How Hormones Work

As we described in the Causes of Gender Dysphoria section, every human’s DNA contains the genetic instructions for both male and female bodies, and which set of instructions gets used is controlled by what hormones your gonads produce. That differentiation occurs entirely based on whether you happen to have an SRY gene which, between the sixth and eighth weeks of gestation, kicks off a chain reaction that produces testes instead of ovaries. From that point on, every sexual attribute of the human body (primary and secondary) is a result of the hormones that those gonads produce.

If they produce estrogens (primarily estradiol), the genitals form into a vulva, vagina, and uterus. If they produce androgens (primarily testosterone), the genitals form into a penis and scrotum, shifting the Skene’s gland downward and enlarging it into a prostate. Differentiation ends here until the onset of puberty, nine to ten years later, and we all know what puberty does.

So how does this work? Why do the cells differentiate like this? Well, before we can explain that, first we have to explain the concept of a receptor.

Hormone Receptors

In simplest terms, a receptor is like the keyed lock ignition on a car (do new cars still have keyed ignitions?). Every cell in the body has a set of locks which activate different functions within that cell. They’re like switches which signal to the cell that it should activate a different part of its genetic sequence. Each receptor can only accept certain chemical compounds, much like how a lock can only accept certain keys, and different chemicals have different capabilities at turning the key. Some can completely start the car, while others only turn it to Accessory Mode.

The ability for a chemical to fit into a receptor is called relational binding affinity, and is measured as a percentage of how likely a chemical will bind to a receptor compared to another. So, for example, if hormone B binds only 10% of the time in relation to hormone A, then it is said to have a 10% binding affinity. Similarly, the ability for a chemical to turn the key is called transactivational ability. Compounds which fit into a receptor but don’t do anything are called antagonists; compounds which are able to turn the key are called agonists. If it can only turn the key a tiny bit, it’s called a partial agonist.

You can think of antagonists like bouncers at a club. They stand in the doorway and prevent anything else from getting through, but don’t enter the club themselves. Most antagonists are referred to as blockers. This is different from an inhibitor, which is a compound that slows down a chemical reaction, or an activator, which speeds up a reaction. In receptors, an inhibitor lowers the ability of the receptor, causing it to respond less effectively to things that bind to the receptor, and an activator increases the ability of the receptor, making it respond stronger, like a booster.

In some cases, a hormone can function as an inhibitor or an activator for a different hormone by slowing down or increasing behavior in a cell. For example, progesterone increases cell activity, making cells respond more effectively to estrogens and androgens, and testosterone increases the transactivational ability of dopamine receptors, so less dopamine is needed in the brain for the same effect.

What’s in a Hormone

There are four main kinds of hormones:

• Amino acids such as melatonin (which controls sleep) or thyroxine (which regulates metabolism).
• Peptides like oxytocin and insulin, which are collections of amino acids.
• Eicosanoids that are formed from lipids and fatty acids and predominantly affect the immune system.
• Steroids, which signaling molecules produced by various internal organs in order to pass messages to other organs within the body.

For the purposes of transition, this last category is what we care about the most, as all of the sex hormones are steroids. They fall into seven main categories:

• Androgens
• Estrogens
• Progestogens
• Glucocorticoids
• Mineralocorticoids
• Neurosteroids
• Aminosteroids

The first three of these are what we care about most when it comes to hormone therapy. Note: All human beings, regardless of phenotype, have some of every one of these hormones in their bodies. The ratios are what affect body shape.

Androgens

There are nearly a dozen different androgens, but the ones we care about the most are testosterone and dihydrotestosterone.

Testosterone is the primary masculinizing hormone for the human body and is produced in the adrenal glands, the testes, and in the ovaries (where it is immediately converted into estrone and estradiol). It tells both muscle and bone cells to grow and, in higher concentrations, encourages larger muscle mass and thicker skeletal structure. This also means that testosterone is critical for bone health, as it affects calcium distribution within the skeletal structure. Thus, severe depletion of testosterone can result in osteoporosis and fragile bones. Testosterone also plays a major role in sex drive and libido, encouraging mating behavior within the cerebral cortex.

