The Cyclical HRT Protocol

Design Philosophy

Standard trans feminine HRT holds estradiol and progesterone at static levels: the same dose, the same schedule, week after week. This maintains therapeutic ranges, but it doesn't reflect how these hormones actually behave in a cycling body. Cis women experience a 28-day (approximate) rhythm of rising and falling estrogen, a progesterone surge in the luteal phase, and a withdrawal-driven menstrual period. The entire endocrine system, including mood, energy, immune function, bone metabolism, and breast tissue development, evolved around this fluctuation.

This protocol attempts to replicate that rhythm using injectable estradiol valerate and vaginal bio-identical progesterone on a fixed 28-day cycle. Perfectly reproducing cis female hormone curves isn't achievable with exogenous dosing and no functioning ovaries. The goal is to approximate the shape, hit the key inflection points, and observe what happens.

Patient Baseline

• Trans woman, several years on estrogen-based HRT
• Vaginoplasty using peritoneal flap with AlloDerm graft. This is clinically relevant because peritoneal tissue is well-vascularized^[1], and its absorptive characteristics likely differ from both penile inversion skin and natal vaginal mucosa, though direct pharmacokinetic comparisons have not been published. Literature-derived absorption values for cis women may not accurately predict what occurs in a peritoneal neovagina.
• No gonads, so all sex hormones are exogenous. Adrenal contribution is negligible. This places the endocrine baseline in the same category as postmenopausal cis women: hypogonadal, with no significant endogenous sex steroid production. Most of the pharmacokinetic and safety literature referenced in this protocol is derived from that population for this reason. The HPG axis is suppressed when estradiol is in therapeutic range (LH and FSH flatlined at ~0.08–0.09 mIU/mL), but the pituitary is still functional. During the pre-protocol washout, with E2 near trough (~66 ng/mL E3G), FSH rose to 1.25 mIU/mL as the body attempted to signal for hormone production it can't actually initiate. This is expected and is itself useful data: it confirms the feedback loop is intact and responsive to the cycle's low-E2 phases.
• Prior steady-state regimen: 6mg estradiol valerate SubQ weekly + 200mg progesterone nightly (oral, later switched to vaginal).
• Known symptomatic low-E2 threshold: mood deterioration and vasomotor symptoms appear when estradiol drops below approximately 50–60 pg/mL for more than a few days.

Medications

Estradiol Valerate (EV)

• Route: SubQ injection
• Concentration: 20mg/mL
• Cyclic protocol uses variable doses per injection (see schedule)
• Estimated SubQ half-life in this patient: 4–5 days (see Pharmacokinetic Observations below)
• Estimated time to peak: Day 2–3 post-injection

Progesterone (bio-identical, micronized)

• Form: 200mg capsules
• Route: Vaginal insertion, not oral. Vaginal administration largely bypasses first-pass hepatic metabolism, resulting in a higher ratio of active progesterone to neurosteroid metabolites (such as allopregnanolone) compared to oral administration^[2][3][4]. Vaginal progesterone also produces greater and more consistent systemic bioavailability when measured by LC-MS/MS^[5].
• Cyclic protocol uses variable dosing by phase (see schedule)

Vaginal Estradiol Cream

• Estradiol 0.01% vaginal cream, 1g application twice weekly on a fixed schedule
• Purpose: Local tissue health maintenance for neovagina
• Systemic contribution: Negligible (~5–15 pg/mL). Does not meaningfully affect the cyclic estradiol curve.
• Continuous throughout all cycle phases and not modulated.

Reference Targets: Cis Female Menstrual Cycle

These are the approximate serum hormone levels this protocol is designed to track. They represent a composite of published reference ranges for normally cycling cis women, informed primarily by Stricker et al. (2006)^[6].

The 28-Day Cycle

Estradiol Injection Schedule

Four injections per cycle, totaling approximately 11mg EV. Doses are timed to produce peaks that align with the follicular rise, ovulatory surge, luteal secondary rise, and late luteal maintenance.

Days 1–4 are deliberately unmedicated. Estradiol is at its lowest point of the cycle, declining from the previous cycle's final injection. This trough is what drives the withdrawal/menstrual window.

Progesterone Schedule

Progesterone is absent during the follicular and ovulatory phases (Days 1–14), matching the cis pattern. It's introduced at the start of the luteal phase, escalated to mimic peak luteal levels, then abruptly stopped to trigger withdrawal.

The escalation from 200mg nightly to 400mg BID on Day 19 mimics the ramp from early to mid-luteal progesterone. The abrupt stop on Day 27 is what creates the withdrawal. Both estradiol and progesterone are declining simultaneously, which is the hormonal trigger for menstruation.

Menstrual / Period Window

In this protocol, the withdrawal window spans approximately Days 27–28 (pre-menstrual) through Days 1–5 of the next cycle (menstrual). Expected symptoms include cramping, lower abdominal discomfort, breast tenderness, bloating, mood dip, fatigue, and irritability.

Total Monthly Medication Use

• Estradiol valerate: ~11mg per cycle (significantly lower than the ~24mg/month from prior 6mg weekly steady-state dosing)
• Progesterone: ~7,200mg per cycle (36 capsules)
• Vaginal estradiol cream: Unchanged, continuous

Monitoring Methodology

At-Home Tracking: Inito Fertility Monitor

I use an Inito monitor with first morning urine (FMU) to track urinary metabolites throughout each cycle. Inito measures E3G (estradiol metabolite), PdG (progesterone metabolite), LH, and FSH.

