This page adapted from original article on IndigoWiki.
The best advice
Arguably, hormonal therapy is the most important step a transsexual can take. Whether MTF or FTM, hormones have both the potential to move us far along our journey and carry the risk of negatively impacting our health. Their importance, the risks inherent in their use, and the extreme variability of response dictate that when it comes to hormonal therapy the best advice I can give is that you learn as much as you can from as many sources as you can and decide for yourself what makes the most sense for you.
Do not take what you read here as gospel. Do not trust what your endo or GP says as gospel. Do not trust what someone on IRC said as gospel. Instead, learn as much as you can about hormonal physiology and the basics of HRT (hormone replacement therapy) for yourself. Starting and managing your HRT is one of the most important things you’ll ever do, the effort it will take to learn the basics will serve you well. Though the subject may at first seem a difficult one to get a grasp of, once you understand a few basic concepts it’s really quite simple.
The basics
The first thing to understand is that hormones don’t directly do much of anything. Instead, hormones act as a kind of messaging system used to indirectly regulate nearly every physiologic process.
A hormone molecule is essentially a molecular-level key with a physical and chemical (the two being related, of course) configuration particular to that kind of hormone. In most of the cells of the human body (or of most any plant or animal, for that matter) there are what are called receptor sites. These can be thought of as molecular-level locks, coded to accept a particular kind of hormonal key.
When the hormone-key meets the receptor site-lock, a transcription response is initiated. Basically this means that a chunk of DNA is turned on or turned off. This causes that cell to do or not do something, what exactly depends on the hormone in question and the type of cell. Where some hormones are fairly specific in what they do, the so-called “Sex Hormones” (the ones we’re interested in here) are extremely broad and affect virtually every cell in the body in some way or other.
It’s all in the family
The sex hormones fall into three different families—
- Progestogens (C21)
- Androgens (C19)
- Oestrogens (C18)
While each family consists of a number of hormones, most of those are only really interesting as intermediate steps to the five hormones that are of a great deal of interest to us—
- Progestogens
- Progesterone
- Androgens
- Testosterone
- Dihydrotestosterone (DHT)
- Oestrogens
Study of the other hormones within these families should not be entirely ignored, but these are the biggies.
So how do the hormones in each family get made? Ignoring centuries of A&P professors telling bad jokes about unpaid prostitutes, each comes from the one before it—hormones are made from other hormones. The human body starts with the humble and much-maligned cholesterol molecule and from there it makes progestogens. From progestogens are made Androgens. From androgens are made oestrogens.
The early parts of all of this occur primarily in the adrenal cortex. When a cholesterol molecule meets a P450scc (cholesterol side-chain cleaving) enzyme, a proto-hormone called Pregnenolone results. There are all sorts of useful things the body makes out of pregnenolone, but what interests us is that the adrenals, via a few more enzyme-induced conversions, use it to make both progesterone and an androgen called androstenedione.
In and of itself androstenedione, as it isn’t very bio-active, isn’t overly interesting stuff. However, androstenedione stands at the crossroads of the four most powerful sex hormones. If androstenedione meets up with one particular enzyme (17β-hydroxysteroid dehydrogenase, also known as 17-ketosteroid reductase), that androstenedione will become Testosterone, a very bio-active Androgen. Further, if that Testosterone meets up with another particular enzyme (5α-reductase) it will become Dihydrotestosterone (DHT), the most active of the human Androgens (roughly 10 times more active than Testosterone).
On the other hand, both that Androstenedione and any resulting Testosterone could go a completely different direction. Should androstenedione meet up with another particular enzyme (Aromatase) it will become Estrone, a very bio-active oestrogen. Should Testosterone meet up with that same particular enzyme (aromatase) it will become 17β-Estradiol, the most bio-active of the human oestrogens.
It’s important to note that some of these conversions are bi-directional—the body can convert from one hormone to the other and then back again. Some are mono-directional—once a conversion is done, there is no going back. As a general rule of thumb, intra-family conversions are often bi-directional; inter-family conversions are always mono-directional. The body can convert from Androstenedione to Testosterone and then back to Androstenedione, for instance, but it cannot convert from Androstenedione to Estrone and then back to Androstenedione—no inter-family back-conversion pathway exists.
