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Progestogens

Progestogens are a class that includes progesterone (the bio-identical hormone produced by ovaries) and progestins (synthetic compounds with progesterone-like activity but different molecular structure). The two are not interchangeable — they have meaningfully different effects on mood, breast tissue, cardiovascular markers, and cancer risk.

Whether to take a progestogen at all in feminizing HRT is the most contested decision in this whole drug list. The Endocrine Society 2017 guideline does not recommend routine progestogen use, citing limited evidence of benefit. Community experience is mixed: some report better sleep, libido, mood, and rounder/firmer breast development; others see no change or feel worse on it. There's no universally right answer.

If you do use a progestogen, bio-identical micronized progesterone is preferred over synthetic progestins — the synthetics (especially MPA) have stronger associations with depression and increased breast cancer risk in long-term cis-female HRT studies.

Doses are reference, not prescription

Doses below come from hemingways.org provider regimens (2002-era) and current community practice. The Endocrine Society 2017 guideline does not endorse specific progestogen targets for feminizing HRT. Don't titrate without monitoring.

At a glance

Drug Brand(s) Type Route Typical M2F dose Notes
Micronized progesterone (P4) Prometrium, Utrogestan Bio-identical Oral / rectal / vaginal 100–200 mg/day oral Modern preference if any progestogen is used
Medroxyprogesterone acetate Provera, Depo-Provera Progestin Oral / IM 2.5–10 mg/day oral Cardiovascular & cancer signals; usually avoided
Dydrogesterone Duphaston, Dufaston Progestin Oral 5–20 mg/day Common in EU/UK/Asia; not FDA-approved in US
Norethindrone acetate Aygestin Progestin Oral 2.5–15 mg/day Rare in modern feminizing HRT
Hydroxyprogesterone caproate (Delalutin — withdrawn) Progestin IM 125 mg every 2 weeks Rare in modern feminizing HRT

Should you take a progestogen at all?

The honest answer: the evidence is thin in either direction. The Endocrine Society 2017 guideline doesn't recommend routine use because the studies that exist are small, short, and inconsistent. Most observed benefits are anecdotal.

Arguments for adding bio-identical progesterone:

  • Promotes lobular and alveolar (glandular) breast tissue development — estrogen alone develops fatty/connective tissue, so progesterone may contribute to firmer, rounder shape
  • Inhibits 5α-reductase (T → DHT) — overlaps with finasteride's effect
  • Many users report better sleep (oral P4 is mildly sedating) and improved mood
  • Activates the P53 tumor suppressor gene (laboratory finding; clinical significance in trans HRT unclear)

Arguments against (or for caution):

  • No consistent breast-development gain in the small studies that exist
  • Excess progesterone can decrease libido and trigger PMS-like mood symptoms
  • Decreases insulin sensitivity (mild glucose elevation)
  • High doses can stimulate prolactin release, potentially leading to lactation or, rarely, prolactinoma
  • Synthetic progestins specifically (MPA, norethindrone) carry stronger cardiovascular and breast cancer signals from cis-female HRT studies — these concerns largely don't apply to bio-identical P4

If you do try progesterone, the common pattern is to wait until estradiol levels are stable and breast development has plateaued (often 2+ years on E2), then add a moderate dose and watch for changes over 3–6 months.

The DHT "backdoor" pathway concern

The biochemistry: DHT can be made via two routes. The classical pathway is testosterone → DHT via 5α-reductase — this is what spironolactone, bicalutamide, and finasteride/dutasteride all act on. A second route, the backdoor pathway, produces DHT from progesterone or 17α-hydroxyprogesterone without ever passing through testosterone. The 5α-reduction step happens at the start of the chain instead of the end (P4 → 5α-DHP → ... → androsterone → DHT).

The theoretical concern for trans women: if exogenous progesterone feeds the backdoor pathway, supplementing it could in principle generate DHT — driving body hair, scalp hair loss, and acne — even when testosterone is fully suppressed by an anti-androgen.

What the evidence actually shows: the backdoor pathway is most active in fetal male sexual differentiation, congenital adrenal hyperplasia (21-hydroxylase deficiency), and PCOS-like states with very high 17OHP. In adult bodies with gonadal output suppressed by estrogen + AA, the enzymatic capacity to drive the backdoor pathway from supplemented P4 appears low. Clinical reviews of progesterone in trans women have not found meaningful T or DHT elevation from typical doses, and progesterone's net effect in feminizing HRT is anti-androgenic — it suppresses the HPG axis (lowering gonadal T production) and competitively blocks 5α-reductase (interrupting the classical pathway).

Practical takeaway: the concern is real biochemistry, but doesn't appear to materialize for most users at typical doses. If you start progesterone and notice new acne, body hair, or scalp shedding, that's worth flagging to your provider — but the population-level data doesn't suggest this is common. Some users who are particularly worried about scalp hair add finasteride or dutasteride alongside progesterone as belt-and-suspenders.

Micronized progesterone (Prometrium, Utrogestan)

Bio-identical to the progesterone produced by cis ovaries. The "micronized" preparation breaks the molecule into very fine particles suspended in oil, which lets the gut absorb it — without micronization, oral progesterone is essentially destroyed by the digestive tract.

