Basic Science

• 1: What are steroid hormones?
• 2: Sex Hormones: how do they work?
• 3: The different estrogens, androgens and progestogens, and their binding affinity
• 4: The self-regulation mechanism, and how to use it in our benefits
• 5: Growth hormones
• 6: DHEA and intracrinology

1 - What are steroid hormones?

First of all, what are hormones? Hormones are chemical substances produced by the body, and functioning as a messenger between organs. There is usually an organ that produces and an organ that receives. You can think of hormones as the wireless counterpart of the nervous system. It connects parts of the body remotely, to give them various orders; and it is much slower than the wired nervous system. Some common and known hormones that act as neurotransmitters are dopamine, serotonin, oxytocin, melatonin… Closer to our topics, we find the GnRH (Gonadotropin Releasing Hormone), FSH (Follicle Stimulating Hormone) and LH (Luteinizing hormone). Those last three, as we’ll see, play an important role in controlling sex hormones, and we’ll see what we can do with that.

So, the hormones that interest us here, the “sex hormones” - estrogens, androgens, and progestogens - are steroids that act as hormones. That’s why we call them steroid hormones. And those three groups - androgens, estrogens, and progestogens - are only three among five subgroups of steroid hormones; the two other being glucocorticoids (like cortisone and cortisol - the so-called stress hormone), and mineralocorticoids. We don’t need to know about those two here.

So what are steroids, and what do they have to do with “steroids” used by some bodybuilders and intense sportspeople (you know, -“this guy is buying steroids online, he wants to grow bigger and bigger!) ? Well, the products that these sportspeople use are part of the same group of molecules called steroids - and they are grouped together because of their particular molecular composition and organization, and the way they interact with their target cells. Steroids used in sports are a subgroup of steroid hormones called anabolic steroids, and it includes “natural” androgens like testosterone, but many other synthetic androgens. Anabolic steroids are all androgenic - various molecules similar to testosterone, and activating the androgen receptors -, but we chose here to speak of anabolic steroids to designate both “natural” (biosynthesized, naturally present in the body) and synthetic androgenic hormones (including the one used and abused in sport); and androgens to designate only the bioidentical molecules produced by the body (mainly testosterone and DHT).

But, yes, if you get estrogen treatment to grow boobs, then you can say that technically, you’re taking steroids. Not anabolic, but steroid still.

But let’s keep it simple and call them hormones, because they act just like hormones.

2 - Sex Hormones: how do they work?

And first, what are they? As we said before, sex hormones is a group that covers 3 subgroups of steroid hormones: androgens (among which the famous testosterone), estrogens (estradiol will be our main friend for feminizing HRT), and progestogens (progesterone is the main naturally occuring one). That’s why they are sometimes called sex steroids, but also gonadal steroids, since they are mostly produced in our gonads: testes and ovaries.

It is common to picture the mode of actions of hormones as the key and keyhole image. The hormones are keys that circulate in the body until they reach a cell with the right keyhole. We call those keyholes receptors. Estrogens are all the keys that can only open estrogenic keyholes (receptors) - be it synthetic or natural estrogens, and the same goes for androgens.

We all have those different receptors: it is not because you were assigned male at birth and produce mostly testosterone that your cells won’t have estrogen receptors. If it were the case, HRT for trans people would not work at all. There can be, however, differences between people, moments of life, and hormone balance exposure, in terms of the repartition and sensitivity of those receptors in the body cells.

If the binding happens (the key gets into the hole), then the cell is given the order to express a certain aspect of itself coded in DNA. For example, when an estrogen hits and opens the receptor of skin cells, those cells get the message to produce less sebum, which leads to less greasy skin - in the limits given by the DNA. In other words, sex hormones will only “unlock” and express what is already coded in DNA, which cannot be changed by any medication. This explains the differences in development observed between people with the same profile and the same hormone levels.

In short, we call estrogens all hormones that fit in the estrogen receptors, androgens all those that fit in the androgens receptors, and the same goes for progestogens. And this means that there is not just one estrogen, androgen, and progestogen. Let’s have a look now at these different kinds of each sex hormone, and why it matters to know about them.

3 - The different estrogens, androgens and progestogens, and their binding affinity

Let’s speak first of binding affinity. Binding affinity designates the ability and “ease” with which one hormone will bind to its receptor. If we use the key and keyhole metaphor, you can imagine that several keys can open the same lock, but some will enter and turn with much difficulty, when others will do it quite smoothly. This is binding affinity: it is high when the key gets in without effort, and opens efficiently, and it is low when the key can open the lock, but not without effort. The different kinds of each sex hormone come with different binding affinity, which is why we will prefer some over others for efficient feminization/masculinization.

