miscarriage)!

    There’s almost no published research into DES sons, and I think that’s because all the bodies who would normally conduct that research (regulatory authorities, pharmaceutical companies and medical organisations) were all implicated to some extent in the DES disaster, and would have a great deal of explaining to do if the truth of what happened ever became public knowledge!

    Research:
    https://www.facebook.com/notes/des-diethylstilbestrol-info/des-exposure-and-potential-psychological-side-effects/429990600360298

    This particular article confirms a suspicion I’ve had that these prenatal hormone exposures can do a great deal more to you psychologically apart from just making you transgendered. If (as appears to be the case with me), you’ve got a brain that’s partly developed as male and partly as female, then I think that your different brain regions tend not to work together very well – particularly if you try to make yourself fit better into one gender category by suppressing all the non gender conforming parts of who you are! This, I think, can manifest itself as all sorts of seemingly non gender related psychological problems such as depression or ADHD, or in some cases more serious psychological disorders too.

    https://www.facebook.com/notes/des-diethylstilbestrol-info/prenatal-exposure-to-diethylstilbestrol-des-in-males-and-gender-related-disorder/325722867453739
    To my knowledge, Drs Kerlin and Meyer’s work is the only serious attempt to look at the gender related effects of DES exposure. I joined the DES sons group a couple of years ago, and looking back through the message archive, they mainly seem to be people who stumbled on the group by chance after discovering that they were DES-exposed. In other words, as a group they’re probably fairly representative of DES sons as a whole, and the results Dr Kerlin reported on completion of his study are scientifically valid.

    As far as I’m concerned, if being prenatally exposed to one artificial hormone can make people transgendered, then it’s highly likely that other artificial hormones can do the same thing too. Although I’m unlikely to ever be able to prove it, for a variety of reasons I’m fairly sure that what happened to me involved contraceptive pills and not DES. The main hormonal component of these is norethisterone acetate, a progestin, and progestins are still in use today as a treatment to prevent miscarriages. This is why I think making people aware of what happened to me and to the DES sons is so important, it shows both that pharmaceutical hormones can interfere with sexual development in the unborn child, and that the problem isn’t limited to DES but is likely to be a property of artificial sex hormones in general (and perhaps corticosteroids too).

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