📄 Archived: 2025-08-31 14:21:40 UTC
🔗 Source: https://papers.lgbt/papers/roadmap

### /roadmap

# the timeline for MTF HRT and non HRT transsexual treatment for those past puberty

by emily/endocrinemoder/adenine

## abstract

in this paper, i go through a summary of the optimal times to take certain medications to achieve the best possible transition in my eyes. this is a review backed by my own papers and evidence for all medications listed (except for domperidone, in which the paper is in progress). in this i talk about almost every single possible side effect of these medications, but it’s very very likely that NONE of them happen to you, i just feel obligated to talk about them to cover all bases. i also talk about getting blood tests, i would like the reader to keep in mind that these are recommended IF POSSIBLE, but not required, as many would not be able to afford or access these.

mtf hrt nhtc bicalutamide estradiol pioglitazone domperidone progesterone igf-1 mk-677 roadmap

# the timeline for MTF HRT and non HRT transsexual treatment for those past puberty

## Summary Timeline of Transition Phases

Timeline | Key Actions & Medications | Expected Effects & Notes
--- | --- | ---
Pre-Start (Month 0) | Preparation: Baseline labs IF POSSIBLE (CBC, CMP, LFTs, electrolytes, lipids, HbA1c, prolactin, etc). Consider sperm banking before HRT (if future fertility is desired). Begin Estradiol Enanthate (E): e.g. 6 mg intramuscular or subcutaneous weekly (titrate as needed). OR Add Bicalutamide (B): 50 mg/day as anti-androgen and move estradiol dose to 4mg | Notes: Estradiol enanthate is a long-acting estrogen; weekly injections maintain female-range estradiol levels and suppress testosterone over time. Bicalutamide blocks androgen receptors (preventing testosterone effects) but does not itself lower testosterone production, so it is started early to block male hormones while estradiol levels build. Expected early changes (1–3 mo): decreased libido and spontaneous erections, softer skin, some emotional changes. Possible mild breast tingling as buds begin (typically by ~3–6 months).
Early Transition, Months 1–3 | Dose Adjustment: At ~4–6 weeks, evaluate estradiol levels; increase estradiol enanthate dose if needed to reach target female estradiol (100–200 pg/mL mid-cycle equivalent). Maintain bicalutamide 50 mg daily (or consider 25 mg twice daily or 25 mg 2–3×/week in those with risk factors, to reduce hepatic load). Monitoring: Check serum estradiol and total testosterone at 3 months (testosterone should be dropping towards female range <50 ng/dL). | Effects by 3 months: noticeable skin softening and decreased oil/acne, reduced muscle tone, and body fat may start shifting from abdomen to hips (very gradually). Breast buds (Tanner stage II) often form by 3–6 months. Mood swings or hot flashes can occur as hormones adjust. Note: Bicalutamide’s androgen blockade may cause a mild rise in estradiol via testosterone aromatization, potentially aiding feminization but necessitating liver monitoring (rare idiosyncratic hepatotoxicity is reported). Avoid hepatotoxins (excess alcohol, acetaminophen) during use.
Mid Transition, Months 3–6 | Progesterone Introduction (≈Month 6): If breast development has begun (buds present), introduce micronized progesterone 100 mg nightly taken rectally, increasing to 200 mg nightly as tolerated. This can be taken continuously or cyclically (e.g. 2 weeks on, 2 weeks off) – many start around 6–12 months to potentially enhance breast maturation (alveolar/lobular growth). GH Boost (Month 3–6): In individuals in or past theirmid-20s, and/or in those with minimal breast response, consider a 6-month course of MK-677 (Ibutamoren) ~10–25 mg at bedtime. MK-677 is an oral growth hormone secretagogue that raises IGF-1 (insulin-like growth factor 1) levels, mimicking the pubertal GH surge to synergize with estradiol. (for more info read my paper about IGF-1!!!!) Monitoring: Re-check estradiol, testosterone, and electrolytes at 6 months; If MK-677 is used, check fasting glucose or HbA1c at ~3 months (due to risk of insulin resistance) and IGF-1 levels if available. | Effects by 6 months: noticeable breast growth (often Tanner III, chest tissue rounding out), with progesterone potentially contributing to fuller breast shape (anecdotal). Further body feminization: hips and thighs gain fat, face looks slightly softer. Muscle mass and strength decline, and facial/body hair growth may slow (though not fully stop without other interventions). Libido remains low. Notes: Progesterone may improve areolar development and mood/libido for some, though evidence is mixed. It can cause sedation (take at night) and sometimes mild depression – monitor individual response. MK-677 use should be time-limited; it can increase appetite, water retention, and blood sugar. Watch for side effects like edema (ankle/hand swelling), joint pain, or signs of acromegaly (jaw/foot size changes) – these are signs to discontinue MK-677 to avoid “masculinizing” overgrowth.
Late Transition, Months 6–12 | Anti-Androgen Taper (~9–12 months): By 9–12 months, estradiol therapy often suppresses testosterone near female levels. If so, consider tapering off bicalutamide after 6–12 months of use to reduce long-term liver risk. (If an orchiectomy is performed, bicalutamide can be stopped immediately post-op.) If an alternative anti-androgen (e.g. cyproterone acetate) is used instead of bicalutamide, continue as needed with monitoring. Body Fat Redistribution (~12 months): Once bicalutamide is discontinued (or at least past month 12), an optional trial of Pioglitazone 15–30 mg daily for ~3–6 months can be introduced to enhance subcutaneous fat deposition. Pioglitazone (a PPAR-γ agonist) has been shown to shift fat from visceral (abdominal) stores to subcutaneous regions (buttocks/thighs), promoting a more “pear-shaped” feminine fat distribution. Monitoring: Check estradiol and testosterone at 12 months; ensure T remains low after anti-androgen removal. During pioglitazone use, monitor weight and signs of fluid retention (edema) at least monthly; check liver enzymes every ~3 months (pioglitazone’s risk of serious hepatotoxicity is low, but it’s prudent to monitor, especially since it must not be combined with bicalutamide due to combined liver risk). Also track fasting glucose (pioglitazone improves insulin sensitivity and can cause weight gain). If progesterone was started at 6 months, continue it (some trans women will experiment with cycling it monthly at this stage). If MK-677 was used since the 6 month mark, plan to stop by 12 months to prevent long-term risks (one could alternatively pause after 6 months and possibly resume a second 3–6 month cycle in the second year if needed). | Effects by 12 months: significant breast development (often 1–2 cup sizes increase from baseline; many will be Tanner IV). Maximum breast size is usually reached by 2–3 years on HRT, but the first year yields substantial growth. Body fat redistribution becomes more evident – a narrowing waist and fuller hips/gluteal region may be noticeable, especially if pioglitazone is used to amplify this (case reports show waist circumference drops and hip/thigh gains after ~1 year on TZDs). Skin is markedly softer; muscle mass has reduced further (strength/endurance may decline accordingly). Facial hair is usually finer but not gone – many will still require laser or electrolysis for complete removal. Note: Pioglitazone’s feminizing effect is primarily on fat distribution; it will cause overall fat gain (which may increase breast fat as well). It is generally used short-term because of potential risks (water retention, weight gain, and a possible link to increased risk of heart failure and, with very long use, possibly bladder cancer). Weigh the benefits (improved hip/thigh curves, modest breast fat increase) against these risks. Typically a 3–6 month course at 15 mg/day (low dose) is tried in otherwise healthy individuals. Discontinue earlier if significant edema, shortness of breath, or rapid weight gain occur (signs of fluid overload).