If we take a look at estrogen first, we can count four of them present in the body (at least the main ones) in differents amount: Estrone (E1), Estradiol (E2), Estriol (E3) and Estetrol (E4). But really, keep in mind only estradiol (E2), and to a lesser extent estrone (E1). Estradiol is the main active estrogen in our bodies, and it has a much higher binding affinity than estrone, so that is the one we will use for feminizing HRT. There are also a number of synthetic estrogens, developed by pharmaceutical laboratories in particular for the use in birth control pills: a common one is Ethinylestradiol (EE). As a synthetic derivative of estradiol, EE also comes with more (and more frequent) side effects. This is why it is not recommended to use birth control pills for feminizing HRT.

Let’s now have a look at androgens. We mostly know of testosterone, and it is indeed the most present androgen naturally produced by the body. However, the body is also able to convert testosterone into a much more potent form in terms of masculinizing effects: DHT (dihydrotestosterone). This conversion is made with the help of an enzyme called 5a-reductase - which is good to know since a number of antiandrogens medication (Finasteride and Dutasteride) prescribed to transfeminine people consists in inhibiting this enzyme and by doing so preventing the conversion of testosterone into its more potent form, DHT. And there are finally all the synthetic androgens that we put before in the category of anabolic steroids.

The same goes for progestogens: the main - naturally occurring - one is progesterone; but pharmaceutical labs have also created a vast amount of synthetic progestogens, lots of them - once again - for the use in birth control medication. The well known cyproterone acetate (Androcur) is one of them; and even though it is a progestogen that activates the progestogens receptors, its action (and side effects) is far from being the same as bioidentical progesterone. Another progestogen commonly found in birth control pills is Levonorgestrel.

4 - The self-regulation mechanism, and how to use it in our benefits

If the body naturally and continuously produces sex hormones, why don’t we end up with too much of them? Well, obviously because the body is smart and able to self-regulate the production. And understanding the way it does that can help us understand and choose better the ways of our medical transitions (at least for transfeminine people).

The production of sex hormones is the final step of a chain of signals and reactions that starts in the brain. A part of the brain (the hypothalamus) releases in a pulsatile way (i.e. in a regular temporal pattern) a hormone called GnRH (Gonadotropin releasing hormone). GnRH is received by a gland in the lower part of the brain - the pituitary gland (or hypophysis), which, in response, releases two hormones called gonadotropins: FSH (Follicle Stimulating Hormone) and LH (Luteinizing hormone). Those two will go down to the gonads (ovaries and testes) which, in response, will produce testosterone (for the testes), and estradiol and progesterone (for the ovaries).

This sex hormone production will continue, and the levels of estradiol/progesterone/testosterone will rise, and circulate in the body. They will be received by the brain, and after reaching a threshold, eventually send the signal to both hypothalamus and hypophysis to stop the production of both GnRH, and FSH/LH. In other words, when the sex hormones reach a level that the body judges to be correct, they turn into a messenger ordering to stop their own production. This part of the circle is what we call negative feedback.

It should be noted that this mechanism is a bit more complex for AFAB people with a full reproductive system, as the regulation of hormones must allow for the cycle to work with the different phases (stimulation, ovulation, menstruation…). We will not detail this system here as this is not a website about reproductive health.

Now, what does this mean for us? It means that we have a way to control the production of our sex hormones - or at least to stop them.

• On the one hand, the brain will respond indifferently to all androgens, estrogens and progestogens to activate the negative feedback. For the brain, they are all read as sex hormones.
• On the other hand, the gonads can produce only one type of hormone, the one type whose production will be stopped by the negative feedback mechanism. That means that by adding enough of any sex hormone in the bloodstream from the outside (this is called exogenous - from an outside source - as opposed to endogenous - body made), and even if it is not the hormone that your body produces naturally, you can stop the production of the only hormone your body can produce.

So, in the case of feminizing HRT, we add exogenous estradiol; if the levels are high enough, the brain will receive the signal “ok, enough sex hormones” and send the signal to the gonads: “stop the production”. If you’re AMAB, with testes, the only thing your body can do is to stop the production of testosterone. If you keep this level, you end up with the ideal hormonal balance for feminization. Your estradiol will be medium-high to high, your testosterone will be low, and so will be your LH/FSH. Inversely, for AFAB people, taking testosterone will decrease your LH/FSH, and as a consequence, stop or significantly reduce your production of estradiol.

5 - Growth hormones

A hormonal factor that is not often addressed is the role of growth hormones. As its name states, growth hormone is a key component in tissue growth and repair. It is released in a pulsatile way (at a regular time in the day - actually usually at night during sleep), and its average levels vary in the different stages of life. High during childhood and puberty, they decrease in our twenties. After that, their levels are dependent on the needs: spurts will occur after body traumas in order to stimulate healing, or after intense physical activity (which actually creates many little muscle traumas). In the frame of medical transition, you could compare the role of growth hormones to the role of building workers when sex hormones are the architects. Sex hormones decide what and where to build, growth hormones do the actual building.

The age-related factor explains why starting hormone therapy at younger age (before or in the early twenties) usually leads to faster and stronger development.

