Androgens consist of the three anabolic steroid hormones, testosterone, dihydrotestosterone (DHT), and androstenedione (A4). Anti-Androgens (AAs) are medications which either prevent the production of these hormones or prevent the body from using them. A4 is largely only involved in metabolizing other hormones, and isn’t something to be concerned about for HRT. DHT is more troublesome, however, as it is the primary cause of male pattern baldness, but DHT is metabolized from testosterone, so if you reduce T production, you reduce DHT production as well.
{!{ <divclass="gutter d-md-block d-sm-none"><divclass="card"><divclass="card-body"><h4class="card-title">Note, it is not always necessary to use an Anti-Androgen</h4> }!}
Due to the way the body’s own regulation system works, if you put enough sex hormones into the body, be they androgens, estrogens or progestins, the body stops producing its own, and this can be a very effective way to shutdown testicle function.
Unfortunately, it is not very common for this to be possible with the cis female ranges that many doctors target, and typically requires a larger than cis normal blood level to achieve total testicular deactivation. Thus, the use of an AA may be needed depending on what your doctor is willing to do.
The three most common anti-androgens are **Spironolactone**, **Cyproterone Acetate** and **Bicalutamide**. A fourth method often used is a Gonadotropin-Releasing Hormone (GnRH) agonist, such as **Leuprolide** (Lupron) or **Goserelin** (Zoladex) which works by overloading GnRH receptors until they stop responding.
Spironolactone (commonly shortened to "spiro") is the most commonly used AA in the United States, largely because it is extremely cheap, is manufactured by a lot of companies, and because Cypro isn’t available in the US due to an FDA ban. The official on-label use for spiro is as a potassium-sparing diuretic; spiro causes your body to release more water, washing away sodium and other minerals, but keeping potassium. In short, the drug makes you pee… a lot. It’s meant to be used to treat high blood pressure and cirrhosis of the liver. [The fact that it suppresses testosterone production is considered a side-effect](https://howwegettonext.com/how-the-worst-blood-pressure-medication-became-the-best-testosterone-blocker-9afec005ede0). Spiro is often also prescribed for severe androgen related acne, heart conditions, and is given to cis women with PCOS.
How does spiro work? Well if receptors are locks, spiro is a master key. It fits into a bunch of steroid receptors, androgen, progesterone, and cortisol. For some it binds exceptionally well (aldosterone and dexamethasone), and some just ok (testosterone). For aldosterone it functions as a powerful antagonist, preventing the kidneys from receiving aldosterone from the adrenal glands. Aldosterone slows down kidney function so that body retains water, and spiro blocks that message, causing them to release the water instead.
In androgen and progesterone receptors it is a partial agonist, turning the key just a little bit, just enough to make the radio turn on, but not strongly activating the cell’s response to those chemicals. It is only enough to tell the hypothalamus that there are androgens and progestins present in the blood stream, so it slows down testosterone production.
The other way that spiro works is that it prevents the formation of various enzymes that the body needs in order to produce testosterone. Without these enzymes, the testes and adrenal glands literally cannot form testosterone molecules.
Both of these functions are very weak, however, and require pretty large doses of spiro to be effective (relative to the diuretic affect). Spiro only actually works well as an anti-androgen in about 20% of subjects, and [doesn’t work at all in another 30%](https://www.liebertpub.com/doi/10.1089/trgh.2017.0035?utm_source=sfmc&utm_medium=email&utm_campaign=TRGH+FP+May+17+2018&d=5%2F17%2F2018&mcid=511450069&#B17).
I mentioned above that the third receptor spiro fits into is the cortisol receptor (technically, the glucocorticoid receptor), and it fits in REALLY well, binding just as well as actual cortisol. Cortisol is released by the adrenal glands in response to stress, it causes your body to raise its blood sugar, suppresses the immune system, and increases the metabolism of glucose and lipids (fat). The problem is, spiro doesn’t *activate* the cortisol receptor, [it blocks it](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277847/), preventing your body from receiving the cortisone it produces.