Keep in mind that not all intra-family conversions are bi-directional. The conversion between Testosterone and Dihydrotestosterone, for instance, is mono-directional. Many intra-family conversions are bi-directional, however. Both the conversion between Androstenedione and Testosterone, for instance, and that between 17β-Estradiol and Estrone are bi-directional and, in fact, use the same conversion enzyme ((17β-hydroxysteroid dehydrogenase, also known as 17-ketosteroid reductase).
What tangled webs we weave!
So now we know that hormones come from a long series of conversions that start with cholesterol, how is all of this conversion regulated?
The endocrine system is basically a rather large set of interrelated and interdependent positive and negative feedback loops. A good way to imagine it is as a large spider web. Each thread is connected to others; pull on one thread and you affect the entire web. HRT is akin to lengthening some of those threads and shortening others. To one degree or another, this affects every thread in the entire web.
For sex hormone production, the most important loop starts with the hypothalamus (a part of the brain sometimes referred to as ‘The Master Gland’), which releases GnRH (Gonadotropin Releasing Hormone). GnRH tells the anterior pituitary to release LH (Luteinizing Hormone) and FSH (Follicle Stimulating Hormone). LH and FSH in turn tell the gonads (ovaries or testes) to make hormones and perform other functions (spermatogenisis, follicle maturation, et cetera).
LH and FSH each have slightly different jobs, but for practical purposes they can be lumped together into one ‘axis’ here.
The production of GnRH, LH/FSH, and gonadal hormones are not static; typically, in fact, all of them vary quite a bit. The primary feedback loop is between pituitary LH/FSH and gonadal hormone production. When LH/FSH levels go up, gonadal hormone production goes up. When gonadal hormones reach the proper levels, the pituitary lowers LH/FSH levels. This cause gonadal production to go down, until eventually the levels fall below the desired level and the anterior pituitary increases LH/FSH levels. A similar but slower responding loop exists between the hypothalamus, GnRH production, and gonadal hormone levels.
The body uses these kinds of homeostatic feedback loops extensively. Where gonadal hormone production and transition-related HRT are concerned, the properties of this particular feedback loop have a number of implications. The most important is that the pituitary and hypothalamus are not particularly specific about what they’re looking for. They want a particular level of androgens or oestrogens — but they don’t particularly care which.
Both androgens and oestrogens act as anti-gonadotropins, in a sense, in that an increase in either causes a decrease in the signal to produce gonadal hormones. The pituitary and hypothalamus have no way of knowing whether the androgens or oestrogens in your bloodstream are endogenous (produced within the body) or exogenous (from outside the body). Nor do they care if what they’re seeing is androgens or oestrogens, as long as one is present in sufficient amounts.
What this basically means is that the oestrogens or androgens a Trans person takes as part of their HRT act in part to reduce gonadal hormonal production. Beyond a certain level the LH/FSH axis will ‘crash’ (id est, drop to zero) and endogenous gonadal hormonal production will cease entirely. Endogenous gonadal hormonal production will stay at zero until and unless LH/FSH levels again rise. In other words, beyond a certain level exogenous hormones will cause a complete cessation of endogenous gonadal hormone production.
Given that lowering endogenous gonadal hormonal production is generally one of several HRT goals, a way of ‘naturally’ eliminating endogenous androgen or oestrogen production without the need of an anti-hormone has obvious utility. Unfortunately, there are a couple of potential problems.
The first is that what level of exogenous hormone is needed to bring the LH/FSH axis down to zero varies widely from individual to individual and is probably not static. The only way to know if a particular dose of exogenous hormones is sufficient to do the job is to actually measure LH and FSH levels periodically. This can be done, and sometimes is, but it isn’t cheap and it’s less than clear whether or not there’s any reason to bother. While some in the medical community feel that the point at which the LH/FSH axis crashes is an optimal HRT level, the majority seem to feel that such levels are unnecessarily excessive.
Don’t cross the streams
Okay, so we’ve covered a little bit about hormones and how they’re produced and regulated by the body. What about anti-hormones? What’s up with those?
If you want to stop a particular hormone from being active in the body, there are a number of ways to go about it:
- Interfere with the signal that tells the body to produce the hormone in the first place.
Aside from accomplishing it naturally, as discussed above, the most common way to accomplish this option is to stop the production of GnRH in the hypothalamus. No GnRH, no LH/FSH, no gonadal hormonal production. This is accomplished by using one of a number of drugs referred to as anti-gonadotropins, many of which work by convincing the hypothalamus that it has produced plenty of GnRH when in fact it hasn’t. This is very effective, but a bit like hitting a fly with a sledgehammer. Such drugs tend to be extremely expensive and are rarely really needed except in unusual cases.