Route matters a lot. Oral progesterone has very low bioavailability (~10%) because most is metabolized in the liver before reaching circulation. Rectal administration bypasses first-pass metabolism and produces dramatically higher serum levels at the same dose. Vaginal administration is similar to rectal. Some users take the same Prometrium capsule rectally for higher serum effect.

Full detail (formulations, dosing, source notes)

Pharmacology: Same molecule as endogenous progesterone. NOT a progestin (the term "progestin" refers to synthetic analogues with different structure and effects). Activates the progesterone receptor with the body's natural binding profile.

Delivery:

  • Oral capsules: 100, 200 mg (Prometrium in peanut oil; Utrogestan with various oils — check formulation if you have nut allergies)
  • Vaginal cream and suppositories
  • Rectal: oral capsules used off-label for higher serum levels
  • Compounding pharmacies prepare custom transdermal creams (effectiveness debated)

Source dose ranges: Pre-op 100–400 mg/day; post-op 50–400 mg/day. Modern community/clinical practice is typically 100–200 mg/day oral, taken at bedtime to leverage the sedating effect.

Side effects: Generally mild and transient. At higher doses: drowsiness, mood changes, decreased libido, breast tenderness, fluid retention, mild glucose intolerance.

Comments from source: "Those allergic to peanuts, beware: Prometrium uses a peanut oil medium." Compounding pharmacies may also use peanut oil — check before ordering.

Contraindications: Active or past blood-clotting disorders, liver dysfunction or disease.

Medroxyprogesterone acetate (Provera, Depo-Provera)

The most widely-used synthetic progestin historically — and the one with the worst safety signals. The Women's Health Initiative trial (cis-female postmenopausal HRT) linked MPA + estrogen to increased breast cancer, stroke, and coronary heart disease compared to estrogen alone. Bio-identical progesterone in similar studies did not show the same risks.

For feminizing HRT, MPA was once a default add-on but has been largely displaced by micronized progesterone. If you're currently on Provera, ask your provider about switching.

Full detail (mechanism, side effects, source notes)

Pharmacology: Synthetic progestin — chemically derived from progesterone but with structural differences that change its receptor binding and metabolic profile. Notably, MPA is a 5α-reductase blocker at 0% effectiveness (per the Prometrium-vs-Provera comparison study), versus 97% for natural progesterone.

Delivery: 2.5, 5, 10 mg oral tablets; 400 mg/mL sustained-release IM injection (Depo-Provera).

Source dose ranges: 2.5–10 mg/day oral with estrogens, or 50 mg every 2 weeks IM.

Side effects: Headache, insomnia, depression (frequently reported and severe in some users), GI upset, fluid retention, weight gain, decreased glucose tolerance. Cholestatic jaundice in rare cases. Cardiovascular: increased clotting, blood pressure.

Comments from source: "Multiple reports describe inexplicable or exacerbated depression during treatment, suggesting natural progesterone as an alternative." Source also notes some research suggests MPA may "promote bone formation, and may counter bone loss" from androgen blockade — useful context but not enough on its own to outweigh the depression/cancer signals for most users.

Contraindications: Active or past blood clotting disorders, breast or gonadal tumors, liver dysfunction, sensitivity to MPA.

Dydrogesterone (Duphaston, Dufaston)

A synthetic progestogen common in the UK, EU, and parts of Asia. Structurally closer to progesterone than MPA or norethindrone, and lacks androgenic activity — typically better tolerated than older progestins.

Important correction: the hemingways.org source page says "Approved by U.S. FDA." This is incorrect. Dydrogesterone was withdrawn from the US market in the 1970s and has never been re-approved by the FDA. It remains available outside the US and is used by some informed-consent providers via international prescription.

Full detail (mechanism, dosing, source notes)

Pharmacology: Orally active progestogen. "Acts directly on the uterus, producing a complete secretory endometrium in an estrogen-primed uterus." Non-androgenic, non-estrogenic, non-corticoid, non-anabolic.

Delivery: 5, 10, 20 mg oral tablets (UK formulations); 10 mg in some markets.

Source dose ranges (UK community practice): Pre-op 5–20 mg/day; post-op 2.5–10 mg/day.

Side effects: Swollen feet/ankles, weight gain, nausea, vomiting, breast tenderness, depression, headache.

Contraindications: Long-term liver problems, heart or circulatory problems including clotting disorders, diabetes.

Norethindrone acetate (Aygestin)

A synthetic progestin most familiar as the active ingredient in low-dose progestin-only contraceptives. Rarely chosen for feminizing HRT in the modern era — bio-identical progesterone or dydrogesterone are usually preferred when a progestogen is wanted. Listed for completeness.

Source dose: 2.5–15 mg/day pre-op (post-op data unspecified).

Hydroxyprogesterone caproate (formerly Delalutin)

An injectable progestin. Was used for cis-female obstetric and gynecologic conditions (preterm birth prevention as Makena, withdrawn 2023). Rarely used in feminizing HRT — the once-every-two-weeks IM route doesn't fit naturally with the daily oral schedule most people use for progesterone, and there's little community experience to draw on.

Source dose: 125 mg IM every 2 weeks.

Sources