Without cortisol, the body resists releasing fats for consumption, it just retains it. This not only makes it easier to put weight on, and harder to lose the weight you have, but it hinders fat redistribution for feminization. New fats go on in estrogenic ways, but the old masculine fats struggle to release. For late transitioners this can result in the dreaded “grandma” effect, where the combined masculine and feminine fats make one look much older than they are. There is also a community term “spiro belly” which refers to the way the drug causes fats to pool in the abdomen.
Reduced cortisol function also affects working memory within the brain, causing one to be more distracted and have greater difficulty working on tasks. This is effectively the same as ADHD symptoms, and some transfemmes notice their ADHD getting much worse on the drug. Personally I found the drug made it harder to drive a vehicle, I could tell my road awareness was hindered. Many people report coming off of spiro to feel like walking out of a mental fog.
Spironolactone is typically prescribed in doses of 100 or 200mg for HRT, and can be taken as high as 400mg, but is not recommended due to all the other side-effects. The drug can also be very hard on the liver and kidneys in high doses, and dehydration is a common risk. Potassium overdose is also a possibility, and it is recommended that you avoid eating foods rich with potassium like bananas, avocados and even potatoes.
Also, again, spiro makes you pee. A lot. This is both a problem because bathrooms, but also because it makes you pee out all your body’s sodium, which then triggers a salt craving in order replenish lost sodium. The community joke about trans women being obsessed with pickles comes from this effect, as pickles are an excellent source of salt, along with olives, sauerkraut, kimchi, bacon, and many salty snack foods. Unfortunately, without cortisol, your body struggles to absorb sodium, as well, so it takes a lot to fulfill the craving.
Another common sign of low sodium is muscle spasms and leg cramps (charley-horse).
### Cyproterone Acetate (Brand Name: Androcur):
Cyproterone Acetate (commonly shortened to "cypro") is probably the most commonly used transgender anti-androgen outside of the United States, where it was never approved by the FDA for sale to patients. This is mainly because no company has ever found it profitable to undergo the complicated process necessary for FDA approval. Additionally, the the drug has a troublesome history, with early studies finding it connected to high liver cancer risks. It also picked up a stigma of causing blood clots due to its pairing with ethinyl-estradiol in the contraceptive Diane-35.
Cypro works in two ways, first by functioning as a powerful receptor antagonist, competing with testosterone for androgen receptors. Additionally, cypro functions as a mild progesterone agonist with poor transactional ability, just enough to convince the hypothalamus that the body is flush with progesterone and thus reducing hormone production. Unfortunately, this means that cypro competes with progesterone, and can hindering its effectiveness, but it does make it quite affective at lowering testosterone levels in the blood stream.
The common dosage for cypro in trans HRT is 25mg, with a maximum dose of 100mg. Because the drug is so hard on the liver, staying below 50mg is recommended.
Bicalutamide (commonly shortened to "bical") is also a receptor antagonist, much like spiro and cypro. It is actually a very good androgen blocker, competing quite strongly for androgen receptors, and does a fantastic job of suspending androgens within the body. However, as bical does not activate the receptors it blocks, and does not activate any other sex hormone receptors, there is no feedback to the body to tell it to halt testosterone production. Quite the opposite, the hypothalamus thinks there is *no* T in the body and cranks up production to compensate.
This makes it extremely difficult to determine if the drug is actually working. Eventually, as estrogen levels rise, T production drops off due to the overall total sex hormones present in the body, but this takes time. It does have one benefit, however, that the high levels of T also mean that some of the testosterone will aromatase into estrogen.
Bical has the same high liver risks as spiro and cypro, and for this reason many doctors are reluctant to prescribe it, especially in older patients. Aside from this, it has relatively few negative side-effects for transfemmes.