- Interfere with the body’s ability to make the hormone.
Depending on the hormone in question, this can be a relatively simple matter. A few of the critical conversions are handled by a single enzyme that is not otherwise important. Interfere with that enzyme and you stop production of that hormone dead in its tracks. This is the case with finasteride (Proscar, Propecia), which interferes with 5α-Reductase and thus stops the conversion of testosterone to Dihydrotestosterone (DHT). Another example is anastrozole (Arimidex), which interferes with aromatase and thus stops the conversion of androgens to oestrogens (testosterone to 17β-Estradiol and Androstenedione to Estrone). This can be very effective, but, depending on the drug in question, does have its limitations. Finasteride, for instance, only reduces DHT levels and does not affect other androgens. Anastrozole is only really effective in the absence of otherwise functional ovaries as they are capable of essentially ‘overwhelming’ its effect.
- Come up with something that binds to that hormone’s receptors but does not activate them.
Drugs that do this are generally referred to as hormone antagonists. They are chemically and physically similar enough to a particular hormone to bind to its receptor, but not close enough to activate the receptor. The receptor site is thus not available for binding to and being activated by the ‘real’ hormone. A good example of this is Cyproterone Acetate (Androcur). A progestin, cyproterone acetate binds with androgen receptors without activating them. Another, if somewhat more complicated, example are SERMs (Selective Estrogen Receptor Modulators) like Tamoxifen. These drugs bind to some Estrogen receptors, thus blocking them, but ignore others.
- Interfere with the ability of cells to respond to a particular hormone (interfere with the transcription response).
Drugs that do this are being worked on, but in the main are not practical for our purposes right now.
- Remove the gonads.
An orchiectomy or oophorectomy obviously removes any gonadal hormonal production.
It’s not uncommon for an anti-hormone drug to fall into more than one category. Cyproterone acetate, for instance, is an androgen-antagonist but it also has a mild progestogenic effect as well as acting as a mild anti-gonadotropin.
Pills and patches and needles, oh my!
Now that we’ve covered anti-hormones, what about hormones? The exogenous hormones used in transition-related HRT can be broken down by the properties they all share:
- Type
- Route
- Dose
- Interval
Type
Where hormones are concerned, the most important thing to know about a particular drug is whether it’s endogenous-identical, converted by the body to an endogenous-identical, or an artificial.
Endogenous-identical means that the drug in question is molecularly exactly the same as what the human body produces. Examples of this would be Estrace/Estrofem (17β-estradiol) and Prometrium/Utrogestan (progesterone). The advantages of using an endogenous-identical drug are hopefully fairly obvious. Since they are the same as what the body produces, they should work identically with an extremely low risk of unexpected side effects (though oils or binders used in making the drug can cause allergic reactions). The down side to an endogenous-identical is that since they are the same as what the body produces, the body is also very good at getting rid of (metabolising) them. This gives them a generally short half-life.
Converted to endogenous-identical are drugs that are generally close to what the body makes and are converted by the body to a form identical to what the body makes. Examples of this would be estradiol valerate and testosterone valerate, both of which are converted by the body to an endogenous-identical form. These drugs have a somewhat longer half-life than straight endogenous-identicals, but have more variability in individual response.
Artificials are those hormones that do not exist naturally in the human body and are not converted by the body to a form natural to the human body (id est, are non-endogenous identical). Estinyl (Ethinyl Estradiol) is probably the best known drug in this class, though Premarin (conjugated equine oestrogens) would also fit as many of the equine hormones it contains do not occur in humans. Because artificials are not native to the human body, the body is not very efficient about getting rid of (metabolising) them. This gives them a much longer half-life and generally means a much lower dosage is required. Also some natural processes the body uses to measure and/or regulate hormones may or may not effect or be effected by artificial hormones. An example would be ethinyl estradiol, which does not bind to SHBG (Sex Hormone Binding Globulin). The disadvantage of artificials is that there appears to be a much higher degree of variability in how well they’re tolerated and how well they work. Their very long half-lives can be an issue both because of the potential for an increase in risk of a negative side-effect (the majority of reported thrombo-embolisms, for instance, appear to involve artificial oestrogens) and because of the longer amount of time it can take for the body to clear itself of the drug if there is a negative side-effect. Lastly, artificials are not measured by standard serum hormone tests.