What you can do, however, is to aim at adopting a lifestyle that will naturally stimulate the production of growth hormones. Such lifestyle includes:

• Relatively intense exercise (i.e. is “intense” an exercise the day after which you feel pain in your muscles)
• Sleeping (avoid sleep deprivation, and get as much sleep as possible)
• High protein intake (plant-based protein is protein too).
• Low sugar intake

Sources

Growth Hormone-Releasing Hormone: Clinical Studies and Therapeutic Aspects

Arginine Stimulates Growth Hormone Secretion by Suppressing Endogenous Somatostatin Secretion Get access Arrow

Reciprocal interactions between the GH axis and sleep

Human growth hormone response to repeated bouts of aerobic exercise

6 - DHEA and intracrinology

As we have explained, most of our sex hormones are produced in our gonads: ovaries and testes. That means that in case of surgical removal of the gonads (orchiectomy/vaginoplasty, ovariectomy…), the vast majority (95%) of our sex hormones circulating in the body will be gone. This also means that after such surgery, transfem people on HRT could stop taking anti-androgens.

However, does suppressing our gonad-produced sex hormones really means the end of all masculinizing/feminizing effects of endogenous hormones?

Not exaclty. And this is where intracrinology and DHEA enters into the game.

Intracrinology is a subfield of endocrinology developped in the 1980s. In the framwork of sex hormones, it is mostly based on the activity of DHEA. DHEA is a hormone massively produced in small glands situated right above the kidneys, called adrenal glands. They produced a bunch of other stuff (including small amount of testosterone and estrogens directly).

Intracrinlogy figured out that DHEA (that makes for the most present hormone in the body) travels to target cells (such as skin, hair follicules, prostate cells…) and is converted there, on the spot, by those very cells, into testosterone and DHT. That means that there is a peripheral production of androgens: not in the gonads, but direclty in the target cells. And what matters is that these androgens will actually direclty activate the androgen receptors in the target cells that has just produced them. After that, they will be metabolized and realeased into the bloodstream as something else. Research has shown that surgical or chemical castration (i.e. by GnRHa) in AMAB people leads to an approximately 50% drop of androgens in the target cells of the prostate. That is far from the 95% reduction observed in the bloodstream androgen levels. And this is likely to be true of skin cells, including hair follicule.

This means two things:

• After a gonad-removal surgery, a masculinzing activity is likely to continue, namely in the prostate (which is not much of an issue for transfem people if you don’t have prostate cancer), but also in the skin and facial hair follicule (more anoying for many transfem), since around only 50% of androgens acting on those cells will be gone. However, if you were not taking an androgen blocker of the receptor blocker category (Bicalutamide) before surgery, this will not affect you much. Indeed, if before surgery you had manage to reduce your androgen level either by monotherapy, or by any other blockers than an androgen receptors blocker such as biculutamide, then your target cells were already affected by the local production of androgens from DHEA.
• The bloodtest values after surgery will not reflect the masculinzing activity happening from and in the cells, since, as we said, the androgens localy produced from DHEA do not leave the cell into the bloodstream before being metabolized into something else. This is why bloodtest results ususally show a 95% reduction of androgen after gonadal production suppression. Your bloodtest results will most likely show near 0 androgen (not actual 0 - which you do not want anyway - since the adrenal gland also direclty produces a small amount of androgens that is released into the bloodstream).

I speak here of “masculinizing activity”, and of the consequences of DHEA activity for transfem people, because the conversion of DHEA in the skin cells goes only towards androgens. AFAB people will also sythetise androgen in their skin cells from DHEA. In other words, skin cells are only equipped, in every people, to locally sythetize androgens. The vaginal cells, however, will locally produce estrogens from DHEA (which is why DHEA becomes a central hormone for people postmenopause, as it becames the main source of estrogens for the vaginal tissue.)

It is commonly observed a rise in andrenal activity in the few weeks following gonad-removal surgery. DHEA is increased, which leads to masculinzing effects (acne, facial hair growth…) for AMAB people after orchiectomy/vaginoplasty.

This data leads to reconsider the affirmation that an adrogen blocker is useless after surgery. This is true of most androgen blockers that acts - direclty or not - on the levels of the gonads, that is by stopping the gonadal production of androgens. The gonads gone, there is indeed nothing left to block.

However, it makes the case for continuation of androgen receptor blockers, namely bicalutamide, which will be the only solution to block the masculinzing effects of the locally produced androgens, sythetized from DHEA. This is especially true if you were already taking bicalutamide before, without any problem. You could, however, consider lowering the doses. Bicalutamide could prove particularly useful at least in the first few weeks after MTF/MTX bottom surgery, in order to block the effects of the increased activity of the adrenal glands typically observed after removal of the testes.

This also suggests the superiority of bicalutamide (and receptor blockers in general, but you might want to avoid spironolactone for other reasons) as an androgen blocker before surgery, since it is the only one who’s able to block the masculinizing effects of the adrenal activity.

Sources

Intracrinology

Is dehydroepiandrosterone a hormone?

Intracrinology and The Skin

DHEA, important source of sex steroids in men and even more in women

DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology

Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials