Biological Concepts in HRT

Author: Zennith. Reviewed by Dashie and Tilt Wolf.
First posted: 2023

Hormone Replacement Therapy (HRT) includes a broad set of approaches that use medications to change how a person’s body produces and/or responds to hormones, including but not limited to testosterone and estrogen. HRT is applied in a wide variety of cases such as menopause, protecting bone health, increasing alertness, and gender affirmation.

Here, we aim to help you understand the general concepts of how sex hormones work, and the factors that go in to considering the types of HRT that may be most appropriate for a person’s gender affirmation goals.

As always, we strongly encourage you to discuss details carefully with a medical professional before deciding upon a course of action. We hope that the information here can help you be a more informed and proactive patient. Ultimately it’s you, not your medical professional, who has to live with the results!

Hormones traditionally associated with sexual characteristics include testosterone and estrogen. These hormones are produced by the body starting by a series of biochemical reactions that begin with a cholesterol molecule. Reactions result in the production of various progestogen-class hormones (including pregnenolone and progesterone), then various androgens (including testosterone), and finally get converted into estrogens (including estradiol). These chemical reactions occur in all people. But, as you might expect, masculine traits are associated with more androgens/testosterone being present, whereas feminine traits are associated with more estrogens being present.

The biochemical reactions are performed by several enzymes. Major enzymes related to differentiating between sex characteristics include (1) some 17β-hydroxysteroid dehydrogenases (17β-HSDs), (2) 5ɑ reductases, and (3) aromatase.

First, various enzymes within the 17β-HSD group can convert hormones between their less-active and more-active forms, and vice-versa. For example, 17β-HSD3 creates testosterone from the less-active precursor, androstenedione. In comparison, 17β-HSD2 does basically the opposite, returning testosterone and estradiol to the less-active forms. That is to say – the 17β-HSD enzymes are complex, and end result is a bidirectional reaction network! (Please note that while enzyme-catalyzed reactions tend to proceed in one direction, we have not evaluated evidence for one-way directionality for each relevant 17β-HSD family member. This is outside our scope at this time. At the end of the day, the cumulative effect of these 17β-HSD enzymes is a bidirectional reaction network.)

Relatively simpler are 5ɑ reductases. This group of enzymes includes at least three members: SRD5A1, SRD5A2, and SRD5A3. The first two are well known to convert testosterone to dihydrotestosterone (DHT) in an irreversible reaction (Azzouni et al, Adv Urol, 2012). DHT is, crudely, an even more active form of testosterone, though it doesn’t circulate as much in the blood.

Finally, no discussion of sex hormones is complete without mentioning aromatase. Unlike the above groups of enzymes, aromatase is only produced from a single gene. Aromatase performs one-way reactions of both androstenedione to estrone, and of testosterone to estradiol (Abaffy and Matsunami, J Endocr Soc, 2021).

Testosterone, estrogen, and other hormones are produced at various sites throughout the body (not just the gonads), circulate throughout the bloodstream, are received by cells throughout the body, and ultimately get degraded or reprocessed into other molecules.

Cells throughout the body are continuously looking for hormonal signals. Everything from the brain, muscles, bone, fat, breasts, reproductive organs, and even blood vessels constantly receive hormonal signals. These signals influence how tissues grow, change in response to stimuli, and maintain homeostasis. Hormone signaling even has feedback loops, and can change how hormones are produced or received by cells over time. Incorrect hormonal signals can cause psychiatric symptoms, cardiovascular problems, brittle bones, and other health issues throughout the body.

Cells watch for hormones by producing a variety of receptor proteins. Some of these receptors are highly specific for one hormone, while others are promiscuous. You can guess, based on their names, that the Androgen Receptor (AR, a.k.a. gene NR3C4) preferentially detects androgens like testosterone, that Estrogen Receptors Alpha and Beta (ERɑ and ERβ, a.k.a. genes NR3A1 and NR3A2) prefer estrogens, and that the Progesterone Receptor (PR, a.k.a. gene NR3C3) prefers progesterone. Other receptors for these hormones include GPER, GPRC6A, ER-X, OXER1, ZIP9, and PAQRs.

Cell types across the body differ in the types of hormone receptors they express. This is true even when comparing the main Estrogen Receptors ERɑ and ERβ. Both ERɑ and ERβ are expressed in the central nervous system, the cardiovascular system, the ovaries, and adipose tissue. However, ERɑ is more prominent in mammary glands, the uterus, and bone, whereas ERβ plays a larger role in the bladder, the colon, and the immune system (Paterni et al, Steroids, 2014).

The differences between tissues in how they express hormone receptors, and how they interpret signals, help explain why hormones have such complex and far-ranging effects. Some parts of the body can grow while others shrink, and some seemingly-unrelated physiological processes may change, when HRT is applied. At the end of the day, some HRT drugs will be more appropriate (in terms of both effectiveness and safety) to use in a given situation than others. And, as with many things in medicine, it is genuinely possible for doctors to be unsure as to which specific treatment would be optimal for you at first.

Medications that modify sex hormone signaling ultimately change how many types of cells and tissues make decisions throughout someone’s body. They can work in any of the following mechanisms: (1) by directly providing functional hormones (like testosterone or estradiol), (2) by targeting the enzymes that convert one hormone into another, or (3) by specifically targeting particular hormone receptors, to change how cells interpret hormones that are circulating. Only some medications that affect sex hormones can be used for Hormone Replacement Therapy and gender affirmation.