Route
The route by which a drug is administered can be boiled down to parenteral or oral. Oral is hopefully obvious, parenteral is everything else. Parenteral would include things like IM (Intra-Muscular) injections, transdermal (patches, creams, etc.), pessary (vaginal), nasal sprays, and a host of others that don’t involve swallowing a pill, capsule, or potion. Sub-lingual (under the tongue) and buccal (between the cheek and gum) fall into a grey area between them as some drug is absorbed parenterally and some is inevitably swallowed.
Each of the possible routes have different advantages and disadvantages, but the biggest gap is between oral and all of the various possible parenteral routes.
Oral is easily the most convenient route for drug administration. Take a pill, capsule, or potion, and that’s that. Oral also happens to be the least efficient route. Things that you swallow go into the digestive tract and the job of the digestive tract is to break things down into their smallest usable components. The digestive tract is also designed to be somewhat selective about what it absorbs. The long and short of it is that only a small percentage of what’s in that pill you swallowed will likely ever make its way into your bloodstream.
The second major problem with the oral route is what’s called ‘The First-Pass Effect’. The first-pass effect has to do with your liver. The liver is the organ that, among many other things, handles the breaking down (metabolising) of things like hormones. Everything absorbed by the digestive tract first goes to the liver before going out to the bloodstream. What of that hormone pill you took which survived the digestive tract now has to face the liver trying to break it down into a less active or even bio-inactive form. What survived digestion ends up even further reduced by the liver and, worse yet, the liver ends up a bit stressed in the process.
For MTFs, the first-pass effect adds another wrinkle to things. When the liver sees a ‘spike’ of oestrogens – as it will shortly after you take an oestrogen pill – it releases clotting factors. The reason is an old bit of mammalian programming that assumes that a sudden spike in oestrogens means that you’ve just given birth and eaten the rich-in-oestrogens placenta. The increase in clotting factors is to try and prevent you from bleeding to death. Unfortunately, this increase in clotting factors means an increase in risk of a DVT (Deep Vein Thrombosis, a clot, usually in the leg) and its potential negative, potentially lethal, consequences.
Some studies have indicated that with regular use of oral oestrogens, over a period of time (approximately one year, by best estimates) the liver will stop trying to increase clotting factors. It should also be kept in mind that non-oral routes do not entirely avoid this liver response, but they do greatly reduce it, generally to the point where it is of little or no importance.
Compared to oral, parenteral routes tend to be much less convenient but far more efficient.
Dose
The dose of a particular drug or hormone will in part depend on its potency, in part on the route of administration, and in part on individual factors. Dosages of various drugs can range from single-digit micrograms (μg) to the multi-hundred milligrams (mg).
Interval
Half-life is probably the most important factor in determining how frequently a drug should be administered. Half-life refers to the amount of time it takes the body to metabolize half of a dose of a particular drug. The term is also sometimes used more loosely to refer to the length of time between when a drug is administered and when serum concentrations of that drug fall below useful levels. Half-life can vary quite a lot depending on drug, route, and dose.
Let my hormones go!
Whether endogenous or exogenous in origin, only a small percentage of the hormones in your system are ‘free’, unbound and completely bio-available, generally speaking. Most of your hormones are bound, mostly by one of two transport proteins.
The first is called Albumin. Albumin-bound hormones are somewhat bio-available in that they can be disassociated at target tissues.
The second transport protein depends on whether we’re talking about progestogens or androgens and oestrogens. Besides albumin, progestogens are also bound to Cortisol Binding Globulin. Besides albumin, androgens and oestrogens bind to something called, conveniently enough, Sex Hormone Binding Globulin (SHBG).
SHBG is somewhat problematic stuff in that there are some things about it we don’t seem to understand very well. Hormones bound to albumin are weakly-bound and essentially bio-available; hormones bound to SHBG are tightly-bound and are not bio-available. SHBG is produced by the liver and its level is somewhat dependent on serum hormone levels. SHBG levels go up with oestrogen levels and down with Androgen levels. Complicating matters, no one seems to be entirely sure what happens to SHBG bound androgens and oestrogens. Does SHBG act as a storage and regulation mechanism, with the bound hormones eventually being released back into the bloodstream? Or are SHBG bound hormones simply metabolised, for our purposes essentially wasted?
