Talk:Experimental feminizing HRT

From Mad Gender Science!

Highly-Experimental Research

PLEASE DON'T TRY THIS AT HOME! This is highly experimental and incredibly dangerous stuff.
Though if you are a professional looking for some new research idea, then by all means you're welcome to use our hypothesis in a study. ❤

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.
Therefore this is not medical advice, and any information you find here should be verified through professional sources before regarding it as fact. ❤

Experimental Regimen: Potion for epigenetic AR downregulation and ERa upregulation

List of ingredients that may trigger and potentiate the desired epigenetic effects.
Ingredient Sources Effects Risks Roadblocks
Curcumin Tumeric * HDAC inhibitor, interfering with AR transcription
* Synergizes with EGCG to downregulate AR
* Traditionally used to reverse hirsutism when used topically
* Although turmeric can cause gastronomic disturbances orally it is not generally considered toxic even at high doses.
* When taken topically it may stain the skin yellow due to it's intensely pigmented nature.
* Has low bio-availability
* Is insoluble in water
* Has a short half-life in the body due to speedy metabolization.
EGCG Green tea * Downregulates AR [1]
* Upregulates ERa especially when used in conjunction with HDAC inhibitors (like Curcumin)[2]
* Shown to reverse androgenic alopecia in mice when taken topically [3]
* Oral consumption of high doses potent extracts is known to cause gastronomic disturbances and possibly liver damage, but is generally shown to be safe in reasonable doses like traditional tea consumption.
* Is known to cause the body to expel fats undigested, and inhibit fat cell development.
* When taken in green tea may include caffeine which can accelerate 17b-estradiol metabolism.
* Bio-availability is determined by a wide variety of factors that must be adhered to to maximize potency, otherwise the effects can be unreliable.[4]
Piperine Black pepper * Increases bioavailability through a variety of pathways * Can potentially have dangerous contraindications with many medications by potentiating them beyond safe levels.
Quercetin Capers, Dill... Inhibits an enzyme responsible for the metabolization of curcumin
Omega-3 fatty acids Fish oil, Flax seed oil, Hemp seed oil, Avocados... Potentiates EGCG
Vitamin C Citrus fruit, especially oranges Potentiates EGCG
Albumins Egg whites Potentiates EGCG

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,[5][footnote 1] [6][footnote 2]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. [7][footnote 3].

The idea

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,[8][footnote 4][9][footnote 5] so it follows that perhaps free estrogen levels can be raised by increasing insulin and prolactin through some artificial means.

The experiment

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,[10][footnote 6][11][footnote 7] and wild asparagus in particular is also known to increase prolactin secretion,[12][footnote 8] 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:

  1. Avoid consuming dietary asparagus prior to experiment to establish a baseline.
  2. Measure free vs. bound estrogen for later comparison.
  3. Create a standardized A. racemosus extract or obtain a drug with similar effect.
  4. Begin regularly consuming the A. racemosus extract for a predetermined time.
  5. Re-test free vs. bound estrogen to compare to the baseline.
  • Hypothetically free estrogen levels would increase, while bound estrogen decreases.

Alternative experiment

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:

  1. Avoid consuming dietary asparagus prior to experiment to establish a baseline.
  2. Measure free vs. bound estrogen, and prolactin for later comparison.
  3. Create a standardized A. officianalis extract or obtain a drug with similar effect.
  4. Begin regularly consuming the A. officianalis extract for a predetermined time.
  5. 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. [13][footnote 9]
  • Some substances have been shown to decrease insulin levels such as cinnamon[14][footnote 10] and green tea extract,[15][footnote 11][16][footnote 12] 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.[17]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:

  1. Measure PSA levels as a baseline measurement of the expression of androgen-dependent genes, as well as free/bound T levels.
  2. 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.
  3. 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.
  4. 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.
  5. Measure PSA levels again. PSA should be near nil before moving to the next step.
  6. 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.
  7. 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.

Add estradiol or progesterone to taste at any point in this therapy, since those don't interact.

Experimental Regimen: Fixing breast development with prolactin linked with IGF-1

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.

High levels of prolactin can cause prolactinemia a benign growth and milk production, and prolactinoma, a brain cancer. So it's important we don't cross 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.

Making it

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.[18][footnote 13][19][footnote 14][20] So what if we could block these genes in adult humans?

RNA Interference

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.

Synthesis Steps

  • 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

Research Wishlist

  • 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? :)


  1. 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.
  2. 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.
  3. 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
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Ingestion of 3 g cinnamon reduced postprandial serum insulin and increased GLP-1 concentrations without significantly affecting blood glucose, GIP, the ghrelin concentration, satiety, or GER in healthy subjects.
  11. 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).
  12. "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."
  13. 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.
  14. 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.


  1. | Tea polyphenols down-regulate the expression of the androgen receptor in LNCaP prostate cancer cells
  2. | Synergistic epigenetic reactivation of estrogen receptor-α (ERα) by combined green tea polyphenol and histone deacetylase inhibitor in ERα-negative breast cancer cells
  3. | Effects of topical application of EGCG on testosterone-induced hair loss in a mouse model.
  4. | Epigallocatechin-3-gallate (EGCG) for Clinical Trials: More Pitfalls than Promises?
  5. | Estradiol increases the production of sex hormone-binding globulin but not insulin-like growth factor binding protein-1 in cultured human hepatoma cells.
  6. | The free hormone hypothesis: a physiologically based mathematical model.
  7. | Response of serum testosterone and its precursor steroids, SHBG and CBG to anabolic steroid and testosterone self-administration in man.
  8. | The relationship between serum levels of insulin and sex hormone-binding globulin in men: the effect of weight loss.
  9. | Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin.
  10. | Asparagus officinalis extract controls blood glucose by improving insulin secretion and β-cell function in streptozotocin-induced type 2 diabetic rats.
  11. | Antihyperglycaemic activity of Asparagus racemosus roots is partly mediated by inhibition of carbohydrate digestion and absorption, and enhancement of cellular insulin action.
  12. | A Double-Blind Randomized Clinical Trial for Evaluation of Galactogogue Activity of Asparagus racemosus Willd.
  13. | Role of endocytosis in cellular uptake of sex steroids.
  14. | Effects of 1 and 3 g cinnamon on gastric emptying, satiety, and postprandial blood glucose, insulin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and ghrelin concentrations in healthy subjects.
  15. | Green Tea Extract and Catechol-O-Methyltransferase Genotype Modify Fasting Serum Insulin and Plasma Adiponectin Concentrations in a Randomized Controlled Trial of Overweight and Obese Postmenopausal Women.
  16. | Does supplementation with green tea extract improve insulin resistance in obese type 2 diabetics? A randomized, double-blind, and placebo-controlled clinical trial.
  17. The Androgen Receptor Recruits Nuclear Receptor CoRepressor (N-CoR) in the Presence of Mifepristone via Its N and C Termini Revealing a Novel Molecular Mechanism for Androgen Receptor Antagonists
  18. | DMRT1 prevents female reprogramming in the postnatal mammalian testis
  19. | Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.
  20. | Sexual Cell-Fate Reprogramming in the Ovary by DMRT1