If you’re taking estrogen, or are interested in taking estrogen, you probably have some knowledge of what changes can happen in the body when exposed to estrogen. That’s right, we’re Gettin’ Nerdy on Gettin’ Curvy: Estradiol, Progesterone, and SERMs (and a few of the other tools in our gender affirming tool kit.) Estrogen is prescribed as estradiol. You may have read some guides (like our All The E) which go into some depth about what to expect from gender affirming hormone treatment (GAHT.) You may have even read our progesterone handout or read our blog on blockers. Today, we’d like to dive deep into HOW and WHY they do what they do.
First, what are estradiol and progesterone?
Estradiol and progesterone are hormones. Hormones are chemicals that tell cells what to do. They are, to borrow a phrase, small but fierce!
Hormones are created by endocrine glands and released directly into the body by those glands (most are released directly into the bloodstream.) One way to think of how hormones work is the wooden block shape sorter toys loved by toddlers all over the world.
Each hormone is a shape, and cells all over the body have receptors that match those shapes. We can affect hormone-driven processes in the body by:
* Increasing hormones – if you take estradiol, more estrogen is available to fit cells that have estrogen receptors
* Decreasing hormones – by decreasing the amount of hormones that are produced in the body
* Interfering with receptors –
* By capping receptors so that hormones in the bloodstream don’t attach
* By turning receptors off or on by location
When a hormone matches a receptor, cells are then primed to do something. This is where the real science and magic of gender affirming care happens.
When Gettin’ Curvy, we are generally interested in:
* Increasing the amount of estrogen, as estradiol, and sometimes progesterone in the body
* Decreasing the amount of testosterone in the body
* Turning receptors for estradiol and testosterone on or off
* Preventing the conversion of starter hormones into testosterone or its more active form dihydrotestosterone (DHT)
We do this by:
*adding estrogen to bodies that make less of it (usually in the form of estradiol,)
*adding progesterone to bodies that make less of it by utilizing both progesterone capsules and progesterone cream
* utilizing hormone blockers like:
* androgen blockers including spironolactone (aldactone), bicalutamide (casodex), and finasteride (Proscar and Propecia )
*GnRH (gonadotrophin releasing hormone) analogues (AKA puberty blockers,)
* SERMs (selective estrogen receptor modulators) including raloxifene
If a patient wants to get angular instead of curvy, we might employ aromatase inhibitors.
How does the body regulate estrogen/estradiol, progesterone, and testosterone?
Luteinizing and follicle-stimulating hormones!
The pituitary gland can be viewed as a conductor of other glands – it tells other glands to make more or less hormones, in addition to making and releasing hormones itself. The pituitary gland is regulated by the hypothalamus. We won’t go into all of the functions of the pituitary gland, but we will mention that the pituitary gland is responsible for follicle-stimulating hormone and luteinizing hormone (FSH and LH) which help the ovaries and testes know when to produce estrogen, progesterone, and testosterone. The pituitary is also in charge of endorphins and oxytocin, which feel really good, and we like feeling good. (FYI it has other jobs too, but we won’t list them here.)
Luteinizing hormone in the blood tells testes to make testosterone.
Gonadotrophin-releasing hormone is released by the hypothalamus, and it goes to the pituitary where it binds to GRH receptors. This tells the pituitary to create and release luteinizing hormone. LH goes to the testes and binds with receptors there, which tells the cells to make more testosterone! As more testosterone enters the bloodstream and is sensed by the hypothalamus, the hypothalamus will then control how much GRH is puts out based on circulating testosterone levels.
Follicle-stimulating hormone acts similarly: the hypothalamus pays attention to circulating levels of testosterone and tells the pituitary to make more or less FSH. If testosterone levels are high, production of FSH is decreased, which binds to fewer receptors in the testes, which then make less testosterone. FSH levels increase when testosterone levels decrease.
For youth, we put a pause on puberty by utilizing GnRH agonists. GnRH agonists don’t directly affect how cells use testosterone or estrogen, but tell the hypothalamus to stop telling the pituitary to make LH and FSH, which stops the body from making testosterone and estrogen in the gonads.
Ok, there’s a feedback loop. But does it matter as long as we’re decreasing testosterone production?
Your body already produces estradiol and progesterone!
And you might want some testosterone (or its effects!)
Whoa.