Advanced Transition, Months 12–24 | Breast Enhancement & Lactation (~18 months): After 1–2 years, breast growth from estradiol tends to plateau. For those seeking additional breast fullness or the ability to lactate, consider introducing Domperidone around 18–24 months. Domperidone 10 mg three times daily can be started and gradually increased to 20 mg four times daily as tolerated. It is a peripheral dopamine antagonist that raises prolactin levels, thereby promoting milk gland development and lactation. For maximal effect, combine domperidone with continued high-dose estradiol and progesterone (mimicking late pregnancy hormonal milieu) and regular breast stimulation (e.g. using a breast pump ~6–8× daily). Long-Term HRT: Estradiol enanthate injections continue on a maintenance schedule (typically 5–10 mg weekly or biweekly, adjusted to keep estradiol in a mid-female puberty range). Progesterone may be continued nightly if it seems beneficial for breast shape or mood, but some may experiment with taking breaks or cycling. Anti-androgen therapy should be discontinued by now in most cases – either due to orchiectomy or because estradiol alone is sufficient for T suppression. Pioglitazone, if used, should be stopped after the short course (cumulative use >2 years is discouraged due to rising long-term risks). MK-677, if used in the first year, is not typically repeated in the second year unless under medical supervision; any extended use requires close monitoring for adverse effects. Monitoring: At 18–24 months, check prolactin level (especially if on domperidone, to gauge response and ensure levels aren’t excessively high which could signal risk of pituitary issues). Obtain an ECG before and shortly after reaching max domperidone dose – do not start domperidone if baseline QT interval is prolonged (>470 ms) and discontinue if any significant QT prolongation or arrhythmia symptoms occur. Continue periodic labs: estradiol and testosterone (if testes intact) every 6–12 months, metabolic panel annually, and consider a DEXA bone density scan by ~2 years if there were periods of low hormones or risk factors for osteoporosis. | Effects by 2 years: Feminization is near maximal for many attributes. Breast development is usually at its apex by 2 years (though minor increases in volume can occur up to 5 years); adding domperidone + pumping can induce actual lactation and sometimes increase breast volume by adding glandular tissue and milk fat. Note: Trans lactation case studies show success with estradiol, progesterone, and domperidone – one patient was able to produce sufficient milk to exclusively feed an infant. Even without pregnancy, this regimen can significantly enlarge the breasts due to milk production, though results vary. Body fat distribution should now be distinctly feminine: relatively more fat on hips, thighs, buttocks, and breasts, and less visceral abdominal fat. The overall figure is typically softer and curvier. Skin and hair: skin thickness diminishes and collagen changes (less coarse), and body hair is less dense. Facial hair still requires external removal in most cases. Libido and spontaneous erections are very low or absent (many trans women report little erectile function by this point). Fertility is effectively very low (do not rely on HRT as contraception, but the likelihood of sperm production is minimal after years of high-dose estrogen). Mental/Emotional: Many individuals report improved gender dysphoria and psychological well-being after 1–2 years on a comprehensive regimen. Continue mental health support as needed.
Beyond 2 Years, Maintenance | Ongoing Care: Continue estradiol injections for life to maintain female secondary characteristics and bone health (typical maintenance dosing might be adjusted to keep estradiol in mid-normal female range; some reduce dose slightly after maximum changes are achieved, though there is no requirement to lower dose if well-tolerated). Progesterone use long-term is optional – some continue it for potential benefits in mood or breast morphology, while others discontinue after a couple of years if no clear benefit or if side effects (there is no definitive research that long-term progesterone is required in trans HRT, so it’s individualized). Adjuncts: By this stage, all temporary adjunct medications should have been tapered off: bicalutamide (no longer needed; long-term use is not advised), pioglitazone (course completed), MK-677 (discontinued), domperidone (stopped once lactation goals are met, or by ~6–12 months of use to minimize cardiac risk). General Health: Follow standard preventive care guidelines adopted for transsexual female patients: for example, begin breast cancer screening (mammograms) ~5–10 years after starting estrogen or by age 50 (whichever is later), since long-term estrogen exposure might confer some breast cancer risk (though data in trans women are still emerging). Continue prostate screening as recommended for natal males (trans women retain a prostate unless surgically removed). Ensure bone density maintenance – if estradiol is ever interrupted (e.g. in post-op recovery or etc.), supplement with calcium/Vitamin D and monitor bone health. Monitoring: Once hormone levels are stable, annual labs (CMP, estradiol, testosterone) are typically sufficient. If on progesterone, there is no specific lab to monitor (clinical observation of mood and physical effects guides its use). If on long-term domperidone (generally discouraged), periodic ECGs are needed. | Long-term outcomes: With diligent care, adult transitioners can maintain feminization lifelong. Many effects (breast growth, fat distribution, decreased body hair) are permanent or semi-permanent after years on HRT, though some regression can occur if hormones are stopped (e.g. breast tissue may shrink a bit, muscle mass can increase again with testosterone, etc., but changes like breast development do not fully reverse – residual breast tissue remains). Staying on a stable estradiol dose post-transition helps preserve bone density and female secondary characteristics. Cost considerations: over the long term, estradiol injections are relatively affordable (often tens of dollars per vial that lasts months), especially compared to some newer therapies. Most adjunct meds were short-term investments. The overall regimen can be managed via informed consent clinics or endocrinologists experienced in transgender care. Regular follow-ups ensure that the therapy remains safe and effective as the individual ages.