Important caveat: Inito is designed for cis women tracking fertility, and its ovulation predictions are meaningless in this context because there will never be an LH surge. I ignore its algorithmic interpretations and use it strictly as a metabolite measurement device.

Testing frequency: ~13 tests during the first (calibration) cycle, reducible to 6–8 per cycle once the curve shape is confirmed. Tests are always FMU, always before any morning medication.

Serum Validation: Paired Blood Draws

At-home urinary testing is useful for observing the general shape of a hormone cycle (the rises, peaks, and declines), but urinary metabolites are inherently lagging indicators of serum levels. When serum hormones are rising, urine hasn't caught up yet and will underestimate relative to serum. When serum hormones are falling, urine still reflects earlier peaks and will overestimate. This means there is no single static conversion ratio between Inito readings and serum values.

Two paired draws (Inito FMU + serum blood draw on the same day) illustrate this:

Paired Draw 1: Mid-range, post-peak (depot contaminated)

Caveat: This draw was taken during a period where a prior injection had formed a subcutaneous depot that was slowly releasing over several weeks, contaminating absolute values. Serum E2 was elevated and likely post-peak, so the relatively high apparent ratio reflects urine tracking a declining serum value.

Paired Draw 2: Trough (pre-protocol washout)

This draw was taken near the end of the washout period with E2 at trough. The lower apparent ratio reflects urine lagging behind a serum value that had not yet begun to rise.

What this means for Inito data on this site: Inito readings are reported as trend data, useful for confirming the shape and timing of the cycle's hormone curve but not for deriving precise serum equivalents at any single point. When serum values are available from blood draws, those are the definitive numbers. Additional paired draws are planned across different cycle phases to build a fuller picture of how the lag behaves at different points on the curve.

Two more paired calibration draws for Cycle 1 are planned; one on Day 13 to capture the Ovulatory Peak and on Day 21 to capture the mid-luteal peak. The draw on Day 13 will be a simple estradiol panel, while the Day 21 panel will include estradiol, progesterone, total testosterone, and SHBG.

Pharmacokinetic Observations

These are derived from pre-protocol data and will be refined as cycles accumulate:

SubQ EV half-life: Estimated 4–5 days, based on observed concentration decay between paired measurements in this patient. Published pharmacokinetic data for estradiol valerate is predominantly from intramuscular injection; no SubQ-specific half-life has been formally reported. Two large studies found no significant differences in achieved estradiol levels between IM and SC routes at equivalent doses^[7][8], suggesting the PK profiles are broadly comparable.

4mg EV dose response: Estimated peak ~350–440 pg/mL E2, decaying to ~227 pg/mL by day 9 (upper-bound estimate due to depot contamination)

Vaginal progesterone PK (peritoneal neovagina):

• 200mg single dose: estimated peak ~3.5–4 ng/mL
• 400mg single dose: peaks ~7–8 ng/mL at 6–8 hours post-insertion, drops to ~1.5–3 ng/mL by 16–20 hours
• 400mg BID: sustains ~8–12 ng/mL (mid-to-peak luteal range)

Notes for Anyone Considering This

The total monthly estradiol dose is significantly lower than typical static protocols. I went from ~24mg/month (6mg weekly) to ~11mg/month. The tradeoff is intentional because the protocol relies on timing rather than volume. But the trough days (1–5) are real, and if your symptomatic low-E2 threshold is higher than mine, those days may be rough. Doses can be scaled proportionally while maintaining the same ratios and timing.

Injection site matters. A thigh injection early in my pre-protocol phase created a subcutaneous depot that leaked slowly for weeks and contaminated my tracking data. Abdominal SubQ has been more predictable. Rotate sites, and if you notice a knot forming, note it because it will affect your levels in unpredictable ways.

SHBG will fluctuate with the cycle. In normally cycling cis women, SHBG increases in the luteal phase following the preovulatory estradiol rise, with a mean increase of approximately 15% from follicular to luteal phase^[9][10]. High estradiol phases drive SHBG up (reducing bioavailable E2), and low phases let it drop (increasing bioavailable fraction). This partially self-corrects the effective range, meaning the bioavailable E2 swing is likely narrower than total E2 numbers suggest. Whether and to what degree this occurs in a synthetic cycle with exogenous estradiol has not been studied.

Vaginal progesterone absorption in a peritoneal neovagina likely differs from what literature reports for cis women, though the direction and magnitude of this difference have not been directly measured. In cis women with a uterus, vaginally administered progesterone is substantially absorbed locally via the "first uterine pass effect," achieving uterine tissue concentrations more than 10-fold higher than those from systemic administration, despite lower plasma levels^[11][12]. Without a uterus, this local absorption pathway does not exist, which would be expected to result in a higher proportion of vaginally administered progesterone reaching systemic circulation. This inference is mechanistically sound but has not been directly studied in post-vaginoplasty trans women. The progesterone doses in this protocol were calibrated using my own paired serum data, not literature estimates. If you're replicating this with different anatomy, your levels will differ.

You can abort at any time. Resuming steady-state dosing (your previous weekly injection and nightly progesterone) is always an option. This is not a commitment. It's an experiment.

What Comes Next

Each cycle will be documented in its own post with actual Inito readings, serum results when available, observed symptoms mapped to cycle phase, dose adjustments, and narrative commentary. Cycle 1 is a calibration run, and the protocol will be refined based on what the data shows.

References