Unfortunately there doesn’t seem to be a definitive answer to that question currently. Either way, for FTMs it’s less critical; their use of exogenous androgens is going to push SHBG levels down. For MTFs, the question is of more importance, as their use of exogenous oestrogens is going to push SHBG levels up substantially. If SHBG bound hormones are simply metabolised, this would somewhat call into question the typical and understandable MTF HRT goal of pushing endogenous Androgen production to as close to zero as possible—developmentally speaking, that may not be wise.
Whatever the particulars, given SHBGs role as a hormone transport protein it is something to be aware of. SHBG levels are typically measured as part of a Liver Panel, a test commonly run by doctors monitoring HRT. Unfortunately SHBG often gets overlooked or ignored by doctors for whatever reason and it may be of benefit for the patient to bring up the subject—especially if there are problems with development. Where SHBG is concerned it is also important to keep in mind that a ‘Total’ serum hormone reading will include SHBG-bound hormones. For this reason such tests do not tell you much of anything useful.
Lastly, keep in mind that some artificials are sufficiently different from endogenous hormones that they do not bind to SHBG.
Steady as she goes!
As a general rule, the goal in administering a particular drug is to reach a sufficient serum level of that drug for it to be effective and to maintain that level as closely and for as long as it is needed. Generally speaking the doctor prescribing HRT will pick their favourite drug, uses a standard dose, and often tests serum levels periodically looking for a particular target level. This treatment philosophy has certain advantages, but there are also potential issues that TSs undergoing HRT should be aware of.
The first is that while in treatment philosophy a steady-state is considered a desirable goal, that is not something that ever naturally occurs in the human body. In cisgender (cis) men, androgen levels vary quite a lot on both a diurnal and seasonal basis. In cis women the endogenous oestrogen levels can vary by as much as an order of magnitude within a roughly 28 day cycle. To say that a normal hormonal level is not steady-state would be rather an understatement.
Second, the body tends to adjust to whatever the current hormonal level is. As discussed above, SHBG levels are effected by both androgens, oestrogens, and their relative levels. Androgen and oestrogen levels effect a host of body systems, even the density of their own receptors within the cytoplasm of cells varies depending on overall serum hormone level. Under normal conditions this is a dynamic process. As hormone levels vary, so do all of the other things they effect.
Third, determining what the proper target serum level of a particular hormone should be is far more problematic than is generally acknowledged exactly because of the natural variability. Serum Testosterone levels in a post-pubescent cis man can range from 179 – 756ng/dL (nano-grams per decalitre). Oestrogen levels vary even more wildly, from a Follicular phase low of 27pg/mL (pico-grams per millilitre) to a periovulatory phase high of 382pg/ml. Worse, these norms are for those post-pubescent and may not take into account more extreme shifts experienced and possibly necessary for optimal development. The range of normal for either hormone family is rather gargantuan, any number picked within that range as a target is wholly arbitrary.
Lastly, a number of exogenous hormones that are commonly used are not properly measured by standard tests. As importantly, the efficacy of several of the common anti-hormones is not adequately measured by standard tests. Anti-hormones that work on the conversion level will show a decrease in the target hormone, but anti-hormones that work wholly or partially on the receptor-site level (hormone antagonists) will not necessarily show a decrease in the target hormone.
That all of this works at all is something of a miracle—or, more accurately, a testament to the adaptability of the human body—but the fact is that it generally works pretty well.
One alternative to steady-state that has long been used amongst MTFs is referred to as cycling. Cycling is an attempt to approximate a cis women’s endogenous progesterone/oestrogen cycle. Given the complexity of said cycle, trying to replicate it exogenously would be difficult to impossible, nor is there any clear reason to try, at best one has to settle for an extraordinarily gross approximation.
The general cycling technique has been to take progesterone or a progestin a set number of days a month (seven to ten being typical) whilst lowering or dropping oestrogens entirely for that time. Whether or not this technique results in better development long-term is unknown, what is known is that it does have its downside in that, unsurprisingly, substantially varying hormone levels can result in anything from mood swings to severe emotional issues. Adding those on top of the generally substantial emotional issues faced by a Trans person is generally not a good thing and for this reason cycling is generally no longer recommended.
A variant on cycling, common amongst both MTFs and FTMs, comes from the observation that varying one’s regimen, either by drug type or dose, tends to result in a sudden burst of developmental activity. From this some have concluded that cycling one’s regimen, changing dose and/or drug types from time to time, is desirable. It remains unclear whether this technique actually results in better development long-term.
See also
- Hormones: Urban Legends
- Hormone replacement therapy (trans)
- Hormone therapy
- List of transgender-related topics
- Hormone techniques
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