Table: Timeline overview of an estradiol-enanthate–based MTF transition protocol, with phased interventions, expected effects, and monitoring. (E = Estradiol, B = Bicalutamide)

##

## Phase-by-Phase Protocol Details and Rationale

### Phase 0 – Baseline Preparation & Initiation (Month 0)

- Baseline Workup & Precautions: Before starting, baseline laboratory tests are ideal. This includes a complete blood count (CBC), comprehensive metabolic panel (CMP – especially liver enzymes, since multiple HRT drugs affect the liver), kidney function, lipid profile, HbA1c (for glucose metabolism), and baseline hormone levels (testosterone, estradiol, prolactin). Discuss sperm banking prior to starting HRT, as estrogen can reduce fertility significantly (often to near-zero after several months). With preparation complete, the feminizing regimen is initiated:
- Estradiol Enanthate (Monotherapy Base): Start injectable estradiol enanthate as the primary estrogen. A typical starting dose for adult transsexual female individuals might be around 5 mg intramuscular (IM) weekly, or 10 mg IM every 2 weeks, though many practitioners now favor weekly or even twice-weekly injections for more consistent levels, as inconsistency can cause mood swings. (Estradiol cypionate is a similar alternative, and is another long-ester estradiol – kinetics are comparable, with a ~5–8 day half-life.) Weekly injection is recommended for smoother hormone levels. The dose can be adjusted based on serum levels and clinical response: the goal is to achieve mid-cycle premenopausal female estradiol levels (roughly 100–200 pg/mL). Starting at 5 mg/week and later increasing to 7.5 mg or 10 mg/week if needed is a common strategy. Some clinicians will start slightly lower (e.g. 2.5 mg weekly, fuck WPATH) in older patients or those with risk factors, then titrate up. However, because injectable estradiol bypasses first-pass liver metabolism (unlike oral estrogen).
- Early Anti-Androgen – Bicalutamide: To accelerate feminization and counteract testosterone in the early phase, 50 mg of bicalutamide daily is added at start (month 0). Bicalutamide is a non-steroidal anti-androgen originally developed for prostate cancer; it blocks the androgen receptor, thereby preventing testosterone and DHT from activating male characteristics. It does not reduce testosterone levels (in fact, the blockade can cause a reflex rise in testosterone, which then aromatizes into more estrogen). The main effect is blocking T/DHT action on skin, hair, and breast tissue. Bicalutamide is used off-label in trans women (common anti-androgens in some regions are spironolactone or cyproterone acetate – but bicalutamide has been explored as an alternative, especially since the others have major downsides).
- Cost and Access (Initiation): Estradiol enanthate injections are prescribed outside of the United States or DIY-able but generally not expensive. In the U.S., a 5 mL vial of 20 mg/mL estradiol valerate (a similar injectable estradiol) might cost ~$50 with a coupon, lasting several months, and similar prices can be achieved through an online DIY pharmacy. Estradiol enanthate specifically may be sourced through compounding pharmacies or international pharmacies if not locally available; costs are comparable (often $10–30 per month of treatment).
  For grey market access, you can find it on diyhrt.market or contact me (@endocrinemoder on Twitter!!) for help.

### Phase 1 – Early Changes & Titration (Months 1–6)

During the first 3–6 months, the focus is on reaching therapeutic hormone levels and observing the initial body changes. It is also a critical period for monitoring safety and adjusting doses.

