Quote from: spacerace on February 11, 2015, 10:56:47 AM
Thank you for all the information you have posted Hugh. I have more reading to do. It has been really helpful - I appreciate it. One thing I was going to ask you, as I saw it mentioned on of those threads - were you talking about progestins still in use causing both FTM and MTF development in different ways? How does that work in terms of what binds to what receptors, and when?
I'm not sure how much you know about synthetic hormones, but they're manmade compounds that are designed to activate the same receptors that the steroid hormones naturally produced in the human body do.
Steroid hormones control all sorts of different aspects involved in the day to day running of your body, which makes them potentially very useful from a medical point of view. However, the natural hormones suffer from a number of limitations: they're largely or completely destroyed by the liver if taken by mouth, so they generally have to be administered by injection; their biological half life tends to be quite short (particularly with progesterone) so they need to be frequently re-administered; and they often get converted into other hormones with completely different properties (eg testosterone converts to estradiol). Also, they're naturally occurring substances, so can't be patented!
Hence, the pharmaceutical industry developed synthetic hormones to overcome those limitations. Most of them are chemically modified versions of the naturally occurring hormones, although a few (DES is one) have a completely unrelated structure to the hormone they're mimicking. One thing pretty much all synthetic hormones have in common is that they're resistant (or often completely untouched) by all the systems the human body has in place for controlling and limiting what the natural hormones can do, and getting rid of them if they get into the "wrong" place. This is great from a medical point of view, since it means that they're generally more potent and longer acting than the natural hormones (and often orally active too), however it also means that they can cross the placenta and potentially have all kinds of effects on an unborn baby that the natural hormones wouldn't have.
There's 5 different classes of synthetic hormones (corresponding to the 5 different types of hormone receptor): estrogens, progestins, androgens (aka anabolic steroids), glucocorticoids (aka corticosteroids), and mineralocorticoids. The important ones from our point of view are the sex hormone mimics, the two female ones (estrogens and progestins), and the male one (anabolic steroids). Anabolic steroids mimic the action of androgens (testosterone and DHT); estrogens and progestins mimic the action of estradiol and progesterone respectively.
As far as I can gather, the only anabolic steroid that's seen any significant use during pregnancy is danazol, however, due to the fact that an insufficiency of female hormones has long been regarded as one of the main causes of miscarriage, both estrogens and progestins have been used very extensively.
Being female hormone derivatives, one property both estrogens and progestins share is that they're basically completely incompatible with maleness. Quite modest doses of either (well below what are commonly used for medical treatment in women) will completely suppress T production in an adult man. For instance, a dose of between 1 and 3 mg per day of DES is enough to completely suppress T production in prostate cancer patients, whereas the doses being used for miscarriage prevention were much higher than that - greater than 50mg per day throughout the second half of the pregnancy, which appears to be the critical period for gender development in the brain.
A similar situation applies with progestins. They're also highly effective at suppressing T production in adult men (the drug most commonly used to chemically castrate sex offenders in the US is Depo Provera, a progestin that's also used as an injectable contraceptive in women, and (I think) has been used in the past for miscarriage prevention). Apparently the same dose as is used for contraception in women (one 160mg shot every 3 months) is enough to maintain a state of full chemical castration in a man, although I've heard they double up the dose for sex offenders just to make sure!
Provera is the main progestin that's been used in males, however I understand that there's one called hydroxyprogesterone caproate that's sometimes used as part of MTF transgender HRT, and of course plenty of trans women have used birth control pills or contraceptive injections as a stopgap measure when they haven't been able to obtain legitimate access to hormones. Although they often add a small amount of estrogen to increase the effectiveness, progestins are the main hormonal component in womens contraception, and they all seem to work really well when it comes to shutting down T production in a male body. Hence, it's easy to how both estrogens such as DES, and progestins, could cause female brain development in biological males (and MTF transsexuality), by suppressing T production during the second half of the pregnancy.
However, there's a second property of progestins that mean that, under the right circumstances, they might be able to cause the opposite effect too, of causing male brain development in female fetuses.
One thing that happens when you start tinkering around with the chemical structure of hormones is that they often start to cross-react with non target receptor types. This is particularly a problem with progestins and anabolic steroids. Although they're based on testosterone and meant to target androgen receptors, a lot of anabolic steroids cross-react with progesterone receptors and thus, to varying degrees, act as progestins too. Likewise, most progestins cross-react with androgen receptors and have some anabolic effects. While the pharma industry carefully selected compounds that maximised the progestin effect and minimised the androgenic effects in adults, some of the early progestins turned out to have very strong androgenic effects on female fetuses (I gather this is thought to have been due to hormonally active breakdown products of the parent compound accumulating to an unexpectedly high level in the fetus).
There's yet a further complication to the story: there are two subtypes of androgen receptor, one of which is activated by either testosterone or DHT, the other only responding to DHT. We know from the monkey research that either T or DHT will drive brain masculinization (there's a condition called 5-ARD which confirms the same applies to humans too), which means the (T + DHT) receptor subtype must be the main one in fetal brain tissue. Conversely, genital masculinization only occurs in the presence of DHT, meaning that the DHT-only subtype must be the main one expressed in genital tissue.
What this means is that, if a particular progestin causes genital masculinization, then it's virtually certain that it activates the other, less selective receptor subtype as well, and can masculinize the brain. However, there's no guarantee of the reverse - just because it's not activating the DHT-only receptor subtype and causing genital masculinization, doesn't mean it isn't capable of activating the (T + DHT) receptors and masculinizing the brains of female fetuses exposed to it. In other words, since some progestins have been associated with virilizing effects, IMO that makes the whole lot suspect when it comes to brain masculinization (at least until proven otherwise).
