Part 2 – Sex Steroids, Estrogen Blockers and What’s in Your Bones

In our last episode, Robin had entered the Bat Cave unannounced and unwittingly walked in while Batman was giving himself his bi-weekly injection of testosterone cypionate.  Robin stopped dead in his tracks and stood staring.  Batman glanced up and, without a word, turned his attention back to his injection.

As Batman silently pushed the thick liquid into his muscular thigh, Robin could stand it no more.  His fists clenched, his brow furrowed, he blurted out, “Holy gender conundrum Batman!! You are so binary!!”   Batman plucked the needle from his leg, dropped it into the sharps container and replied, unfazed, “Take it easy, Boi Wonder.  We each have our own process.  And hand me the pump, will ya?  I got a date tonight.”

Well, okay, so that wasn’t really our last episode.  What we were really talking about was the different types of estrogen blockers.  Not nearly as much fun as Batman and Robin, but maybe more interesting.  (Or not.)

As a quick review, there are three main types of estrogen “blockers”:

  • SERMs (selective estrogen receptor modulators) that can act as an agonist or an antagonist on the estrogen receptors
  • Aromatase inhibitors that block enzymatic production of estrogen from androgen (estradiol from testosterone, for example)
  • GnRH analogs which shut down release of hormones from the pituitary that would stimulate the ovary to produce estrogen

The original reason for this post was to talk about the effects of sex steroids on bone.  Okay, so why would we care about blocking estrogen when we talk about bone health in men, whether they be trans or non-trans?  After all, men have testosterone (well, many do anyway).  What’s the big deal about estrogen?  Well, read on for the exciting answer…

Sex steroid hormones and their action on bone

Bone is a dynamic tissue.  During growth, there is bone modeling, which results in an increase in bone mass.  In adulthood, there is bone remodeling, which, in the “normal” state, is a balance of bone resorption and deposition, called bone homeostasis.  Also, there are different types of bone (woven & lamellar), bone structures (cortical, trabecular, etc) and  other details of bone biology that I won’t go into here.  For the purposed of this post, I am making a very simplified description of bone biology, so if you would like to know more, you can read about basic bone biology or, if you want a little more to sink your teeth into, there’s this free review article on bone biology.

After all the talk about estrogen and some about testosterone, we can look at how these hormones affect bone.  The importance of estrogen for bone health in natal females is well-known.  Just about all of use have a female relative who must remain vigilant about her bone health following menopause because the significant drop in her estrogen levels can lead to osteoporosis.  In other words, in females, estrogen supports balanced bone remodeling. Without estrogen, bone resorption outweighs deposition and the bone becomes weak.

The importance of sex steroids for bone health in natal males, however, has offered up a few surprises relatively recently.  The assumption for years was that testosterone maintained bone health and bone mineral density (BMD) in natal males.  Compared to natal females, natal males put down more bone during growth, have a greater peak bone mass, lose less bone with aging and have a relatively stronger skeleton, all of which were attributed to the effects of testosterone.  Because estrogen levels in the blood of natal males are relatively low, at the level of those seen in post-menopausal natal females, the importance of estrogen on male bone health was considered to be insignificant.  Mother Nature, however, taught us different lesson.

In the mid-1990s, several reports of men with mutations in their genes for estrogen receptor alpha (ERα) or aromatase provided a surprise.  Even with testosterone coursing through their veins, the men with these genetic mutations had severe osteopenia (low BMD) and failure of the epiphyseal plates to fuse in their long bones.  If that wasn’t surprising enough, the men with mutations of their aromatase genes responded to replacement therapy with estrogen with an increase in BMD and closure of the growth plates of the long bones.

In other words, estrogen, aromatized from testosterone locally in the bone tissue and acting through the ERα, is required in males for optimum bone maturation.

The importance of estrogen for bone maintenance in natal males was also shown in cases where the individuals were being treated for androgen-sensitive prostate cancer with GnRH analogs.  Even though testosterone was absent in those males, BMD was maintained with raloxifene, a SERM that is an ER agonist in bone.