Estradiol, Progesterone, and Testosterone Levels in the Body
It’s important to mention that testes produce both testosterone and estradiol, and testes and adrenal glands produce progesterone and testosterone! Other parts of the body produce estradiol as well – the brain, fat tissue, skin, and bone – all of them play a role in how much estradiol is in the body and how it gets used. If you’re looking to get curvy, you already have estradiol and progesterone receptors, and part of the fun is using them more efficiently!
It’s also important to note that testosterone can convert into other hormones, and this is how most of the estrogens in bodies with testes are created within the body. Namely, testosterone can convert to:
* estradiol
* estrone (a steroid with weaker estrogenic effects,)
* dihydrotestosterone (DHT,) which has powerful androgenic effects.
The enzyme aromatase converts testosterone into estradiol, while 5 alpha-reductase converts testosterone into DHT. DHT is a key player in how hair and skin behave, and most notably, in the growth of coarse facial hair and the hair loss patterns on the scalp.
5 alpha-reductase inhibitors like the drug finasteride block the conversion of testosterone to DHT. Aromatase inhibitors block the conversion of testosterone to estradiol.
Androgen blockers like spironolactone can both fit into testosterone receptors and/or lower the amount of testosterone made by the body. Well, theoretically. In practice spironolactone does not actually lower blood serum levels of testosterone significantly, 2. GnRH analogs can be used to stop production of testosterone, but not its use in the body. Bicalutamide can block receptors but not the production of testosterone.
Estradiol Dosing
Dosing is a hot topic. You’ve no doubt seen tips on how to increase estradiol levels.
It is very important to remember that everyone is different, and that the extent and rate at which your changes take place depend on many factors. These factors include your genetics, the age at which you start taking hormones, and your overall state of health.
It is also important to remember that because everyone is different, your medicines or dosages may vary widely from those of your friends, or what you may have read in books or online. Many people are eager for changes to take place rapidly.
We know that sufficient estradiol levels can shut off testosterone production in people who still have testes. We also know that after orchi, we can often lower dosing of estradiol and maintain bodily changes. BUT – we also know that higher dosing of estradiol, after a point, doesn’t necessarily mean faster changes in the body. More isn’t necessarily better, and changes take time.
Part of this is LH and FSH telling the body to make more or less of the hormones it has the gonads to make. Part of this is the availability of hormone receptors in the places we want them to get used. Part of this is what amounts of which hormones are circulating in the body versus bound to circulating proteins.
Hormones are also important for overall health. We don’t have to monitor LH and FSH, but knowing if LH and FSH levels are high or low can help us understand if the body has enough estrogen to protect bones as well as be curvy. Get your labs done!
This brings us back to hormone receptors.
Estrogen Receptors
There are multiple kinds of estrogen receptors. (Just when you thought it was already too complicated!)
Type 1 – ERα (Estrogen Receptor alpha)
Found in the hypothalamus, the lining of ducts in the testes, and in endometrial, breast, and ovarian cells.
Type 2 – ERβ (Estrogen Receptor beta)
Widely found in the body – in skin, kidneys, the brain, bones, the heart, the lungs, in intestinal mucosa, in the prostate, and in the linings of blood and lymphatic vessels
Estradiol (what we prescribe for Gettin’ Curvy) fits into both types of receptors. That’s why we see broad types of changes on estradiol (and it’s one of the big reasons we use estradiol rather than estrone…)
Estrone (one of the hormones T converts to) likes to fit into alpha receptors
Aren’t they pretty?
Fun fact: oral E may result in higher levels of estrone in the blood compared to other forms of E, and may be one of the reasons different forms “feel” different and affect the body differently. It also increases sex hormone binding globulin (SHBG) which means more hormones are bound instead of free circulating.
SERMs (selective estrogen receptor modulators) come in a variety of forms.
We go into detail about SERMs here.
Raloxifene takes up receptor spaces in breast tissues, and can minimize, but not eliminate, breast development in a person using estrogen. It avoids receptors in skin and can increase the effectiveness of estrogen in getting softer and smoother.
Tamoxifen can also use up receptors in breast tissue, thus decreasing estrogen’s effect, and is used in gender affirming care to reduce breast development if you’ve grown more than you like. But, it is much more toxic with more intense side effects than raloxifene, so it is used for a short course in someone who has stopped estradiol therapy.
Progesterone Receptors
In gender affirming care, progesterone is most known for its effect on breast development: it affects tissue growth and adding progesterone can stimulate the body to grow bigger and rounder breasts. We discuss progesterone in our clinical use here. Progesterone affects areolar size during cis puberty, but we don’t know much yet about how it might be used to increase areolar size when gettin’ curvy.
