I’m thinking that maybe I should take a class on how to write better titles for posts. I guess I was looking for some continuity from the previous posts on biology. If only I had not been trying to make a joke when I wrote that first title…
Anyway, the title notwithstanding, I have been wanting to write something about the effects of sex steroids on bone ever since I saw a post by a guy on one of the lists who mentioned that his endocrinologist said that taking estrogen blockers didn’t matter. So I am here to say that estrogen blockers can matter when it comes to bone. Some times. But most likely not. Well, it depends.
Estrogen Blockers – What Are They?
The first thing I should have done when I saw that post was ask what exactly he meant by “estrogen blockers” because there are different ways to “block” estrogen.
- Blocking the binding of estrogen to its receptors
- Inhibiting the synthesis of estrogen
- Inhibiting the hormones from the brain that induce the ovaries to make estrogen (in the case of individuals who actually have ovaries or ovarian tissue)
Let’s take a look at the three different types. In doing so, please keep in mind that I am not a medical doctor (and I don’t play one on TV) and I am not offering advice on the clinical use of these drugs. That is a conversation to have with a clinician.
Blocking the binding of estrogen to its receptors:
Selective Estrogen Receptor Modulators (SERMS)
SERMS are chemical compounds that are able to bind to estrogen receptors (ERs; ERα and ERβ), and if given at the proper doses, they occupy the ERs in the body so that estrogen is blocked from binding. SERMS can act either as agonists, in that they activate the ERs like estrogen does, as antagonists, in that they occupy the ERs in place of estrogen but do not activate them, or as mixed agonists/antagonists. Their uses depend on their activities.
Agonists and one antagonist are used to treat infertility, menopause and reproductive issues and antagonists are used to treat estrogen-sensitive breast cancer. The mixed agonists/antagonists are also used to treat ER-positive breast cancer and have selective activity depending on the tissue. For example, raloxifene is an antagonist in breast tissue (hence the anti-cancer use) but an agonist in bone to prevent osteoporosis. Information about SERMs can be found here on Wikipedia – the most accurate source of information in the universe – or on the National Cancer Institute web site, which is probably even more accurate.
Inhibiting the synthesis of estrogen: Aromatase inhibitors
Estradiol is the product resulting from enzymatic aromatization of the A ring of testosterone. One way to “block” estrogen, then, would be to stop its production by inhibiting the enzyme that makes it: aromatase.
Aromatase inhibitors are used to treat a variety of different medical issues, such as infertility (lack of ovulation), gynecomastia (even by body builders because the anabolic steroids they use can be aromatized to estrogens and stimulate breast tissue growth), short stature (due to a number of different causes), genetic activation of the aromatase gene (familial gynecomastia and familial hyperestrogenism) and estrogen-sensitive breast cancer. Regarding the latter, the three aromatase inhibitors used for treatment of estrogen-sensitive breast cancer are:
|Brand Name||Chemical Name|
Some doctors will also prescribe an aromatase inhibitors to hypogonadal natal men along with hormone replacement therapy to reduce the risk of gynecomastia from the testosterone being aromatized to estrogen. With regard to FTMs, I have seen a couple posts on the lists where trans men have asked about or mentioned being prescribed aromatase inhibitors as part of their medical transition.
Inhibiting the hormones from the brain that induce the ovaries to make estrogen: GnRH analogs
Gonadotropin releasing hormone (GnRH) is a 10-amino acid peptide that is produced in the brain by neurons of the hypothalamus. GnRH acts on the pituitary to promote release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), gonadotropic glycoprotein hormones that stimulate testicular and ovarian function. With regard to estrogen, it’s production by the follicles of the ovary is under the control of FSH. Therefore, blocking GnRH action at the level of the pituitary would result in removing FSH (and LH) from the picture, and voilà – no more estrogen.
Well, no more estrogen from the ovary, anyway. There is local production of estrogen in a number of tissues and organs besides ovary, such as skin, bone, brain, blood vessels and adipose (fat). Estrogen produced in those locations, however, tends to act locally. The adrenal glands also produce a relatively low level of estrogens, but the main source is the ovarian follicle in female-bodied and some intersex individuals.
So, in order to stop estrogen production by ovaries, how to block GnRH action at the pituitary? There are analogs of GnRH that bind to the GnRH receptor and block binding of endogenous GnRH. And similar to the SERMs mentioned above, the GnRH analogs can act as agonists, antagonists or both. The American Society of Reproductive Medicine gives a very nice definition of GnRH analogs:
GnRH analogs are synthetic hormones similar to the naturally occurring gonadotropin releasing hormones (GnRH) produced by the hypothalamus. GnRH analogs, when given in short pulses, stimulate the pituitary gland to produce FSH and LH. However, when given in more prolonged doses, they decrease FSH and LH production by the pituitary, which in turn decreases ovarian hormone production. Brand names are Lupron®, Synarel®, and Zolodex®.
Clinical uses of GnRH analogs in transgender medicine
Another use of GnRH analogs has been to block puberty in trans adolescents in order to inhibit irreversible development of unwanted secondary sex characteristics. Treatment with GnRH analogs is begun at a certain stage of development (called Tanner stages) and then when the adolescents reach pubertal age (16-18 years) they can be treated with cross-sex hormones to induce secondary sex characteristics that are consistent with the person’s gender. Or, if the individual chooses not to take cross-sex hormones and wants to undergo puberty that is consistent with their birth sex, they can stop the treatment with the GnRH analogs because the effects are reversible.
This treatment modality is described in the Endocrine Society’s clinical practice guideline, “Endocrine Treatment of Transsexual Persons” and is used at the Amsterdam Gender Clinic, among others. For adult FTMs, GnRH analogs can also be used to induce menopause (arrest of menstrual cycles) and eliminate estrogen production by the ovaries prior to beginning testosterone hormone therapy, as described in “Endocrine Treatment of Transsexual Persons.”
This type of estrogen blocking treatment is likely the one I read about on the FTM lists. The disadvantage of using GnRH analogs is that they are very expensive and sometimes not covered by health insurance. As mentioned in the guide from the Endocrine Society, depot medroxyprogesterone, which is cheaper, can be administered –it will feed back to the brain and shut down FSH and LH release from the pituitary. Something to note about medroxyprogesterone – it is a female hormone and has some side effects worth considering.
In fact, every drug and hormone I’ve mentioned in this post has side effects worth considering and discussing with a doctor if you are thinking about using them.
Next up in Part 2: Sex steroid hormones and their action on bone, potential effects of estrogen blockers on bone, ramifications for FTMs
In Part 2 of this post, I will talk about the effects of sex steroids and the different types of estrogen blockers on bone and related considerations for trans men. In the meantime, for more in-depth reading of the points that I have covered here, please see a list of references below.
References for this post:
Clinical management of gender identity disorder in adolescents: a protocol on psychological and paediatric endocrinology aspects, Delemarre-van de Waal HA & Cohen-Kettenis PT, 2006, Eur J Endocrinol, Vol 155, suppl_1, S131-S137
Emerging drugs for the management of cancer treatment induced bone loss, Bertoldo F, Pancheri S, Zenari S, Boldini S, 2010, Expert Opin Emerging Drugs 15(2): Expert Opin Emerg Drugs, Apr 9. [Epub ahead of print]