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the timeline for mtf hrt and non-hormonal adjuncts

by emily/endocrinemoder/regardlessofit

abstract

In this paper, I review the optimal timing for various medications to achieve the best possible transition outcomes. This timeline integrates standard hormone replacement therapy (HRT) with experimental adjuncts like MK-677 and Pioglitazone, backed by clinical case reports and biological rationale. While I discuss nearly every potential side effect to be thorough, serious complications are rare when protocols are followed correctly. I also reference blood tests frequently; keep in mind that while these are recommended for safety, access issues may make them difficult for some to obtain.

The Roadmap: Optimizing Transition

Summary Timeline

Timeline Actions & Medications Expected Effects
Month 0 (Start) Baseline Labs.
Start Estradiol Enanthate (EEn): 5mg/week injection.
Start Bicalutamide: 50mg/day (Anti-androgen). 		Libido drops. Skin softens. Emotional changes. T is blocked at the receptor, not suppressed yet.
Months 1–3 Check labs at 6 weeks.
Titrate EEn to reach 100-200 pg/mL trough.
Maintain Bicalutamide. 		Breast buds (Tanner 2) appear [2]. Skin becomes less oily. Mental state shifts.
Months 3–6 Add Progesterone: 100-200mg rectal/oral at bedtime (once buds form).
Optional: MK-677 Cycle (10-25mg) for 3-6 months to boost IGF-1. 		Breast volume increases. Fat redistribution begins. Muscle mass decreases.
Months 6–12 Taper Bicalutamide: EEn monotherapy should now suppress T.
Optional: Pioglitazone Cycle (15-30mg) for 6 months to force fat redistribution. 		Waist narrows, hips widen (if using Pio). T should be <50 ng/dL without blockers.
Months 12–24 Advanced Breast Growth: Domperidone (10-20mg TID) + Pumping if lactation/growth desired.
Stop adjuncts (Pio/MK-677). 		Peak breast maturation. Lactation possible. Maximum feminization usually reached by year 2-3.

Phase-by-Phase Protocol

Phase 0: Baseline & Initiation

Preparation: Before starting, get baseline labs (CBC, Metabolic Panel, Lipid Profile, Hormones). If fertility is a concern, sperm banking must happen now—hormones will sterilize you, often permanently, within months.

Estradiol Enanthate (Monotherapy Base): We start with injectable Estradiol (EEn) at 5 mg weekly (IM or SubQ). Injections bypass the liver, reducing clot risk and providing stable levels. The goal is to suppress Testosterone via the pituitary (HPG axis shutdown) using estrogen alone over time.

The Bridge: Bicalutamide: Estrogen takes time to shut down T production. Bicalutamide (50mg/day) is an androgen receptor blocker. It doesn't lower T; it stops T from working. It preserves libido and energy better than Spironolactone and doesn't cause brain fog, making it the superior choice for the first year [3].

Phase 1: Early Changes (Months 1–6)

Titration: Check bloods at month 3. Your goal is Estradiol at trough (right before next shot) between 100–200 pg/mL [1]. If T is still high, the Bicalutamide protects you. If T is <50 ng/dL, you are in the ideal range.

Physical Changes: Breast buds (hard lumps behind the nipple) usually appear between 3 and 6 months [2]. Nipples become sensitive. Skin dries out and softens. You may experience emotional volatility as your brain adjusts to the new fuel.

Phase 2: Maximization (Months 6–12)

Progesterone (The controversial adjunct): Once you have distinct breast buds (Tanner Stage 3), consider adding Micronized Progesterone (100-200mg). While clinical data is mixed, patient surveys overwhelmingly report improved breast shape (rounding) and mood [4]. Take it rectally for best absorption, or orally at night for sleep benefits.

