Experimental feminizing HRT
PLEASE DON'T TRY THIS AT HOME! This is highly experimental and incredibly dangerous stuff.
This is not a Guide
We strive to provide non-biased, well cited, and accurate information, but this wiki is written by people who may or may not be professionals.
- 1 Experimental regimen: bicalutamide and raloxifene
- 2 Experimental Regimen: Sex hormone potentiation though Decreased SHBG levels
- 3 Experimental Regimen: Epigenetic change reversal with Bicalutamide or Mifepristone
- 4 Experimental Regimen: Fixing breast development with prolactin linked with IGF-1
- 5 Experimental Regimen: Neo-ovaries/testicles through RNA interference with FOXL2 and DMRT1
- 6 Experimental Regimen: Obliterating the androgen machinery
- 6.1 Life of an Androgen Receptor
- 6.2 Okay, so that stops when I go on blockers, right?
- 6.3 Okay, but surely there's someone to take the trash out inside the nucleus, right?
- 6.4 But... I want to flip it to zero!
- 6.5 I'm in. Let's do this.
- 6.6 Details
- 6.7 Footnotes
- 7 References
Experimental regimen: bicalutamide and raloxifene
The goal of this regimen is to allow AMAB people (specifically, people with testes and relatively little preexisting breast tissue) to develop feminine features without growing breasts.
Important: Like everything else on this wiki, this is not medical advice. There may even be a critical flaw in this regimen; see #Open questions.
Bicaluamide is an androgen receptor antagonist. It prevents testosterone and DHT from binding to the androgen receptor, thus reversing some masculinization and preventing further masculinization.
Raloxifene is a SERM. It blocks estrogen receptor activity in some tissue and acts as an estrogen in other tissue. Specifically, it is known to be antiestrogenic in breast tissue and estrogenic in bone. Furthermore, there are some indications that it induces a female-pattern fat distribution.[footnote 1]
Indirect interaction of bicalutamide and raloxifene in people with testes
Bicalutamide causes an 80% increase in testosterone in people with testes. In the body, testosterone is converted to estradiol via aromatase, so the increased testosterone levels lead to increased estradiol levels. The reason bicalutamide doesn't increase testosterone levels even more is thought to be due to the increased estradiol inducing negative feedback on the HPG axis, thus limiting the production of testosterone.[footnote 2]
Raloxifene causes a 13%-26% increase in testosterone in people with testes. This is because its antiestrogenic effects prevent negative feedback on the HPG axis, leading to increased testosterone secretion by the testes.
This may be a problem when raloxifene is taken together with bicalutamide. Raloxifene blocks the negative feedback that is hypothesized to limit testosterone production in people taking bicalutamide. Taken together, they may lead to large increases in testosterone levels, greater than that of either taken alone. This effect has been experimentally demonstrated with tamoxifen and bicalutamide (see table below). The increase in testosterone could potentially counteract the antiandrogenic effects of bicalutamide (i.e., high concentrations lead to testosterone and/or DHT binding to the AR instead of bicalutamide). The increased testosterone may also lead to increased concentrations of its metabolites (see diagram on right). Furthermore, high testosterone may be associated with cardiovascular events.
|Male endocrine response to bicalutamide, raloxifene, and tamoxifen|
|Drug||Population||PMID||Dose||LH||T (total)||T (free)||DHT||E (total)||E (free)||SHBG|
|raloxifene||10 healthy men,
|43 healthy men,
|bicalutamide||23 men with
|390 men with
|150 mg/day bicalutamide &
X mg/day tamoxifen
|282 men with
|Self-reporteda hormone levels for bicalutamide + raloxifene|
|Subject||Drugs||Duration (days)||FSH (IU/L)||LH (IU/L)||Prolactin (mIU/L)||Estradiol (pmol/L)||Total testosterone (nmol/L)||SHBG (nmol/L)||Free testosterone (pmol/L)||Free testosterone (%)||Bioavailable testosterone (nmol/L)||PSA (ng/mL)|
||Lab reference ranges||1.5-9.7||1.8-9.2||90-400||<160||12.0-31.9||17-56||260-740|
|0||4.0||4.1||187||65||6.2 L||37||103 L|
|37||6.9||8.1||239 H||42.7 H||51||791 H|
|59||5.9||8.6||200 H||35.0 H||51||612|
||Lab reference ranges||7.1-27||13.3-89.5||273.5-495.7c||1.6-2.9||<4|
|90||51.2 H||73.9||772.4c H||1.51 L||18.9||0.2|
Publications on the topic of bicalutamide/NSAA + SERM/AI, which may have more information on hormone levels with the combination: Studies. Reviews.
