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Notes on thrawling pubmed for studies on HRT efficacy

Useful topics

Menopause: People with low levels of both estrogens and androgens; people supplementing estrogens to achieve feminising effects.

Prostate/testicle cancer: People with an urgent need to block androgens as thoroughly as possible; androgenic effects even after T/DHT are blocked.

Sport science, fertility studies, cis-masc sexual health: Lots of data on enhancing androgen activity.

Gynecomastia: People with testes growing breast tissue.

Polycistic ovary syndrome (PCOS): People who do not want androgens trying to get rid of them. (but they have ovaries; see below for implications.)

Androgenic alopecia: People trying to block DHT from acting on head scalp (and the same methods that would prevent scalp hair _loss_ would also prevent facial hair _growth_).

Hirsutism: People trying to get rid of body/facial hair. Idiopathic hirsutism: Investigations on why body/facial hair sometimes grows even without androgens.

Premature telarche, precocious puberty: Environmental factors causing feminisation.

Libido and sex health: Ways to enhance or inhibit sexual feelings that do not necessarily involve changing sex hormones levels.

Ethnobotany: Finding out about traditional sex-related compounds to try, and indications of which ones seem to do something. Chinese and Indian labs put out a lot of stuff.

Breast cancer: a field focused in *inhibiting* breast tissue growth; great if you have chest dysphoria. For those who want breasts, the main value is to help you find the right kind of cell growth and not be killed by your own boobs (e.g. using alcohol to enhance cell multiplication is a bad idea). But the information on that is of limited use; a lot of stuff that would be healthy growth without cancer is dangerous growth with cancer.

The endocrine iceberg

Picture the conventional approach to transgender HRT: altering T and E2 serum (blood) levels to match those of cis averages. You do this by adding more of one hormone, and maybe stopping the gonads from producing the other, or blocking the other at the receptor.

That’s the tip.

Hormones are produced by the adrenals too. How, if at all, each blocker will affect the adrenals is unclear in most cases, as is the effects of exogenous and anciliary hormones on their feedback cycles.

Hormones are produced in-tissue too. E.g. prostate/testicle cancer rebounds some 2 years after castration; this seems to be due to surviving cancer cells converting A4 to stronger androgens in-tissue. Implications for us should be clear. If you see masculinisation symptoms post-SRS don’t hesitate to try blockers again (cypro is dangerous long-term but because it nukes everything it’s a great one to test for a while and see if it makes a difference.)

It’s the hormones that effectively hit the tissue receptors that will cause bodily / mental changes, not the serum levels.

Research has focused on the androgens T and DHT, and the estrogen E2, because they’re the ‘strongest’. Other sex hormones (estriol/estrone/estretol, androsterone) have been relatively dismissed, as well as anciliary hormones like A4 or LH. However, recent results on cancer studies suggest the whole picture is more complex, and these other hormones affect tissue growth in various ways. Exogenous hormones like phytoestrogens or dietary/environmental endocrine disruptors have been similarly dismissed by formal endocrinology, but recent research shows effects that go beyond how much a receptor is tickled in vitro.

Body variation is only starting to be accounted for. For example, only now studies are beginning to show that certain genetic or epigenetic mutations are responsible for why retinoic acids either cause or inhibit androgenic skin effects. A lot of the mixed/insatisfactory treatment results may be due to substances just not having the same effect in different people. There is as of yet no formal study of trans women who seem to produce a lot of E1 and/or feminise well on it.

Feedback and homeostatic loops are complex. High levels of T will block estrogens from activating the receptors; lots of E will act as a T inhibitor. (All the documented cases of phytoestrogenic gynecomastia I could find were in a low-T context; the soy milk guy was elderly, the boys with the lavender oil were prepubescent etc.). SHBG will bind both to androgens and estrogens, but will prefer androgens, and if you have too many sex hormones of either kind it will fire up, but how much is ‘too much’ depends on the person, also boron inactivates it. FSH/LH fires up the gonads, and high E2 will inhibit FSH/LH, but LH has also been found to be involved directly in tissue growth in breast, bone, and cancer cells.

And there's the receptors themselves. the number of receptors is variable and their effectiveness tunable. Skin treatments of the retinoic (vitamin A) family treat acne by messing up with receptors without changing hormone levels; they have variously caused or improved hirsutism, depending on the specific compound or study. Milk thistle is an antiandrogen by degrading receptors via isosylibins (10.1038/onc.2008.45, 10.1002/mc.20670 ).

Aromatase turns androgens into estrogens in-tissue. Aromatase inhibitors and upregulators will have the effect one expects. For example, melatonin increases tissue E2 in postmenopausal ovary by enhancing aromatase, while phosphorylation of the aromatase enzyme depending on calcium/magnesium changes the amount of E2 in the brain. However, aromatase can also degrade E2 in certain situations; another of the homeostatic loops. Most phytoestrogens mess with aromatase, or the plants contain other stuff that messes with aromatase. This may be one way in which ‘weak’ exogenous hormones have such tangible effects.