That isn’t to say that testosterone isn’t important for bone in males.  Studies with men and animals provided evidence that testosterone is important for deposition of cortical bone in growing males and works to inhibit resorption of bone and maintains bone deposition in adult males.  For example, in men treated with a GnRH analog to artificially induce hypogonadism (lack of testosterone), administration of both estrogen and testosterone resulted in a bone metabolism that was closest to the normal state.  These actions of testosterone on bone are communicated via the androgen receptor (AR) and are independent of the aromatization to estrogen and its actions thereof.

What does this all mean for transmasculine people who are taking estrogen blockers?

When I began this topic, in Part 1, I said that estrogen blockers can matter when it comes to bone. Or not.  It really does depend.

First, for guys who have had their ovaries removed and are not on testosterone hormone replacement therapy, for whatever reason, their bones are at risk for osteopenia/osteoporosis, similar to severely hypogonadal males or post-menopausal females — in other words, just like any individual who lacks both androgen and estrogen.

With regard to estrogen blockers, I’m going to leave the SERMs out of the discussion because my impression is that the major type of estrogen blocker used to treat trans guys is in the GnRH analog group.

One would not expect issues with bone if a guy taking a GnRH analog was also on testosterone hormone replacement therapy.  The testosterone would have direct effects on bone and would also be aromatized to estrogen, which would support bone homeostasis.  (I won’t speak about trans children on GnRH analogs to delay puberty because other hormones are involved in bone growth in those cases.)

This brings us to the final estrogen “blocker” — the aromatase inhibitors.  Even if a guy is taking testosterone hormone replacement therapy, concomitant treatment with an aromatase inhibitor would not allow aromatization of androgens, so there would not be any estrogen present to support bone homeostasis.  Intuitively, one should be concerned about osteopenia/osteoporosis in this case.  There is clear evidence of osteoporosis in post-menopausal females who take aromatase inhibitors to treat estrogen-sensitive breast cancer.  However, the jury is still out on pre-menopausal females who take aromatase inhibitors for the same reason.

Therefore, trans guys who are considering taking aromatase inhibitors to block estrogen, even if they are on testosterone, should have a serious conversation with their doctor about their bone health and whether their BMD should be monitored during the course of treatment.

And there you have it– the slimmed down version of estrogen blockers and bone homeostasis.  There are a few references at the end here for those who would like to dive into the subject a little deeper.  For information on this subject as it pertains to trans men, I highly recommend the section in Dr. Nick Gorton’s et al. free book, “Medical Therapy and Health Maintenance for Transgender Men: A Guide for Health Care Providers,” pages 59-61.

Sorry there aren’t photos and more in-depth details in this post, but I had to write it in a rush.  I gotta cut outta here — I’m Batman’s wing man for his date tonight…

— ATM

References for this post:

Estrogens as regulators of bone health in men, Vandenput L, Ohlsson C, 2009, Nature Rev Endocrinol 5:437-443.

Medical Therapy and Health Maintenance for Transgender Men: A Guide for Health Care Providers, 2005, Gorton N, Buth J, Spade D, pages 59-61.

Regulation of adult bone turnover by sex steroids, Frenkel B, Hong A, Baniwal SK, et al., 2010, J Cell Physiol 16 Apr [Epub ahead of print].

Sex steroids and the male skeleton:  a tale of two hormones, Callewaert F, Boonen S, Vanderschueren D, 2010, Trends Endocrinol Metab 21(2):89-95.

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13 Responses to Part 2 – Sex Steroids, Estrogen Blockers and What’s in Your Bones

  1. Lloyd says:

    Anderson:

    Thank you for these posts on bone health! I had greatly oversimplified the issue. These posts will help many of us more intelligently raise and discuss these issues with our physicians.

    • Aw shucks, thanks Lloyd. I appreciate it.

      By the way, I had 2 comments stuck in the spam filter and deleted them just as I realized one of them wasn’t spam. If someone posted a comment and they don’t see it here, please repost. Sorry for the mistake.

  2. Josh says:

    So what catagory does Tamoxifen fall under?

  3. Alabastardragon says:

    I have both osteopenia and osteoarthritis and have been taking T for 8 years this year. Although I have them, I’m thinking they would probably be much worse if I wasnt on T!

  4. Sean says:

    Excellent articles!