This problem may be ameliorated by replacing bicalutamide with an antigonadotropin that inhibits the production of testosterone rather than acting as an antagonist at the receptor, such as a GnRH agonist, GnRH antagonist, or cyproterone acetate. Raloxifene has been used to prevent bone density loss in premenopausal women with long-term GnRH agonist use, so there is some evidence that the combination of raloxifene with a GnRH agonist is safe. Alternatively, the addition of a sufficiently high dosage of a progestogen, due to their antigonadotropic effects, can reinstate negative feedback on the HPG axis and thereby block the increase in testosterone levels caused by bicalutamide and raloxifene. An example might be norethisterone acetate (a prodrug of norethisterone), which is available in generic high-dose 5 mg tablets in the United States (10 times the dose found in birth control pills). Other progestogens available in high doses include megestrol acetate (available in 40 mg tablets, antigonadotropic effects demonstrated at 40-80 mg/day) and medroxyprogesterone acetate (available in 10 mg tablets).
Another potential option is to use a 5α-Reductase inhibitor like dutasteride. This should allow for a lower dose of bicalutamide, since 5α-reductase inhibitors prevent the conversion of testosterone into 5α-DHT, and testosterone has a 2- to 3-fold lower affinity to the androgen receptor than DHT. In particular, finasteride decreases 5α-DHT levels by about 70% when taken alone. Additionally, a 5α-reductase inhibitor would avoid the increased concentrations of 5α-DHT metabolites. Note, however, that 5β-DHT and its metabolites would not be blocked, and may be present in increased concentrations. Some of these metabolites have neurological activity (in particular, 3α,5β-androstanediol and etiocholanolone). Note that there is some evidence that this will not work: Subject 2 from the "self-reported hormone levels" table above used bicalutamide, raloxifene, and finasteride, but still had relatively high PSA levels compared to those of trans women taking cyproterone acetate and estradiol (see PSA article). Assuming PSA is a suitable proxy for androgen receptor activity, this indicates that Subject 2's regimen was not effective.
Experimental Regimen: Sex hormone potentiation though Decreased SHBG levels
Consuming high levels of estrogen does not necessarily increase it's feminizing effects, this may be due to estrogen's ability to increase Sex hormone binding globulin (SHBG) secretion,[footnote 3] [footnote 4]thereby dampening it's own effects. Testosterone on the other hand can decrease SHBG secretion, and applying higher levels of it can in fact increase it's effects to some extent. [footnote 5].
Thus it may be possible to increase the bioavailiability of estrogen by decreasing levels of SHBG, thereby possibly potentiating it's activity. Insulin and prolactin are known to decrease SHBG levels,[footnote 6][footnote 7] so it follows that perhaps free estrogen levels can be raised by increasing insulin and prolactin through some artificial means.
Insulin levels can be modified by foods, high calorie foods in particular will cause a spike in it's levels, though it is not always ideal to consume high calorie foods. Though asparagus is known to raise insulin levels despite being low-calorie,[footnote 8][footnote 9] and wild asparagus in particular is also known to increase prolactin secretion,[footnote 10] and though this has only been shown for A. racemosus so far it may very well also be true for A. officianalis (aka common asparagus).
It would be rather simple to test the effectiveness of this idea, here's a rough overview of how the experiment might work:
- Avoid consuming dietary asparagus prior to experiment to establish a baseline.
- Measure free vs. bound estrogen for later comparison.
- Create a standardized A. racemosus extract or obtain a drug with similar effect.
- Begin regularly consuming the A. racemosus extract for a predetermined time.
- Re-test free vs. bound estrogen to compare to the baseline.
- Hypothetically free estrogen levels would increase, while bound estrogen decreases.