Progesterone receptors are also found in the brain, pancreas, bone, gonads, and the lower urinary tract, as well as in skin and hair follicles. Progesterone also affects the cardiovascular system and the nervous system.
Some of the more fascinating impacts of adding progesterone to estradiol when gettin’ curvy may be seen in hair growth: progesterone competes with 5 alpha-reductase. If you remember from above, 5 alpha-reductase converts T into DHT, and DHT promotes coarser facial hair and male-pattern hairlines. Adding progesterone may make the process of getting softer and less hairy go faster and be more effective. It may also help reduce oil production by the skin, affect body odor, and modulate how changing levels of estrogen in the body are experienced, thus evening out highs and lows and mood changes when using injectable E.
Sleep and other benefits of progesterone
Sleep is necessary for health. Progesterone helps regulate sleep and can help you get deeper and less interrupted sleep (as well as fewer hot flashes!) Good sleep makes almost everything better.
While there is little research on progesterone in gender diverse patients, we can pull on research from other populations which indicates progesterone improves bone health and cardiovascular health. If we use micronized progesterone (Prometrium), which is bioidentical there is NO increased risk of blood clots, known as venous thromboembolism or VTE. This also seems to be true with bioidentical compounded progesterone cream. Due to the lack of research there are no recommendations or guidelines for progesterone levels, but we shoot for levels found in bodies with ovaries.
Putting it all together! YOU and estradiol, progesterone, and SERMs:
We believe that gender affirming care is about YOU, and we try to individualize treatment plans to help you achieve your goals. Getting nerdy about how hormones work and interact in the body can help steer your body towards your goals.
NOTE: every body is different, and how and how quickly things happen in gender affirming care is unique to you. We can estimate the timelines of body changes, but we can’t know for sure how quickly they’ll happen, or exactly how much your body will change. This depends to some degree on dosing and medications chosen, your pre-existing genetics, and the duration of your previous exposure to androgens, like testosterone.
However, we can try to encourage or discourage some changes through the use of different forms of estrogen and using or not using progesterone, anti-androgens, and/or SERMs.
We can work to maintain erectile function while creating curves. We can also try to encourage soft skin and less/lighter/finer body and facial hair while discouraging breast growth. We can encourage breast growth with topical progesterone, and even out E troughs with oral progesterone. Some patients after orchi may find benefit in microdosing T.
How do you want your body to be? Find out more about how we do gender affirming care at QueerDoc by requesting a free 15-minute introductory appointment.
Citations and Further Reading
1. Liang JJ, Jolly D, Chan KJ, Safer JD. TESTOSTERONE LEVELS ACHIEVED BY MEDICALLY TREATED TRANSGENDER WOMEN IN A UNITED STATES ENDOCRINOLOGY CLINIC COHORT. Endocr Pract. 2018 Feb;24(2):135-142. doi: 10.4158/EP-2017-0116. Epub 2017 Nov 16. PMID: 29144822.
2. Angus, L., Leemaqz, S., Ooi, O., Cundill, P., Silberstein, N., Locke, P., Zajac, J. D., & Cheung, A. S. (2019). Cyproterone acetate or spironolactone in lowering testosterone concentrations for transgender individuals receiving oestradiol therapy, Endocrine Connections, 8(7), 935-940. Retrieved Jan 9, 2022, from https://ec.bioscientifica.com/view/journals/ec/8/7/EC-19-0272.xml
Jerilynn C Prior, Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen, The Journal of Clinical Endocrinology & Metabolism, Volume 104, Issue 4, April 2019, Pages 1181–1186, https://doi.org/10.1210/jc.2018-01777
Salisbury BH, Tadi P. 5 Alpha Reductase Inhibitors. [Updated 2021 Sep 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK555930/
Ishikawa T, Glidewell-Kenney C, Jameson JL. Aromatase-independent testosterone conversion into estrogenic steroids is inhibited by a 5 alpha-reductase inhibitor. J Steroid Biochem Mol Biol. 2006 Feb;98(2-3):133-8. doi: 10.1016/j.jsbmb.2005.09.004. Epub 2005 Dec 28. PMID: 16386416.
https://transcare.ucsf.edu/guidelines/feminizing-hormone-therapy
https://transcare.ucsf.edu/article/information-estrogen-hormone-therapy
The Endocrine System and Hormones:
https://training.seer.cancer.gov/anatomy/endocrine/
https://www.yourhormones.info/hormones/follicle-stimulating-hormone/