- Hormone Level Titration: After about 4–8 weeks on estradiol enanthate, a trough estradiol level (just before the next injection) can be checked to ensure it’s in the desired range. If levels are low (or if clinical feminization is minimal by 2–3 months), the estradiol dose may be increased (for instance from 5 mg to 7.5 mg weekly, or shortening the interval from biweekly to weekly injections). By 3 months, testosterone should show a substantial drop from baseline – often into the low male or female range if estrogen is dosed adequately and bicalutamide is blocking the androgen receptor (which helps nullify any remaining T). If testosterone is high (e.g. >100 ng/dL), one might confirm injection technique and adherence; some patients metabolize injections faster and might benefit from more frequent dosing (e.g. split weekly dose into twice weekly). In rare cases of very high T, an additional suppression method (like GnRH agonist) could be considered, but typically with consistent weekly injections and an anti-androgen OR monotherapy, levels come down. Keep in mind bicalutamide’s mechanism means the absolute T number is less important for feminization (since receptors are blocked), but for long-term metabolic health and complete male suppression, we still aim to reduce T over time via estrogen’s HPG-axis suppression.
- Possible changes:
  - Physical Changes Expectation: It’s helpful to outline to the patient what changes typically occur in this early window. Between 1–3 months, breast tenderness is common as the breast buds start forming behind the nipples. By 3–6 months, many will notice small mounds or buds (Tanner stage II–III). The chest can be slightly painful to touch – a good sign that breast tissue is growing. Skin often becomes softer and less oily within 1–2 months (trans women frequently report a change in how their skin feels by 3 months). This is due to sebaceous glands becoming less active with lower androgen effect; acne usually improves.
  - Sexual changes: libido typically decreases noticeably by ~1–3 months, and spontaneous or morning erections become less frequent. Erectile function may require more stimulation and some find erections are softer – this can be an emotional relief if the patient experiences bottom dysphoria, but discuss it ahead of time so the patient isn’t caught off guard. Some report that orgasms change in quality (more “full-body” and less genital-focused) with time on estrogen.
  - Emotional changes: mood shifts can happen as hormone levels fluctuate, but many trans women also experience a positive shift in mood and reduced gender dysphoria early on. Tearfulness or feeling emotions more easily is commonly noted anecdotally.
- Monitoring & Follow-up (3 months): At roughly the 3-month mark, labs should be rechecked: estradiol, testosterone, and critical safety labs (electrolytes and kidney function if on spironolactone – not applicable for bicalutamide; liver enzymes for bicalutamide; prolactin if the patient has dose-dependent nipple discharge or significant new headaches, otherwise prolactin can be checked less frequently unless domperidone is introduced later). Often, if no issues by 3–6 months, the risk of later hepatic events is low – but periodic checks (say, at 6 and 12 months) are still wise. EXTREMELY RARE but I should still say it, inquire about any signs of liver trouble: unexplained nausea, fatigue, dark urine, or yellowing of eyes/skin should prompt immediate lab checks.
- Anti-Androgen Effects: With bicalutamide on board, by 3–6 months many androgen-driven processes slow down. Body hair growth rate may decelerate (it will still grow, but perhaps finer and a bit sparser). Some trans women on bicalutamide report reduced face/body hair after several months, owing to the blocking of DHT on hair follicles. However, significant hair reduction often requires additional therapies (electrolysis/laser or 5α-reductase inhibitors like finasteride for scalp hair) – bicalutamide isn’t a magic bullet for hair, but it does help prevent further masculine hair changes. Scalp hair: if there was male-pattern baldness progressing, blocking DHT with bicalutamide (and/or finasteride) plus estrogen’s lower T can slow or halt hair loss. Some even see minor regrowth of thin vellus hairs on the scalp. The earlier in life HRT is started, the better for hair preservation.
- Introducing Progesterone (around Month 6): There is ongoing debate about the role of progesterone in transsexual female HRT. While not all providers include it, many community members and some clinicians believe micronized progesterone can enhance breast development (specifically aiding development of lobules and alveoli for a fuller breast), improve nipple prominence, and even help with libido and mood in some individuals. There is no definitive study proving these benefits, but importantly, there is no evidence of harm from adding bioidentical progesterone. Therefore, by ~6 months, once estrogen has initiated breast budding, a prudent approach is to add oral micronized progesterone (Prometrium or equivalent). A typical regimen is 100 mg at bedtime for the first few weeks (it’s sedating, which can actually help with sleep), then increase to 200 mg at bedtime if tolerated. Some will use it continuously (daily), while others mimic a menstrual cycle by taking it 2–3 weeks on, 1 week off per month – there’s no consensus on which is superior in care. Anecdotally, cyclic progesterone may better imitate the ebb and flow that cis women have (potentially benefiting breast tissue cycling), whereas continuous progesterone avoids any hormonal fluctuation that could affect mood. The patient’s preference and reaction can guide the schedule. For example, if continuous use causes moodiness, switching to cyclic (so they get a “progesterone-free” week) might help. Common side effects of progesterone include sedation, dizziness, or “foggy” feeling (often improves after a few weeks) and sometimes increased appetite. Some transsexual women report depressive feelings or irritability on progesterone; if this occurs and doesn’t resolve, discontinuing it is reasonable. Overall, adding progesterone at 6–12 months is a reasonable option to support breast development, especially if breast growth seems to be stalling or if the patient desires it.