One could use common asparagus in the experiment and use it as a chance to test whether it also increases prolactin as it's wild cousin does:
- Avoid consuming dietary asparagus prior to experiment to establish a baseline.
- Measure free vs. bound estrogen, and prolactin for later comparison.
- Create a standardized A. officianalis extract or obtain a drug with similar effect.
- Begin regularly consuming the A. officianalis extract for a predetermined time.
- Re-test free vs. bound estrogen, and prolactin to compare to the baseline.
- Hypothetically prolactin and free estrogen levels would increase, while bound estrogen decreases.
- The free hormone hypothesis in somewhat under debate, as there has been some evidence that hormones bound to SHBG can still activate endocytic receptors even though SHBG can not enter the cell itself. [footnote 11]
- Some substances have been shown to decrease insulin levels such as cinnamon[footnote 12] and green tea extract,[footnote 13][footnote 14] and may need to be avoided in order for asparagus' effects to be noticeable.
Experimental Regimen: Epigenetic change reversal with Bicalutamide or Mifepristone
Some androgen receptor antagonists, such as mifepristone or potentially bicalutamide, actually have the ability to cause the androgen receptor to start recruiting corepressors instead of coactivators, which may undo the irreversible or slowly reversible changes in gene expression caused by the AR.While further research is needed, it appears that other anti-androgens don't cause corepressors to be recruited by the AR, or they still prevent the translocation of the AR from the cytosol into the nucleus. The following plan bears many similarities to the hormone therapy used for prostate cancer.
Here's an example plan:
- Measure PSA levels as a baseline measurement of the expression of androgen-dependent genes, as well as free/bound T levels.
- Nil out bodily production of testosterone using GnRH agonists/antagonists, so that available androgen receptors are mostly in the cytosol. Wait 1-2 weeks for magic to happen.
- Measure PSA and T levels again. Low T levels should confirm that testosterone is no longer actively circulating, so new androgen receptors are sitting bored in the cytosol waiting for somebody to come bind to them. Existing androgen receptors may still be in the nucleus! PSA levels should be trending downwards due to ARs slowly going away, but not nil yet.
- Run a course of bicalutamide or mifepristone. This will bind to the ARs in the cytosol, bring them into the nucleus and start assembling the AR protein complex around the AREs (e.g. the promoter and the enhancer PSA gene AREs.) However, in the absence of T, corepressors will be attached to the AR rather than coactivators. Thus, the histones will be deactivated and the androgen-dependent genes such as PSA will no longer be expressed.
- Measure PSA levels again. PSA should be near nil before moving to the next step.
- Discontinue bicalutamide or mifepristone. At this point, the epigenetic changes should have been undone! Additionally, any testosterone left should have been kicked out of the ARs by bicalutamide/mifepristone, and degraded via aromatase.
- GnRH antagonists can now be withdrawn (since they're crazy expensive), and replaced with an anti-androgen which prevents the translocation of the ARs into the nucleus (e.g. cyproterone acetate), or even spironolactone + estradiol, as long as T levels remain safely in cis female ranges.
Breast development is directed by estrogen, but fueled by Insulin-like Growth Factor 1. IGF-1 starts high, spikes during puberty and crashes down starting around age 23 in us humans. This is probably why HRT works the earlier, the better! Once IGF-1 crashes, you might be out of luck, depending on your genes.
So clearly, this sucks. But if we just need IGF-1, could we just boost some from the nearest bodybuilder and start doping ourselves?
Sadly, no! One could, but it seems decidedly ill-advised. IGF-1 grows you, beyond healthy adult phase, causing acromegaly (super-sharp jaws and chin and wide mandibles), which is irreversible! If we could rewind IGF-1, we could play ourselves back to early childhood.
...which would be amazing, and I should write about it, but not tonight!
So what we need is targeted IGF-1, growing only the estrogen-sensitive tissues in our skin. This would include widening the hips, no idea on ribcage/other skeletal muscles, but most tittlingly (I had to go there, sorry!) the breasts!