    Here’s something I’ve been trying to figure out…and that is how much estrogen does a transman need for bone health? Since biologically, a transman is a woman who’s wired to have a higher ratio of estrogen to testosterone. I have severe osteoporosis and have been to about a dozen doctors who can’t give me a definate answer. They always assume as long as your within a biological-male range you should be alright…but well we aren’t really wired in a biological-male fashion. Just curious if you’ve done any type of research on this subject? Not sure if you came across this article…it’s definately a good read.

    http://ajpendo.physiology.org/cgi/content/full/295/5/E1213

    • Thanks for the nice comment and for the reference.

      I have seen the animal studies out there, and there are plenty of them. When I wrote these posts, I decided to focus only on the human data because there is a good amount of it and also because I wasn’t so interested in writing about the molecular and physiological mechanisms behind bone biology, and that’s what the animal studies are really good for teasing out.

      As for a paper that provides information for how much estrogen a trans guy needs for bone health based on the female range, I didn’t really look into that as I was viewing trans men more similar to men because of the presence of testosterone. There is one paper that I referenced in my post that explains the levels of estrogen and testosterone needed in men for bone health, and there is very brief mention of levels for women and references therein that you can check out: http://www.ncbi.nlm.nih.gov/pubmed/19528961

      As for your severe osteoporosis, I’m not a doctor and you’ve already been to a dozen, so I can’t offer much in the way of advice except for one thing. I have heard quite a few trans guys talk about taking natural supplements for one thing or another, and personally, I don’t trust natural supplements because we don’t know all their effects and they’re not regulated by the FDA. I have heard that there are some that have activity as aromatase inhibitors, so if you’re on testosterone and you’re taking a natural supplement that is inhibiting aromatase, there might not be enough conversation of testosterone to estrogen in the bone. That’s just a comment based on anecdotal information.

      There are certainly drugs out there to treat osteoporosis. I hope you find a doctor who can take adequate care of you. Finding a trans-experienced doctor might help, if you haven’t already. In the meantime, here is a review of drugs that are being used for cancer treatment induced bone loss: http://www.ncbi.nlm.nih.gov/pubmed/20377485

      • Sean says:

        Oh yes, I certainly agree with you on certain supplements…one can never be sure what those things are doing to your body (my liver’s been through enough)! 🙂

        Your link sparked my memory of a medicine my doctor wanted to place me on but it wasn’t available until now, Denosumab. I guess it was designed to provent bone loss related to aromatase inhibitors. I’m currently taking Forteo (eating right, blah blah blah) and so far no progress but I’ve got a ton of other neurological things going on which might be interferring with everything.

        Thanks again for your suggestions!

        EVERYONE who’s taking hormones should read your blog on bones!

  5. maddox says:

    Just checking this out, because even though it’s a year old it’s still super useful. So far my research has led me nowhere, mostly because all layperson’s information assumes you are a cis- female or male. Also I am not very adept at teasing out and making sense of dense medical information, so you are a godsend!

    As a non-binary person, I’ve been particularly interested in learning the effects of hormones. My ideal would be to have no hormone effects: no feminizing, no masculinizing.

    Whenever I’ve asked someone about this, they say hormones are necessary for bone health, but until now I had not really had _evidence_ as to how or why. Basically, we need a sex hormone – androgen or estrogen – in our bodies (actually just estrogen, because androgens are aromatized to it), otherwise we are at severe risk of osteoporosis. Moreover, I believe estrogen doesn’t really continue to feminize you in any way, so there’s no drawback in having it in “full dose” in your system is there? Still, I wonder if there were a way to maintain a minimal magic balance.

    Thanks again for writing this Batman!

    • Well thanks Maddox! (I almost called you Robin but thought that might be stretching it.)

      I absolutely know what you mean about wanting NO hormonal effects – no feminizing, no masculinizing. I had that for a while. Post-menopausal with no exogenous hormones, and I liked it. It felt good to have no hormones. Eventually, however, I lost bone mineral density and became osteopenic. Still, I think that a person, a young person who gets a lot of exercise and eats well with plenty of natural calcium and Vitamin D in their diet, can go for a little while without hormones and not have to worry about their bones. (Not sure how long “a while” would be.) Sooner or later though, one would need to pay the piper…

      By the way, I know a genderqueer person who is striving for the minimal magic balance, post-menopausal and taking low doses of both estrogen and testosterone. They feel comfortable with both. Not sure yet how that’s working out with the bone density.

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