  Mechanistic note: Estrogen is the primary driver of ductal growth in the breasts, while progesterone is important for lobulo-alveolar development (the glands that would produce milk) – in puberty, progesterone levels rise after the first year or two of estrogen exposure (with ovulatory cycles). By adding progesterone around month 6, we attempt to replicate that sequence. There is theoretical concern that too-early progesterone might androgenize (since some synthetic progestins can bind androgen receptors), but bioidentical progesterone at typical doses has minimal androgenic activity. In fact, some research suggests a possible anti-androgen effect centrally by suppressing gonadotropins, though in the presence of high exogenous estradiol, that may not matter much. Bottom line: It’s safe to try, and many patients subjectively endorse its benefits (from breast shape to improved sleep quality).
  Cost: Micronized progesterone is generic; in the U.S. a month of 100 mg nightly is ~$15–20, and 200 mg nightly ~$30–40 (if not covered). International prices vary but are generally moderate (it’s a common medication, often sold as 100 mg capsules).
- Considering Growth Hormone/IGF-1 Augmentation: By the 4–6 month mark, one can assess if breast growth is robust or underwhelming. Some older transitioners (or even young ones who just aren’t seeing much breast development) might have blunted response because growth factors that aid breast growth decline with age. In cis-girls’ puberty, growth hormone (GH) and IGF-1 levels surge and play a permissive role in breast development – IGF-1 is required for estrogen to fully exert breast tissue proliferation. In an adult starting HRT, especially if they are, say, 30s or 40s, their baseline GH/IGF-1 may be lower than that of a 13-year-old girl, possibly limiting breast growth. Therefore, an experimental adjunct is to raise IGF-1 levels during the active breast growth phase of HRT (roughly months 3–18).
- AN accessible approach is using MK-677 (Ibutamoren) – an oral GH secretagogue that stimulates the pituitary to release more growth hormone, thereby increasing IGF-1. MK-677 is not FDA-approved, but it has been studied: a 12-month trial in older adults showed it can significantly raise IGF-1 and increase lean mass. For our purposes, the goal is to mimic teenage GH peak. If used, introduce MK-677 around month 6 (once the body is accustomed to estrogen and some breast bud development has begun). A low dose (10 mg at night) can be used initially, because MK-677 often causes sleepiness and increased appetite; it can be titrated up to 20–25 mg nightly. Most commonly, a dose of 25 mg/night is used in studies to boost IGF-1. This typically raises IGF-1 by ~40% or more. I recommend a short-term course (e.g. 6 months) of MK-677, from month 6 to 12, to potentially enhance breast (and hip) development. Benefits could include a bit of extra breast tissue growth (via IGF-1’s synergy with estradiol in developing terminal end buds in the breast) and possibly softer skin or slight muscle gain (GH has anabolic effects, but in the context of estrogen and no T, you won’t gain male muscle – you might instead gain lean female body composition and some subcutaneous fat).
- Risks of MK-677 (READ THIS): MK-677’s side effect profile mirrors that of elevated GH: increased appetite (almost universally – it can cause significant hunger, which may lead to weight gain in fat and muscle), water retention/edema (some users get swollen ankles or mild carpal tunnel syndrome from soft tissue swelling), and insulin resistance (GH counteracts insulin, so blood sugar can rise – watch for thirst or fatigue). Long-term or excessive GH can cause acromegaly – abnormal bone and organ growth (jaw, hands, feet enlargement), which is irreversible and undesirable, especially in a transsexual female person (acromegaly changes can masculinize appearance). The doses/duration proposed here are much lower than acromegaly-inducing levels, but one should still be cautious. If any signs of acromegaly or ill effects appear, stop MK-677 immediately.
- IGF-1 can promote tumor growth – anyone with a history of cancer or uncontrolled proliferative conditions should avoid GH/IGF augmentation. Due to these risks, MK-677 should be taken only under guidance and with monitoring. It’s not required, but if you have the money and time, consider checking IGF-1 levels at baseline and on treatment to ensure they aren’t skyrocketing beyond the normal range for puberty. It’s also wise to limit the course to 6–12 months max. Many will choose to do 6 months on, then stop – by that time, most breast growth potential from IGF-1 is realized, and continuing further could shift risk > reward (e.g. diabetes risk).
- Access Note: Use a white market peptide place like Simple Peptide or another, MK-677 is what I recommend.
- Summary: By the end of Phase 1 (around 6 months in), the regimen likely consists of estradiol enanthate injections (possibly at a higher dose than initial if titrated), continuing bicalutamide (or no bica for monotherapy), added micronized progesterone nightly, and possibly MK-677 if the patient opted for that route. Feminization is well underway, and we prepare to move into Phase 2 where we reassess the anti-androgen need and introduce measures for body contouring.