If we want to target IGF-1 only breast tissue, we can link IGF-1 with another peptide, prolactin, which guides Tanner Stage IV breast development, conjugating the peptides together with a simple protein linkage to act like a chain between two barbells. This hybrid prolactin-IGF-1 protein would latch onto prolactin receptors, activating them (which is also crucial in guiding breast development, not just the areola!) Anchored to this prolactin receptor, the IGF-1 ligand would bounce around until it latches onto an IGF-1 receptor, activating it.
So we've activated the IGF-1 receptor, and the prolactin receptor together! Which is good. Both activate signaling pathways, which work in concert to develop and kick the breasts past Tanner Stage V.
The half-life of both IGF-1 and prolactin are very short, on the order of ~15 minutes. Fortunately, we can use that to our advantage! We want to make sure that the prolactin reaches her target and, once there, the IGF-1 should stay where she puts her.
Fortunately, we can use IGF-1 LR3, a modified form of IGF-1 that has a biological half-life of ~24 hours, instead of 15 minutes. This way, IGF-1 has 15 minutes to find its way onto the breasts' prolactin receptors, and then it will be cleaved, leaving IGF-1 LR3 around the cells for the rest of the day activating things!
Next, we want to keep the IGF-1 from activating any other tissues -- only the breasts -- so we can evade the pitfall of acromegaly, and benign brain tumors like prolactinoma! In order to do this, we have to:
1. Keep the IGF-1 end from activating any tissue which doesn't have prolactin.
Fortunately, prolactin has 198 amino acids, while IGF-1 has only 70. So it won't feasibly fit into IGF-1 receptors unless it's bound or cleaved! And by the time it's cleaved, the IGF-1 should mostly be socializing with the mammary cells in the breasts.
2. Keep the prolactin end from crossing the blood-brain barrier.
Fortunately, since prolactin has to be dragged across the BBB. IGF-1 may be enough of an impedance to prevent the prolactin end from hitting the tight junction.
Buuuut, if you have to, you could conjugate the IGF-1 to IGFBP-3, its bulky binding protein. That should keep the assembly from being large enough to cross! Especially if it folds in the prolactin residue either (eh, find out during folding!)
Outline of the Plan
Initially, we proof-of-concept on computers. Use docking software to simulate different prototype proteins, looking at their folded structure and scoping out their binding affinity for the prolactin receptor and IGF-1 receptors.
Using the computer, start with the simplest versions, and go more complex:
1. IGF-1-prolactin linkage by itself... do the proteins hug? Hugs aren't drugs!
2. Prolactin end still binds to prolactin receptor.
3. IGF-1 end still binds to the IGF-1 receptor.
4. Play with different residue chain lengths.
5. Try docking IGF-1-prolactin with IGFBP-3.
Okay, now that that's over, we need to make it!
1. Get DNA sequence + simple prokaryote promoter sequence synthesized by one of those internet sites.
2. PCR to amp DNA up a bit!
3. Make DNA get sticky ends, integrate into bacteria.
4. Culture bacteria.
5. Extract protein, centrifuge, LC/MS chromatography to confirm fraction is pure.
The fraction will be added to PBS or TRIS or whatever, and potentially IGFBP-3 would be mixed in. Then you take the fraction to bacteriostatic water, add preservative, bottle, inject!
Experimental Regimen: Neo-ovaries/testicles through RNA interference with FOXL2 and DMRT1
This is a moon-shot project to reprogram the testes into ovaries, or the ovaries into testes! (Kinda.)
The war between FOXL2 (♀) and SOX9/DMRT1 (♂)
In the SRY signaling cascade, gonads have a sort of "toggle switch." If FOXL2 is active, then SOX9 is suppressed and the gonads become ovaries. If SOX9 is active, then FOXL2 is suppressed an the gonads become ovaries. Remarkably, researchers have reprogrammed the ovaries into testes by blocking FOXL2 in adult mice! Similarly, blocking DMRT1 in adult mice reprograms the testes into "mini-ovaries." Unfortunately, both variants were infertile, but we saw the cells reorganize, "cis" levels of hormones produced etc.[footnote 15][footnote 16] So what if we could block these genes in adult humans?