A lot of hormonal tissue activity is regulated by growth hormones, IGF-1 in particular. Notice that people in first puberty have high growth hormone levels; after adulthood, not so much.

5α-reductase, which converts T into DHT, is crucial. Many masculinisation effects, notoriously on skin and hair, are due to DHT conversion, so 5α-reductase inhibitors can have a lot of impact. Notice however that there’s other routes that end up in tissue DHT, such as the A4 pathway.

Everything influences everything: nutrition and herbs

Low levels of zinc, selenium, magnesium will inhibit IGF-1. High protein diets boost it. Calcium and magnesium affect aromatase. Fat cells affects estrogens. Emotional states and dopamine affect GABA which affects gonadotropins. Studying compounds in isolation is useful and informative, but not definitive.

Dietary and herbal sources have a lot more things in them than what seems to be ‘the’ active compound, and that’s not always a minus. The immunostimulant effects of Sutherlandia were originally dismissed, because the beneficial flavonoids wouldn’t be absorbed by the human body via digestion. That is until someone realised that the plant is also rich in saponins, and because saponins are soap-like, they affect cell membrane permeability. Sutherlandia has been since shown to improve immune function.

Or consider the traditional use of nettles as a galactagogue. Nettles are a 5α-reductase inhibitor, so they should stop DHT from affecting breast tissue; but the effect on breast milk production couldn’t be demonstrated. However, nettles are especially nutritious, high in fiber, protein, vitamins A and C, calcium and iron. It is easy to imagine that habitual consumption as slow cold infusions would have positive long-term effects on breast milk for the extra nutrition alone, especially for lower-class women who may have difficulty in keeping a rich diet while not working. How these effects could synergise with the hormonal effects, and those with the anti-inflamatory, anti-allergic, and vasodilator effects, isn’t a topic that has been researched; but it’s clear that testing one kind of extract in short-term lab tests only investigates that specific question.

The trans body

Cis people have gonads that generate the hormone they want. we have no gonads, or (pre-SRS) counterproductive gonads. if a compound increases T *in cis guys*, that doesn't mean that it would increase T in a trans guy; e.g. if it's messing with GABAs that tune the pituritary to put out FSH/LH that will fire up a cis guy’s testes, it might end up firing a trans guy’s ovaries instead. When evaluating studies it is important to understand *how* are the hormone levels being affected.

In general exogenous hormones are our main method of activating the receptors we want. But I see potential in experimenting with things that increase endogenous hormones in cis people too, if you're post-SRS or very confident in your blockers. If a herb reduces hot flashes in menopause, maybe it has something to do with tissue estrogens or progestins or adrenals or receptors etc., it's not ~necessarily~ on the uterus. If a herb increases tissue E2 in the uterus it might also be useful for transfeminine folk, if the reason it does that is by globally upregulating aromatase.

Individual body variation probably has a greater impact on HRT results than standard practice assumes. Rather than staying forever with the first prescription one manages to wrestle from the cistem, it makes a lot of sense to experiment with different doses, routes, blockers etc. and see what works best.

The iceberg of the endocrine system probably has a greater impact on HRT results than standard practice assumes. One way it could do that is by all those feedback loops and homeosthases. For example, if LH does anything in conjunction with E2, this pair can only be achieved briefly on E2 level changes, before the system inhibits LH again. This may be a reason for the reports on women who stop HRT for a month then find stronger results upon restarting it, or for high-impact of a new mode of administration that seems to subside after some time in it. This is an argument to try out different things whenever transition seems stalled.

Keeping a healthy scepticism

One shouldn’t easily trust traditional prescriptions, alternative therapies, or clearly biased studies funded by the same people who are trying to sell you something. This much is, I hope, clear to everybody.

But too many people lower their guard with the exterior performance of science. Writing an article in LaTeX full of Greek words with a list of references at the end does not make a piece of information any more reliable than your grandma’s teas. Throwing some drugs at a bunch of rats then propping up a bunch of other rats as a null hypothesis (or, how Gelman calls it, a ‘strawman hypothesis’) to get a p-value to draw conclusions from amounts to little more than an oracle, about as informative as an anecdote. It’s probably less informative than a *relevant* anecdote. This kind of statistical-significance methodology is flawed beyond repair; there’s a crisis of reproducibility in science for a reason, it affects the fields that rely on bad methods. (There’s no crisis of reproducibility in space science or geology or particle physics; but nutrition, medicine and social sciences are a minefield.)

A statistical-significance study that shows an effect for a compound should be taken as one very small piece of evidence, a suggestion that maybe this thing is worth experimenting with. A study failing to find an effect should be taken as more ‘unproved’ than ‘disproved’. A series of studies done by different people reproducing the same results is a lot more reliable. A p-value-free, concrete demonstration of causal mechanisms is a lot more reliable. Long-term followup studies looking at the end results in humans (as opposed to rat cells after a week) is a lot more reliable.