Finasteride (brand name Propecia) and Dutasteride (brand name Avodart) are 5-alpha reductase (5a-R) inhibitors. 5a-R is an enzyme that is critical to the body’s metabolism of androgens and estrogens from other compounds. Note, this is an *inhibitor*, not a blocker. Finasteride does not prevent 5a-R production, it merely lowers the potency of the 5a-R chemical reactions that causes testosterone to convert into DHT.
The on-label use of Finasteride is for fighting prostate cancer and preventing male pattern hair loss. **It does not have any anti-androgenic affects, and should not be prescribed as an AA**. It is, however, useful to prescribe to Transmascs who are concerned about hair loss.
Tip: Insurance companies are more likely to fully cover the cost of the 5mg dose, rather than the 1mg, as the larger dose is usually prescribed for prostate cancer, where the smaller is just for hair loss.
Gonadotropin-Releasing Hormone (GnRH) is the hormone that the hypothalamus produces in order to control the release of other sex hormones. It releases GnRH in controlled pulses as a sort of morse-code for the pituitary gland, which then reacts to those pulses by secreting either [Luteinizing Hormone](https://en.wikipedia.org/wiki/Luteinizing_hormone) (LH) or [Follicle Stimulating Hormone](https://en.wikipedia.org/wiki/Follicle-stimulating_hormone) (FSH), based upon [the frequency of the pulses](https://web.archive.org/web/20150923190449/http://www.biolreprod.org/content/56/4/1012.full.pdf). The intensity of the pulse tells the pituitary how much to produce.
LH causes the production of testosterone in both the testes and the ovaries, but in the ovaries that testosterone is immediately metabolized into estrogens. LH also induces luteinization of mature ovarian follicles (hence the name), which produces progesterone and even more estrogens, and triggers ovulation.
GnRH Agonists, as the name implies, interface with GnRH receptors on the pituitary gland and trigger a constant stream of LH, which initially causes the testes and ovaries to crank up production. However, because the drug doesn’t pulse, the receptors eventually become overloaded and stop listening, causing LH levels to plummet, and shutting down both testicle and ovarian function.
GnRH Agonists are extremely effective and have very minimal side-effects and are the preferred method for blocking puberty in adolescents of both sexes. Unfortunately, GnRH Agonists are extremely expensive (upwards of $1000 per dose, or more) and are rarely covered by insurance for use in adults.
The three most common GnRH Agonists are Leuprolide Acetate (brand name Lupron), Goserelin (brand name Zoladex), and Histrelin Acetate (brand names Vantas and Supprelin). Leuprolide is a shot delivered every 2-3 months. Goserelin and Histrelin are annual implants, typically placed under the skin of a forearm.
In all cases except for bicalutamide, the best way to know if your androgens have been sufficiently suppressed is with a blood test. That will tell you how well suppression is functioning, and if more intervention is needed. Typically one wants to target cis female ranges of 20-50 nm/dL (0.7-1.7 nmol/L). Total testicular suppression usually sits around 10-15 nm/dL (0.3-0.7), which is the amount of testosterone produced by the adrenal glands.
One does not want to have a T level below 10 nm/dL for an extended length of time, as the body does need *some* testosterone to function properly.
#### But I can’t get testing.
The second best way to determine if you’ve achieved shutdown is through masturbation. Ejaculate will be very thin and clear, lacking any semen. At this point you are effectively sterile, and your testicles will begin to atrophy.
## Testicle Atrophy
Once shutdown has been achieved the testicles will start to shrink from lack of function, potentially by as much as half their size. This can often be accompanied with pain, which manifests in different ways for different people. Some experience it as a dull throbbing soreness, much like having been kicked in the crotch. Others feel it as quick stabbing pains, like a needle jabbed into the testes. Still others experience it as a sort of lightning quick shock which travels down the perineum and into the anus.
Atrophy pain comes and goes and typically lasts for 6 months to a year (unless they’re removed sooner).