RNA interference is a technique to silence the transcription of selected genes, by producing an RNA strand complimentary to the mRNA transcript of the selected gene which will be recognized as belonging to an invading virus by the body, and blocked from getting to the ribosome. SNALPs are lipid membranes which contain copies of siRNA. When they hit a cell, they fuse with the cell membrane, disbursing the interfering RNA into the cell.
We could use RNA interference to block either FOXL2 or DMRT1. Several drugs currently in phase III FDA trials use RNAi, which seems to demonstrate that in principle enough of the kinks have been worked out to try on humans. We'd find a region of messenger RNA for FOXL2 or DMRT1 that could be blocked using RNAi, then encase the interfering siRNA in SNALPs and deliver it to the cells, probably by injection or whatever the FDA trials did. We should be able to judge efficacy by trying it in testis/ovary tissue culture.
- Identify interfering siRNA sequence
- Acquire DNA for siRNA
- RNA polymerase to amplify siRNA
- SNALP formation
- Sonication to embed siRNA within SNALP
- Safety checks on siRNA purity
- SNALP preparation protocol
- Protocols used by FDA trials of RNAi
- Previous roadblocks with RNAi
Experimental Regimen: Obliterating the androgen machinery
Ever wonder why you still have dark body hair, after being on estrogen for two years? Maybe some patches of hair, perhaps on your arms, have lightened up, and you still have brown chest hairs? Why do you have to get laser or electrolysis in the first place?
Life of an Androgen Receptor
Why's masculine body hair dark?
Androgen receptors (ARs) chill in the cytosol, outside the nucleus of a cell, feeling single and lonely. Testosterone swims by outside, doing laps until a hexagonal gate in the cell membrane opens, pulling it in down a slippery slide of electromagnetic charge. The testosterone swims in the cytosol for a while, until it activates an AR. Once testosterone, like a key, fits inside the AR's lock, the ARs twist open to expose a foot. Next, a rowboat comes up, grabs ahold of the two ARs' feet and paddles down to the nucleus, where it's shuttled inside. That's where all the cool DNA hangs out. It's in the VIP room, baby!
Next to the genes for facial and male-pattern body hair (HHA6 and HHA7, I think, too lazy to look it up), there's a little palindrome of DNA (AGAACA, upside-down and reversed on the other strand spells the same) called an Androgen Response Element! (ARE.) Each AR has a single arm on it, which latches onto only that palindrome. Behold! With both their arms, they clamp down on the ARE and snap tight. The AR's other head is a handle for RNA polymerase, which kicks off making the gene south of the ARE into a protein. The AR flips a switch, the HHA6 and HHA7 keratin is made, and your hair is black.
(Btw, if you don't have dark body hair, it's because you have different keratins in your DNA. Each hair is a braid of different keratins.))
Okay, so that stops when I go on blockers, right?
Nope! That AR is good and stuck on there. Your blockers just prevent more T from being produced. But those ARs in the nucleus? That machinery already has its T. And it has staying power! Proteins outside the nucleus get scavenged all the time -- busy like outdoor downtown New York, with street sweepers and trash collectors. But inside? You're in the VIP room! They don't come in there! They need a badge, and the ones they let in are selective.
Okay, but surely there's someone to take the trash out inside the nucleus, right?
Well, kinda. Think of the AR machinery as a button that got pressed. Normally, when you press a button inside the nucleus, you want it to stay pressed. Unless you decide to un-press it, because of the little molecular program you got going on there. Think of DNA binding proteins as 1s in the memory bank of the cell. The absence of a protein is a zero. Testosterone just flips the 0 to a 1, and suddenly the cell's function changes! Fucking magic!
But... I want to flip it to zero!
Okay, story time's over now. Down to business. When someone wants to take a hit out on a 1, they need a... professional. Too chicken, I guess, to do it themself? E3 ubiquitin ligase is the best in the business.... discreet, clean and efficient. But it won't work for free... it needs... you know, payment for services rendered.
We gotta pay for our hit on the androgen receptor.
I'm in. Let's do this.
Okay, so here's the plan: we wanna send in a Proteolysis-targeting chimera. Here's how you build it:
Our in is dioxin. Dioxin's the poison they used on Victor Yushchenko. It works by paying off our professional, E3UL, to remove all the nuclear receptors, indiscriminately. As Paracelsus said, every medicine is at some dose a poison. Every poison at a smaller dose is a medicine! No, really! You're skeptical, but hear me out. We tie dioxin to testosterone, linking it together.