Dihydrotestosterone (DHT), which is converted from testosterone in the prostate, skin, and liver, plays a major role in the development of the male genitalia during puberty by inducing random erections, and the growth of facial and body hair. Paradoxically, DHT is also what causes male pattern baldness, as it chokes off blood circulation to the follicles on the top of the scalp (sorry, trans guys, it’s a double-edged sword). DHT binds to androgen receptors ten times more strongly than testosterone, which is why it is critical to eliminate it for feminizing transition.

Estrogens

There are four estrogens: estradiol, estrone, estriol and estetrol. The latter two are only produced during pregnancy and are important for fetal health, but have no bearing on transition.

Estradiol is the feminizing hormone, as it is the primary signaling hormone for growth in the mammary glands (breast tissue), and because it encourages fat deposits in the thighs, hips, butt, chest, and arms, while discouraging fat deposits in the abdomen, thus producing a curvier figure. Estradiol also promotes increased collagen production, resulting in softer skin and more flexible tendons & ligaments.

Estrone’s role in the body has been something of a puzzle in medical research, as it has significantly lower binding affinity compared to estradiol (0.6%) and very low transactivational ability (4%). The hormone doesn’t appear to do anything; it just sits in the bloodstream. However, it has a unique ability to convert to and from estradiol via an enzyme group called 17β-HSD, making it ideally suited to function like an estrogen battery within the body.

New research is starting to suggest that the body may regulate total estradiol levels by releasing HSD17B1 to turn estradiol into estrone, and releasing HSD17B2 to convert it back, but this is a very early study. Both enzymes are produced in breast tissue, and may play a role in the presence of cyclical period-like symptoms in estrogenic individuals who do not have ovaries, such as trans women.

Progestogens

The primary progestogen is progesterone, which plays numerous roles in the body and has been found to be an important component for feminizing hormone therapy.

One of the largest roles that the progestogen receptor plays is in the regulation of gonadal function (ovaries and testes). The hypothalamus is positively littered with progestogen receptors and responds strongly to their activation, downregulating the production of GnRH, which then reduces the production of luteinizing hormone by the pituitary gland.

LH is what tells the ovaries and testes to produce estrogen and androgens. LH and its sibling hormone FSH both play central roles in ovulation, which is another large source of estrogen in ovary-havers. Thus, synthetic progestogens (chemicals that fit into progestogen receptors) are often included in birth control in order to prevent ovulation. In AMABs, progestogens are a useful tool for blocking testosterone production.

Another type of cell that is full of progestogen receptors is mammary tissue. Progesterone plays a major role in the growth and maturation of milk ducts within breast tissue. While little formal research has been conducted into progesterone’s effect on breast development, anecdotally it has been seen widely across the transfem community to provide significant improvements in breast fullness. Progesterone has also been demonstrated to increase blood flow to breast tissue, and encourages fat deposits in the breasts, both of which increase breast size.

Additionally, progesterone promotes better sleep, improves cardiovascular health, increases ketogenesis (reducing triglycerides), increases metabolic function, and has been found to reduce breast cancer risk.

Mineralocorticoids

Mineralocorticoids play no role in transition, but they are worth mentioning because of one major hormone: aldosterone.

Aldosterone is what instructs the kidneys to stop extracting water from the bloodstream. It is produced by the adrenal glands in order to regulate body hydration. Why is this significant?

Because one drug that is very commonly used in trans hormone therapy is an extremely powerful aldosterone antagonist: spironolactone. Spiro binds to mineralocorticoid receptors more strongly than aldosterone does, but does not activate the receptor. It just clogs it, preventing the kidneys from receiving the signal to stop extracting water.

This is why spiro makes people pee so much.