### Phase 2 – Maximizing Feminization, Anti-Androgen Transition, Body Fat Redistribution (6–12 months)

Around the 6 to 12-month mark, several changes to the regimen are considered. By now, estradiol’s full HPG suppression effect is approaching. Testosterone production should be significantly lowered due to estradiol’s negative feedback on the pituitary (high estradiol -> low LH/FSH -> testes make less testosterone).

- IF USING BICALUTAMIDE, Tapering/Discontinuing Bicalutamide: Assuming the patient has no contraindication to continuing (normal LFTs and no adverse effects), you’ll have used bicalutamide for about a year as a bridging agent. At this point (somewhere between months 9 and 12), check a hormone panel: if testosterone is already well-suppressed (e.g. <50 ng/dL), you can safely taper off the bicalutamide. A taper can be simply reducing to 25 mg/day for 2–4 weeks, then 25 mg every other day for a couple weeks, then stop. (There is no known “rebound” effect from stopping bicalutamide, especially if estradiol is sufficient – the taper is more to be cautious and observe if any androgenic symptoms return, which is unlikely in presence of high E.) If testosterone is still a bit above target (say 100–200 ng/dL), one could choose to continue bicalutamide a bit longer or switch to an alternative like spironolactone and then stop bicalutamide. However, in most cases, estradiol monotherapy after a year can maintain low T. Notably, if the patient undergoes orchiectomy (surgical removal of testes) at any point, all anti-androgens can be stopped immediately after surgery, and the HRT regimen simplifies to estradiol ± progesterone only. Some trans women elect orchiectomy once they are sure they don’t want biological children, as it eliminates the need for T-blockers and can allow a lower dose of estrogen to maintain levels. That decision is personal and beyond the scope of this med-focused protocol, but it is a consideration around 1–2 years in. In absence of orchiectomy, we rely on medication to handle T – either via ongoing anti-androgen or just high-dose estrogen. After stopping bicalutamide, it’s important to recheck testosterone in 4–6 weeks to ensure it’s still in range. If T unexpectedly rises (which could happen in a subset of patients with high T or strong gonadal function), you might introduce another blocker (e.g. spironolactone 100–200 mg/day) or resume bicalutamide at a lower dose. Most often, though, estradiol will keep T low on its own by this time.
- Why stop bicalutamide? Mainly to reduce cumulative liver risk and because it may no longer be necessary. Long-term bicalutamide in transsexual female care has sparse data, but given the reports of rare fulminant hepatitis, best practice is to limit exposure. Additionally, one theoretical downside of bicalutamide’s mechanism: by not reducing testosterone (just blocking it), the circulating T (which partly converts to estradiol) could maintain certain functions like sex drive or fertility longer than desired. Some trans folks actually appreciate that bicalutamide allows some libido and erectile function to remain (because T isn’t eliminated), but others may want complete androgen suppression. After a year on HRT, most will have significantly reduced sperm count and possibly be functionally infertile, but bicalutamide alone (if estrogen dose was too low, for example) might preserve fertility longer than expected. In any case, once it’s safe to drop it, doing so streamlines the regimen.
- Pioglitazone for Fat Redistribution: By ~10-12 months, many trans women are happy with breast growth but might desire better hip/butt development. Estrogen on its own does shift fat gradually, but some individuals, especially those with a tendency toward abdominal (android) fat, may find they still carry a “male” fat pattern. Pioglitazone is an insulin-sensitizing medication (a thiazolidinedione, TZD) primarily for type 2 diabetes, but it has a unique effect on fat distribution: it promotes differentiation of subcutaneous fat cells and uptake of fat into subcutaneous (under-the-skin) depots, away from visceral fat in the abdomen. Essentially, it can help transform an “apple” shape into more of a “pear” shape. A seminal case report in 2009 demonstrated that adding a TZD (rosiglitazone) to a trans woman’s regimen after years on estrogen led to significant waist reduction and thigh enlargement over ~1.5 years. Pioglitazone is now sometimes used off-label in gender care for this purpose. BUT IF YOU WANT MORE INFO READ ABOUT IT HERE
- When to introduce: It’s recommended to wait until after 6–12 months of estrogen therapy (and ideally after initial breast budding) before using pioglitazone. Starting it too early, when high doses of estrogen are stimulating breast tissue, has a theoretical concern: TZDs like pioglitazone could reduce local estrogen effects in breast tissue by down-regulating aromatase or other mechanisms. However, clinical experience (e.g. Dr. Will Powers, a physician who has used pioglitazone in many trans patients) suggests that if you start pioglitazone after the “budding” phase (i.e. once some breast tissue is established), it does not hinder breast growth – rather, “90% of fat gains outweigh any theoretical aromatase hit” meaning breasts may still enlarge due to fat accumulation. If started very early, a few patients reported slightly slower ductal growth, so that’s why we time it at ~12 months, not at initiation.
- Dose and duration: A low dose like 15 mg daily can be effective, with the option to increase to 30 mg daily if tolerated over the course of a month or two. For reference, in diabetes, up to 45 mg is used, but we likely don’t need that much for a non-diabetic person just aiming for redistribution. I suggest a trial of 3–6 months on pioglitazone, starting at month 12 and going to month 18 (for example). The full effect on fat distribution might take the entire 6 months or longer, since fat cells remodel gradually. It could be continued up to 12 months if well-tolerated and if additional benefit is observed, but extending beyond 1–2 years is not advised because long-term use of TZDs is where risks like bladder cancer have been reported. In fact, studies showed a possible signal that >2 years on pioglitazone (especially with a cumulative dose >28,000 mg) might increase bladder cancer risk. Shorter courses have not shown this link clearly, but it’s a precaution.
- Monitoring and side effects: Pioglitazone’s main side effects are edema (fluid retention) – which can lead to swelling in ankles or even congestive heart failure exacerbation – and weight gain (because it increases adipose tissue mass, even as it shifts where it goes). The weight gain is mostly subcutaneous fat and some fluid; it can be on the order of a few kilograms. In a trans context, some of that weight will ideally go to breasts, hips, buttocks, giving a more feminine contour. But patients should monitor their waist circumference and overall weight – if they gain a lot centrally or overall obesity becomes a concern, the trade-off might not be worth it.
- As for liver safety, unlike its older cousin troglitazone (removed for hepatotoxicity), pioglitazone rarely causes liver issues. The FDA once recommended periodic LFTs for TZDs; significant liver injury is very uncommon with pioglitazone. Nonetheless, since many trans patients may still be on other meds or have had bicalutamide, if you WANT, you can get liver enzymes checked. If ALT rises to >3× normal on pioglitazone, discontinue it (standard practice).
- Heart failure risk: Pioglitazone is contraindicated in patients with Class III/IV heart failure because it can cause edema and precipitate fluid overload. Ensure the patient has no history of heart failure, and educate them to report any shortness of breath or rapid weight gain (>5 lbs in a week). If such signs occur, stop pioglitazone immediately. Also, pioglitazone can increase fertility in diabetic PCOS patients by improving insulin resistance (leading to ovulation); in trans women this isn’t directly relevant, but be aware it might increase androgen metabolism in some complex way via SHBG changes (some studies in PCOS showed increased SHBG). However, no direct interactions with estradiol are expected aside from possibly a modest increase in sex hormone-binding globulin which could actually reduce free testosterone slightly – a potentially positive effect in trans women.
  Cost: Pioglitazone is very inexpensive as a generic – often on $4 prescription lists in the U.S. A month of 15 mg/day might cost ~$5–10. It’s widely available internationally too for a low price (since it’s been generic for a long time).
  Expected outcome: If pioglitazone is successful, by the end of the trial the patient might notice their waist-to-hip ratio has improved (waist smaller, hips larger). The 2009 case reported a trans woman’s waist dropping from 100 cm to ~82 cm and hips from 105 cm to 93 cm (actually a slight hip reduction in that case as visceral fat lost, but thighs increased) with rosiglitazone, giving her a more hourglass figure. More commonly, we’d expect visceral fat to reduce (so a flatter tummy) and subcutaneous fat to increase in the hips and thighs (so a rounder butt and thighs). An important point: pioglitazone will increase overall fat mass, so the patient should be prepared for some general weight gain. Emphasize healthy diet and perhaps focus on lower-body exercises to help shape the gained fat. If undesired fat is accruing (like too much belly fat still, or they simply gain too much weight), one can stop the drug. Interestingly, one could pair pioglitazone with a mild caloric surplus targeted to gluteal muscles (for example, doing squats or hip exercises and eating protein) to try to ensure those calories go to the right place. There is also discussion in the community about using GLP-1 agonists (like semaglutide) concurrently to reduce overall fat while pioglitazone redistributes it, but that’s experimental – basically trying to lose visceral fat while gaining subQ fat. That might be considered in overweight patients (GLP-1 for weight loss, pioglitazone to direct remaining fat to hips). In any case, by the end of Phase 2 (1 year), the patient’s medication regimen could now be: estradiol injection (likely a full dose, e.g. 7.5–10 mg weekly), micronized progesterone nightly, possibly MK-677 completed (if they did that 6-month course, they’d stop at 12 months), no bicalutamide anymore, and possibly on pioglitazone (if chosen) for the next few months. The feminization at 1 year is considerable, with breasts perhaps an A or B cup, and the figure starting to feminize especially if weight was gained. The next phase focuses on the second year of HRT, where remaining changes occur and specialized interventions like domperidone can be used for additional breast enhancement.

