This page tries to bring together an overview of the biology and endocrinology involved in Hormone Replacement Therapy (HRT) to give trans people a better understanding of their own healthcare. I've tried to use clear and simple language to explain the concepts while also using and explaining the technical language. Understanding the technical language is important, because it helps us to communicate with our doctors and healthcare professionals in a clear way. If something on this site doesn't make sense, please get in contact, so I can make it clearer.
The fundamental premise of Hormone Replacement Therapy is to increase the hormone that causes the desired effects and to reduce the one that causes undesired effects. We achieve this via medication, providing the desired hormone. When taking hormones as medication, they are called Exogenous Hormones.
Exogenous Hormones are hormones (estradiol, testosterone, etc.) that are from outside your body. Your body also naturally produces hormones. These naturally produced hormones are called Endogenous Hormones.
To manage the production of hormones, your body has a system to balance the amount of hormones your body produces. This balancing system ensures your hormone levels are at the correct level that the body needs. When you take hormones as medication, your body detects the rise in total hormones, the endrogenous and exogenous, and decreases its own production so that the total level of hormones comes back to the correct level.
Your body is also metabolising the circulating hormones within the liver, allowing the level of hormones to go down when needed and continuously producing more to replace them. There are multiple feedback systems for all the hormones that your body produces (androgens, estrogens, insulin, cortisol, etc.) and the organs that produce them (thyroid, pancreas, adrenal glands, etc.) are called the endocrine system.
The endocrine system is mainly controlled by the hypothalamus and pituitary gland, these monitor your hormone levels and release hormones that request more of a specific type of hormone to be produced. This system of monitoring and requesting production balances the hormone levels and they control other endocrine organs which do the actual production of hormones somewhere else in the body. For HRT we are specifically looking at the parts involved with sex hormones which is mainly the gonads (testes and ovaries) but also a smaller amount from the adrenal glands as well as the liver that metabolises hormones and has a secondary system if hormones get too high. These two feedback systems are called the Hypothalamic-Pituitary-Gonadal axis and the Hypothalamic-Pituitary-Adrenal axis.
The Hypothalamic-Pituitary-Gonadal axis, abbreviated as the HPG axis, is the main sex hormone production feedback loop. It is responsible for keeping the main sex hormones levels at the right set-point based on your genetics. For this system there are three main parts:
When you start to take hormones, it increases the total amount of hormones circulating in your body. This system detects the increase and starts to reduce the amount of hormones it is producing. As you continue to increase the amount you take as medication, production will decrease to compensate until production is at the minimum level. This process is known as monotherapy where you only take the hormone (Estradiol or Testosterone) and no hormone blockers.
Often trans feminine people are given medication know as anti-androgens. Also called androgen blockers or just blockers. This medication helps to reduce or block the effect of Testosterone on the body. The can work in the following ways:
Blockers that act on GnRH or LH work to reduce primary sex hormones (estrogens and androgens) in both sexes. Progestins have secondary actions on other body tissues in people with a uterus and ovaries however which generally prevent their use in trans masculine people.
Blockers are common for trans feminine because of ongoing, if overstated, concerns of estrogens causing blood clots (see risks). These concerns lead doctors to try and use the least amount of estrogen to cause the desired effects of feminisation and use anti-androgens to reduce or block the action of testosterone. Reducing testosterone levels is the most important action for feminisation.
There is a second process that generates a low level of hormones in your body which is part of a system called the HPA axis - The Hypothalamic–Pituitary–Adrenal axis.
The HPA axis is mainly focused around producing cortisol, the stress hormone. However, the adrenal cortex (part of the adrenal glands) also produces low levels of Androgens (DHEA) which can be converted to Testosterone, and Estrogens in other parts of the body.
Research shows that this system is somewhat impacted by LH and has cells with LH receptors which controls the amount of androgens produced. This system is partially affected by antiandrogens that interact with the HPG axis. They will be blocked by the ones that block the androgens at the androgen receptor level.
The liver has two main functions in hormone levels. It helps to process hormones into metabolites which can be excreted from the body, and it has a backup system for reducing the effects of hormones if they get too high. The first is important for medication half-lives, the second produces Sex Hormone Binding Globulin.
All medications have a time in which it is available in the body before it gets removed. As soon as medication enters the body the liver starts to process it and convert it to other forms. This processing is called metabolism. Some medication can be excreted directly, but others need to be processed first to make removal easier. Once metabolised the processed medication is removed from the body as part of the digestive system as faeces or via the kidneys in urine.
The feedback system that the body uses to ensure consistent levels of hormones in the body requires them to be continuously removed, this allows controlling the ongoing production to manage the level of hormones available. Generally these days we favour bio-identical hormones as they have less negative side effects and risks. However, the body is good at processing these hormones, and it can make it difficult to achieve the required levels for transition. Taking too much hormone increases risks and side effects, while taking lower amounts may require frequent dosing.