That said, it’s a safe bet that:

• Masculinizing HRT may use testosterone (the first mechanism). (Deutsch, 2016 A)
• Feminizing HRT may use estradiol (the first mechanism). Additionally, feminizing HRT commonly adds another medication to suppress androgen/testosterone signaling in some way (mainly by the third mechanism, but also sometimes by the second). (Deutsch, 2016 B)

Non-binary HRT is less well-trodden. It may use different dosages than binary gender affirmation HRT, mixtures of feminizing and masculinizing therapies, and/or different drugs altogether (Hastings, 2016; Xu J et al, 2021).

Keeping these types of medications in mind may help you more actively discuss and work with your medical professional to ultimately make the best decisions for your care.

There’s one other concept that’s worth discussing in this overview: route of administration. Route of administration is how a drug gets into the body.

The body has optimized how to produce hormones, circulate them with carrier proteins such as Albumin and Sex Hormone-Binding Globulin, and increase their concentrations where they are needed. But, hormones provided from outside the body have to jump through extra hoops.

Oral medications have to cross the barrier of your gastrointestinal tract and make it past your liver in order to be effective. Generally, avoiding the digestive system results in more efficient drug delivery. Depending on the drug, it may be better to absorb medications under the tongue, apply them intranasally, inject them into fat or muscle, or absorb them through the skin or other topical application.

There’s one more rub though: pharmacokinetics. Even if you get a drug into the bloodstream efficiently, how long will it stay at the right concentration? It depends on how the drug is carried through the blood stream, as well as how the drug is ultimately metabolized and degraded. Some strategies include delivering drugs as “prodrugs”, chemically modifying drugs so they are metabolized slower, and/or slowly releasing drugs from their vehicle.

You probably don’t need to worry about too many of these details, but some of the specifics do matter, especially when a drug is available in multiple forms. For example, estradiol taken orally has inefficient absorption, induces unwanted and potentially dangerous estrogen hormonal signaling in the liver at higher doses (Aly, 2020), and will tend to get converted into the less-active form, estrone. Estradiol applied through other routes reduces or avoids these problems (Aly, 2020).

When working with medical professionals to decide on a course of treatment, please keep route of administration in mind. It can impact both the effectiveness and safety of the therapy.

On this page, we have discussed how sex-related hormones are made biochemically, and how the body’s cells and tissues react when receiving hormonal signals. We then introduced the idea that drugs that modify sex hormone signaling tend to work by (1) directly using hormonally active molecules as medicines, (2) changing how the body produces hormones, or (3) changing how cells receive or interpret hormonal signals. Importantly, only some types of hormone signal-modifying drugs are appropriate to consider for gender affirmation. Finally, we discussed how routes of administration can affect the outcomes of HRT.

Based on the above, you might be able to start anticipating the actions of drugs, as well as how and why drugs might cause side-effects. These concepts may be helpful when exploring an HRT approach that is most likely to be efficacious and safe. Of course, there’s a lot of detail that we haven’t covered here. We haven’t even touched peptide hormones, which is a whole other can of worms and/or wyrms, though generally outside of scope for current gender affirmation practices.

Nevertheless, a lot of the fundamental concepts we’ve discussed will continue to apply as you learn more about hormonal signaling, and, if appropriate for your goals, how you might start to bend hormone signaling to your will ( >:3 ).

https://transcare.ucsf.edu/guidelines/feminizing-hormone-therapy – Medically practical details for feminizing therapies. This is a concise and actionable summary – almost everything is on one page – of the things to consider before prescribing feminizing HRT. 

https://transcare.ucsf.edu/guidelines/masculinizing-therapy – Medically practical details for masculinizing therapies. This is a concise and actionable summary – almost everything is on one page – of the things to consider before prescribing masculinizing HRT. 

https://transcare.ucsf.edu/guidelines/gender-nonconforming – Includes suggestions for medical professionals on how to adapt binary HRT for nonbinary individuals. 

https://transfemscience.org/ – Very detailed content covering many scientific aspects of feminizing therapies, though very technical. If you have access to a medical professional, they should already know many of these technical details and you shouldn’t need to worry about them unless you’re interested in the specifics. If you know what “PK/PD/ADME” means, you’ll love this!

Abaffy T and Matsunami H. J Endocr Soc, 2021. “19-hydroxy Steroids in the Aromatase Reaction: Review on Expression and Potential Functions” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169043/ 

Aly. 2020. “Estrogens and Their Influences on Coagulation and Risk of Blood Clots” https://transfemscience.org/articles/estrogens-blood-clots/#estradiol-and-the-liver-first-pass-with-oral-administration 

Azzouni F, Godoy A, Li Y, Mohler J. Advances in Urology, 2012. “The 5 Alpha-Reductase Isozyme Family: A Review of Basic Biology and Their Role in Human Diseases”. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253436/

Deutsch, M. 2016 A. “Overview of masculinizing hormone therapy”. https://transcare.ucsf.edu/guidelines/masculinizing-therapy 

Deutsch, M. 2016 B. “Overview of feminizing hormone therapy”. https://transcare.ucsf.edu/guidelines/feminizing-hormone-therapy 

Hastings J. 2016. “Approach to genderqueer, gender non-conforming, and gender nonbinary people”. https://transcare.ucsf.edu/guidelines/gender-nonconforming 

Paterni I, Granchi C, Katzenellenbogen J, Minutolo F. Steroids, 2014. “Estrogen Receptors Alpha (ERɑ) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192010/

Xu JY, O’Connell M, Notini L, Cheung AS, Zwickl S, Pang KC. Front Endocrinol (Lausanne), 2021. “Selective Estrogen Receptor Modulators: A Potential Option For Non-Binary Gender-Affirming Hormonal Care?” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253879/