### Phase 3 – Second Year and Additional Feminizing Interventions (12–24 months)

By the second year, the rapid changes of the first puberty-like phase slow down. Many trans women find that from months 12 to 24, changes still occur but at a more gradual pace. Breast growth might have another “spurt” around 12–18 months (some experience a delayed onset of significant breast growth), and body shape continues to refine. The medications in use will mostly be the foundational ones: estradiol (and progesterone). However, this is the window where we consider domperidone for those interested in maximizing breast development or lactation, and we wrap up any adjunct therapies (completing the pioglitazone course, ensuring MK-677 is stopped, etc.).

- Domperidone Introduction (~18 months): Domperidone is a prolactin-boosting medication that can induce lactation. It works by blocking dopamine D2 receptors mainly outside the blood-brain barrier (in the pituitary gland), which causes an increase in prolactin secretion. Elevated prolactin, in the presence of estrogen and progesterone, stimulates the mammary glands to develop milk-producing structures (alveoli) and can lead to breast growth in tanner stage 5. In cis women, prolactin is high in late pregnancy and postpartum for breastfeeding. In trans women, we mimic that scenario pharmacologically. The famous 2018 case report (Reisman and Goldstein) used domperidone along with high-dose estradiol patches and progesterone to help a trans woman successfully breastfeed her baby. If we look at cis women, it should theoretically increase breast size and also induce possible lactation.
- Dosage and regimen: A typical regimen is 10 mg three times daily to start. After one week, increase to 20 mg three times daily. If well-tolerated, after another week, increase to 20 mg four times daily (total 80 mg/day). Many protocols cap at 20 mg QID, though some go up to 30 mg QID in refractory cases. The patient should also begin breast pumping or manual expression when starting domperidone – initially maybe 5–10 minutes per breast, 3–4 times a day, then increasing frequency up to every 3 hours (6–8 times a day). The mechanical stimulation is crucial for maximizing prolactin’s effect and actually drawing out milk. Without pumping, domperidone may still enlarge breasts somewhat (more engorgement with fluid), but pumping truly triggers the lactation feedback loop. Within 4–6 weeks of this regimen, many will start producing measurable milk. If lactation is achieved, one can then adjust the pumping schedule to maintain supply or meet the infant’s feeding needs. If the goal was just breast growth and not ongoing lactation, one might stop domperidone after a couple months and cease pumping – the milk production will dry up, but any new glandular tissue might remain, potentially leaving a slightly larger breast than before.
- Regulatory note: In the U.S., domperidone can be obtained via compounding pharmacies or through the FDA’s Investigational New Drug (IND) program with physician authorization. A month’s supply of 80 mg/day could be ~$30–60 depending on source. Compounded domperidone in the U.S. might be pricier. Patients should be aware they are using it off-label and against FDA guidance, albeit under many physicians’ supervision in practice.
  Breast screening: If a trans woman has been on HRT > 1–2 years and especially if using domperidone (which can cause breast changes like galactorrhea), it’s wise to get a baseline breast exam or imaging if there are any unusual findings (like a dominant lump, though often any “lump” during lactation could just be a clogged duct). Current trans healthcare guidelines suggest starting routine mammograms at age 50 or 5–10 years after starting HRT, whichever is later. So if our patient is, say, 25 at this stage, they wouldn’t need routine mammograms yet, but if they are older (45 and 2 years on HRT, maybe start at 50). Inducing lactation per se doesn’t mandate a mammogram, but clinical judgment should be used.
- Wrapping up other adjuncts: By 18–24 months,
  - if the patient was on pioglitazone, this is the time to end that course (we suggested a 6-month trial from 12 to 18 months). Evaluate the outcomes: hopefully there’s satisfaction with increased hip/thigh mass. After stopping pioglitazone, encourage maintaining a healthy diet/exercise to keep visceral fat low, as there could be some regression in distribution if significant weight changes occur. If the patient had success and no side effects, some might consider extending to a full 12 months (to 24 months) – if so, ensure no signs of bladder issues (blood in urine, etc., which could signal bladder irritation – though extremely unlikely in that timeframe). In general, we caution against going past 12–24 months on pioglitazone given the uncertainty in long-term risk.
  - For MK-677, ideally it was stopped at 12 months. If, for some reason, someone did a shorter trial (say 3 months at 6–9 months) and wanted to do another 3-month trial at 18 months, that could be considered if IGF-1 levels were back to baseline and there were no adverse effects the first time. Perhaps they might attempt a second “booster” of MK-677 to see if any further breast growth can be achieved. There’s no data on doing this, but conceptually a second puberty spurt could be tried. If so, all the same precautions apply and it should still be limited duration. Most will have discontinued it and rely on normal nutrition and time for any further IGF-1 mediated changes (and note: estrogen itself increases IGF-1 somewhat in younger people).
- Assessing Results at 2 Years: By the end of year 2, we assess whether the goals have been met.
  - Breasts: If despite all interventions the patient is unhappy with breast size (say, only an A-cup and wanted a C-cup), this is when many consider surgical augmentation. No medication will miraculously create very large breasts if genetics/hormones didn’t after 2 years of maximal therapy. We have given the best possible regimen (high estrogen, added progesterone, occasional GH support, possibly prolactin via domperidone). If that still doesn’t yield the desired result, a breast augmentation surgery can be discussed – ideally after 18–24 months of HRT so that existing tissue is matured (surgeons often ask patients to be ~1–2 years on HRT before implants for best outcomes).
  - Body shape: If hip fat is still lacking, some may consider procedures like fat transfer or gluteal implants, but again, our regimen with pioglitazone aimed to mitigate that. If weight was a limiting factor (patient didn’t want to gain weight), results will vary.
  - Facial/body hair: At 2 years, any hair not gone will likely remain. The patient should pursue laser or electrolysis for beard removal as needed; medications have limited further effect by this time (though continuing finasteride can help scalp hair maintenance).
  - Mental health: Check-in on the psychological aspect – often this is a time of social transition consolidation, and the patient might be living fully in their affirmed gender. Ensure they have the support they need (voice therapy, etc., if needed – note hormones do not affect voice in trans women, so voice training is often undertaken in parallel during these two years).
- Long-term maintenance plan: After 2 years, we transition to a maintenance approach. This means continuing estradiol for life (unless contraindications develop). Many providers will try to use the lowest effective estradiol dose to maintain feminization once maximal changes are achieved, but there is no hard rule – some trans women continue with their same dose and do fine; others choose to reduce slightly to, say, a mid-dose that keeps estradiol in mid-normal female range rather than high-normal. The rationale for reduction could be minimizing long-term risks (e.g. thromboembolism or high triglycerides) while still preventing any regression. So, for example, if someone was on 10 mg enanthate weekly during transition, they might downshift to 5 mg weekly in maintenance and still maintain female hormone levels, especially if testes are non-functional by now. This must be individualized and guided by hormone levels and symptoms.
- Progesterone can be continued or not. There is no requirement; some trans women feel it helps maintain breast volume and libido, so they keep it (often cyclically to mimic a “period” even though they won’t bleed – some like the psychological rhythm). Others stop it after a couple years once breasts are developed, to simplify the regimen (particularly if they suspect it causes them mood issues or if they have risk factors like migraines that progesterone might exacerbate). Micronized progesterone in the long term has not shown a significant risk increase in cis women (unlike synthetic progestins which in the Women’s Health Initiative were linked to slightly higher breast cancer risk with estrogen). So continuing it is likely safe, but again, optional.
- Ongoing monitoring: After two years of more intensive follow-up, one can scale back. Annual check of estradiol and testosterone is reasonable (if gonads are removed, checking T becomes unnecessary as it will be near zero; if still present, an annual T ensures no spike due to noncompliance or other issues). Routine metabolic monitoring (CMP, lipid profile) can be done yearly. Because estrogen can affect lipids (typically raising HDL, sometimes raising triglycerides), keep an eye on those. If the patient has other conditions (e.g. high blood pressure), manage them in context of HRT (estrogen can slightly elevate blood pressure in some, though often not drastically). Bone density: if the patient had an orchiectomy and is on estrogen, their bone density will generally be preserved (estrogen is bone-protective). If they ever stop HRT (which is not recommended without another plan), they should have bone monitoring. Typically, a DEXA scan is advised around age 65 for everyone, but in trans individuals, some suggest a scan 5–10 years after gonadectomy or after starting HRT if there’s any question of adherence or sufficient dosing. In our patient’s case, if all went well, they likely have good bone density thanks to continuous estrogen from age 18+ onward.
- Health maintenance: As noted in the summary table, adopt appropriate screening: Mammograms by age ~50 (or earlier if strong family history of breast cancer). Prostate: yes, trans women retain a small prostate and can get prostate cancer, though androgen deprivation actually lowers that risk somewhat. Nonetheless, some guidelines say consider PSA screening by age 50 (keeping in mind PSA is lower in trans women due to low T, so it may be an unreliable test). Colonoscopies, etc., are as per general population guidelines (not affected by HRT). If the patient is on domperidone long-term (some stay on a low dose to keep producing milk for a baby’s first year), they need periodic ECGs and perhaps electrolyte checks. Most will stop it when done nursing.