To get around this, biochemists have come up with ways of increasing the half-life of the hormones by a process called esterification. On taking these ester versions of the hormones, it takes time for the liver to metabolise them back into hormones which introduces them more slowly into circulation. This provides a better, more sustained release into the body which is much better by allowing the hormone levels to be controlled.
These esterified hormones have names like Estradiol Valerate, Estradiol Cypionate, Estradiol Enantate, Testosterone Cypionate, Testosterone Enanthate, and Testosterone Undecanoate. Different esters have different processing half-lifes with esters in this list for each hormone being arranged in increasing order with Valerate the quickets and Undecanoate the slowest.
During pregnancy hormone levels can get too high for the body, as a way of managing this it uses Sex Hormone-Binding Globulin (SHBG). Specifically, too much estrogen in the body triggers the liver to start to produce SHBG to mop up what it considers excess hormones in the body. For this reason, taking high doses of estrogen isn’t useful because it will cause SHBG to be produced and excess estrogen will be bound to that SHBG making it unable to interact with the body.
As estrogen decreases into the bodies expected range then the levels of SHBG will also naturally decrease. So if estrogen gets too high, there can be less actually available to the body because much more of it is bound to SHBG. Because it is a process driven by excess estrogen, it is not generally important for trans masculine people as their levels of SHBG are not likely to rise during transition. Androgens like testosterone can also cause the SHBG to decrease. However, if they do have high SHBG it will impact their available testosterone as SHBG binds with androgens (like Testosterone) in preference to estrogens.
We measure the amounts of hormones in our blood, called serum levels, because we are all slightly different in the way our bodies work.
There are two reasons for blood tests:
Often medical and scientific literature simplifies our bodies to an average body that is based on data from the whole population, this is useful for understanding the ways in which things happen to us on average but each of our bodies will be unique from the average and have slightly different set points for hormones and other systems.
These are based on our genetics which are unique for every person, and there can be differences in hormone levels between ethnic groups. If you look at what pathology labs consider ‘normal’ ranges, you will find that different countries have different ranges because of the genetic makeup of people in those countries.
This comes out very explicitly in dosing for hormone replacement therapy. You will find that almost everyone you meet on it will be on a slightly different amount of medication. We can actually use serum levels to tell us what dose of hormones our body actually wants.
For people who use blockers (especially trans fems) as part of their medication, it’s important to know what menopause symptoms are because having them is a sign you need to adjust your medication dosage. You need to be able to spot them. Menopause symptoms are caused by hormone levels that are too low, ie both Testosterone and Estrogen are low. This happens to people with ovaries after the ovaries run out of follicles to produce eggs, roughly around the age of 45 for the average person.
In feminisation HRT it is common to use a blocker to lower testosterone and also common for estrogen to be underdosed, especially at the start of transition. Then the estrogen doesn't make up for the lack of testosterone leading to low total sex hormones. In masculinising HRT, blockers are not as common that decreases the risk of low total sex hormones.
The symptoms are:
Some of these symptoms overlap with other medication side effects or mental health issues. Look for symptom changes when your medication dose has changed recently, within a few weeks of the change. Ongoing symptoms that don't change with medication changes are more likely to be from other sources.
Experiencing these symptoms are a sign you should get your levels checked and most likely hormone dosage increased.
Based on the information on this page we can use blood tests and the following rules to help guide correct dosing of medication to give our bodies the right level of hormones that it needs. These try to take into account suppression of the HPG axis while not increasing SHBG (if applicable) which will help you get the best results.
Also provided here are the serum level guidelines provided by the professional associations to give an idea of where hormone levels should be for the average person. Most of the professional associations for trans healthcare refer to and work with WPATH to provide standards of care. AusPath (the Australian association) and PATHA (the Aotearoa New Zealand) do provide their own standards of care as well. However, PATHA acknowlage that their standards of care might be out of date compared to the WPATH ones and to refer to newer WPATH SoC for more up-to-date level targets and other information. As such, AusPATH and WPATH targets are provided but note that they use different measurement units.
The most important metric for feminisation is that testosterone levels are low. Assuming a blocker isn’t used we can do the following:
Blockers like Cyproterone Acetate and Leuprorelin that interact with the HPG axis will decrease LH and FSH to under 1 with just about any level of estradiol. If you are using them you will need to:
The guideline serum levels from healthcare associations are:
| Hormone | AusPATH | WPATH |
|---|---|---|
| Testosterone | Under 2 nmol/L | Under 50 ng/dl |
| Estradiol | Between 250-1000 pmol/L | Between 100-200 pg/ml |
Bicalutamade and Spironolactone allow the max testosterone values to increase by blocking its action in the body.
The basics of testosterone therapy for masculinising (also called virilisation) more simple:
The guideline serum levels from healthcare associations are:
| Hormone | AusPATH | WPATH |
|---|---|---|
| Testosterone | Between 10-15 nmol/L | Between 400-700 ng/dl* |
| Estradiol | - | - |
* WPATH suggests different measurement times in cycle and different dosage adjustment styles depending on if you are specifically on testosterone undecanoate or not.