The Growth Boost (MK-677): For those starting transition after age 25, natural Growth Hormone (GH) levels are low. MK-677 is a secretagogue that forces your pituitary to release GH, boosting IGF-1. This mimics a teenage puberty environment.
Warning: This increases appetite massively and can raise blood sugar. Use for 3-6 months max to avoid insulin resistance.

Phase 3: Body Sculpting (Months 12–18)

Dropping the Blocker: By month 9-12, your T production should be nuked by the Estrogen. You can verify this with bloodwork. If T is <50 ng/dL, wean off Bicalutamide. Long-term use puts unnecessary stress on the liver.

Pioglitazone (The Fat Shifter): Now that T is gone, we want to maximize female fat distribution. Pioglitazone (15-30mg daily) activates PPAR-γ, forcing the body to store new fat in the subcutaneous layer (hips/thighs) rather than the visceral layer (gut) [5].
Warning: Do not use if you have heart issues. Causes water retention. Use for a 6-month cycle to "program" new fat cells.

Phase 4: Advanced Breast Development (18+ Months)

Domperidone & Lactation: If breasts have plateaued, inducing lactation can force the final maturation of the mammary gland (Tanner Stage 5). This requires Domperidone (to raise prolactin) and mechanical pumping. A case study by Reisman & Goldstein (2018) proved this works in trans women [6].
Warning: Domperidone can lengthen the QT interval of the heart. ECG monitoring is required.

Q&A

1. Why injections over pills?

Injections bypass the liver (first-pass metabolism). Oral pills increase SHBG (which binds hormones) and IGF-1 suppression, potentially stunting growth. Injections give better levels with lower risk.

2. Will Bicalutamide hurt my liver?

Rarely. The rate of liver injury is approx 1 in 4000. We test liver enzymes (ALT/AST) to be safe, but 50mg is a low dose compared to cancer patients (150mg).

3. Can I take Progesterone sooner?

It is advised to wait until breast buds form. Taking it too early (Month 0) theoretically might fuse the milk ducts too early, limiting final size, though this is debated.

4. Is fertility gone forever?

Assume yes for reproduction, assume no for contraception. Most trans women become sterile within 6 months, but some recover sperm after stopping HRT. Sperm banking beforehand is the only guarantee.

5. Why cycle MK-677 and Pioglitazone?

To minimize risk. Long-term MK-677 causes diabetes risk. Long-term Pioglitazone (>2 years) has a weak link to bladder cancer. Short cycles get the benefit while minimizing exposure.


Important Safety Disclaimers

  • MK-677: Research chemical. Risks include insulin resistance and edema. Monitor blood glucose.
  • Domperidone: Not FDA approved in the US. Risk of QT prolongation/arrhythmia.
  • Pioglitazone: Off-label use. Contraindicated in heart failure.
  • Bicalutamide: Liver toxicity risk (low but present). Monitor LFTs.

References

[1] Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2017;102(11):3869–3903.

[2] de Blok CJM, Klaver M, Wiepjes CM, et al. Breast Development in Transwomen After 1 Year of Cross-Sex Hormone Therapy: Results of a Prospective Multicenter Study. The Journal of Clinical Endocrinology & Metabolism. 2018;103(2):532–538.

[3] Neyman A, Fuqua JS, Eugster EA. Bicalutamide as an Androgen Blocker With Secondary Effect of Promoting Feminization in Male-to-Female Transgender Adolescents. Journal of Adolescent Health. 2019;64(4):544-546.

[4] Chang JJ, Tran NK, Flentje A, et al. Progestogen Experience Among Transgender Women and Gender Diverse Adults Assigned Male at Birth in the United States. Endocrine Practice. 2025;31(11):1449–1461.

[5] Malik I, Barrett J, Seal L. Thiazolidinediones are useful in achieving female-type fat distribution in male-to-female transsexuals. Endocrine Abstracts. 2009;19:P74.

[6] Reisman T, Goldstein Z. Case Report: Induced Lactation in a Transgender Woman. Transgender Health. 2018;3(1):24-26.