Summary of Costs (All Medications): To ensure practical planning, here is a recap of the medications introduced and their cost estimates (U.S. context, with notes on international):

Medication | Typical Dosing (for this protocol) | Est. Monthly Cost (USD) & Availability
--- | --- | ---
Estradiol Enanthate | 5–10 mg IM or SQ weekly (or 10–20 mg biweekly). | ~$10–40/month in US with generic (vial ~$50 for 5 mL of 20 mg/mL, which lasts ~4–5 months at 5 mg/week). Widely available; valerate or cypionate forms similar cost. Often covered by insurance. International: cheap (e.g. a few dollars per ampoule).
Bicalutamide | 25–50 mg daily (months 0–12). | ~$20/month (generic). With coupons, as low as $7–15. Covered by many insurance plans (as it’s used for prostate conditions). International: ~$1–2 per pill. Used short-term in this protocol.
Micronized Progesterone | 100–200 mg nightly (introduced ~6 mo, ongoing). | ~$20–30/month generic. (Prometrium brand ~$200 without insurance, but generic capsule much cheaper). Readily available in US and abroad.
MK-677 (Ibutamoren) | 10–25 mg nightly (for 3–6 month cycle, optional). | ~$60–100/month (not pharmacy – sold via research chem companies). Price varies by supplier. Note: being non-FDA approved, quality and legality considerations apply.
Pioglitazone | 15–30 mg daily (for ~6 months, e.g. months 12–18). | ~$5–15/month (generic Actos). Often on $4 formulary in US. International: inexpensive (widely used for diabetes).
Domperidone | 10–20 mg 3–4× daily (for a few months to induce lactation, or longer if breastfeeding). | If obtained via international pharmacy: ~$30–50/month (example: 100 tabs of 10 mg ~$40, which lasts 25 days at 40 mg/day). US compounding pharmacies may charge more ($90–150/month). Not FDA-approved (personal importation is common).

(These costs are approximate and can vary by location and insurance. Patients should consult with healthcare providers about affordable sourcing – e.g., compounding pharmacies for estradiol if standard injections are in shortage, patient assistance programs, etc.)

## Q&A

1. Why use estradiol enanthate instead of oral estrogen?

injectable estradiol enanthate bypasses first-pass liver metabolism, resulting in more stable blood levels and a lower risk of blood clots compared to oral estrogens.

also i prefer enanthate compared to other esters because of lower price from places like astrovials and general ease of dosing, if you prefer another ester you can use that instead

2. How quickly will breast buds form on this regimen?

most adult trans women notice breast buds (tanner stage ii) between 3–6 months of consistent estradiol therapy

3. Is bicalutamide safe as an anti-androgen?

bicalutamide effectively blocks androgen receptors and is well tolerated at 25–50 mg/day.

4. When should I introduce progesterone?

add micronized progesterone (100–200 mg at night) around 8 months into HRT, once breast budding is underway, to support lobulo-alveolar maturation and potential fullness

5. What is mk-677 and why use it?

mk-677 is an oral gh secretagogue that raises igf-1 levels, mimicking the pubertal growth hormone surge to possibly augment breast and hip development when used short-term (3–6 months) alongside estradiol

6. How do I monitor safety on mk-677?

check fasting glucose or hba1c at 3 months due to potential insulin resistance, and watch for edema or joint pain; discontinue if signs of acromegaly appea

7. When is pioglitazone introduced and what does it do?

pioglitazone (15–30 mg/day) is best started after 12 months of HRT to shift fat from visceral to subcutaneous depots, enhancing hip and thigh curves over a 3–6 month course (read about it at hrt.fm!!!!!!!)

8. What side effects should I watch for with pioglitazone?

monitor for peripheral edema, weight gain, and periodic liver enzymes; stop if shortness of breath or rapid weight gain (>5 lbs/week) suggest fluid overload

9. Can I stop anti-androgens after 12 months?

yes,by 9–12 months, high-dose estradiol usually suppresses testosterone into the female range, allowing a taper off bicalutamide to reduce long-term liver risk

10. How is lactation induced?

domperidone (10 mg TID, up to 20 mg QID) plus progesterone and regular pumping (6–8×/day) around 18–24 months can raise prolactin and stimulate milk production in trans women

11. How long before I see maximum breast growth?

breast development typically plateaus by 18–24 months on hrt, with the most rapid changes in the first year and slower growth thereafter.

12. Will body hair stop growing?

estrogen and bicalutamide slow body and facial hair, but permanent removal usually requires laser or electrolysis since hormones alone rarely eliminate all hair

13. Is fertility permanently lost?

high-dose estradiol and anti-androgens often render sperm production very low within months, but sperm banking beforehand is recommended if future biological children are desired

14. How often should labs be done?

check estradiol and testosterone at 3 and 6 months, liver function monthly for the first 3 months on anti-androgens, then every 6–12 months once stable; metabolic panels annually

15. What about bone health?

estradiol preserves bone density; consider a dexa scan in older patients or those with interrupted hrt; ensure calcium/vitamin d intake throughout treatment

16. Can I adjust dosing if side effects occur?

yes, estradiol dose if migraines or hypertension arise, lower bicalutamide for mild liver enzyme elevations, and pause adjuncts (mk-677, pioglitazone) if intolerable side effects develop

17. Do I need estrogen for life?

Yes, continuing estradiol indefinitely is crucial to maintain secondary sex characteristics and bone health; doses may be lowered to the minimal effective maintenance level once transition goals are met.

18. What if I want larger breasts after 2 years?

if medication yields insufficient growth by 18–24 months, surgical augmentation is the next option, implants or fat transfer after breasts have matured on hrt for at least 1–2 years