E3UL does good work, as long as he has a contract. We have to tie the money to a particular hit, not just "kill some random guy."
We'll kill all the ARs by making a contract with E3UL, paying it to kill only ARs.
Let's take dioxin and testosterone, and weld them together! Dioxin activates the Dioxin receptor, which is a brand of E3UL. Testosterone loves cozying up to androgen receptors. That'll let us shoot the AR in the head. If we want to shoot AR in the stomach, we can stick something that looks like an AGAACA on it. We can't use straight AGAACA though, because the DNA cops outside the nucleus rip all the DNA they see to shreds. Fucking DNA cops, man. ADNACAB!!! Let's assume we're going with the head-shot for now.
So, we get someone to synthesize our welded T-dioxin kill contract together. It's easy to stick things onto T, so it shouldn't cost much, and you can get batches of this stuff from labs around the world, shipped to your house's door. We don't need much... nowhere near enough to be dangerous like dioxin is. Near-homeopathic amounts of the stuff.
Then all you have to do is inject it, just like you'd do a shot of estrogen! With more careful measuring and your finger on the dial to 911, of course.
...Maybe I should volunteer myself, since I have good health insurance? :)
- "These results highlight the positive effect of RLX on lipids and suggest for the first time that RLX promotes the shift from android to gynoid fat distribution and prevents the uptrend of abdominal adiposity and body weight compared with untreated women."
- "Testosterone concentrations, although elevated, remain within the normal range, possibly because the increased concentration of oestradiol limits increases in LH secretion."
- Estradiol did not affect the intracellular or extracellular IGFBP-1 concentration, whereas the intracellular SHBG concentration increased significantly in response to 0.5-2.5 microM of E2.
- The free hormone hypothesis states that the biological activity of a given hormone is affected by its unbound (free) rather than protein-bound concentration in the plasma.
- In conclusion, self-administration of testosterone and anabolic steroids soon led to impairment of testicular endocrine function which was characterized by low concentrations of testosterone precursors, high ratios of testosterone to its precursor steroids and low SHBG concentrations
- As SHBG is not known to alter the production or metabolism of insulin, whereas insulin has been shown in vitro to decrease the synthesis of SHBG, it seems a reasonable conclusion that the predictable inverse relationship between serum insulin and SHBG indicates that insulin controls SHBG synthesis in vivo.
- We conclude that insulin and PRL inhibit SHBG production and confirm that T4, T, and E2 stimulate SHBG production in vitro. These findings suggest that insulin and PRL may be important factors in the regulation of SHBG production in vivo.
- The insulin:glucose ratio was significantly increased at both doses in the A. officinalis-treated rats. Both qualitative and quantitative improvements in β-cell function were found in the islets of the A. officinalis-treated rats.
- These findings indicate that antihyperglycaemic activity of A. racemosus is partly mediated by inhibition of carbohydrate digestion and absorption, together with enhancement of insulin secretion and action in the peripheral tissue.
- The oral administration of the research drug led to more than three-fold increase in the prolactin hormone level of the subjects in the research group as compared to the control group.
- Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG.
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- Participants randomly assigned to GTE with baseline insulin ≥10 μIU/mL (n = 23) had a decrease in fasting serum insulin from baseline to month 12 (-1.43 ± 0.59 μIU/mL), whereas those randomly assigned to placebo with baseline insulin ≥10 μIU/mL (n = 19) had an increase in insulin over 12 mo (0.55 ± 0.64 μIU/mL, P < 0.01).
- "Within-group comparison also revealed that the GTE group had significant reductions in waist circumference (WC), HOMA-IR index, and insulin level, and a significant increase in the level of ghrelin."
- Here we show that sexual fate is also surprisingly labile in the testis: loss of the DMRT1 transcription factor3 in mouse Sertoli cells, even in adults, activates Foxl2 and reprograms Sertoli cells into granulosa cells. In this environment, theca cells form, oestrogen is produced and germ cells appear feminized.
- Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis.
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